Proceedings of the 28th European Paediatric Rheumatology Congress (PReS 2022)

Oral Communications Session 1 - Autoinflammation/SJIA/MAS

O01. Modeling HLH & MAS susceptibility identifies the characteristics of hyperinflammatory CD8 T-cells

E. Landy¹, V. Dang², J. Varghese², P. Tsoukas³, S. Canna²

¹University of Pittsburgh, Pittsburgh, ²The Children’s Hospital of Philadelphia, Philadelphia, United States, ³Hospital for Sick Children, Toronto, Canada

Correspondence: S. Canna

Introduction: Life-threatening hyperinflammatory Syndromes like Hemophagocytic Lymphohistiocytosis (HLH) and Macrophage Activation Syndrome (MAS) often result from the interactions of multiple susceptibility factors and environmental insults. Recent studies in both HLH and MAS patients demonstrate CD8 T-cell activation profiles in peripheral blood.

Objectives: We wished to test how two independent and synergistic susceptibility factors, perforin insufficiency and excess IL-18, drove pathology in a spontaneous murine model of HLH/MAS.

Methods: We bred and examined transgenic mice bearing knock-out alleles in perforin (Prf1^+/- and -/-) as well as transgenic expression of mature murine IL-18 (Il18tg) by “clinical” measures, cytokine levels, flow cytometry, bulk RNA- and TCR-sequencing, and in functional studies.

Results: Mice bearing dual susceptibility factors (DS mice, Prf1^-/-Il18tg) develop spontaneous HLH/MAS - even Prf1^+/-Il18tg mice develop spontaneous HLH-like immunopathology - in a manner dependent on IFNg. Detailed flow cytometric organ phenotyping reveals a dense expansion of CD8 T-cells bearing high levels of the IL-18 receptor as well as multiple markers associated with exhaustion (PD-1, Lag-3, CD39), yet overproduce IFNg. Such “hyperinflammatory CD8 T-cells” are present in the reticuloendothelial organs (spleen, bone marrow, and liver) but not lymph nodes, peripheral blood, or thymus. RNAseq analyses of hyperinflammatory CD8 T-cells alongside well-described exhausted cells reflects a pattern of activation distinct from acute effector, effector-memory, tissue-resident memory, or exhaustion. Multiple features suggest cells that have received recent antigen stimulation but are terminally-differentiated. TCR sequencing of bulk splenic CD8 T-cells shows oligoclonal expansion in DS mice. Attempts to circumvent CD8 T-cell activation, using inducible deletion of Il18r1 only on CD8 T-cells, or by promoting allelic exclusion by fixing the T-cell receptor of DS mice, shows that IL-18 responsive, oligoclonal CD8 T-cells circumvent these efforts to hinder their ability to expand. In vitro studies show that the effects of IL-18 require recent TCR stimulation, but do not inhibit activation-induced cell death.

Conclusion: Both perforin deficiency and excess IL-18 seem to exert preferential effects on post-thymically activated CD8 T-cells in reticuloendothelial organs. These are precisely the sites where hemophagocytosis is most commonly observed. These data suggest a requirement for TCR stimulation reminiscent of the infectious triggers common to HLH and MAS, demonstrate these cells remarkable resilience, and identify potentially-targetable nodes of T-cell activation.

Patient Consent: Not applicable (there are no patient data)

Disclosure of Interest: E. Landy: None declared, V. Dang: None declared, J. Varghese: None declared, P. Tsoukas: None declared, S. Canna Grant / Research Support with: AB2Bio, Novartis, SOBI, IMMvention Therapeutix, Consultant with: Simcha Therapeutics, Speaker Bureau with: Clinical Viewpoints

O02. Characteristics and disease course of patients with systemic juvenile idiopathic arthritis without arthritis in the German AID-NET cohort

C. Hinze¹, H. Wittkowski¹, E. Lainka², J.-P. Haas³, T. Kallinich⁴, D. Föll¹ on behalf of for the AID-registry investigators

¹Pediatric Rheumatology and Immunology, University Hospital Münster, Münster, ²Pediatrics II, University Hospital of Essen, Essen, ³German Centre for Paediatric and Adolescent Rheumatology, Garmisch-Partenkirchen, ⁴Paediatric Rheumatology, Charity-University Medicine, Berlin, Germany

Correspondence: C. Hinze

Introduction: In systemic juvenile idiopathic arthritis (SJIA), arthritis is often absent during the initial presentation and may not develop at all in some patients (pts). It is unclear how SJIA pts with and without arthritis differ otherwise.

Objectives: To evaluate the clinical characteristics and disease courses in pts diagnosed with SJIA and compare those between pts who had or developed chronic arthritis and those who did not.

Methods: The German AID-Net cohort enrolled pts between 2009 and 2018, some of them retrospectively. Pts with physician-diagnosed SJIA were analyzed in regards to clinical and laboratory parameters at study inclusion and during the disease course. Pts were considered in the arthritis group if arthritis was recorded at the time of enrolment and/or if it was recorded during the disease course for a duration of at least 6 weeks. Distributions and frequencies of clinical parameters were compared between the groups.

Results: The study included 262 pts with SJIA, with a median (interquartile range) age at inclusion of 10.2 (6.0-14.4) yrs, a median age at diagnosis of 7.6 (3.7-12.0) yrs and a median follow-up of 4.1 (1.4-8.1) yrs. At baseline, 147 pts (56%) had arthritis recorded, and of the remaining 115 pts (44%), 30 later developed arthritis (11% of all patients) after 11 (2-20) months, i.e., 85 (32%) pts never had arthritis according to the case definition. Demographic data and clinical parameters that differed significantly between the groups (arthritis versus no arthritis) at baseline are shown in the table. The following parameters did not show significant differences in those for whom the parameters was available: sex, time from onset to diagnosis, adenopathy, macrophage activation syndrome (MAS) (11%:14%), leukocyte count, CRP, S100A8/A9, interleukin-18 or CXCL9 at the time of highest S100A12 level. Medication use was more variable in SJIA patients with arthritis, and the following medications were used more frequently in SJIA with arthritis versus never arthritis (chi square p<0.05): methotrexate (81%:48%), anakinra (47%:27%), etanercept (34%:2%), ciclosporin A (27%:12%), azathioprine (19%:4%), adalimumab (18%:1%), and leflunomide (11%:0%). Concerning the outcomes during the disease, significant differences were seen in the proportion of active disease at the last study visit (25%:13%), and the proportion of pts on glucocorticoids (GC) (23%:11%). There were no significant differences concerning MAS (13%:8%) or death (3 [2%]:0 [0%]).

Conclusion: In this German registry-based cohort of patients with physician-diagnosed SJIA, about one third of pts did not have chronic arthritis. SJIA pts without arthritis on average were older and inflammatory signs were more frequent at baseline, while MAS was similarly frequent. The pharmacologic therapy was substantially more variable in SJIA with arthritis. During the follow-up, SJIA pts without arthritis tended to have better outcomes, i.e., less frequently active disease, less GC use, and no significant difference in MAS occurrence. Limitations include overall shorter follow-up for SJIA pts without arthritis.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

Table 1 (abstract O02). See text for description

O03. Impact of interferon signalling on response to canakinumab treatment in systemic juvenile idiopathic arthritis as revealed by whole blood RNA sequencing

T. Hinze, C. Hinze², C. Kessel², A. Huge², C. Farady³, S. McCreddin⁴, K. Gandhi⁵, D. Foell²

¹Department of Pediatric Rheumatology and Immunology, ²University of Münster, Münster, Germany, ³Novartis Pharma AG, Basel, Switzerland, ⁴Novartis Ireland Limited, Dublin, Ireland, ⁵Novartis Pharmaceuticals Corporation, East Hanover, NJ, United States

Correspondence: T. Hinze

Introduction: Active systemic juvenile idiopathic arthritis (SJIA) is characterized by marked innate immune overactivation and dysregulation of immune-related peripheral blood gene expression. Canakinumab (CAN), an interleukin (IL)-1β blocking antibody has shown to be effective in patients with SJIA. We had previously observed that patients with a higher serum protein IL-18:CXCL9 ratio responded better to CAN than those with a lower ratio. However, it is unclear which factors specifically govern differences in treatment response.

Objectives: The objective of this study was to identify differences in peripheral blood gene expression patterns between patients with active SJIA who subsequently showed sustained complete response to CAN and those that did not.

Methods: Whole blood RNA samples from (1) CAN-naïve patients from an open-label randomized CAN trial (NCT02296424) in active disease (AD), (2) CAN-treated patients enrolled in a randomized controlled CAN trial (NCT00891046) in inactive disease (ID), and (3) paediatric healthy controls (HC) were studied via whole RNAseq on the Illumina NextSeq 2000 platform, assessing 58395 genes overall. For a proof-of-principle analysis, gene expression patterns were compared across SJIA patients with AD (n=10), ID (n=10), and HC (n=10). CAN-naïve patients were further categorized according to their subsequent treatment response. We specifically considered patients with subsequent sustained complete response (SCR) (n=5), i.e., inactive disease or ACR100 response within 4 weeks of treatment, no subsequent flares or macrophage activation syndrome [MAS] during the study, and non-responders (NR) who did not have an ACR30 response (n=4). Differential gene expression was analysed using the R package deseq2. Adjustment of p-value for multiple comparisons was achieved via a false discovery rate (FDR) <0.05 or <0.1.

Results: The proof-of-principle analysis demonstrated marked differential gene expression when comparing AD versus both ID and HC, assuming an FDR<0.05 (AD versus HC: 1872 genes up, 326 down; AD versus ID: 2269 up, 618 down). The prominently upregulated genes included multiple neutrophil-related genes (e.g., CD177, CD93, HK3, MMP9, NLRC4, PADI4, NCF4, NCF1B, PSTPIP2, S100A8, S100A9). When comparing 5 patients with SCR and 4 with NR, assuming an FDR <0.1, 98 genes were differentially regulated (14 up in SCR, 84 up in NR). The 14 genes up in SCR included several type 1 interferon (IFN)-regulated genes, including ERAP2, RSAD2 and SIGLEC1. The 84 genes up in NR included multiple erythropoiesis-related genes, including EPB42, GYPC, PRDX2, RHAG, SPTA1, SPTB, TFR2, TMOD1, TFRC, and TRIM58.

Conclusion: As expected, there was marked dysregulation of peripheral blood gene expression in patients with active SJIA, prominently including the overexpression or overrepresentation of neutrophil-related genes. Relative overexpression of peripheral blood type 1 IFN-stimulated genes may correlate with an excellent response to CAN. In contrast, relative overexpression of erythropoiesis-related genes, which in turn may correlate with ineffective erythropoiesis/occult MAS and IFN-γ activity, may correlate with a poor response to CAN. In summary, these findings support the notion that dysregulation of the type 1 IFN-IL-18-IFN-γ axis may play a role in the treatment response to CAN in SJIA.

Patient Consent: Not applicable (there are no patient data)

Disclosure of Interest: T. Hinze Grant / Research Support with: Novartis Pharma AG, C. Hinze: None declared, C. Kessel Grant / Research Support with: Novartis, Consultant with: Novartis, Sobi, A. Huge: None declared, C. Farady Employee with: Novartis Pharma AG, S. McCreddin Employee with: Novartis Ireland Limited, K. Gandhi Employee with: Novartis Pharmaceuticals Corporation, D. Foell Grant / Research Support with: Novartis, Consultant with: Novartis

O04. Systemic juvenile idiopathic arthritis associated lung disease in Europe

C. Bracaglia¹, F. Minoia², C. Kessel³, S. Vastert⁴, M. Pardeo¹, A. Arduini¹, O. Basaran⁵, N. Kipper⁶, M. Kostik⁷, M. Glerup⁸, S. Fingerhutova⁹, R. Caorsi¹⁰, A. Horne¹¹, G. Filocamo², H. Wittkowski³, M. Jelusic¹², J. Anton¹³, S. Khaldi-Plassart¹⁴, A. Belot¹⁴, G. Horneff¹⁵, S. Palmer Sarott¹⁶, E. Cannizzaro Schneider¹⁶, P. Dolezalova⁹, A. Ravelli¹⁷, S. Ozen⁵, F. De Benedetti¹ on behalf of MAS/sJIA working party

¹Division of Rheumatology, IRCCS Ospedale Pediatrico Bambino Gesù, Roma, ²Fondazione IRCCS Ca’ Grande Ospedale Maggiore Policlinico, Milano, Italy, ³Department of Pediatric Rheumatology & Immunology, WWU Medical Center (UKM), Munster, Germany, ⁴Pediatric Rheumatology & Immunology, University Medical Center Utrecht, Utrecht, Netherlands, ⁵Department of Pediatrics, Division of Pediatric Rheumatology, ⁶Department of Pediatrics, Division of Pediatric Pulmonology, Hacettepe University, Ankara, Turkey, ⁷Saint-Petersburg State Pediatric Medical University, Saint-Petersburg, Russian Federation, ⁸Department of Pediatrics, Aarhus University Hospital, Aarhus, Denmark, ⁹Centre for Paediatric Rheumatology and Autoinflammatory Diseases, Department of Paediatrics and Inherited Metabolic Disorders, 1st Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic, ¹⁰Department of pediatrics and Rheumatology, IRRCS Istituto G. Gaslini, Genova, Italy, ¹¹Department of pediatric rheumathology, Karolinska University Hospital and Department of pediatrics, Karolinska Institute, Stockholm, Sweden, ¹²Department of Paediatrics, University of Zagreb School of Medicine, University Hospital Centre, Zagreb, Croatia, ¹³Pediatric Rheumatology, Hospital Sant Joan de Déu, Universitat de Barcelona, Barcelona, Spain, ¹⁴Pediatric Nephrology, Rheumatology, Dermatology Unit, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Lyon, France, ¹⁵Pediatrics, Asklepios Clinic Sankt Augustin, Sank Augustin, Germany, ¹⁶Paediatric Rheumatology, University Children’s Hospital Zurich, Zurich, Switzerland, ¹⁷IRRCS Istituto Giannina Gaslini and Università degli Studi di Genova, Genova, Italy

Correspondence: C. Bracaglia

Introduction: Chronic parenchymal lung disease (LD) is a new emerging severe life-threatening complication of sJIA. The number of sJIA patients with LD is apparently increasing and interestingly they are reported more frequently in North America. Data regarding frequency and features of sJIA-LD in Europe are not available.

Objectives: To evaluate the burden of sJIA-LD in Europe.

Methods: Patients with diagnosis of sJIA with LD, including pulmonary alveolar proteinosis (PAP), interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH), followed in European paediatric rheumatology centres were identified through a survey sent to the members of the MAS/SJIA Working Party.

Results: Data from 34 sJIA-LD patients, diagnosed in 15 European paediatric rheumatology centres between 2007 and 2022, were collected. 33 patients were Caucasian and 1 was African-American; 21 were female. The median age at sJIA onset was 6 years and LD occurred after a median time of 2 years. 19 patients had a chronic persistent sJIA course, 14 had a polycyclic course and only 1 patient had a monocyclic course; 29 (85%) had active sJIA at time of LD diagnosis. During the disease course, 28 (82%) patients developed MAS, 12 (35%) of whom had MAS at sJIA onset and 19 (56%) had full-blown MAS at time of LD diagnosis; 23 (68%) patients had >1 MAS episode. 28 (82 %) patients were treated with at least one IL-1 or IL-6 inhibitor before LD diagnosis: 15 with canakinumab, 24 with anakinra and 13 with tocilizumab; 13 (38%) patients experienced drug adverse reaction to a cytokine inhibitor: 9 to tocilizumab and 4 to anakinra. 24 (70%) patients developed ILD, 6 (18%) PAP and 4 (12%) PAH. 15 (44%) patients presented acute digital clubbing; 16 (47%) patients developed hypoxia and 9 (26%) developed pulmonary hypertension. A chest CT scan was performed in all patients with evidence of septal thickening, peri-bronchovascular thickening and ground glass opacities in the majority of patients (26, 18 and 18 respectively). In 17 patients a bronchoalveolar lavage was performed and 12 underwent a lung biopsy. The histopathological pattern was alveolar proteinosis in 5 patients, endogenous lipoid pneumonia in 3, vasculitis in 1 and fibrosis in 1. Half of the patients (17) required ICU admission and 6 (18%) died. All the patients were treated with glucocorticoids (GCs) at time of diagnosis, and 26 received IL-1 or IL-6 inhibitor after the diagnosis (13 canakinumab, 20 anakinra, 14 tocilizumab).

Conclusion: Lung involvement is an emerging life-threatening complication of sJIA and patients are also diagnosed in Europe. Prompt recognition is crucial and new therapeutic strategies are needed to reduce the risk and improve the outcome of this complication.

Patient Consent: Yes, I received consent

Disclosure of Interest: C. Bracaglia Consultant with: Sobi, Novartis, F. Minoia Consultant with: Sobi, C. Kessel Grant / Research Support with: Novartis, Consultant with: Novartis, Speaker Bureau with: Sobi, S. Vastert: None declared, M. Pardeo: None declared, A. Arduini: None declared, O. Basaran: None declared, N. Kipper: None declared, M. Kostik: None declared, M. Glerup: None declared, S. Fingerhutova: None declared, R. Caorsi Consultant with: Sobi, Novartis, A. Horne: None declared, G. Filocamo Consultant with: Sobi, H. Wittkowski: None declared, M. Jelusic: None declared, J. Anton Grant / Research Support with: Sobi, Novimmune, Novartis, Abbvie, Pfizer, GSK, Roche, Amgen, Lilly, BMS, Sanofi, Consultant with: Sobi, Novimmune, Novartis, Pfizer, GSK, Speaker Bureau with: Sobi, Novimmune, Novartis, GSK, Pfizer, S. Khaldi-Plassart: None declared, A. Belot Consultant with: Sobi, Novartis, Roche, Pfizer, G. Horneff Grant / Research Support with: MSD, Novartis, Roche, Speaker Bureau with: Abbvie, Chugai, Lilly, Sanofi, Novartis, Pfizer, S. Palmer Sarott: None declared, E. Cannizzaro Schneider: None declared, P. Dolezalova: None declared, A. Ravelli: None declared, S. Ozen Consultant with: Sobi, Novartis, Speaker Bureau with: Sobi, Novartis, F. De Benedetti Consultant with: Abbvie, Sobi, Novimmune, Novartis, Roche, Pfizer

O05. Analysis of pyrin inflammasome activation defines surf patients from FMF and other recurrent fevers

S. Palmeri¹, A. Bertoni², R. Papa², F. Penco², A. Corcione², R. Caorsi², C. Matucci-Cerinic¹, M. Bustaffa², F. Schena², P. Bocca², S. Volpi^1,2, A. Rubartelli², M. Gattorno², I. Prigione²

¹Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova, ²Center for Autoinflammatory Diseases and Immunodeficiencies, IRCCS Istituto Giannina Gaslini, Genova, Italy

Correspondence: S. Palmeri

Introduction: The best known of recurrent fevers, familial Mediterranean fever (FMF), is genetically determined and its pathogenetic mechanism has already been extensively investigated, revealing a role of the pyrin inflammasome (1). However, cohorts of patients with undifferentiated, genetically negative forms of relapsing fever (SURF) are still poorly studied. These patients are genetically negative, and their clinical picture resemble FMF, including the good response to colchicine. However, the underlying inflammatory mechanisms of SURF are not yet known (2).

Objectives: To assess the in vitro activation of the pyrin inflammasome in a cohort of patients with SURF, compared with FMF and Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis (PFAPA) patients; to stratify the response between in vivo colchicine-treated and untreated individuals; to dissect the in vitro response to colchicine in the same cohort of patients.

Methods: Peripheral blood mononuclear cells (PBMC) of a subset of SURF (N=15, colchicine-treated and untreated), FMF(N=8), PFAPA (N=8) and HD (N=13) were tested for ASC speck formation and IL-1beta production in response to different stimuli. Clostridium difficile toxin A (TcdA) and PKN1/2inhibitor (UCN-01) were used to trigger pyrin inflammasome. Colchicine was added in vitro to evaluate the pyrin inflammasome inhibition. We used a flow cytometric method to measure the percentage of ASC speck formation in monocytes and ELISA assay to quantify the secretion of IL-1beta on cell supernatants. We performed non-parametric Mann-Whitney test (MW) for the analysis of differences between groups.

Results: in SURF patients, we did not observe spontaneous activation of the inflammasome in the absence of clinical flare. FMF, SURF, PFAPA and HD displayed no differences in TcdA-induced activation of pyrin inflammasome (% of ASC speck formation). However, in vivo colchicine-untreated SURF patients showed a reduced response to TcdA, with a normalization of values in SURF patients after treatment (% of ASC speck formation, MW, p<0,05; IL1-beta (pg/mL) MW, p<0,05). In contrast with FMF, SURF, PFAPA patients and HD showed the following features: i) UCN-01 mediated-pyrin dephosphorylation was not sufficient to trigger Pyrin inflammasome activation; ii) the in vitro colchicine administration caused a huge inhibition of TcdA-induced pyrin inflammasome activation.

Conclusion: we applied functional in vitro tests for pyrin inflammasome activation analysis to a clinically homogeneous group of subjects with SURF. These preliminary data show that SURF patients differ from FMF, PFAPA, and HD. SURF subjects showed a different response to TcdA, with a normalization after colchicine therapy, suggesting an involvement of pyrin inflammasome in the physiopathology of SURF.

References:

1) Magnotti F. et al. “Fast diagnostic test for familial Mediterranean fever based on a kinase inhibitor.” Annals of the rheumatic diseases vol. 80,1 (2021): 128-132.

2) Papa R. et al. “Syndrome of Undifferentiated Recurrent Fever (SURF): An Emerging Group of Autoinflammatory Recurrent Fevers.” Journal of clinical medicine vol. 10,9 1963.

Trial registration identifying number:

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

O06. MIS-C phenotypes vary between SARS-COV-2 variants

G. Mastrangelo¹, E. Go^1,2,3, P. Tsoukas^1,2, H. Lu^1,2, A. Hoi Hin Cheng^1,2, R. S. Yeung^1,2,4 on behalf of on behalf of SickKids MIS-C Working Group

¹Division of Rheumatology, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, ²Cell Biology Program, The Hospital for Sick Children Research Institute, Toronto, Canada, ³Division of Pediatric Rheumatology, Riley Hospital for Children, Indianapolis, United States, ⁴Department of Immunology and Institute of Medical Science, University of Toronto, Toronto, Canada

Correspondence: G. Mastrangelo

Introduction: Multisystem Inflammatory Syndrome in Children (MIS-C) is a serious complication associated with COVID-19, presenting as a hyperinflammatory disorder characterized by fever and multiorgan dysfunction. Whether the MIS-C phenotype varies accordingly to the SARS-CoV-2 variants is still unclear.

Objectives: We aim to compare MIS-C clinical features, treatments, and outcomes across the various waves of COVID-19, dividing the patient population into three cohorts according to the Alpha/Beta/Gamma, Delta, and Omicron MIS-C waves. Our secondary objective is to evaluate if the clinical phenotype (shock, Kawasaki Disease (KD), fever with hyperinflammation) varies across the three cohorts.

Methods: We performed a prospective cohort study of 252 patients with MIS-C, at a tertiary care pediatric center from March 2020 to March 2022. Clinical and laboratory features, complications, treatments, and outcomes were evaluated. The association with SARS-CoV-2 variants and MIS-C cohorts was assumed based on local epidemiology and sequencing data, representing the predominant strain across the three-time periods. The starting date of each MIS-C wave for study purposes was set at two weeks after the first case of COVID-19 from that respective variant in the community, as the actual time lag for developing MIS-C is within 2-6 weeks after the acute infection. Descriptive statistics were performed to assess differences between the three MIS-C cohorts and clinical phenotypes.

Results: Of the 252 patients (150 with Alpha/Beta/Gamma variants, 59 with Delta, 43 with Omicron), the median age was 5.2 years, 58.7% were male, and 50% had SARS-CoV-2 exposure. The three cohorts showed a significant difference in MIS-C phenotype distribution (p=0.003). Fever and hyperinflammation was the predominant phenotype (20%) in the Alpha/Beta/Gamma cohort; shock represented the majority (39%) in the Delta cohort; and the KD phenotype was prevalent (67%) in the Omicron cohort. Cardiac and gastrointestinal involvements were the most common features in all the cohorts, whereas, neurological involvement was the least prevalent. The Omicron cohort had more mucocutaneous involvement and renal abnormalities compared to the others. The main difference between the various waves was reflected in measures of complications and outcome with the MIS-C cohort associated with the Delta variant capturing the most severe phenotype with a higher incidence of shock (39%), MAS (22%), and PICU admission (34%). The proportion of children developing coronary artery lesions was similar in all groups. Among all the three MIS-C cohorts, the majority of patients received either IVIG alone or together with upfront steroids. Pulsed high-dose steroids and anticoagulation therapy were more commonly used among children in the Delta MIS-C cohort, findings in keeping with the prevalence of the MIS-C shock phenotype in this group.

Conclusion: The MIS-C phenotype varies accordingly to the SARS-CoV-2 variants, and patients with the Delta variant had a more severe phenotype with a greater proportion of complications. This is the first study that compares MIS-C phenotypes stratified by virus variant waves, including the Omicron wave. These findings provide new insights into disease phenotype and SARS-CoV-2 variants and may have important implications for diagnosis and management.

Patient Consent: Not applicable (there are no patient data)

Disclosure of Interest: None declared

O07. Development of the oncoreum score for differential diagnosis between childhood cancer with arthropathy and juvenile idiopathic arthritis

A. Civino¹, F. Bovis², M. Ponzano², S. Magni-Manzoni³, S. Sorrentino⁴, L. Vinti⁵, M. Romano⁶, N. Santoro⁷, G. Filocamo⁸, C. Gorio⁹, F. Santarelli¹⁰, M. Cattalini¹¹, F. Diomeda¹², G. Alighieri¹³, E. Prete¹⁴, G. Stabile¹⁵, R. Rondelli¹⁶, V. Conter¹⁷, A. Pession¹⁸, A. Ravelli^19,20 on behalf of ONCOREUM Study group

¹Reumatologia e Immunologia Pediatrica, Ospedale “Vito Fazzi”, Lecce, ²Dipartimento di Scienze della Salute, Sezione di Biostatistica, Università di Genova , Genova, ³Reumatologia Pediatrica, Ospedale Pediatrico Bambino Gesù IRCCS, Roma, ⁴Dipartimento di Oncoematologia Pediatrica, IRCCS Istituto ‘Giannina Gaslini’, Genova, ⁵Dipartimento di Oncoematologia Pediatrica, Ospedale Pediatrico Bambino Gesù IRCCS, Roma, ⁶Divisione di Reumatologia, ASST G. Pini-CT, Milano, ⁷Oncoematologia Pediatrica, Azienda Ospedaliero Universitaria Consorziale Policlinico di Bari, Bari, ⁸Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milano, ⁹Unità di Oncoematologia Pediatrica e TMO, “Spedali Civili”, Brescia, ¹⁰Dipartimento di Pediatria, Ospedale Pediatrico “Regina Margherita”, Torino, ¹¹Clinica Pediatrica, Università degli Studi di Brescia e ASST Spedali Civili, Brescia, ¹²Clinica Pediatrica, Università degli Studi di Bari Aldo Moro, Bari, ¹³UO Neonatologia-UTIN, Azienda Ospedaliera “A. Perrino”, Brindisi, ¹⁴Dipartimento di Ematologia, Azienda Ospedaliera “Cardinale G. Panico”, Tricase (Lecce), ¹⁵Consorzio Interuniversitario Cineca, Casalecchio di Reno, ¹⁶Oncoematologia Pediatrica, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, ¹⁷Oncoematologia Pediatrica, Fondazione MBBM, Università Milano Bicocca, Monza, ¹⁸Clinica Pediatrica, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, ¹⁹Direzione Scientifica, IRCCS Istituto Giannina Gaslini, ²⁰Dipartimento di Neuroscienze, Riabilitazione, Oftalmologia, Genetica e Scienze Materno-Infantili (DiNOGMI), Università degli Studi di Genova, Genova, Italy

Correspondence: A. Civino

Introduction: Pediatric cancer with musculoskeletal symptoms at onset can mimic rheumatic diseases, particularly juvenile idiopathic arthritis (JIA). This could lead to inappropriate steroid treatment or immunosuppressive therapy with a delay in the diagnosis.

Objectives: To develop and validate a weighted score, named ONCOREUM Score, that aids physicians in timely differentiation of cancer with arthropathy from JIA.

Methods: Data were extracted from the ONCOREUM Study, a multicenter, prospective, cross-sectional study aimed to compare patients with cancer and arthropathy with those affected by JIA. Patients were younger than 16 years and were newly diagnosed with cancer at 25 Italian pediatric hemato-oncology centers or with JIA at 22 Italian pediatric rheumatology centers. Details concerning study design have been described in detail previously.¹

A multiple imputation by chained equations approach with 10 imputations was first performed. Then, 80% of patients were assigned to the developmental data set and 20% to the validation data set.

Three statistical approaches were applied to develop the ONCOREUM Score, two based on multivariable analysis of different sets of variables (Models 1 and 2) and one based on a Bayesian Model Averaging method (Model 3). The β coefficients estimated in the models were used to assign points to the scores. Discriminating performance was evaluated by calculating sensitivity, specificity and AUC in the validation sample.

Results: The study dataset included 772 patients, 95 with cancer and arthropathy and 677 with JIA. The highest AUC in the validation data set was yielded by Model 1, which was selected to constitute the ONCOREUM Score. Sensitivity, specificity, and AUC of the cutoff in the validation sample were 81.3%, 96.4%, and 0.89, respectively. The formula used to calculate the score includes 9 variables weighted according to the estimated coefficients, as follows (clinical features are included in the model only if present): ONCOREUM score = - 4.1 + 8.4 x limb bone pain + 4.7 x weight loss + 5.1 x thrombocytopenia - 5.2 x morning stiffness - 3.7 x joint swelling - 5.0 x small hand joint involvement + 4.1 x monoarticular involvement + 2.4 x hip involvement + 1.2 x male sex.

The score ranges from - 18 to 21.8 and the optimal cutoff obtained through ROC analysis was – 2, with patients being classified at higher risk of having cancer and arthropathy if score is ≥ - 2, and at higher risk of having JIA if score is < - 2.

Conclusion: The ONCOREUM score is composed of 9 clinical features that can easily be recorded at initial encounter with the patient. It is a powerful tool that may facilitate early differentiation of malignancies with arthropathy from JIA and timely referral of the child to the appropriate pediatric specialist.

1. Civino A, Alighieri G, Prete E et al. Musculoskeletal manifestations of childhood cancer and differential diagnosis with juvenile idiopathic arthritis (ONCOREUM): a multicentre, cross-sectional study. Lancet Rheumatol. 2021; 3 (7): e507-e516.

Trial registration identifying number: ONCOREUM study group members

Italian Association of Paediatric Haematology and Oncology (AIEOP) Centres

Massimo Eraldo Abate (Bologna), Annalisa Arlotta (Parma), Catia Atzeni (Cagliari), Tamara Belotti (Bologna) Patrizia Bertolini (Parma), Barbara Bigucci (Rimini), Andrea Biondi (Monza), Roberta Burnelli (Ferrara), Maurizio Caniglia (Perugia), Ilaria Capolsini (Perugia), Anna Maria Caroleo (Genova), Maria Giusepina Cefalo (Roma), Monica Cellini (Modena), Simone Cesaro (Verona), Adele Civino (Tricase, Lecce), Elisa Coassin (Aviano), Antonella Colombini (Monza), Valentino Conter (Monza), Carmela De Fusco (Napoli), Raffaela De Santis (San Giovanni Rotondo), Andrea Di Cataldo (Catania), Elena Fabbri (Rimini), Franca Fagioli (Torino), Monica Ficara (Modena), Ilaria Fontanili (Parma), Alberto Garaventa (Genova), Chiara Gorio (Brescia), Saverio Ladogana (San Giovanni Rotondo), Franco Locatelli (Roma), Chiara Mainardi (Padova), Maurizio Mascarin (Aviano), Chiara Messina (Padova), Concetta Micalizzi (Genova), Rossella Mura (Cagliari), Daniela Onofrillo (Pescara), Roberta Pericoli (Rimini), Andrea Pession (Bologna), Cristina Pizzato (Treviso), Fulvio Porta (Brescia), Carmelo Rizzari (Monza), Andrea Roncadori (Bologna), Roberto Rondelli (Bologna), Elisa Rossi (Bologna), Giovanna Russo (Catania), Nicola Santoro (Bari), Giulia Stabile (Bologna), Elisa Tirtei (Torino), Assunta Tornesello (Lecce), Federico Verzegnassi (Trieste), Luciana Vinti (Roma)

Italian Paediatric Rheumatology Study Group (IPRSG) Centres

Giovanni Alighieri (Tricase), Martina Amatruda (Roma), Patrizia Barone (Catania), Luciana Breda (Chieti), Michela Cappella (Reggio Emilia), Marco Cattalini (Brescia), Adele Civino (Tricase, Lecce), Rita Consolini (Pisa), Elisabetta Cortis (Orvieto), Sergio Davì (Genova), Alessandro De Fanti (Reggio Emilia), Fabrizio De Benedetti (Roma), Giovanni Filocamo (Milano), Romina Gallizzi (Messina), Maria Francesca Gicchino (Napoli), Francesco La Torre (Brindisi), Bianca Lattanzi (Ancona), Loredana Lepore (Trieste), Maria Cristina Maggio (Palermo), Silvia Magni-Manzoni (Roma), Andrea Magnolato (Trieste), Manuela Marsili (Chieti), Silvana Martino (Torino), Angela Miniaci (Bologna), Alma Nunzia Olivieri (Napoli), Serena Pastore (Trieste), Maria Antonietta Pelagatti (Monza), Rosa Anna Podda (Cagliari), Eleonora Prete (Tricase), Angelo Ravelli (Genova), Francesca Ricci (Brescia), Donato Rigante (Roma), Micol Romano (Milano), Francesca Santarelli (Torino), Francesca Soscia (Orvieto)

Patient Consent: Not applicable (there are no patient data)

Disclosure of Interest: None declared

O08. NLRP3 splicing variants as a regulatory mechanism of inflammasome priming in auto-inflammation

R. Erkens^1,2, M. van Haaren², R. Sanchez Rodriguez², J. Calis², S. Vastert^1,2, J. van Loosdregt²

¹Pediatric Rheumatology, Wilhelmina Children’s Hospital, ²Center for Translational Immunology, UMC Utrecht, Utrecht, Netherlands

Correspondence: R. Erkens

Introduction:

The activation of the NLRP3 Inflammasome is both transcriptionally and post-translationally regulated. Recently, it has been demonstrated that various isoforms of NLRP3 are expressed in human macrophages and that isoforms that lack certain exons due to alternative splicing are not able to form a functional inflammasome by being unable to bind to NEK7, an essential mediator of NLRP3 activation. Inflammasome activation seem to play an important role in systemic Juvenile Idiopathic Arthritis (SJIA) pathophysiology, characterized by high levels of IL-18 and IL-1 pathway activation. Here, we assessed whether NLRP3 splicing changes upon neutrophil and monocyte activation and investigated the role of alternative splicing in the auto-inflammatory setting of SJIA.

Objectives:

To explore the effects of alternative RNA splicing products of NLRP3 in neutrophils and monocytes in healthy individuals and SJIA patients on the activation of the NLRP3 inflammasome.

Methods:

We assessed NLRP3 isoform expression using third generation mRNA Nanopore sequencing, qPCR and western blot. The compared conditions included ex-vivo and 3 hours 100ng/ml LPS stimulated neutrophils and monocytes isolated from peripheral blood of healthy donors and SJIA patients. Inflammasome activation was assessed by measuring IL-1β production using ELISA after LPS priming and subsequent nigericin activation.

Results:

We identified various NLRP3 RNA isoforms in both neutrophils and monocytes using Nanopore sequencing and qPCR. Full length NLRP3 and NLRP3 δexon5 isoforms were found to be the most dominant. In monocytes and neutrophils, LPS mediated priming induces NLRP3 expression and a shift to full length NLRP3 expression due to a decrease in NLRP3 δexon5. Ex-vivo neutrophils and monocytes of biological and steroid naïve patients with active SJIA express relatively more full length NLRP3 compared to samples from healthy donors. After 3 days of treatment with anakinra, exon 5 inclusion decreased in both neutrophils and monocytes of the SJIA patients, but remains increased in neutrophils compared to healthy controls. These data suggest that neutrophils of active SJIA patients are more primed for NLRP3 inflammasome activation.

Conclusion:

Priming of neutrophils and monocytes induces profound changes in NLRP3 isoform expression. These changes after LPS priming might increase the potential of the cell to form an active inflammasome upon a second stimulation. Similarly, we demonstrated that neutrophils and monocytes from patients with active SJIA express more full-length NLRP3, able to form inflammasomes, compared to healthy controls. This observation could contribute to the increased inflammasome activation found in SJIA. Taken together, these results suggest an important level of regulation of inflammasome activation by alternative splicing. Further research is necessary to elucidate the pathophysiology of inflammasome activation in auto-inflammation in general as this opens a window for new therapeutic options.

Patient Consent: Yes, I received consent

Disclosure of Interest: R. Erkens: None declared, M. van Haaren: None declared, R. Sanchez Rodriguez: None declared, J. Calis: None declared, S. Vastert Consultant with: Sobi and Novartis, J. van Loosdregt: None declared

O09. Candidate gene sequencing in systemic juvenile idiopathic arthritis implicates rare variation in hereditary periodic fever and familial hemophagocytic lymphohistiocytosis genes

M. Correia Marques, D. Rubin, E. Shuldiner, E. Schmitz, E. Baskin, A. Patt, M. Ombrello on behalf of Incharge Consortium

Translational Genetics and Genomics Section, NIAMS, National Institutes of Health, Bethesda, United States

Correspondence: M. Correia Marques

Introduction: Systemic juvenile idiopathic arthritis (sJIA) is a genetically complex inflammatory condition. It can be marked by severe systemic inflammation that resembles the hereditary periodic fever syndromes (HPF). Sometimes that inflammation leads to macrophage activation syndrome (MAS), a secondary form of hemophagocytic lymphohistiocytosis (HLH). The HPFs and familial forms of HLH (fHLH) are caused by rare genetic mutations, and it has been hypothesized that genetic variants of HPF or fHLH genes are involved in the pathophysiology of sJIA. Several studies have examined this question, but none have had the statistical power to provide an unequivocal answer.

Objectives: We used targeted sequencing of HPF and fHLH genes in a large patient cohort to determine whether rare variation in these genes contributes to the risk of developing sJIA.

Methods: Targeted sequencing of HPF (MEFV, MVK, NLRP12, NLRP3, NOD2, PSTPIP1, TNFRSF1A) and fHLH (LYST, PRF1, RAB27A, STX11, STXBP2, UNC13D) genes was performed in sJIA cases and control subjects from the International Childhood Arthritis Genetics Consortium cohort using Illumina Nextera Custom Capture Assays and Illumina sequencers. Sequence reads were aligned to human genome assembly hg19 with the Burrows-Wheeler Aligner. Data processing and quality control was performed using the Genome Analysis Toolkit. Variants were filtered to retain rare (minor allele frequency < 0.01), protein-altering variation that mapped to Ensembl canonical transcripts. The distribution of rare variants among sJIA cases was compared to the distributions among INCHARGE healthy controls or simulated data from the 33,370 Non-Finnish European (NFE) reference subjects from the Exome Aggregation Consortium (ExAC) using rare variant association testing (RVT). RVT was performed in R using the data-adaptive sum test and the sequence kernel association test (SKAT). Significance was evaluated at a threshold of p < 0.05 after 100,000 permutations.

Results: Targeted sequencing was performed in 525 sJIA cases and 366 control subjects. Six sJIA cases were discovered to have a genetic diagnosis of either an HPF (n=4) or fHLH (n=2) and were excluded. We also found that 39 cases and 1 control subject were ancestrally dissimilar from the larger cohort by principal component analysis, leading to their exclusion. Sequencing of the remining 480 sJIA cases identified 78 rare fHLH gene variants and 62 rare HPF gene variants. RVT comparing the distribution of rare variants of sJIA cases with that of the ExAC NFE population revealed significant rare variant associations between sJIA and LYST, STXBP2, UNC13D and MEFV. We also discovered recurrent mutations of STXBP2, UNC13D, and MEFV among the sJIA cohort that were not observed in the ExAC population. A sub-analysis of 123 sJIA cases with known MAS status (32 with MAS, 91 without MAS) identified a significant association between rare variation of UNC13D and the development of MAS in sJIA (SKAT p=0.024).

Conclusion: The observations of this study connect HPF and fHLH genes to the pathophysiology of sJIA. The distributions of rare genetic variants of LYST, STXBP2, UNC13D and MEFV were statistically different in children with sJIA than in the general population. We also identified novel, recurrent mutations in 3 of these 4 genes in children with sJIA. These results highlight the potential value of studying rare genetic variation in sJIA. To expand this approach, we have established a collaborative infrastructure to perform an exome sequencing-based study of rare variation across all protein-coding genes in sJIA.

Patient Consent: Not applicable (there are no patient data)

Disclosure of Interest: None declared

Oral Communications Session 2 - CTD, Vasculitis Oral Communications

O10. CD14+ Monocyte-Derived oxidised mitochondrial DNA amplifies the inflammatory interferon type 1 signature in Juvenile dermatomyositis

M. Wilkinson^1,2,3, D. Moulding⁴, T. C. R. McDonnell⁵, M. Orford⁴, C. Wincup^1,5, J. Y. J. Ting³, G. W. Otto^2,6, R. Restuadi^2,3, D. Kelberman^2,7, S. Castellano^2,6, S. Eaton⁴, C. Deakin^1,2,3, E. C. Rosser^1,5, L. R. Wedderburn^1,2,3 on behalf of UK Juvenile Dermatomyositis Research Group and the Centre for Adolescent Rheumatology Versus Arthritis

¹Centre for Adolescent Rheumatology Versus Arthritis at UCL UCLH and GOSH, UCL, ²NIHR GOSH BRC, ³Infection, Immunity and Inflammation Research and Teaching Department, ⁴Developmental Biology and Cancer Research & Teaching Department;, UCL GOS Institute of Child Health, ⁵Centre for Rheumatology Research, UCL, ⁶Genetics and Genomic Medicine Research & Teaching Department, UCL GOS Institute of Child Health, ⁷Genetics and Genomic Medicine Research & Teaching Department, UCL, London, United Kingdom

Correspondence: M. Wilkinson

Introduction: JDM is a rare childhood autoimmune myositis that presents with proximal muscle weakness and associated skin changes. There is an unmet need to develop new targeted treatments.

Objectives: This study aimed to identify dysregulated biological processes up-stream of the known, pathological interferon (IFN) type 1 signature in JDM by RNA-sequencing and develop functional assays to confirm these pathways.

Methods: Peripheral blood samples were obtained from JDM patients [pre-n=10 on-n=11 treatment] and age/sex-matched child healthy controls [n=8]. CD4⁺, CD8⁺, CD14⁺ and CD19⁺ cells were sorted by flowcytometry from PBMC, and RNA was extracted and RNA-sequenced. Mitochondrial morphology and mitochondrial superoxide was assessed in CD14+ monocytes by fluorescence microscopy using MitoTracker and MitoSox dyes quantified by volume, JDM [n=6] and control [n=9]. Oxidised mitochondrial DNA (oxmtDNA) from CD14+ monocytes was measured by western dot-blot, JDM [n=10] and control [n=11]. Healthy control PBMC samples [n=6] were cultured with IFN-α or oxmtDNA (+ LL37) with or without TLR-9 antagonist or n-acetyl cysteine (NAC). Post-culture, IFN type 1 gene expression was measured by qPCR.

Results: RNA-seq confirmed a strong IFN type 1 signature pre-treatment, and genes involved in mitochondrial function were abnormally expressed in both pre- and on-treatment CD14+ monocytes vs. controls, suggesting that mitochondrial dysfunction is not corrected by current treatment strategies. Investigating abnormal mitochondrial biology in JDM CD14+ monocytes by microscopy, we identified that the mitochondria were significantly more fragmented in JDM vs. control (p=0.0044) and evidence of megamitochondria. Analysis of the RNA-seq data showed that the oxidative phosphorylation pathway the gene expression of superoxide dismutase (SOD1) were downregulated in JDM pre- and on-treatment vs. controls. We showed an increase in mitochondrial superoxide in CD14+ monocytes JDM vs. control (p=0.0005, p=0.017). By western dot-blot there was an increase in oxmtDNA in CD14+ monocytes JDM vs. control (p=0.0178). In vitro, oxmtDNA and IFN-α induced a comparative up-regulation IFN1 genes compared to unstimulated control (MX1 (p<0.0001, p<0.0001); RSAD2 (p=0.1508, p=0.001)). Both TLR-9 antagonist and NAC were able to down-regulate IFN type 1 genes after 24hr of oxmtDNA stimulation, suggesting that both could translate to therapeutic targets (TLR-9 (MX1, p=0.0001; RSAD2, p=0.0374); NAC (MX1, p<0.0001; RSAD2, p=0.00014)).

Conclusion: Here, we show that dysregulated mitochondrial biology in JDM CD14+ monocytes is associated with increased oxidised mitochondria DNA (oxmtDNA) and which amplifies the interferon type 1 signature which characterises JDM, which represents a therapeutically targetable mechanism in JDM and potentially other IFN type 1-driven autoimmune diseases.

Patient Consent: Yes, I received consent

Disclosure of Interest: M. Wilkinson Grant / Research Support with: CureJM, NIHR GOSH BRC fellowship grants, non-renumerated collaboration with Novartis, D. Moulding: None declared, T. McDonnell: None declared, M. Orford: None declared, C. Wincup: None declared, J. Ting: None declared, G. Otto: None declared, R. Restuadi: None declared, D. Kelberman: None declared, S. Castellano: None declared, S. Eaton: None declared, C. Deakin: None declared, E. Rosser: None declared, L. Wedderburn Grant / Research Support with: NIHR (Senior Investigator award and the NIHR GOSH BRC), Myositis UK, Versus Arthritis and Great Ormond Street Childrens Charity. This research was supported by the NIHR Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust (GOSH). The JDCBS is also supported by grants from Cure JM, Versus Arthritis (21593, 21552), Great Ormond Street Childrens Charity (W1143), Myositis UK, the NIHR GOSH BRC and the Remission Charity. Non-renumerated collaboration with Novartis

O11. A novel in vitro model to study precision targeting of IFN-mediated responses

S. R. Veldkamp¹, M. Reugebrink¹, B. Lerkvaleekul^1,2, E. P. A. H. Hoppenreijs³, S. Kamphuis⁴, W. Armbrust⁵, J. M. van den Berg⁶, P. C. E. Hissink Muller⁷, J. Wienke¹, M. H. A. Jansen², A. van Royen-Kerkhof², F. van Wijk¹

¹Center for Translational Immunology, University Medical Center Utrecht, ²Pediatric Rheumatology and Immunology, Wilhelmina Children’s Hospital, University Medical Center Utrecht, Utrecht, ³Department of Paediatrics, Paediatric Rheumatology, Amalia Children’s Hospital, Radboud University Medical Centre Nijmegen, Nijmegen, ⁴Paediatric Rheumatology, Sophia Children’s Hospital, Erasmus University Medical Centre, Rotterdam, ⁵Department of Pediatric Rheumatology and Immunology, Beatrix Children’s Hospital, University Medical Center Groningen, Groningen, ⁶Department of Pediatric Immunology, Rheumatology and Infectious Diseases, Emma Children’s Hospital, Amsterdam University Medical Centers, Amsterdam, ⁷Department of Paediatric Rheumatology, Leiden University Medical Centre, Leiden, Netherlands

Correspondence: S. R. Veldkamp

Introduction: A dysregulated interferon (IFN) pathway is an important hallmark of JDM pathogenesis. Siglec-1, a macrophage/monocyte-restricted surface marker, was recently identified as a novel type I IFN-related activation marker in patients with JDM that correlated with clinical disease activity and could predict treatment response.

Objectives: Our aim was to develop an in vitro model to study the inhibition of IFN-mediated responses with Siglec-1 as a read-out.

Methods: PBMCs from healthy donors were stimulated in vitro for 0, 6 and 18 h with various TLR agonists (TLR-3, -4, -7, -9) or cytokines (IFNα/β/γ, TNFα, IL-1β). Pre-incubation for 1 h with various concentrations of JAK-inhibitors ruxolitinib (JAK1/2), baricitinib (JAK1/2), tofacitinib (JAK1/3), or filgotinib (JAK1), a TYK2-inhibitor (deucravacitinib) or an anti-IFNα/βR2 blocking antibody was performed to study their inhibitory effect on Siglec-1 induction. Furthermore, PBMCs were treated for 18 h with plasma of JDM patients or healthy donors (20% v/v), with or without anti-IFNα/βR2 blocking antibody. In all experiments, Siglec-1 expression was measured in CD14⁺ PBMCs by flow cytometry.

Results: Siglec-1 expression was induced after 18 h by IFNα, IFNβ, and agonists of TLR-7 (imiquimod), TLR-9 (Class A CPG ODNs), and, most potently, TLR-3 (poly I:C). Induction by all these stimuli could be completely inhibited by IFNα/β receptor blockade. Pre-incubation with 1 μM ruxolitinib, baricitinib, or tofacitinib, or 10 μM filgotinib fully prevented induction of Siglec-1 by poly I:C. For full inhibition of IFNα-induced Siglec-1 expression, however, 10 μM of all JAK inhibitors was required. In contrast, deucravacitinib, a TYK2-inhibitor, was able to inhibit Siglec-1 induction by either poly I:C or IFNα at a concentration of 0.1 μM. Treating healthy donor PBMCs with JDM patient plasma induced Siglec-1 expression, while healthy donor plasma did not. The effect of the patient plasma could be inhibited by IFNα/β receptor blockade.

Conclusion: Siglec-1 expression on monocytes was previously shown to be increased ex vivo in JDM patients and correlate with disease activity. These in vitro studies show that Siglec-1 expression can be induced in PBMCs by type I IFNs as well as certain TLR ligands, the latter of which mediate through type I IFN secretion. Siglec-1 induction can be inhibited to different extents by JAK/TYK inhibitors. Compared to the JAK-inhibitors, the TYK2-inhibitor deucravacitinib showed the strongest effect on inhibiting the IFN-mediated monocyte activation. This in vitro model has the potential to provide a biological basis for precision treatment of IFN-related systemic inflammatory diseases such as JDM and to study underlying mechanisms of derailed IFN responses.

Patient Consent: Not applicable (there are no patient data)

Disclosure of Interest: None declared

O12. Predicting immunoglobulin resistance in Kawasaki disease in multi-ethnic populations in europe: a multicenter cohort study

N. Ouldali^1,2, R. M. Dellepiane³, S. Torreggiani³, L. Mauri⁴, G. Beaujour², C. Beyler⁵, M. Cucchetti⁶, C. Dumaine², A. La Vecchia⁷, I. Melki², R. Stracquadaino⁷, C. Vinit², R. Cimaz⁸, U. Meinzer^1,2

¹Université Paris Cité, Center of Reserach on Inflammation, Inserm 1149, ²National Reference Centre for Rare Paediatric Inflammatory Rheumatisms and Systemic Autoimmune diseases RAISE, Hôpital Robert Debré, APHP, Paris, Paris, France, ³Pediatric Intermediate Care Unit, ⁴Department of Paediatric Cardiology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy, ⁵Department of Paediatric Cardiology, Hôpital Robert Debré, APHP, Paris, Paris, France, ⁶Department of Clinical Sciences and Community Health, Research Center for Adult and Pediatric Rheumatic Diseases, University of Milan, ⁷University of Milan, ⁸Department of Clinical Sciences and Community Health, Research Center for Adult and Pediatric Rheumatic Diseases, University of Milan, Milan, Italy

Correspondence: U. Meinzer

Introduction: Early identification of high-risk patients is essential to stratify treatment algorithms of Kawasaki disease (KD) and to appropriately select patients at risk for complicated disease who would benefit from intensified first-line treatment. Several scores have been developed and validated in Asian populations but have shown low sensitivity in predicting intravenous immunoglobulin (IVIG) resistance in non-Asian populations.

Objectives: We sought methods to predict the need for secondary treatment after initial IVIG in non-Asian populations.

Methods: We conducted a retrospective, multicenter study including consecutive patients with KD admitted to two tertiary pediatric hospitals in France and Italy from 2005 to 2019. We evaluated the performance of the Kawanet-score and compared it with the performances of initial echocardiography findings, and of a newly proposed score combining the Kawanet-score and initial echocardiography findings. For each score, we assessed the AUC, sensitivity and specificity for predicting the need for second-line treatment.

Results: We included 363 children with KD, 186 from France and 177 from Italy, of whom 57 (16%) required second-line therapy after the first IVIG dose. The Kawanet score, coronary artery dilation or aneurysm with maximal Z-score ≥2.0 at baseline, and abnormal initial echocardiography had a sensitivity of 43%, 55% and 65% and a specificity of 73%, 78%, 73%, respectively, for predicting the need for second-line treatment. The Kawanet-score was significantly improved by combining it with initial echocardiography findings. The best predictive performance (Sensitivity 76%, Specificity 54%) was obtained by combining the Kawanet-score with abnormal initial echocardiography, defined by the presence of either coronary artery maximal Z-score ≥2.0, pericarditis, myocarditis and/or ventricular dysfunction. This score predicted the need for second-line treatment in European, African/Afro-Caribbean and Asian ethnicity with a sensitivity of 80%, 65% and 100%, respectively, and a specificity of 56%, 51% and 61%, respectively.

Conclusion: Our study proposes a score that we named the Kawanet-echo score, which allows early identification of children with KD who require a second-line treatment in multi-ethnic populations in Europe.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

O13. TIF1-GAMMA and NXP2 autoantibodies in children with JDM are underrepresented when assessed by immunoblot compared to immunoprecipitation

H. D. Nguyen¹, C. Papadopoulou², D. Cancemi¹, L. R. Wedderburn^1,2,3, S. L. Tansley^4,5 on behalf of on behalf of the UK Juvenile Dermatomyositis Cohort and Biomarker Study

¹UCL Great Ormond Street Institute of Child Health, ²NIHR Biomedical Research Centre at Great Ormond Street Hospital for Children, ³Centre for Adolescent Rheumatology Versus Arthritis at UCL, UCLH and GOSH, London, ⁴Royal United Hospitals, ⁵The University of Bath, Bath, United Kingdom

Correspondence: H. D. Nguyen

Introduction:

Juvenile Dermatomyositis (JDM) is a rare chronic autoimmune disease that causes proximal muscle weakness and skin rash in children and adolescents. Myositis specific and associated autoantibodies (MSA and MAA) are important prognostic biomarkers for JDM, yet the screening process of MSA and MAA is not standardised across healthcare centres, raising concerns about reliability or inter assay validity for this important prognostic tool. Although immunoprecipitation is considered the reference standard method to detect relevant autoantibodies, most autoantibody-testing laboratories use blotting-based immunoassays, for reasons of practicality and cost. A recent study suggested that immunoblot can be limited at detecting certain clinically important MSA subtypes ¹.

Objectives:

To compare relevant autoantibody frequencies detected by immunoprecipitation (IP) with autoantibody frequencies detected in immunoblots, and to determine the different levels of sensitivity of these techniques in detecting different myositis relevant autoantibody subtypes, in the UK Juvenile Dermatomyositis Cohort and Biomarker Study (JDCBS).

Methods:

A total of 472 JDM patients recruited to JDCBS were included. MSA/MAA status of each patient was determined by radio-labelled protein immunoprecipitation at the University of Bath (383 patients) or by immunoblot assays provided via the patients’ centre of care (89 patients).

Results:

The female distribution was 70.9% in immunoprecipitation cohort and 72.7% in immunoblot cohort. Regarding ethnicity, most patients in both cohorts identified as White: 77.1% of immunoprecipitation cohort and 65.9% of immunoblot cohort. Immunoprecipitation and immunoblot methods detected a myositis relevant autoantibody in 225 of 383 (58%) and 47 of 89 (53%) of samples respectively. The frequency of autoantibodies detected however, varied between the two cohorts. Anti-TIF1γ was identified in 70 patients (18.1%) in the immunoprecipitation cohort, followed by anti-NXP2 in 61 (15.8%), and anti-MDA5 in 23 (5.9%) patients. In contrast, in the immunoblot cohort, anti-MDA5 was the most prevalent autoantibody found in 15 (15.5%) patients, followed by anti-TIF1γ in 11 (11.3%), and anti-NXP2 in 9 (9.3%) of patients.

Excluding anti-Ro52, which is not detected by immunoprecipitation, the identification of more than one autoantibody in a single patient was rare in both groups. Detection of more than one autoantibody was more prevalent in the immunoblot cohort (2.2%) versus immunoprecipitation (0.5%). Anti-Ro52 was present in 8 (9%) patients in the immunoblot cohort, and most commonly occurred in conjunction with anti-MDA5 (7 patients (7.9%)).

Conclusion:

The differing prevalence of autoantibodies in our cohort when analysed by immunoprecipitation and immunoblot raises concerns regarding the sensitivity and specificity of immunoblot to detect key autoantibodies relevant to patients with JDM. Poor sensitivity for immunoblot to detect anti-TIF1γ, in keeping with our data, has previously been reported but this is the first report of a potential reduction in sensitivity for anti-NXP2. The titre of anti-MDA5 has been shown to reduce with treatment ². The increase in prevalence of anti-MDA5 in the immunoblot cohort could relate to the analysis of earlier pre-treatment samples in this group, rather than false positive results. Further work is required to understand the reliability of immunoblot to detect myositis autoantibodies in JDM.

References:

1. Tansley SL, Li D, Betteridge ZE, McHugh NJ. Rheumatology (Oxford). 59(8), 2109-2114 (2020).

2. Sato S, Kuwana M, Fujita T, Suzuki Y. Mod Rheumatol. 23, 496–502 (2012).

Patient Consent: Yes, I received consent

Disclosure of Interest: H. Nguyen Grant / Research Support with: NIHR Biomedical Research Centre at GOSH, C. Papadopoulou Grant / Research Support with: NIHR Biomedical Research Centre at GOSH, D. Cancemi Grant / Research Support with: NIHR Biomedical Research Centre at GOSH, L. Wedderburn Shareholder with: non-remunerated collaboration with Novartis, Grant / Research Support with: NIHR Biomedical Research Centre at GOSH; The JDCBS is supported by Cure JM, GOSCC, Myositis Remission, and the NIHR, S. Tansley: None declared

O14. Comparing the use of 1g/kg intravenous immunoglobulin (IVIG) dose against the standard dose of 2g/Kg IVIG in patients with juvenile dermatomyositis (JDM): a retrospective cohort study

R. Ebrahim¹, M. Al-Obaidi², C. Papadopoulou²

¹University College London, ²Great Ormond Street Hospital, London, United Kingdom

Correspondence: R. Ebrahim

Introduction: Juvenile Dermatomyositis (JDM) is a rare childhood inflammatory disease affecting skin and muscle usually treated with corticosteroids alongside adjunctive therapies including intravenous immunoglobulins (IVIG). While typically dosed at 2g/kg on the recommendation of the Childhood Arthritis and Rheumatology Research Alliance (CARRA), national shortages in 2019 have meant JDM patients now receive a dose of 1g/kg IVIG.

Objectives: This study aims to evaluate differences in remission odds, disease activity improvement and reduction of concomitant medication use in JDM patients receiving either dose.

Methods: Data was collected from 48 JDM patients receiving IVIG for at least 6 months seen at London’s Great Ormond Street Hospital (GOSH) and part of the UK Juvenile Dermatomyositis Cohort and Biomarker Study (JDCBS). The primary outcomes were odds of remission at 0, 6 and 12 months post-IVIG initiation while disease improvement and reduction of concomitant medication were secondary outcomes measured at the same timepoints. Remission was defined using the Paediatric Rheumatology International Trials Organisation (PRINTO) criteria by meeting at least three of the following: CK ≤150U/I, CMAS >50/52, MMT8 >78/80, PGVAS ≤0.2/10. Logistic regression analysis was used to demonstrate effect of dose on remission odds while Friedman’s ANOVA and McNemar’s test measured disease activity improvement and reduction of medication.

Results: Of the 48 patients, 41 were taking 2g/kg IVIG while only 7 were taking 1g/kg IVIG. There was no significant difference in remission odds after 6 (p=0.957) and 12 months (p=0.894) between IVIG doses after adjusting for confounders including age, sex, ethnicity, disease onset age (years) IVIG start age (years) time starting IVIG post diagnosis (weeks) Myositis Specific Antibodies (MSA) presence, MSA subtype, and treatment received. Improvements were noted at 6 and 12 months for both groups in skin, muscle and global disease activity, the most notable of which were significant improvements in the modified skin disease activity score in both the 2g/kg group (χ2=10.150, p=0.006) and 1g/kg group (χ2=7.176, p=0.028). There was a significant reduction in corticosteroid use after 12 months (p=0.035) but no significant difference between IVIG doses after 6 months (p=0.241) and 12 months (p=0.253).

Conclusion: This study is the first to describe the effects of different IVIG doses in a large cohort of JDM patients and found that there is no significant difference in treatment outcomes and effect between JDM patients taking 1g/kg IVIG and 2g/kg IVIG. The results of this study further confirmed findings in the wider literature surrounding IVIG treatment in JDM with many patients achieving remission and improvement in muscle, skin and systemic disease. Meanwhile, the overall result of this study has important financial and clinical implications to reduce treatment cost and patients’ hospitalisation and thus presents an attractive proposition to healthcare providers to change their dose from 2g/kg IVIG to 1g/kg IVIG.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

O15. Measuring IFNA2 levels by a single-molecule array in clinical practice of childhood-onset SLE patients does matter; results from a single center longitudinal study

M. J. Wahadat^1,2, H. Qi³, C. van Helden-Meeuwsen², E. Huijser², L. van den Berg¹, J. Göpfert⁴, M. Verkaaik¹, M. Schreurs², S. Kamphuis¹, M. Versnel²

¹Department of Paediatric Rheumatology, Sophia Children’s hospital, Erasmus University Medical Center, ²Department of Immunology, ³Department of Biostatistics, Erasmus University Medical Center, Rotterdam, Netherlands, ⁴Department of Applied, Biomarkers and Immunoassays, NMI Natural and Medical Sciences Institute at the University of Tübingen, Reutlingen, Germany

Correspondence: M. J. Wahadat

Introduction: Type-I interferon (IFN-I) pathway activation plays a pivotal role in the pathogenesis of SLE and has been proposed as biomarker for disease activity. IFN-I pathway activation can be measured by determining the expression of IFN-I stimulated genes or a so-called IFN signature. Ultrasensitive single-molecule array (Simoa) technology enables measurement of IFN protein concentrations at subfemtomolar concentrations. Parallel use of these measuring methods in longitudinal cohorts of childhood-onset SLE (cSLE) patients in relation to disease activity could help in translating the most relevant technique for use in clinical practice.

Objectives: To determine the association of serum IFNa2 levels and whole blood IFN-I stimulated gene expression with disease activity and study their potential to mark specific disease activity states in a longitudinal cohort of cSLE patients.

Methods: Serum IFNa2 levels were measured in 338 samples from 48 cSLE patients and 67 healthy controls using an IFN-a2 Simoa assay (Quanterix) on an HD-X analyser. A 5 gene IFN-I signature was measured by RT-PCR in paired whole blood samples. Disease activity was assessed by the clinical SELENA-SLEDAI (cSLEDAI) and BILAG-2004. Low disease activity was defined by the Low Lupus Disease Activity State (LLDAS) and flares were characterized by the SELENA-SLEDAI flare index. Analysis was performed using linear mixed effect models.

Results: A clear positive correlation was present between serum IFNa2 levels and the IFN-I gene signature (r=0.78, p<0.0001). Serum IFNa2 levels and the IFN-I gene signature showed the same significant negative trend in the first three years after diagnosis. In this timeframe, mean baseline serum IFNa2 levels decreased with 55.1% (delta 172 fg/mL, p<0.001) to a mean value of 164 fg/mL, which was below the calculated threshold of 219.4 fg/mL. In the linear mixed model, serum IFNa2 levels were significantly associated with both the cSLEDAI and the BILAG-2004 (p<0.001 and p<0.01), while the IFN-I gene signature did not show this association (p=0.35 and p=0.23). Moreover, 69.7% of the time points in LLDAS had a serum IFNa2 level under the calculated threshold, while only 31.9% of the time points in LLDAS reached an IFN-I gene signature below the calculated threshold. Both techniques were equally capable of marking disease flares (79.2% above threshold vs 87.5% above threshold).

Conclusion: Serum IFNa2 levels measured by Simoa, but not the type-I IFN gene signature, are associated with disease activity scores and characterize disease activity states in cSLE patients. Hence, this technique has the potential to be implemented in clinical practice.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

O16. Panel sequencing links rare, possibly damaging genetic variants to a subset of patients with juvenile-onset SLE with distinct clinical phenotypes and outcomes

A. Charras¹, S. Haldenby², E. Smith^1,3, C. Roberts¹, M. Beresford^1,3, C. Hedrich^1,3 on behalf of On behalf of the UK JSLE Cohort Study

¹Department of Women’s and Children’s Health, Institute of Life Course and Medical Sciences, University of Liverpool, ²Institute of Infection, Veterinary & Ecological Sciences, University of Liverpool, Centre for Genomic Research, ³Alder Hey Children’s NHS Foundation Trust Hospital, Department of Paediatric Rheumatology, Liverpool, United Kingdom

Correspondence: A. Charras

Introduction: Juvenile-onset systemic lupus erythematosus (jSLE) affects 15-20% of lupus patients. Clinical heterogeneity across ethnicities, age groups and individual patients suggests a variable pathophysiology.

Objectives: The aim of this study was to identify damaging high-penetrance mutations in genes associated with SLE or SLE-like diseases in a large national cohort (UK JSLE Cohort Study and Repository) and to compare demographic, clinical and laboratory characteristics in sub-cohorts of patients with “genetic” SLE versus other SLE patients.

Methods: Based on a 2018 literature search targeting known Mendelian disease causes and risk alleles (using PubMed, OMIM and Ensembl), target enrichment and next generation sequencing was performed in 348 patients. Using in silico screening (SnpEFF) for ‘high impact’ variants with low minor allele frequencies (MAF <5%) followed by inheritance pattern analysis (using OMIM, ClinVar and SNPnexus), patients with predicted ‘high impact’ variants and autosomal dominant (AD) inheritance were included. Furthermore, patients with variants following autosomal recessive inheritance were included, if ≥1 additional “high impact” mutations were present on the second allele (compound heterozygote) or if ≥1 other SLE-associated gene in the same immunological pathway had a “high impact” mutation. Results were integrated with demographic, clinical and treatment-related datasets.

Results:

Variants predicted to be damaging were identified in approximately 3.5% of jSLE patients. Affected genes and associated pathways are summarised in the table.

Compared to the rest of the cohort, patients with damaging gene variants (“genetic” SLE”) were younger and more frequently of African/Caribbean ancestry. Patients with “genetic” SLE had less overall organ involvement and associated damage, but neuropsychiatric involvement developed over time. Less aggressive first-line treatment was chosen in patients with “genetic” SLE, but more second- and third-line agents were used. “Genetic” SLE is associated with anti-dsDNA antibody positivity at diagnosis, and reduced ANA, anti-LA and anti-Sm antibody positivity at the last visit.

Conclusion: “Genetic” jSLE associates with younger age at disease-onset, reduced persistent antibody positivity, less organ involvement, fewer disease flares and less damage, but the development of neuropsychiatric disease over time. Routine sequencing may allow patient stratification, risk assessment and targeted treatment, thereby increasing efficacy and reducing toxicity.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

Table 1 (abstract O16). See text for description

O17. Genetical and phenotypical findings of childhood-onset systemic lupus erythematosus

P. Morán Álvarez¹, C. Passarelli², V. Messia¹, M. Pardeo¹, E. Marasco¹, A. Insalaco¹, F. De Benedetti¹, C. Bracaglia¹

¹Ospedale Pediatrico Bambino Gesù, Rome, Italy, ²Pediatric Rheumatology, Ospedale Pediatrico Bambino Gesù, Rome, Italy

Correspondence: P. Morán Álvarez

Introduction: Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease which leads to inflammation and organ damage caused by immune complex deposition. Classically, childhood SLE (cSLE) has been considered as a polygenic autoimmune disease; however, a pediatric monogenic lupus-like phenotype is emerging due to the recent recognition of several related novel high-penetrance gene variants in the last years. This fact associated to the high degree of concordance among monozygotic twins, supports the importance of genetic background in the cSLE pathogenesis.

Objectives: To identify the presence of variants in gene related to monogenic lupus and their relationship with clinical manifestations in cSLE or lupus-like phenotype.

Methods: A descriptive, observational, cross-sectional study was carried out in children with a diagnosis of cSLE or with lupus-like. The genetic analysis (Sanger/Clinical Exome Sequencing) was performed from isolated DNA obtained from blood sample.

Results: Forty-two children were included in the study. The genetic analysis detected at least one variant in 11 (26.1%) children, 5 (45.4%) with cSLE (ADAR, TNFAIP3, RNASEH2B, SHOC2, IFIH1) and 6 (54.5%) with lupus-like phenotype (TREX, DNASE1,RNASEH2B, C1S, TLR7, STAT5A, TNFRSF13B). Of those who carry a genetic variant, the median age at disease onset was 11 years (range: 2-16) and 72.7% were female. Most of them were Caucasians (72.7%). Four (36.3%) and 3 (27.2%) out of 11 patients had a positive family history and/or a personal history for autoimmune diseases, respectively.

Regarding the clinical manifestations at onset, musculoskeletal was the most frequent (8 patients, 72.7%), followed by hematological (6 patients, 54.5%), cutaneous (6 patients, 54.5%), constitutional with fever (5 patients, 45.45%), neurological (4 patients, 36.3%), renal (3 patients, 27.2%), cardiac (3 patients, 27.2%) and pulmonary (2 patients, 18.1%) manifestations.

Related to immunological parameters, 10 (90.9%) were ANA positive, 5 (45.4%) anti-dsDNA, 4 (36.3%) ENA and 2 (18.1%) were antiphospholipid antibodies and lupus anticoagulant positive. Both C3 and C4 were low in 5 (45.4%) children and isolated C3 levels were low in 4 (36.3%) patients.

Among the variants, we found that only two patients who carry a TREX variant showed normal C3 and C4 levels; one of them presented with lupus pernio as reported in literature. The same RNASEH2B (c.868G>A) variant was identified in two siblings with similar phenotype. The patient who carried the SHOC2 variant presented polyarthritis and serositis, while the patient with the TNFRSF13B variant onset with a glomerulonephritis. Those manifestations have already been described related to these gene variants.

Conclusion: Around 25% pediatric patients with cSLE or lupus-like phenotype in our cohort showed at least one variant in gene related to monogenic-lupus and some of them had a phenotype similar to those already described. The evidence of these variants may suggest the genetics potential contribution to the cSLE pathogenesis. Further studies in larger cohorts are necessary to confirm these data.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

O18. Patient-specific and disease-related determinants for cardiovascular disease (CVD) risk stratification in the apple (atherosclerosis prevention in paediatric lupus erythematosus) clinical trial cohort

J. Peng^1,2, G. Robinson^1,2, S. Ardoin³, L. Schanberg⁴, E. Jury¹, C. Ciurtin²

¹Centre for Rheumatology Research, Division of Medicine, ²Centre for Adolescent Rheumatology Versus Arthritis, Division of Medicine, University College London, London, United Kingdom, ³Department of Medicine, Nationwide Children’s Hospital, Ohio State University, Columbus, ⁴Duke Clinical Research Institute, Duke University School of Medicine, Durham, United States

Correspondence: J. Peng

Introduction: The risk of developing CVD through atherosclerosis in juvenile-onset systemic lupus erythematosus (JSLE) patients is significantly increased.

Objectives: This study aimed to stratify and characterize JSLE patients at elevated CVD-risk using patient/disease-related factors and metabolomic data from patients recruited to the APPLE (Atherosclerosis Prevention in Paediatric Lupus Erythematosus) clinical trial, designed to assess atherosclerosis development.

Methods: Unsupervised hierarchical clustering was performed to stratify patients by arterial intima-media thickness (IMT) measurements at baseline (N=151) and carotid (c)IMT progression over 36 months (placebo arm only, N=60). Baseline metabolomic profiles (~250 serum metabolites) were compared between clusters using conventional statistics, univariate logistic regression, sparse Partial Least-Squares Discriminant Analysis (sPLS-DA) and random forest classifier. An independent cohort (UCL-JSLE cohort, N=89) with matching metabolomics, immunophenotyping and proteomics, was used to validate the discovered CVD risk-related signatures from the APPLE cohort.

Results: Baseline IMT stratification identified 3 clusters with high, intermediate, and low baseline IMT measurements and progression trajectories over 36 months, each having distinct racial/BMI/household education/income characteristics. Analysis of cIMT progression over 36 months identified 2 patient groups with high and low IMT progression. Unique metabolomic profiles differentiated high and low cIMT progression groups, with good discriminatory ability (0.81 AUC in ROC analysis) using the top 6 metabolites (Total cholesterol esters, Total cholesterol, Phospholipids in small LDL particles, Total cholesterol in small LDL particles, Free cholesterol in medium LDL particles and Total lipids in small LDL particles) selected from the analysis. cIMT progression over 36 months in the placebo group correlated positively with baseline disease activity (SLEDAI), damage score (SLICC), white blood cell count, serum complement C3, blood pressure (both systolic and diastolic) and BMI. Metabolomics signatures discovered from the APPLE cohort were applied to stratify JSLE patients in the validation cohort (UCL-JSLE), where 3 groups were identified with distinct metabolomics profiles indicating JSLE patients with high risk (N= 20), intermediate risk (N= 43) and low risk (N= 26) CVD-risk. Significant differences were observed in the frequency of classical monocytes (p=0.015) and nonclassical monocytes (p=0.005) when comparing high and low CVD risk group in the UCL-JSLE cohort.

Conclusion: Complex analysis of IMT patterns and progression in the APPLE trial cohort identified novel key determinants that could guide further research for CVD-risk stratification in JSLE.

Disclosure of Interest: None declared

Oral Communications Session 3 - JIA

O19. Outcomes of patients with juvenile idiopathic arthritis following biologic switching in the childhood arthritis and rheumatology research alliance registry

M. Mannion¹, S. Amin², S. Balevic³, C. Correll⁴, T. Beukelman¹, for the CARRA Registry Investigators²

¹Pediatric Rheumatology, University of Alabama at Birmingham, Birmingham, ²Childhood Arthritis and Rheumatology Research Alliance, Washington, DC, ³Duke Clinical Research Institute, Duke University, Durham, NC, ⁴Division of Rheumatology, Department of Pediatrics, University of Minnesota, Minneapolis, MN, United States

Correspondence: M. Mannion

Introduction: Tumor necrosis factor inhibitors (TNFi) are the most commonly used first biologics to treat juvenile idiopathic arthritis (JIA), but it is unknown what subsequent biologic medications are most effective after failure of an initial TNFi.

Objectives: We compared the effectiveness of using a 2^nd TNFi versus a non-TNFi following failure of a 1^st TNFi in routine clinical practice.

Methods: We included individuals with a primary diagnosis of non-systemic polyarticular course JIA who received a TNFi as their 1^st biologic medication and started a 2^nd biologic (index date) within 90 days of stopping the 1^st TNFi on or after enrollment in the Childhood Arthritis and Rheumatology Research Alliance Registry. Included patients had a 6 month follow up visit (+/- 3 months) after the index date and prior to February 29, 2020. Exclusion criteria included active uveitis on the index date and no Registry visit within 4 weeks of the index date. The primary outcome was inactive disease (ID) and minimal disease activity (MiDA) based upon the clinical juvenile arthritis disease activity score (cJADAS; cJADAS ID<2.5, cJADAS MiDA<5) at the 6 month visit. We used fully conditional specification multiple imputation to account for missing data. Propensity scores (PS) for likelihood of being in the 2^nd TNFi group were calculated by logistic regression (LR) with covariates from index date including active and limited joint count, physician and parent global assessments, childhood health assessment questionnaire, pain, erythrocyte sedimentation rate, time from diagnosis to index date, time from diagnosis to start of 1^st TNFi, sex, JIA category, methotrexate (MTX) use, glucocorticoid use, cJADAS, 1^st TNFi, index date calendar year, uveitis history. We used LR to compare outcomes following switch to a 2^nd TNFi versus non-TNFi between index date and 6 month follow up unadjusted and adjusted for PS quintile.

Results: 216 individuals were included in the study, 84% receiving etanercept initially and most patients stopping for ineffectiveness (74%). 183 (85%) started a 2^nd TNFi and 33 (15%) started a non-TNFi. Adalimumab was the most common 2^nd biologic (71% overall, 84% of 2^nd TNFi) and tocilizumab was the most common non-TNFi 2^nd biologic (9% overall, 58% of non-TNFi). On the index date, 56% of patients had used MTX (55% 2^nd TNFi and 58% non-TNFi) and 12% of patients used glucocorticoids (11% 2^nd TNFi and 15% non-TNFi). There was no difference in meeting cJADAS ID or MiDA criteria by treatment group even after adjusting for PS quintile.

Conclusion: Among polyarticular course JIA patients in a large North American registry following failure of a 1^st TNFi, switch to a 2^nd TNFi was more common than switch to a non-TNFi. There were no differences between those starting a 2^nd TNFi or non-TNFi in achieving cJADAS inactive disease or MiDA after 6 months. More research is necessary to determine which patients would benefit from change in treatment mechanism.

Patient Consent: Not applicable (there are no patient data)

Disclosure of Interest: M. Mannion Grant / Research Support with: Rheumatology Research Foundation Norman B Gaylis, MD Clinical Investigator Award, S. Amin: None declared, S. Balevic Grant / Research Support with: National Institutes of Health, US Food and Drug Administration, Patient-Centered Outcomes Research Institute, Rheumatology Research Foundation Scientist Development Award, Childhood Arthritis and Rheumatology Research Alliance, Purdue Pharma, Consultant with: UCB, C. Correll: None declared, T. Beukelman Consultant with: Novartis, UCB, ,. for the CARRA Registry Investigators: None declared

Table 1 (abstract O19). Logistic regression estimates for meeting cJADAS ID or cJADAS MiDA at 6-months for patients with polyarticular course JIA following start of a 2^nd biologic, referent group are those who started a non-TNFi. Models are adjusted for PS quintiles

O20. Orofacial manifestations of juvenile idiopathic arthritis from diagnosis to adult care transition: a population-based, cohort study

M. Glerup¹, A. Tagkli², A. Küseler², A. Estmann³, C. Verna⁴, A. E. Bilgrau⁵, S. E. Nørholt^6,7, T. Herlin⁸, T. K. Pedersen^2,6, P. Stoustrup²

¹MG and AT Contributed Equally to the Study and Shares the First Authorship. Department of Paediatrics and Adolescent Medicine, Aarhus University Hospital, ²Section of Orthodontics, Aarhus University , Aarhus, ³Department of Pediatrics, Odense University Hospital, Odense, Denmark, ⁴Department of Pediatric Oral Health and Orthodontics and UZB University Center for Dental Medicine Basel, University of Basel, Basel, Switzerland, ⁵Department of Mathematical Sciences, Aalborg University, Aalborg, ⁶Department of Oral and Maxillofacial Surgery , Aarhus University Hospital , ⁷Department of Dentistry and Oral Health, Aarhus University, ⁸Department of Paediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark

Correspondence: M. Glerup

Introduction: Juvenile idiopathic arthritis (JIA) involvement of the temporomandibular joint (TMJ) may cause orofacial symptoms and dysfunction that can persist into adulthood. Contemporary, population-based estimates for the prevalence of JIA-related orofacial manifestations are unavailable. Such estimates are important for patient counseling, critical for clinical decision-making, and planning of the transition to adult rheumatology care. Furthermore, much attention has been devoted to the identification of risk factors of poor outcome in JIA but knowledge about risk factors exclusive of TMJ involvement is limited.

Objectives: 1) To estimate the cumulative incidences of orofacial conditions followed by temporomandibular joint (TMJ) arthritis in juvenile idiopathic arthritis (JIA) from diagnosis in childhood until transition to adult care. 2) To identify features in JIA associated with involvement of the temporomandibular joint (TMJ).

Methods: A population-based cohort analysis was conducted, involving longitudinal data on orofacial health from 2000 to 2018. Regardless of TMJ status, the patients were referred to the Regional Craniofacial Clinic of Western Denmark for routine orofacial examinations according to a standardized protocol. All patients received tax-funded health care. Data collection included information about disease-specific background information, TMJ involvement, JIA-induced dentofacial deformity, and orofacial symptoms and dysfunction. The association between JIA disease parameters and the diagnosis of TMJ involvement at transition to adult care (16-18 years of age) was assessed using multivariate regression statistics.

Results: 613 patients were followed with a mean clinical TMJ observation time of 4.0 years (range: 0-15.3 years; 0.25/0.75 percentiles: 0/6.7 years). From JIA onset to transition to adult care, the cumulative incidence of patients with JIA involvement of the TMJ was 30.0% during the 18 years of observation. Furthermore, 20.6% of the cohort had developed arthritis-induced dentofacial deformity. A substantial proportion of the cohort experienced several events of orofacial symptoms (23.5%) and dentofacial dysfunction (52%). In a multivariate analysis, the following baseline variables were significantly adversely associated with TMJ involvement: young age at diagnosis (<9 years), female gender, and ANA positivity. However, HLA-B27 positivity was associated with a lower risk of TMJ involvement. Of the orofacial symptoms and dysfunctions during the disease course TMJ pain during function, reduced translation, asymmetric mandibular mouth opening, and crepitation were significantly associated with TMJ involvement.

Conclusion: Orofacial signs and symptoms were frequent findings in children and adolescence with JIA. Involvement of the TMJ was seen in 30% of the cohort. 20.6% of the total cohort developed JIA-related dentofacial deformity before transition into adult care. TMJ involvement and dentofacial deformity were associated with JIA diagnosis at age younger than 9 years, ANA positivity, and several events of orofacial symptoms and TMJ dysfunction. This is the first population-based study in the biologic era to document these frequent orofacial complications in children with JIA.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

O21. Joint-specific responses to tofacitinib in JIA: a post HOC analysis of the open-label period of a phase 3 clinical trial

R. Micheroli¹, D. J. Lovell², A. Martini³, L. Stockert⁴, H. Jo⁵, K. Kwok⁵, A. Diehl⁴, T. Killeen⁶, C. Ospelt¹, H. I. Brunner², N. Ruperto³ on behalf of on behalf of PRINTO/PRCSG

¹University Hospital Zürich, Zürich, Switzerland, ²Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States, ³IRCCS Istituto Giannina Gaslini, Genova, Italy, ⁴Pfizer Inc, Collegeville, PA, ⁵Pfizer Inc, New York, NY, United States, ⁶Pfizer Ltd, Tadworth, United Kingdom

Correspondence: T. Killeen

Introduction: Joint involvement in juvenile idiopathic arthritis (JIA) varies substantially.¹ Tofacitinib is an oral Janus kinase inhibitor for the treatment of active polyarticular-course JIA and active juvenile psoriatic arthritis. The effect of tofacitinib on specific joints has not been well studied.

Objectives: Explore joint-specific responses to tofacitinib in the open-label phase of a clinical trial in patients with JIA.

Methods: This was a post hoc analysis of week (W)18 data from the open-label treatment phase of a Phase 3 clinical trial² (N=225) in children with JIA aged 2–<18 years, where patients received oral tofacitinib (weight-based doses; ≤5 mg twice daily); 65% received concomitant methotrexate. Tenderness was defined as pain on motion and/or tenderness. Paired joint pathology scores (PJPS; range: 0 [neither side swollen and/or tender] to 4 [both sides swollen and tender] for each pair of joints) and PJPS % change from baseline (%Δ) were calculated; data were available for 34 joint pairs. Small joints of the hands and feet were grouped; for each grouping, PJPS was calculated as the mean of the included paired joints’ PJPS, and %Δ was calculated using the assigned % value (-100–100% by 25% increments) based on a combination of baseline and post-baseline scoring, which was calculated as mean of the individual paired joints’ PJPS.

Results: Baseline joint involvement and PJPS were greatest in the ankle, knee and wrist, followed by the metacarpophalangeals and proximal interphalangeals (Table). PJPS decreased in all joints by W4, continuing up to W18. Greatest %Δ PJPS responses were observed in the ankle, knee and wrist; with metatarsophalangeals, toes and distal interphalangeals responding least (Table).

Conclusion: Joint-specific responses to tofacitinib in JIA were strongest in the frequently involved ankle, knee and wrist, improving over time up to W18. This analysis was limited by its post hoc nature and lack of a placebo group.

Trial registration identifying number: ClinicalTrials.gov (NCT02592434)

References

[1] Eng SWM, et al. PLOS Med 2019; 16: e1002750

[2] Ruperto N, et al. Lancet 2021; 10315: 1984-96

Acknowledgements: Study sponsored by Pfizer Inc. Medical writing support was provided by Karen Thompson, PhD, CMC Connect, and funded by Pfizer Inc.

Patient Consent: Not applicable (there are no patient data)

Disclosure of Interest: R. Micheroli Speaker Bureau with: AbbVie, Eli Lilly, Gilead Sciences and Pfizer Inc, D. J. Lovell Grant / Research Support with: Bristol-Myers Squibb, Janssen, Novartis, Pfizer Inc, Roche and UBC, Consultant with: AstraZeneca, Boehringer Ingelheim, GSK, Novartis, Pfizer Inc, Roche, Takeda and UBC, and DSMB chairperson for NIH, A. Martini: None declared, L. Stockert Shareholder with: Pfizer Inc, Employee with: Pfizer Inc, H. Jo Shareholder with: Pfizer Inc, Employee with: Syneos Health, K. Kwok Shareholder with: Pfizer Inc, Employee with: Pfizer Inc, A. Diehl Shareholder with: Pfizer Inc, Employee with: Pfizer Inc, T. Killeen Shareholder with: Pfizer Inc, Employee with: Pfizer Ltd, C. Ospelt Grant / Research Support with: Novartis Foundation for Biomedical Research, H. I. Brunner Grant / Research Support with: Bristol-Myers Squibb, MedImmune, Novartis and Pfizer Inc, Consultant with: AbbVie, AstraZeneca/MedImmune, Bayer, Biocon, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Janssen, Novartis, Pfizer Inc, Roche and R Pharm, Employee with: Cincinnati Children’s Hospital Medical Center, Speaker Bureau with: GSK, Novartis and Roche, N. Ruperto Grant / Research Support with: Bristol-Myers Squibb, Eli Lilly, F. Hoffmann-La Roche, GSK, Janssen, Novartis, Pfizer Inc and Sobi, Consultant with: Ablynx, AstraZeneca/MedImmune, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, EMD Serono, F. Hoffmann-La Roche, GSK, Janssen, Merck Sharp & Dohme, Novartis, Pfizer Inc, R-Pharm, Sanofi, Servier, Sinergie and Sobi, Speaker Bureau with: Ablynx, AstraZeneca/MedImmune, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, EMD Serono, F. Hoffmann-La Roche, GSK, Janssen, Merck Sharp & Dohme, Novartis, Pfizer Inc, R-Pharm, Sanofi, Servier, Sinergie and Sobi

Table 1 (abstract O21). PJPS at baseline, joint grouping/joint grouping

O22. Distinguishing Kawasaki disease from other febrile conditions in a US cohort with the Kawasaki disease gene expression profiling (KIDS-GEP) classifier

D. Van Keulen¹, C. Shimizu², V. J. Wright³, D. Habgood-Coote³, D. Huigh¹, A. H. Tremoulet², R. Kuiper¹, C. J. Hoggart^3,4, J. Rodriguez-Manzano³, J. A. Herberg³, M. Kaforou³, D. Tempel¹, M. Levin³, J. C. Burns²

¹SkylineDx, Rotterdam, Netherlands, ²Department of Pediatrics, Rady Children’s Hospital and University of California San Diego, La Jolla, California, United States, ³Department of Infectious Disease, Imperial College London, London, United Kingdom, ⁴Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York City, New York, United States

Correspondence: D. Van Keulen

Introduction: Timely diagnosis of Kawasaki disease (KD) is challenging but may become more straightforward with the Kawasaki Disease Gene Expression Profiling (KiDs-GEP).

Objectives: To compare the KiDs-GEP classifier score between KD patients and febrile controls in a US cohort.

Methods: Biobanked whole blood RNA samples from 100 KD patients and 400 febrile controls who were diagnosed at Rady Children’s Hospital in San Diego between 2010 and 2019 were retrospectively collected. All patients were under 18 years of age and blood samples were obtained within the first 12 days of illness and prior to treatment with IVIG. RNA expression of the collected blood samples was measured with qRT-PCR and analyzed with the KiDs-GEP classifier.

Results: The KD patients had a median age of 3.05 years and 56.0% were male, which was comparable to the febrile control group (median age of 3.30 months and 56.3% male). KD patients had a significantly higher KiDs-GEP classifier score (mean 25.6 [IQR 24.0-27.1] than the febrile control patients (mean 21.0 [IQR 19.4-23.0], p<1x10^-10). The lowest classifier score was observed for patients with viral infections (mean 20.4 [IQR 19.1-22.1]), making them easiest to distinguish from KD patients with the KiDs-GEP classifier.

Conclusion: The KiDs-GEP classifier score was significantly higher in KD patients than in febrile control patients. These results are consistent with our previous study and indicate that the KiDs-GEP classifier may be a useful tool to discriminate KD patients from febrile control patients.

Patient Consent: Yes, I received consent

Disclosure of Interest: D. Van Keulen Shareholder with: Option holder of SkylineDx, Employee with: Employee of SkylineDx, C. Shimizu: None declared, V. Wright: None declared, D. Habgood-Coote: None declared, D. Huigh Shareholder with: Option holder of SkylineDx, Employee with: Employee of SkylineDx, A. Tremoulet: None declared, R. Kuiper Shareholder with: Option holder of SkylineDx, Employee with: Employee of SkylineDx, C. Hoggart: None declared, J. Rodriguez-Manzano: None declared, J. Herberg: None declared, M. Kaforou: None declared, D. Tempel Shareholder with: Option holder of SkylineDx, Employee with: Employee of SkylineDx, M. Levin: None declared, J. Burns: None declared

O23. Challenges for Ukrainian patients with rheumatic diseases: how to survive

Y. Vyzhga

National PIROGOV Memorial Medical University, Vinnytsya, Vinnitsya, Ukraine

Correspondence: Y. Vyzhga

Introduction: We used to know that patients with rheumatic diseases – is potentially vulnerable group not just due to the aggressive diseases course, but as well due to irregularity of the medical care, access to drugs in dependence to country of origin.

Objectives: The aim of my study was to analyse the impact of war on access and quality of medical care for children with rheumatic diseases in Ukraine.

Methods: The social networks started to be the separate platform for direct communication between patients and doctors, as well that’s a way to share correct and updated professional information with them. I supervise my medical blog for more than 1 year, and by now my audience is more than 13 thousand of subscribers, among them more than 1.5 thousand – patients with rheumatic diseases, both adults and children, their parents. At the end of March, in 1 month after the war started, I proposed my subscribers to complete questionnaire in goggle-form, that counted 15 questions highlighted current medical and social situation. Results of the questionaries were analysed with description statistical methods.

Results: Had been analysed 278 unique completed questionaries from the patients with rheumatic diseases and their parents. Among the patients mainly were children diagnosed with JIA (79.5 %), adults with RA (15.8 %), patients with SLE (1.4 %), dermatomyositis (0.7 %) and autoinflammatory syndromes (2.6 %). Geography of the patients before the war counted 15 regions from 24 available in Ukraine. 52,5 % of the responders were forced to leave their usual place of residence due to the war, among them – 42.7 % went abroad. Among the countries that mainly accepted our patients were: Poland, Germany, Czech Republic, Slovak, Italy, Belgium, Great Britain, France, Ireland, Portugal. 67.7 % of the patients that had gone abroad, recieved medical care from paediatric rheumatologists, 17.7 % were able to get medical support by general practitioners at the country of temporary residence. Among the patients that stayed in Ukraine, 74 % were able to receive consultation of general practitioner, without access to rheumatologist, 11 % were consulted by rheumatologist online. 47.8 % of the responders admitted worsening of the disease status or flare that occurred within the last month. Majority of the patients – 81 % were able to continue their DMARD therapy at least partially, 15 % of the patients temporarily interrupted their therapy due to the lack of the access to treatment. 33 % of the responders received immune-biologic therapy of rheumatic disease before the war, that represents general trend through the country. 65 % of the patients were able to continue it, among them 38% continued abroad. Among the patients settled abroad, 34 % received medical care thanks to PRINTO contacts, 22 % with patient’s organizations and societies support, 15 % - were assisted by volunteers and others – by general practitioners’ admissions. The separate aspect of the questionnaire counted psychological condition of the patients with its evaluation in 10 points score. According to parental evaluation, just 8 % of responders were not influenced by the war, all of them are infants. Absolut result was 7±2 points, that confirms absolute negative impact.

Conclusion: War makes unreversible influence on humanitarian life aspects and when we discuss problems of the patients with rheumatic disease, its difficult to predict final outcomes. But its possible to improve cooperation and networking between European centres, that will help our patient to win in every life causality.

I want to thank our association, every doctor and nurse, every member of our society, patients’ organization, European citizens, that didn’t allow us and our patient to feel themselves alone.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

O24. Disease activity in juvenile idiopathic arthritis from childhood to adulthood in the nordic JIA cohort

V. Rypdal^1,2 on behalf of Nordic Study Group of Pediatric Rheumatology (NoSPeR), M. Glerup³, M. Rypdal⁴, E. D. Arnstad^5,6, K. Aalto⁷, L. Berntson⁸, A. Fasth⁹, T. Herlin¹⁰, S. Nielsen¹¹, M. Rygg^12,13, E. Nordal^1,2

¹Dep.of Pediatrics, University Hospital of North Norway, ²Dep.of Clinical Medicine, UIT the Arctic University of Norway, Tromsø, Norway, ³Dep.of Pediatrics, Aarhus University Hospital, Aarhus, Denmark, ⁴ Dep.of Mathematics and Statistics, UIT the Arctic University of Norway, Tromsø, ⁵Dep.of Pediatrics, Levanger Hospital, Nord-Trøndelag Hospital Trust, Levanger, ⁶Dep.of Clinical and Molecular Medicine, NTNU, Trondheim, Norway, ⁷Dep.of Pediatrics, New Children’s Hospital, Helsinki University Hospital, Helsinki, Finland, ⁸Dep.of Women’s and Children’s Health, Uppsala University , Uppsala, ⁹Dep.of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden, ¹⁰Dep. of Pediatrics, Aarhus University Hospital, Aarhus, ¹¹Dep.of Pediatrics, Rigshospitalet Copenhagen University Hospital , Copenhagen, Denmark, ¹²Dep.of Clinical and Molecular Medicine, NTNU , ¹³Dep.of Pediatrics, St. Olavs Hospital, Trondheim, Norway

Correspondence: V. Rypdal

Introduction: Inactive disease (ID) is the primary goal of the treat-to-target (T2T) strategy in juvenile idiopathic arthritis (JIA). The Juvenile Arthritis Disease Activity Score (JADAS) has cut-off values for ID, low disease activity (LDA), moderate disease activity (MDA), and high disease activity (HDA) for oligo- and polyarticular disease courses. Few studies have assessed the disease activity trajectories in a population-based setting from childhood into adulthood.

Objectives: This study aimed to evaluate JADAS10 through a disease course of 18 years, and to investigate if there are identifiable clusters of JADAS10 development over time among the Nordic patients with JIA.

Methods: Patients with JIA (n=510) from centers participating in the Nordic JIA study were included at disease onset and followed prospectively. There were three major study visits: the baseline, the 8-year, and 18-year visit. The patients were divided into poly- and oligoarthritis groups if >4 joints or ≤4 joints were affected, respectively. Descriptive statistics and K-means clustering were used to present differences in disease activity states throughout the follow-up period. McNemar’s test was used to determine if there were statistically significant changes in disease activity states from baseline to the 18-year visit.

Results: At baseline, JADAS10 was available in 219 patients with a median score of 5.0 (IQR 2.0-11.0). At the 8-year visit, JADAS10 was available in 240 patients with a median score of 1.2 (IQR 0-4.2), and at the 18-year visit 268 patients had a JADAS10 score of median 2.2 (IQR 0.8-6.0). From baseline to the 8-year visit the proportion of ID increased (p<10^-4, table), however, ID significantly decreased from the 8-year to the 18-year follow-up both for the oligo- and the polyarthritis groups (p=0.004 and 0.03, respectively). In addition, there was a significant increase of HDA in the oligoarthritis group (p=0.02). We identified three distinct JADAS10 patterns over time among 105 patients with complete JADAS10 information in the 3 major visits. Cluster 1: patients with high disease activity early in the course and improvement during the period. Cluster 2: patients with remaining low disease activity, and Cluster 3: patients with early low disease activity with worsening during the disease course.

Conclusion: We found increasing disease activity on long term follow-up after initial improvement the first years after onset of JIA. We identified a subset of children with increasing disease activity over time that may need tighter follow-up with a T2T-strategy. The impact of different JADAS cut-offs for oligo- and polyarticular JIA should further be investigated.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

Table 1 (abstract O24). See text for description

O25. Anti-TNF agents impair seroprotection in paediatric patients with juvenile idiopathic arthritis and inflammatory bowel disease vaccinated against meningococcal ACWY: the 24 months post vaccination follow-up data

M. Ohm¹, J. W. van Straalen², M. Zijlstra³, A. J. Sellies², G. C. De Joode-Smink², J. F. Swart², S. J. Vastert², J. M. van Montfrans², M. Bartels⁴, A. van Royen-Kerkhof ², J. G. Wildenbeest⁵, C. A. Lindemans^2,6, V. M. Wolters³, R. A. Wennink⁷, J. H. de Boer⁷, M. W. Heijstek⁸, F. M. Verduyn Lunel⁹, G. Berbers¹, N. M. Wulffraat², M. H. Jansen²

¹Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, ²Department of Pediatric Immunology and Rheumatology, ³Department of Pediatric Gastroenterology, ⁴Department of Pediatric Hematology, ⁵Department of Pediatric Infectiology and Immunology, Wilhelmina Children’s Hospital, University Medical Center Utrecht, ⁶Stem cell transplantation, Princess Máxima Center for Pediatric Oncology, ⁷Department of Ophthalmology, ⁸Department of Rheumatology and Immunology, ⁹Microbiology and Virology, University Medical Center Utrecht, Utrecht, Netherlands

Correspondence: M. H. Jansen

Introduction: In 2018, the meningococcal C vaccination was replaced by the meningococcal ACWY (MenACWY) vaccination in the Dutch Immunisation Programme. Therefore, we investigated the immunogenicity and safety of the MenACWY vaccine in paediatric patients with (auto)immune disease, here focussing on Juvenile Idiopathic Arthritis (JIA) and Inflammatory Bowel Disease (IBD). We now present the 24 month follow-up data and the results of the serum bactericidal antibody (SBA) assay.

Objectives: To assess immunogenicity and safety of the MenACWY vaccine in paediatric patients with JIA or IBD and study the effect of biological DMARDs on seroprotection.

Methods: In this prospective study, patients with immune disorders from the Wilhelmina Children’s Hospital Utrecht were sampled at baseline and 3, 12 and 24 months post vaccination. Serology was performed using the Fluorescent bead-based Multiplex ImmunoAssay (MIA) and the SBA assay. We assessed immunogenicity by determining geometric mean concentrations (GMCs) for polysaccharide-specific IgG concentrations. We assessed the proportion protected at 12 months post vaccination in a subset of the patients with the internationally-accepted correlate of protection (SBA titre ≥8). Safety was measured by questioning adverse events 3 months post vaccination. Alterations in disease activity were measured by the Clinical Juvenile Arthritis Disease Activity Score-27 (cJADAS-27) in JIA patients and the Paediatric Crohn’s Disease Activity Index (PCDAI) and Paediatric Ulcerative Colitis Activity Index (PUCAI) in IBD patients.

Results: 229 patients were included (33% IBD and 67% JIA). 40% were male and median age was 16 years (IQR: 14 – 17). At baseline, 72% of the patients were using DMARDs, of which 48% biologicals (39% anti-TNF agents). Except for MenC at 3 months, GMCs were significantly lower for each serogroup at all post vaccination time-points in patients who were treated with anti-TNF agents. The proportions protected (SBA titre ≥8) for MenA, C, W, Y 12 months post vaccination were 94%, 96%, 85% and 96%, respectively. This was significantly lower for anti-TNF users for serogroup W but not for A, C and Y. The MenACWY vaccine did not increase disease activity and no severe adverse events were reported.

Conclusion: The MenACWY vaccine is well tolerated in JIA and IBD patients but less immunogenic compared to healthy controls. GMC’s are significantly lower for anti-TNF users at 3, 12 and 24 months post vaccination and the proportion protected at 12 months post vaccination was significantly lower in anti-TNF users for serogroup W (but not A, C and Y). We therefore advice to measure antibodies in patients on anti-TNF 12 months post vaccination and to consider a booster vaccination accordingly.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

O26. Factors affecting the scoring of physician global assessment in JIA – survey results from PR-COIN and PRINTO

M. Tarkiainen^1,2, M. Backström^3,4, B. Gottlieb⁵, C. Trincianti⁶, T. Qiu⁷, E. Morgan⁸, D. Lovell⁹, N. Ruperto¹⁰, A. Consolaro^6,10, P. Vähäsalo^11,12,13

¹University of Helsinki, ²New Children’s hospital, Helsinki University Central Hospital, Helsinki, ³Department of Pediatrics, The Wellbeing Services County of Ostrobothnia, Vaasa, Finland, Vaasa, ⁴Pedego Research Unit, University of Oulu, Oulu, Finland, ⁵Cohen Children’s Medical Center, New York, United States, ⁶University of Genova, Genova, Italy, ⁷Department of Biostatistics and Epidemiology, USA., Cincinnati Children’s Hospital Medical Center, Cincinnati, ⁸Seattle Children’s Hospital, Seattle, ⁹Cincinnati Children’s Hospital, Cincinnati, United States, ¹⁰IRCCS Istituto G. Gaslini, Genova, Italy, ¹¹PEDEGO Research Unit, University of Oulu, ¹²Department of Children and Adolescents, Oulu University Hospital, ¹³Medical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland

Correspondence: M. Tarkiainen

Introduction: Evaluating disease activity in juvenile idiopathic arthritis (JIA) is mainly done by rating the juvenile arthritis disease activity score in which the physician global assessment (PhGA) of disease activity has an important role. However, it is not known what affects physicians scoring the PhGA.

Objectives: To assess the heterogeneity of factors affecting PhGA scoring through a global web-based survey.

Methods: An electronic questionnaire regarding factors affecting PhGA was sent to all PRINTO and PR-COIN members. The responders were asked to rate from 0 to 100 the relevance of 17 factors possibly affecting PhGA scoring. These factors were chosen based on consensus of the study panel. Results were analyzed also in groups based on the responders’ level of experience in the field of pediatric rheumatology (<5 years, 5-10 years, or >10 years). Coefficient of variation (CV) was used to measure the heterogeneity in the 17 factors contributing to PhGA soring.

Results: 491 (431 from PRINTO and 60 from PR-COIN) responders completed the questionnaire. A large individual variation was observed in the impact of different factors on PhGA assessing JIA (Table). For systemic JIA, the smallest variations (mean/SD/CV) were seen in fever (89.2/16.4/18.4) and serositis (81.0/20.2/25.0), and the largest in the presence of erosions (48.2/33.8/70.1). To the question, “If a patient with oligoarticular non-systemic JIA and a polyarticular patient with non-systemic JIA had the same clinical picture would your VAS be different?” 244 (49,7%) physicians replied “NO” and 244 (49,7%) “YES”.

Conclusion: In a global perspective, scoring of PhGA is divergent. Especially the roles of the patient’s clinical history (i.e. oligoarticular or polyarticular disease), presence of extra-articular manifestations, or patient-reported outcome measures should be discussed. To obtain consistent patient assessment in clinical trials and routine practice, a consensus on guidelines for scoring the PhGA is required.

Trial registration identifying number: N/A

Patient Consent: Not applicable (there are no patient data)

Disclosure of Interest: None declared

Table 1 (abstract O26). Factors affecting physician´s global assessment in non-systemic JIA. N = 491

O27. Investigation the effects of Tai Chi in children with juvenil idiopathic arthritis: a randomized controlled trial

S. Y. Cetin¹, E. Comak², S. Akman²

¹Department of Physiotherapy and Rehabilitation, Faculty of Health Sciences, ²Department of Child Health and Diseases, Faculty of Medicine, Akdeniz University, Antalya, Turkey

Correspondence: S. Y. Cetin

Introduction: Juvenile idiopathic arthritis (JIA) is the most common childhood rheumatic disease characterized by pain, stiffness and joint swelling. JIA is associated with muscle weakness, impaired mobility, balance, and exercise capacity, resulting in decreased aerobic capacity and functional ability in children. It is stated that exercise programs such as strengthening, stretching and balance are beneficial in terms of increasing functionality and improving the quality of life in these children. Tai Chi is a mind-body Chinese exercise method that consists of a series of gentle movements characterized by balance. As a form of physical exercise, Tai Chi appears to improve cardiovascular fitness, muscle strength, balance, coordination and physical function in rheumatic diseases, and is also associated with improvements in psychological well-being. To the best ourknowledge, there is no study in literature that has investigated the effects of Tai Chi in children with JIA. Consequently, in this study, it was thought that due to the positive effect of Tai Chi in rheumatic diseases, it would also improve balance, functionality and increase the quality of life in children with JIA.

Objectives: The aim of this study was to investigate the effect of Tai Chi exercise program on balance, functional mobility, muscle strentgh of lower extremity, exercise capacity, fatigue and quality of life and compare with home exercises group in children with JIA.

Methods: 20 children with JIA (11 girls, 9 boys) with an average age of 11.85±3,16 years were included in the study. Children were divided into two groups by block randomization method. Group 1 received 1-hour Tai Chi exercise program twice a week for 10 weeks. Group 2 received a 1-hour strengthening, stretching and balance exercise program twice a week for 10 weeks as a home exercises. Functional Reach Test (FRT) was used to evaluate the balance, Timed Up and Go Test (TUG) for functional mobility, 30-sec Sit to Stand Test for muscle strentgh of lower extremity, 6-Min Walk Test (6MWT) for exercise capacity, PedsQL Multidimensional Fatigue Scale for fatigue, PedsQL Arthritis Modul for quality of life and Childhood Health Assessment Questionnarie (CHAQ) for health assessment. All evaluations were performed at baseline and at the end of the 10th week.

Results: When the pre-training values of the groups were compared, there was no statistically significant difference in parameters (p > 0.05). After training, there was a statistically significant difference within groups for the Tai Chi and the home exercise groups for all parameters (p: 0.00-0.04) except for CHAQ scores. When the groups compared after training, FRT, TUG, 6MWT scores and fatigue scores of PedsQL were found to be significantly in favor of the Tai Chi group (p:0.00- 0.04).

Conclusion: Tai Chi should be considered for inclusion in rehabilitation programs as a safe mind-body type of exercise to improve balance, functional mobility, muscle strentgh of lower extremity, exercise capacity, fatigue and quality of life in patients with JIA.

References

1-Kuntze G, Nesbitt C, Whittaker JL, Nettel-Aguirre A, Toomey C, et al. Exercise Therapy in Juvenile Idiopathic Arthritis: A Systematic Review and Meta-Analysis Arc Phys Med Rehabil 2018;99(1):178-193

2-Wang C. Role of Tai Chi in the treatment of rheumatologic diseases. Curr Rheumatol Rep. 2012;14(6):598-603

3-Cetin SY, Erel S, Bas Aslan U. The effect of Tai Chi on balance and functional mobility in children with congenital sensorineural hearing loss, Dis Rehabil, 2020; 42:12, 1736-1743

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

Oral Communications Session 4 - Basic&Translational Science

O28. Sex differences in regulatory T-cells may contribute to autoimmune disease susceptibility

G. A. Robinson¹, J. Peng¹, H. Peckham¹, G. Butler², I. Pineda-Torra³, C. Ciurtin¹, E. C. Jury⁴

¹Centre for Adolescent Rheumatology Versus Arthritis, ²Department of Paediatric and Adolescent Endocrinology, ³Centre for Cardiometabolic and Vascular Science, ⁴Centre for Rheumatology, University College London, London, United Kingdom

Correspondence: G. A. Robinson

Introduction: Men and women have differential immune responses resulting in variation in response to infection, vaccination and autoimmune disease risk. An example is in juvenile-onset systemic lupus erythematosus (JSLE), which predominately affects young women with a common disease onset at puberty. Sexual dimorphisms have been described across both the innate and adaptive immune system which vary depending on age group and pubertal status. We hypothesised that sex-hormones could influence inflammation and autoimmune disease susceptibility following puberty.

Objectives: The aim of this study was to investigate the role of sex hormones and chromosomes in driving inflammatory profiles by sex and/or gender using unique cohorts of young individuals.

Methods: Flow cytometry was used to measure the frequency of 28 immune-cell subsets from young post-pubertal healthy and JSLE cis-men/women (n=17/22, mean age 18/17.5 and n=12/23, mean age 18/20) recruited from University College London Hospital, UK. Immune phenotype data was analysed by logistic regression and balanced random forest machine learning (BRF-ML). RNA-sequencing was used to assess the phenotype of regulatory T-cells (Tregs) isolated from matched healthy and JSLE individuals (n=5 per group), and from age matched transgender individuals under cross-sex-hormone treatment (trans-men/women, n=5/5, mean age 18.2/18.7, puberty blocked for 12-months followed by testosterone/oestradiol treatment). Differentially expressed gene (DEG) data was analysed by cluster, extended-network, pathway and open-target disease analysis. Suppression assays assessed the anti-inflammatory function of Tregs in vitro.

Results: BRF-ML identified increased circulating anti-inflammatory Tregs and decreased pro-inflammatory responder T-cells in healthy young cis-men compared to cis-women (p=0.0097 and p<0.0001, ranked highest in the BRF-ML-model). Tregs from healthy young cis-men were also more suppressive of activated T-cells in vitro. From RNA sequencing analysis, 82 Treg DEGs were identified between healthy young cis-men and cis-women, which could confidently cluster individuals by sex and significantly enriched the PI3K/AKT signalling gene ontology pathway. Importantly, 58.5% of these genes were not located on the X/Y chromosomes, suggesting a role of sex-hormones in Treg function. Despite having no influence on Treg frequency, cross-sex-hormone treatment altered many Treg transcriptomic pathways, including increased cytokine production and decreased immune activation in trans-men and trans-women, respectively, supporting a role of sex-hormones in Treg function. Many of the sex-hormone-induced Treg functional DEGs overlapped with the 82 DEGs identified between cis-men and cis-women and were significantly associated with PI3K/AKT signalling and with SLE by open-target disease analysis (p=0.02). Strikingly, sex differences in Tregs were lost or reversed in young JSLE patients, including Treg frequency, suppressive capacity and gene expression, suggesting that sex-hormone signalling could be dysregulated in autoimmune pathogenesis.

Conclusion: Sex-chromosomes and hormones may drive specific changes in circulating Treg frequency and function, respectively. Healthy young cis-men have a more anti-inflammatory Treg profile which could explain autoimmune susceptibilities by sex and inform sex-tailored therapeutic strategies.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

O29. FOXP3-specific deletion of CREB generates ST-2 positive regulatory T-cells with shifts towards type 2 immune responses

K. Ohl¹, S. H. Subramanyam¹, E. Verjans¹, T. Clarner², S. Böll³, I. G. Costa Filho⁴, L. Gan⁵, H. Huehn⁶, T. Bopp⁷, R. Beyaert⁸, B. Lambrecht⁸, M. Scheld², T. Goodarzi³, N. Wagner¹, M. Zenke¹, K. Tenbrock³

¹RWTH AACHEN University, Aachen, Germany, ²Anatomy, ³Pediatrics, ⁴Computational Genomics, ⁵IZKF, RWTH AACHEN University, Aachen, ⁶HZI, Braunschweig, ⁷Institute of Immunology, Mainz, Germany, ⁸VIB, Ghent, Belgium

Correspondence: K. Tenbrock

Introduction: Regulatory T cells (T_regs) are gatekeepers of immune homeostasis and characterized by expression of Foxp3, which maintains T_reg identity. The transcriptional activator CREB critically stabilizes Foxp3 expression in vitro.

Objectives: To analyze the effect of CREB on regulatory T cells, we generated mice with a deletion of CREB in all hematopietic cells (VAV-CRE) as well as a specific deletion in regulatory T cells (Foxp3-CRE)

Methods: Foxp+ CD4 T cells of mice were analyzed virgorously with flow cytometry, whole transcriptome analysis, ATACseq, TSDR methylation in vitro and in animal models of experimental colitis, ovalbumin induced asthma and TLR7 induced lupus in vivo

Results: Here we demonstrate that in mice with a Foxp3-specific knockout of CREB, T_regs show a reduced Foxp3 expression in vivo, but surprisingly enhanced expression of IL-13, IL-10, ST-2 and CREM. This rendered such T_regs highly suppressive in vitro. In vivo, Foxp3-specific knockout of CREB prevents colitis in a T cell mediated transfer colitis model in an IL-10 dependent way however aggravates disease activity in a murine lupus and asthma model. Mechanistically, in cooperation with CREM, CREB expression in T_regs alters chromatin accessibility to different loci like the ST-2 region and thereby influences T cell specific immune responses by regulation of IL-10.

Conclusion: Our data suggest that CREB expression in T_regs is important for the balance between Th1 and Th2 responses by regulating ST-2 and IL-10.

Disclosure of Interest: None declared

O30. A gene signature for regulatory T cell fitness as a measure of disease activity in juvenile idiopathic arthritis

M. H. Attrill¹, D. Shinko¹, T. Martins Viveiros¹, L. R. Wedderburn^2,3,4, S. G. CHARMS^2,3,4, S. G. JIAP^2,3,4, A. M. Pesenacker¹

¹Infection and Immunity, UCL Institute of Immunity and Transplantation, ²UCL Great Ormond Street Institute of Child Health, ³Centre for Adolescent Rheumatology Versus Arthritis at UCL UCLH and GOSH, ⁴NIHR Biomedical Research Centre at GOSH, London, United Kingdom

Correspondence: A. M. Pesenacker

Introduction: Juvenile Idiopathic Arthritis (JIA) is a disease of flare-ups, which do occur without warning or known trigger on or off treatment, yet there is no reliable biomarker to predict disease course. Better predictability of inflammation flare-ups could lead to more personalised disease management with preventative treatment if a flare is likely, or withdrawing medication safely when sustained remission is indicated.

Objectives: A regulatory T cell (Treg) defect has previously been suggested in JIA. Using our Treg gene signature as a measure of Treg fitness, we aim to identify the nature of Treg fitness changes in active JIA, which may be used as biomarker to predict disease trajectory and those at more at risk of flare-ups. Here, we focus on peripheral blood (PB) samples from clinically active and inactive JIA as well as synovial fluid (SF) from acutely inflamed joints.

Methods: SF mononuclear cells (SFMC, n=30), PBMCs from healthy adults (n=20) and healthy children (n=5) and from active (n= 30) and inactive (n= 17) JIA individuals were thawed, PB/SFMC lysates stored, and remaining cells sorted into CD4+CD25hiCD127low Tregs and CD4+CD25lowCD127hi T-conventional cells (Tconvs) and lysed in RLT buffer. Cell lysates were hybridised to a custom nanoString gene set (48 gene Treg signature plus) and analysed on nanoString nCounter Pro Analysis System. Normalisation by positive control and total sum normalisation, gene expression analysis and biomarker discovery pipeline, via machine learning, were performed using R software. Biomarker discovery analysis used combinations of feature select and classifier-building with logistic or elastic net regression and leave-one-out cross-validation (LOOCV) was used to obtain performance estimates, with the best algorithm chosen.

Results: As expected, the 48 gene signature successfully distinguished between Tregs and Tconvs, regardless of activation or disease state. PCA analysis clustered cells from SF and PB separately, with Tregs also distinguished from unfractionated PBMC and SFMC lysates. Genes usually associated with Treg functionality, such as FoxP3, CTLA-4 and TIGIT, were upregulated in SF Tregs. Interestingly, genes connected to the TGF-beta pathway, although not TGF-beta itself, were reduced in SF Tregs compared to blood Tregs. Crucially, using machine learning we could identify differences between blood Tregs from active and inactive JIA samples.

Conclusion: Our Treg gene signature serves as a measure of Treg fitness and has biomarker potential for immune-mediated conditions, such as JIA. We identified possible mechanisms behind loss of Treg fitness in the inflamed joint with changes in genes stabilising and responding to TGF-beta signalling. Moreover, our biomarker discovery pipeline could be used to establish an algorithm distinguishing active from inactive JIA blood Treg, indicating biomarker potential that could be ultimately used to track and possibly predict disease flares versus sustained remission.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

O31. Evidence-based occupational and physical therapy for children and adolescents with inflammatory pediatric rheumatic diseases suffering from fatigue

U. Nilsson, I. H. Bolstad, K. Krosby, B. W. Njølstad, S. Hansbø, H. Sanner, K. Risum

Oslo University Hospital, Oslo, Norway

Correspondence: U. Nilsson

Introduction: Fatigue is common in children and adolescents with inflammatory pediatric rheumatic diseases (PRD) and there is a need to develop an evidence-based guideline for physiotherapy (PT) and occupational therapy (OT) interventions to standardize and improve the quality of care offered to patients with PRD.

Objectives: To develop an evidenced-based guideline for PT and OT interventions, including identifying measurement tools to assess fatigue and interventions to treat fatigue.

Methods: The guideline is developed according to The Appraisal of Guidelines for Research and Evaluation (AGREE) Instrument, which includes scientific evidence, clinical experience and patient preferences. A systematic literature search of various medical databases was performed, and identified studies were critically evaluated. Occupational therapists and physiotherapists across Norway, working in both hospitals and primary care, contributed with clinical expertise. Patient experiences and preferences were obtained by interviewing representatives from the Norwegian Patient Association for Children with Rheumatic Diseases. Relevant representatives across Norway reviewed the guideline, and then final adjustments were performed.

Results: In total, 159 studies were identified and 17 included. In patients with Juvenile Idiopathic Arthritis, the Visual Analogue Scale is the most used unidimensional measurement tool to assess fatigue and the Pediatric Quality of Life Inventory Multi Fatigue Scale is the most used multidimensional questionnaire to assess fatigue. There is insufficient scientific evidence of the efficacy in interventions to reduce fatigue. However, a few studies showed that exercise significantly could reduce fatigue. The therapists often used a biopsychosocial approach in assessment and treatment of fatigue in PRD. They mainly used self-constructed questions to assess how fatigue affects body functions and structures, activities and participation. The therapists often used a time-schedule to get an overview of patient’s activity pattern and any need for adjustments. Since fatigue is a complex symptom, it is necessary to take several factors into consideration, such as sleep, pain and physical activity. The intervention is adapted by individual factors affecting the patient. The patient representatives highlighted a need for focus on fatigue and support by health care professionals to manage their fatigue. Patients experienced that management to reduce pain also could reduce fatigue.

The guideline is based on a biopsychosocial understanding of fatigue. It is divided into two parts; assessment and intervention. The assessment part contains patient interview, uni- and multidimensional measurements, activity registration, and assessment of different factors that can influence fatigue. The intervention part consists of patient education, understanding, awareness and regulation of activity level, enhancing self-efficacy, intervention of contributing factors to fatigue, and collaboration with other professionals involved in the care of the patients.

A brochure with patient information was developed as a part of the guideline. The guideline will be published and available at the Norwegian Electronic Health Library after final approval by Oslo University Hospital.

Conclusion: Scientific evidence is limited for assessment and interventions of fatigue in children and adolescents with PRD. Thus, the evidenced-based guideline is mainly based on clinical experience and patient preferences. Fatigue is a complex symptom and the guideline provides a framework for PT and OT in clinical care of children and adolescents with PRD suffering from fatigue. When applying the guideline, individual adjustments are necessary.

Patient Consent: Not applicable (there are no patient data)

Disclosure of Interest: None declared

O32. Ultrasound versus MRI in the evaluation of ankle/midfoot joints in juvenile idiopathic arthritis

M. Mazzoni¹, S. Lanni², F. Magnaguagno³, M. Valle³, A. Pistorio⁴, C. Lavarello⁵, M. Gattorno⁵, A. Ravelli⁴, C. Malattia^5,6

¹Struttura Complessa Pediatria, Ospedale di Lavagna, Lavagna, ²UOC Pediatria a Media Intensità di Cura Clinica de Marchi, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milano, ³Radiologia, ⁴Direzione Scientifica, ⁵Clinica Pediatrica e Reumatologia, IRCCS Istituto G. Gaslini, ⁶Dipartimento di Neuroscienze, Riabilitazione, Oftalmologia, Genetica e Scienze Materno-Infantili, Università degli Studi di Genova, Genova, Italy

Correspondence: M. Mazzoni

Introduction: Arthritis of the ankle/midfoot occurs commonly in all subtypes of JIA and might cause considerable functional impairment. Clinical assessment of this region is often challenging due to the multiplicity of joint recesses and surrounding tendons.

Objectives: To set-up an ultrasound (US) scoring system to assess synovial inflammation in ankle/midfoot joints and provide preliminary evidence of its validity by comparing US and MRI findings in JIA patients with this region involvement.

Methods: JIA patients who underwent contrast-enhanced (CE) MRI and US at the study Centre on the same day were included. The tibio-talar (TT) (anterior recess), the subtalar (ST) (lateral aspect) and the talonavicular (TN) (dorsal aspect) joints were examined by B-mode (synovial hypertrophy and/or joint effusion) and power Doppler (PD) mode. The anterior, lateral and posterior ankle tendons were assessed for tenosynovitis. Synovitis was graded using a specifically devised 0-3 semiquantitative joint-specific scoring system for B-mode and PD signal. MRIs were scored by using the Outcome Measure in Arthritis Clinical Trials Rheumatoid Arthritis MRI Scoring System. The agreement between MRI and US scores in each recess was evaluated by calculating Cohen’s kappa coefficient (k). The interpretation of the k coefficient values was as follows: 0–0.20 poor, 0.20–0.40 fair, 0.40–0.60 moderate, 0.60–0.80 good, and 0.80–1 very good.

Results: 67 patients (89.5% F; median age 12.7 y; median disease duration 7.3 y) were included. The agreement between MRI and US B-mode synovitis scores was moderate for the TT (Cohen’s kappa = 0.58; 95% CI = 0.35 - 0.81) and TN joints (Cohen’s kappa = 0.55; 95% CI = 0.31 - 0.79); it was good for the ST joint (Cohen’s kappa = 0.62; 95% CI = 0.39 – 0.85). The agreement between contrast-enhanced MRI and PD score was fair for the TT (k=0.24; 95% CI = 0.07 - 0.41) and ST joints (K= 0.38; 95% CI = 0.19 - 0.57) and moderate for TN joint (K= 0.5; 95% CI = 0.27 - 0.73). Concordance between MRI and MSUS for tenosynovitis was good (k = 0.79; 95% CI = 0.55 -1.00).

Conclusion: The joint specific US B-mode scoring system was accurate to assess and quantify synovitis in the ankle/midfoot joints and tendons. The discordances between US and MRI might be explained by MRI ability to visualize the entire joint, while the US can visualize only the superficial joint recesses. US scanning protocol and equipment settings might explain the lower sensitivity of PD mode compared to CE MRI in detecting hypervascularity in JIA synovial tissue that is an expression of active inflammation. Further studies are required to assess the reproducibility and sensitivity to change of the joint specific ankle/midfoot US score.

Disclosure of Interest: None declared

O33. High-dimensional immunophenotyping reveals altered regulatory T cell fitness between inactive and active disease in juvenile idiopathic arthritis

M. H. Attrill¹, D. Shinko¹, L. R. Wedderburn ^2,3,4, S. G. Charms^2,3,4, S. G. JIAP^2,3,4, A. M. Pesenacker¹

¹Infection and Immunity, UCL Institute of Immunity and Transplantation, ²UCL Great Ormond Street Institute of Child Health, ³Centre for Adolescent Rheumatology Versus Arthritis at UCL UCLH and GOSH, ⁴NIHR Biomedical Research Centre at GOSH, London, United Kingdom

Correspondence: M. H. Attrill

Introduction: Juvenile Idiopathic Arthritis (JIA) is an autoimmune condition in children characterised by unpredictable, T-cell rich inflammatory flares of the joints. Despite increased number of CD4+FoxP3+ regulatory T cells (Tregs) within the synovial fluid (SF) of active joints, these fail to suppress autoimmunity.

Objectives: Here, we take a closer look at the CD4+FoxP3+ Treg populations in JIA. We proposed that through in-depth high-dimensional phenotyping we will be able to identify and distinguish unfit Treg sub-populations present in JIA SF and clinically active peripheral blood (PB) which may be disrupting the immunoregulatory balance leading to ongoing disease.

Methods: Using 5-laser full spectrum flow cytometry, we designed and verified a 33-parameter panel to assess differences in the cellular composition and Treg phenotype between JIA SF mononuclear cells (SFMCs, n=18), JIA PBMCs from clinically active (n=29) and inactive disease (n=17), and healthy adult control PBMCs (n=18). The panel was designed to identify monocyte, B, NK and dendritic cell subsets in addition to T cell phenotype. Incorporating markers and receptors associated with Treg functionality, activation, memory, co-stimulation, and co-inhibition, we were able to characterise Tregs in terms of overall ‘fitness’. In addition to traditional gating analysis via Flowjo, unbiased high dimensional analysis was achieved using the R package and computational tool Spectre, allowing raw data integration, clustering through FlowSOM, dimensionality reduction via UMAP and quantitative statistical analysis and visualisation.

Results: 12/18 clusters in overall cell composition, with most changes among T lymphocytes, and 8/10 Treg clusters had altered frequencies in SF. We found an emergence of more active subtypes in both CD4- and CD4+ T cells, with increased expression of GITR, HLA-DR, CD71 and CD69. This highly activated phenotype was also mimicked in SF Tregs, which additionally adopted a classically “suppressive” phenotype, with high CTLA-4 and PD-1 levels compared to PB. However, despite a shift to a more active state, SF Tregs were not any more proliferative than blood Tregs, with no change in %Ki67+ in Tregs across SF and PB from JIA or healthy adults. Analysis of co-receptors found the upregulation of the co-stimulatory receptor CD226 on SF Tregs, mostly co-expressed with TIGIT, while blood Tregs rarely co-expressed both co-receptors. Moreover, we identified a sub-population of CD137low ID2intermediate Tregs in PB of inactive individuals, with reversed expression pattern in PB Tregs from active disease, highlighting differences in Treg maintenance with disease activity.

Conclusion: High dimensional flow cytometry revealed subsets of Tregs within the inflammatory joint of JIA with a highly active and suppressive phenotype, yet we have identified changes to Treg overall fitness. A shift to a more co-stimulatory receptor presence on SF Tregs could be backing the persistence of inflammation within the joint. Alterations to Treg stability and maintenance in the blood during active disease may also hint towards immunoregulatory disruption in the periphery. These may have biomarker potential for predicting flare-ups and offer new potential mechanistic targets for restoring the immunological balance in JIA.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

O34. New biomarkers from plasma and synovial fluid of oligoarticular juvenile idiopathic arthritis patients

S. Pelassa¹, C. Rossi¹, F. Raggi¹, D. Cangelosi², M. Bartolucci³, A. Petretto³, F. Antonini³, P. Bocca⁴, F. Penco⁴, M. Rossano⁵, F. Baldo⁵, G. Filocamo⁵, C. Trincianti⁶, A. Eva¹, A. Ravelli⁴, A. Consolaro⁴, M. C. Bosco¹

¹Laboratory of Molecular Biology, ²Clinical Bioinformatic Unit, ³Core Facilities, ⁴Pediatric Rheumatology Clinic, IRCCS Istituto G. Gaslini, Genova, ⁵Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milano, ⁶University of Genova, Genova, Italy

Correspondence: S. Pelassa

Introduction: Extracellular vesicles (EVs) from plasma (PL) and synovial fluid (SF) could represent a valuable source of early predictive biomarkers for Oligoarticular Juvenile Idiopathic Arthritis (OJIA), the most common pediatric rheumatic disease in Western countries

Objectives: To identify new low-invasive biomarkers for early diagnosis of OJIA and prediction of disease course through the characterization of the EV miRNome (EVs-miR) and proteome (EV-prot) combined with the study of mononuclear cells in specimens from children with new-onset OJIA

Methods: EVs were isolated using a membrane affinity spin column from PL and SF of 50 OJIA patients at disease onset. Patients were followed up for 12 months, and clinical data were collected. PL samples were also obtained from 24 age/gender-matched control children (CTR-PL). EV-miR and EV-Prot expression profiling was carried out using the TaqMan Array RT-PCR and mass spectrometry, respectively. EVs surface protein expression was assessed by the MACSPlex Exosomes Kit. Macrophages and T cells subsets were isolated from the SF aspirates of 14 patients by MACS magnetic beads and characterized by cytofluorimetryResults: EVs-miR expression profiles were compared between OJIA-SF, OJIA-PL, and CTR-PL samples. We identified 46 EV-miR differentially expressed in SF vs both paired and control PL targeting genes involved in processes related to inflammation, cartilage/bone homeostasis, and hypoxia, suggesting EV-miR role in disease pathogenesis and potential as biomarkers of OJIA development.

Comparative analysis of the EV-miR Nome in OJIA-PL vs CTR-PL samples identified 57 EV-miRs able to differentiate OJIA patients from CTR children, of which 55 were significantly upregulated and 2 significantly downregulated. 15 EV-miR were consensually overexpressed in OJIA-SF and OJIA-PL compared to CTR samples, potentially representing a disease-specific EV-miR signature at both local and systemic levels. Correlation with clinical data demonstrated that a subset of 3 EV-miR was able to stratify OJIA patients in distinct subgroups, suggesting their potential as predictive biomarkers. Comparative analyses were also carried out among EV-Prot expression profiles of SF- and PL from 30 OJIA patients and 24 CTR children. Significant up- and down-regulation of 268 and 263 EV-Prot were demonstrated in SF vs both paired and CTR PL, respectively, several of which are involved in inflammatory and immunological processes. A subset of EV-Prot able to discriminate subgroups of patients was also identified within the OJIA cohort. We also evaluated the expression of surface proteins on EVs from SF and PL patients by flow cytometry, showing modulation of specific immunologic markers. Finally, we phenotypically characterized macrophages and T cell subsets from OJIA-SF samples. We demonstrated that the ratio between T cells (CD3+):macrophages (CD14+) and between cytotoxic T cells (CD8+):helper T cells (CD4+) were higher in patients who developed polyarticular course respect to patients with oligoarticular course .

Conclusion: We provide the first database integrating EV-miR, EV-Prot, and mononuclear cell phenotypic data from PL and SF of new-onset OJIA patients. Results may lead to a better understanding of the molecular mechanisms underlying OJIA development and the identification of new biomarkers for the disease

Patient Consent: Not applicable (there are no patient data)

Disclosure of Interest: None declared

O35. Expansion of autoreactive CD27-IGD- double negative b cells in the joints of antinuclear antibody positive JIA patients

C. Strenzel¹, J. Dirks¹, G. Haase¹, U. Fischer¹, J. Fischer¹, A. Holl-Wieden², C. Hofmann², H. Morbach¹

¹Pediatric Immunology, ²Pediatric Rheumatology and Osteology, University Children’s Hospital, Wuerzburg, Germany

Correspondence: C. Strenzel

Introduction: Juvenile idiopathic arthritis (JIA) is a chronic inflammatory disease of unknown origin which is assumed to be mediated by an autoimmune response. The appearance of antinuclear antibodies (ANAs) in almost half of the patients suggests B cell dysregulation as a distinct pathomechanism of JIA. Furthermore, ANA positive JIA patients seem to constitute a clinically homogenous group of patients. However, the site of dysregulated activation of autoreactive B cells as well as the B cell subsets involved are still unknown.

Objectives: To dissect the distribution of different synovial fluid (SF) B cell subsets in JIA patients and assess their B cell receptor (BCR) specificities on a clonal level.

Methods: Distribution of different B cell subsets within SF were assessed by flow cytometry in a large cohort of JIA patients and correlated to disease subgroup (oligo-JIA, poly-JIA) and ANA status. Single cell sorting was used for generation of monoclonal antibodies (mAbs) from individually sorted B cells by expression cloning of the respective immunoglobulin genes. Generated mAbs from single B cells were assessed for antinuclear autoreactivity using HEp-2 based immunofluorescence tests. The phenotype of each B cell corresponding to the HEp-2 reactive mAbs was retraced by an index sorting algorithm.

Results: SF B cells in JIA patients mainly displayed a phenotype of activated CD21lo/-CD11c+ B cells. We used single B-cell based cloning technology to isolate and express immunoglobulin genes from SF B cells of 5 active JIA patients. By this, we generated 140 mAbs from SF CD21lo/-CD11c+ B cells from 3 ANA positive and 2 ANA negative JIA patients. Of these mABs 17-33% per patient were HEp-2 reactive and thus could be considered as autoreactive. The binding pattern of these mAbs in HEp-2 immunofluorescence tests revealed reactivity against cytoplasmic as well as nuclear antigens. Further flow cytometric analysis of SF B cells in a larger cohort of JIA patients (n=46) revealed a significant expansion of CD21^lo/-CD11c⁺ CD27-IgD- “double-negative” (DN) B cells in ANA positive JIA patients. Retracing by index sort analysis showed that these DN B cells in ANA positive JIA patients were also enriched in autoreactive clones. Interestingly, HEp-2 reactive (“autoreactive”) B cell clones within the DN B cell and CD27+IgD- switched memory B cell compartment differed significantly in the frequency of somatic hypermutation (SHM) events with lower SHM frequencies in the first subset.

Conclusion: Accumulation of autoreactive B cell clones in the inflamed joints is a common phenomenon in JIA patients. However, CD21^lo/-CD11c⁺ DN B cells are particularly expanded in the SF of ANA+ JIA patients and enriched in autoreactive B cell clones. The specific pattern of SHM within autoreactive DN B cell clones particularly expanded in ANA positive JIA patients suggests that different activation pathways may drive this B cell subset.

Disclosure of Interest: None declared

O36. Traditional laboratory parameters and new biomarkers in Macrophage Activation Syndrome (MAS) and Secondary Hemophagocytic Lymphohistiocytosis (SHLH)

A. De Matteis¹, D. Pires Marafon¹, I. Caiello¹, M. Pardeo¹, G. Marucci¹, E. Sacco¹, F. Minoia², F. Licciardi³, A. Miniaci⁴, I. Maccora⁵, M. C. Maggio⁶, G. Prencipe⁷, F. De Benedetti⁸, C. Bracaglia⁸

¹Division of Rheumatology, IRCCS Ospedale Pediatrico Bambino Gesù, Roma, Italy, Roma, ²Pediatric Rheumatology, Fondazione IRCCS Ca’ Grande Ospedale Maggiore Policlinico, Milano, ³ Department of Pediatrics and Infectious Diseases, School of Medicine, University of Turin, Regina Margherita Children’s Hospital, Torino, ⁴Department of Pediatrics, University of Bologna, S. Orsola-Malpighi Hospital, Bologna, ⁵Pediatric Rheumatology Unit, Meyer Children’s University Hospital, Firenze, ⁶University Department Pro.Sa.M.I. “G. D’Alessandro”, University of Palermo, Palermo, ⁷Division of Rheumatology, ERN-RITA Cent, IRCCS Ospedale Pediatrico Bambino Gesù, ⁸Division of Rheumatology, ERN-RITA center, IRCCS Ospedale Pediatrico Bambino Gesù, Roma, Italy

Correspondence: C. Bracaglia

Introduction: MAS and sHLH are hyperinflammatory conditions, in which IFNγ plays a pivotal role. Early recognition and treatment improve the outcome and the mortality rate.

Objectives: This is a retrospective multicenter study. We correlate traditional laboratory parameters of hyperinflammation with IL-18 and IFNγ related biomarkers. We have also evaluated the diagnostic and prognostic role of IL-18, CXCL9, CXCL10 and neopterin in patients with MAS and sHLH.

Methods: One hundred-six patients from 6 Italian centers were enrolled: 41 with sHLH, 41 with MAS in the context of sJIA, and 24 with sJIA without MAS. The samples were collected at three different time points: active disease (T0), 7-10 days from starting therapy (T1) and in clinical inactive disease on medication (from 1 to 3 months from onset) (T2).

Results: A total of 378 samples were collected. Laboratory features at T0 are detailed in table 1. Using the 2016 classification criteria for MAS, we can confirm that platelet count is a specific parameter, whilw ferritin is a sensitive parameter. Lactate dehydrogenase (LDH) values were statistically higher in MAS and sHLH compared to sJIA. ROC curve of LDH values in MAS showed a statistically significant area under the curve (AUC= 078.2%, p-value <0.0001). A cut-off of 683 U/L had a sensitivity of 73.6% and a specificity of 70.3%. IL-18, CXCL9, CXCL10 and neopterin levels in T0 were significantly higher in MAS and sHLH. In MAS, IL-18 levels were significantly higher compared to sHLH (p<0.0001). The ROC curves performed for each biomarker showed a statistically significant AUCs (p<0.01), except for IL-18 in sHLH. We have identified a cut off value for each biomarker in MAS (CXCL9 900 pg/ml, CXCL10 260 pg/ml, neopterin 5.0 ng/ml, IL-18 82996 pg/ml) and sHLH (CXCL9 2145 pg/ml, CXCL10 270 pg/ml, neopterin 7.1 ng/ml). In T0 neopterin correlates significantly with IL-18, CXCL9 and CXCL10 in MAS group but not in sHLH. We found also strong correlation between CXCL9 and CXCL10 only in MAS group.

Conclusion: Platelet count and ferritin have high specificity and sensitivity, respectively, to diagnose MAS in the context of sJIA. Even if LDH is not included in 2016 classification criteria for MAS in sJIA, we have found that this parameter could help to discriminate MAS in sJIA, in addition to the others. Our results confirm that IL-18 and the IFN-γ related biomarkers are significantly higher in patients with MAS and sHLH and might be useful to diagnose MAS/sHLH in addition to the traditional laboratory parameters. Moreover, IL-18 could help to distinguish sHLH from MAS and MAS from active sJIA.

Patient Consent: Yes, I received consent

Disclosure of Interest: A. De Matteis: None declared, D. Pires Marafon: None declared, I. Caiello: None declared, M. Pardeo: None declared, G. Marucci: None declared, E. Sacco: None declared, F. Minoia: None declared, F. Licciardi: None declared, A. Miniaci: None declared, I. Maccora: None declared, M. C. Maggio: None declared, G. Prencipe: None declared, F. De Benedetti Consultant with: Abbvie, SOBI, Novimmune, Novartis, Roche, Pfizer, Employee with: SOBI, C. Bracaglia Consultant with: SOBI and Novartis

Table 1 (abstract O36). Laboratory parameters in T0. Values are shown as median (IQR); p-value: Mann-Whitney U test

Poster session: JIA (oligo, poly, psoriatic)

P001. A retrospective study of subcutaneous golimumab in Juvenile Idiopathic Arthritis (JIA), an alternative biologic in refractory disease

A. R. Al Mheiri, O. Killeen

Rheumatology, National Centre for Paediatric Rheumatology, CHI@Crumlin, Ireland, Dublin, Ireland

Correspondence: A. R. Al Mheiri

Introduction: The introduction of biologics at the turn of this century has greatly improved the clinical outcome of JIA. Golimumab, a monoclonal tumour necrosis factor (TNF)-antagonist antibody was approved for paediatric patients with Polyarticular JIA in 2020.

Objectives: The purpose of this study was to assess the effectiveness of Golimumab and to document our experience of this biologic agent to date in our National Centre.

Methods: This retrospective, observational chart review included all patients followed in our service with JIA, who were treated with golimumab, between November 1, 2017, and November 30, 2020. Data were collected for a minimum of twelve weeks after the start date, or until discontinuation of anti-TNF therapy, whichever occurred last. The primary outcomes were clinical effectiveness at 4-6 months, defined as 1. Active clinical response (decrease in total number of active joints), 2. Clinical inactive disease (no active arthritis; no fever, no rash, serositis, splenomegaly, or generalized lymph- adenopathy attributable to JIA; no active uveitis; normal erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels), 3. Clinical no response (same total active disease or worsening of active joint cunt). A total of 17 patients met the inclusion criteria and included in the final analysis.

Results: Five patients (29.4%) experienced a reduction in the total number of joints with active disease, six patients (35.3%) were in clinical inactive disease, four patients (23.5%) had same number of joints with active disease and two patients (11.8%) were worse at follow-up. No significant change was noticed in the inflammatory markers or CHAQ score. There were no reported significant side effects or any flare of uveitis or psoriasis in any of the patients. Golimumab therapy was discontinued in eight patients (47%) for lack of efficacy or loss of effectiveness.

Conclusion: Data from this analysis demonstrate that Golimumab is an effective therapy in treating patients with refractory JIA. It was well tolerated with no major adverse reactions or flare of extra-articular co morbidities of psoriasis or uveitis.

Disclosure of Interest: None declared

P002. The potential of CD161+ T cells as a surrogate measure of IL-17A expressing T cells in the synovial fluid of JIA patients

V. Alexiou^1,2, B. Jebson^1,2, E. Ralph^1,2,3, M. Kartawinata^1,2, E. Vigorito ⁴, L. R. Wedderburn^1,2,3 on behalf of the CLUSTER Consortium

¹Centre for Adolescent Rheumatology Versus Arthritis at UCL University College London Hospital (UCLH) and Great Ormond Street Hospital (GOSH), ²Infection, Immunity and Inflammation Programme, UCL Great Ormond Street Institute of Child Health, ³National Institute for Health Research (NIHR) GOSH Biomedical Research Centre, London, ⁴MRC Biostatistics Unit, University of Cambridge, Cambridge, United Kingdom

Correspondence: V. Alexiou

Introduction: CD161+ T cells are highly enriched in the synovial fluid (SF) of juvenile idiopathic arthritis (JIA) patients. The group has previously shown that CD161 (a C-type lectin-like receptor encoded by KLRB1) is expressed on Th17 cells undergoing transition to an intermediate Th17/Th1 fate in response to inflammation¹. Therapeutic agents targeting the Th17 cytokine, IL-17A, such as Ixekizumab and Secukinumab are currently used primarily for psoriatic arthritis and ankylosing spondylitis. Their use in JIA could be informed by assessing the levels of IL-17A production in JIA patients. Identifying a reliable surrogate marker for IL-17A which can be easily clinically tested, such as cell surface marker CD161, could be valuable for patient stratification for the administration of IL-17A targeting agents.

Objectives: To explore the relationship between the CD161+ CD4 T cell population and the pro-inflammatory environment of the joint in JIA, and to test the hypothesis that the CD161 molecule is a surrogate marker of IL-17A-expressing T cells in the joints of JIA patients.

Methods: Multi-parameter flow cytometry analysis was performed on paired (collected on the same day or timepoint) samples of peripheral blood mononuclear cells (PBMC) and synovial fluid mononuclear cells (SFMC) of JIA patients (n=47, male:16, female:31). The JIA patients were grouped by ILAR subtype: oligo-articular JIA (n=21), poly-articular JIA (n=15), systemic JIA (n=6), enthesitis-related JIA (n=3) and psoriatic JIA (n=2). T cell populations were analysed based on the expression of CD3, CD4, CD8 and CD161. Following PMA/Ionomycin stimulation in the presence of Brefeldin A, intracellular production of GM-CSF, IFNγ, IL-17A. TNFα and IL-10 was analysed.

Results: Analysis confirmed that the proportion of CD161+ CD4 T cells was increased in SFMC relative to peripheral blood PBMC of JIA patients (p <0.0001). Correlation analysis showed that CD161+ CD4 T cells strongly, positively correlate with IL-17A-expressing CD4 T cells in both PB (r =0.935, P<0.0001) and SF (r =0.823, P=0.0003). The analysis also showed that CD161+ positively correlated with CD4 T cells expressing other pro-inflammatory cytokines, TNFα (r = 0.626, P=0.0165) and GM-CSF (r =0.563, P=0.045), but not those expressing IFNg (r = −0.100, P=0.733). This concurs well with previous studies which have shown that IFNγ is also expressed by the CD161− CD4 T cell population in the joint^1,2. Additionally, IL-17A expressing CD4 T cells correlate between PB and SF of JIA patients (r = 0.414, P=0.013).

Conclusion: These data show that the proportions of IL-17A+ CD4 T cells correlate between the PB and SF of JIA patients and that the CD161+ CD4 T cell population may serve as a surrogate marker of IL-17A expressing CD4 T cells in both compartments. CD161 may represent a reliable indicator of the Th17/Th1 type of inflammation in the joint and extent of inflammation. This could have translational potential, as the detection of a cell surface marker provides a readily measurable biomarker and could be valuable for the provision of treatments targeting IL-17A in JIA.

References:

1. Nistala K, Adams S, Cambrook H, et al. Th17 plasticity in human autoimmune arthritis is driven by the inflammatory environment. Proc Natl Acad Sci U S A. 2010;107(33):14751-14756. doi:10.1073/pnas.1003852107

2. Piper C, Pesenacker AM, Bending D, et al. T cell expression of granulocyte-macrophage colony-stimulating factor in juvenile arthritis is contingent upon Th17 plasticity. Arthritis Rheumatol. 2014;66(7):1955-1960. doi:10.1002/art.38647

Patient Consent: Yes, I received consent

Disclosure of Interest: V. Alexiou Grant / Research Support with: NIHR BRC at GOSH, B. Jebson Grant / Research Support with: NIHR BRC at GOSH, E. Ralph Grant / Research Support with: NIHR BRC at GOSH, M. Kartawinata Grant / Research Support with: NIHR BRC at GOSH, E. Vigorito : None declared, L. Wedderburn Grant / Research Support with: NIHR BRC at GOSH. The CLUSTER Consortium is supported by grants from MRC, Versus Arthritis and GOSCC and has partnerships with AbbVie, GSK, UCB, Sobi and Pfizer inc. LWR declares in kind contributions to CLUSTER by AbbVie, GSK, UCB, Sobi and Pfizer inc and non-renumerated collaborations with Lilly and Novartis.

P003. Inflammatory arthritis as the presentation finding of autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy syndrome

G. Aytac¹, B. Guven ², I. Aydin², E. Topyildiz³, A. Aykut⁴, G. Aksu¹, N. E. K. Edeer Karaca³, N. Kutukculer¹

¹Pediatric rheumatology, Ege University, ²Pediatrik romatoloji, Ege Üniversitesi, ³Pediatrik immunolgy, ⁴Ege University, Izmir, Turkey

Correspondence: G. Aytac

Introduction: Introduction: Autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy (APECED) is an autosomal recessive disorder of immune regulation caused by mutations in the autoimmune regulatory (AIRE) gene. AIRE is a protein involved in the development of central immunological tolerance. APACED is characterized by multiorgan autoimmunity leading to chronic mucocutaneous candidiasis (CMC), hypoparathyroidism and adrenocortical failure.

Objectives: Case: A 3-year-old boy was admitted with complaints of fever, pain and swelling on ankles and nail dystrophy on thumbs for 2 months. He was born to third-degree consanguineous healthy parents. On physical examination, the patient had splenomegaly, onychomycosis on both thumbs with oral candidiasis. Musculoskeletal examination demonstrated joint effusion with a decreased range of motion of wrist and ankles bilaterally and swelling of the knee. Laboratory investigations showed elevated acute phase reactants, hypergammaglobulinemia, and antinuclear antibody positivity. Biochemical parameters, including calcium, were normal. Rheumatic factor, antineutrophil cytoplasmic antibody, and antithyroid antibodies were negative. The patient responded well to nonsteroid antiinflammatory medications. Due to the coexistence of onychomycosis, arthritis, splenomegaly, consanguinity, and hypergammaglobulinemia, targeted next-generation sequencing of a Primary Immune Deficiency Research Panel was performed and a homozygous mutation (c.769C>T, p. Arg257Ter) in the AIRE gene was detected.

Methods: There is no method section as it is a case report.

Results: None

Conclusion: Conclusion: The classical triad of APACED syndrome is CMC, hypoparathyroidism and adrenal failure. Inflammatory arthritis is rarely described in association with APECED. The clinical presentation of our patient reinforces the idea that non-classical manifestations can occur before classic symptoms develop. It is, therefore, useful to consider the diagnosis in patients with CMC and arthritis beyond the first year of life.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P004. The predictors of etanercept efficacy and treatment outcomes in non-systemic juvenile idiopathic arthritis: the data of 375 patients

K. Belozerov^1,1, A. Lobacheva¹, E. Gaidar¹, A. Yakovlev¹, N. Gordeeva², A. Khabirova¹, A. Kupreeva¹, V. Masalova¹, T. Kornishina¹, E. Isupova¹, L. Snegireva¹, O. Kalashnikova¹, L. Sorokina¹, M. Kaneva¹, I. Chikova¹, T. Likhacheva¹, M. Dubko¹, V. Chasnyk¹, M. Kostik¹

¹Department of Hospital Pediatrics, Federal State budgetary Educational Institution of Higher Education «St. Petersburg State Pediatric Medical University» of the Ministry of Healthcare of the Russian Federation, ²Cardiorheumatology, Children’s City Hospital #2 of Holy Mary Magdalene, Saint-Petersburg, Russian Federation

Correspondence: M. Kostik

Introduction: TNF-⍺ is a one of the predominating cytokines in the pathogenesis of juvenile idiopathic arthritis (JIA). There are more than 20 years experience of using TNF-ibhinitors for treatment of JIA.

Objectives: to report about our 10 years experience of treatment JIA with etanercept (ETN).

Methods: We retrospectively studied cases of 375 patients, who were diagnosed as JIA with ILAR 2001 criteria and who used ETN. The treatment compliance, remission achievement, flare, as well as the switching to next biologic and the appearance of uveitis (de-novo) were taken into account.

Results: according to our data, 90.4% of children were receiving DMARDs (mostly methotrexate) at the time of ETN initiation. Other biological agents were used before ETN in 6.9% of cases. Initial JIA remission was observed in 254/322 (78.9%) cases after 6 months (0,3-1,6 years) after starting therapy. Patients who hadn’t previously received biological therapy achieved remission faster (LogRank test, p=0.001), as well as those who used therapy regularly (LogRank test, p=0.004). Cumulative likelihood of flare was higher in ANA-positive patients (LogRank test, p=0.060) and RF-positive polyarthritis. The presence of concomitant non-biological treatment didn’t affect the likelihood of flare. The switch from etanercept to another biological drag occurred in 47/270 (17.4%) children, which in a quarter of cases is associated with the development of de-novo uveitis.

Conclusion: ETN is effective, especially in distinct JIA categories.

Patient Consent: Not applicable (there are no patient data)

Disclosure of Interest: None declared

Table 1 (abstract P004). Outcomes of etanercept therapy for different JIA subtypes

P005. Feasibility study of taking minimally invasive, ultrasound-guided tissue biopsies of synovial tissue in children with juvenile idiopathic arthritis for research

C. Bolton¹, C. G. Smith², A. McNeece¹, S. Sultan³, V. Alexiou¹, A. Hackland², J. Crook⁴, H. D. Nguyen¹, C. C. -⁵, M. Thyagarajan³, Z. Shiekh⁶, C. Cotter³, P. Reis Nisa², E. Al-Abadi³, S. Chippington⁷, S. Compeyrot-Lacassagne⁷, A. Filer³, L. Wedderburn¹, A. Croft²

¹UCL, London, ²University of Birmingham, ³Birmingham Women’s and Children’s NHS Foundation Trust, Birmingham, ⁴Guy’s and St Thomas’ Hospital, London, ⁵CLUSTER Consortium, UK wide, ⁶Birmingham Women’s and Children’s NHS Foundation Trust, ⁷Great Ormond Street Hospital, London, United Kingdom

Correspondence: H D Nguyen

Introduction: When investigating disease mechanisms, site-specific differences in immune cell phenotype and function have highlighted the need to analyse cellular and molecular mechanisms at the tissue site directly¹. In adults, the ability to obtain synovial tissue biopsies using ultrasound-guided techniques, combined with advanced tissue analytics, has revolutionised our understanding of the cellular ecosystem that operates within the joint and how it contributes to disease². However, a similar approach in paediatric disease is lacking.

Objectives: 1) To describe the protocol for undertaking minimally-invasive ultrasound-guided synovial tissue biopsies in children and young people with arthritis, for the purpose of research, alongside routine clinical care. 2) To investigate whether high-quality synovial tissue can be obtained that is suitable for downstream applications including single cell profiling technologies, histology and digital spatial profiling.

Methods: Following ethical approval, treatment-naïve children with a diagnosis of Juvenile Idiopathic Arthritis were recruited from two large UK Paediatric Rheumatology centres. Participating families completed questionnaires prior to and following synovial biopsy. We established a workflow pipeline for performing synovial tissue biopsies in child and young people with arthritis, using standardised procedures for biopsy and sample processing. Procedures were performed by experienced paediatric interventional radiologists with experience of joint biopsy for diagnostic purposes. In brief, children who were referred for aspiration and corticosteroid joint injection were recruited. Following a general anaesthesic, required as part of routine clinical care and the establishment of sterility, synovial fluid was aspirated. Needle-biopsies were undertaken from the same needle insertion site and subsequently corticosteroid was injected into the joint. Thickened synovium was graded via ultrasonography.

Results: 10 participants were recruited to the study over a nine month period, with a median age of 7 years (range 1-16 years); 90% were female. Samples obtained included core synovial biopsies, paired synovial fluid and peripheral blood. Synovial tissue fragments were processed for histology by formalin fixation and cryopreserved for downstream applications, including RNA sequencing and cell culture. Quality control indices included histological analysis to ensure the biopsied material was characteristically synovium and to grade the severity of inflammation. No significant complications were reported, however one child had a mild hemarthrosis controlled with cold saline wash out and cold compresses.

Conclusion: Obtaining biopsies of synovial tissue in children with Juvenile Idiopathic Arthritis for the purpose of research, alongside clinical care is feasible. Analysis of tissue direct from the site of inflammation with single-cell RNA sequencing in children is achievable.

1 Veale DJ, Fearon U. Next-generation analysis of synovial tissue architecture. Nat. Rev. Rheumatol. 2020; 16: 67–68.

2 Croft AP, Campos J, Jansen K, Turner JD, Marshall J, Attar M et al. Distinct fibroblast subsets drive inflammation and damage in arthritis. Nature 2019; 570: 246–251.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P006. IL-4 and S100A9 can differentiate acute lymphoblastic leukemia from juvenile idiopathic arthritis better than existing laboratory values

N. Brix^1,2, M. Glerup ¹, D. Foell³, C. Kessel³, H. Wittkowski³, L. Berntson⁴, A. Fasth⁵, S. Nielsen⁶, E. Nordal ⁷, M. Rygg^8,9, H. Hasle¹, S. Hagstrøm², T. Herlin¹ on behalf of the Nordic Study Group of Pediatric Rheumatology (NoSPeR) group

¹Department of Pediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, ²Department of Pediatrics and Adolescent Medicine, Aalborg University Hospital , Aalborg , Denmark, ³Department of Pediatric Rheumatology and Immunology, Medical Center (UKM), Muenster, Germany, ⁴Department of Women’s and Children’s Health, Uppsala University, Uppsala, ⁵Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden, ⁶Department of Pediatrics, Rigshospitalet, Copenhagen University Hospital, Copenhagen , Denmark, ⁷Department of Pediatrics, University Hospital of North Norway, and Department of Clinical Medicine, UiT The Arctic University of Norway, Tromsø, ⁸Department of Clinical and Molecular Medicine, NTNU - Norwegian University of Science and Technology, ⁹Department of Pediatrics, St. Olavs Hospital, Trondheim, Norway

Correspondence: N. Brix

Introduction: Acute lymphoblastic leukemia (ALL) may be misdiagnosed as juvenile idiopathic arthritis (JIA) with the risk of mistreatment and prolonged diagnostic interval. In demand are sensitive and specific biomarkers in order to optimize the diagnostic process.

Objectives: To evaluate the predictive value of biomarkers of inflammation like phagocyte-related S100 proteins and a panel of cytokines in order to differentiate the child with ALL and arthropathy from the child with JIA.

Methods: In this cross-sectional study, we measured S100A9, S100A12 and 14 cytokines in serum from children with ALL (n=150, including 27 with arthropathy) and JIA (n=238) by multiplexed bead array assay on a MAGPIX instrument using Luminex software. We constructed predictive models using logistic regression, including ‘ten-fold cross-validation and recalibration. Thereby computing the area under the curve (AUC) as well as predicted probabilities in order to differentiate ALL from JIA.

Results: The proinflammatory S100A12 was three-fold higher and the anti-inflammatory IL-10 two-fold lower in the patients with ALL and arthropathy (n = 27) compared to the ALL patients without any arthropathy (p = 0.002 and p = 0.03, respectively). The median levels of IL-4 was 12 pg/mL (IQR 10-14) in ALL with arthropathy versus 89 pg/mL (IQR 55-133) in the JIA patient, p < 0.001. The median levels of S100A9 was 47 pg/mL (IQR 30-113) in ALL with arthropathy versus 511 pg/mL (IQR 315-1281) in JIA, p < 0.001. In predictive models, we found IL-4 and S100A9 to be valuable markers to separate the child with ALL from JIA, with AUCs of 98% (95% CI: 98-100%) and 95% (95% CI: 91-97%), respectively, exceeding both hemoglobin, CRP, ESR and for IL-4 also platelets.

Conclusion: The IL-4 and S100A9 serum concentration may be used as biological serum markers to distinguish ALL with arthropathy from JIA.

Disclosure of Interest: None declared

P007. Economic impact of juvenile idiopathic arthritis in Mexico

R. C. Calderón Zamora¹, A. K. Leos-Leija¹, N. Rubio-Perez¹, A. V. Villarreal-Treviño¹, F. García-Rodríguez¹, I. Peláez-Ballestas², E. Faugier-Fuentes³

¹Department of Pediatrics, Universidad Autónoma de Nuevo León, Hospital Universitario “Dr. José E. González”, Monterrey, ²Rheumatology Unit, Hospital General de México “Dr. Eduardo Liceaga”, ³Rheumatology Department, Hospital Infantil de México “Federico Gómez” , Cd de México, Mexico

Correspondence: R. C. Calderón Zamora

Introduction: Juvenile Idiopathic Arthritis (JIA) is the most common chronic pediatric rheumatic disease. Due to the multidisciplinary treatment and the wide range of therapeutic options, this disease is considered to have a high economic cost (1), however, it depends on factors as family income, coverage for medical services, the cost of medications, the frequency of exams and interventions, and disease activity and progression (2, 3). There are few reports about economic cost of JIA in the world (4), especially in those low and middle-low-income countries.

Objectives: The aim of this study is to estimate the economic costs for the family of patients with Juvenile Idiopathic Arthritis in Mexico.

Methods: Observational and descriptive study including caregivers of pediatric patients with JIA (according to the ILAR Classification) from January to May 2022. Data related to health care, medication, complementary exams, indirect costs, and total family income were collected by the adaptation of the questionnaire “Determination of the Economic Impact on Rheumatic Diseases, Section B. Interview regarding demographic and socioeconomic aspects”. A descriptive analysis of the data was carried out, reporting measures of central tendency and proportions.

Results: Twenty-nine caregivers of patients with JIA were included, with an average age of 37 years (IQR 23-53), 25 were female, 15/29 caregivers had 12 or more years of formal education, and 48% had a remunerated job. The patients had a mean age of 10 years (IQR 5-19), 69% female, the predominant subtype is polyarticular arthritis (18, 62%), followed by oligoarticular and systemic arthritis (4, 13.7% each), no patient had psoriatic or undifferentiated JIA. One third patients had history of hospitalization due to disease activity, only 3 patients reported disability. The most prescribed treatment is DMARDs, 75% synthetics and 31% biologicals. The proportion of total family income used for JIA related costs was 34%, 14.5% associated with treatment and 19.5% from other direct and indirect health care (Table). Half of the caregivers responded that after the diagnosis of JIA in their patient, their economic situation worsened a little, and a third of the relatives considered that the situation worsened significantly.

Conclusion: The results of this study demonstrate the impact of JIA on families. The direct costs of the disease are influenced by the partial or total coverage of public health institutions, however, indirect costs reflect the difficulties to specialized health care for the patients. The impact that JIA causes in the economy of the patient and his family, can significantly affect adherence to treatment and multidisciplinary care, worsen their prognosis.

Trial registration identifying number: 1. Angelis A, BURQOL-RD Research Network, Kanavos P, López-Bastida J, Linertová R, Serrano-Aguilar P. Socioeconomic costs and health-related quality of life in juvenile idiopathic arthritis: a cost-of-illness study in the United Kingdom. BMC Musculoskelet Disord [Internet]. 2016;17(1).

2. Lapsley HM, March LM, Tribe KL, Cross MJ, Courtenay BG, Brooks PM, et al. Living with rheumatoid arthritis: expenditures, health status, and social impact on patients. Ann Rheum Dis [Internet]. 2002;61(9):818–21.

3. Mould-Quevedo J, Peláez-Ballestas I, Vázquez-Mellado J, et al. El costo de las principales enfermedades reumáticas inflamatorias desde la perspectiva del paciente en México. Gac Med Mex. 2008;144(3):225-231.

4. García-Rodríguez F, Gamboa-Alonso A, Jiménez-Hernández S, Ochoa-Alderete L, Barrientos-Martínez VA, Alvarez-Villalobos NA, et al. Economic impact of Juvenile Idiopathic Arthritis: a systematic review. Pediatr Rheumatol Online J [Internet]. 2021;19(1)

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

Table 1 (abstract P007). Characteristics of the patients and caregivers participating in the study (n = 29)

P008. Predictors of 2 and 5 years sustained disease remission among children and young adults with extended oligoarticular, enthesitis-related, or psoriatic juvenile idiopathic arthritis: results from clipper studies

V. Chasnyk¹, I. Nikishina², P. Dolezalova³, I. Rumba-Rozenfelde⁴, N. Wulffraat⁵, R. Burgos-Vargas⁶, J. Chaitow⁷, A. Martini⁸, V. Tsekouras⁹, D. Graham⁹, C. Borlenghi⁹, B. Vlahos⁹, C. Zang⁹, N. Ruperto¹⁰ on behalf of Paediatric Rheumatology International Trials Organisation (PRINTO)

¹Saint-Petersburg State Pediatric Medical University, Saint-Petersburg, ²Pediatric Department, V.A. Nasonova Research Institute of Rheumatology, Moscow, Russian Federation, ³General University Hospital, Faculty of Medicine, Charles University in Prague, Prague, Czech Republic, ⁴University Children Hospital, Riga, Latvia, ⁵Department of Pediatric Immunology and Rheumatology, Wilhelmina Children’s Hospital, Utrecht, Netherlands, ⁶Department of Rheumatology, Hospital General de Mexico, Mexico City, Mexico, ⁷Sydney Adventist Hospital, Wahroonga, NSW, Australia, ⁸Università degli Studi di Genova, Genoa, Italy, ⁹Pfizer, New York, NY, United States, ¹⁰Istituto Gianina Gaslini, Genoa, Italy

Correspondence: N. Ruperto

Introduction: CLIPPER2 (NCT01421069) was an 8-year, open-label extension of the phase 3b, 2-year CLIPPER study (NCT00962741) investigating the long-term safety/efficacy of etanercept (ETN) in patients with 3 subtypes of juvenile idiopathic arthritis (JIA): extended oligoarticular JIA (eoJIA), enthesitis-related arthritis (ERA), or psoriatic arthritis (PsA).

Objectives: To identify predictors of sustained clinical remission over 2 and 5 years.

Methods: Patients with eoJIA (2–17 years), ERA, or PsA (each 12–17 years) who received ≥1 ETN dose in CLIPPER could enter CLIPPER2. Inactive disease was defined according to the American College of Rheumatology (ACR)-approved Juvenile Arthritis Disease Activity Score (JADAS, Consolaro et al. 2009) and Wallace cut-off criteria (Wallace et al. 2004). Sustained clinical remission was defined as consecutive ≥2 years or ≥5 years of inactive disease using either set of criteria. Predictors of sustained disease remission were identified using a stepwise logistic regression model.

Results: Of 127 patients enrolled in CLIPPER, 109 enrolled into CLIPPER2. 84 patients completed CLIPPER2; 27 still received active treatment. 26 patients were in clinical remission ≥2 years after starting CLIPPER according to JADAS criteria and 13 according to Wallace criteria. 6 patients were in JADAS remission and 2 in Wallace remission after ≥5 years. Predictors of response are shown in the Table.

Conclusion: JADAS low disease activity (LDA) at 3 months and lower prorated number of active joints were significant predictors of 2-year sustained JADAS remission; Wallace remission at 3 months, higher Childhood Health Assessment Questionnaire score at baseline, JADAS LDA at 3 months, and baseline methotrexate use were significant predictors of 2-year Wallace remission.

The low number of patients remaining in remission over 5 years limited the predictive power of these data.

Trial registration identifying number: NCT01421069, NCT00962741

Patient Consent: Not applicable (there are no patient data)

Disclosure of Interest: V. Chasnyk Consultant with: Amgen, Bristol Myers Squibb, Eli Lilly, Pfizer, GlaxoSmithKline, UCB, Novartis, I. Nikishina Consultant with: Pfizer, Novartis, MSD, Roche, Sobi, UCB, Eli Lilly, Ipsen, P. Dolezalova Consultant with: Sobi, Novartis, Pfizer, I. Rumba-Rozenfelde Consultant with: Pfizer, N. Wulffraat Consultant with: Sobi, Novartis, UBC, R. Burgos-Vargas: None declared, J. Chaitow: None declared, A. Martini Consultant with: Aurinia, Bristol Myers Squibb, Eli Lilly, EMD Serono, Janssen, Pfizer, Roche, V. Tsekouras Employee with: Pfizer, D. Graham Employee with: Pfizer, C. Borlenghi Employee with: Pfizer, B. Vlahos Employee with: Pfizer, C. Zang Employee with: Pfizer, N. Ruperto Consultant with: Ablynx, Amgen, AstraZeneca-MedImmune, Aurinia, Bayer, Cambridge Healthcare Research, Celgene, Domain Therapeutic, EMD Serono, GlaxoSmithKline, Idorsia, Janssen, UCB, Bristol Myers Squibb, Eli Lilly, Novartis, Pfizer, Sobi, F. Hoffmann-La Roche.

Table 1 (abstract P008). Predictors of sustained clinical remission

P009. Understanding the role of ultrasound in detecting temporomandibular joint involvement in juvenile idiopathic arthritis: a pilot study

C. Eboli¹, E. A. Conti¹, F. Chironi¹, S. Testa¹, F. Lucioni¹, G. B. Beretta¹, A. Marino², P. Cressoni³, S. Lanni¹, M. Rossano¹, G. Filocamo¹

¹Clinica Pediatrica De Marchi, IRCCS Ca’ Granda Ospedale Maggiore Policlinico, ²ASST Gaetano Pini-CTO, ³IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy

Correspondence: A. Conti

Introduction: Involvement of the temporomandibular joint (TMJ) is frequent in juvenile idiopathic arthritis (JIA). Early recognition and treatment of TMJ arthritis may potentially reduce long-term damage, such as facial asymmetry, micro and retro-gnathia, dental malocclusion, and joint ankylosis. A TMJ clinical examination protocol has been recently developed to screen TMJ involvement in JIA, and showed acceptable construct validity and reliability [1]. Ultrasound (US) has been suggested as a useful tool to evaluate inflammation and damage of TMJ in JIA [2].

Objectives: The aim of the study was to establish the validity of US in detecting signs of TMJ arthritis in JIA irrespective of the presence of clinical signs of involvement.

Methods: A sample of consecutive JIA patients, either in remission or with active disease, seen at our Centre underwent clinical evaluation of TMJs. Patients with TMJ disorders (dental problems, pre-existing cranio-maxillofacial disorder, history of facial trauma) unrelated to JIA were excluded. History of TMJ pain or dysfunction was assessed by a TMJ screening questionnaire for parents together with the Italian version of the Juvenile Arthritis Multidimensional Assessment Report (JAMAR). Clinical assessment was performed according the published TMJ screening protocol. Clinical and US examinations were carried out on the same consultation and blindly each other. TMJ was considered clinically involved in case of presence of either signs of active TMJ arthritis or evidence of TMJ deformity. Clinical data were then compared to US assessment.

Results: : A sample of 23 consecutive patients were recruited in the study. Overall clinical and US examinations resulted well accepted by patients and parents.

The table shows the preliminary results on clinical and US assessment.

Conclusion: The results observed in this preliminary cohort of patients do not allow to evidence a strong agreement between US and clinical data in detecting signs of previous or ongoing involvement of TMJ in JIA. Further studies with a larger cohorts of patients and involving the use of MRI will help to clarify the role of US in the assessment of TMJ arthritis in JIA.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

Table 1 (abstract P009). See text for description

P010. Study of diagnostic delay in patients with juvenile idiopathic arthritis

M. Corbeto, E. M. Ruzafa, L. M. Mitjana

Pediatric Rheumatology, Hospital Universitari Vall d’Hebron, Barcelona, Spain

Correspondence: M. Corbeto

Introduction: Juvenile idiopathic arthritis (JIA) is the most common cause of inflammatory arthritis in children under 16 years of age. The only epidemiological project carried out to date in southern Europe estimated a prevalence rate of 39.2/100,000 children. However, we do not have studies evaluating the patient’s journey towards accurate diagnosis and care in our area. The time to diagnosis (TD) is a fundamental quality measure since increases in this can lead to a higher comorbidity of patients with JIA.

Objectives: To describe and analyze the time to diagnosis from the onset of symptoms in patients with JIA and to identify factors associated with the patient related to a longer time to diagnosis.

Methods: We conducted a retrospective cohort study by reviewing the medical records of patients diagnosed with JIA according to the ILAR criteria and treated at the Pediatric Rheumatology Unit (PRU) of the Vall d’Hebron University Hospital from 2009 to the present. Epidemiological variables were collected. Time to diagnosis (TD) was defined as the time elapsed between the onset of symptoms and the diagnosis established in the PRU. Delay in TD has been categorized as times greater than two months. Time to referral (TTR), defined as the time elapsed between the onset of symptoms and the date of referral to the PRU, was also evaluated. Qualitative variables are expressed in absolute values ​​and percentages. Quantitative variables are expressed as medians and IQR as they present a non-normal distribution. In the bivariate analysis, the qualitative variables have been compared with the χ2 test and the quantitative variables with logistic regression. The level of statistical significance has been set at 0.05. Statistical analyzes have been performed with STATA/IC 15.1

Results: 60 patients have been included, 40 girls (66.67%) with a measured age of 8.01 years (SD 4.43). All patients come from an urban environment. The most frequent JIA subtype is oligoarticular with 28 patients (46.67%). 98% of the patients presented joint symptoms at debut followed by systemic manifestations in 21.67% of the patients. 61.67% of the patients were referred by primary care pediatrics. The TD was a median of 3.68 months (IQR 2.34 – 10.10), and the TTR was a median of 2.76 months (IQR 1.25 – 8.32). 11 patients (18.33%) did not present a diagnostic delay compared to 49 (81.66%) who were diagnosed with a delay of more than 2 months. The JIA subtype with the highest TD was polyarticular RF negative 9.26 months, but without finding significant differences between the different subtypes (p=0.523). No significant associations were observed between the delay in diagnosis and the epidemiological, clinical or analytical variables.

Conclusion: The TD in patients with JIA in our cohort is a median of 3.68 months, a time similar to other cohorts previously described at a European level, with RF polyarticular JIA being the one with the highest TD, probably due to the wide differential diagnosis that characterizes this subtype. No significant differences have been found that relate the diagnostic delay and the referral professionals or previous consultations to the emergency room or previous admissions. The retrospective design of the study and the non-inclusion of socioeconomic variables or rural population constitute important limitations of the study to be considered in future research.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P011. Increasing incidence of juvenile idiopathic arthritis? a trend over 31 years in Southern Sweden

E. Berthold^1,2,3, A. Dahlberg^2,4,5, H. Tydén^1,3, B. Månsson^1,3, R. Kahn^1,2,5

¹Skåne University Hospital, Lund and Malmö, ²Wallenberg Center for Molecular Medicine, ³Department of Rheumatology, Clinical Sciences Lund, Lund University, Lund, ⁴Helsingborg Hospital, Helsingborg, ⁵Department of Pediatrics, Clinical Sciences Lund, Lund University, Lund, Sweden

Correspondence: A. Dahlberg

Introduction: The incidences of chronic immune diseases are proposedly increasing(1), but whether this is applicable to juvenile idiopathic arthritis (JIA) is unestablished. Previous studies present conflicting results and reported incidence differs profoundly based on different study design and geographic regions(1-5).

Objectives: To investigate the incidence of JIA over a period of 31 years, using two population-based JIA cohorts.

Methods: Incident cases of juvenile arthritis 1980-2001 in the Swedish region Skåne (population 1 023 479 by 1980) were identified with registered International Classification of Diseases (ICD)-code of juvenile arthritis from both in- and outpatient care, through an ICD-code search at the local database at the regional center for pediatric rheumatology, Lund, and at the diagnosis register at the National Board for Health and Welfare (NBHW). Included ICD-codes were: 696.00, 712, 713.10-19, and 714.93 (ICD-8); 696A, 713B and 714 (ICD-9); and M08-M09 (ICD-10). To validate the diagnoses, medical records were reviewed. In total, 400 cases were confirmed 1980-2001, and to compare the incidences of JIA over time with rate ratios (RR), this new cohort of 400 cases was combined with the previously published population-based cohort of 251 validated JIA cases in Skåne 2002-10(6).

Results: The annual incidence of juvenile arthritis 1980-2010 was 9.9 (95% CI 9.2-10.7) per 100 000 children <16 years, increasing from 5.9 (4.5-7.5) in 1980-84 to 14.0 (12.1-16.2) in 2005-10 with a significant RR of 2.4 (95% CI 1.8-3.2) (Table 1). When comparing the rates from the 90’s to the rates after the millennium, they were significantly higher when comparing the rate in 2005-10 to the rate in 1990-94 and 1995-99 (RR 1.6 (1.2-2.1) and 1.4 (1.1-1.7) respectively). The incidence of JIA in the cohort of 2002-2010 was increasing from 12.1 in 2002-05 to 13.9 in 2006-10, however this increase was not significant (RR 1.2 (0.9-1.5)).

Conclusion: We show a significantly increasing incidence of JIA over a period of 31 years in two population-based cohorts, supporting the theory of increasing occurrence of chronic immune diseases. Although possibly missing a few mild outpatient cases in the 80’s and 90’s due to non-compulsory outpatient registration, most cases of JIA in the region are believed to be included since most cases during this period required inpatient care for treatment. To evaluate if an increasing incidence of JIA is a continuous trend, further studies are necessary.

References:

1. Sevelsted A, et al. Eur J Epidemiol. 2021;36(11):1179-85.

2. Krause ML, et al. Arthritis Rheumatol. 2016;68(1):247-54.

3. Shiff NJ, et al. Arthritis Care Res (Hoboken). 2019;71(3):413-8

4. Cardoso I, et al. Int J Environ Res Public Health. 2021;18(16).

5. Danner S, et al. J Rheumatol. 2006;33(7):1377-81.

6. Berthold E, et al. Arthritis Res Ther. 2019;21(1):218.

Patient Consent: Not applicable (there are no patient data)

Disclosure of Interest: None declared

Table 1 (abstract P011). Incidences of juvenile arthritis divided by lustrum

P012. Interferon signature as possible new marker for the stratification of patients with JIA

L. De Nardi¹, F. Rispoli¹, S. Pastore², A. Taddio^1,2, A. Tommasini^1,2

¹University of Trieste, ²Pediatrics, IRCCS “Burlo Garofolo” - Trieste, Trieste, Italy

Correspondence: L. De Nardi

Introduction: Interferon signature (IS) is a valuable instrument to quantify the expression of interferon-stimulated genes in the bloodstream, providing an indirect estimate of cells’ exposition to type I Interferon-mediated inflammation. Apart from interferonopathies, where the pivotal role of type I interferon (IFN) is recognized, dysregulation in IFN-I production and function has been observed also in some autoimmune diseases. An over-reactive IFN-I signaling pathway has been first described in Systemic Lupus Erythematosus (SLE) and Juvenile Dermatomyositis (JDM), leading to high levels of IS in such conditions. Unfortunately, there is no agreement in literature on the role of IS in other polygenic autoimmune diseases such as Juvenile Idiopathic Arthritis (JIA), whose inflammation can be dominated by other types of cytokines. Furthermore, the growing evidence of JIA heterogeneity encourages physicians to research new markers for integrating clinical and biological data, to identify subgroups of patients which could benefit from a specific therapeutical approach.

Objectives: This study aims to explore the clinical significance of IS among a cohort of patients with JIA, especially concerning its association with disease stratification and prognosis.

Methods: This is a consecutive case series conducted at the Institute for Maternal and Child Health “Burlo Garofolo” of Trieste, Italy. Pediatric patients between 6 months and 18 years old who accessed the Rheumatology Department of the Institute between May 2017 and December 2021 with a diagnosis of JIA (according to 2001 ILAR criteria) were recruited; patients with systemic JIA were excluded. For each patient the following variables were collected: age, sex, age at onset, family history, arthritis type, involved joints, JADAS-27 score, presence of enthesitis, tenosynovitis, uveitis, IS, erythrocyte sedimentation rate (ESR), C-reactive protein, immunoglobulins, anti-nucleus antibody and rheumatoid factor levels. Also information about previous and ongoing therapies were collected.

Results: A total number of 44 patients were recruited (35 F, 9 M). Subtypes of arthritis were distributed as follows: 19 polyarticular, 19 oligoarticular (of which 6 extended), 5 psoriatic (2 oligo- and 3 polyarticular). Twenty-seven patients had a disease which required 2^nd line therapy with any biological drug, while 17 showed disease remission on 1^st line medication. Out of 44 patients, 15 had a positive IS (considered if ≥ 3). This subgroup of patients did not show statistically significant higher frequency of tenosynovitis (p=0.31), enthesitis (p=0.52), uveitis (p=0.43) or cervical spine involvement (p=0.57). IS positivity was not associated with higher levels of JADAS score (p=0.17). However, an association between IS positivity and the number of involved joints was found (p=0.019). Notably, a correlation between IS positivity and polyarticular type was detected (including extended oligoarticular and polyarticular psoriatic type, p=0.013), along with a correlation between ESR values and IS frequency (p=0.010). Patients who required biological drugs, did not have significantly higher IS levels (p= 0.33). Finally, no correlation between IS and age at onset was found.

Conclusion: This study shows an association between the presence of IS positivity and the polyarticular involvement, along with a correlation between IS frequency and ESR levels. Even though these evidences are too limited to consider IS a novel biological marker for the stratification of JIA, we could speculate on the possible role of JAK inhibitors therapy for some refractory cases of JIA with elevated IS levels, in which they could be beneficial and safer. Further studies are needed to explore such clinical associations in a larger cohort of patients.

Patient Consent: Not applicable (there are no patient data)

Disclosure of Interest: None declared

P013. The factors affecting the duration of remission of polyarticular JIA

E. Esen¹, A. P. Kısaarslan¹, S. Ö. Çiçek², M. H. Poyrazoğlu¹

¹Pediatric Rheumatology, Erciyes University Faculty of Medicine, ²Pediatric Rheumatology, Kayseri City Hospital, Kayseri, Turkey

Correspondence: A. P. Kısaarslan

Introduction: Polyarticular Juvenile idiopathic arthritis(polyJIA) is divided into seronegative (RF-) and seropositive (RF+) polyarticular JIA.

Objectives: In this study, we aimed to determine the factors affecting the duration of remission with or without treatment in polyarticular JIA patients.

Methods: The data of 88 patients diagnosed with polyarticular JIA according to the ILAR diagnostic criteria in the Erciyes University pediatric rheumatology were evaluated retrospectively. The factors affecting the duration of remission were analysed by using univariate cox regression analysis.

Results: Seventy(79.5%) patients were female, median age was 175.5(28-270) months,and median follow-up time was 45(4-238) months. Median joint involvement was 10(5-36). Rheumatoid factor positivity was in 11(12.5%), and anti-CCP positivity in 10(11.4%) patients. In our study, 82 (93.2%) patients had at least one large joint involvement with small joints, 8 (9.1%) patients had temporamandibular joint, and 11 (12.5%) patients had cervical vertebral involvements. 65 (73.9%) patients had acute phase reactant elevations at their first admission. Fifteen (17%) patients had accompanying diseases. Ten(11.4%) patients had uveitis. Sixty-three (71.6%) patients received systemic steroids, 22 (25%) patients received intra-articular steroid injection. All of our patientsterated with the disease-modifying drug, which was methotrexate. Sixty-five of them (73.9%) treated with at least one of the biological agents. At the last visit, 68 patients were in remission. JADI-A median score was 0(0-22) and JADI-E median score was 0(0-2). Fifty-one(58%) patients did not have articular sequelae,68 (77.3%) patients did not have extra-articular sequelae. The median time to remission with DMARD was 2(0-47) months. The median time to remission with biological agents was 14(0-50) months, and the median time to remission without medication was 0(0-96) months. The median total remission time (with treatment and without treatment) was 18 (0-114) months. The factors affecting the duration of remission analysed by using cox regression analysis are shown in table 1.

Conclusion: Our results show that steroid dose and duration did not affect the duration of remission periods. Because the total remission time without treatment was very short, we think that especially biological therapy should not be interrupted.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

Table 1 (abstract P013). The factors affecting the duration of remission

P014. Improving sleep reduces pain in childhood arthritis; a crossover randomized controlled trial

S. Dover¹, H. Clairman¹, D. Beebe², B. Cameron¹, R. Laxer^1,3, D. Levy^1,3, I. Narang^1,3, R. Schneider^1,3, L. Spiegel¹, S. Stephens¹, J. Stinson^1,3, G. Tomlinson³, S. M. Tse^1,3, S. Weiss^1,3, K. Whitney¹, B. M. Feldman^1,3

¹The Hospital for Sick Children, Toronto, Canada, ²Cincinnati Children’s Hospital, Cincinnati, United States, ³University of Toronto, Toronto, Canada

Correspondence: B. M. Feldman

Introduction: Childhood arthritis is a chronic childhood disease that is very prevalent and negatively impacts quality of life. It can be a source of discomfort and in refractory cases, despite modern biologic therapies, can lead to persistent pain and stiffness. Adolescents have poor sleep practice, and their poor sleep has been associated with negative outcomes, including pain. Poor sleep, combined with childhood arthritis, may lead to even worse health outcomes. Previous studies have shown a strong link between sleep duration and pain in children with childhood arthritis.

Objectives: The aim of the present study was to determine if longer sleep duration leads to reductions in self-reported pain when compared to restricted sleep duration in adolescents with childhood arthritis.

Methods: Adolescents between 12-18 years of age, with a minimum pain score of 1 on a 10cm visual analog scale, completed a 3-week sleep manipulation protocol involving a baseline week, followed by a restricted sleep (RS) condition (6.5 hrs in bed per night) and a health sleep (HS) condition (9.5 hrs in bed per night). We used a randomized crossover experimental design. Participants’ sleep was monitored at home via self-report and actigraphy. Pain was assessed up to 3 times daily using the iCanCope with Pain app. At baseline and the end of each sleep condition, participants completed validated questionnaires about pain interference, pain behaviour, daytime fatigue, and had their disease activity assessed by a trained clinician. We used Bayesian hierarchical models to estimate the effect of sleep duration on pain, as measured by iCanCope, as well as the effects on pain interference, pain behaviour, and disease activity.

Results: Participants (n=31) had a mean age of 15.0 ± 1.8 years (see Table 1 for basic demographic information). Participants averaged 1.4 (95% credible interval, CrI 1.2-1.6) more hours of sleep per night during the HS condition relative to the RS condition. Compared to the RS condition, participants were 40% (odds ratio 0.61, 95% CrI 0.39-0.95) less likely to report pain in the HS condition. There were no differences between the RS and HS conditions on pain interference, pain behaviour, daytime fatigue, or disease activity.

Conclusion: Adolescents with childhood arthritis improved their sleep duration, and this longer sleep duration resulted in a moderate reduction in pain. These findings complement prior correlational studies and confirm a causal relationship between reduced sleep duration and increased pain.

Trial registration identifying number: Clinicaltrials.gov registration: NCT04133662

Disclosure of Interest: None declared

Table 1 (abstract P014). Participant Demographic Information

P015. Acceptability of preliminary Arabic PGALS in patients with juvenile idiopathic arthritis

H. Ferjani¹, E. Rabhi¹, S. al mayouf², D. Hadef³, L. Loucif³, W. Hamdi¹, H. Foster⁴

¹Rheumatology, Kassab orthopedics institute, Ksar Said, Tunisia, ²pediatrics, King Faisal specialist hospital and research center, Riyadh, Saudi Arabia, ³pediatrics, Batna 2 University, Batna, Algeria, ⁴pediatrics, Population Health Sciences Institute, Newcastle upon Tyne, United Kingdom

Correspondence: H. Ferjani

Introduction: The paediatric Gait, Arms, Legs, and Spine (pGALS) is a quick, easy tool for evaluating musculo-skeletal problems in school-age children. It facilitates early recognition of joint problems and prompts referral to specialist center to optimize clinical outcomes. pGALS hasbeen shown to be practical and useful, with excellent acceptability. Its use was limited in Arabic-speaking countries because of the lack of an Arabic version.

Objectives: Under the umbrella of the musculoskeletal matter, we aimed to translate the English pGALS into Arabic form using the Delphi approach and to evaluate the acceptability of the preliminary version in children and their parents.

Methods: The original pGALS was translated by three native-speaker translators. The different propositions were mixed in a consensual way by a children’s musculoskeletal specialist. The version was validated according to the Delphi method. Delphi method is the consensus-building method, providing the consensual opinion of the experts.

For each translated item of the pGALS, the experts assessed the relevance using a scale ranging from 1 to 9 (not relevant-completely relevant). Then the median was calculated giving for each item the position of the group: disagree (if the median < 3), equivocal (median between 4-6) and agreement (median >7). The degree of the convergence with the group was assessed to clarify this result: the group’s opinion is consensual if 70% of the responses were within the range of the median. For the non consensual and no relevant item, the experts propose a comment to reformulate the sentence. The acceptability of the first form was evaluated using the visual analog scale in patients with juvenile idiopathic arthritis (JIA).

Results: Six experts from different Arabic-speaking countries (pediatricians and rheumatologists) were interviewed during 3 rounds by electronic survey individually and anonymously to validate the Arabic form. After each round: the median, consensus, and comments of every item are collected and a meeting with experts was held to analyze the results. During the first meeting, we were consensual and we had an agreement on 83 % of the items using the Arabic version (30 items were validated, and 6 items were reformulated. Then the forms were reformulated using the results of the preliminary rounds: opinions of the experts and their proposals during the last meeting). We were in agreement and we validated the remaining item during the second meeting. In the last round, we obtained a consensual preliminary version of the Arabic pGALS. After translation–back-translation, the Arabic pGALS was used in five pairs (child and parent) with JIA. The acceptability varied between 8 to 9, and all the questions and maneuvers were understood by the pairs.

Conclusion: After the consensual translation of the Arabic pGALS and evaluation of its acceptability in the small sample, the second step is to validate this form in a large paediatric population and to assess its sensibility and specificity of this form in screening musculoskeletal disorders in Arabic countries.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P016. Quantifying cost impact of withdrawing biologic dmards in children with JIA

A. A. Florax¹, M. J. Doeleman^2,3, S. de Roock^2,3, N. van der Linden¹, E. Schatorjé^4,5, G. Currie⁶, D. A. Marshall⁶, M. J. IJzerman¹, R. S. Yeung⁷, S. M. Benseler⁶, S. J. Vastert^2,3, N. Wulffraat^2,3, J. F. Swart^2,3, M. M. Kip^1,2 on behalf of UCAN CAN-DU and UCAN CURE consortia

¹University of Twente, Enschede, ²University Medical Center Utrecht, ³Utrecht University, Utrecht, ⁴St. Maartenskliniek, ⁵Radboud University Medical Center, Nijmegen, Netherlands, ⁶University of Calgary, Calgary, ⁷ University of Toronto, Toronto, Canada

Correspondence: M. M. Kip

Introduction: The cost impact of withdrawing biologic DMARDs (bDMARDs) in JIA patients in clinically inactive disease is currently unknown.

Objectives: To quantify the difference in costs of hospital-associated care before and after withdrawing bDMARDs (discontinuing or tapering) in JIA patients <18 years old, after they achieved clinically inactive disease on bDMARDs.

Methods: Retrospective analysis of prospective data from electronic medical records of JIA patients at the Wilhelmina Children’s Hospital (Utrecht, the Netherlands), aged <18 years between 8 April 2011 and 8 April 2022, and treated with TNF-α bDMARDs, which were discontinued or tapered during this period. The hospital-associated resource use and associated costs during clinically inactive disease (i.e. pre-withdrawal) were compared to the costs within the first year after initiating withdrawal (i.e. post-withdrawal), grouped by discontinuing and tapering. The paired t-test was used to evaluate the significance of the cost difference between the pre- and post-withdrawal period. Unit prices were obtained from Dutch reimbursement lists, pharmaceutical price lists, and hospital price lists.

Results: Of the 55 JIA patients, 25 discontinued and 30 tapered bDMARDs. The mean annual costs of hospital-associated care per patient were €9,906 in the pre-withdrawal period (mean follow-up of 448 days) and decreased significantly to €5,633 in the post-withdrawal period (fixed follow-up of 365 days, p<0.05). The mean absolute difference in the entire study population is €-4,273 per patient per year (i.e. -43%), Table 1. The medication costs represented 80% and 60% of total mean annual costs in the pre- and post-withdrawal period, respectively. When distinguishing between withdrawal strategies, mean annual costs per patient reduced significantly from €9,670 to €4,338 in the discontinuation group (i.e. -55%, p<0.05), and from €10,103 to €6,712 in the taper group (i.e. -34%, p<0.05).

Conclusion: The mean annual costs of bDMARDs within the first year post-withdrawal period are significantly lower than the annual costs pre-withdrawal. In addition, abruptly discontinuing bDMARDs results in greater cost reductions, although there is substantial patient-level variation.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

Table 1 (abstract P016). Mean annual hospital-associated costs of JIA (and 95% CIs) per patient during clinically inactive disease on bDMARDs (pre-withdrawal) and during the first year following withdrawal of bDMARDs (post-withdrawal, subdivided into discontinuing and tapering)

P017. Juvenile psoriatic arthritis - clinical characterization and differences from adult-onset disease

V. Fraga, A. Ana Catarina, S. Sousa, M. J. Santos

Rheumatology, Hospital Garcia de Orta, Almada, Portugal

Correspondence: V. Fraga

Introduction: Juvenile psoriatic arthritis (jPsA) is a category of juvenile idiopathic arthritis (JIA), clinically heterogenous.

Objectives: Characterize clinical features of jPsA and compare with adult-onset psoriatic arthritis (aPsA).

Methods: Children fulfilling the ILAR criteria for jPsA and adults fulfilling CASPAR criteria for PsA were included. Demographic and clinical data was retrieved from the Portuguese registry Reuma.pt. A cross-sectional descriptive analysis of jPsA followed by a comparison with aPsA was performed.

Results: A total of 11 jPsA and 132 aPsA were included. jPsA represented 8.9% of JIA patients: 8 girls (72.7%), mean age at disease onset 10.4 ± 3.7 years and at diagnosis 11.9 ± 3.9 years, all Caucasian. Five (45.5%) developed psoriasis before arthritis and in 2 patients, psoriasis followed the onset of arthritis. Family history of psoriasis in 1^st degree relatives was positive in 63.6%. The most frequent articular pattern was oligoarthritis (63.6%, n=7) and the most common musculoskeletal features were dactylitis (27.3%, n=3) and enthesitis (27.3%, n=3). Axial involvement was present in only one case. All jPsA patients were rheumatoid factor negative, six (54.5%) were ANA positive and none was HLA-B27 positive. Seven were treated with methotrexate, in combination with a biologic in four of them.

The mean age of aPsA onset was 40.5 ± 18.9 years, 51.5% (n=68) were males, and the most common joint pattern was polyarthritis (59.1%, n=78). Presence of psoriasis at diagnosis was significantly more frequent in aPsA than in jPsA (84,8% vs 45.5%; p-value= 0.01). A total of 77 patients were treated with a biologic, most frequently adalimumab (n=27), etanercept (n=21) and infliximab (n=15). Seventy-two patients were treated with csDMARDs alone or in combination with a biologic.

Conclusion: At disease onset, less than half of the jPsA had psoriasis, and the most common joint pattern was oligoarthritis. The presence of dactylitis, enthesitis, and a positive family history of psoriasis are helpful in establishing the diagnosis. Conversely, aPsA patients were more often male, with psoriasis at the time of diagnosis and with polyarticular disease. No differences were found concerning extra-articular manifestations.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

Table 1 (abstract P017). Extra-articular manifestations in jPsA and aPsA

P018. Validation of a lateral flow rapid test for adalimumab drug monitoring in patients with juvenile idiopathic arthritis

S. Fuehner¹, A. Mureseanu¹, S. de Roock², J. F. Swart², G. Simonini³, E. Marrani³, P. Rovero⁴, F. Real-Fernandez⁴, J. Weber⁵, R. Cotti⁵, K. Minden⁶, D. Foell¹, H. Wittkowski¹

¹Department of Paediatric Rheumatology and Immunology, University Hospital Münster, Münster, Germany, ²Department of Paediatric Immunology and Rheumatology, University Medical Centre Utrecht, Utrecht, Netherlands, ³Rheumatology Unit, Meyer Children Hospital, University of Florence, Florence, ⁴Interdepartmental Laboratory of Peptide and Protein Chemistry and Biology, Department of NeuroFarBa, University of Florence, Sesto Fiorentino, Italy, ⁵BÜHLMANN Laboratories AG, Schönenbuch, Switzerland, ⁶Charité University Medicine and Epidemiology Unit, German Rheumatism Research Centre, Berlin, Germany

Correspondence: H. Wittkowski

Introduction: Therapeutic drug monitoring in patients with juvenile idiopathic arthritis (JIA) could guide dose adjustments and treatment intervals and thereby further improve patient outcomes during treatment with biologic agents. Point-of-care tests become increasingly available for routine clinical care and provide the possibility of immediate therapy decisions at the outpatient clinic.

Objectives: We have tested Lateral Flow Immunoassays (LFIA) with a Point-Of-Care-Device (POC, Quantum Blue® Reader) to investigate whether they can be helpful in the context of therapy decisions and drug monitoring in patients with JIA.

Methods: We included 91 JIA patients from the biobank of the German multicenter inception cohort (ICON), 71 of whom received the anti-TNF biologic adalimumab and a control group of 20 patients treated with etanercept. From these patients, 148 serum samples (stored at -80°C) were identified to measure adalimumab levels with the BÜHLMANN Quantum Blue® Adalimumab rapid test (measuring range 1.3 - 35.0μg/ml) in at least one sample per patient.

Anti-drug antibodies (ADAs) were determined with the BÜHLMANN Quantum Blue® Anti-Adalimumab rapid test (measuring range 0.2 - 12μg_eq/ml). Since this assay is described as drug sensitive, only samples with adalimumab levels below the detection limit (n = 41) were analyzed.

For external validation 10 selected samples were analyzed in a routine laboratory with an enzyme immunoassay (EIA). An additional cross-check was performed with 21 samples from two external cohorts. In these, adalimumab was measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay and assayed for ADAs by radioimmunoassay (RIA) or ELISA (LisaTracker).

Results: In our cohort, adalimumab levels above the detection limit were measured in 87 of 128 samples, from 57 out of 71 JIA patients treated with adalimumab. In 14 patients, although adalimumab treatment was documented, no adalimumab could be measured at any time point. The samples selected for external validation were measured in a routine laboratory with a correlation (Spearman r) of 0.93 (p = 0.0012), thus confirming the rapid test as highly reliable. Furthermore, the comparison of rapid tests with LC-MS/MS measured adalimumab in the external partners’ samples showed a correlation of 0.86 (p = 0.0278). In patients treated with Etanercept no interference occurred and no false positive result was measured using the LFIA.

All samples with adalimumab levels below the detection limit were then tested for ADAs and in only one of these samples, antibodies could be detected with the used rapid test. The external laboratory was able to measure ADAs positively in two out of 10 selected samples. This may indicate that the rapid test is less sensitive than the EIA method.

This trend was also observed in the cross-check measurements using the samples of the external partners. Here, the BÜHLMANN ADA test showed no false-positive result (positive predictive value of 100%) compared to the results measured with RIA and ELISA, but a negative predictive value of only 40% and 85%, respectively.

Conclusion: Adalimumab LFIA rapid test with a POC-Device can be a useful tool for drug monitoring in patients with JIA. The handling is simple and tests are time saving and yet reliable. In patients with undetectable adalimumab levels, a rapid ADA test may be helpful in interpreting the absence of adalimumab. None-detectable ADA levels according to POC-Device should be validated and/or confirmed with conventional laboratory testing.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P019. Cutaneous disorders and systemic manifestations, the importance of the multidisciplinary approach

L. Gago^1,2, M. H. Lourenço^1,2, R. Pinheiro Torres^1,2, M. Guedes³, C. Amaro⁴, M. Costa¹, J. C. Branco^1,2, A. F. Mourão^1,2

¹Rheumatology, Hospital Egas Moniz, ²Centro de Estudos de Doenças Crónicas (CEDOC), Universidade Nova de Lisboa, ³Ophthalmology, ⁴Dermatology, Hospital Egas Moniz, Lisboa, Portugal

Correspondence: L. Gago

Introduction: Wooly hair nevus is a hair change, where there is a curly, hypopigmented patch of hair in a restricted area of the scalp. It may be associated with ophthalmologic, auditory, renal, cutaneos, cardiac and skeletal manifestations.

Objectives: The authors describe a case of a 4-year-old girl with woolly hair nevus and psoriatic arthritis associated with chronic anterior uveitis.

Methods: A 4-year-old girl presented to the dermathology department with confluent erythematous papules on plaques on her thighs, elbows, and knees, and a curly patch of hair that contrasted with her straight hair. No relevant family history. In addition, the patient had a history of frequent falls. She denied arthralgias, myalgias, dactylitis. She also denied visual acuity changes. After careful objective examination she was diagnosed with psoriasis and wooly hair nevus.

An ophthalmological screening was performed which detected the presence of bilateral chronic anterior uveitis, and treatment with topical corticotherapy was initiated.

Due to her history of frequent falls and bilateral uveitis she was referred to our department. On physical examination she presented with arthritis of the right knee, with no associated pain, no enthesitis, dactylitis or other swollen or painful joints. She also had no strength deficits.

Blood tests showed no elevation of inflammatory parameters. She tested positive for the antinuclear-antibodies, and negative for extractable nuclear antigens. She also tested positive for the human leukocyte antigen B27 (HLA-B27). An ultrasound of the right knee was performed with evidence of synovitis of this joint. An echocardiogram was also performed and did not show any alterations.

Results: Considering the presence of right knee arthritis, bilateral uveitis and psoriasis associated with positive HLA-B27, the diagnosis of Psoriatic Juvenile Idiopathic Arthritis was made and the patient was medicated with Methotrexate 7.5 mg/week and prednisolone 7.5 mg, with significant improvement of symptoms. Three weeks after starting therapy the patient had no arthritis or skin lesions, however, bilateral uveitis persisted and for this reason topical ocular corticosteroid therapy was maintained.

Conclusion: Woolly hair nevus may be associated with ophthalmological, auditory, renal, cutaneous, and musculoskeletal manifestations, which makes referral to different specialties extremely important. The ophthalmologic examination is always indicated in these children.

Psoriatic arthritis is rare in children , representing the adult form of spondyloarthritis, but axial involvement is uncommon. Joint involvement may be mono- or polyarticular, symmetrical or asymmetrical. About 30% of patients are HLA-B27 positive.

In this particular case, the ophthalmologic involvement may be related to both wooly hair nevus and psoriatic arthritis, since both conditions are associated with ocular pathology. Thus, early ophthalmologic screening is of utmost importance, for diagnosis and treatment at early stages of the disease, in order to avoid irreversible changes.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P020. Biomarkers related to myeloid derived cells obtained at baseline and at 18-year follow-up in juvenile idiopathic arthritis. relation to remission status and inactive disease

M. Glerup¹, C. Kessel², D. Foell², M. Høllsberg¹, L. Berntson³, A. Fasth⁴, S. Nielsen⁵, E. Nordal⁶, V. Rypdal⁶, M. Rygg⁷, E. Arnstad⁸, S. Peltoniemi⁹, K. Aalto¹⁰, T. Herlin¹ on behalf of the Nordic Study Group of Pediatric Rheumatology (NoSPeR)

¹Department of Paediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus , Denmark, ²Department of Pediatric Rheumatology and Immunology, University Hospital Münster, Münster, Germany, ³Department of Women’s and Children’s Health, Uppsala University, Uppsala, Sweden, ⁴Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden, ⁵Department of Pediatrics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark, ⁶Department of Pediatrics, University Hospital of North Norway, Department of Clinical Medicine, UiT The Arctic University of Norway, Tromsø, Norway, ⁷Department of Clinical and Molecular Medicine, NTNU - Norwegian University of Science and Technology, Department of Pediatrics, St. Olavs Hospital, Trondheim, Norway, ⁸Department of Clinical and Molecular Medicine, NTNU - Norwegian University of Science and Technology, Department of Pediatrics, Levanger Hospital, Nord-Trøndelag Hospital Trust, Levanger, Norway, ⁹Clinic of Rheumatology, Helsinki University Hospital, Helsinki, Finland, ¹⁰Department of Pediatrics, New Children’s Hospital, Helsinki University Hospital, Pediatric Research Center, University of Helsinki, Helsinki, Finland

Correspondence: M. Glerup

Introduction: Several blood biomarkers have been suggested to track with disease activity in juvenile idiopathic arthritis (JIA) and facilitate prediction of clinical outcome.

Objectives: To evaluate whether levels of biomarkers of inflammation in serum from patients with JIA close to disease onset was related to disease activity at baseline and at long-term follow-up (FU).

Methods: Patients from the population-based Nordic JIA cohort study were recruited at disease onset from defined regions of Denmark, Sweden, Norway, and Finland between 1997-2000. Serum was obtained at baseline (within 6 months from disease onset) and at 18-yr FU. S100 proteins, and 14 other inflammatory markers (cytokines, chemokines) were determined by multiplexed bead array assay. Data acquisition and analysis were performed on a MAGPIX instrument using xPONENT v4.2 software (Luminex). The analyzing laboratory in Muenster was blinded for the patients’ clinical data.

Results: Of the 510 patients from the Nordic cohort, serum samples from 236 patients at baseline and 284 patients at 18-yr FU were analyzed. Of these, 150 patients had paired samples taken at both time-points. Median age at onset was 6.0 yrs (IQR 2.9-10.4) and 23.6 yrs (IQR 20.5-27.6) at last FU. Median JADAS10 at baseline was 5.0 (IQR 2.0-11.0) compared to 2.0 (IQR 0.0-6.4) at FU. Inactive disease at 18-yr FU was observed in 58% and remission off medication in 39.4% of the patients.

At baseline levels of IL-1b, IL-6, IL-10, IL-17, IL-18, and sCD25 ranged 1.4-5.5 times higher than at 18-Y FU (all p<0.001) whereas baseline levels for IL-12 and MPO was half the values obtained at FU (both p<0.001). Sampled at baseline IL-6, IL-12p70, GM-CSF and S100A12 correlated significantly with baseline JADAS71 (p<0.01), but IL-1b, IL-4, IL-13 and MMP-3 correlated only weakly (0.01

Patients with active disease at 18-yr FU had significantly higher levels of S100A9, S100A12, IL-1β, IL-6, IL-12p70, IL-13, MMP-3, and GM-CSF at baseline than patients with inactive disease at FU, but levels of TNFα, IL-4, IL-10, IL-17, IL-18, CCL-2, sCD25, and MPO were not significantly different. Patients who achieved remission off medication at 18-y FU had significantly lower levels of IL-1β, IL-12p70, IL-13, MMP-3 measured at baseline compared to the rest of the cohort.

Conclusion: Biomarkers of inflammation obtained within the first 6 months after JIA onset may complement the characterization of disease activity and may even contribute to future prediction models of long-term outcome.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P021. Clinical patterns in psoriatic juvenile idiopathic arthritis in a pediatric rheumatology unit from a tertiary hospital

M. I. Gonzalez Fernandez¹, B. Lopez Montesinos², M. Marti Masanet¹, L. Lacruz Perez², I. Burgos Berjillos², I. Calvo Penades²

¹Pediatric Rheumatology Unit, Medical Research Institute Hospital La Fe, ²Pediatric Rheumatology Unit, Hospital Universitario y Politécnico La Fe, Valencia, Spain

Correspondence: M. I. Gonzalez Fernandez

Introduction: Psoriatic Juvenile Idiopathic Arthritis (PsJIA) is reported to account for around 5% of Juvenile Idiopathic Arthritis (JIA). It is considered a heterogeneous entity, with observation of a bimodal distribution of age at the disease onset (as in JIA globally) and description of an early-onset and a late-onset form.

Objectives: To describe a cohort of patients with PsJIA from a paediatric rheumatology unit in a tertiary hospital.

Methods: Patients seen at our paediatric rheumatology unit between January 2014 and April 2022 who met PsJIA ILAR criteria and with at least 18 months of follow-up were included. Medical records were reviewed to collect demographic, clinical, laboratory, treatment and evolution data.

Results: 39 patients met Vancouver criteria for probable or definite Juvenile Psoriatic Arthritis, of which 34 (87%) fulfilled ILAR criteria for PsJIA. The other 5 patients were all female, ANA-positive, early-onset JIA patients with dactylitis who met probable Vancouver criteria (four of them with psoriasis in a second-degree relative and one with nail pitting).

Median (IQR) age at JIA onset was 2,78 (1,58-6,81) years. 71% were female. Median (IQR) follow-up was 11,45 (8,01-13,74) years. As expected, distribution of the age at JIA onset was not consistent with normality, resembling a bimodal distribution. Patients were divided into 2 subgroups according to the age at disease onset, group of early onset (<=6 years) with 25 patients and group of late onset (>7 years) with 9 patients. Female gender predominance was found in both groups: 18/25 (72%) in early onset and 6/9 (67%) in late onset.

With respect to arthritis, 12/34 (35%) patients had oligoarticular involvement at the beginning of the disease. 26/34 (76%) had polyarticular course: 21/25 (84%) in the early-onset group and 5/9 (56%) in the late-onset group. Only one patient presented sacroilitis, in the late-onset group. 19/34 (56%) had dactylitis and 5/34 (15%) enthesitis.

ANA were positive in 20/34 (59%) patients (68% early-onset group vs 33% late-onset group). HLA-B27 was positive in 5/34 (15%) patients (8% early-onset group vs 33% late-onset group). 9/34 (26%) patients had anterior uveitis, all in the early-onset group.

Nail pitting was observed in 15/34 (44%) patients. Psoriasis appeared in 23/34 (68%) patients over the course of follow-up: 16/25 (64%) in the early-onset group and 7/9 (78%) in the late-onset group. Psoriasis was diagnosed after the arthritis in all patients in the early-onset group and in 3/7 (43%) patients in the late-onset group (p<0,05 Fisher test). Median (IQR) time from JIA diagnose to psoriasis diagnose 6,04 (3,27-9,16) years.

Regarding treatment, all patients received MTX and 24/34 (71%) biological DMARDS. 12/34 (35%) patients switched to a second biologic drug and 2/34 (6%) patients switched to a third biologic agent (early-onset patients).

Median (IQR) time until clinical remission with treatment was 1,62 (1,32-2,46) years. At last visit, 23/34 (68%) patients where in clinical remission (5/34 (15%) off therapy).

Conclusion: In our cohort of PsJIA, the form of early onset is more represented, with higher tendency to ANA positivity and chronic anterior uveitis. Female gender predominance was observed in both groups. High percentage of patients were treated with biological agents, in relation with uveitis and high frequency of polyarticular course. Psoriasis diagnosis was made a median (IQR) of 6,95 (4,24-9,46) years after arthritis diagnosis in early-onset patients.

Disclosure of Interest: M. I. Gonzalez Fernandez Consultant with: Novartis, B. Lopez Montesinos: None declared, M. Marti Masanet: None declared, L. Lacruz Perez: None declared, I. Burgos Berjillos: None declared, I. Calvo Penades Consultant with: Novartis, Speaker Bureau with: Novartis, Sobi, Abbvie

P022. The effect of nutritional status on disease activity and disease course in juvenile idiopathic arthritis and use of malnutrition screening tests

A. Günay¹, Ö. F. Beşer², A. Adroviç Yıldız³, S. Şahin³, M. Yıldız³, F. Haşlak³, A. Günalp³, Ö. Kasapçopur³, K. Barut³

¹Department of Pediatrics, ²Department of Pediatric Gastroenterology, Hepatology & Nutrition, ³Department of Pediatric Rheumatology, Istanbul University, Cerrahpaşa - Cerrahpaşa Medical Faculty, Istanbul, Turkey

Correspondence: K. Barut

Introduction: Juvenile idiopathic arthritis is the most common chronic, systemic, autoimmune connective tissue disease of unknown etiology in children. Malnutrition can be seen frequently during the course of chronic diseases. Depending on the severity of malnutrition, the course of chronic diseases may be adversely affected. For these reasons, it is emphasized that malnutrition screening tests should be routinely applied in chronic patients in order to detect nutritional status disorders that may occur during the course of chronic diseases. During the course of JIA, nutritional status disorders can often be encountered as a result of various complications or related to the severity of the disease and this may adversely affect the course of the disease. There are screening tests used to determine the risk of malnutrition. Pediatric Yorkhill Malnutrition Score (PYMS) and Screening Tool for Risk of Impaired Nutritional Status and Growth (STRONGKids) are two accepted tests.

Objectives: We aimed to determine the frequency of malnutrition in JIA and the possible malnutrition status that may develop in JIA patients with screening tests. Also we aimed to reveal the factors in patients with existing malnutrition and/or patients who will develop malnutrition.

Methods: JIA (n=150) and FMF (n=156) patients were included in the study. All physical examinations of the patients were performed, height and weight measurements were recorded with the scale and meter in the outpatient clinic, BMI was calculated, laboratory values ​​at the time of admission were examined, disease activities of JIA patients were determined according to JADAS and Wallace criteria. All patients’ malnutrition risk scores were determined by applying PYMS and STRONGKids malnutrition screening tests. Afterwards, the files of all patients were analyzed retrospectively. All patients were made an appointment again at least 3 months after the examination. Anthropometric measurements of each patient were repeated in the outpatient clinic, and their BMIs were calculated. Physical examinations of all JIA patients were performed, laboratory parameters were requested and the results were recorded, and the activity level of the disease was determined again.

Results: According to PYMS values, malnutrition risk is seen in 11.3% (n=17) of JIA group cases. According to STRONGKids values, malnutrition risk is observed in 9.3% (n=14) of JIA group cases. According to the two screening tests, there is no statistically significant difference in the subtypes, ages, age at onset of disease, diagnosis age, drugs used, duration of drugs used and total doses of prednisolone used according to malnutrition risk. Although it is not statistically significant, it is noteworthy that the probability of malnutrition is higher in polyarticular JIA and enthesitis-related arthritis subgroups compared to other subgroups. According to PYMS and STRONGKids; JADAS applied at the time of admission and at least 3 months later and Wallace applied at the time of admission, the rate of being active was found to be statistically significantly higher than those without the risk of malnutrition.

Conclusion: Our study indicates the importance of determining the risk of malnutrition in this patient group by showing that the frequency of disease activity increases in patients at risk for malnutrition in JIA cases. It is emphasized that patients in polyarticular and enthesitis-related arthritis subgroups, whose prognosis is worse than other subgroups, should be followed more closely in this regard.

Disclosure of Interest: None declared

P023. A10-year inception cohort of mexican-mestizo patients with juvenile idiopathic arthritis (JIA) from 3 tertiary centers in Mexico City. A Real-World Evidence (RWE), based on real world data from routine clinical assessment

R. Gutiérrez Suárez

Pediatric Rheumatology, Shriners Hospital of Mexico City, Mexico, Mexico

Correspondence: R. Gutiérrez Suárez

Introduction: Cohort studies can provide useful access to RWE which reflects the reality of daily clinical practice. RWE is becoming highly valuable and complementary to randomized clinical trials (RCT) in the generation of clinical evidence due to their high external validity, better generalisability, time and resource-efficiency and the possibility of long term surveillance.

Objectives: To evaluate propectively several disease outcome measures, in a 10-year period inception cohort of Mexican-Mestizo patients JIA, with the aim of generating real world diagnostic, therapeutic and prognostic evidence of this patients.

Methods: A10-year inception cohort was designed and conducted in three tertiary referal centers in Mexico City. Incident and prevalent JIA Mexican-Mestizo patients according to ILAR criteria were included in the cohort since its inception on January, 2012; and evaluated clinically and with laboratories at 12, 26 and 54-weeks periods and thereafter at year: 2, 3, 5, 7.5 and 10. Different demographical (referal time, time to adequate diagnosis and treatment, family income, parents education and social security); clinical (MD-centered measures: MD-VAS for disease activity and joint count; and parent/patient-centered measures: VAS of well-being and pain; disease activity (JADAS-71), functional capacity (CHAQ), articular and extra-articular damage (JADI-A and JADI-E); criteria for minimal disease activity (MDA), remission with (RWT) and without treatment (RWOT)); laboratory (RF, ESR CRP, antinuclear antibodies and HLA-B27) and therapeutic (NSAID’s, Steroids, Non biological and biological drugs: time and availability) variables were collected. Descrptive and some inferential statistics were performed for the 7-JIA subtypes according ILAR

Results: A total of 265 (60 % female) Mexican-Mestizo JIA patients according with ILAR criteria were included in the inception cohort. Age at onset (median ± IR); 6.5 (3-16) years; referal time (years): 2.5 (0.1-7.2); time to adequate diagnosis (years): 2.8 (0.1-7.5) time to adequate treatment; (years): 2.8 (0.2-7); family income per month; 300 USD (50-1100 USD). There were several differences between different subtypes in terms of disease activity (JADAS-71) functional capacity (CHAQ), articular and extra-articular damage (JADI-A and JADI-E). Also a high frequency of oligoarhritis patients complete criteria for minimal disease activity (MDA) and remission with (RWT) and without treatment (RWOT)): Patients with enytehsitis related arthritis and polyarthritis RF (+) were unable in a high proportion of patients to complete MDA or RWT and without treatment RWOT. Biological availabilty for treatment (4% of patientes in the inception cohort) Principally TNF inhibitors were used.. Time for Biological treatment (years): 1.5 (0.3-10). a large proportion of patients in RF (+) polyarthritis required combination or 2 or 3 non biological drugs related to the biological avaliability.

Conclusion: RWE reflects the reality of daily clinical practice and is a complement for RCT in the generation of clinical evidence. This studies enables research into the general quality of pediatric Rheumatogy care and provide insights into a broader optimization of pediatric Rheumatogy care, refined therapeutic strategies for patient subgroups as well as avenues for further research in pediatric Rheumatology.

Patient Consent: No, I have not receive consent

Disclosure of Interest: None declared

P024. Validation of the parent global assessment as a quality of life measure in juvenile idiopathic arthritis: results from reacch-out

K. Oen¹, K. Toupin-April², B. M. Feldman³, R. A. Berard⁴, C. M. Duffy⁵, L. B. Tucker⁶, J. Tian⁷, D. G. Rumsey⁸, J. Guzman⁶ on behalf of ReACCh-Out Investigators

¹Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, ²School of Rehabilitation Sciences and Department of Pediatrics, University of Ottawa, Ottawa, ³Pediatrics and Medicine, University of Toronto, Toronto, ⁴Pediatrics, London Health Sciences Centre, London, ⁵Pediatrics, Children’s Hospital of Eastern Ontario and University of Ottawa, Ottawa, ⁶Pediatrics, BC Children’s Hospital and UBC, Vancouver, ⁷Statistics and Actuarial Science, Simon Fraser University, Burnaby, ⁸Pediatrics, Stollery Children’s Hospital and University of Alberta, Edmonton, Canada

Correspondence: J. Guzman

Introduction: The Juvenile Idiopathic Arthritis (JIA) parent global assessment (parent global) is a visual analogue scale anchored by the words 0 very well and 10 very poor, and headed by the instruction: “Considering all the ways that arthritis affects your child, rate how your child is doing by placing a mark on the line.” Despite its extensive use there has been no formal conceptualization or validation of the parent global, resulting in uncertainty as to what it measures. We hypothesized that the parent global is an assessment of a child’s health as affected by arthritis, and should be considered a disease-specific health-related quality of life (HRQoL) measure.

Objectives: To 1) validate the parent global as a HRQoL measure, 2) evaluate measurement properties of accepted HRQoL measures relative to those of the parent global, and 3) assess causal pathways determining parent global scores.

Methods: Data from the Research in Arthritis in Canadian Children emphasizing outcomes (ReACCh-Out) cohort were used. Measurement properties were assessed in 344 patients at enrolment and 6 months later. Causal pathways were tested by structural equation modelling to understand root causes and mediators leading to parent global scores.

Results: Construct validity was supported by moderate to high Spearman correlations (0.53-0.70) of the parent global with the Juvenile Arthritis Quality of Life Questionnaire (JAQQ), Quality of My Life health scale (HRQoML), Pediatric Quality of Life Inventory (PedsQL)-Parent, and Child Health Questionnaire (CHQ)-Physical; and lower correlations (0.14-0.49) with disease activity measures (physician global assessment of disease activity (PGADA), active joint count, erythrocyte sedimentation rate(ESR)). Responsiveness of the parent global to improvement according to parent ratings (0.51) was acceptable and within the range (0.32-0.71) of that of other measures. Reliability estimates and measurement errors for all measures were unsatisfactory, likely due to the prolonged time between assessments. Causal pathways for the parent global matched those previously reported for HRQoML [1].

Conclusion: Our results support the parent global as a valid measure of HRQoL. If confirmed, the findings of previous studies using this measure and its role in JIA core sets and composite measures should be re-interpreted in this light.

[1] K Oen et al, Causal Pathways to Health-Related Quality of Life in Children with Juvenile Idiopathic Arthritis: Results from the ReACCh-Out Cohort. Rheumatology (Oxford) 2021;60(10):4691-4702

Disclosure of Interest: None declared

Table 1 (abstract P024). Spearman correlations of parent global with recognized HRQoL measures and other JIA measures at study enrolment

P025. Juvenile psoriatic arthritis: a case report

A. Harbi, N. Balhoudi, B. Ibrahim, H. Mejaouel

Pediatric department, Medical School, Kairawan , Tunisia

Correspondence: A. Harbi

Introduction: Psoriatic arthritis is a heterogeneous entity defined by the association of psoriasis and arthritis with two forms: one more frequent in girls with an age of onset of about 6 years, close to oligoarthritis with a risk of uveitis, the other later, around 11-12 years, more frequent in boys, close to spondylarthropathies. It is an autoimmune inflammatory disease with hyperproduction of pro-inflammatory cytokines, particularly TNF alpha.

Objectives: The objective of our case study is to describe a rare and interesting case of Juvenile psoriatic arthritis .

Methods: We describe a clinical case of a child aged 13 years, complete vaccination according to age with a history of myositis post viral infection 5 years ago. Currently he presents walking disorder for 3 weeks, spinal pain, diffuse polyarthralgia with functional repercussions and interruption of his education.

The muscular testing globally at 3+ but it is generated by the pain, X-ray of the painful joints: without abnormalities with an ENMG having shown no myogenic attack nor motor or sensory deficit with a cerebral-medullary MRI without abnormalities. Ultrasound of the joints: discrete effusion of the knees bilaterally .Biology: antinuclear antibodies, antiAMAM2 rheumatoid factor, anti LKM, anti SLA LC1: negative, thyroid check-up correct with the fundus showing no uveitis.

On skin examination, he has erythematous scaly patches on 2 knees with post-inflammatory hypopigmentation on the elbows, nails punctuated with thimbles, distal interphalangeal attack, oral mucosa: no abnormalities: it is psoriasis, hence the need for local treatment. It is a case of juvenile psoriatic arthritis and is treated with NSAIDs, with a good outcome.

Results: Juvenile idiopathic arthritis is considered an autoimmune disease, which may result from an abnormal immunological response triggered by environmental factors such as infection or trauma in a genetically susceptible individual. Psoriatic arthritis is less than 10% of JIA.

In more than 60% of cases, arthritis precedes the skin manifestations of psoriasis, sometimes by several years, and usually presents as an asymmetric oligoarthritis. Monoarthritis is relatively common initially, with isolated involvement of the knee and small joints of the hands and feet.

The Edmonton diagnostic criteria are used. Psoriatic arthritis is characterized by the presence of arthritis and psoriasis, or failing that, by arthritis accompanied by at least two of the following signs: - Dactylitis - Nail staining or onycholysis - Family history of psoriasis in a first degree relative.

Management should be done in a specialized setting, in the context of a pediatric rheumatology consultation. As with other JIAs, treatment is based on non-steroidal anti-inflammatory drugs (NSAIDs). NSAIDs are indicated as the first-line treatment; they are prescribed in sufficient and continuous doses. They may be combined with intra-articular injections of delayed corticoids. Background treatment involves methotrexate and biotherapies.

Conclusion: Psoriatic arthritis is characterised by the presence of arthritis associated with psoriasis. Non-steroidal anti-inflammatory drugs have traditionally been the main treatment for all forms of juvenile idiopathic arthritis (JIA) and other paediatric rheumatic diseases.

Trial registration identifying number: .

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P026. Evaluation of comorbidities in patients with juvenile idiopathic arthritis: a cross-sectional single center study

F. Haslak, V. Guliyeva, B. Hotaman, C. Duman, M. Yildiz, A. Gunalp, A. Aliyeva, A. Adrovic, S. Sahin, K. Barut, O. Kasapcopur

Pediatric Rheumatology, Istanbul University-Cerrahpasa, Cerrahpasa Medical Faculty, Istanbul, Turkey

Correspondence: M. Yildiz

Introduction: Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in childhood. The most common subtype is the oligoarticular one. While autoimmunity is generally responsible for the pathogenesis of subtypes other than systemic, evidence of autoinflammation is usually pointed out in the pathogenesis of the systemic subtype. Although there are previous studies evaluating JIA patients in terms of other accompanying autoimmune diseases, psychiatric diseases, and cardiovascular diseases, there is a lack of data in the literature to evaluate all comorbidities together.

Objectives: We aimed to evaluate all the comorbidities of our JIA patients and compare the results between those with systemic JIA and those with other subtypes.

Methods: Among the patients with JIA under 21, who were admitted for the routine control between September 2020 and November 2020 were included in the study. Those with additional rheumatic diseases other than JIA and those with less than six months of follow-up duration were excluded from the study. Data were obtained from face-to-face interviews and their medical records cross-sectionally during these three months.

Results: The study included 459 participants (Female: 62.1%) (Systemic JIA group: 57, Non-systemic JIA group: 402). The median age was 12.87 (1.53-20.95) years, and 36.8% (n=169) of the patients were under biologic therapy. About one-third of the patients (n=155) had at least one non-rheumatic disease. The most common comorbidities were allergic rhinitis (n=38, 8.27%), attention deficit-hyperactivity disorder (n=35, 7.62%), atopic dermatitis (n=28, 6.1%), allergic asthma (n=14, 3.05%) and migraine (n=10, 2.17%). While atopic diseases were seen in 16.5% (n=76) of the patients, autoimmune disease frequency was 3.26% (n=15). Although the incidence of autoimmune disease and atopic disease was not significantly different in systemic and non-systemic JIA groups, no autoimmune disease was detected in any patient in the systemic JIA group.

Conclusion: The increased comorbidity burden in JIA patients brings problems of care, follow-up, treatment adherence, and decreased quality of life. This study showed that JIA patients need to be followed up with a multidisciplinary approach. Although autoimmunity was held responsible for the pathogenesis of most subtypes of JIA, it was remarkable that the most common comorbidities were atopic diseases, not autoimmune. On the other hand, none of the detected autoimmune diseases were in the systemic JIA group, and this finding was compatible with the idea of autoinflammation rather than autoimmunity is responsible for the pathogenesis of systemic JIA.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P027. Neutrophils extracellular traps formation may serve as a biomarker for disease activity in oligoarticular juvenile idiopathic arthritis

M. Heshin-Bekenstein^1,2, S. Baron^2,3, G. Schulert⁴, A. Shusterman³, R. Shukrun^2,3, Y. Binenbaum^2,3, R. Elhasid^2,3,5

¹Pediatric Rheumatology, Tel Aviv Medical Center, ²Sackler School of Medicine, Tel Aviv University, ³Pediatric Hemato-Oncology Research Laboratory, Tel Aviv Medical Center, Tel Aviv, Israel, ⁴Division of Rheumatology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States, ⁵Department of Pediatric Hemato-Oncology, Tel Aviv Medical Center, Tel Aviv, Israel

Correspondence: M. Heshin-Bekenstein

Introduction: Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in children, causing significant morbidity. Despite the dramatic improvement in treatment, many patients do not achieve complete remission, and biomarkers for subclinical disease, flares and response to treatment are lacking. Neutrophils and neutrophil extracellular traps (NETs) were revealed to partake in pathogenesis of autoimmune and inflammatory conditions, but their role in JIA pathogenesis and as biomarkers for JIA disease activity are largely unexplored.

Objectives: In this study, we aimed to characterize the neutrophil enzymatic activity and NETs in oligoarticular and polyarticular JIA and explored its association with disease activity.

Methods: Neutrophils from 7 patients with oligoarticular and RF negative polyarticular JIA were isolated at time of diagnosis and after glucocorticoid intraarticular injection with or without DMARD treatment. Enzymatic activity of neutrophil granular enzymes were monitored by colorimentry, while NET formation was assessed using confocal fluorescence microscope.

Results: In oligoarticular JIA patients (n=4), all disease activity parameters and neutrophil function-related parameters decreased following intraarticular steroid injection. However, only three parameters exhibited statistically significant decline, including Physician Global Assessement (PhGA), Juvenile Activity Disease Activity Score-10 (JADAS-10) and clinical JADAS-10 (cJADAS-10). Importantly, NET formation was strongly positivily correlated with the cJADAS-10 at all time points (R=0.93, p=0.007). In polyarticular JIA patients (n=3), neither clinical disease activity parameters, the CRP, or the neutrophil function-related parameters showed consistent and significant decreases after steroid injections. Similarly, there was no significant correlation was found between NETs formation and cJADAS-10 in polyarticular JIA patients.

Conclusion: This is the first study exploring the link between NETs formation and JIA activity. In this pilot study we demonstrated a statistically significant linear correlation between cJADAS-10 and NETs formation in oligoarticular but not in polyarticular JIA patients. Hence, we suggest that NETs might play a role in JIA activity and may serve as a putative biomarker for treatment response. Further work is needed to validate these initial results and determine dynamics of NETosis in JIA.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P028. Functional state of the right ventricle of the heart in adolescents with juvenile idiopathic arthritis

T. Holovko^1,2, N. S. Shevchenko^1,2, L. Bogmat^1,2, V. Nikonova¹

¹Department of rheumatology and comorbid states, SI “Institute for Children and Adolescents Health Care of the NAMS of Ukraine”, ²Department of pediatrics № 2, V.N.Karazin Kharkiv national university, Kharkiv, Ukraine

Correspondence: T. Holovko

Introduction: The relevance of cardiovascular complications in patients with rheumatoid arthritis remains. This is due to the high frequency of vascular accidents (myocardial infarction and stroke) against the background of atherosclerotic vascular lesions, as well as the development of cardiopathy with the formation of heart failure.

The development of chronic heart failure is manifested by a violation of the left ventricle of the heart and, above all, a decrease in its systolic function. The state of the right ventricle is not characterized. However, it is known that the functioning of the left and right ventricles of the heart is closely interconnected due to their common blood supply, the anatomical structure of muscle fibers, the common interventricular septum, pericardium, and innervation.

Objectives: To study the systolic and diastolic function of the right ventricle (RV) of the heart in adolescents with juvenile idiopathic arthritis (JIA).

Methods: 53 patients with polyarticular JIA, mostly girls (69.82%), mean age 13.36±0.39 years, disease duration 68.29±5.67 months were examined. All patients were on basic therapy with methotrexate at a dose of 10-15 mg/m2 of body surface, the average dose was 11.74 ± 0.37 mg/m2, the duration of treatment was 44.64 ± 5.17 months. The obtained results were compared with the indicators of healthy peers comparable in sex and age (54 adolescents, mean age 14.63 ± 0.29 years), who were in the control group.

The study program included an ultrasound study of the morpho-functional state of the heart with Doppler echocardiography using a LOGIO V2 General Electric device (USA), a 3Sc-RS sensor. The systolic function of the right ventricle was characterized by indicators: ejection fraction (EFF), stroke volume (SV), right ventricular minute volume (RV). To assess the diastolic function of the right ventricle, the maximum flow rate in the early diastolic filling phase (E), the flow rate in the late diastolic flow phase (A), their ratio (E/A), the flow rate deceleration time in the early diastolic filling phase (DT) and isovolumetric relaxation time (IVRT).

Results:

Conclusion: The study of RV systolic function in patients with JIA showed a significant decrease in RVF compared with adolescents in the control group, and RV stroke volume and RV minute volume were significantly higher than in healthy children.

Thus, in adolescents with JIA, there is a decrease in the systolic function of the right ventricle, which is accompanied by an increase in the strength of its contraction. There is also a significant increase in the rate of blood flow during the period of late diastolic flow, which indicates the inclusion of cardiac compensatory mechanisms to ensure proper intracardiac hemodynamics.

Disclosure of Interest: None declared

Table 1 (abstract P028). Morphological and functional parameters of the right ventricle of the heart

P029. Α2-fraction and haptoglobin as biomarkers for disease activity in oligo- and polyarticular juvenile idiopathic arthritis

L. Zeller¹, P. Tyrrell², S. Wang², N. Fischer¹, J.-P. Haas¹, B. Hügle¹

¹German Center for Pediatric and Adolescent Rheumatology, Garmisch-Partenkirchen, Germany, ²Department of Statistical Sciences, Institute of Medical Science, Toronto, Canada

Correspondence: B. Hügle

Introduction: Unlike in adult rheumatology, in most forms of juvenile idiopathic arthritis (JIA) no reliable biomarkers currently exist to assess joint and disease activity. However, electrophoresis is frequently changed in active juvenile arthritis.

Objectives: The objective of this study was to evaluate the α2-fraction of serum electrophoresis and its main components as biomarkers for JIA, categories extended/persistent oligoarthritis and seronegative polyarthritis, in comparison with the conventionally used erythrocyte sedimentation rate and C-reactive protein.

Methods: Serum samples and clinical data from 181 patients with JIA were collected. Serum electrophoresis and α2-fraction and its components were determined using standard methods. Relationship between calculated α2-fraction of serum electrophoresis (CA2F) and its components, acute-phase parameters and cJADAS27 was assessed using Pearson’s correlation coefficient and linear regression modelling, adjusting for confounding effects. Results were confirmed in a second cohort with 223 serum samples from 37 patients, using a mixed model to account for repeated measures.

Results: Compared to ESR and CRP, CA2F showed higher correlation to cJADAS27, in particular for persistent oligoarthritis. Of the three components of the α2-fraction, haptoglobin showed the highest correlation to cJADAS27. Regression analysis demonstrated higher ability to predict cJADAS27 for CA2F, and especially for haptoglobin as a component thereof, than for CRP and ESR.

Conclusion: Compared to conventional methods, α2-fraction of serum electrophoresis and specifically, haptoglobin show higher correlations with disease activity in common subtypes of JIA, representing excellent candidates as biomarkers for disease activity. Further studies are necessary to determine diagnostic value and correlations in other subtypes.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P030. Liver stiffness in low-dose methotrexate use in JIA patients

V. Iacomi, N. Revenco, R. Eremciuc

Pediatrics, SUMPh “Nicolae Testemitanu”, Chisinau, Moldova, Republic of

Correspondence: V. Iacomi

Introduction: Evaluation of methotrexate treatment results in JIA patients is challenging in the of absence of validated predicting models or screening methods. The disease activity score is the main reference value in monitoring the therapeutic effects. Low-dose treatment may involve the liver damage that expresses the outcomes.

Objectives: Assessment of the interdependence of JIA disease activity score and the degree of liver fibrosis in children that use low-dose methotrexate.

Methods: Children with JIA who received low-dose methotrexate at least 6 months underwent evaluation by transient unidimensional liver elastography with the M probe. The data results were adjusted according to the EFSUMB guidelines.

Results: Out of 68 JIA who were examined in our clinic, only 50 eligible patients have performed liver elastography. A sample of 38 (76%) were confirmed with the liver stiffness median greater than 4,8 kPa after 24 weeks of methotrexate use (p < 0,005). We noted a substantial decrease in DAS28, up to 1,09 compared to 2,87 (p <0,0005), in children with high liver stiffness. We also noted a decrease in liver stiffness after 144 weeks of methotrexate administration and a remaining low disease activity score for this sample.

Conclusion: Low-dose methotrexate treatment has an impact on the liver stiffness in JIA. This is the toxicity outcome. The use of liver elastography as a method of its evaluation, allows to monitor it in compliance with the disease activity.

Patient Consent: Not applicable (there are no patient data)

Disclosure of Interest: None declared

P031. A clinical case of a patient with down syndrome and juvenile idiopathic arthritis: difficult to diagnose, difficult to treat, difficult to manage severe comorbid problems

K. Zarina, V. Matkava, N. Irina, B. Leonid, A. Svetlana

Pediatric Department, V. A. Nasonova Research Institute of Rheumatology, Moscow, Russian Federation

Correspondence: N. Irina

Introduction: There is a lot of difficulties in the medical management of patient with Down syndrome and joints involvement on the stage of diagnosis, choice of therapy and resolving numerous problems associated with comorbid conditions, including COVID19 infection.

Objectives: To describe the difficulties of caring for a patient with Down’s syndrome and multiple comorbidities who has had a COVID-19 infection.

Methods:Case report: Girl N., 9 years old was admitted to our observation in November, 2021. Diagnosis: Down syndrome; congenital heart defect, high pulmonary hypertension. Grade 2A circulatory insufficiency. Dislocation of left patella, subluxation of right patella Since 2018 she had pain in the wrist, knee, ankle joints and the diagnosis of Down’s arthropathy was suspected. Juvenile idiopathic arthritis (JIA) was diagnosed in March 2020, methotrexate (MTX) was started with insufficient effect. Persistent tendency to leukopenia limited the regular therapy.

Results: The patient had swelling and hypermobility of all joints, inadequate assessment of the patient’s subjective pain perception. There were no laboratory activity, ANA, RF were negative. A Whole-body MRI (WB-MRI) scan detected polyarthritis with synovitis and areas of osteitis, which confirmed the inflammatory origin of the disease. Due to inefficacy of MTX therapy, leukopenia, severe multimorbidity, planned orthopedic surgery and a psychological barrier for use of injections, oral JAK inhibitor Tofacitinib (TOFA) 5 mg BID was chosen. Good results were achieved rapidly. Open reduction of the left patella was performed in January 2022. The early post-operative period was uneventful. Before discharge from the surgical hospital on 1 February a PCR revealed COVID-19 infection, up to 15% lung involvement according to CT, persistent hypercoagulability (D-dimer >10000). Girl was hospitalized in infectious department. She was treated by monoclonal antibodies, Heparin with further switched to Warfarin 5mg/d under INR control (target 2-3). This choice was apparently made due to a previously performed cardiac surgery. Warfarin was continued but adequate INR monitoring was not performed. The spokes were removed at the outpatient orthopedic clinic on 30 March as was planned. The surgeon was not informed about the warfarin treatment. Bleeding from the post-operative wound and haemarthrosis of the left knee were developed a day later. The girl admitted to the ICU in a severe condition with haemorrhagic syndrome, great anaemia, no coagulation. Warfarin an TOFA were withdrawn, blood components transfusion and aspiration of blood from the left knee were done. The condition was improved. In May 2022 the girl was admitted to our center with the clinical picture of JIA exacerbation. Control WB-MRI showed inflammatory lesions with polyarthritis, increased areas of osteitis. Due to the positive effect of earlier therapy with TOFA and the negative dynamics of interrupted treatment, the decision was made to continue treatment with TOFA. In addition, for the preventing of infectious complications intravenous immunoglobulin at the dose of 0.2 mg/kg was added to the treatment.

Conclusion: In this case we met a lot of problems and obstacles regarding to diagnosis verification and choice of medicine. WB-MRI is a useful tool for identifying the inflammatory origin of arthritis in a child with Down syndrome. Peroral TOFA is preferred for patients with multimorbidity and intolerance to injections. It extremally important to keep good coordination between doctors and parents, especially in case of life-threatening condition during COVID-19 pandemic. Because of the high risk of hospital-acquired COVID-19, it is recommended to postpone any planned surgery, as possible.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P032. Ana status is not associated with altered b cell subset distribution in the peripheral blood and synovial fluid of JIA patients

B. Jebson^1,2, N. de Gruijter^1,3, M. Kartawinata^1,2, V. Alexiou^1,2, L. Wedderburn^1,2,4,5, E. Rosser^1,3

¹Centre for Adolescent Rheumatology Versus Arthritis at UCL, UCL, UCLH, GOSH, ²UCL GOS Institute of Child Health, ³Centre for Rheumatology, Division of Medicine, UCL, ⁴Great Ormond Street Hospital for Children NHS Trust, NHS, ⁵NIHR Biomedical Research Centre at GOSH, NIHR, London, United Kingdom

Correspondence: B. Jebson

Introduction: In Juvenile Idiopathic Arthritis (JIA), many patients are positive for autoantibodies known as anti-nuclear antibodies (ANA), which are secreted by B cells. Production of ANA is a hallmark of a breakdown in B cell tolerance and cellular dysregulation. Despite this, B cell biology remains understudied in JIA and the mechanisms controlling ANA production, and their contribution to pathogenicity, remain unclear.

Objectives: To assess whether B cell phenotype is altered in the peripheral blood mononuclear cells (PBMC) and synovial fluid mononuclear cells (SFMC) of JIA patients compared to PBMC from age-matched healthy children and whether altered B cell subset distribution is associated with ANA status.

Methods: B cell phenotype was analysed based on CD19, CD24 and CD38 expression using multiparameter flow cytometry analysis and was performed on PBMC from JIA patients (n=185), age-matched healthy controls (n=37) as well as SFMC from JIA patients (n=52, n=47 of which were paired with blood samples from the same patient). JIA patients were further stratified by ANA titre with levels of ≥1:160 being positive and <1:80 negative tested at Great Ormond Street Hospital (PBMC n=117 ANA+, n=56 ANA-), (SFMC n=24 ANA+, n=16 ANA-). Where ANA status was not available, patients were excluded from later analysis.

Results: In our large cohort, the frequency of total B cells (CD19+) was significantly higher within PBMC of JIA patients compared to healthy control samples (p=0.0004). There were also higher levels of immature B cells (CD19^posCD24^hiCD38^hi, p=0.0037) and lower levels of memory B cells (CD19^posCD24^hiCD38^lo, p=0.0104) within PBMC of JIA patients compared to healthy controls. In agreement with previously published data¹, when comparing B cell phenotype between JIA PBMC and SFMC, we observed that there were significantly higher levels of ‘atypical’ (CD19^posCD24^loCD38^lo, p=<0.0001) memory B cells, memory (CD19^posCD24^hiCD38^lo, p=<0.0001) B cells and plasmablast (CD19^posCD24^loCD38^hi, p=<0.0001) within JIA SFMC. Interestingly, despite a recently published study describing B cell subset differences in the SFMC of ANA+ JIA patients compared to ANA- patients², using our B cell phenotyping strategy we found no differences in the frequency or phenotype of PBMC and SFMC B cells in this cohort of ANA+ and ANA- JIA patients.

Conclusion: In this JIA cohort, we found that there were B cell subset abnormalities in patients versus controls, but that these differences were independent of ANA. These data suggest that mechanisms other than altered B cell subset distribution are driving a breakdown of B cell tolerance and ANA production in JIA. Uncovering these mechanisms will form the basis of our future work.

REFERENCES

1. Corcione, A. et al. Phenotypic and functional characterization of switch memory B cells from patients with oligoarticular juvenile idiopathic arthritis. Arthritis Research & Therapy11, R150 (2009).

2. Dirks, J. et al. CD21lo/−CD27−IgM− Double-Negative B Cells Accumulate in the Joints of Patients With Antinuclear Antibody-Positive Juvenile Idiopathic Arthritis. Frontiers in Pediatrics9, 143 (2021).

Patient Consent: Yes, I received consent

Disclosure of Interest: B. Jebson: None declared, N. de Gruijter: None declared, M. Kartawinata: None declared, V. Alexiou: None declared, L. Wedderburn Grant / Research Support with: MRC, Versus Arthritis, GOSCC, AbbVie, GSK, UCB, Sobi, Pfizer, Novartis, Lilly, Sobi, E. Rosser Grant / Research Support with: NIHR BRC

P033. Juvenile psoriatic arthritis: data from the pera psoriasis study group

S. G. Karadağ¹, T. Coşkuner², F. G. Demirkan³, H. E. Sönmez⁴, S. Özdel⁵, M. Çakan², G. Otar Yener⁶, K. Öztürk⁷, F. Demir⁸, B. Sözeri², N. Aktay Ayaz³

¹Pediatric Rheumatology, University of Health Sciences, Basaksehir Cam and Sakura City Hospital, ²Pediatric Rheumatology, University of Health Sciences, Ümraniye Research and Training Hospital, ³Pediatric Rheumatology, Istanbul University, Faculty of Medicine, İstanbul, ⁴Pediatric Rheumatology, Kocaeli University, Faculty of Medicine, Kocaeli, ⁵Pediatric Rheumatology, University of Health Sciences, Sami Ulus Maternity and Children’s Diseases Training and Research Hospital, Ankara, ⁶Pediatric Rheumatology, Şanlıurfa Training and Research Hospital, Şanlıurfa, ⁷Pediatric Rheumatology, Istanbul Medeniyet University, Göztepe Prof. Dr. Süleyman Yalçın City Hospital, ⁸Pediatric Rheumatology, Acıbadem Healthcare Group, İstanbul, Turkey

Correspondence: S. G. Karadağ

Introduction: Juvenile psoriatic arthritis (JPsA) is one of the 7 subtypes of juvenile idiopathic arthritis (JIA) according to the International League of Associations for Rheumatology (ILAR) classification criteria. JPsA is the rarest subgroup of JIA, so the corresponding literature describing the clinical characteristics, long-term outcomes, or treatment status of JPsA is limited

Objectives: To describe demographic and clinical features of children with JPsA and to compare distinct patterns of the disease between early onset and late onset groups.

Methods: Patients classified as JPsA according to ILAR criteria in 7 different pediatric rheumatology centers and followed regularly for at least 6 months between 2010 and 2020 were included in the study. The files of the patients were reviewed retrospectively, and their demographic, clinical and treatment characteristics were evaluated.

Results: A total of 87 (46 male/41 female) patients were included in the study. The mean age at diagnosis of JPsA was 11.9 ± 4.5. While 57 (65.5%) of the patients had psoriasis at the time of diagnosis, arthritis preceded psoriasis in 10 (11.5%) patients. There were 32 (36.8%) patients with a history of psoriasis in the first-degree relatives. Thirty (34.5%) patients had dactylitis, 28 (32.2%) had nail pitting, 36 (41.4%) had small joint involvement, 20 (23%) had enthesitis, and 14 (16.1%) had axial involvement. Sacroiliitis was detected in 11 (12.6%) patients on magnetic resonance imaging. Uveitis developed in 4 (4.5%) patients during the follow-up period. Anti- nuclear antibodies (ANA) were positive in 35 (40.2%) patients. Twelve children were in the early-onset (<5 years) group. Uveitis and ANA positivity were more common in the early early-onset group.

Conclusion: About one-third of patients with JPsA do not have psoriasis at the time of diagnosis. In some patients, no skin lesion is seen during the course of the disease. Children with psoriatic arthritis seem to displaying two different phenotypes. Younger children tend to have female predominance, ANA positivity and uveitis, while older children have more axial involvement .

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P034. Investigation of physical activity levels of patients with juvenil idiopatic arthritis era COVID 19

E. P. Kısa¹, E. Tarakcı², G. Leblebici³, Ö. Kasapçopur⁴

¹Department of Physiotheraphy and Rehabilitation,Health Science Faculty, Biruni University, ²Physiotheraphy and Rehabilitation,Health Science Faculty, İstanbul University- Cerrahpasa, ³Department of Physiotheraphy and Rehabilitation,Health Science Faculty, Medeniyet University, ⁴Department of Pediatric Rheumatology, Cerrahpaşa Faculty of Medicine, İstanbul University- Cerrahpasa, İstanbul, Turkey

Correspondence: E. P. Kısa

Introduction: Childhood rheumatic diseases are a group of diseases that can affect many organs and systems with problems such as pain, joint stiffness, atrophy and weakness. The presence of physical inactivity is one of the most frequently reported conditions. Exercise and physical activity are recognized as an important part of the treatment of children with rheumatic disease. Physical inactivity and the accompanying sedentary lifestyle aggravate problems common in pediatric rheumatic diseases such as weakness, atrophy and muscle dysfunction, chronic pain, fatigue, bone loss, insulin resistance, and decreased health-related quality of life. Conversely, some of these symptoms create a fear of the thought that physical activity may cause an exacerbation of the disease and may be significant barriers to increasing physical activity. In addition to all these problems we have already encountered in the course of the disease, the increase in the time spent at home due to the Covid-19 pandemic has made these problems even more evident.

Objectives: The aim of the study was to examine the physical activity levels of children with Juvenile Idiopathic Arthritis in the COVID 19 era and to compare them with their healthy peers.

Methods: Fifty-five patients with a diagnosis of oligoarticular JIA, aged 7-18 years, who applied to the Istanbul University-Cerrahpaşa Pediatric rheumatology clinic, and 52 healthy controls in the same age group were included. Participants were invited to the study by making an announcement. All participants were informed about the purpose and procedure of the study before the evaluation. The participant statement was read to the families of all participants included in the study.

The sociodemographic characteristics of the participants (age, gender, height, body weight, disease duration, joint involvement, exercise habits) were evaluated with a sociodemographic questionnaire. Pain status and general well-being level in activity status were questioned with the Visual Analogue Scale (VAS). Physical activity levels and energy expenditure levels were evaluated with the 1-day physical activity scale (1-day activity diary), and functional levels were evaluated with the Childhood Health Assessment Questionnaire (CHAQ). Statistical analysis was performed using SPSS for Windows (Statistical Package ort he Social Sciences-24.0, Inc., Chicago, IL). P≤0.05 was considered statistically significant in all analyzes.

Results: Fifty-five patients and 52 controls with a mean age of 12.43±6.33 and 13.24±3.17 years, respectively, were included. The mean disease duration was 4.5 years. Compared to the control group, the JIA group had significantly less time in physical activity (p=0.001), decreased energy expenditure (p=0.042), and higher CHAQ scores (p=0.001) (Table 1).

Conclusion: This study demonstrated that children with JIA had significantly lower levels of physical activity, energy expenditure, and functional ability during the COVID-19 pandemic than healthy controls. It has been revealed that patients with JIA who have low physical activity levels due to pain, fatigue and fear of avoiding movement are more inactive duege to inevitable reasons during the pandemic process. This result shows us that children need correct guidance to use the time they stay at home more efficiently in order to increase their physical activity level.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

Table 1 (abstract P034). See text for description

P035. Serum calprotectin (S100A8/A9): a promising biomarker of activity and erosive changes in different subtypes of juvenile arthritis

A. Kozhevnikov^1,2, N. Pozdeeva¹, S. Vissarionov¹, S. Bogdanova¹, G. Novik²

¹H.Turner National Medical Research Center for Сhildren’s Orthopedics and Trauma Surgery, ²Saint-Petersburg State Pediatric Medical University, Saint-Petersburg, Russian Federation

Correspondence: A. Kozhevnikov

Introduction: Juvenile arthritis (JA) is an autoimmune inflammatory joint disease. Some laboratory tests neither rule in nor rule out juvenile arthritis. An elevated ANF titer is not a diagnostic criteria for JA. C-reactive peptide and erythrocyte sedimentation rate can be normal despite marked involvement of arthritis. Calprotectin is a heterodimeric complex of S100A8/9 (MRP8/14) has been proposed as serum biomarker that reflects disease activity (J.Hurnakova et al., 2015; T. Marushko et al., 2019; Y. Boyko et al., 2020; M. Romano et al., 2021).

Objectives: The aim of this study was to test the hypothesis that calprotectin is associated with structural joint damage and reflects disease activity in children with juvenile arthritis.

Methods: We evaluated the level of serum calprotectin in 70 children with JIA and 20 adolescents with non-rheumatic joint pain. All children fulfilled the ILAR criteria for JIA. 50 children had active JIA, 17 of them had oligoarticular disease subtype (oJA, mean age 7,2±2,2 years), 15 – polyarthritis (pJA, mean age 9±2,3 years), 18 – enthesitis-related arthritis (erJA, mean age 13±2,7 years). 20 children were with inactive disease by DMARDs. Quantitative indicators distribution is given as a median [5th; 95th percentile]. Clinical data, radiology and laboratory results (serum Calprotectin level/sCal, Vimentin, serum IL6/sIL6, serum TNF-alpha/sTNF) were collected and evaluated in all 90 children.

Results: Level of sCal in the active oJA was 2,61 μg/ml [1,015; 3,935], inactive oJA was 1,258 μg/ml [0,772; 2,254], active pJA was 5,845 μg/ml [3,408; 8,005], inactive pJA was 1,36 μg/ml [0,678; 2342], active erJA was 2,98 μg/ml [0,897; 6,876], inactive erJA was 0,94 μg/ml [0,429; 1,92]; sCal level in children with non-rheumatic joint pain was 1,288 μg/ml [0,513; 2,364]. All children with active JIA were divided into three groups depending on their treatment and aggressive disease. 1^st gr – consist of 12 children with non-erosive erJA (JADAS10-ESR 3.2 – 4.6), 2^nd gr – 16 children with erosive JA which start to therapy of methotrexate (4 erJA /10 oJA /2 pJA, JADAS10-ESR 4.8 – 8.2), 3^rd gr - 22 children with erosive JA which switch to anti-TNF drugs (2 erJA /7 oJA /13 pJA, JADAS10-ESR > 13). In the 1^st group sCal level were 1,0175 μg/ml [0,45; 2,378], sIL6 - 2,94 pg/ml [1,549; 5,617], Vimentin - 9,872 U/ml [3,87; 18,81], sTNF - 1,144 pg/ml [0,397; 3,757]. In the 2^nd sCal level were 3,81 μg/ml [2,48; 5,992], sIL6 16,15 pg/ml [1,769; 48,85], Vimentin - 13,632 U/ml [2,319; 44,492], TNF - 1,18 pg/ml [0,204; 3,54]. In the 3^rd sCal level were 4,828 μg/ml [2,93; 7,954], sIL6 - 11,048 pg/ml [1,5; 33,7], Vimentin - 17,22 U/ml [4,212; 52,1], TNF - 10,5 pg/ml [0,5; 50,43]. Statistic analysis were revealed a correlation between sCalc and active erosive JA (R² = 0.4159, T = 4.336, OR erosive JA = 3.3193, 95%CI 1,7006-6.4789, p=0.0079). Serum Level of vimentin, IL6 and TNF-alpha were not correlated with active stage JA and erosive joint damage. The ROC analysis of the sCalc showed that a cut-off point more of 2,9 μg/ml may be high prognostic factor for related erosive JA (AUC 0,837±0,0553, 95%CI 0,711-0.923).

Conclusion: The serum levels of calprotectin are significantly associated with oligo and polyarticular JA disease activity. These results suggest that calprotectin might be superior to serum IL6 and TNF-alpha for erosive joint damage in children with JA.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P036. Disease activity assessment for juvenile idiopathic artritis in transitional care

F. La Torre¹, F. Cardinale¹, M. G. Anelli², F. Cacciapaglia², G. Lopalco², F. Iannone²

¹Department of Pediatrics, Pediatric Rheumatology Center, Giovanni XXIII Pediatric Hospital, University of Bari, ²Department of Emergency and Organs Transplantation (DETO), Rheumatology Unit, University of Bari, Bari, Italy

Correspondence: F. La Torre

Introduction: Although Juvenile Idiopathic Arthritis and Rheumatoid Arthritis have well-defined disease activity scores, there is no validated score during transition. In clinical practice a patient with JIA who transfer to the adult rheumatologists is evaluated with the disease activity scores validated for RA (DAS28, SDAI and CDAI) and not for JIA.

Objectives: Given the differences between the “scores” used in adulthood and pediatric age, the primary objective of our study was to identify which of those scores was the best one in assessing disease activity for JIA during transitional care.

Methods: Data from all cases of Juvenile Idiopathic Arthritis (JIA) with almost one year of transition follow-up, older than 16 years at time of baseline visit, were collected. In each visit (at baseline and after 12 months of follow-up) we calculated the disease activity scores used in childhood (JADAS and cJADAS) and in adulthood (DAS28, SDAI and CDAI). Because JADAS10 and JADAS27 may have a joint count lower than the active joints in a subject with polyarticular JIA, and since the need to identify a single score to correlate to the adult ones, JADAS71 was chosen. The linear regression model has been applied to continuous variables. For the discrete variables, instead, the Kendall’s tau test was used. For both methods the concordance is poor between 0-0.4; it’s fair between 0.4-0.6; it’s good between 0.6-0.8 and finally if it assumes values between 0.8-1 the agreement is excellent.

Results: We recruited 26 patients with JIA, 11 patients were Polyarticular (42.3%) and 15 patients were Oligoarticular (53.1%). No patient was lost during the follow-up. All the disease activity scores were calculated at baseline and 12-month evaluation. The linear regression analysis was used to correlate continuous variables (applied to the values expressed in mean ± SD) and the results were expressed as R-square. The R-square value was 0.690 for the correlation between JADAS71 and DAS28; 0.865 for the correlation between JADAS71 and SDAI; 0.809 for the correlation between JADAS71and CDAI (Table). To correlate the discrete variables (expressed as a percentage) the Kendall’s tau test was used; the cutoffs for correlation are the same seen for R-square in the linear regression analysis. The Kendall’s tau value was 0.797 for the correlation of JADAS71 with DAS28 and 0.788 between cJADAS71 and DAS28; 0.831 for the correlation with SDAI both for JADAS71 and cJADAS71; and 0.831 for the correlation of JADAS71 with CDAI and 0,813 between cJADAS71 and CDAI (Table).

Table shows the correlation between JADAS71 and cJADAS71 to the other scores used in adulthood (DAS28, SDAI, CDAI).

Conclusion: Our study confirms that the Simplified disease activity score(SDAI)is the adult score that correlates better with JADAS71. This best agreement is expressed by excellent correlation evaluated by linear regression with R-square value for continue variables (0.865) and with of k (Kendall’s) value for discrete variables (0.831). New prospective studies for disease activity score in transitional care with a large number of patients will be needed to confirm these preliminary results.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

Table 1 (abstract P036). See text for description

P037. Patterns of biological switching among children with non-systemic juvenile idiopathic arthritis

M. Lindegaard Pedersen¹, A. Neve-Græsbøll², M. Bonde Glerup², T. Herlin²

¹MP and AG contributed equally to the study and shares the first authorship. Department of Paediatrics and Adolescent Medicin, ²Department of Paediatrics and Adolescent Medicin, Aarhus University Hospital, Aarhus N, Denmark

Correspondence: M. Lindegaard Pedersen

Introduction: With the advent of biological agents (BA) for the treatment of patients with juvenile idiopathic arthritis (JIA) achievement of remission has become a realistic goal. However, clinical remission is unattainable in some patients despite BA therapy and switching to another BA is required. The best choice of second-line BA remains unclear.

Objectives: This retrospective observational study aims to describe the pattern, timing, frequency, and reasons for BA switching among children diagnosed with non-systemic JIA treated at Aarhus University Hospital, Denmark.

Methods: Patients were identified by combining unique personal identification numbers, the International Code of Diagnosis (ICD10) for JIA and biologic therapy: Etanercept, adalimumab, golimumab, infliximab, anakinra, canakinumab, tocilizumab, abatacept, rituximab, tofacitinib and baricitinib. Clinical characteristics were collected retrospectively from the electronic medical records. 200 children diagnosed with non-systemic JIA who started their first biologic drug between January 1st, 2012, and March 1st, 2021, were included in the study. We compared characteristics of non-switchers vs switchers and early switchers (≤6 months) vs late switchers (>6 months).

Results: We found that 37% switched to a different BA after median 6.3 (3.8-9.4) years after diagnosis and 17.5% of patients switched at least twice. In total, 6% of patients switched three or more times. The most common reason for switching was inefficacy (57%) followed by injection/infusion reactions (15%) and uveitis (13%). 77% were late switchers, and switched primarily due to inefficacy, and 23% were early switchers who switched more often due to other reasons (61%). All patients started a tumor necrosis factor inhibitor (TNFi) as initial BA (etanercept (ETN): 49.5%, other TNFi: 50.5%). The patients who started ETN as first-line BA were more likely to be switchers compared to those who started another TNFi.

Conclusion: During a 6-year observation period biologic switching was observed in more than one third, primarily due to inefficacy.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

Table 1 (abstract P037). Clinical characteristics among biologic switchers and non-switchers in juvenile idiopathic arthritis (JIA)

P038. Normal neonatal TREC and KREC levels in early onset juvenile idiopathic arthritis

J. A. Gudmundsdóttir¹, S. Thorgeirsdóttir², V. Lundbäck³, C. Göngrich³, J. Lingman Framme², K. Rydenman², E. Kindgren⁴, B. R. Ludviksson⁵, S. Nilsson⁶, R. Zetterström³, O. Ekwall⁷, S. Lindgren^2,7

¹Children’s Medical Cente, Landspitali, Reykjavik, Iceland, ²Department of Pediatrics, Institute of Clinical sciences, Göteborg, ³Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, ⁴Division of Pediatrics, Biomedical and Clinical Sciences, Linköping, Sweden, ⁵Department of Immunology, Landspital, Reykjavik, Iceland, ⁶Department of Mathematical Sciences, Chalmers University of Technology, ⁷Department of Rheumatology and inflammation research, Institute of Medicin, Göteborg, Sweden

Correspondence: S. Lindgren

Introduction: Disturbed central tolerance mechanisms predispose to autoimmune diseases. Reduced thymic output as well as compromised central B cell tolerance checkpoints have been proposed in the pathogenesis in juvenile idiopathic arthritis (JIA).

Objectives: The aim of this study was to investigate neonatal levels of T cell receptor excision circles (TRECs) and kappa-deleting element excision circles (KRECs), as markers of T- and B-cell output at birth, in patients with early onset JIA.

Methods: TRECs and KRECs levels were quantitated by multiplex qPCR from dried blood spots (DBS), collected 2-5 days after birth, in 156 children with early onset JIA and 312 matched controls.

Results: When analysed from neonatal dried blood spots, the median TREC level was 78 (IQR 55-113) in JIA cases and 88 (IQR 57-117) copies/well in controls. The median KREC level was 51 (IQR 35-69) and 53 (IQR 35-74) copies/well, in JIA cases and controls, respectively. Stratification by gender and age at onset of disease did not reveal any difference in the levels of TRECs and KRECs.

Conclusion: T- and B-cell output at birth, as measured by TRECs and KRECs levels in neonatal dried blood spots, does not differ in children with early onset JIA compared to controls.

Patient Consent: Not applicable (there are no patient data)

Disclosure of Interest: None declared

P039. Temporomandibular Joint (TMJ) involvement in Juvenile Idiopathic Arthritis (JIA) at disease onset: a rheumatologist’s, orthodontist’s and radiologist’s joint venture

S. Giancaspro^1,2, G. Tarantino³, P. Festa^2,4, G. Vallogini², L. M. Gregori⁵, D. Pires Marafon³, A. Aquilani³, R. Nicolai³, E. Marasco³, F. De Benedetti³, V. Quinzi¹, A. Galeotti², S. Magni-Manzoni³

¹Dep.of Health, Life and Environmental Science, University of L’Aquila, L’Aquila, ²Dentistry Unit, IRCCS Bambino Gesù Children’s Hospital, ³Rheumatology, IRCCS Bambino Gesù Children’s Hospital, Rome, ⁴AORN Santobono-Pausilipon, Naples, ⁵Imaging Dep., IRCCS Bambino Gesù Children’s Hospital, Rome, Italy

Correspondence: S. Magni-Manzoni

Introduction: TMJ arthritis in JIA often occurs asymptomatic in the initial stages. The frequency of TMJ involvement at JIA onset has been scarcely investigated.

Objectives: To assess in a multidisciplinary approach the frequency of TMJ involvement in a prospective cohort of patients at JIA onset; to describe demographic and clinical features of JIA patients with TMJ involvement at JIA onset and follow up.

Methods: Consecutive patients at JIA onset in a single tertiary care centre, who provided consent, underwent rheumatologic and orthodontic assessments. Demographic, clinical features and joint counts were registered by rheumatologists. Diagnostic Criteria for Temporomandibular Disorders (DC/TMD) Axis I and Axis II assessment protocol was runned in each patient in separate orthodontic examination. The following features were registered by consensus of at least two orthodontists: presence and type of myalgia of the masticatory muscles, myofascial pain, TMJ arthralgia, TMJ associated headache, disc displacement, intermitted locking, limited opening, clinically detectable osseous changes, subluxation. The overall orthodontic assessment required 50-60 minutes. Results of the rheumatologic and orthodontic evaluations in each patient were regularly discussed in periodic multidisciplinary meetings for the definition of the subsequent diagnostic and therapeutic program. Only patients with time frame of less than 8 weeks between rheumatologic and orthodontic assessment were included in the analysis. Descriptive statistics was used.

Results: One hundred and fifteen patients at JIA onset seen at the study centre from 2018 to 2021 were invited to participate. Twenty-three (22%, 78% female) performed complete rheumatologic and orthodontic assessment maximum 2 months apart; 66% and 30% were respectively affected by oligoarticular and polyarticular RF-negative JIA subtype, and presented a median age at disease onset of 5.2 years (IQR 2.8-8.5). Five patients (22%) showed at least one pathologic feature at the DC/TMD assessment; 3 of them presented any TMJ sign/symptom also at the rheumatologic examination. TMJ MRI investigation was required in one patient (female, oligo JIA, of 9 years of age), with confirmation of TMJ active involvement. MRI follow up after 11 months, with meaningwhile subcutaneous methotrexate and TNF-inhibitor treatment, showed structural improvement and no disease progression. At the last follow up, after a median of 24 months (IQR 7-27), only 2 of the 5 JIA patients with baseline pathological signs/symptoms still presented clinically detectable TMJ involvement, with no progression; 1 patient negative for TMJ involvement at JIA onset (6%) reported mild TMJ symptoms at the last follow up visit, with no indication to imaging exam or medical treatment.

Conclusion: Though the relatively low rate of combined rheumatologist’s and orthodontist’s assessment in the study cohort, TMJ involvement was detected in a relatively high proportion of patients at JIA onset. Joined efforts are required for increasing the performance of the clinical and imaging tools for quick identification and treatment of this potential invalidating feature of JIA. Improvement in the feasibility of the diagnostic investigations are also urgently required.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P040. Factors increasing the risk of flare in JIA with inactive disease under MTX monotherapy

R. Isguder, Z. Kizildag, R. Torun, T. Aydın, B. Makay, S. E. Unsal

Pediatric Rheumatology, Dokuz Eylül University Faculty of Medicine, IZMIR, Turkey

Correspondence: R. Isguder

Introduction: Juvenile idiopathic arthritis (JIA) is a chronic and heterogeneous disease causing structural changes in the joints. Treatment aims to stop inflammation, relieve pain, maintain joint function, prevent damage, and suppress disease activity. As treatment options increase, maintenance of drug-free inactive disease (ID) has gained more importance. Methotrexate (MTX) is the most commonly used agent among synthetic DMARDs in JIA. Nevertheless, there is no consensus on how and when to stop MTX to maintain drug-free remission after ID. Factors that increase the risk of flare, apart from the drug withdrawal strategy are also unclear.

Objectives: To determine the factors that increase the risk of disease flare in patients with JIA who stopped MTX monotherapy following inactive disease.

Methods: Files of all JIA cases between 1992-2022 were examined retrospectively. Patients who stopped MTX monotherapy following inactive disease were evaluated. Patients with disease flare and ongoing ID were compared.

Demographic data, JIA subgroup, age of disease onset, autoantibodies, acute phase reactants, MTX dose and administration route, MTX discontinuation method, and time interval were recorded.

Results: Among the files of 1,036 patients with JIA, a total of 333 patients were identified as MTX monotherapy, and ID was achieved in 138 (41.5%). Among 138 patients, 105 (76%) were female and median age was 5.8 years. Oligoarticular JIA was the most frequent type. Other subtypes included polyarticular JIA, systemic-onset JIA (SoJIA), and juvenile psoriatic arthritis (JpsA) (Table-1). Patients reached ID in median 7.9 months after starting MTX, and MTX treatment was discontinued median 1.02 year after ID.

The disease flare developed in 67 (48.6%) of the cases. The ID continued in 71 patients (51.4%) (Table-1). The flare developed median 1.6 years after ID and median 8.8 months after discontinuation of MTX. The follow-up period of cases with persistent inactive disease was 3.06 years.

The age at disease onset and at diagnosis were lower in the group with flare, and SoJIA cases were less frequent in this group. The anti-nuclear antibody (ANA) positivity was more frequent in cases with flare. At MTX initiation visit, the median C-reactive protein (CRP) value in the group with the flare was found to be higher compared to the patients with ongoing ID (Table-1).

The risk of flare increased in cases with a CRP value above 6.7 mg/L at the onset of MTX, age at disease onset below 5.1 years, and age at diagnosis below 5.9 years.

There was no difference between the two groups in terms of MTX dose and administration route, the duration to reach inactive disease, MTX discontinuation time, and method.

Conclusion: In this study, risk of flare was associated with early disease onset, ANA positivity and high CRP values at the beginning, rather than the administration and discontinuation method of MTX.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

Table 1 (abstract P040). Comparison of “flare” and “persistent ID” groups

P041. Charcot’s neuropathic arthropathy – when no pain is not pleasure!

N. Maldar, A. Khan, A. Prabhudesai, R. Khubchandani

Pediatric Rheumatology, NH SRCC Children’s Hospital, Mumbai, India

Correspondence: N. Maldar

Introduction: Charcot’s neuropathic osteoarthropathy (CNA) is a rare eponymous condition associated with autonomic sensory neuropathy, first described in 1868. Warm, painless boggy joints and instability, erosive arthropathies, chronic osteomyelitis and deformities are the predominant manifestations. Differentials are congenital insensitivity to pain and anhidrosis (CIPA), familial dysautonomia(Riley-Day syndrome), hereditary sensory motor neuropathy (Charcot-Marie-Tooth disease), traumatic nerve injuries, syringomyelia and meningomyelocele. CIPA is caused by mutations in NTRK1 gene and is classified as type IV hereditary sensory and autonomic neuropathy according to the Dyck’s classification.

Objectives: We present a case series of 3 CNA misdiagnosed as inflammatory/infective conditions.

Methods: Case 1: 18 months-old girl born of third-degree consanguinity, presented with low grade fever, tender hard swelling around the right shoulder extending to the distal forearm with palmoplantar skin rash. Suspecting hereditary autoinflammatory bone disease with chronic non-bacterial osteomyelitis as a feature, a clinical exome was performed. On reverse phenotype corelation there was history of self-mutilation, absence of pain during immunization with anhidrosis.Case 2: An 8-year-old boy was referred for fever and right ankle swelling, misdiagnosed as JIA, was on steroids and disease modifying drugs. There were hyperkeratotic lesions on both heels and large warm, boggy left ankle swelling albeit with a full and painless range of motion. Neurological evaluation suggested gait disturbance, normal muscle power, intact temperature and deep tendon reflexes with insensitivity to pain. Suspecting a syndromic arthropathy, a whole exome was sent.

Case 3: 7-year-old boy had trauma induced fracture in distal shaft of left tibia. In a few months, this was followed by painful swelling that progressed into chronic osteomyelitis of tibia. He had a limp, boggy left ankle, high steppage gait with foot drop and reduced sensations in the affected foot. He was treated by debridement with saucerization of left distal tibia with common peroneal nerve release.

Results:

Conclusion: While traditional teaching includes Blau syndrome and pigmented villonodular synovitis as differentials of a large boggy warm joint, addition of the adjective painless, should bring to mind CNA. This entity may remain undiagnosed for long and be mistaken for commoner rheumatological entities. Management consists of counselling regarding the disease, need for orthotics and prevention of accidental or thermal injuries. Simple questions pertaining to pain perception, sweating, local hair loss and bedside neurological evaluation easily provide the diagnosis.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

Table 1 (abstract P041). See text for description

P042. Predicting drug-free inactive disease two years after diagnosis of non-systemic juvenile idiopathic arthritis

M. Mannion¹, C. Chen², O. Halyabar³, S. Paetkau⁴, T. Qui², B. Huang² on behalf of for the PR-COIN Investigators

¹University of Alabama at Birmingham, Birmingham, ²Division of Biostatistics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, ³Boston Children’s Hospital, Boston, MA, United States, ⁴parent, Hospital for Sick Children, Toronto, Canada

Correspondence: M. Mannion

Introduction: The goal of treatment for juvenile idiopathic arthritis (JIA) is inactive disease (ID). The best treatment for each patient to maximize ID and minimize overtreatment is unknown.

Objectives: The objective of this study was to assess if clinical measures could predict the onset of ID or drug-free inactive disease (DFID) within 2 years of diagnosis of non-systemic JIA.

Methods: Using an inception cohort from a large pediatric rheumatology clinic in the US from 2009 to 2020, we identified patients with non-systemic JIA in the electronic health record (EHR) with ≥ 2 clinical visits and ≥ 2 years of follow up following diagnosis. JIA category at baseline is reported; oligoarticular (oligo), rheumatoid factor (RF) - polyarticular (poly), RF+ poly, and all other non-systemic. Medications were classified into systemic corticosteroids, non-biologic (nb) disease modifying anti-rheumatic drug (DMARD), biologic (b) DMARD, and intra-articular corticosteroid injections. ID was defined as no active joint count (AJC), no enthesitis, no active uveitis, and physician global (PGA) <1. Descriptive statistics and Kaplan-Meier curves for time to ID and DFID were calculated based on baseline characteristics. Cox Proportional hazard (CoxPH) modeling was used to evaluate the effect of baseline characteristics and 1^st year medication use on onset of ID and DFID.

Results: 605 patients with JIA were included (Table). By 1(2) years post diagnosis, 52(73)% and 28(42)% achieved ID and DFID respectively. Time to 1^st ID or DFID is significantly different (Log-rank test P=0.001 for ID; P<.0001 for DFID) by category; median (95% CI) time to ID and DFID in oligo 0.76 years (0.63, 0.90), 1.65 (1.08, 2.24), RF- poly 1.23 (1.01, 1.49), 5.05 (3.21, 7.83), RF+ poly 1.36 (0.63, 2.79), >2.22, and other types 0.90 (0.73, 1.18), 2.87 (1.99, 4.67). Of 30 RF+ poly patients only 10 achieved DFID, the median time to DFID could not be estimated. JIA category was not significant in multivariable CoxPH analyses, but lower clinical juvenile disease activity score (cJADAS), shorter time from symptoms to diagnosis, and private insurance were significantly associated with sooner time to ID and DFID. Less DMARD use (b and nb) was associated with sooner DFID, but more bDMARD use was associated with sooner ID.

Conclusion: In the two years after diagnosis, 73% of JIA patients achieved ID and 42% achieved DFID. There are disease characteristics associated with sooner time to ID and DFID, but further research is needed to predict medication needs for patients with JIA.

Patient Consent: Not applicable (there are no patient data)

Disclosure of Interest: M. Mannion Grant / Research Support with: Rheumatology Research Foundation Norman B Gaylis, MD Clinical Investigator Award, C. Chen: None declared, O. Halyabar: None declared, S. Paetkau: None declared, T. Qui: None declared, B. Huang: None declared

Table 1 (abstract P042). Disease and treatment characteristics stratified by ILAR classification. Values are median (IQR) or n (%). Medication use is in the 12 months after diagnosis. All p-values <0.0001

P043. Short term outcomes following tolerated disease activity level for individuals with juvenile idiopathic arthritis in the childhood arthritis and rheumatology research alliance registry

M. L. Mannion, F. Xie, T. Beukelman, J. R. Curtis on behalf of for the CARRA Registry Investigators

University of Alabama at Birmingham, Birmingham, United States

Correspondence: M. L. Mannion

Introduction: Current recommendations suggest treatment escalation for juvenile idiopathic arthritis (JIA) until the disease activity target is reached.

Objectives: We compared patient reported outcomes (PRO) 6 months after maximally tolerated disease activity level.

Methods: We included all individuals enrolled with non-systemic JIA in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry. We defined the maximally tolerated disease activity at the registry visits with no medication change for >180 days prior. Individuals could contribute more than one observation but were excluded for a medication change between the index and 6 month follow up visit. Individuals were considered to have polyarticular (poly) course if total joint count was >4 and oligoarticular (oligo) course if total joint count was ≤ 4. Disease activity was classified based on clinical Juvenile Arthritis Disease Activity Score (cJADAS) inactive disease (ID; oligo ≤1.1, poly ≤2.5), cJADAS low disease activity (LDA; oligo ≤2, poly ≤3.8), American College of Rheumatology (ACR) provisional criteria for clinical inactive disease (ACRCID) and ACR preliminary criteria for clinical inactive disease (Wallace). Change in outcome variables (Patient Reported Outcomes Measurement Information System [PROMIS] pain interference, mobility, and pediatric global health) from index to 6 month visit was stratified by disease activity status at the index visit and presented as relative change determined by measure specific minimal clinical important difference. The association with tolerated disease activity state was compared by descriptive statistics.

Results: 6,235 individuals with JIA and 10,653 observations were included. The tolerated disease activity state was cJADAS ID in 36%, cJADAS LDA in 41%, ACRCID in 32%, and Wallace criteria in 33%. At the index visit the median (interquartile range; IQR) pain interference was 49 (40.6, 56.6, n=6359), mobility was 56 (43, 58.5, n=6670), and global health was 42.1 (37.9, 45.7, n=8445). cJADAS ID, cJADAS LDA, ACRCID, and Wallace were all associated with differences in relative change of mobility, but only cJADAS ID and cJADAS LDA were associated with relative change in pain interference or global health.

Conclusion: Individuals with JIA often have higher than ID or LDA at the time of no medication change and have a lower global health than population norms. There were similar frequency of worsening for all measures and tolerated disease activity states; these results do not suggest preference of one criteria set over another.

Patient Consent: Not applicable (there are no patient data)

Disclosure of Interest: M. Mannion Grant / Research Support with: Rheumatology Research Foundation Norman B Gaylis, MD Clinical Investigator Award, F. Xie: None declared, T. Beukelman Consultant with: Novartis, UCB, J. Curtis: None declared

Table 1 (abstract P043). Relative change in variables from index to 6 month follow up visit stratified by disease activity state at index visit. Minimal clinical important difference for each variable were determined to be: pain interference improvement -3 and worsening +3, mobility and global health improvement +3 and worsening -3

P044. Impact of weekdays versus weekend days on accelerometer measured physical behavior in adolescents with Juvenile Idiopathic Arthritis (JIA): results from the ActiMON study

F. Milatz¹, R. Trauzeddel², T. Kallinich^3,4, M. Klaas⁵, H. Girschick⁵, S. Hansmann⁶, G. Horneff^7,8, D. Windschall^9,10, J.-P. Haas¹¹, N. Baumeister¹², M. Niewerth¹, K. Minden^1,13

¹Epidemiology and Health Services Research, German Rheumatism Research Centre, ²Department of Paediatrics, Helios Klinik Berlin-Buch, ³Pathophysiology of Rheumatic Inflammation, German Rheumatism Research Centre , ⁴Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, University Medicine Charité Berlin, ⁵Children’s Hospital, Vivantes Hospital im Friedrichshain, Berlin, ⁶Center for Pediatric Rheumatology, autoinflammation reference centre Tuebingen (arcT), University Children’s Hospital Tuebingen, Tuebingen, ⁷Department of Paediatrics, Asklepios Clinic Sankt Augustin, Sankt Augustin, ⁸Department of Pediatric and Adolescents Medicine, University of Cologne, Cologne, ⁹Clinic of Paediatric and Adolescent Rheumatology, Northwest German Center for Rheumatology, St. Josef-Stift Sendenhorst, Sendenhorst, ¹⁰Medical Faculty, Martin Luther University of Halle-Wittenberg, Halle, ¹¹Center for Pain Treatment in Young People, German Center for Paediatric and Adolescent Rheumatology, Garmisch-Partenkirchen, ¹²Department of Sport and Health Sciences, Technical University of Munich, Munich, ¹³Department of Rheumatology and Clinical Immunology, University Medicine Charité Berlin, Berlin, Germany

Correspondence: F. Milatz

Introduction: JIA have been linked to reduced physical activity (PA) and increased time spent sedentary [1]. While structured activities in which young patients participate (e.g. at school) are consistent and limited in scope, after-school or weekend activities, in contrast, encompass a broader range of behaviors. Rrecording a wide range of intensity under daily life conditions is an important prerequisite for deriving measures to promote PA.

Objectives: Since it is assumed that adolescents’ PA is lower on weekends compared to weekdays or school days, this study aimed i) to objectively assess PA in detailed intensity range over the course of a week and ii) to determine the proportion of patients achieving the WHO recommended minimum level of at least 60 minutes moderate-to-vigorous physical activity (MVPA) daily.

Methods: Within the framework of the ActiMON study as part of the TARISMA research network, data were collected at several German paediatric rheumatology centres. In the period from June 2021 to April 2022, measurements were collected exclusively outside lockdowns and during compulsory attendance at schools. The study sample included 12- to 18-year-olds with JIA who wore an accelerometer (ActiGraph wGT3X-BT) on an elastic waist band during the waking hours of a 7-day period for measuring PA in categories, including sedentary behavior, as well as light, moderate and vigorous PA. Absolute and percentage intensity distributions were evaluated daily. Clinical parameters of participating patients were used from the National Paediatric Rheumatologic Database (NPRD).

Results: Data of 54 patients (mean age 14.9 ± 1.8 years, female 71%, patients’ disease duration 7.9 ± 4.6 years, polyarthritis 41%, cJADAS-10 2.3 ± 2.4) were available for evaluation. Almost 70% of participating adolescents met the WHO-recommended minimum level of MVPA, while the average daily step count achieved was 7107. The average wear time was 857 min daily from Monday–Thursday with significant deviations from the mean on Friday (+46 min), Saturday (–40 min), and Sunday (–117 min). While the number of steps was slightly higher during the week than at the weekend, absolute MVPA times were lower. However, the percentage distribution remained constant over all days both for girls and boys. The average daily time spent sedentary was 10.8 ± 1.9 hours (no gender differences), with no relevant differences between weekdays and weekend.

Conclusion: While a large proportion of patients achieve the WHO recommended minimum level of PA, they exhibit very pronounced sedentary behavior. The percentage distributions of the different physical behavior intensity categories are similar over all weekdays and weekend days. Interventions should generally try to shift activity away from sedentary behavior towards a more active lifestyle. Further results are expected with ongoing recruitment.

References:

[1] Gualano B et al. Physical activity for paediatric rheumatic diseases: standing up against old paradigms. Nat Rev Rheumatol 2017;13:368-379.

Acknowledgement: ActiMON is funded by the Federal Ministry of Education and Research (01EC1902F)

Trial registration identifying number: German Clinical Trials Register DRKS00022258

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P045. Parents´ experiences of a one-year support program when their child was diagnosed with juvenile idiopathic arthritis – a qualitative interview study

K. Mördrup¹, J. G. Jungner², E. Broström³, C. Bartholdson³

¹Women’s and Children’s Health, Karolinska University Hospital, ²Women’s and Children’s Health, Karolinska Institutet, ³Women’s and Children’s health, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden

Correspondence: K. Mördrup

Introduction: Juvenile Idiopathic Arthritis (JIA) is one of the most common acquired diseases during childhood in Sweden with approximately 200 children diagnosed every year¹. Being diagnosed with JIA can be shocking and overwhelming for the child and the parents², in addition all information given directly after the diagnose can be difficult to assimilate^3,4. They therefore need supportive care by repeated information and communication between the scheduled visits⁵. A one-year support program, including scheduled visits and the possibility of direct contact with a nurse was therefore developed and offered to all newly diagnosed children and their parents to improve quality of care.

Objectives: To explore parents experiences of participating in the support-program.

Methods: When the child was diagnosed with JIA, the child and the parents were offered to participate in the support program from the time of diagnose to one year ahead. The program included seven structured person-centered visits. The nurse was coordinating and participating in all the visits (including visits with physicians) from the start. After completing the program, parents were invited to participate in semi-structured interviews. Fieldnotes were taken by the researcher who conducted the interviews and qualitative analysis was performed.

Results: The interviewed parents were ten mothers and six fathers, and their children were between 1 and 16 years old when they were diagnosed with JIA. Data from the field notes show that the families greatly appreciated the possibility of direct contact by phone with the coordinating nurse i.e. good accessibility. They also found continuity as important at the unit and that they expressed great trust for the healthcare professionals. The parents described a professional and holistic care where their child have been listened to and treated from a child’s perspective. The family felt safe about the disease and medication. The coordination of the visits were described as good and the advantage to have a patient responsible nurse was mentioned. Some parents experienced that they felt they were included in a new familly.

Conclusion: The 16 Swedish parents who had participated in the one-year support program after their child was diagnosed with JIA were very satisfied with the care they had received. We thus conclude that the new one-year program is a suitable way to improve quality of pediatric rheumatology care and supports the families during their first year.

Patient Consent: Not applicable (there are no patient data)

Disclosure of Interest: None declared

P046. The parent/child juvenile idiopathic arthritis disease activity score: responsiveness to change and factor analysis

R. Naddei¹, F. Bovis², F. Ridella², C. Trincianti², S. Pastore³, K. Minden⁴, M. Ekelund⁵, P. Barone⁶, S. Scala¹, E. Patrone¹, N. Ruperto¹, A. Ravelli¹, A. Consolaro¹ on behalf of The Paediatric Rheumatology International Trials Organisation (PRINTO)

¹Istituto Giannina Gaslini, ²Università degli Studi di Genova, Genoa, ³IRCCS Burlo Garofolo, Trieste, Italy, ⁴German Rheumatism Research Centre, Berlin, Germany, ⁵Ryhov County Hospital, Jonkoping, Sweden, ⁶Catania University Hospital, Catania, Italy

Correspondence: R. Naddei

Introduction: Assessment of disease activity is a crucial component of the clinical management of children with juvenile idiopathic arthritis (JIA). According to the most recent requirements, both parent’s and children’s perception should be considered when evaluating the disease course and assessing effectiveness of therapy. Therefore, a new disease activity evaluation tool, based on parent/patient-centered outcome measures, is under development and named parent/child Juvenile Arthritis Disease Activity Score (par/childJADAS).

Objectives: Aim of this study was to evaluate responsiveness to change of the parJADAS and to conduct an explanatory factor analysis (EFA) on the scores’ items.

Methods: The parJADAS and childJADAS include 4 measures: 1) parent/child assessment of disease activity, rated on a 0-10 visual analogue scale (VAS); 2) assessment of pain intensity, rated on a 0-10 VAS; 3) self/proxy count of any swollen or painful joint up to a maximum of 10 joints; 4) assessment of morning stiffness (MS) on a Likert scale, ranging from no MS (0 points) to > 2 hours of MS (10 points). Responsiveness to change was assessed by computing the standardized response mean (SRM) in a subgroup of JIA patients enrolled in the PharmaChild registry, including subjects having a study visit at the time of biologic treatment initiation and a subsequent study visit no more than 6 months later, with a subjective rating of improvement by the attending physician. An EFA on the 4 items of the par/childJADAS was performed on a multinational dataset of JIA children enrolled in the study of Epidemiology, treatment and Outcome of Childhood Arthritis (EPOCA). The factors were extracted according to the principal factors method and the optimal number of factor extraction was based upon eigenvalues ≥ 1. The factors were rotated by the varimax method.

Results: Since the amount of children’ observations in the corresponding dataset was not sufficient, responsiveness to change was assessed only for the parJADAS. Sixty patients met the requirements for SRM analysis. Second visit was at a median of 37 days after biologic treatment initiation. The SRM value obtained was 0.71. The EFA was conducted on data from 8,431 parents and 5,873 children of EPOCA dataset, who had the 4 items of the scores available. The Kaiser–Meyer–Olkin measure was 0.79 and 0.78 for the parents’ and the children’s samples, respectively, indicating that both samples were adequate, and the Bartlett’s test of sphericity resulted significant (p<0.0001) for both scores, indicating that a EFA may be useful. The EFA showed that one factor explained 59.0% of the variance in the parent sample and 61.0% in the child one. The factor loadings were high for both the samples, ranging from 0.60 (joint count and MS) to 0.90 (parent/patient assessment of disease activity, pain intensity level).

Conclusion: The parJADAS SRM was in moderate range in patients judged as improved by the caring physician after starting a biological medication, suggesting that the responsiveness to change of the score is good. The EFA showed that the 4 items of both parJADAS and childJADAS work well together, indicating a good internal consistency.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P047. A decade of progress in juvenile idiopathic arthritis treatments and outcomes in Canada: results from reacch-out and the CAPRI registry

K. Nguyen¹, J. Barsalou², S. Benseler³, R. Berard⁴, G. Chédeville⁵, P. Dancey⁶, E. Dermikaya⁴, C. Duffy⁷, K. Houghton⁸, A. Huber⁹, N. Johnson³, D. Levy¹⁰, L. Lim¹¹, K. Oen¹², J.-P. Proulx-Gauthier¹³, A. Rosenberg¹⁴, D. Rumsey¹¹, H. Schmeling³, L. Tucker⁸, R. Yeung¹⁰, J. Guzman⁸

¹University of British Columbia, Vancouver, ²Pediatrics, University of Montreal, Montreal, ³Pediatrics, University of Calgary, Calgary, ⁴Pediatrics, Western University, London, ⁵Pediatrics, McGill University, Montreal, ⁶Pediatrics, Memorial University, St. John’s, ⁷Pediatrics, U of Ottawa, Ottawa, ⁸Pediatrics, University of British Columbia, Vancouver, ⁹Pediatrics, Dalhousie University, Halifax, ¹⁰Pediatrics, University of Toronto, Toronto, ¹¹Pediatrics, University of Alberta, Edmonton, ¹²Pediatrics, U of Manitoba, Winnipeg, ¹³Pediatrics, Laval University, Quebec City, ¹⁴Pediatrics, U of Saskatchewan, Saskatoon, Canada

Correspondence: K. Nguyen

Introduction: Treatments for juvenile idiopathic arthritis (JIA) have evolved at an accelerated pace over the last decade. It is important to document these changes and whether there has been concurrent improvements in patient outcomes.

Objectives: To compare JIA treatments and outcomes in the first year after diagnosis from two cohorts in Canada, the 2005-10 Research in Arthritis in Canadian Children emphasizing Outcomes (ReACCh-Out) cohort and the 2017-21 Canadian Association of Pediatric Rheumatology Investigators (CAPRI) Registry cohort.

Methods: To enhance the validity of the comparison, we included only patients recruited within three months of JIA diagnosis, used the same outcome criteria in all subjects, and compared Kaplan-Meier estimates at 70 weeks in both cohorts (1 year plus window for data capture). Inactive disease was defined as per Wallace criteria and inactive and minimally active disease were defined according to clinical Juvenile Arthritis Disease Activity Score 10 (cJADAS10) using the recently revised cut-offs [1].

Results: The 2005-10 cohort included 1128 subjects. The 2017-21 cohort 721. The cohorts were comparable in proportion of JIA categories and median cJADAS10 at subject enrollment, 8.2 (IQR 4.4, 14.6) and 8.0 (4.5, 13), respectively. Median age at disease onset was 8.5 years (3.2-12.2) and 8 years (4.1-13.2). The use of disease-modifying antirheumatic drugs (DMARDs) and biologics increased substantially (Table 1). By 70 weeks after diagnosis, 6% of subjects had started a biologic in the 2005-10 cohort compared to 26% in the 2017-21 cohort. The proportion of patients attaining inactive disease increased from 63% to 84% by Wallace Criteria.

Conclusion: The main changes observed in JIA treatments in Canada between 2005-2010 and 2017-2021 were increased use of DMARDs and biologics. There was a concomitant increase in attainment of inactive and minimally active disease within 70 weeks of diagnosis, suggesting more aggressive treatment was associated with improved outcomes.

[1] Trincianti C, et al. Arthritis Rheumatol 2021; 73: 1966-75.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

Table 1 (abstract P047). Kaplan-Meier estimates, % (95% CI), for use of selected medications and attainment of inactive or minimally active disease within 70 weeks of JIA diagnosis

P048. Tofacitinib in the therapy of different kind of pediatric rheumatic deseases: real clinical practice experience of a single center

I. Nikishina¹, S. Arsenyeva¹, V. Matkava¹, M. Kaleda¹, S. Salugina¹, E. Fedorov¹, A. Shapovalenko¹, T. Pachkoria¹

¹Paediatric, V.A. Nasonova Scientific Research Institute of Rheumatology, Moscow, Russian Federation

Correspondence: I. Nikishina

Introduction: Tofacitinib (TOFA) is new therapy approach in pediatric rheumatology for management children with different rheumatic diseases (RD). In Russia TOFA was approved from September 2021 for the treatment of polyarticular juvenile idiopathic arthritis (JIA). The unique mechanism of action of Janus-kinases suggests that TOFA can be a useful option in the treatment of various RD in children.

Objectives: To evaluate efficacy and safety of TOFA in children with different kind of RD.

Methods: We analyzed data base of 52 patients (pts) who were treated by TOFA since 2018 to 2022. The data includes JIA, juvenile ankylosing spondylitis (JAS), chronic recurrent multifocal osteomyelitis (CRMO), juvenile dermatomyositis (JDM), and rare genetic syndromes such as fibrodisplasia ossificans progressive (FOP), STING-Associated Vasculopathy with onset in Infancy (SAVI), Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated Temperature (CANDLE), Blau syndrome, camptodactyly-arthropathy-coxa vara-pericarditis syndrome (CACP). All cases of «off-label» TOFA use were approved by Local Ethic Committee.

Results: The prospective analysis includes data of 52 pts (18/35% boys; 34/65% girls). The largest number of pts had JIA: 26/63% RF-negative polyarticular subtype of JIA (7 was combined with psoriasis, 3-with uveitis, 2-with Blau syndrome, 1 – with Chron’s disease, 1 – with congenital insensitive to pain and CRMO, 1 – with Down’s syndrome, 1 – with CACP syndrome), RF-positive – 2/3%. 4/8% were diagnosed as systemic JIA (2 pts were in clinical trials, 2 – without current systemic features). JAS was presented in 3 pts, 1 of them was associated with CRMO. 1 pt has JDM with severe course of the disease. All other pts (16/31%) had rare genetic disorders: 2 pts with SAVI syndrome and 1 pt with CANDLE were treated by TOFA as first line with excellent effects (relief of fever, reduction of skin manifestations and pulmonary lesions); 13 pts with extremely rare genetic disease FOP (TOFA was administered due to strong uncontrolled progression of heterotopic ossification). Presence of synovitis, sacroiliitis and axial damage confirmed by X-ray/MRI/CT allowed us to establish alternative diagnosis of JAS in 6 pts and JIA in 7 cases for legal prescription. The dosage of TOFA was up to 5 mg twice a day. All JIA pts received methotrexate. The mean duration of TOFA therapy is 10.8 months (from 1.5 to 43,9). The majority of TOFA administration was as a first-line treatment (27/52%), in 2-nd line – 12/23%, 3-d line – 4/7%, 4-th line – 3/6%, 5-th line – 5/10%, 6-th line – 1/2%. Approximately all patient had a good response on TOFA therapy with relief of active arthritis and uveitis, significant reduction of psoriasis skin lesions. In most FOP pts new nodes formation immediately stopped and improvement of motions was registered. Also, we noticed regression of sacroiliitis and coxitis activity by MRI under TOFA therapy Drug tolerance was good in 51/98% pts. In 1 pt TOFA therapy was withdrawn due to adverse event presented by extended maculopapular skin rash which appeared 3 days after TOFA initiation. 3 more withdrawals were due to primary inefficacy (2 pts with sJIA from clinical trial, 1 received TOFA as 5-th line therapy).

Conclusion: We found that TOFA is highly efficient, well-tolerated medicine which may be a promising option for the difficult to treat variants of JIA (including psoriasis and CRMO- associated) and rare autoinflammatory diseases, such as FOP, Blau syndrome, CANDLE, SAVI, CACP. The anti-inflammatory action of TOFA seems to be preferable to the direct anti-cytokine effect of most biologics. The further study of the therapeutic potential of JAK-kinase inhibitors in pediatric RD is needed.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P049. Drug survival of abatacept therapy in children with rheumatic diseases: 10 years experience in a single center

S. Arsenyeva, I. Nikishina, V. Matkava, M. Kaleda, A. Shapovalenko

Paediatric, V.A. Nasonova Scientific Research Institute of Rheumatology, Moscow, Russian Federation

Correspondence: S. Arsenyeva, I. Nikishina

Introduction: Among the wide spectrum of Biologics used in pediatric rheumatology, abatacept (ABA) has a special place, which differs from other Biologics with direct anti-cytokine action. In addition to therapy with ABA in patients (pts) with juvenile idiopathic arthritis (JIA) in real clinical practice there is experience of its use “off-label” in such systemic rheumatic diseases (RD) as juvenile systemic scleroderma (jSS), juvenile dermatomyositis (JDM), systemic lupus erythematosus with juvenile onset (jSLE) and its overlaps.

Objectives: To evaluate the drug survival of ABA therapy in children with different RD with focus on adverse events (AE).

Methods: The study based on cohort of pts who were treated by ABA from 2010 to 2021 in our clinic. These pts are fulfilled the criteria for JIA and the criteria of above-mentioned RD. Data of the disease course were used to estimate drug survival with Kaplan-Meier and calculate AE rates.

Results: The retrospective analysis includes data of all pts, who received ABA in our center, 205 pts in total. The largest number of patients were presented by RF-negative polyarticular subtype of JIA - 131/64%, RF-positive – 40/20%, persistent oligoarthritis – 8/4% (6 of them with uveitis). 15/7% were diagnosed as systemic JIA without current systemic features. 36/18% pts suffered from active uveitis. All other pts (11/5%) had systemic RD (jSS – 5, JDM – 3, jSLE – 3). In group of JIA pts we identified overlap-syndrome with JDM, jSLE, jSS features in 31/15% cases. 28/14% had Sjogren’s syndrome. The average age of disease onset was 5.9 years (from 1.25 to 17.2). The average age of ABA initiation (first-line) was 10,7 years (from 2 to 17.8 years). The mean duration of disease was 4.8 years. The mean duration of ABA treatment was 4,4 years. The majority of pts received ABA as first-line therapy (164), 2-nd line – 29, 3-rd line – 8, 4-th line – 4. There were 71 cases of ABA withdrawals. The most often reasons for drug discontinuation were inefficacy – 48/ 68%, secondary mostly (in 1^st line -30 from 164 (18%), 2^nd line- 10/29 (34%), 3^rd line- 4/8 (50%), 4^th line-4/4 (100%). Non-medical «organizational» problems led to the cancellation of therapy in 12/17%. Just in 1 pt ABA was stopped because of remission. AE were as reason ABA withdrawn in 10/15% (3 pts due to post-infusion reactions, 2 pts (the both with early oligoarticular onset) developed uveitis de-novo, one had verruca vulgaris, 2 - psoriasis de novo). In 1 girl we observed the development of cryptogenic epilepsy after 3-year ABA treatment, but therapy was continued. In 2 cases ABA was cancelled due to multiple sclerosis development. The first pt had 70-90% ACR response, however in 2 years of ABA-treatment the psoriasis was developed, ABA was continued. After 4 years of the therapy (at the age of 13) neurological symptoms appeared (headache, loss of sensitivity, ataxia, visual field defect) and multiple sclerosis was diagnosed. In 2-nd pt CNS demyelination was verified after 2 years of ABA therapy with appearance of dizziness, unilateral numbness. MRI-evidence was observed in both cases. ABA treatment survival at 1 year for the 1^st line was 88% and 2-4^th lines 84%, at 5 years 60% and 45% respectively. There were not significant differences in drug survival according to kind of RD.

Conclusion: Our data showed great experience of ABA use in wide spectrum of pediatric RD. ABA often is the front-line therapy for certain subtype of JIA, especially in overlap-syndrome. It may be good option for the some pts with jSS, JDM, jSLE despite of indication «off label». Drug survival of ABA was higher in biologics-naïve patients. ABA had satisfactory safety profile in the long-term period, but rare adverse events, such as CNS demyelination and uveitis or psoriasis de novo were found.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P050. Assessment of liver stiffness and steatosis in juvenile idiopathic arthritis patients treated with methotrexate

C. Niyasom¹, C. Lertudomphonwanit¹, S. Getsuwan¹, S. Vilaiyuk¹, A. Sobhonslidsuk ², P. Kaewduang², S. Soponkanaporn¹

¹Pediatric, ²Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand

Correspondence: C. Niyasom

Introduction: Monitoring serum transaminases is unreliable to detect liver stiffness and steatosis in patients with juvenile idiopathic arthritis (JIA) who have been treated with methotrexate. Transient elastography (TE) with controlled attenuation parameter (CAP) (FibroScan®) has emerged as a non-invasive tool to assess liver stiffness and steatosis.

Objectives: To evaluate the prevalence and predictors of liver stiffness and steatosis in JIA patients treated with MTX by using TE with CAP.

Methods: A cross-sectional study was conducted at Ramathibodi Hospital. Included subjects were JIA patients aged 1-18 years who received methotrexate (MTX) for at least 1 year, while patients with known chronic liver disease were excluded. Clinical features, medication information, and laboratory data were collected. TE measured liver stiffness and reported as liver stiffness measurement (LSM) with a cut-off >7 kilopascal (kPa) indicating significant liver stiffness. Steatosis was diagnosed if CAP >225 decibels/meter (dB/m).

Results: Sixty JIA patients were enrolled with a median age (IQR) of 12.8 (10.6–15.0) years and a median disease duration (IQR) of 4.2 (2.1–7.8) years. The most common JIA subtype was systemic JIA (28.3%), followed by rheumatoid factor-positive polyarthritis (25%), and enthesitis-related arthritis (18.3%). A cumulative median (IQR) dose of MTX and steroids was 3,768 (1,806–6,466) mg, and 1,563 (0–7,694) mg, respectively. A median (IQR) duration of MTX and steroid usage was 45 (22–85) months, and 5.3 (0–29) months, respectively. None of them had significant liver stiffness with the median LSM (IQR) was 4.10 (3.43–4.58) kPa. Thirteen patients (21.7%) were diagnosed with steatosis. There was a significant higher median body mass index (BMI) Z-score in patients with steatosis (0.86, IQR 0.23–1.44) when compared to non-steatosis (-0.32, IQR -0.95–0.38) (p=0.007). Median cumulative dose of MTX in steatosis patients was 5,405 mg (IQR 2,760–9,761) which were significantly higher than in non-steatosis patients (3,370 mg, IQR 1,438–5,614) (p=0.017). Similarly, there were significantly higher median cumulative dose of steroids in steatosis patients 1,732 mg (IQR 0–26,657) VS 1,410 mg (IQR 0–6,545) than in non-steatosis patients (p=0.069). From multivariable logistic regression analysis, the only predictor of steatosis was BMI Z-score (OR 2.78 [95%CI 1.23– 6.13], p=0.013).

Conclusion: Long-term low-dose MTX usage with median duration of 45 months does not increase the risk of liver stiffness in JIA patients. Since levels of liver enzymes can be normal in patients with steatosis, caution and monitoring for steatosis using TE in JIA patients with high BMI Z-score might be useful during MTX treatment.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P051. Cognitive impairment associated with higher C-reactive protein values in patients with juvenile idiopathic arthritis: a prospective cohort study

F. Ortiz-Márquez¹, R. Redondo-Rodríguez¹, L. Martín-Pedraz², C. Padilla-Leiva³, G. Díaz-Cordovés¹, R. Galindo-Zavala², E. Núñez-Cuadros²

¹Instituto de Investigación Biomédica de Málaga (IBIMA). UCG de Reumatología , Hospital Regional Universitario de Málaga, ²UCG Pediatría, Hospital Materno-Infantil de Málaga, ³Universidad de Málaga, Málaga, Spain

Correspondence: F. Ortiz-Márquez¹

Introduction: Cognitive impairment is a comorbidity that affects rheumatological patients. Despite this, it hasn’t been studied in Juvenile Idiopathic Arthritis patients yet.

Objectives: Prospectively evaluate changes in the cognitive function of patients with juvenile idiopathic arthritis (JIA) and associated factors.

Methods: Design and protocol: We performed a prospective cohort study with JIA patients that participated in a previous cross-sectional study (2019) to evaluate cognitive function. After 24 months, the patients were administered the same test battery previously used through an established protocol, and data was collected from their clinical histories. The neuropsychological tests were corrected by a neurologist and neuropsychologist.

Study population: Inclusion criteria: Patients aged ≥16 years with JIA classified according to the criteria of ILAR 2001. Patients with inflammatory or rheumatic diseases other than JIA, previous neurological disease not associated with the course of JIA, and patients with scores lower than the normal in the manual skill test were excluded. Outcomes: The main variable was cognitive impairment, defined as worsening of ≥2 scaled points after 24 months (V24) in any of the subtests used to evaluate each cognitive area in the Wechsler Adult Intelligence Scale (WAIS). The evaluated cognitive domains and their respective subtests were: Attention/concentration (Digit Span); verbal function (Vocabulary); visuospatial organization (Block Design); working memory (Letter-Number Sequencing); problem-solving (Similarities). Depression was evaluated by The Beck Depression Inventory-II (BDI-II): minimal (0-13), mild (14-19), moderate (20-28), and severe (29-63). Other variables: Clinical-epidemiological characteristics; treatments; and inflammatory activity evaluated as the C-reactive protein average (CRP) and JADAS-27 along the 2 years of follow-up.

Statistical analysis: Descriptive analysis, followed by χ2 and paired T-test. Multivariate analysis to identify independent variables associated with impairment of cognitive function in JIA.

Results: Fifty two patients with JIA were included. The clinical characteristics are shown in Table 1. Fifteen patients (28.8%) showed impairment in one or more cognitive functions. The most frequent impaired cognitive functions were working memory (17.3%) and attention/concentration (9.6%); followed by verbal function (7.7%), visuospatial organization (7.7%) and problem solving (3.8%). The variables independently associated with cognitive impairment were the mean CRP along the follow-up (OR [IC 95%], 1.291 [1.002-1.663]; p=0.047), depression (OR [IC 95%], 1.178 [1.001-386]; p=0.049) and biological treatment (OR [IC 95%], 0.196 [0.039-0.978]; p=0.049). This model would explain the 45% of the cognitive impairment in JIA (R2=0.45).

Conclusion: Thirty percent of the patients with JIA showed cognitive impairment after 24 months of follow-up. Cognitive impairment was associated with higher inflammatory activity and depression. Biological therapy improves cognitive function.

Patient Consent: Not applicable (there are no patient data)

Disclosure of Interest: None declared

Table 1 (abstract P051). Clinical, laboratory, and treatment characteristics

P052. Cluster analysis of patients with oligoarticular, RF negative polyarticular and undifferentiated juvenile idiopathic arthritis

S. Ozdemir Cicek¹, N. Şahin², A. Paç Kısaarslan³, M. H. Poyrazoğlu³

¹Pediatric Rheumatology, University of Health Sciences, Kayseri City Research and Training Hospital, Kayseri/Melikgazi, ²Pediatric Rheumatology, Kocaeli Derince Training and Research Hospital, Kocaeli, ³Pediatric Rheumatology, Erciyes University, Kayseri/Melikgazi, Turkey

Correspondence: S. Ozdemir Cicek

Introduction: In recent years, attempts have been made to classify JIA into more homogeneous clinical groups.

Objectives: We planned to classify the patients with oligoarticular, RF- polyarticular and undifferentiated groups according to ILAR criteria, according to their clinical and laboratory findings.

Methods: Two hundred three patients with oligoarticular, RF- polyarticular JIA and undifferentiated arthritis included to the study. RF+ polyarticular JIA, enthesitis-related arthritis, psoriatic arthritis and systemic JIA patients were not included. Eighteen clinical and laboratory variables evaluated with TwoStep Cluster analysis. Categorical variables were sex, affected joints(hip, knee, ankle, shoulder, elbow, wrist, small joints of the hand and foot, cervical vertebra and temporomandibular joint), laboratory findings which determines the JIA subtype(ANA, RF and HLA B27 positivity), continuous variables were the age of disease onset, the number of affected joints, ESR and CRP values at disease onset. Clinical and laboratory features of the resulted clusters were then compared with each other.

Results: Two hundred three JIA patients included to the study. The median age of patients was 13 (2.5-21.07) years, the age of diagnosis was 7 (1-16) years and 133 (65.5%) of the patients were female. Two clusters were generated as the result of cluster analysis. Cluster 1 had 94 (46.3%) and cluster 2 had 109 (53.7%) patients. The most important indicators in differentiating of the two clusters were small joint involvement, the number of involved joints, wrist, knee and elbow arthritis.

In the first cluster, small joint involvement was observed, the number of affected joints was higher, TMJ, shoulder, wrist, elbow and ankle arthritis were higher, and initial acute phase reactants were found to be higher than the second cluster. Corticosteroids, DMARDs and biological treatments were at higher rates in the first cluster, and the remission rates at twelfth months and last visit were lower according to the second cluster. All of the patients in the second cluster had knee involvement and IAS was used more frequently compared to first cluster.

Conclusion: Our results classified current oligoarticular, RF negative polyarticular and undifferentiated arthritis subgroups patients into two clusters. Small joint, wrist, elbow involvement and the number of involved arthritis were the most important factors for differentiating two groups.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

Table 1 (abstract P052). Characteristics of all JIA patients and comparisons of cluster 1 and cluster 2

P053. How to diagnose juvenile psoriatic arthritis? Multicenter prospective observational study in children with suspected diagnosis

N. Palmou-Fontana¹, A. Garcia-Rogero², C. Redondo-Figuero¹, A. Lopez-Sundh¹, P. Mesa-del-Castillo³, G. Diaz-Cordoves⁴, B. Magallares-Lopez⁵, M. J. Cabero-Perez⁶, M. A. Gonzalez-Gay¹, P. Collado-Ramos⁷ on behalf of Sociedad Española de Reumatología Pediátrica (SERPE)

¹Servicio de Reumatologia, Hospital Universitario Marques de Valdecilla, Santander, ²Gerencia de Atencion Primaria, Servicio Cantabro de Salud, Castro Urdiales, ³Servicio de Reumatologia, Hospital Universitario Virgen de la Arrixaca, Murcia, ⁴Servicio de Reumatologia, Hospital Regional Universitario, Malaga, ⁵Servicio de Reumatologia, Hospital de la Santa Creu i Sant Pau, Barcelona, ⁶Servicio de Pediatría, Hospital Universitario Marques de Valdecilla, Santander, ⁷Servicio de Reumatologia, Hospital Universitario Severo Ochoa, Madrid, Spain

Correspondence: N. Palmou-Fontana

Introduction: Juvenile idiopathic arthritis (JIA) constitutes a heterogeneous group of inflammatory joint diseases. The International League of Associations for Rheumatology (ILAR) classifies and defines seven subtypes of JIA by specific and non-specific clinical features with exclusions. Among these diseases is Juvenile Psoriatic Arthritis (JPA).

There are two pediatric diagnostic classifications based on clinical criteria: ILAR classification criteria and Vancouver classification criteria. Classification of JIA has been a great debate since this entity disappeared. (1) The CASPAR criteria are standard in adults. These criteria have a specificity of 91.4% and a sensitivity of 98.7%, making diagnostic classification easier. However, the peculiarities of childhood cause some differences to consider.

Objectives: To compare the performance of the three different PsJIA classification criteria (ILAR, Vancouver and CASPAR criteria) in children identified as such in the routine rheumatology Clinic.

Methods: Multicenter prospective observational study started in 2020. Patients seen in the pediatric rheumatology outpatient clinic with suspected PsJIA diagnosis were consecutively included. Sociodemographic, clinical characteristics and family history of Psoriasis were collected to assess compliance with diagnostic classification criteria (ILAR, Vancouver, and CASPAR).

Results: Thirty-two children were included, predominantly female (24 girls). The median age at diagnosis was 13.5 (IQR: 4.5). Clinical onset was predominantly oligoarticular (19, 59.5%), followed by polyarticular (n:5, 18.6%), monoarticular (n:5, 18.6%), and onychopathy (n:2, 6.2%). Cutaneous Psoriasis was present in 20 children (62.5%). Family history of Psoriasis was recorded in 24 patients, 1st degree in 19 patients (54%), and a second degree in 5 (15.6%). Among the extra-articular manifestations, dactylitis stood out (n:14, 3.8%). Twelve patients (37,5%) had nail involvement. Rheumatoid factor (RF) was negative in 100% of the children, ANAS were positive in 11 children (34.4%), whereas HLAB27 was positive in 3 children (9.4%). Twenty-seven children met the VANCOUVER criteria: twenty children, defined dco (62.5%) and 7 (21.9%) probable diagnosis. Twenty children (62.5%) met the ILAR criteria. Twenty-seven (84.4%) children were diagnosed according to the CASPAR criteria. The diagnostic agreement between the ILAR and CASPAR criteria on the one hand, and between the ILAR and Vancouver criteria on the other hand, was weak (K=0.17 and K= 0.41). In contrast, the agreement was total (K=100) between the CASPAR and Vancouver criteria.

Conclusion: Despite minimal changes between the Vancouver and ILAR criteria, the ILAR exclusion criteria limit the diagnosis of PsA in childhood. Given that CASPAR and Vancouver criteria were able to detect a more significant number of patients with PsA in our series (predominantly adolescents), the application of the CASPAR Criteria in the subgroup of children with late onset could be considered. (1)

(1) Martini A, Ravelli A, Avcin T, et al, for the Pediatric Rheumatology International Trials Organization (PRINTO). Towards New Classification

Patient Consent: Yes, I received consent

Disclosure of Interest: N. Palmou-Fontana Consultant with: ABBVIE, AMGEN, PFIZER, Speaker Bureau with: ABBVIE, AMGEN, PFIZER, A. Garcia-Rogero Speaker Bureau with: GSK, C. Redondo-Figuero: None declared, A. Lopez-Sundh: None declared, P. Mesa-del-Castillo: None declared, G. Diaz-Cordoves: None declared, B. Magallares-Lopez: None declared, M. J. Cabero-Perez: None declared, M. A. Gonzalez-Gay: None declared, P. Collado-Ramos: None declared

P054. Early cervical involvement in children with juvenile idiopathic arthritis and its variants: a frequently neglected domain in paediatric pathology

E. Pardo Campo¹, S. Burguer¹, M. Pino Martinez¹, I. Braña Abascal ¹, S. Murias Loza², J. Rodriguez², S. Alonso Castro ¹, S. Fernandez Aguado¹, M. Alperi Lopez¹, R. Queiro Silva¹

¹Rheumatology, ²Pediatrics, Hospital Univ Central De Asturias, Oviedo, Spain

Correspondence: E. Pardo Campo

Introduction:

Cervical spine involvement is often unrecognized in the early stages of juvenile idiopathic arthritis

(JIA), as it is a rare manifestation. We know that JIA is the most common chronic rheumatic disease

in childhood.

However, cervical involvement is a rare manifestation in the early stages of the disease, and is

extremely infrequent as the only manifestation.

It is for this reason that the exact frequency, clinical features and evolution of these patients are not

yet known.

It has been described as a late complication and is considered to have a poor prognosis.

Objectives: Therefore, our aim is to describe the clinical characteristics of patients with JIA who have experienced cervical involvement as a manifestation at the onset of the disease.

Methods:

An observational study was performed on patients with JIA who presented cervical involvement as

the form of onset of the disease. Data was obtained from a total of 75 patients with JIA being

followed by the Pediatric Rheumatology Unit of the Hospital Central de Asturias. Hospital Central de Asturias.

We have reviewed the clinical histories and selected those with cervical involvement as a form of onset.

Results:

Three cases of JIA were detected in which cervical involvement was the form of onset of the

disease in three different types of JIA. (Table 1)

Conclusion:

JIA in its different forms should be considered as a differential diagnosis in children presenting with

cervical pain, cervical limitation or stiffness.

This manifestation can go unnoticed in our patients and delay diagnosis. We should consider its

occurrence in different categories within JIA.

MRI can be of great help in the diagnosis of these patients. Early targeted therapy with anti-TNF

inhibitors can help in the remission of cervical symptomatology.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

Table 1 (abstract P054). Number of Patients (3)

P055. Juvenile psoriatic arthritis: a case series

S. Pastore¹, F. Corona², A. Taddio³, A. Tommasini³

¹Institute of Maternal and Child Health IRCCS “Burlo Garofolo, ²Department of Medicine, Surgery, and Health Sciences, ³Institute of Maternal and Child Health IRCCS “Burlo Garofolo”, University of Trieste, Trieste, Italy

Correspondence: S. Pastore

Introduction: Juvenile psoriatic arthritis (JPsA) has been a recognized entity since the 1970s. In 1989 the Vancouver criteria were proposed to identify cases of probable or definite diagnosis. Subsequently, the Vancouver criteria were replaced with ILAR criteria, revised for the last time in 2004 and still used in clinical practice. With these criteria JpsA is permitted also in the absence of frank psoriasis in children with arthritis accompanied by two of the following: dactylitis; nails pitting or oncycholysis, or psoriasis in a first-degree relative. Recently, the Pediatric Rheumatology International Trials Organization suggested new criteria for the diagnosis of Juvenile Idiopathic Arthritis (JIA), but psoriatic arthritis subgroup is missing.

Objectives: To describe clinical and lab features of patients with JPsA, and therapeutic strategies.

Methods: We retrospectively enrolled all patients cared at the Rheumatology Service of the Institute for Maternal and Child Health IRCCS “Burlo Garofolo” (Trieste) with JPsA diagnosis according 2001 ILAR criteria. For each patient we collected: age, sex, age at onset, familiar history, number of involved joints, inflammatory indexes at onset disease, anti-nuclear antibodies (ANA), human leukocyte antigen (HLA) B27 expression, presence of enthesitis, tenosynovitis and uveitis, concomitant autoimmune diseases. We collected also treatments and treatment response assessed by Wallace remission criteria.

Results: 21 patients (16 F, 5 M) with juvenile psoriatic arthritis are enrolled. Seven out of 21 had a oligoarticular pattern, 14/21 had a polyarticular pattern (2/14 oligoextended). Out of 21, 3 patients had onset disease before age six. Thirteen out of 21 (62%) had high inflammatory indexes at onset disease: 7/13 had only high Erythrocyte Sedimentation Rate (ESR > 25 mm/h), 6/13 also had elevated C-Reactive Protein (CRP > 1 mg/L). Out of 21, 10 had ANA positivity and 2 had HLAB27 positivity. Seventeen out of 21 (81%) had fingers or toes dactylitis or both. Ten out of 21 patients (48%) had psoriasis, which in 9/10 appeared before arthritis. Six out of 21 (28%) had tenosynovitis of ankle. Two patients developed anterior uveitis. One of these is a girl with disease onset before the age of 6, positive ANA and HLAB27, with recurrent and symptomatic iridocyclitis unresponsive to first and second line therapies. Five patients had a concomitant autoimmune disease (3 celiac disease and 2 hypothyroidism). Seven out of 21 (33%) achieved disease remission with a modifying antirheumatic drug (DMARD): 6 with methotrexate and one with sulfazalazine. Nine out of 21 patients (43%) achieved disease remission with adalimumab; then one of these had loss of response. Three out of 21 (14%) achieved disease remission with etanercept. Two patients had a severe disease non responsive to different drugs, non-biologic and biologic DMARDs.

Conclusion: In our patients with psoriatic arthritis tenosynovitis is the predominant clinical feature; most patients have dactylitis. More than half of the patients have high ESR at onset disease. In most patients disease remission was achieved with biologic therapy.

Disclosure of Interest: None declared

P056. The current state of global research on juvenile idiopathic arthritis

M. Pavlenko¹, D. Pavlenko²

¹Universum Clinic, ²Department of Ophthalmology, Bogomolets National Medical University, Kyiv, Ukraine

Correspondence: M. Pavlenko

Introduction: Juvenile idiopathic arthritis is the most common chronic rheumatic disease in children.

Objectives: To describe the current state of research articles on juvenile idiopathic arthritis using bibliometric analysis.

Methods: An advanced search was performed in May 2022 within all titles in the Core Collection of Clarivate Web of Science to identify all articles on juvenile idiopathic/rheumatoid arthritis until 2021. The predominant language, h-index of the research topic, and the number of citations were identified according to the built-in Analyze Result and Citation Report. Biblioshiny application of Bibliometrix (Aria, M. & Cuccurullo, C., 2017) R-package (RStudio, PBC, Boston, MA, USA) was used for scientific production, author, authors collaboration, and citation analyses.

Results: Only articles, which comprised 46.7% (n=4,271) of all 9,144 publications between 1970 and 2021, were analysed. They were written by 13,018 authors, and published in 810 sources. Almost all articles were written in the English language (n=4,049; 94.8%). Singled-authored documents were rare (n=194; 4.5%) and were written by 1.1% (n=146) of all authors. The average years from publication was 14.8. The collaboration index was 3.2. There were 0.3 documents per author and 3.1 authors per document and 6.8 co-authors per document. The annual growth rate was 2.1%. The most productive year was 2021 (n=259; 6.1%). Source clustering through Bradford’s law revealed that Journal of Rheumatology (n=454; 10.6%; h-index=58), Arthritis and Rheumatism (n=253; 5.9%; h-index=83), Pediatric Rheumatology (n=239; 5.6%; h-index=26), Rheumatology (n=157; 3.7%; h-index=43), Clinical and Experimental Rheumatology (n=149; 3.5%; h-index=29), Annals of the Rheumatic Diseases (n=145; 3.4%; h-index=49), and Clinical Rheumatology (n=114; 2.7%; h-index=21) formed the core sources. Martini A (n=177; 4.1%; h-index=57), Ravelli A (n=128; 3.0%; h-index=49), and Ruperto N (n=112; 2.6%; h-index=48) contributed most and had the highest local impact. The most relevant affiliations included University of Toronto (n=244), University Genoa (n=199), and University Cincinnati (n=170). The h-index of the research field was 123. Totally, there were 110,668 citations with average citations per document of 25.9 and average citations per year per document of 2.0. Each publication had an average of 12.8 references. Top-5 cited papers are depicted in Table 1. The corresponding authors were most likely from the United States (n=871; 22.5%), Italy (n=328; 8.5%), and Germany (n=285; 7.4%). The United States (n=3426; 20.6%), Canada (n=1515; 9.1%), and Italy (n=1397; 8.4%) were the most productive countries. The United States, Italy, and the United Kingdom were cited mostly (30,558, 12,883, and 8,274 citations, respectively). When average article citations were considered, Italy, Canada, and Switzerland were in the top (39.28, 38.34, and 35.51 citations/article, respectively).

Conclusion: In this study, the current state of research related to juvenile idiopathic arthritis was quantitatively characterized. The United States was the most prolific country and its research had the highest number of total citations. University of Toronto was the most common affiliation. Italy had the highest average article citations.

Patient Consent: Not applicable (there are no patient data)

Disclosure of Interest: None declared

Table 1 (abstract P056). Top-5 cited publications on juvenile idiopathic arthritis

P057. The adulthood transition of patients with polyarticular juvenile idiopathic arthritis in the era of biologic agents

E. Pelechas, E. Kaltsonoudis, P. Karagianni, P. V. Voulgari, A. A. Drosos

Rheumatology, University of Ioannina, Ioannina, Greece

Correspondence: E. Pelechas

Introduction: Polyarticular JIA (rheumatoid factor positive and rheumatoid factor negative), years after the first diagnosis, can affect significantly the patients’ quality of life (1). In the pre-biological era, conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) and glucocorticoids (GCs) were the mainstay treatments affecting patients with the development of new comorbidities and complications at a very sensitive age (2).

Objectives: Evaluation of the comorbidities and complications from csDMARDs and GCs in 23 patients with transition to adulthood in a tertiary university hospital in Greece.

Methods: 23 patients (16 women) with a mean age 32 years and a mean follow-up of 5±2 years were evaluated. Average disease duration 12±3 years. Nineteen received biologic DMARDs (17 anti-TNFα, 1 Tocilizumab and 1 abatacept), and 4 csDMARDs with or without low dose GCs. Nine of the patients due to disease duration (pre-biological) received large doses of GCs for long periods of time (>10mg for >3 years) and the rest received short-term GCs. Twelve, had uncontrolled disease (DAS28 >3,2) for at least 3 years. Due to the nature of the data the JADAS score could not be used and the DAS28 has been used instead. In addition, the SF-36 (Short Form 36 Health Survey) has been used in order to evaluate health status of the patients.

Results: osteoporosis resulted in 15 patients (9 due to high and prolonged GC intake and significant disease activity, and 6 only due to prolonged GC intake). Underdevelopment in 8 patients (height <1,55m), and 8 with emotional instability (all had received large doses of GCs and had significant disease activity). Two patients required total knee arthroplasty due to severe disease and one of them had to operate both knees. One patient had total hip arthroplasty due to osteonecrosis of the right hip. The SF-36 score was lower than 50% in most patients, and more specifically the components of the test with the worst scores were a) role limitations due to emotional problems (approx. 10%), b) general health (approx. 25%), c) energy/fatigue (approx. 30%). Nevertheless, the transition to the adulthood was without significant problems and the therapeutic interventions required were minimal.

Conclusion: the advent of biological agents has significantly improved the quality of life and comorbidities of patients with polyarticular JIA. The increasing number of biological treatment options in recent years is expected to improve further the final outcomes of the disease.

Patient Consent: Not applicable (there are no patient data)

Disclosure of Interest: None declared

P058. Calcium intake and bone mineral density in juvenile idiopathic arthritis

E. Rabhi¹, K. Maatallah², H. Ferjani², W. Triki², D. Ben Nessib², D. Kaffel², W. Hamdi²

¹Rheumatology, ²Kassab orthopedics institute, Ksar Said, Tunisia

Correspondence: E. Rabhi

Introduction: Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in childhood. It’s an inflammatory condition that can lead to bone metabolism disturbance and osteoporosis (OP). We have increasing data on the negative effect of disease activity on bone mineral density (BMD) [1]. It is therefore essential to ensure optimal management of inflammation and a balanced diet to avoid adverse consequences on the bone.

Objectives: Our study aimed to assess bone mineral density (BMD) and calcium intake in children with JIA.

Methods: We conducted a retrospective study including children fulfilling the international league against rheumatism (ILAR) 2010 criteria. We collected epidemiological, clinical, juvenile arthritis disease activity score (JADAS), daily calcium intake, and therapeutic data.

Results:

Among 43 patients, thirteen underwent a bone mineral density measurement and were thus enrolled. There were 9 males and 4 females. The mean age was 13.1 ± 2.8 [10-20] years. The mean duration of the disease was 4.3 ± 3.2 years [1-11]. The mean body mass index (BMI) was 19.9 ± 5.9 [14-35.25]. The mean daily calcium intake was 574 ± 5.97 mg [252-725]. The mean JADAS was 2.7 ± 2.48 [0-6].

The main bone density was 0.975 ± 0.124 [0.73 -1,14] g/cm2 and the Z score ranged from -2.5 to 1.5 standard deviations (SD). Seven children had a low bone density (Z score<-2SD). Four patients had a history of bone fractures.

Calcium intake was significantly correlated with BMD (p<0.05). However, there was no association between BMD and BMI (p=0.23) or JADAS (p=0.4).

Among 43 patients, thirteen underwent a bone mineral density measurement and were thus enrolled. There were 9 males and 4 females. The mean age was 13.1 ± 2.8 [10-20] years. The mean duration of the disease was 4.3 ± 3.2 years [1-11]. The mean body mass index (BMI) was 19.9 ± 5.9 [14-35.25]. The mean daily calcium intake was 574 ± 5.97 mg [252-725]. The mean JADAS was 2.7 ± 2.48 [0-6]. The main bone density was 0.975 ± 0.124 [0.73 -1,14] g/cm2 and the Z score ranged from -2.5 to 1.5 standard deviations (SD). Seven children had a low bone density (Z score<-2SD). Four patients had a history of bone fractures. Calcium intake was significantly correlated with BMD (p<0.05). However, there was no association between BMD and BMI (p=0.23) or JADAS (p=0.4).

Conclusion:

Our study showed that more than half of the patients had a low bone density and all of them had, according to the recommendation of the international osteoporosis foundation, a low calcium intake. These results emphasize the need to screen for calcium deficiency intake in order to avoid the aggravation of bone fragility.

Our study showed that more than half of the patients had a low bone density and all of them had, according to the recommendation of the international osteoporosis foundation, a low calcium intake. These results emphasize the need to screen for calcium deficiency intake in order to avoid the aggravation of bone fragility.

References

1. John Burnham, Justine Shults, Sarah E Dubner, Harjeet Sembhi, Babette S Zemel, Mary B Leonardi. Bone density, structure, and strength in juvenile idiopathic arthritis: Importance of disease severity and muscle deficits. 2008 Aug;58(8):2518-27

Disclosure of Interest: None declared

P059. Defining KLRB1/CD161 expression in synovial fluid immune cells in patients with juvenile idiopathic arthritis using single-cell RNA sequencing

E. Ralph^1,2,3, Y. Sanchez-Corrales^3,4, T. Xenakis^3,4, V. Alexiou^1,2,3, C. Bolton^1,2,3, S. Castellano^3,4, L. Wedderburn^1,2,3

¹Infection, Immunity and Inflammation Department, UCL Great Ormond Street Institute of Child Health, University College London, ²Centre for Adolescent Rheumatology Versus Arthritis at UCL University College London Hospital (UCLH) and Great Ormond Street Hospital (GOSH), ³NIHR Great Ormond Street Hospital Biomedical Research Centre, ⁴Genetics and Genomic Medicine Department, UCL Great Ormond Street Institute of Child Health, University College London, London, United Kingdom

Correspondence: E. Ralph

Introduction: CD161 is a C-type lectin receptor encoded by the gene KLRB1 and is expressed on a variety of immune cells. It has been shown that CD161+ cells are highly enriched in the synovial fluid of Juvenile Idiopathic Arthritis (JIA) patients, with CD161 expressed on several cell populations including Th17, Th17/1, and some Th1 cells (‘ex-Th17’ cells)¹, regulatory CD4+ T cells², some CD8 cells (e.g. MAIT cells), NK cells and innate lymphoid cells (ILC)³. Previous studies have generally relied on pre-selected populations and/or bulk studies, often using flow cytometry. Thus, there has not been a comprehensive survey of KLRB1/CD161 expression in the different cell types present in synovial fluid with single-cell resolution.

Objectives: To map the diversity of synovial inflammatory cells expressing CD161 using single-cell RNA sequencing to define expression of CD161 in immune populations in the joints of patients with JIA.

Methods: Single-cell RNASeq analysis was carried out on synovial fluid mononuclear cell (SFMC) samples of JIA patients (n=6), targeting 50,000 cells per patient. Gene expression and TCR libraries were prepared using the Chromium Single Cell 5' Reagent Kit (v2, Dual Index) (10X Genomics) and sequenced on a NovaSeq 6000 (Illumina). Sequencing reads were pre-processed and aligned to the GrCh38 reference genome using Cell Ranger v6 (10x Genomics). Quality control, downstream analysis and average gene expression was performed using Seurat v4. Cell type annotation was performed using a single-cell multimodal PBMC reference⁴. Normalised data counts were used to calculate average gene expression per cell type. Units are transcripts per million (TPM) defined as TPM = (number of counts mapped to a gene x 10^6) / Total number of counts per cell).

Results:KLRB1 expression was detected in 32% of the total SFMCs and was enriched in 7 of 30 clusters. Expression of KLRB1 was highest in MAIT cells, with 98.9% of these cells expressing KLRB1, with an average expression level of 1903 TPM. The cluster identified as cytotoxic CD4+ T cells also expressed high levels of KLRB1, (89.8%, 1099 TPM), as did ILCs (80.3%, 1138 TPM), gamma delta T cells (70.4%, 911 TPM), natural killer (NK) cells (76.9%, 833 TPM), NK CD56^bright cells (70.1%, 697 TPM), and proliferating NK cells (58.8%, 314 TPM ). Central memory, effector memory and proliferating CD4+ T cells, as well as effector memory, naïve and proliferating CD8+ T cells, and regulatory T cells also expressed KLRB1, but at lower levels.

Conclusion: We have generated a single cell map of CD161-expressing populations in JIA synovial fluid cells. We have shown that KLRB1 is expressed in a variety of immune cells and quantify cell expression heterogeneity that has not been previously described. Future work will investigate the expression of CD161 on CD4+ T cell subsets, its correlation with inflammatory markers and clinical outcomes.

REFERENCES

1. Nistala K. et al. Th17 plasticity in human autoimmune arthritis is driven by the inflammatory environment. Proc Natl Acad Sci U S A. 2010 Aug 17;107(33):14751-6.

2. Pesenacker A.M. et al., CD161 defines the subset of FoxP3+ T cells capable of producing proinflammatory cytokines. Blood. 2013 Apr 4;121(14):2647-58.

3. Del Castillo Velasco-Herrera, M. et al. A novel innate lymphoid cell delineates childhood autoimmune arthritis. bioRxiv 416784.

4. Hao Y. et al., Integrated analysis of multimodal single-cell data. Cell. 2021 Jun 24;184(13):3573-3587.e29.

Disclosure of Interest: E. Ralph Grant / Research Support with: ER holds a personal Fellowship from NIHR Great Ormond Street Hospital Biomedical Research Centre, Y. Sanchez-Corrales: None declared, T. Xenakis: None declared, V. Alexiou: None declared, C. Bolton: None declared, S. Castellano: None declared, L. Wedderburn Grant / Research Support with: LW is a PI for the CLUSTER Consortium. The CLUSTER Consortium is supported by grants from MRC, Versus Arthritis and GOSCC and has partnerships with AbbVie, GSK, UCB, Sobi and Pfizer inc. LW declares in-kind contributions to CLUSTER by AbbVie, GSK, UCB, Sobi and Pfizer inc and non-renumerated collaborations, unrelated to this work, with Lilly and Novartis.

P060. Juvenile arthritis or recessive multiple epiphyseal dysplasia – differential diagnosis

A. Kozhevnikov, V. Kenis, E. Melchenko, A. Ramazanova

National Medical Children’s Orthopedics and Trauma Surgery Research Center Named after H. Turner, Saint Petersburg, Pushkin, Russian Federation

Correspondence: A. Ramazanova

Introduction: Chronic undifferentiated progressive arthropathy (CUPA) of children is a large group of musculoskeletal diseases. A form of juvenile arthritis (JIA), the clinical finding of which includes not only chronic synovitis, but also progressive contractures of several joints, requires differential diagnosis with the genetic disorders e.g., skeletal dysplasia. Frequent misinterpretations of the results of examinations of children with recessive multiple epiphyseal dysplasia (rMED/MED4, gene SLC26A2 Mut, OMIM 229600) in favor of rheumatic pathology demonstrate the relevance of this problem.

Objectives: The aim of the study is to determine the diagnostic criteria of skeletal dysplasia for differential diagnosis with JIA.

Methods: We retrospectively analyzed clinical unit, laboratory findings, ultrasound, x-ray, MRI in our series of patients with CUPA (low laboratory activity, enthesopathy or synovitis with progressive idiopathic contracture). The study included 74 children who were treated at the National Medical children’s orthopedics and trauma surgery Research Center, Saint-Petersburg between 2005 and 2020.

Results: We divided children into two groups: patients with rMED (52) and patients with JIA (22). Children with other monogenic mutations similar to arthritis and other forms of dysplasia were excluded from the study.

Distinctive features in the clinical picture of the rMED were disproportionate constitution, absence of morning stiffness, symmetrical contracture formation, axial deformities of the lower extremities, and absence of physiological hypermobility at an early age with impaired motor activity. Laboratory data in children with rMED were normal or indicated moderate inflammatory response without any specific changes. Radiographic data demonstrated bilateral and symmetric flattening of epiphyse with epimetaphyseal widenings, double-layered patella, dystrophic spondylolisthesis at the L5-S1 vertebrae to 10-12 years of life. X-ray of the hip joints in young children with rMED showed symmetrical delay in ossification of the femoral heads, and some patients developed bilateral extrusion subluxation of the epiphyses and avascular necrosis. In JIA, we could see a staging of radiological phases: accelerated ossification of cartilaginous epiphyses, erosive-dystrophic changes, arthrosis-arthritis.

Ultrasound and MRI are not helpful in making the diagnosis because signs of synovitis exist in both groups. Sensitivity to anti-inflammatory therapy was also not a pathognomonic criterion due to its effect on synovitis.

Conclusion: Early diagnosis and non-surgical treatment rMED are important for recovery. Because in the opposite case, progressive arthritis leads to significant disability. A comprehensive approach in the evaluation of medical data and their dynamics, which takes into account the anatomical and physiological features of children, allows us to identify the true cause of arthropathy.

Patient Consent: Not applicable (there are no patient data)

Disclosure of Interest: None declared

P061. Phenotypes of presentation of psoriatic arthritis in pediatric patient

P. P. Ramos, H. F. Menchaca-Aguayo, E. R. Mercedes-Pérez, N. De la Rosa-Encarnación, M. I. De la Cera-Rodríguez, A. Guzmán-Revilla, A. Barba-Aguilar, K. Primero-Nieto, H. Bermudez-Canales, S. Rodríguez-Aguayo, E. Faugier-Fuentes

Reumatología Pediátrica., Hospital Infantil De México Federico Gomez, Mexico, Mexico

Correspondence: P. P. Ramos

Introduction: Juvenile idiopathic arthritis (JIA) unifies all forms of chronic arthritis, affecting not only the joints but also other systems. Psoriatic JIA (JPsA) is an uncommon category in childhood and there are few reports describing the characteristics and long-term outcome of patients with psoriatic JIA than other subtypes of JIA.

Objectives: To describe the case and evolution in a patient with a diagnosis of JPsA.

Methods: Description of a clinical case and review of the literature.

Results: A 12-year-old female with 2 months of evolution with constitutional syndrome and arthralgias in the right hip and proximal interphalangeal joints associated with morning stiffness. Polyarticular JIA was diagnosed FR negative and methotrexate was started, and sulfasalazine was added due to persistent activity. He lost follow-up for four years. Subsequently, she presented with disease activity and clinical signs of sacroiliitis. MRI of the sacroiliacs was normal. She persists with arthritis of more than 10 joints, the change from methotrexate DMARD to leflunomide was performed, and the dose of sulfasalazine was increased. Approach for biologic therapy was performed. She lost follow-up for two years. She came again with disease activity, with arthritis and joint limitation, dermatosis in elbows and nail pitting; new laboratory studies, imaging and skin biopsy were performed. Due to the clinical features, a diagnosis of psoriasis was integrated and management with calcineurin inhibitor was started. Six years after the onset of symptoms, bilateral sacroiliitis was documented clinically and in sacroiliac MRI. Skin biopsy: psoriasis. Management with infliximab and double DMARDs was started. She does not present uveitis. Current treatment: methotrexate, sulfasalazine, infliximab, and topical tacrolimus.

Conclusion: There are few reports describing the evolution of AIJps and it can be confusing when classifying it. In the case of the patient, regardless of the irregularity of adherence to treatment, the clinical expression presented different phenotypes: polyarticular JIA, spondyloarthropathy and psoriatic JIA; being a complex diagnosis at the time of classification.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P063. Efficacy of secukinumab in enthesitis-related arthritis and juvenile psoriatic arthritis: results from a phase 3 study (JUNIPERA)

N. Ruperto¹, E. Chertok², J. Dehoorne³, G. Horneff⁴, T. Kallinich⁵, I. Louw⁶, M. Alessio⁷, S. Compeyrot-Lacassagne⁸, B. Lauwerys⁹, N. Martin¹⁰, K. Marzan¹¹, W. Knibbe¹², R. Martin¹³, X. Zhu¹⁴, S. Whelan¹⁵, L. Pricop¹⁴, D. J. Lovell¹⁶, A. Martini¹⁷, H. I. Brunner¹⁶ on behalf of PRINTO/PRCSG

¹IRCCS Istituto Giannina Gaslini, Genova, Italy, ²Voronezh State Medical University, Voronezh, Russian Federation, ³University Hospital Gent, Gent, Belgium, ⁴Asklepios Klinik Sankt Augustin GmbH, Sankt Augustin, ⁵Charité-Universitätsmedizin Berlin, Berlin, Germany, ⁶Panaroma Medical Centre, Cape Town, South Africa, ⁷Università degli Studi della Campania Luigi Vanvitelli , Napoli, Italy, ⁸Great Ormond Street Hospital for Children, London, United Kingdom, ⁹Cliniques Universitaires Saint-Luc, Bruxelles, Belgium, ¹⁰Yorkhill Hospital, Glasgow, United Kingdom, ¹¹Children’s Hospital Los Angeles, Los Angeles, ¹²St Lukes Intermountain Research Center , Boise, ¹³Novartis Pharmaceutical Corporation, ¹⁴Novartis Pharmaceuticals Corporation, East Hanover, United States, ¹⁵Novartis Ireland Ltd., Dublin, Ireland, ¹⁶University of Cincinnati, Cincinnati, United States, ¹⁷Università di Genova, Genova, Italy

Correspondence: N. Ruperto

Introduction: Juvenile idiopathic arthritis (JIA) categories of enthesitis-related arthritis (ERA) and juvenile psoriatic arthritis (JPsA) represent paediatric counterparts of adult non-radiographic axial spondyloarthritis and psoriatic arthritis, respectively.^1,2 JUNIPERA, a 2-year, randomised, double-blind, placebo (PBO)-controlled trial demonstrated significantly longer time to flare with secukinumab (SEC) vs PBO with sustained improvements up to Week (Wk) 104.³

Objectives: To evaluate the effect of SEC on axial and peripheral manifestations in active ERA and JPsA patients (pts).

Methods: Pts (2–<18 years age) with active disease (both ≥3 active joints and ≥1 active enthesitis site) were treated with open-label (OL) s.c. SEC (75/150 mg in pts <50/≥50 kg) in treatment period (TP)1. SEC was administered at baseline (BL) and Wks 1–4, 8 and 12. Responders at Wk 12 (JIA-ACR30 response) were randomised into the double-blind, withdrawal TP2 to continue SEC or PBO every 4 wks until a disease flare or up to Wk 100. The time to flare in ERA and JPsA pts in TP2 is reported here. JIA-ACR responses, resolution of enthesitis and dactylitis, JADAS-27, and axial, peripheral and skin manifestations were also assessed.

Results: A total of 52/86 (60.5%) pts with ERA (mean age, 13.7 years) and 34/86 (39.5%) pts with JPsA (mean age, 12.2 years) were enrolled in the OL TP1. Flare risk reduction in TP2 was 55% (HR 0.45, 95% CI: 0.16–1.28, P=0.075) in ERA pts and 85% (HR 0.15, 95% CI: 0.04–0.57, P<0.001) in JPsA pts. Improvements in JIA-ACR responses, inactive disease and JADAS-27 were observed with SEC treatment at Wk 12 and at the end of TP2 (Table). Axial symptoms in ERA with SEC and PBO at the end of TP2 were: modified Schober’s test, 100% and 100%; inflammatory back pain, 100% and 50%; Flexion, ABduction and External Rotation (FABER) test, 100% and 83.3%; and clinical sacroiliitis, 100% and 50%. Pts with CHAQ score of 0 at the end of TP2 with SEC and PBO treatment were 9 each in ERA and 8 each in JPsA. Sustained improvements were also observed in enthesitis, dactylitis and other psoriatic skin manifestations (data not shown).

Conclusion: In pts with active ERA and JPsA, SEC demonstrated a longer time to disease flare with flare risk reduction compared to PBO up to Wk 104 and exhibited rapid and sustained improvement of axial, peripheral and skin manifestations.

References

1. Pagnini I, et al. Front Med 2021;8:6673052

2. Zisman D, et al. J Rheumatol 2018;94:11–16

3. Brunner H, et al. Arthritis Rheumatol 2021;73(10)

Trial registration identifying number: NCT03031782

Patient Consent: Not applicable (there are no patient data)

Disclosure of Interest: N. Ruperto Grant / Research Support with: Bristol Myers and Squibb, Eli Lilly, F Hoffmann-La Roche, Novartis, Pfizer and SOBI, Consultant with: Ablynx, Amgen, Astrazeneca-Medimmune, Aurinia, Bayer, Bristol Myers and Squibb, Cambridge Healthcare Research (CHR), Celegene, Domain therapeutic, Eli Lilly, EMD Serono, GlaxoSmith and Kline, Idorsia, Janssen, Novartis, Pfizer, SOBI and UCB, Paid Instructor with: Eli Lilly, GlaxoSmith and Kline, Pfizer, SOBI and UCB, Speaker Bureau with: Eli Lilly, GlaxoSmith and Kline, Pfizer, SOBI and UCB, E. Chertok: None declared, J. Dehoorne Grant / Research Support with: Abbvie, Roche, Consultant with: Abbvie, Roche, Pfizer, Speaker Bureau with: Abbvie, Roche, G. Horneff Grant / Research Support with: Pfizer, Novartis, Roche, MSD, Speaker Bureau with: Novartis, Pfizer, Janssen, T. Kallinich Speaker Bureau with: Roche, I. Louw Consultant with: Pfizer, Abbvie, Janssen, Amgen, Cipla, Speaker Bureau with: Pfizer, Abbvie, BMS, M. Alessio: None declared, S. Compeyrot-Lacassagne: None declared, B. Lauwerys Employee with: UCB Pharma, N. Martin: None declared, K. Marzan Grant / Research Support with: Novartis, Sanofi, W. Knibbe Speaker Bureau with: Novartis, Amgen, UCB, Abbvie, R. Martin Shareholder with: Novartis, Employee with: Novartis, X. Zhu Shareholder with: Novartis, Employee with: Novartis, S. Whelan Shareholder with: Novartis, Employee with: Novartis, L. Pricop Shareholder with: Novartis, Employee with: Novartis, D. J. Lovell Grant / Research Support with: Astra Zeneca, Boehringer Ingelheim, GSK, Hoffman LaRoche, Novartis, UBC, Consultant with: Astra Zeneca, Boehringer Ingelheim, GSK, Hoffman LaRoche, Novartis, UBC, A. Martini Consultant with: Eli-Lilly, EMD Serono, Janssen, Novartis, Pfizer, AbbVie, Idorsia, H. I. Brunner Grant / Research Support with: Novartis, Consultant with: Novartis

Table 1 (abstract P063). Efficacy of SEC in ERA and JPsA pts

P064. Exploratory methods identify novel autoantigens in juvenile idiopathic arthritis

S. Arve-Butler^1,2,3, E. Rydén^1,2, A. Mossberg^1,2, R. Kahn^1,2

¹Wallenberg Center for Molecular Medicine, Lund University, ²Department of Pediatrics, ³Department of Rheumatology, Clinical Sciences, Lund University, Lund, Sweden

Correspondence: E. Rydén

Introduction: Specific autoantibodies in Juvenile idiopathic arthritis (JIA) remain mostly unidentified, although they may serve as potential biomarkers for disease outcome and uveitis.

Objectives: To investigate different strategies for autoantibody discovery of JIA-specific autoantigens.

Methods: Serum (n =57) and plasma (n=6) were collected from JIA patients with oligoarticular or seronegative polyarticular JIA at the Department of Pediatrics at Lund University Hospital with informed consent and assent. Anonymized serum samples from pediatric controls (n=22) were available. Ethical permission was granted by the Regional Ethical Review board for southern Sweden (LU 2016/128). Plasma from six patients with ANA positive persistent oligoarticular JIA positive were included in two exploratory analyses to identify novel autoantigens. Two pools with three patients in each (with or without uveitis) was used. First, an assay covering 42 100 unique recombinant peptides of 50-150 amino acid each, from 18 000 different proteins was used. This explored approximately 94% of the human proteome by printing the peptides on glass slides which then were incubated with the two plasma pools. Second, immunoprecipitation (IP) by plasma incubated with mixed with cell lysates from the human epithelial cell line followed by liquid chromatography mass spectrometry at BioMS (Lund University) of captured proteins was used. Peptides or proteins identified in either of the two assays in combination with autoantigens found in literature made up a selection of peptides being further investigated in a targeted array (SciLifeLab, Stockholm). In this array, patient serum (n=57) was tested individually, as well as serum from controls (n=22). The array used color coded magnetic beads, individually coated with one of the peptides and was analyzed by flow cytometry (Luminex). The data was given as raw MFI and autoantigens were defined as reactive in <10% of controls and >10% of the patients after adjustment to background beads.

Results: In the autoimmune profiling planar array, reactivity was detected to 332 peptides in at least one of the two plasma pools. Thirty-four peptides showed reactivity in both pools, 75 in the non-uveitis pool and 223 in the uveitis pool. Immunprecipitation followed by mass spectrometry showed reactivity for 131 full length proteins. Ninety-five of the precipitated proteins were overlapping in the two patient pools, 14 showed reactivity only in the non-uveitis pool and 22 in the uveitis pool. Unexpectedly, only two proteins showed reactivity in both the planar array and the IP. For targeted bead array, we selected 335 peptides for validation with an additional method and patient cohort. 174 from the planar array, 97 from IP and 102 from the literature. There was an overlap between peptides found in literature and in the IP or planar array. Of the 335 peptides, 4 were excluded due to weak coupling to the beads and 73 peptides due to high reactivity to control serum. Twenty antigens showed high reactivity in JIA patients. Fifteen of these were chosen from the planar array, three found in the literature as well as by IP and one each found exclusively in IP or in literature.

Conclusion: Autoantibody discovery is highly dependent on the choice of method, as there was almost no overlap of autoantigens found by planar array and immunoprecipitation followed by mass spectrometry. The planar array identified 15 novel potential autoantigens and the IP identified one that was not previously mentioned in literature. Our findings show that established methods can be used to discover novel autoantigens in JIA.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P065. Polyarticular JIA has a distinct co-inhibitor receptor profile among other JIA subtypes

E. Sag^1,2, Z. Balik³, S. Sener³, U. Akca Kaya³, S. Demir³, M. Kasap Cuceoglu³, E. Atalay³, S. Bocutcu³, T. Vural¹, Y. Bilginer³, B. Deleuran⁴, S. Ozen^1,3

¹Pediatric Rheumatology Unit, Translational Medicine Laboratories, Hacettepe University, ²Pediatric Rheumatology Clinic, Ankara Training and Research Hospital, ³Pediatric Rheumatology, Hacettepe University, Ankara, Turkey, ⁴Institution of Biomedicine, Aarhus University, Aarhus, Denmark

Correspondence: E. Sag

Introduction: Juvenile idiopathic arthritis (JIA) is the most common inflammatory joint disease in children, driven by continuous T-cell activation. T cell activation is counter-balanced by signals generated by co-inhibitory receptors (co-IRs) such CTLA-4, PD-1, LAG-3, and TIM-3.

Objectives: We aimed to identify the role of co-IRs in the pathogenesis of different subtypes of JIA.

Methods: In total, we included patients with oligoarticular JIA (n=67), polyarticular JIA (n=12), enthesitis related arthritis (n=17), systemic JIA (n=11) and healthy controls (HC, n=10). We collected plasma samples from the patients during the active phase of their disease. We measured the soluble plasma levels of co-IRs by commercial pre-defined cytometric bead array kits and their cellular expression by flow cytometry in blood mononuclear cells. We compared the plasma levels and cellular expressions of different coIRs within different JIA subgroups.

Results: IL-2 levels were lower than HC in all JIA subgroups. The polyarticular JIA group distinguished from the four different JIA subgroups, by having different co-IR pattern. In this specific subgroup, CTLA4, PD-1 and 4-1BB levels were higher than other groups. Polyarticular JIA is the more chronic and severe form of JIA, especially when compared to oligoarticular JIA.

We investigated the correlations between disease activity markers and plasma co-IRs. Plasma TIM3 levels correlated with erythrocyte sedimentation rate, C-reactive proteins and JADAS in the polyarticular JIA group. In oligoarticular JIA group, JADASs correlated with plasma PD-1 levels, C-reactive protein with PD-L1 plasma levels. Erythrocyte sedimentation rates correlated with IL-2, CD86, PD-L1 and PD-1 plasma levels. There was no correlation between disease activity markers and co-IRs levels in the systemic JIA group and enthesitis related arthritis group.

Finally, we analysed the cellular surface expression of different co-IRs on the PBMCs of different JIA subtypes. Similar to plasma levels, both the percentage and the MFI (mean fluorescence intensity) of CTLA4 expression was higher in polyJIA subgroup.

Conclusion: This is the first report studying the effects of different co-IRs in in different subtypes of JIA. Polyarticular JIA patients had a different co-IR profile, having more CTLA-4, PD-1 and 4-1BB in their plasma than the other subtypes of JIA, which may due to both increased degree of cellular activation and exhaustion of cells in this more resistent form of JIA.

Acknowledgement

This work was supported by a research grant from FOREUM Foundation for Research in Rheumatology

Patient Consent: Not applicable (there are no patient data)

Disclosure of Interest: None declared

P066. Evaluation of comorbidities in patients with juvenile idiopathic arthritis

N. Sahin, S. Asadova², S. N. Taşkın³, S. Doğantan³, S. Özdemir Çiçek⁴, E. Esen³, A. Paç Kısaarslan³, M. H. Poyrazoğlu³

¹Pediatric Rheumatology, Derince Training and Research Hospital, Kocaeli, ²Pediatrics, ³Pediatric Rheumatology, Erciyes University, Faculty of Medicine, ⁴Pediatric Rheumatology, Kayseri City Hospital, Kayseri, Turkey

Correspondence: N. Sahin

Introduction: Juvenile idiopathic arthritis (JIA) is a common chronic rheumatologic disease in children. In chronic diseases, comorbidities can adversely affect the course of the disease.

Objectives: In this study, we aimed that investigated comorbidities in patients with juvenile idiopathic arthritis and their effects on the disease course.

Methods: We retrospectively analyzed 204 patients under 18 years and with juvenile idiopathic arthritis. Patients were stratified into two groups with comorbidities and without comorbidities. Clinical findings, JIA subtypes, JADAS27, JSPADAS, JADI-A and E, and CHAQ scores were investigated in two groups.

Results: The number of patients with comorbidity was 99 (48.5%). The most common comorbidity was familial Mediterranean fever (FMF) in 31 (31.3%) and uveitis in 23 (23.2%). The clinical and laboratory characteristics of the patients are summarized, and the comorbidities in table 1. There was no difference between patients with and without comorbidity in terms of age, age at diagnosis, duration of JIA, and sex. The most common JIA subtype in both groups was oligoarticular JIA, followed by enthesitis-related arthritis and polyarticular JIA. There was no significant difference in the number of comorbidities by JIA subtype (p=0.79). In addition, no correlation was found between the duration of JIA disease and the number of comorbidities (Rho=-0.69, p=0.49). According to the presence of comorbidity, there was no difference in the scores of JADI-A, JADI-E, CHAQ disability, CHAQ discomfort, and CHAQ pain (respectively, p= 0.52, p=0.33, p=0.77, p=0.44, p= 0.19). There was no significant difference in JSPADAS or JADAS 27 scores between the two groups (p=0.63, p=0.55, respectively).

Conclusion: There was comorbidity in approximately half of the patients with juvenile idiopathic arthritis. Although the frequency was low, comorbidities involving all systems were observed. However, the presence of comorbidity did not affect the course of JIA.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

Table 1 (abstract P066). See text for description

P067. Conventional dendritic cells type 1 (CDC1) are strongly enriched, quiescent and relatively tolerogenic in local inflammatory arthritis

A. Boltjes¹, A. Samat¹, M. Plantinga¹, M. Mokry¹, B. Castelijns², J. F. Swart³, B. J. Vastert^1,3, M. Creyghton^2,4, S. Nierkens^1,5, J. V. Loosdregt^1,3, F. V. Wijk^1,3

¹Center of Translational Immunology, University Medical Center Utrecht, ²Hubrecht Institute, ³Pediatric Rheumatology & Immunology, Wilhelmina Children’s Hospital, Utrecht, ⁴Erasmus University Medical Center, Rotterdam, ⁵Princess Maxima Center for Paediatric Oncology, Utrecht , Netherlands

Correspondence: A. Samat

Introduction: Dendritic cells (DC) are crucial for initiating and shaping immune responses. So far, little is known about the functional specialization of human DC subsets in (local) inflammatory conditions.

Objectives: We profiled conventional (c)DC1, cDC2 and monocytes based on phenotype, transcriptome and function from the synovial fluid (SF) from Juvenile Idiopathic Arthritis patients (JIA).

Methods: Paired peripheral blood (PB) and synovial fluid (SF) samples from 32 JIA and 4 RA patients were collected for mononuclear cell isolation. Flow cytometry was done for definition of antigen presenting cell (APC) subsets. Cell sorting was done on the FACSAria II or III. RNA sequencing was done on SF APC subsets. Proliferation assays were done on co-cultures after CD3 magnetic activated cell sorting (MACS). APC Toll-like receptor (TLR) stimulation was done using Pam3CSK4, Polyinosinic:polycytidylic acid (Poly(I:C)), Lipopolysaccharide (LPS), CpG-A and R848. Cytokine production was measured by Luminex.

Results: cDC1, a relatively small DC subset in blood, were found to be strongly enriched in SF, and showed a quiescent immune signature without a clear inflammatory profile, low expression of pattern recognition receptors (PRR), chemokine and cytokine receptors, and poor induction of T cell proliferation and cytokine production. In stark contrast, cDC2 and monocytes from the same environment, showed a pro-inflammatory transcriptional profile, high levels of (spontaneous) pro-inflammatory cytokine production, and strong induction of T cell proliferation and cytokine production, including interleukin-17 (IL-17).

Conclusion: At the site of inflammation, there is specific functional programming of human DCs, especially cDC2. Monocytes in particular seem to be the most pro-inflammatory, producing high levels of IL-6 and tumor necrosis factor alpha (TNF-a) and cDC2 also show a strong pro-inflammatory profile with high T cell activation capacity. In contrast, the enriched cDC1 remain relatively quiescent and seemingly unchanged under inflammatory conditions, pointing to a potentially more regulatory role.

Patient Consent: Yes, I received consent

Disclosure of Interest: A. Boltjes: None declared, A. Samat: None declared, M. Plantinga: None declared, M. Mokry: None declared, B. Castelijns: None declared, J. Swart Consultant with: Personal fees from Amgen outside of the relevant work, B. Vastert Consultant with: Personal fees from SOBI & Novartis outside of the relevant work , M. Creyghton: None declared, S. Nierkens: None declared, J. Loosdregt: None declared, F. Wijk Grant / Research Support with: ReumaFonds Nederland; grants from Sanofi, Regeneron and Leo Pharma outside of the relevant work, Consultant with: Johnson&Johnson and Takeda outside of relevant work

P068. Effect of drug therapy for juvenile idiopathic arthritis on the level of cystatin c as a marker of renal dysfunction

S. Samsonenko, T. Borysova

Pediatric, “Dnipro State Medical University”, Dnipro, Ukraine

Correspondence: S. Samsonenko

Introduction: Juvenile idiopathic arthritis (JIA) is a chronic disease requiring years of therapy with non-steroidal anti-inflammatory drugs (NSAIDs), immunosuppressant’s, cytostatics, immunobiological agents. The aforementioned drugs, namely NSAIDs and cytostatics are potentially nephrotoxic. The above drugs, namely NSAIDs and cytostatics, are potentially nephrotoxic. About 8% of children with JIA have kidney damage, which develops on average 5 years after the onset of the disease. It has been established that the main risk factor for the development of kidney damage is the long-term exposure to NSAIDs and methotrexate in children with active forms of JIA. Early diagnosis of kidney damage will allow timely correction in the dosage of drugs and avoid their nephrotoxic effects.

Objectives: To determine the effect of drug therapy in children with JIA on eGFR by using the Cystatin C-based equation and the Hoek formula based on the serum cystatin C study.

Methods: 80 children with JIA participated in the study. The age of subjects was 10.4±4.41 (10.6-15.0) years. All children received methotrexate as a base drug. At the moment of examination 22 children received NSAIDs, 25 children received immunobiological preparations. Serum cystatin C content was determined by enzyme immunoassay. The Cystatin C-based equation 2012 and Hoek formulas were used to set the GFR by serum cystatin C levels.

Results: Non-steroidal anti-inflammatory drugs led to a decrease in GFR as found by both the Cystatin C-based equation 2012 and the Hoek formula. The incidence of GFR reduction in patients treated with NSAIDs using the Cystatin C-based equation 2012 was 100%, and using the Hoek formula was 81.8%.The use of NSAIDs in children with JIA is a risk factor for the development of reduced GFR calculated by the Hoek formula. The incidence of reduced GFR in children with NSAID use was 54.5%, 6.7 times greater than in those without NSAIDs (OR = 12.9; CI: 3.76-44.25; p<0.001). There was a low chance of a Hoek formula decrease in GFR in children with JIA who received immunobiological therapy 9.1% vs 46.8% (OR = 0.11; CI: 0.03-0.42; p<0.001).

Conclusion: Use of NSAIDs in children with JIA was more often associated with a reduction in GFR: by Cystatin C - based equation 2012 in 100% of cases p<0.01, by Hoek in 81.8%, p<0.001. The average of GFR was significantly lower in children treated with NSAIDs than in children without NSAIDs. Immunobiological therapy had a positive effect on the GFR value. The frequency of a decrease in GFR was significantly lower in the children treated with immunobiological therapy compared with those without immunobiological therapy 9.1% vs 46.8% (OR = 0.11; CI: 0.03-0.42; p<0.001).

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P069. A key role of IL-6/STAT signaling and cell-cell interactions in monocyte function in oligoarticular juvenile idiopathic arthritis

T. Schmidt^1,2, E. Rydén^1,2, A. Dahlberg^1,2, S. Arve-Butler^1,2,3, A. Mossberg^1,2, R. Kahn^1,2

¹Wallenberg Center for Molecular Medicine, Lund University, ²Department of Pediatrics, ³Department of Rheumatology, Clinical Sciences, Lund University, Lund, Sweden

Correspondence: T. Schmidt

Introduction: Synovial monocytes in oligoarticular juvenile idiopathic arthritis (oJIA) are polarized, displaying markers of both pro- and anti-inflammation.

Objectives: To study the function of synovial monocytes, and to unravel how they obtain their phenotype.

Methods: Synovial fluid (SF) and blood (which served as control) were collected from untreated oJIA patients upon therapeutic joint aspiration (total n=26). Surface markers (CD16, MerTK, HLA and CD86), cytokine production (IL-1ß, IL-6, IL-8 and TNF) and STAT phosphorylation (STAT1, STAT3 and STAT6) were analyzed in synovial- and circulating monocytes using flow cytometry. Isolated monocytes were used for efferocytosis assays using apoptotic neutrophils and co-stimulation of CD3 activated T cells from healthy donors. The influence of SF on healthy monocytes was analyzed by liquid-chromatography mass spectrometry and broad-spectrum phosphorylation assays. The mechanisms of how synovial monocytes obtain their functional phenotype was studied in vitro through stimulation of healthy monocytes using SF, migration using a transwell system or co-culture with fibroblast-like synoviocytes.

Results: Monocytes from the joint of oJIA patients display functional alterations with pro- and anti-inflammatory features. Synovial monocytes, as compared to circulating monocytes, express markers of antigen presentation (HLA, CD86), induce proliferation and activation markers (CD25, HLA and CTLA-4) in healthy T cells and are primed for STAT1 phosphorylation. In contrast, synovial monocytes also express markers of clearance (MerTK, CD16), display less production of the pro-inflammatory cytokines (IL-1ß, IL-6, IL-8 and TNF) upon activation, and have increased efferocytosis. In healthy monocytes, SF from oJIA patients, as compared to serum, induces upregulation of biological processes involved in immune responses and regulation of lymphocyte proliferation, cell-cell adhesion, and endocytosis. At the phosphorylation level, synovial fluid induces mainly STAT3, which correlates with IL-6 levels in the synovial fluid (r=0.78, p<0.0011) and is fully blocked by pre-incubation with the anti-IL-6R antibody tocilizumab (p<0.0001) or the JAK inhibitor tofacitinib (p<0.0001). At the functional level, synovial fluid, mainly through an IL-6/STAT mechanism, induces the anti-inflammatory aspects observed in the patients’ synovial monocytes, such as surface markers (CD16, MerTK (p<0.0001), increased efferocytosis (p<0.0001) and resistance to production of IL-1ß, IL-6, IL-8 and TNF (p=0.0002) upon activation. The pro-inflammatory aspects are driven through cell-cell interactions in vitro, either through migration or co-culture, which result in increased expression of CD86, HLA and T cell activation (p<0.0001).

Conclusion: Synovial monocytes from patients with oJIA display both pro- and anti-inflammatory functional alterations. This phenotype can be replicated in vitro, where SF induces the anti-inflammatory aspects mainly through IL-6/STAT signaling, whilst the pro-inflammatory aspects is replicated by cell-cell interactions through migration or co-culture with fibroblast-like synoviocytes. These data support a role of monocytes in the pathogenesis of oJIA and highlight potential impact of current and future drugs for the treatment of oJIA.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P070. Rare association of juvenile polyarthritis and steroid-resistant nephrotic syndrom – case report

V. Selmanovic¹, A. Cengic², A. Mustajbegovic³, D. Pokrajac⁴, T. Avcin⁵, M. Debeljak⁶, I. Sefic-Pasic⁷, M. Bukvic⁷, A. Dzananovic⁷

¹Department for Allergology, Rheumatology and Clinical Immunology, Children’s Hospital University Clinical Center Sarajevo, ²Department for Allergology, Rheumatology and Clinical Immunology, Children’s Hospital University Clinical Center Sarajevo, ³Department for Nephrology, ⁴Department fo Nephrology, , Children’s Hospital University Clinical Center Sarajevo, Sarajevo, Bosnia and Herzegovina, ⁵Departmentfor Allergology, rhjeumatology and Clinical Immunology, Childen’s Hospital University Clinical Center Ljubljana, ⁶Department for Allergology, rheumatology and Clinical Immunology, Children’s Hospital University Clinical Center Ljubljana, Ljubljana, Slovenia, ⁷Institut for Radiology, institut for Radiology, Sarajevo, Bosnia and Herzegovina

Correspondence: V. Selmanovic

Introduction: Renal disease is rare in children with juvenile idiopathic arthritis. The majority of children with nephrotic syndrome have minimal change disease, generally responsive to steroids. Only 10-20% are steroid-resistant.

Objectives: to describe a case of rare association of early-onset polyarthritis, steroid-resistant nephrotic syndrom and MEFBgene mutation

Methods: case report

Results: boy,4,5y, first child of healthy non-consanguineous Caucasian parents, unremarkable family history. Disease onset: age 18mo with nephrotic sy. Treated accordingly with steroids; experienced 3 relapses by age 3y. At age 2y2mo, while od steroids, developed symmetrical arthritis of hips, knees, ankles. ANA, RF, HLAB27 were negative. There were positive Scl-70 antibody, repeatedly negative. Treatment was quickly escalated and cyclosporin A was succesfully added. Kidney biopsy showed minimal change disease, without signs of amiloidosis. No signs of other organ involvement. On follow up, at age 4,5y, child has preserved renal function, normotensive, mildly active left knee arthritis. Bilateral pes equinovarus was surgically corrected in infancy. Gene panels for nephrotic syndrome and arthritis revealed MAFBgene mutation NM_005461.5:c[125C>A];[=] in patient and mother, associated with hereditary osteolysis of carpal bones with and without nephropathy. Both are not fullfilling diagnostic criteria, so there is highly unlikely that the variant is disease causing.

Conclusion: Pediatric rheumatologist treat early onset polyarthritis on everyday basis as well as nephrologist children with nephrotic syndrom of which 10-20% are steroid-resistant. Concomitant association of these two entities is rarely described, raising question whether are they part od the same still undefined disease and question of disease evolution. In this case, genetics were not diagnostic.

Disclosure of Interest: None declared

P071. Analysis the survival of genetically engineered biological therapy in children with juvenile idiopathic arthritis

V. Sevostyanov¹, P. Lototskaya², N. Babich¹, D. Rassoha¹, E. Zholobova³

¹Department of Propaedeutics of Children’s Diseases, ²Department of Rheumatology No. 1 of the University Children’s Clinical Hospital, ³Department of pediatrics, I.M. Sechenov First Moscow State Medical University Ministry of Health of Russia (Sechenov University), Moscow, Russian Federation

Correspondence: V. Sevostyanov

Introduction: At present, the issue of studying effectiveness and safety of various genetically engineered biological drugs is of great interest. A clear analysis of the reasons for drug withdrawal and an algorithm for biology switching will allow a more balanced attitude towards the initiation of this type of therapy and development of individual plans for monitoring, including management of patients receiving genetically engineered therapy.

Objectives: To analyze the survival of genetically engineered biological therapy in children with juvenile idiopathic arthritis.

Methods: An observational analytical cross-sectional study was conducted and included patients with juvenile idiopathic arthritis aged 0 to 17 years old, living in Moscow, who had history of switching and/or discontinuation of a biology in their anamnesis. This study assessed the following indicators: the period of biology therapy in months; the reason for changing or canceling therapy; the drug to which the switch was made.

Results: The switching frequency was 9.9%. The main reasons for switching/cancellation were secondary failure - 57.8%, primary failure - 12.5%, therapy intolerance - 10.9%, and the development of “de novo” uveitis in 9.4% of cases. Cancellation of therapy due to the achievement of remission was noted in 6.2% of cases. There is a trend that more often patients were switched to adalimumab (29.3%); and when adalimumab was canceled, switching was carried out to tocilizumab and golimumab. When tocilizumab has been discontinued, the majority of patients were switched to canakinumab therapy.

Conclusion: This analysis, being one of the first presenting the data from Russian Federation on the topic, shows that further accumulation and analysis of data, including cases of discontinuation of therapy, switching between drugs, as well as the duration of therapy before the event that caused the change or discontinuation of therapy are required.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P072. Clusters of JIA at methotrexate initiation identified using topological data analysis

S. J. W. Shoop-Worrall^1,2, K. L. Hyrich^1,3, L. R. Wedderburn^4,5,6, N. Geifman⁷ on behalf of CLUSTER, BSPAR-ETN Study, BCRD Study, CAPS, CHARMS

¹Centre for Epidemiology Versus Arthritis, ²Centre for Health Informatics, The University of Manchester, ³NIHR Manchester BRC, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, ⁴Centre for Adolescent Rheumatology Versus Arthritis, GOS Institute of Child Health, University College London, ⁵Paediatric Rheumatology, Great Ormond Street Hospital NHS Foundation Trust, ⁶NIHR Great Ormond Street Hospital Biomedical Research Centre, NIHR Great Ormond Street Hospital Biomedical Research Centre, London, ⁷School of Health Sciences, Faculty of Health and Medical Sciences, The University of Surrey, Guildford, United Kingdom

Correspondence: S. J. W. Shoop-Worrall

Introduction: Stratified medicine requires the identification of unique strata of a disease within which to base prognostic and treatment decisions. Juvenile idiopathic arthritis (JIA) offers a unique challenge in its inherent heterogeneity. The current ILAR classification, whilst useful for clinical categorisation, does not correlate with treatment outcomes. Therefore, further refinement, clustering and correlation of patient characteristics with treatment response are urgently required.

Objectives: To identify novel, phenotypically consistent subgroups of children and young people (CYP) with JIA at the point of starting methotrexate, across 19 patient and disease characteristics.

Methods: MTX-naïve CYP with JIA were selected if enrolled prior to April 2021 in one of four national JIA studies contributing to the UK CLUSTER consortium. Data from 19 harmonised study variables were extracted at point of starting MTX. Topological data analysis using a Gower similarity metric was used to identify clusters with distinct characteristics. Intervals and percent overlap between clusters were varied until an optimal model identified stable, potentially clinically plausible clusters. Significant differences in characteristics between identified clusters were tested using Kruskall-Wallis and Chi-Squared statistics.

Results: Of 2915 CYP included, the majority were female (68%), of white ethnicity (90%); with the most common ILAR categories being oligoarthritis (35%) and RF-negative JIA (34%).

The optimal TDA model identified six clusters which significantly differed across 16 of the 19 clinical variables at MTX initiation: Adolescents with low-moderate disease (Cluster 1, 41%), adolescents with predominantly sJIA and moderate-high disease (Cluster 2, 4%), children with predominantly sJIA and high disease (Cluster 3, <1%), children with oligo/RF-polyarthritis and low-moderate disease (Cluster 4, 43%) and two ANA-positive groups of largely females with moderate (Cluster 5, 11%) and high (Cluster 6, 1%) disease. Clustered groups also significantly differed in gender proportions (p<0.001), ethnicities (p<0.001), history of uveitis (p<0.001) and disease duration to both diagnosis (p<0.001) and MTX initiation (p<0.001), but did not differ in limited joint count (p=0.117), height (p=0.245) or BMI (p=0.394) z-scores.

Conclusion: This study shows substantial heterogeneity in JIA at the point of MTX initiation, with six clusters identified across 19 demographic and clinical variables. ILAR categories across clusters were not always indicators of disease activity or symptom burden. Future analyses will correlate MTX treatment response within each cluster to understand what role these combined factors may have on initial treatment response.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P073. What are the outcomes of persistent oligoarthritis? A systematic review plan

A. Smith^1,2, C. Swindells-Macleod ^1,2, L. Kearsley-Fleet ¹, K. Hyrich ^1,2, S. Shoop-Worrall ^1,3

¹Centre for Epidemiology Versus Arthritis, University of Manchester, ²NIHR Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, ³Centre for Health Informatics, University of Manchester, Manchester, United Kingdom

Correspondence: L. Kearsley-Fleet

Introduction: Oligoarthritis, a sub-type of JIA, can be categorised as persistent or extended. Children with persistent oligoarthritis, involving <5 joints, are often excluded from clinical trials as it is considered a milder form of JIA and managed less aggressively. Therefore, less is known about the longer term outcomes of those with persistent oligoarthritis. This knowledge could lead to better targeting of existing therapies for individuals and higher quality patient information.

Objectives: To conduct a systematic literature review on the clinical and patient-reported outcomes of persistent oligoarthritis. This abstract presents the plans and current status of the review.

Methods: Inclusion criteria for this systematic review are 1) inception cohorts with at least partial prospective data collection, 2) available in English language, 3) includes at least 50 patients with persistent oligoarthritis using ILAR criteria, 4) investigates clinical or patient-reported outcome. Exclusion criteria are 1) not specifically presenting or analysing outcomes in persistent oligoarthritis and 2) not reporting disease duration or follow-up time points from diagnosis at the point of outcome measurements.

Search terms related to ‘oligoarthritis’, (variants of juvenile oligoarthritis plus outcomes of interest) were used in MEDLINE and Embase from 01/01/1997 to 30/05/2022 to cover the advent of current ILAR categories to present. These terms were also entered into PubMed from 30/05/2020 to 30/05/2022 to include publications published online ahead of print.

Quality assessment, including common biases, of selected articles will be assessed using relevant questions from the Pasma et al. quality assessment (QA) tool.

Primary outcomes to be extracted are the core JIA outcome variables (active joint counts, limited joint count, physician’s global assessment, parent global evaluation, erythrocyte sedimentation rate and additional functional status (CHAQ/HAQ). Additional outcomes are 1) remission status, 2) uveitis status, 3) pain, 4) Health-related Quality of Life and 5) treatment response.

One reviewer will initially screen titles and abstracts. Two reviewers will then screen the full text of selected articles independently and agree the master list. The first reviewer will then extract data regarding study populations and outcome and another reviewer will check a selection of the extracted data. If there is disagreement or uncertainty between the two reviewers at any stage, a third reviewer will adjudicate. The review has been registered with Prospero (ID: CRD42022291943).

Results: To date 1051 publications have been highlighted for initial review (title and abstract) by the first reviewer. The second review is now underway and preliminary results will be ready to present.

Conclusion: There is an unmet need for improved understanding of outcome in persistent oligoarthritis. This systematic review will help inform treatment targets and future research in this common ILAR JIA category.

Patient Consent: Not applicable (there are no patient data)

Disclosure of Interest: None declared

P074. Circulating mirnas as non-invasive biomarkers for juvenile idiopathic arthritis disease activity monitoring

A. Snipaitiene¹, K. Snipaitiene², I. Juskeviciute², B. Skerbaite², A. Baranauskaite³, S. Jarmalaite²

¹Academy of Medicine, Pediatric Department, Lithuanian University of Health Scienses, Kaunas, ²Human Genome Research Group, Life Sciences Center, Vilnius University, Vilnius, ³Academy of Medicine, Rheumatology Department, Lithuanian University of Health Scienses, Kaunas, Lithuania

Correspondence: A. Snipaitiene

Introduction: New biomarkers for defining the disease activity in the juvenile idiopathic arthritis (JIA) patients are needed to predict disease course and tailor the individual treatment strategy. Several previous studies have shown that epigenetic regulation of inflammation through microRNAs (miRNAs) has significant impact on cytokine production and disease course in adult rheumatoid arthritis.

Objectives: The aim of this study was to analyze if urine- and serum-derived inflammatory miR-16, -146a, and -155 could represent the disease activity in JIA patients.

Methods: Twenty-three children diagnosed with JIA were included into the study (oligoarthritis and polyarthritis, excluding systemic JIA). For comparison, 5 healthy controls (HC) without any signs of inflammation were enrolled. Serum and urine samples were prospectively collected from Methotrexate- or anti-TNF-treated JIA patients and HC. JIA disease activity was evaluated using JADAS27, and JIA patients were divided into remission (R1, N=13) and active disease group (R0, N=10). The urinary and serum levels of selected miRNAs were evaluated by using quantitative reverse transcription PCR (RT-qPCR) method.

Results: Eighty-seven % (20/23) of included JIA patients were female, and the mean age of JIA patients was 12.8 yrs (range 3-17 yrs). Significantly lower miR-16 serum levels were detected in JIA patients compared to HC (p=0.021). miR-16 levels were also significantly decreased in separate R0 and R1 groups vs. HC (p=0.023 and p=0.039, respectively). None of analyzed miRNAs were able to dichotomize JIA from HC in urine, however, significantly higher miR-16 levels were detected in R1 and R0 group patients vs. HC (p=0.013 and p=0.028, respectively). Furthermore, urinary and serum miR-16 levels were higher in those JIA patients who had the lowest patient global assessment (PGA) evaluation in compare to higher scores (PGA≤2 vs. ≥6, p=0.022 and vs. 3-5, p=0.041, respectively). Regarding the medications, serum miR-16 level was decreased in Methotrexate- vs. anti-TNF-treated group (mostly R0 vs. R1, p=0.067), resembling the lowest miR-16 abundancy in active disease. Moreover, male patients had lower urinary levels of miR-146a than females (p=0.011), and serum miR-155 was less abundant in younger patients (p>0.05). Bodily fluid comparison showed significantly higher levels of miR-146a in serum samples than in urine (p=0.005), whereas higher levels of miR-155 were detected in urine (p=0.013). Serum miR-16 demonstrated high diagnostic potential (AUC=0.85; p=0.017) with 85% sensitivity and 80% specificity.

Conclusion: Findings of the study suggest that inflammatory miR-16 analysis in bodily fluids of JIA patients can be considered as potential diagnostic tool for disease activity and could be applied for non-invasive monitoring of children with JIA.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P075. Cardiovascular risk assessment in children with juvenile idiopathic arthritis based on aerobic capacity, echocardiographic and laboratory parameters

A. Stasiak¹, A. Ryk², J. Stańczyk¹, E. Smolewska¹

¹Department of Pediatric Cardiology and Rheumatology, ²Department of Biostatistics and Translational Medicine, Medical University of Lodz, Lodz, Poland

Correspondence: A. Stasiak

Introduction: Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in children. It is believed that children with JIA have lower cardiopulmonary capacity and worse exercise tolerance. The gold standard for assessing physical fitness is aerobic fitness, commonly referred to as the maximum or peak oxygen uptake volume (VO2 peak) measured during a maximum load exercise test. Reduced aerobic fitness may play a key role in predicting the health of JIA patients as it has been associated with cardiovascular diseases and increased adult mortality. The likely cause of this significant impairment is multifactorial and should be investigated to improve treatment strategy. Exercise programs should be applied and individualized or at least modified according to different types of the disease to improve aerobic fitness.

Objectives: The aim of this study was to assess the oxygen capacity of adolescents with JIA along with echocardiographic and laboratory parameters in order to determine a group of patients with increased risk of developing cardiovascular diseases in comparison with healthy individuals.

Methods: Determining cardiopulmonary parameters such as peak oxygen consumption, tidal volume, minute ventilation, exercise time, heart rate or oxygen pulse in combination with echocardiographic parameters and early markers of heart failure, such as NT-proBNP allowed to identify a group of patients with potential risk of developing cardiovascular disease, including heart failure. Patients were assessed based on parameters such as age, sex, BMI, type of JIA, disease activity, laboratory parameters, treatment.

Results: Study consisted of 50 patients with JIA and 50 healthy patients who served as a control group. Patients with JIA had lower median values of peak VO2 (29.05 vs 38.02 ml/min/kg, p<0.001), O2 pulse (7.00 vs 11.40 ml/beat, p<0.001), minute ventilation (55.5 vs 84.5 l/min, p<0.001), oxygen uptake efficiency slope (1.62 vs 2.17, p<0.001), and cardiac output (8.25 vs 12.75 l/min, p<0.001) than in the control group. The ventilatory anaerobic threshold (VAT) was achieved earlier and at lower VO2 values ​​in children with JIA (p=0.0001). Children with JIA also had lowered respiratory parameters such as maximum voluntary ventilation (p= 0.0031) and tidal volume (p=0.0002). Echocardiography revealed a significantly lower shortening fraction (p=0.0389); the ejection fraction was also lower in the JIA group, but it was not statistically significant. Fourteen patients (28%) had enlarged right ventricular dimensions in relation to BSA. Two patients had E/A on the mitral valve greater than 2, indicating a higher risk of left ventricular diastolic dysfunction. NT-proBNP levels of all but four patients were within norm range. Twenty-two patients attended any form of physical activity and they had significantly higher peak VO2 (p=0.0099) and ΔVO₂/ΔWR relationship (p=0.0041) values than JIA patients who were not physically active. There were no statistically significant correlations between peak VO2 and disease duration and treatment.

Conclusion: Children with JIA show moderate to severe physical impairment compared to healthy peers. Some of the patients had abnormalities in laboratory tests and echocardiographic examination, which may suggest an increased risk of cardiovascular complications. Patients who were physically active had significantly better aerobic capacity than those who were not physically active. Exercise programs tailored to the patient’s abilities should be implemented to reduce the risk of developing cardiovascular diseases.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P076. The relationship between pain, kinesiophobia and proprioception in children with juvenile idiopathic arthritis

E. Tarakcı¹, E. P. Kısa², G. Leblebici³, O. Kasapcopur⁴

¹Health Science Faculty, Department of Physiotheraphy and Rehabilitation, Istanbul University Cerrahpasa, ²Health Science Faculty, Department of Physiotheraphy and Rehabilitation, Biruni University, Istanbul, ³Health Science Faculty, Department of Physiotheraphy and Rehabilitation, Medeniyet University, İstanbul, ⁴Department of Pediatric Rheumatology, Cerrahpaşa Faculty of Medicine, Istanbul University Cerrahpasa, Istanbul, Turkey

Correspondence: E. Tarakcı

Introduction: Juvenile idiopathic arthritis (JIA) is a group of diseases that can affect many joints and systems with problems such as pain, joint stiffness, muscle atrophy and weakness. Pain is one of the most frequently reported conditions. The thought that pain may cause an exacerbation of the disease creates a fear and there may be significant barriers to increasing the level of activity. In the case of pain caused by the disease, kinesiophobia may develop in children.

Objectives: The aim of the study is to evaluate the perception of kinesiophobia and proprioception due to pain status in children with knee involvement.

Methods: Fifteen patients aged between 4 and 16 who were followed up with rheumatism diagnosis and treatment in Istanbul University Cerrahpaşa Health Sciences Physiotherapy and Rehabilitation Unit were included in the study. Sociodemographic information, involved joint location and disease duration of all cases who voluntarily accepted to participate in the study were questioned with a case report form. “Visual analog scale (VAS)” was used for pain, “Tampa Kinesiophobia scale (TKS)” for kinesiophobia, and “universal goniometer” for proprioception assessment. The target angle to be reached was determined as 60 degrees of knee flexion. The difference between the targeted angle and the achieved angle was recorded as the “achieved proprioception angle”. Statistical analysis of the data was performed using the SPSS 24.0 (Statistical Package for Social Sciences) program. P≤0.05 was considered statistically significant in all analyzes.

Results: The age of 15 children (4 boys, 11 girls) included in the study was calculated as 11.16±2.44, while the disease duration was calculated as 42.20±23.30 months. Pain status were determined as 4±2.39 (min:0- max:7). While there was a positional correlation between reaching the “achieved proprioception angle” by disease duration and TKS (p≤0.05), a positive correlation was found between reaching the proprioception angle determined by TKS and pain status (p≤001). No significant correlation was found between disease duration and pain status.

Conclusion: It showed that the sensation of pain due to the disease in children with JIA may cause fear and avoidance behavior towards movement in children. Considering the duration of the disease, the importance of directing the children to movement with methods that will relieve pain in the early period and adding proprioception exercises to the treatment made us think. Although the small number of patients seems to be a limitation in the results of our study, it is not easy to use the TKS in children. The sample group of our study continues to be expanded.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

Table 1 (abstract P076). See text for description

P077. Adalimumab and anti-drug antibodies in a cohort of children with juvenile idiopathic arthritis: a single-center experience

G. Tarantino¹, D. Pires Marafon¹, F. Comitini², R. Simeoli³, A. Aquilani¹, R. Nicolai¹, E. Marasco¹, F. De Benedetti¹, S. Magni Manzoni¹

¹Rheumatology, Ospedale Pediatrico Bambino Gesù, Rome, ²Paediatrics, Ospedale Di Cagliari, Cagliari, ³Metabolic Disease, Ospedale Pediatrico Bambino Gesù, Rome, Italy

Correspondence: G. Tarantino

Introduction: Adalimumab (ADA), a fully humanized antibody against tumor necrosis factor (TNF)-α, has revolutionized treatment of patients with juvenile idiopathic arthritis (JIA). Although most of these respond within the first weeks, a minority may show loss of response (LOR) after continued exposure. Many studies demonstrate the influence of anti-adalimumab antibodies (AAA) on serum drug concentrations and clinical outcome in adults. However, little information about AAA and LOR is available for children with JIA.

Objectives: To describe demographic and clinical features in a single-center cohort of JIA patients treated with ADA, grouped according to frequency of drug administration (1W vs 2W); to assess ADA levels versus AAA titer and, finally, to investigate possible correlation between LOR to ADA and AAA.

Methods: Records of JIA patients on ADA treatment were retrospectively reviewed with focus on medical history and ELISA (enzyme-linked immunosorbent assay) ADA/AAA levels in a 6-month-period (Feb 2021-Jul 2021). Children with idiopathic uveitis were excluded. Samples furthest from last drug administration was defined as “trough level”. Data were analyzed via descriptive statistics (STATA 15.1).

Results: Of 51 JIA patients treated with ADA (39% females), 28 had ANA positive oligoarthritis with almost one large joint involvement at disease onset (T0). None of them presented RF-positive polyarthritis, nor systemic JIA (s-JIA). The median age at T0 was about 3 years. Half of study cohort was b-DMARDS naive at ADA start (T1), while all children were on c-DMARDs. Chronic recurrent uveitis was the main reason for ADA starting, followed-by tenosynovitis and spine or hip active arthritis. At the first ADA/AAA sampling (T2), approximately 10% of patients had active disease, with elbows or wrists as the most frequently involved. Extreme variability was observed between AAA titers (median 8.4 AU/ml) and ADA levels (median 16.4 micrograms/ml), regardless from 1 or 2-weekly administration. ADA levels, compared to the days from last drug administration, reached plateau values corresponding to a pharmacokinetic steady state. Among both study groups, a possible inverse correlation between ADA and AAA was found. We identified 20 JIA patients with clinical (presence of arthritis or uveitis) or laboratory (ESR ≥15 mm/h; CRP> 0.5 mg/dL) disease activity. Among these in only 3 we found very high AAA titers (350.0 - 113.4 AU/mL). In the subgroup of 27 patients with “trough-level” sampling heterogeneous data about AAA titers and drug level distribution were observed.

Conclusion: Our preliminary data showed a possible association between occurrence of AAA and lower ADA levels. However, a targeted risk analysis about high AAA titers and LOR incidence was not available. Monitoring of drug immunogenicity should be implemented in daily practice and become subject of future studies JIA.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P078. Intra-Articular Glucocorticoid Injections (IAGI) in Juvenile Idiopathic Arthritis (JIA): a single center experience straddling COVID-19 pandemic

G. Tarantino, D. Pires Marafon, A. Aquilani, R. Nicolai, E. Marasco, F. De Benedetti, S. Magni Manzoni

Rheumatology, Ospedale Pediatrico Bambino Gesù, Rome, Italy

Correspondence: G. Tarantino

Introduction: IAGI allow precise release of steroids in inflamed sites, with proven efficacy in JIA. In younger children and in multiple injections procedures IAGI usually require general sedation, whereas local anesthesia in older patients and in single/few injection(s) procedures is well tolerated. It is not known whether COVID-19 pandemic conditioned the access of JIA children to IAGI and the procedure setting.

Objectives: To observe the frequency and the features of IAGI procedures in JIA patients straddling COVID-19 pandemic.

Methods: Records of JIA patients, who underwent IAGI from January 2019 to May 2021, with available information in the medical reports were retrospectively reviewed. Demographic and clinical features, including type, number and setting of intra/peri-articular injections, were registered. Data were analyzed through descriptive statistics.

Results: Of a total of 297 Caucasian patients included in the study (78.8% females), 152 (51.2%) had persistent oligoarthritis, 46 (15.5%) extended oligoarthritis, 89 (30.0%) polyarthritis (only 4 RF-positive), 6 (2.0%) systemic arthritis, 2 (0.7%) psoriatic arthritis and 2 (0.7%) enthesitis-related arthritis (ERA). The median age at IAGI was of 9.4 years in patients undergone general sedation, and of 16.2 years in those in local anesthesia. At GCs injection, 167 patients (56.2%) were off therapy, 77 (25.9%) on treatment only with Methotrexate, 30 (10.1%) with TNF-inhibitors association. During the study period, 434 IAGI were practiced , without significant differences in frequency of procedures between the time interval before and after the COVID-19 pandemic outbreak (Nr.16/month and 14/month, respectively) and the setting (general sedation in 73% and 70%, respectively) . The median age of children at IAGI was of 9.4 yrs in those who underwent general sedation, whereas was of 16.2 yrs in those treated in local anesthesia. Most of patients (73%) underwent only one procedure, 19% two and 9% three or more. Of the 149 procedures with single injection, 69% were performed in local anesthesia. Of note, in 117 procedures with multiple injections (27%) 5 or more sites were injected. Of a total of 396 sites injected, 80% were large joints, 47% tendons/bursae, 40% small joints. As expected, the knee, the tibiotalar, the elbow and the wrist were the most frequently injected joints (55.3%, 36.9%, 16.4%, 14.8% respectively). Notably, all of hip injections (n=6) were performed after the COVID-19 outbreak.

Conclusion: The frequency of IAGI procedures in JIA patients did not change with the COVID-19 outbreak at the study center. The knee, the tibiotalar, the elbow and the wrist were the most frequently injected joints. Hip injection were performed only during COVID-19 pandemia. Our results suggest that JIA patients and their caregivers were not limited by the pandemic in accessing the procedures and/or rely on the benefits of this treatment strategy despite potential logistic difficulties

Patient Consent: No, I have not receive consent

Disclosure of Interest: None declared

Table 1 (abstract P078). See text for description

P079. Children with extended oligoarticular and polyarticular juvenile idiopathic arthritis have a cytokine profile in peripheral blood sustaining b cell activation

C. Tomé¹, F. Oliveira-Ramos^1,2, R. Campanilho-Marques^1,2, A. F. Mourão^3,4, S. Sousa⁵, A. T. Melo^1,6, R. L. Teixeira^1,6, A. P. Martins⁷, S. Moeda⁸, P. Costa-Reis^1,8, R. P. Torres^3,4, H. Fonseca⁸, M. Gonçalves⁷, M. J. Santos^1,5, L. Graca^1,9, J. E. Fonseca^1,6, R. A. Moura¹

¹Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon Academic Medical Center, ²Pediatric Rheumatology Unit, Centro Hospitalar Universitário Lisboa Norte, EPE, Hospital de Santa Maria, Lisbon Academic Medical Center, ³Rheumatology Department, Centro Hospitalar Lisboa Ocidental, EPE, Hospital de São Francisco Xavier, ⁴NOVA Medical School, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisbon, ⁵Reumatology Department, Hospital Garcia de Orta, Almada, ⁶Rheumatology Department, Centro Hospitalar Universitário Lisboa Norte, EPE, Hospital de Santa Maria, Lisbon Academic Medical Center, ⁷Pediatric Surgery Department, Centro Hospitalar Universitário Lisboa Norte, EPE, Hospital de Santa Maria, Lisbon Academic Medical Center, ⁸Pediatric Department, Centro Hospitalar Universitário Lisboa Norte, EPE, Hospital de Santa Maria, Lisbon Academic Medical Center, Lisbon, ⁹Instituto Gulbenkian de Ciência, Oeiras, Portugal

Correspondence: F. Oliveira-Ramos

Introduction: Juvenile idiopathic arthritis (JIA) is the most common pediatric rheumatic disease and encompasses several different categories. Recently, our group has described that most patients diagnosed with the categories of extended oligoarticular JIA (eoJIA) and polyarticular JIA (pJIA) fulfil classification criteria for rheumatoid arthritis (RA) in adulthood. Moreover, we have also shown that B cell alterations and a B-cell related cytokine pattern are present since the first weeks of RA development. Therefore, we hypothesized that eoJIA and pJIA could also exhibit a cytokine profile in peripheral blood sustaining B cell activation.

Objectives: The main goal of this study was to evaluate a panel of proinflammatory and anti-inflammatory cytokines and chemokines relevant for B cell triggering and function in serum samples of eoJIA and pJIA when compared to healthy controls and persistent oligoarticular JIA (poJIA).

Methods: Blood samples were collected from eoJIA (n=15), pJIA (n=19) and poJIA (n=28) patients treated with disease modifying anti-rheumatic drugs. A group of age-matched healthy individuals (n=16) was used as control. Serum levels of APRIL, BAFF, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-17A, IL-21, IL-22, IFN-γ, PD-1, PD-L1, sCD40L, CXCL13 and TNF were measured by LEGENDplex^TM multiplex bead-based immunoassay and/ or ELISA in all groups included.

Results: Children with eoJIA and pJIA, but not poJIA, had significantly increased serum levels of APRIL and BAFF when compared to controls. Furthermore, APRIL and BAFF serum levels were significantly correlated in JIA patients. No significant differences were detected in serum levels of other cytokines between all groups analyzed.

Conclusion: Patients diagnosed with eoJIA and pJIA, but not poJIA, have elevated serum levels of APRIL and BAFF in comparison to controls. These results indicate an involvement of these cytokines in the pathogenesis of these JIA categories, suggesting a B cell activation profile. Nevertheless, influence of treatment on the pattern of cytokine environment cannot be excluded. Further studies on B cell immune responses should be explored in JIA.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P080. Do we all score the physician global assessment in the same way? Results from a large international survey with 17 case scenarios

C. Trincianti¹, M. Backström², M. Tarkiainen ³, F. Bovis ¹, T. Qiu⁴, M. Esi⁵, D. J. Lovell⁶, N. Ruperto⁷, B. Gottlieb⁸, P. Vähäsalo ^9,10,11, A. Consolaro^1,7

¹University of Genova, Genova, Italy, ²Department of Pediatrics, The Wellbeing Services County of Ostrobothnia, Vaasa, , ³New Children’s Hospital, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland, ⁴Department of Biostatistics and Epidemiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, ⁵University of Washington and Seattle Children’s Hospital, Seattle, Washington, ⁶Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, United States, ⁷Pediatric Rheumatology Unit, IRCCS Istituto G. Gaslini, Genova, Italy, ⁸Cohen Children’s Medical Center, Lake Success, New York, United States, ⁹Pedego Research Unit, University of Oulu, Oulu, ¹⁰Department of Children and Adolescents, Oulu University Hospital, Oulu, ¹¹Medical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland

Correspondence: C. Trincianti

Introduction: The physician’s global assessment of disease activity (PhGA) is a key outcome measure of juvenile idiopathic arthritis (JIA). It consists of the rating of the overall level of child’s disease activity on a 100-mm or 21-numbered circle visual analogue scale (VAS), with anchors of ‘0 = no activity’ and ‘100 = maximum activity’. The PhGA is a complex construct that captures the examiner’s subjective appraisal of patient’s disease activity at the time of the visit. However, physicians do not always seem to use the VAS in a uniform way.

Objectives: Aim of the study is to show the heterogeneity in PhGA scoring by comparing the assessment of a large international cohort of pediatric rheuamtologists evaluating multiple JIA patient’s case scenarios proposed through a web-based survey

Methods: A questionnaire including 17 detailed JIA patient cases was sent electronically to all PRINTO and PR-COIN members. The cases were structured to represent a wide spectrum of clinical situations and the PhGA was assessed by the responders on a scale from 0 to 100. To demonstrate the consistency among the VAS scores provided by multiple physicians we assessed the inter-rater reliability using the intra-class correlation (ICC). ICC estimates and their 95% confidence intervals (CI) were calculated using the “psych” package available in R (version 3.5) based on a single-rating, 2-way random-effects model. ICC values less than 0.5 indicate poor reliability, values between 0.5 and 0.75 indicate moderate reliability, values between 0.75 and 0.9 indicate good reliability, and values greater than 0.90 indicate excellent reliability. Moreover, the variability of scoring in each case was compared by the interquartile range (IQR) of the PhGA scoring.

Results: Out of 491 physicians who completed the survey, 418 (85.1%) completed the VAS scoring for all the 17 patients. The ICC of this group was 0.53 (95%CI: 0.38-0.72) indicating moderate to poor reliability. Considering the IQR of the single cases, those with the highest variability were: Case 1 (a polyarticular JIA patient with no joint involvement but with active uveitis, IQR= 37); Case 17 (an enthesitis related arthritis subject with 1 swollen joint, several restricted joints, complaining of important pain and morning stiffness, IQR= 30.5); Case 13: a RF positive polyarticular arthritis child with 10 active and 21 limited joints with 0.5 as pain VAS and no morning stiffness (IQR=28).

Conclusion: The scoring of the PhGA seems to have a poor to moderate reliability throughout the world and, in some clinical pictures, the variability expressed as IQR of this measure result higher than the expected. Shared guidelines for scoring the PGA are therefore needed to obtain consistent patient assessment in clinical trials and routine practice.

Patient Consent: Not applicable (there are no patient data)

Disclosure of Interest: None declared

P081. Natural antibodies levels depend on the activity of juvenile idiopathic oligoarthritis

E. Tsitsami¹, I. Sarrigeorgiou², M. Tsinti¹, P. Lymberi²

¹First Department of Pediatrics, University of Athens Medical School, Children’s Hospital Aghia Sofia, ²Laboratory of Immunology, Department of Immunology, Hellenic Pasteur Institute, Athens, Greece

Correspondence: E. Tsitsami

Introduction: Natural (auto)antibodies (NAAs) are primarily polyreactive antibodies encoded by germline V-gene segments. They detect autoantigens and new antigenic determinants with low affinity, and present prior to the body encountering cognate antigens. Therefore, NAAs provide a first line of defense allowing time for a specific antibody response to be elicited. Moreover, they play several roles in the immune system, including regulation of B-cell responses, control of B-cell development, selection of the B-cell repertoire, protecting thus the organism against autoimmune diseases. The IgM-NAAs are the most abundant in the body and the best studied while IgA-NAAs against lipopolysaccharides (LPS) have been considered as an endogenous homeostatic mechanism with innate specificity to microbiota.

Objectives: Given the autoimmune nature of juvenile idiopathic oligoarthritis (JIO), this study was scheduled to examine the possible involvement of NAAs in its pathogenesis.

Methods: Seventy JIO patients (aged 8,13±4,45 years, 14 males) were enrolled. The IgM antibody activity against the hapten trinitrophenyl (TNP) (proposed as a surrogate measure for polyreactivity because it is a synthetic molecule not present in the environment, to which individuals are not normally exposed), actin (a highly conserved cytoskeletal protein) and F(ab’)₂ IgG fragments (proposed as an index of immunoregulatory function) as well as concentrations of IgM ([IgM]) were measured by in-house ELISAs. Similarly, the IgA antibody activity against LPS and the concentration of IgA ([IgA]) were measured. Multivariate analysis was performed with ratios of specific IgM and IgA activities to the total IgM and IgA concentration as dependent variables and the clinical parameters of patients as independent variables.

Results: Patients with active JIO presented with ratios of IgM activities against TNP, actin and F(ab’)₂ IgG fragment to the [IgM] as well as the ratio of IgA anti-LPS activity to [IgA] significantly lower than those with inactive disease. These findings were independent of patients’ gender and age, the age at disease onset, the duration of disease, the antinuclear antibodies (ANA) positivity and the presence of uveitis.

Conclusion: Our results provide evidence supporting the autoimmune etiology of JIO. They also postulate a contribution of IgM-NAAs in the emergence of oligoarthritis flares. It is well known that the lower activity of IgM NAAs induces disturbances in tissue homeostasis, in the modulation of the immunological response and in the apoptotic clearance of cells that could drive disease flares. Finally, the observed correlation between IgA anti-LPS NAAs and disease activity might be related to the recently uncovered involvement of microbiota in the disease pathogenesis.

Patient Consent: Not applicable (there are no patient data)

Disclosure of Interest: None declared

P082. Body mass index is related to disease variables in young adults with juvenile idiopathic arthritis

A.-K. Tuomi¹, K. Rebane², E. D. Arnstad^3,4, L. Berntson⁵, A. Fasth⁶, M. Glerup⁷, T. Herlin⁷, H. Kautiainen^8,9, E. Nordal¹⁰, S. Peltoniemi¹¹, M. Rygg^12,13, V. Rypdal¹⁴, M. Zak¹⁵, K. Aalto²

¹Department of Pediatrics , New Children’s Hospital, Helsinki University Hospital, ²Department of Pediatrics, New Children’s Hospital, Helsinki University Hospital, Helsinki, Finland, ³Department of Pediatrics, Levanger Hospital, Nord-Trøndelag Hospital Trust, Levanger, ⁴Department of Clinical and Molecular Medicine, NTNU, Trondheim, Norway, ⁵Department of Women’s and Children’s Health, Uppsala University, Uppsala, ⁶Department of Pediatrics, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden, ⁷Department of Pediatrics, Aarhus University Hospital, Aarhus, Denmark, ⁸Primary Health Care Unit Kuopio, Kuopio University Hospital, Kuopio, ⁹Folkhälsan Research Center, Helsinki, Finland, ¹⁰Department of Pediatrics, University Hospital of North Norway and UIT, Tromso, Norway, ¹¹Department of Pediatrics, Helsinki University Hospital, University of Helsinki, Helsinki, Finland, ¹²Department of Clinical and Molecular Medicine, NTNU, Norway, ¹³Department of Pediatrics, St. Olavs University Hospital , Trondheim, ¹⁴Department of Pediatrics, University Hospital of North Norway and UiT, Tromso, Norway, ¹⁵Department of Pediatrics, Rigshospitalet Copenhagen University Hospital, Copenhagen, Denmark

Correspondence: A.-K. Tuomi

Introduction: Obesity is a worldwide problem¹ but relatively little is known about its influence on the disease activity, functional ability, and quality of life (QoL) of patients with juvenile idiopathic arthritis (JIA).

Objectives: To investigate the disease variables and QoL of patients with JIA divided into different body mass index (BMI) categories.

Methods: This study is a part of the population-based Nordic JIA cohort study. All newly diagnosed JIA patients were recruited from defined regions of Finland, Sweden, Norway, and Denmark between 1997-2000². Altogether 434 patients attended a follow-up visit (mean disease duration 17.5 ± 1.7 years) and 355 were included. Patients were categorized according to their (BMI): BMI<25.0, BMI 25.0-29.9, and BMI≥30.0. Disease characteristics were collected, and QoL (Fatigue Severity Scale FSS, Pittsburg Sleep Quality Index PSQI, SF36) was measured.

Results: In total, 355 (81.7 %) patients were included (mean age 24,7 years, females 72 %). Fifty-five percent of patients in the group with BMI<25.0 had oligoarthritis, whereas in the group with BMI≥30.0 (obesity) 32 % belonged to either psoriatic or enthesitis-related JIA. BMI was also found to be related to higher disease activity score (DAS28).

Higher BMI was related to lower functional ability, measured by Health Assessment Questionnaire (HAQ) (p<0.001). Patients with higher BMI reported significantly more pain (p=0.005) and had higher number of tender joints (p=0.006). Likewise, they had significantly higher CRP and ESR (p=0.002) and global VAS (p<0.001). They reported lower functional ability, experienced more fatigue, and their sleep quality was assessed to be inferior. Significant relationship was also found in the two domains of QoL: Bodily pain and general health. BMI was not found to be correlated with physical activity.

Conclusion: BMI was related to disease activity, disability, and quality of life. The role of obesity in inflammatory conditions, like JIA, needs more attention in future research.

References: 1) www.who.int/health-topics/obesity 2) Glerup M, Rypdal V, Arnstad ED, Ekelund M, Peltoniemi S, Aalto K, et al. Long-Term Outcomes in Juvenile Idiopathic Arthritis: Eighteen Years of Follow-Up in the Population-Based Nordic Juvenile Idiopathic Arthritis Cohort. Arthritis Care and Research. 2020;72(4)

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

Table 1 (abstract P082). Disease variables and QoL in young adults with JIA in different BMI groups

P083. Prevalence of autoimmune diseases in parents of children with juvenile idiopathic arthritis: results from the international pharmachild register

J. W. van Straalen¹, S. de Roock¹, V. Stanevicha², L. Lamot³, A. Estmann Christensen⁴, I. Rumba-Rozenfelde⁵, C. Lazar⁶, Y. Uziel⁷, T. Arkachaisri⁸, N. M. Wulffraat¹, N. Ruperto⁹, J. F. Swart¹ on behalf of Paediatric Rheumatology INternational Trials Organisation (PRINTO)

¹Department of Pediatric Immunology and Rheumatology, Wilhelmina Children’s Hospital, Utrecht, Netherlands, ²Riga Stradins University, Children University Hospital, Riga, Latvia, ³University Hospital Center Zagreb, University of Zagreb School of Medicine, Zagreb, Croatia, ⁴Department of Pediatrics, Odense University Hospital, Odense, Denmark, ⁵Pediatric Rheumatology, University of Latvia, Riga, Latvia, ⁶Spitalul Clinic de Urgenta pentru Copii, Cluj-Napoca, Romania, ⁷Pediatric Rheumatology Unit, Department of Pediatrics, Meir Medical Centre, Kfar Saba, Israel, ⁸Translational Immunology Institute, DukeNUS Medical School, SingHealth Academic Medical Center, Singapore, Singapore, ⁹Clinica Pediatrica e Reumatologia, IRCCS Istituto Giannina Gaslini, Genoa, Italy

Correspondence: J. W. van Straalen

Introduction: Autoimmune diseases (ADs) tend to cluster within families. However, little is known about the disposition to AD among children diagnosed with juvenile idiopathic arthritis (JIA).

Objectives: To determine the prevalence of and factors associated with ADs in parents of children with JIA.

Methods: Data were collected from the international Pharmachild register. Characteristics were compared between patients with and without a family history of AD. Prevalence rates of familial ADs were calculated and compared with general population prevalence rates as reported in the literature.

Results: The most common ADs in parents of the included JIA patients (n = 8,673) are listed in Table 1. For several ADs, prevalence was higher compared to reported numbers in the general population. Clinical Juvenile Arthritis Disease Activity Scores (cJADAS) at study entry and last follow-up were not significantly different between patients with (n = 1,231) and without a family history of AD (n = 7,442) (P = 0.61 and P = 0.82, respectively). Factors associated with a family history of AD were older age at JIA onset (P < 0.01), Scandinavian residence (P < 0.01), enthesitis-related arthritis, psoriatic arthritis and undifferentiated arthritis (P < 0.01), ANA positivity (P = 0.03) and HLA-B27 positivity (P < 0.01).

Conclusion: Several ADs have an increased prevalence in parents of children with JIA. Familial AD therefore proves to be a risk factor for JIA development and certain diseases should not be overlooked during family health history at the diagnosis stage. A family history of AD is associated with the JIA subtype but does not influence the severity or disease course.

References1. Parisi R, Iskandar IYK, Kontopantelis E, Augustin M, Griffiths CEM, Ashcroft DM. National, regional, and worldwide epidemiology of psoriasis: systematic analysis and modelling study. BMJ. 2020;369. 2. Vanderpump MPJ. The epidemiology of thyroid disease. Br Med Bull. 2011;99(1):39-51. 3. Almutairi K, Nossent J, Preen D, Keen H, Inderjeeth C. The global prevalence of rheumatoid arthritis: a meta-analysis based on a systematic review. Rheumatol Int 2020 415. 2020;41(5):863-877. 4. Stolwijk C, Onna M van, Boonen A, Tubergen A van. Global Prevalence of Spondyloarthritis: A Systematic Review and Meta-Regression Analysis. Arthritis Care Res (Hoboken). 2016;68(9):1320-1331. 5. Ng SC, Shi HY, Hamidi N, et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies. Lancet. 2017;390(10114):2769-2778. 6. Thierry S, Fautrel B, Lemelle I, Guillemin F. Prevalence and incidence of juvenile idiopathic arthritis: A systematic review. Jt Bone Spine. 2014;81(2):112-117. doi:10.1016/j.jbspin.2013.09.003

Patient Consent: Not applicable (there are no patient data)

Disclosure of Interest: None declared

Table 1 (abstract P083). Most common ADs in parents of children with JIA (n = 17,346) from the Pharmachild register

P084. How ready are adolescents with JIA for transfer to adult care?- parental perspective

A. Vermé, J. Granhagen Ljugner, C. Bartholdson

Karolinska Institutet, Stockholm, Sweden

Correspondence: A. Vermé

Introduction: In Sweden, approximately 1500-2000 children suffers from Juvenile Idiopathic Arthritis (JIA). The transfer from pediatric rheumatology care to adult rheumatology care is often perceived as difficult and creates a great deal of concern for the adolescents and their parents. Releasing control and allowing the adolescents to take greater responsibility is, for example, one if the difficulties in the transition process. It´s important that parents feel confident and ready to handover the responsibility to facilitate and give support to the adolescent during the transition process.

Objectives: The purpose of the study is to investigate parent’s perspective of how ready adolescents with Juvenile Idiopathic Arthritis (JIA) are to transfer to adult care and to take responsibility for their own health.

Methods: Parents to members of The Swedish National Organization for Young Rheumatics and parents to patients at the pediatric rheumatology clinic at Astrid Lindgren´s Children´s hospital in Sweden, aged 14-18, received an invitation to participate in the study by responding to questions included in the Readiness for Transition questionnaire.

Results: Key results:

- Most of the parents felt that their adolescents took responsibility for talking to the healthcare professionals when they visit the clinic but few took talked with healthcare professionals via phone.

- Only a few percent (3%) of the parents reported that the felt that their adolescents where fully ready to transfer to adult care.

The data consist of 96 parents who answered the questionnaire (women n= 67, men n= 28). The results show that parents perceive that adolescent’s responsibility varies greatly depending on the area of responsibility. When it came to areas concerning their own care parents reported that the adolescents took greater responsibility than when it came to for example taking contact whit the clinic in different ways.

Furthermore, the results show that a little more than a quarter of the parents felt that their adolescent didn’t take any responsibility for regularly blood test, but it was also little more than a quarter of the parents who felt that their adolescents almost always took responsibility for regularly blood test. The parents additionally reported that the adolescents often took responsibility for their medications, showing up at booked visits at the clinic and talking to the healthcare professionals. The areas that the parents reported that the adolescents took little responsibility for were booking visits to the clinic, talking on the phone with healthcare professionals and renewing prescriptions. When the parents were asked to tell how ready they felt their adolescent where to take full responsibility for their health only 4 % reported that the adolescent where fully ready and 43% reported that their adolescent was not ready at all. Similar results were reported when the parents where asked how ready the adolescents where to transfer to adult care. Only 3% reported that their adolescent was fully ready for transfer and 47% was not ready at all to transfer to adult care.

Conclusion: The result demonstrates that parents to Swedish adolescents with juvenile arthritis didn´t perceive that their adolescents where ready to transfer to adult care. Parents need support to be able to find strategies to help the adolescents to increase their participation and knowledge in their own care. One possible way to meet those needs is to introduce a structed transition program in pediatric rheumatology care in Sweden.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P085. Adaptation and validation of the methotrexate intolerance scale (Miss - Methotrexate Intolerance Severity Score) in children with juvenile idiopathic arthritis

S. Zhukov, V. A. Malievsky

Pediactric, BSMU, Ufa, Russian Federation

Correspondence: S. Zhukov

Introduction: Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in children. According to modern criteria, JIA is arthritis of unknown etiology, which begins before the age of 16 years, with a duration of more than 6 weeks. International and domestic protocols for the management of children with this pathology provide for the early prescription of basic antirheumatic drugs, mainly methotrexate (MT). Methotrexate is widely used for the treatment of JIA as a starting, basic drug with proven efficacy, but at the same time, the possibility of long-term therapy with methotrexate may be limited by a number of undesirable effects, the risk of which increases in proportion to the duration of the drug. A group of Dutch scientists developed the Methotrexate Intolerance Inventory (MISS). which have proven to be highly effective in clinical practice. In Russia, in the Republic of Bashkortostan, the necessary questionnaire was validated, which made it possible to successfully introduce the methotrexate intolerance questionnaire into the work of the department.

Objectives: Adaptation and validation of the Russian version of the MISS questionnaire (assessment of the severity of methotrexate intolerance).

Methods: The text of the questionnaire was translated and tested at the departments of hospital pediatrics (head of the department - Doctor of Medical Sciences, Professor Malievsky V.A.) and foreign languages ​​​​with a Latin language course of the Bashkir State Medical University (head of the department - candidate of philological sciences, associate professor Mayorova O.A.). The validation procedure for the MISS questionnaire included language and cultural adaptation, which, according to international recommendations for the validation of questionnaires, took place in several stages. Under our supervision there were 100 children whose age at the onset of the disease ranged from 3 to 17 years inclusive (32 boys, 32.0% and 68 girls, 68.0%). The most common variant of JIA was polyarthritis (58 children, 58.0%). 36 children (36.0%) had persistent oligoarthritis. 3 children (3.0%) had juvenile arthritis with a systemic onset. Spreading oligoarthritis was diagnosed in 3 children (3.0%).

Results: The value of the ɑ-Kronbach coefficient according to the scales of the MISS questionnaire

All scales of the questionnaire have a ɑ-coefficient >0.7, which corresponds to the optimal level of internal constancy of the questionnaire adopted for group studies. In addition, these data are comparable with the results obtained by the authors of the original questionnaire.

Conclusion: The MISS questionnaire has been adapted and validated in accordance with generally accepted requirements. An analysis of the reliability of the Russian version of the questionnaire based on the calculation of the Cronbach’s alpha coefficient indicates its sufficient reliability and the possibility of use in clinical practice.

Patient Consent: Not applicable (there are no patient data)

Disclosure of Interest: None declared

Table 1 (abstract P085). See text for description

Poster session: Systemic JIA

P086. Aortic stiffness comparison between healthy and juvenile rheumatoid arthritis children

P. Avramovski¹, S. Stoilova², M. Lazarevski³, S. Talev⁴, M. P. M. P. Avramovska⁵

¹Internal medicine, Clinical hospital D-r T. Panovski - Bitola, ²High medical scholl, St Klemet of Ohrid - Bitola, Bitola, ³Internal medicine, GOB 8th september, Skopje, ⁴Chirurgie, ⁵Gynecology and obstetric, Clinical hospital D-r T. Panovski - Bitola, Bitola, North Macedonia

Correspondence: P. Avramovski

Introduction: Aortic pulse wave velocity (PWV) is indicator of arterial stiffness. It is advances with age and seems accelerated in certain disease conditions like rheumatoid arthritis (RA), diabetes and chronic kidney disease.

Objectives: The aim of this study was to find the difference between PWVs between healthy and RA patients.

Methods: arotid-femoral PWV was assessed by pulsed-Doppler ultrasound synchronized with electrocardiography (ECG) in 65 healthy and 87 juvenile rheumatoid arthritis children aged 10.3 ± 4.1 years. Demographic data: age, height, weight, heart rate (HR) and high-sensitive C-reactive protein (hs-CRP) were measured or taken from a health record.

Results: The median PWV were: 4.52 (3.24 to 5.21) vs. 4.71 (3.47 to 5.56) in healthy and RA patients. PWV is significantly higher in RA patients (P = 0.0007). PWV significantly correlates with age (r = 0.245, P = 0.022), height (r = 0.312, P = 0.003), but not with HR (r = 0.176, P = 0.102) and weight (r = 0.187, P = 0.082) in RA patients group. PWV significantly correlated with CRP in juvenile RA patients (r = 0.241, P = 0.024), but not in healthy control (r = 0.179, P = 0.154).

Conclusion: Arterial stiffness or precisely PWV was more pronounced in the child with juvenile RA than in the healthy control. Hs-CRP as a marker of acute and low-grade inflammation is correlated with artery elasticity in juvenile RA patients

Patient Consent: No, I have not receive consent

Disclosure of Interest: None declared

P087. Polyserositis as the initial presentation of systemic JIA

J. N. Bathia¹, P. Pal¹, I. R. Chaudhury², P. P. Giri³, R. Kapoor³

¹Department of Pediatric Rheumatology, ²Department of Pediatric Medicine, ³Department of Pediatric Intensive Care, Institute of Child Health, Kolkata, India

Correspondence: J. N. Bathia

Introduction: In systemic onset juvenile idiopathic arthtitis (sJIA), polyserositis may precede the development of arthritis but they constitute rare and incidental findings

Objectives: to describe a three years old who presented with polyserositis to be later diagnosed as sJIA on development of arthritis.

Methods: Following a trauma to the left ankle this 3 year old boy presented with high grade fever for 15 days. This was associated with shortness of breath for 5 days. there was history of a transient erythematous rash over the trunk extremities 2 days prior to admission. On examination, the child was febrile, there was pallor, air entry was decreased in the right chest, abdominal examination revealed hepatosplenomegaly, ascites, and there a tender swelling over the left groin. Initial investigations revealed: Hb-7.9 gm/dL, total leucocyte count was 43. 6 x 10³/μL neutrophils 79%, lymphocytes 18%, Platelet-120 x 10³/μL ,serum albumin 2.3 g/dL, serum globulin 5.8gm/dL, serum ferritin 534 ng/ml, CRP- 168 mg/L. Initial Chest Xray was apparently normal however a ultrasonography of the chest done a few days later revealed right sided pleural effusion. USG guided pleural tap was done which revealed fibrinopurulent collection. Ascitic tap was also done. Blood and pleural fluid culture revealed no growth

Results: Considering sepsis the child was started on broad spectrum antibiotics. The fever was persistent despite adequate antibiotic coverage of 2 weeks. Bone marrow and echo-cardiogram were normal. Tuberculosis ruled out. However, the fever still persisted. With a suspicion of an autoinflammatory disease child given pulse methyl prednisolone followed by oral prednisolone following which the fever subsided and the child’s condition improved. The child was then discharged on oral oral steroids. On follow up, as the steroid were tapered the child developed arthritis of bilateral ankle joints. At this juncture the diagnosis of systemic onset juvenile idiopathic arthritis (sJIA) was made. Subcutaneous methotrexate was added and the child currently remains in remission

Conclusion: Systemic onset juvenile idiopathic arthritis may present with persistent fever and polyserositis that may resemble a disseminated sepsis without any arthritis or specific sign to establish diagnosis.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P088. Vaccination with SRP as a trigger of systemic juvenile idiopathic arthritis

H. Bermúdez Canales, E. Faugier, S. Rodríguez Aguayo, K. Primero Nieto, A. Barba Aguilar, A. Guzmán Revilla, N. De la Rosa Encarnación, P. Ramos Tiñini

Reumatología, Hospital Infantil de México Federico Gómez, Ciudad de México, Mexico

Correspondence: H. Bermúdez Canales

Introduction: Vaccines have been considered triggers of autoimmune diseases in genetically predisposed individuals through various mechanisms, such as molecular mimicry, the formation of immune complexes and the activation of polyclonal lymphocytes. However, for most patients, viral vaccines don’t carry a risk of systemic autoimmune disease and should be administered according to current recommendations because of their remarkable efficacy in reducing morbidity and mortality in all age groups.

Objectives: Describe the case of a patient who triggered Systemic Juvenile Idiopathic Arthritis after vaccination with SRP.

Methods: Caso clínico

Results: One year old female. Her condition began 5 days after administration of the vaccine (SRP). Clinical manifestations: evening fever (39°C) associated with salmon-colored and evanescent macular exanthema. She was diagnosed with Kawasaki disease and was treated with intravenous immunoglobulin (2grkgdo), acetylsalicylic acid (50mgkgday) and methylprednisolone (2mgkgday). Referred for treatment due to persistent symptoms and arthritis of the knees, carpals and ankles of 4 months of evolution. At evaluation, febrile, arthritis in shoulders, elbows, carpus, knees and ankles, lymphadenopathies in right anterior cervical region of 2 x 2 cm and bilateral inguinal region of 1 x 1 cm, in addition to erythematous macules predominantly in trunk, upper extremities and pelvic limbs, 2 to 5 mm in size were evident. Laboratory: leukocytosis with neutrophilia; anemia and thrombocytosis. Elevation of acute phase reactants (ESR and CRP). Renal and hepatic function preserved. Chest X-ray and echocardiogram without alteration. Negative infectious approach (blood cultures, urine culture, procalcitonin and viral serology). Oncological approach, bone marrow aspirate negative for malignancy. Diagnosis of Systemic Juvenile Idiopathic Juvenile Arthritis was integrated and treatment with prednisone (2mgkgday) and Tocilizumab (162mg subcutaneous every 2 weeks) was started, achieving clinically inactive disease.

Conclusion: There is limited data on the relationship of immunization and systemic autoimmunity. We report the exceptional case of Systemic Juvenile Idiopathic Juvenile Arthritis following vaccination with SRP. The comprehensive and thorough evaluation of the patient with systemic manifestations allows a timely diagnosis and initiation of appropriate treatment to control the disease without complications or sequelae.

Disclosure of Interest: None declared

P089. Prolonged fever, rash, arthritis and hyperferritinemia in a child: a case of systemic idiopathic juvenile arthritis with suspicion of occult MAS

M. E. Caseiro Alves¹, A. Sampaio Mesquita², H. Sousa², M. Paula Ramos³

¹Departamento de Pediatria Médica, Hospital De Dona Estefania - Centro Hospitalar e Universitário de Lisboa Central, ²Serviço de Pediatria, Hospital de Vila Franca de Xira, ³Unidade de Reumatologia Pediátrica, Hospital De Dona Estefania - Centro Hospitalar Universitário de Lisboa Central, Lisboa, Portugal

Correspondence: M. E. Caseiro Alves

Introduction: Systemic Juvenile Idiopathic Arthritis (sJIA), mediated by autoinflammatory cytokines, is an unique form and the most severe one of Juvenile Idiopathic Arthritis. Its diagnosis is usually challenging and a high index of suspicion is needed. Macrophage activation syndrome (MAS) is a known potentially fatal complication of sJIA which needs prompt treatment.

Objectives: To describe a case of severe SJIA complicated with MAS and to explore therapeutic options

Methods: An 11 year-old african male child, brought to the emergency room of a second level portuguese hospital, for a 1 month daily fever, anorexia, fatigue and joint pain with 8-Kg weight loss. The patient also reported feeling illness, with intermittent low-grade fever and an evanescent erythematous exanthem in the previous six months, already evaluated in a medical appointment. Upon observation, the patient appeared fatigued, febrile with an evanescent exanthema (face and trunk), hepatomegaly and bilateral arthritis of small joints of the hands and feet, wrists and ankles. Blood tests revealed microcytic hypochromic anemia (Hb 9.4 g/dL) with leukocytosis, neutrophilia, thrombocytosis, hypoalbuminemia, with elevated C-Reactive protein (15 mg/dL), erythrocyte sedimentation rate (VS 113 mm/h), fibrinogen and ferritin (1703 ng/mL). Cardiac evaluation was normal. Infectious, neoplasic and others auto-immune diseases were excluded.

Results: Ceftriaxone and ibuprofen were started. Progressive worsening in the next 24 hours with unremitting fever and prostration. Blood tests revealed a slight decrease of hemoglobin and increase in ferritin levels (15.637 ng/mL) and soluble CD 25. Concerning of installation of MAS, bolus of methylprednisolone was initiated. Treatment was maintained with prednisolone (PRD) and methotrexate (anti-IL1 was not authorized for the hospital administration) with improvement of systemic manifestations but refractory arthritis. Six months later, still in PRD, he was referred to a central hospital and interleukin-6 (IL-6) inhibitor was started with good disease control, allowing complete weaning of PRD 6 months later.

Conclusion: Diagnosis of sJIA may be rather difficult with unspecific manifestations, as reported in this case with several months of disease evolution and a severe presentation on admission.

Even though not fulfilling the 2016 criteria of MAS in sJIA, the clinical deterioration with extreme hyperferritinemia (>10,000ng/mL), strongly suggested rapidly evolving MAS. Prompt and life-saving treatment prevented the child of a high morbi-mortality risk.

Nonethless, in sJIA the precocious treatment with anti-IL1/6 is usually related to better prognosis.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P090. Comparative analysis of serum biomarkers and peripheral blood gene expression in systemic juvenile idiopathic arthritis and macrophage activation syndrome

C. Hinze¹, M. Saers¹, C. Kessel¹, G. Prencipe², F. de Benedetti², D. Föll¹, C. Bracaglia²

¹Paediatric Rheumatology and Immunology, University Hospital Münster, Münster, Germany, ²Paediatric Rheumatology, Ospedale Pediatrico Bambino Gesù, Rome, Italy

Correspondence: C. Hinze

Introduction: Systemic juvenile idiopathic arthritis (SJIA) is characterized by severe inflammation and may be complicated by life-threatening macrophage activation syndrome (MAS) which is driven by activation of the interleukin (IL)-18-interferon (IFN)γ-axis. How peripheral blood gene expression and respective serum biomarkers are related in SJIA and MAS is incompletely understood.

Objectives: To evaluate the relationship of peripheral blood innate immunity-driven gene expression and related serum biomarkers in a cohort of patients with SJIA in different disease states.

Methods: Seventy-five whole-blood-derived RNA and parallel serum samples from 45 patients (median age at sample 6.2 years) from 2 centres were analyzed using a 24 gene custom NanoString panel including IL-1/NFkB, type 1 interferon (IFN), and type 2 IFN-related genes, and a 23-plex Luminex panel. The panels included 9 related targets, i.e., both gene in the NanoString panel and related protein in the Luminex panel (CXCL9/CXCL9, CXCL10/CXCL10, IL1A/IL-1a, IL1B/IL-1b, IL1RN/IL-1RA, IL6/IL-6, IL18/IL-18, S100A9/S100A9, and S100A12/S100A12. Four different disease states were considered (18 clinically inactive disease [CID], 37 active disease [AD], 9 MAS [as defined by ACR/EULAR], and 11 pre-MAS, i.e., prior to the development of full-blown MAS). Normalized NanoString counts and composite IL-1/NFkB-related, type 1 interferon (IFN) and type 2 IFN scores, and Luminex MFI values were used for comparisons. Correlation analyses were performed. Groups were compared using non-parametric statistics.

Results: There was mild to moderate correlation between the respective gene expression and serum protein levels as measured by Spearman rank correlation across all samples for the following genes/proteins: CXCL10 (r=0.40), IL6/IL-6 (r=0.40), IL1A/IL-1a (r=0.59), IL1B/IL-1b (r=0.45), IL18/IL-18 (r=0.40), S100A9/S100A9 (r=0.50) but not between CXCL9/CXCL9 and IL1RN/IL-1RA. When comparing the individual parameters across the different disease states, significant differences across disease states were seen for most of the serum proteins, and especially prominent for CXCL9, CXCL10, and IL-18. Strong correlations were seen, for example, between the following composite gene expression scores and serum proteins: IL-1/NFkB-related score with CXCL9 (r=0.60), IL-1a (r=0.64), IL-6 (r=0.72), S100A9 (r=0.55), type 1 IFN score with CXCL10 (r=0.58), and type 2 IFN score with FasL (r=0.85), CXCL10 (r=0.78), TNF (r=0.71) but not with CXCL9 (r=0.08).

Conclusion: In patients with SJIA in different disease states, a marked dysregulation of inflammation-related serum proteins is observed, and especially IL-18 and CXCL9 in pts with MAS or pre-MAS. There was a strong correlation between IL-1/NFkB-related, type 1 IFN, and type 2 IFN gene expression signatures with several of the serum proteins assessed. IL-1RA serum levels were strongly confounded by anakinra (recombinant IL-1RA) therapy, explaining a lack of correlation between IL1RN expression and IL-1RA levels. In summary, both assessment of serum biomarkers and peripheral blood gene expression signatures may be instructive when assessing different disease states in SJIA.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P091. Speaking the same language: international cross-validation of emerging biomarkers for juvenile idiopathic arthritis - the 2022 CARRA-PRES collaborative research award

C. Kessel¹, R. Marsh², C. Wouters³, P. Proost⁴, P. Matthys⁴, D. Foell¹, S. Canna⁵, G. Prencipe⁶, C. Bracaglia⁶, F. De Benedetti⁶, D. Dissanayake⁷, R. Laxer⁷, S. Vastert⁸, F. Minoia⁹, K. L. Brown¹⁰, D. A. Cabral¹¹, G. Schulert¹² on behalf of PReS sJIA/MAS working party

¹Department of Pediatric Rheumatology & Immunology, University Children’s Hospital Muenster, Muenster, Germany, ²Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital, Cincinnati, United States, ³ Department of Pediatrics, University Hospitals Leuven, ⁴Department of Microbiology, Immunology and Transplantation, Rega Institute KU Leuven, Leuven, Belgium, ⁵Children’s Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, United States, ⁶Bambino Gesù Children’s Hospital, Rome, Italy, ⁷Department of Pediatrics, Hospital for Sick Children, Toronto, Canada, ⁸Department of Pediatric Rheumatology and Immunology, University Medical Center Utrecht, Utrecht, Netherlands, ⁹Pediatric Rheumatology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy, ¹⁰Department of Pediatrics, British Columbia Children’s Hospital Research Institute, ¹¹BC Children’s Hospital University of British Columbia, Vancouver, Canada, ¹²Cincinnati Children’s Hospital, Cincinnati, United States

Correspondence: C. Kessel

Introduction: : Over the past decade, several studies have validated the use of key biomarkers such as IL-18, CXCL9 and S100 proteins in diagnosis and follow-up of children with polyarticular course and systemic juvenile idiopathic arthritis (JIA). Despite the promise of these biomarkers, their utility is limited by their availability in only some specialized labs and medical centers. In addition, as opposed to CRP the appropriate reference ranges for these biomarkers is not standardized. Finally, even though good correlation of biomarker levels acquired in different centers using different assays may occur, absolute values can vary substantially. Collectively, this hampers a wider introduction of these markers into routine clinical care.

Objectives: In this project we set out to cross-validate emerging JIA, systemic JIA and MAS biomarkers across different measurement platforms and different international centers involved in CARRA and PReS.

Methods: We have assembled an international consortium of four CARRA Registry sites (Cincinnati, Philadelphia, Toronto, Vancouver) and four PReS (Leuven, Muenster, Rome, Utrecht) clinical research centers. In a first step we will distribute healthy donor serum samples spiked with defined concentrations of recombinant S100 proteins, CXCL9 and IL-18 to all participating centers. IL-18, S100 proteins, and CXCL9 will be determined using locally used platforms including specific ELISA, luminex, mesoscale and Ella assay. In a second step patients’ samples enrolled in the FROST study will be shipped to co-investigators labs for respective biomarker analyses. Following this all data will be analyzed for correlation coefficients and spike recovery to determine agreement across identical platforms in different labs. Linear fit models will be used to determine conversion of results across different platforms.

Results: Data collection is still in progress and ongoing.

Conclusion: The findings of this project will be highly significant because broad standardization of biomarker levels and interpretation across centers is essential for international collaborative research. Our efforts can strongly impact any future (clinical) research study in the field and beyond, that involves IL-18/CXCL9/S100 protein-driven differential diagnosis, disease activity assessment or guided treatment. The results from our study will enable wide interpretation and translation of respective biomarker data and pave the way towards their wider use in routine clinical practice.

Disclosure of Interest: C. Kessel Grant / Research Support with: Novartis, Consultant with: Novartis and SOBI, R. Marsh: None declared, C. Wouters: None declared, P. Proost: None declared, P. Matthys: None declared, D. Foell Grant / Research Support with: Novartis, SOBI, Pfizer, Consultant with: Novartis, SOBI, Chugai-Roche, S. Canna Consultant with: Novartis, SOBI, AB2 Bio, Johnson & Johnson, Simcha Therapeutics, G. Prencipe: None declared, C. Bracaglia Consultant with: Novartis, SOBI, F. De Benedetti Consultant with: Hoffmann-La Roche, Novartis, AbbVie, Novimmune, and SOBI, D. Dissanayake Grant / Research Support with: Gilead Sciences, Consultant with: Novartis, R. Laxer Consultant with: SOBI, Novartis, Eli Lilly Canada, Sanofi, S. Vastert Grant / Research Support with: Novartis and SOBI, Consultant with: Novartis and SOBI, F. Minoia: None declared, K. Brown: None declared, D. Cabral: None declared, G. Schulert Consultant with: Novartis

P092. Predictors of remission in children with systemic juvenile idiopathic arthritis receiving tocilizumab: a retrospective cohort study

E. Krekhova^1,2, E. Alexeeva¹, T. Dvoryakovskaya ¹, K. Isaeva², R. Denisova ², A. Chomakhidze ², O. Lomakina ², A. Mamutova ², A. Fetisova ², M. Gautier ², C. Chibisova ², I. Kriulin ¹, I. Tsulukia ²

¹Pediatric, Sechenov First Moscow State Medical University, ²Rheumatology, National Medical Research Center of Children’s Health, Moscow, Russian Federation

Correspondence: E. Krekhova

Introduction: Tocilizumab (TOC) is a highly effective biological drug for therapy of systemic juvenile idiopathic arthritis (sJIA). The identification of early prognostic factors of response to TOC is necessary to increase treatment efficacy and predict long-term outcomes in children with sJIA.

Objectives: This study aimed to identify possible predictors of response to the TOC treatment in patients with sJIA.

Methods: We analyzed retrospectively the 258 prescribing of TOC to the patients with sJIA treated at the National Medical Research Center of Children’s health, Moscow, Russia (initiation between July 2009 and February 2021). Predicted outcomes included inactive disease after 12 months of therapy with TOC (according to C. Wallace criteria and JADAS71). Probable prognostic factors (n=115) included baseline demographic, clinical, laboratory variables, previous or concomitant therapies and changes some of them on the 1^st and 3^rd month of the therapy. We determined predictors of response using multivariate logistic regression analysis.

Results: After 12 months of TOC therapy, in 179 cases (76%) was achieved inactive disease according to C. Wallace criteria and in 170 cases (72%) was achieved JADAS remission.

The predictors of achieving the stage of inactive disease/remission according to C. Wallace criteria by the 12 month of TOC therapy were: duration of morning stiffness at sJIA onset, its dynamics after 1 and 3 months of treatment, the physician global assessment of disease activity after 1 month of therapy, and the patient/parent global assessment of overall well-being after 3 months of therapy.

The duration of morning stiffness at sJIA onset and upon treatment initiation, the physician global assessment of disease activity after 1 and 3 months, and number of painful joints after 3 months were associated with remission according to JADAS71 index by the 12 month of TOC therapy.

Conclusion: Our results showed that the characteristics of joint syndrome before and 1–3 months following treatment initiation, dynamics of objective and subjective assessment of disease activity after 1-3 months of therapy, could predict the effectiveness of TOC by 1 year of therapy in sJIA patients.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P093. SARS-COV-2 in systemic juvenile idiopathic arthritis: can ANTI-IL-1 drugs prevent MIS-C? A monocentric data collection

M. C. Maggio, G. Corsello

PROMISE “G. D’Alessandro”, University of Palermo, Palermo, Italy

Correspondence: M. C. Maggio

Introduction: The worldwide pandemic of SARS-CoV-2 continues to have a serious impact on global health care across the world. The risk of severe COVID-19 is of concern for patients with rheumatic diseases and especially systemic Juvenile Idiopathic Arthritis (sJIA) using disease-modifying anti-rheumatic drugs (DMARDs) including biologics. Even if COVID-19 shows to be milder in children than in adults, multisystem inflammatory syndrome in children (MIS-C) is a fearful and a life-threatening complication.

Objectives: The international literature showed that COVID-19 underwent without serious complications in sJIA patients controlled by biologics, but not by steroid therapy. Many studies sustain the hypothesis that uncontrolled sJIA and its underlying inflammatory state are a risk factor for severe COVID-19 in children, and that immunosuppression associated with prolonged corticosteroid treatment represents another risk factor for severe disease.

Methods: We describe the case series of 5 patients affected by sJIA, acquiring SARS-CoV-2 infection. 4/5 was treated for sJIA with anti-IL-1 beta biologic drug, at the dosage of 4 mg/kg/4 weeks and showed a good control of the sJIA. One patient, with a concomitant mutation of NLRP-3, was treated with anakinra and prednisone for the difficult control of the disease. 60% of the patients previously received 2 doses of the SARS-CoV-2 vaccine.

Results: All the patients showed persistent fever (100%), arthralgia and or arthritis (80%), respiratory symptoms (100%), with a good saturation in air, abdominal pain (40%). They were treated with ibuprofen, and they continued anti-IL-1 treatment. The acute phase resolved in a variable period of 5-10 days and the haematological parameters returned to the normal range.

The patient with the worse control of the disease and the NLRP3 mutation, 4 weeks later, showed fever, rash, cheilitis, conjunctivitis, significant increase of AST, ALT, gamma-GT, pro-BNP, troponin. The diagnosis of MIS-C was defined, and the treatment choice was with IVIG (2 gr/kg), methylprednisolone (2 mg/kg/day i.v.) and the increase of anakinra dose to 4 mg/kg/day. The acute phase of the disease was controlled, with the complete recovery of the child.

Conclusion: Our case series confirm a good outcome of the disease in children with SARS-CoV-2 infection, when the rheumatic disease is well controlled. The NLRP3 gene mutations increase IL-1 beta synthesis, with and underlying amplification of the risk of MIS-C. furthermore, the undergoing treatment with steroids in a patient with a bad control of sJIA is a further risk factor for a poor outcome. The vaccination with the SARS-CoV-2 vaccine can be a further protective factor for patients with sJIA.

Disclosure of Interest: None declared

P094. The emerging role of cardiovascular magnetic resonance in the assessment of cardiac involvement in systemic juvenile idiopathic arthritis: early treatment for an early resolution

M. C. Maggio¹, A. Alaimo², F. Finazzo³, G. Corsello⁴

¹University Department PROMISE “G. D’Alessandro”, University of Palermo, ²U.O.C. of Paediatric Cardiologic Division, Children Hospital “G. Di Cristina”, ³U.O.C. of Paediatric Radiology, Children Hospital “G. Di Cristina”, ARNAS, ⁴University Department PROMISE “G. D’Alessandro”, University of Palermo, Palermo, Italy

Correspondence: M. C. Maggio

Introduction: Systemic Juvenile Idiopathic Arthritis (sJIA) may seriously damage various structures of the cardiovascular system. However, cardiovascular disease (CVD) is understudied and, than, underestimated in patients with sJIA, but chronic systemic inflammation associated with cardiovascular risk factors are causes of CVD. The initial evaluation of sJIA patients is based on non-invasive modalities, however frequently they fail to detect subclinical forms of CVD.

Objectives: Cardiovascular magnetic resonance (CMRI) can offer early and non-invasive information about CVD in sJIA, allowing timely starting of cardiologic and anti-rheumatic drugs.

Methods: A 11-year-old girl presented with flu-like symptoms, systemic inflammation with myocarditis, and cardiomyopathy. She was treated with paracetamol and FANS, however, for the worsening of clinical conditions, she was transferred to our paediatric rheumatic unit. She showed fever, with 2-3 spikes over the day > 39°C, associated with evanishing rash, and with spontaneous defervescence during the day. She showed arthralgia at the legs, back pain, with functional limitation, with a polyarticular localization, without swelling. ECG and echocardiography were normal in the first days of the disease. During the first weeks of the follow-up, she presented infero-lateral negative T wave. She showed enhanced troponin levels, and for the suspicion of myocarditis, CMR was performed. The delayed myocardial enhancement exhibited focal myocardial fibrosis.

Results: She was treated with steroids and after a gradual tapering, with canakinumab, a biological drug against IL-1 beta, at the dosage of 4 mg/Kg/every 4 weeks. Her condition improved dramatically, with a complete recovery of ventricular function. ECG documented the complete resolution of negative T wave and CMR showed the resolution of myocardial fibrosis. She is still followed in our unit. She reached complete remission, and canakinumab is now administered every 10 weeks.

Conclusion: Myocarditis is a well-documented complication of sJIA. This unusual case emphasizes the important role of canakinumab in the treatment of sJIA and the efficacy of a early treatment with biological drugs in these cases. Furthermore, we can speculate that the early treatment with canakinumab contributed to the prompt remission of the patient, to the complete recovery of the myocarditis and to the sJIA remission of the disease.

Disclosure of Interest: None declared

P095. Fever with rash - the path leads us here

S. Maity

Department of Pediatrics, P D Hinduja National Hospital and Medical Rsearch Centre, Mumbai, India

Correspondence: S. Maity

Introduction: 8 year old male child, 1^st by birth order , born out of non-consanguineous union presented with complaints of high grade fever upto 102-103 degree F , 2-3 spikes/day , since last 2.5 months with intact activity in inter-febrile period. History of rash over face , usually at the time of fever and subsiding with fever . Weight loss 3-4kgs. No history of joint pain/ swelling/ redness.

Objectives: 1) To determine the etiology of the illness

2) To start necessary treatment /intervention at the earliest .

Methods: On examination , the child had Left upper cervical and bilateral inguinal lymph nodes palpable. No systemic localizing sign ,No hepatosplenomegaly.

Laboratory Evaluation :

CBC-Hemoglobin 11.3 gm%, Total Leucocyte count 27900, N92L6, PLATELET 2.66 LAKHS, PCV 32, ESR 37. Given antibiotics- azithromycin and amoxiclav-clavulinic acid , without resolution. Blood and urine cultures were negative ,sputum for Tuberculosis work-up was negative. CSF- Protein-112, sugar- 64, WBC- 10/hpf, CSF for TB work-up- Negative.

Shifted to tertiary care center .CT chest done, no significant abnormality found. Broncho alveolar lavage fluid sent for evaluation , negative for TB workup and malignant cells . 2D Echo showed no vegetations. ANA, ANCA, C3 -normal. Ferritin was high- 1354 (<140). Bone marrow study -normal. MRI brain with spine s/o no brain demyelination or meningeal enhancement , bilateral Atlantoaxial joint effusion was noted.

Results: In view of

• 1) Quotidian fever for more than 6 weeks associated with evanescent rash

• 2) lymphadenopathy and

• 3) Radiological evidence of joint involvement ,

Diagnosis of SYSTEMIC JUVENILE IDIOPATHIC ARTHRITIS (SJIA) was considered. Started on steroid and weekly methotrexate, responded well to the treatment.

Conclusion: High grade fever with evanescent rash for prolonged duration in an otherwise well child should raise the suspicion of SJIA and the child should be worked-up accordingly. The take home message is , subtle radiological evidences of joint involvement can help in the diagnosis of the same.

Statement : I tried to include the image in this submission but unable to do so, kindly note that i can communicate the necessary image via amail or any appropriate portal.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P096. Atypical skin manifestations at onset of systemic juvenile idiopathic arthritis are associated with failure of first-line corticosteroid treatment and difficult-to-treat disease

L.-A. Eveillard¹, P. Quartier², N. Ouldali³, B. Badder-Meunier², F. Aeschlimann², C. Abasq-Thomas⁴, C. Ballot⁵, P. Bouric⁶, A. Desdoits⁷, C. Dumaine³, C. Galeotti⁴, V. Hentgen⁸, A. Lefèvre-Utile⁹, A. Chausset¹⁰, T. Hubiche¹¹, I. Kupfer-Bessaguet¹², S. Leclerq-Mercier¹³, S. Mallet¹⁴, I. Melki³, E. Merlin¹⁵, J. Miquel¹⁶, M. Piram¹⁷, D. Talmud¹⁸, N. Garcelon¹⁹, C. Vinit³, A. Welfringer²⁰, E. Bourrat²¹, U. Meinzer³

¹Department of Infectious Disease and Internal Medicine, Reference centre for Rheumatic, AutoImmune and Systemic diseases in children (RAISE), Robert Debré University Hospital, Assistance Publique Hôpitaux de Paris, ²Pediatric Immunology-Hematology and Rheumatology Unit, Rare Disease Reference Centre (RAISE), IMAGINE Institute, Necker-Enfants Malades Hospital, Assistance Publique Hôpitaux de Paris, Université de Paris, ³General Paediatrics, Department of Infectious Disease and Internal Medicine, Reference centre for Rheumatic, AutoImmune and Systemic diseases in children (RAISE), Robert Debré University Hospital, Assistance Publique Hôpitaux de Paris, Université de Paris, Paris, ⁴Department of Pediatric Rheumatology Reference Centre for Autoinflammatory diseases and amyloidosis (CEREMAIA), Hôpital Bicêtre, Assistance Publique Hôpitaux de Paris, Le Kremlin-Bicêtre, ⁵Paediatric haematology, Jean-Minjoz Hospital, Besançon, ⁶Department of Biochemistry and Molecular Biology, CNRS, Recombinaisons genetiques, Rennes, Rennes, ⁷Department of pediatric surgery, AutoImmune and Systemic diseases in children (RAISE), Reference Centre for Autoinflammatory Disorders (CEREMAI), CHU de Caen, Caen, ⁸Reference Centre for Autoinflammatory Disorders (CEREMAI), Centre Hospitalier de Versailles, Le Chesnay Cedex, ⁹General Pediatrics and Pediatric Emergency Department, Jean Verdier Hospital, Université de Paris, INSERM, U976 HIPI Unit, Institut de Recherche Saint-Louis, F-75006,Assistance Puplique-Hôpitaux de Paris (APHP), Paris, ¹⁰Inserm CIC 1405, service de pédiatrie, CHU Estaing, Clermont-Ferrand, ¹¹Department of Dermatology, Université Côte d’Azur, Nice, ¹²Department of Dermatology, Centre Hospitalier de Quimper, Quimper, ¹³Pathology Department, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, Paris, ¹⁴Department of Dermatology, Timone Hospital, Marseille, ¹⁵Department of Pediatrics, Clermont-Ferrand University Hospital, Clermont-Ferrand, France, ¹⁶Department of Pediatrics, CHU Reunion Saint Pierre, Saint-Pierre, Réunion, ¹⁷Pediatric dermatology unit, Department of Pediatrics, CHU Sainte Justine, CHU Sainte Justine Research Centre, University of Montreal, Montréal, Canada, ¹⁸Pediatric Department, American Memorial Hospital, CHU de Reims, Reims, ¹⁹Institut Imagine, Centre de Recherche des Cordeliers, UMR 1138, INSERM, ²⁰Department of Dermatology, Reference Centre for Genodermatoses and Rare Skin Disease (MAGEC), Necker-Enfants Malades hospital, Assistance Publique Hôpitaux de Paris, Université de Paris, ²¹Department of Dermatology, Robert Debré University Hospital, Assistance Publique Hôpitaux de Paris, Université de Paris, Paris, France

Correspondence: L.-A. Eveillard

Introduction: The rash in systemic juvenile idiopathic arthritis (SJIA) is usually transient, but cases of atypical skin lesions because of their fixed nature have been reported.

Objectives: To describe the spectrum of typical and atypical skin lesions present at onset of SJIA in children and examine whether their presence may be an early clinical marker associated with difficult-to-treat patients.

Methods: A retrospective French multicenter study from 2002 to 2020, including pediatric patients with SJIA meeting the PRINTO classification criteria with documented skin lesion.

Results: 80/112 (71%) patients presented typical and 32/112 (29%) atypical skin lesions. Patients with atypical skin lesions had a higher CRP level (p=0.002) and higher ferritin (p=0.0015). The presence of atypical skin disease was associated with a risk of first-line treatment failure at 1 year (OR 10.6 CI[3.4; 46.8]), failure of glucocorticoids as first-line treatment at 1 year (OR 5.6 CI[2.2; 16.4]), need for biotherapy treatment at one year (OR 5.5 CI[1.9; 19.7]) and at two years (OR 8.2 CI[2.2; 53.3]).

Conclusion: Initial atypical skin lesions are associated with a poorer disease evolution, and may require the use of first-line biotherapies. Initial diagnostic evaluations for SJIA should include an examination by a dermatologist.

Trial registration identifying number: CNIL 1980120

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P097. Clinical features of systemic juvenile idiopathic arthritis associated with interstitial lung disease: single center’s experience

M. Kaleda, I. Nikishina, E. Nikolaeva, S. Salugina, E. Fedorov

Pediatrics, V.A. Nasonova Research Institute of Rheumatology, Moscow, Russian Federation

Correspondence: M. Kaleda, I. Nikishina

Introduction: It’s now well known, that systemic juvenile idiopathic arthritis (sJIA) may be associated with lung disease (LD), which albeit insufficiently defined and characterized.

Objectives: to characterize the clinical features all cases of LD associated with sJIA (sJIA-LD) based on long-term experience of the single center.

Methods: Retrospective study of all consequently pts with sJIA-LD in pediatric department of single center for the last 10 years.

Results: sJIA-LD is rare pulmonary complications which found in 5.0% of our cases of sJIA - 6 pts in total (4 were girls). The median (Me) age of sJIA at onset was 2.7 y.o. [IQR 1.8; 5.9]. The Me of the number of systemic manifestations at onset was 4.5 [3;6], 83.3% of pts had typical rash. The Me of the number of active joints at the time of sJIA verification was 8.0 [6; 18]. The Me of CRP level at onset was 72.5 mg/l [IQR 45.2; 112.4]), the Me of ferritin level - 892.5 ng/ml [IQR 349.0; 7256.0]). 5 pts had the history of macrophage activation syndrome (MAS) – 13.5% from all pts with MAS in our cohort of sJIA. All of them had MAS at onset, 4 – recurring MAS. There was a known family history of lung abnormalities in 1 patient – ​​2 of her older sisters died in the neonatal period from unidentified pulmonary pathology. 1 patient had the history of repeated episodes of eosinophilia (max 16%) and atypical urticarial rash that occur before LD detection. The therapy in all pts included steroids (100%), DMARDs (methotrexate (MTX) alone – 2 pts, MTX and cyclosporine consecutive – 4 pts), biologics (B) – all pts. The Me disease duration prior to start of treatment with B was 11.0 months [IQR 3.0; 18.0]. All pts were treated by tocilizumab (TCZ) as the 1^st line of B. 1 patient received TCZ only. 5 pts had anaphylactic reactions on TCZ so they have got from 2 to 5 B consecutively (in 3 pts TCZ switched to canakinumab (CAN), in 1 – to rituximab-anakinra-CAN, in 1 – to adalimumab-abatacept-CAN-sarilumab). The reasons for substitution therapy for the other B were loss of efficacy. The median of disease duration at the time of sJIA-LD verification was 4.0 years [IQR 2.8; 6.25]. At LD diagnosis, respiratory signs and symptoms were subtle in 4 pts, absent in 2 pts, although hypoxia was in 2 pts. The clinical signs of pulmonary hypertension were absent. All pts had bulbous deformity with erythematous clubbing of fingers. All pts had pulmonary involvement on chest CT scans (4 - septal thickening involving the periphery of multiple lobes, most marked in the lower lung zones, with ground-glass opacities, 1 – predominance of peribronchovascular consolidation, 1 - crazy-paving). 2 pts died, the duration of the disease at the time of death was 4.0 and 4.5 years. They had progressive LD with multiple organ failure, but without new episodes of MAS, 1 patient received TCZ, 1 - CAN. Other pts continued to receive B in stable mode with steroids in a low dose without evidence of LD progression and without of recurrent MAS during the last year of follow-up.

Conclusion: According to our data, patients with sJIA-LD mostly had an early onset of sJIA, the history of MAS, and an anaphylactic reactions on TCZ. The vast majority of pts had difficulties with the choice of therapy of sJIA. Usually lung involvement had hidden course for the years just with small subclinical signs. The establishment of predictors for early recognition of sJIA-LD, prevention strategies and special approaches to the choice of therapy are very important to ensure a better prognosis.

Patient Consent: No, I have not receive consent

Disclosure of Interest: None declared

P098. Dynamics of vascular condition and endothely functions in patients with systemic form of juvenile idiopathic arthritis on the treatment

T. Marushko¹, O. Onufreiv¹, Y. Marushko²

¹Pediatrics-2, Shupyk National Healthcare University of Ukraine, ²Pediatrics of postgraduate education, Bogomolets National Medical University, Kyiv, Ukraine

Correspondence: O. Onufreiv

Introduction: The course of systemic juvenile idiopathic arthritis (JIA) is characterized by damage to small vessels. Diagnosis of vascular changes in people with risk factors for their early development, including the systemic form of JIA, in childhood in the subclinical stage is important for the prevention of cardiovascular disease in these patients in adulthood.

Objectives: To analyze the condition of blood vessels and endothelial function in patients with the systemic form of JIA on the background of basic therapy and treatment with immunobiological drugs.

Methods: We observed 24 patients with the systemic form of JIA, 15 received methotrexate, 9 patients were prescribed tocilizumab due to insufficient effectiveness of basic therapy. The mean patient age was 9.2±0.5 years. The average duration of the disease was 2.8±0.9 years. At the time of tocilizumab administration systemic glucocorticoid therapy (GC) (methylprednisolone) was administered for 15 (62.5%) over an average of 2.3 years, with a mean dose of 0.2 mg/kg for prednisolone. To assess the effect of immunobiological drugs on the condition of blood vessels, patients underwent duplex sonography to determine the thickness of the intima-media complex of the common carotid arteries (CCA), the IMT of the abdominal aortic, the stiffness index of CCA, differences in diastolic velocities and diameters of the brachial artery using the test for endothelium-dependent dilatation of the vessel and the index of left ventricular myocardial mass (LVM). The difference between the values of these indicators before investigation and after 6 months of therapy was also calculated.

Results: The inclusion of tocilizumab in the complex therapy of patients with systemic JIA, who had insufficient effect from treatment with methotrexate and GC, led to the elimination of systemic manifestations of the disease within six months, reducing the severity of joint syndrome, average number of joints with synovitis per patient and normalization of laboratory parameters. In patients with JIA who received tocilizumab in combination therapy, the magnitude of the change in the IMT of CCA, the IMT of the abdominal aortic, the stiffness index of CCA and the index of LVM mass were significantly smaller than in children receiving methotrexate. In the group of children receiving methotrexate, in all patients the value of these indicators increased over 6 months of follow-up, which indicated the progression of subclinical vascular damage despite a decrease in JIA activity. The mean differences in the difference in diastolic velocities and brachial artery diameter in children receiving tocilizumab before to immunobiological administration were significantly lower than those in the methotrexate group. After six months of therapy with immunobiological drug, the value of these indicators increased significantly compared to their initial values. These data indicate that before starting treatment with immunobiological drugs in patients with JIA there was endothelial dysfunction, which after 6 months of therapy was not detected again.

Conclusion: In children with JIA on immunobiological therapy, the rate of progression of subclinical vascular wall lesions and increase in LVM mass was significantly lower than in patients receiving basic treatment. In patients with systemic JIA on complex therapy with tocilizumab for six months the rate of increase in the IMT of CCA, the IMT of the abdominal aortic, the stiffness index of CCA and the index of LVM mass was significantly lower than in patients with JIA who received standard base therapy. There was observed normalization of endothelial function during 6 months of using tocilizumab.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P099. Fever of unknown origin: an unexpected outcome

M. Rodriguez Ortiz¹, S. Murias Loza¹, L. Calle Miguel¹, M. A. Alonso Álvarez¹, J. Rodríguez Suárez¹, E. Pardo Campo², J. Zanabili Al-Sibai³, S. Rodríguez Ovalle¹

¹Pediatrics Department, ²Rheumatology Department, ³Hematology Department, Hospital Universitario Central de Asturias, Oviedo, Spain

Correspondence: M. Rodriguez Ortiz

Introduction: Most of fever of unknown origin (FUO) cases are caused by infectious diseases, but autoinflammatory entities, such as Systemic onset Juvenile Idiopathic Arthritis (SoJIA) must be included in the differential diagnosis of FUO, since early therapeutic approach is key to improve prognosis.

Objectives: We herein present a 15-month-old male patient admitted for FUO. We describe the initial stages of the disease, and the unexpected outcome after diagnosis.

Methods: Medical chart was reviewed.

Results: A 15-month-old male patient presented with fever >39,5°C for 11 days; evanescent maculopapular erythematous rash which intensifies with fever; generalized adenopathies; carpus and right knee arthritis; increased acute phase reactants (APR), and anemia. Infectious and neoplastic aetiology were ruled out by complementary examinations (including PET-CT and bone marrow aspirate). SoJIA was then diagnosed, and corticosteroids were started on 19th day of fever with rapidly good response, which allowed hospital discharge with oral prednisolone (2 mg/kg/day dosage with subsequent tapering) and prophylactic trimethoprim-sulfamethoxazole. After 12 days, while receiving prednisolone 0.6 mg/kg/day, inflammatory symptoms reappeared. Given SoJIA relapse he was hospitalized and anti-IL1 biological agent (Anakinra) was started. However, no response was observed and the child showed clear clinical worsening which led to Anakinra withdrawal after 3 days. Analytical criteria for Macrophage Activation Syndrome (MAS) secondary to SoJIA were then met. Megaboluses of methylprednisolone and cyclosporine were started, followed by frank progressive clinical and analytical improvement. Unexpectedly, he developed severe neutropenia (up to 10 neutrophils/μL), being the only altered analytical parameter. Filgrastim was thus started but no increase of neutrophils count was reached after 9 days. Review of all medications was then performed, leading to trimethoprim-sulfamethoxazole discontinuation due to its known myelotoxicity. Three days later, laboratory examinations showed recovering of neutrophils count up to 13,000/μL, with good parallel outcome of MAS and SoJIA.

Conclusion: When suspecting SoJIA, early treatment must be started, and close clinical and analytical monitoring should be carried out to assess response and identify the possibility of MAS as a potentially serious complication. In the case of neutropenia with no clear origin after conventional studies, it is key to collect information on treatments, suspending those that are potentially myelotoxic. Trimethoprim-sulfamethoxazole is a widely used antibiotic as prophylactic agent, thus its potential adverse events should be always taken into account.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P100. Establishing the CARRA Registry research network for systemic juvenile idiopathic arthritis-associated lung disease (CARE-NETS)

G. Schulert^1,2, E. Verweyen¹, S. Thornton^1,2, C. S. Lages¹, E. Eloseily¹, M.-L. Chang³, M. E. Riordan⁴, A. Russell⁵, M. Natter³, Y. Kimura⁴ on behalf of CARRA Registry SJIA-LD Cohort Investigators

¹Cincinnati Children’s Hospital, ²University of Cincinnati College of Medicine, Cincinnati, ³Boston Children’s Hospital, Boston, ⁴Hackensack Meridian Health, Hackensack, ⁵Duke Clinical Research Institute, Durham, United States

Correspondence: G. Schulert

Introduction: Systemic juvenile idiopathic arthritis (SJIA) associated lung disease (SJIA-LD) is an emerging and life-threatening clinical problem, and currently affects as many as 1 in 20 SJIA patients. Despite recent advances, there remain key unanswered questions regarding disease prevalence, influence of biologic treatments, pathogenesis, and outcomes.

Objectives: The central objective of this project is to establish a cohort of patients with SJIA-LD within the CARRA Registry to accelerate clinical and translational research to understanding SJIA-LD.

Methods: Existing or newly enrolled CARRA Registry patients with SJIA and suspected, probable, or definite SJIA-LD were enrolled in the cohort. In addition to standard registry data, lung disease specific clinical data was obtained at baseline and at 6 month follow-up. In addition, CARRA standard biosamples were collected at baseline and follow-up. Multiparameter flow cytometry panel was developed and validated using peripheral blood mononuclear cells (PBMC) previously collected locally using CARRA standard biosamples kits and standard operative procedures (SOP). Flow cytometry data was collected using the Aurora spectral cytometer (Cytek) and analyzed using FlowJo (v10.7.1).

Results: As of May 1, 2022, 24 patients were enrolled in the SJIA-LD cohort from 12 CARRA Registry sites. Patients were 58% female and median age at enrollment was 4.5 (IQR 6.5). 55% of patients had definite (biopsy-proven) SJIA-LD, 36% probable SJIA-LD, and 9% suspected SJIA-LD. Median SJIA duration at time of lung disease diagnosis was 1.8 years. Most common clinical features were clubbing (60%), tachypnea (60%) and cough (40%). Most common radiographic findings were bronchial wall or peribronchovascular thickening (63%), ground-glass opacities (60%), and septal thickening 56%). Patients had a median Physician Global Assessment of Lung Disease (PGALD) of 3.5 (range 0-8/10) at time of cohort enrollment. Baseline biosamples have been obtained from 19 patients collected at 10 sites. To allow for immunophenotyping of PBMC from patients with SJIA-LD, we have developed a 27-color flow cytometry panel including lineage markers, surface activation markers, and intracellular cytokines. Validation experiments showed this panel could reliably identify monocyte (classical, non-classical, intermediate), dendritic cells, T cell (CD4 vs CD8, Th1/2/17, resting, memory, effector), B cells (naïve, regulatory, plasma), and NK cell subsets, as well as differences in expression of activation markers and cytokines in cellular subpopulations.

Conclusion: The CARRA SJIA-LD cohort is actively enrolling patients and collecting biosamples across the network. We have developed a multiparameter flow cytometry panel suitable for analysis of longitudinal biosamples. Ongoing goals include characterizing clinical features of the SJIA-LD cohort, disease progression over time, and defining cellular populations associated with disease trajectory. The SJIA-LD cohort will serve as an ongoing prospective cohort study for future clinical and translational research in this emerging clinical entity.

Patient Consent: Yes, I received consent

Disclosure of Interest: G. Schulert Consultant with: Novartis, E. Verweyen: None declared, S. Thornton: None declared, C. Lages: None declared, E. Eloseily: None declared, M.-L. Chang: None declared, M. E. Riordan: None declared, A. Russell: None declared, M. Natter: None declared, Y. Kimura: None declared

P101. Patterns of disease course in systemic juvenile idiopathic arthritis – preliminary data from the CAPS cohort

P. Sinnappurajar¹, S. Shoop-Worrall², A. Ramanan¹, K. Hyrich², G. Cleary³, C. Ciurtin⁴, F. McErlane², L. R. Wedderburn⁴, A. Chieng⁵

¹Paediatric Rheumatology, Bristol Royal Hospital for Children, Bristol, ²Arthritis Research UK Centre for Epidemiology, University of Manchester, Manchester, ³Paediatric Rheumatology, Alder Hey Children’s Hospital, Liverpool, ⁴Centre for Adolescent Rheumatology Versus Arthritis, UCL UCLH GOSH, London, ⁵Paediatric Rheumatology, Royal Manchester Children’s Hospital, Manchester, United Kingdom

Correspondence: P. Sinnappurajar

Introduction: Systemic juvenile idiopathic arthritis (sJIA) is thought to follow a monocyclic, polycyclic or persistent course. The reported proportions of children following each course varies in the literature, with the percentages ranging from 15% to 83% for a persistent course in different cohorts. This study examined the clinical course of children with sJIA in the Childhood Arthritis Prospective Study (CAPS), a UK multi-centre cohort.

Objectives: To determine the patterns of disease course in sJIA patients in the CAPS cohort.

Methods: Data from children with sJIA were extracted from the CAPS database, which captures clinical outcome data at presentation (baseline), 6 months, 1 year then annually to 5 years. Cases were included from the cohort inception in 2001 until 2016, ensuring all cases had opportunity for 5 years of follow up. Clinically inactive disease (CID) was defined at each time point using the 2004 Wallace criteria (no active joints, no fever/rash/serositis/splenomegaly/lymphadenopathy, no active uveitis, normal ESR/CRP, physician’s global assessment (PGA) indicating no disease activity), with modifications that reflected the core clinical outcomes seen in systemic JIA. Wallace criteria 1 excluded uveitis outcomes, whilst Wallace criteria 2 excluded both uveitis outcomes and PGA. CRP data was also excluded from both criteria as the results are not standardised between different laboratory assays. If CID status could not be generated due to missing data at individual time points, it was replaced using last-observation carried forward.

Children were classed as having a persistent course if they never attained CID by the above definitions, a monocyclic course if they attained CID then maintained it throughout the 5-year follow up period, and a polycyclic course if they attained CID and subsequently flared during the follow up. Children who only first attained CID at the last follow up visit were excluded, due to the inability to further define their clinical course.

Results: There were 96 cases of systemic JIA identified in the CAPS database between 2001 and 2016. 59% were female, and the mean age at onset was 7.5 years (SD 4.8).

Based on Wallace criteria 1 (excluding uveitis and CRP), two cases that first reached CID on the last visit (5^th year), were excluded. Of the remaining 94 patients, 82% (77/94) were defined as having a persistent course (never achieved CID), 12% (11/94) had a monocyclic course (reached CID and subsequently maintained remission throughout the follow up period) and the remaining 6% (6/94) had a polycyclic course (achieved CID and subsequently flared).

Using Wallace criteria 2 (excluding uveitis, CRP and PGA), three cases that attained CID on the last visit were excluded, leaving 93 patients for analysis. By this definition of CID, the proportions of children were similar across the 3 clinical patterns with 39% (36/93) having a persistent course, 34% (32/93) having a monocyclic course and 27% (25/93) exhibiting a polycyclic course.

Conclusion: Following this preliminary analysis of the CAPS database, we found that similar percentages of children with sJIA will follow either monocyclic, polycyclic or persistent disease patterns over a 5-year time period, which is broadly in keeping with the literature. A higher percentage of children attain CID when PGA is excluded. This cohort will be further examined to identify whether the proportions following the three disease patterns have changed over time, and whether any variables at disease onset correlate to the disease patterns, which could ultimately help guide early treatment decisions.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

Poster session: Spondyloarthritis (SpA) and enthesitis related arthritis (ERA)

P102. Childhood-onset sacroiliitis: rheumatic causes and the correlation between clinical findings and magnetic resonance imaging

P. O. Avar-Aydin¹, Z. B. Ozcakar¹, S. Kaynak-Sahap², F. Aydin¹, C. Arslanoglu¹, N. Cakar¹, O. S. Fitoz², F. Yalcinkaya¹

¹Department of Pediatric Rheumatology, ²Department of Pediatric Radiology, Ankara University Faculty of Medicine, Ankara, Turkey

Correspondence: P. O. Avar-Aydin

Introduction: Childhood-onset sacroiliitis is a challenging condition that requires to consider several causes in the differential diagnosis including infections, malignancies, medications, and rheumatic diseases.

Objectives: To evaluate the etiology and the features of MRI-proven sacroiliitis in pediatric patients with rheumatic diseases in a referral center from an Eastern Mediterranean country.

Methods: Demographic and clinical data were extracted from the electronic medical records of the patients with sacroiliitis followed in the last 5 years. Active inflammatory changes of the sacroiliac joint (SIJ) were scored by the inflammation score according to the degree, intensity, and depth of the bone marrow edema (BME) and the presence of enthesitis, capsulitis, and structural damage lesions was evaluated by the modified SPARCC scoring system.

Results: A total of 46 patients were found to have MRI-proven sacroiliitis with a mean follow-up of 3.13±2.15 years. There were three groups of patients diagnosed with sacroiliitis when classified according to etiology: JIA (n:17), FMF (n:14), and CNO (n:8). Seven patients, FMF and JIA (n:6) and FMF and CNO (n:1) had a co-diagnosis that might cause sacroiliitis and they were excluded from the group analyses. Thirty patients (65.2%) were male. The mean age at disease onset was 10.97±3.93 years and six patients diagnosed with FMF or CNO were younger than 6 years. The prevalence of sacroiliitis in the relevant cohorts was 11.9% for JIA, 3.8% for FMF, and 34.6% for CNO groups. On the MRI of the SIJ, capsulitis was present in 17 patients (37.0%) and enthesitis in 14 patients (30.4%) in addition to BME with a mean total inflammation score of 22.50±13.80. Besides, structural damage lesions were present in 73.9% of the patients at the onset of sacroiliitis. Nonsteroidal anti-inflammatory drugs were used in all patients as the first-line treatment. Disease-modifying anti-inflammatory drugs were given to 67.4% and TNFi to 54.3% of the patients.

In the comparative analyses of three groups of patients, the weight and height percentiles were significantly lower in FMF group and HLA-B27 was more frequent in JIA group. Other findings of demographics, family history, differential blood counts, acute phase reactants, and the usage of TNFi were similar. BME intensity score on MRI and the frequency of capsulitis and enthesitis were significantly higher in CNO group. There was a significantly strong or moderate correlation between total inflammation score and inflammatory back pain, JSpADA score, ISSF score, clinical CNO score, and CRP; BME intensity score and inflammatory back pain, JSpADA score, and CRP; BME depth score and ISSF score, clinical CNO score, CRP, and ESR; and the presence of sclerosis/erosion and clinical CNO score.

Conclusion: This is the first study to evaluate the etiology of sacroiliitis in children with various pediatric rheumatic diseases and the relationship between clinical and MRI findings of newly-diagnosed sacroiliitis. We demonstrated that JIA, FMF, and CNO were the causes of childhood-onset sacroiliitis in our region. Characteristic findings on MRI might help the differential diagnosis of patients with sacroiliitis. Moreover, inflammatory and structural damage lesions found on MRI correlated with several clinical and laboratory features.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P103. Inflammatory marker profiles in pediatric familial Mediterranean fever and accompanying spondyloarthritis: siblings or distant cousins?

S. Bocutcu Cetin¹, E. Sag², K. Cankirili³, M. Kasap Cuceoglu¹, E. D. Batu¹, O. Basaran¹, Y. Bilginer¹, S. Ozen¹

¹Pediatric Rheumatology, Hacettepe University, ²Pediatric Rheumatology, Ankara Training and Research Hospital , ³Translational Medicine Laboratory, Hacettepe University, Ankara, Turkey

Correspondence: S. Bocutcu Cetin

Introduction: Familial Mediterranean fever (FMF) is a hereditary disease characterized by recurring, self-limited inflammatory episodes. The disease is caused by a gain-of-function mutation in MEFV (Mediterranean FeVer) gene, causing an excessive activation of pyrin inflammasome and thus overproduction of proinflammatory cytokines.¹ Spondyloarthropathies accompanying FMF include inflammatory arthritides, sacroiliitis, spondylitis, enthesitis, and extraskeletal manifestations, and in children, enthesitis-related arthritis (ERA).² Although the evidence supporting the role of innate immunity is overwhelming, the exact pathogenesis of the aforementioned diseases is yet to be determined.

Objectives: In this study, chosen inflammatory marker levels are evaluated in order to gain further knowledge on the pathogenetic mechanisms of FMF and accompanying spondyloarthritis (SpA).

Methods: Between December 2020 and June 2021, we collected four groups of patients with FMF-SpA with high disease activity, ERA with high disease activity, FMF during the attack period, and FMF remission period. Having collected 20 samples from 16 patients, the inflammatory marker levels of these groups were compared with each other and the healthy donors.

Results: TNF-α levels are significantly increased in all the patient groups compared to the healthy controls. No statistically significant difference in IL-1β levels was found among the patient groups or the healthy controls. However, transcriptomic studies found a significant difference between the patient groups and the healthy controls. IL-6 levels showed a significant decrement in remission period in FMF patients compared to the attack period. IL-18 levels were significantly increased in the FMF-SpA group, suggesting the possibility of a potential inflammatory biomarker for ERA/spondyloarthritides in the FMF group.

Conclusion: This study is the first to investigate the inflammatory pathogenesis of FMF and accompanying spondyloarthropathy. Corroboratory studies are needed to further evaluate the role of these cytokines and their incorporation into personalized medicine.

References

1. Chae JJ, Cho Y-H, Lee G-S, Cheng J, Liu PP, Feigenbaum L, et al. Gain-of-function Pyrin mutations induce NLRP3 protein-independent interleukin-1β activation and severe autoinflammation in mice. Immunity. 2011;34(5):755-68.

2. Sönmez, H. E., Batu, E. D., Demir, S., Bilginer, Y., & Özen, S. (2017). Comparison of patients with familial Mediterranean fever accompanied with sacroiliitis and patients with juvenile spondyloarthropathy. Clinical and experimental rheumatology, 35(6), 124-127.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P105. MRI evaluation of active sacroiliitis in juvenile spondyloarthritis treated with TNF inhibitors

K. Yamazaki¹, A. Fujikawa², T. Nozaki³, Y. Motonaga⁴, M. Mori⁴

¹Division of Rheumatology and Allergology, Department of Internal Medicine, ²Department of Radiology, St. Marianna University School of Medicine, Kawasaki, ³Department of Radiology, St. Luke’s International Hospital, Tokyo, ⁴St. Marianna University School of Medicine, Division of Rheumatology and Allergology, Kawasaki, Japan

Correspondence: K. Yamazaki

Introduction: Even though magnetic resonance imaging (MRI) assessment of the sacroiliac joints (SJ) is useful in the early diagnosis of spondyloarthritis (SpA), the evaluation of MRI features in juvenile SpA has not been well established.

Objectives: We aimed to evaluate JSpA-specific MRI features of SJ for use in the early diagnosis of sacroiliitis.

Methods: We collected seven cases clinically diagnosed with JSpA and successfully treated with TNF inhibitors. Two pediatric musculoskeletal radiologists retrospectively evaluated the MRI features of sacroiliac joints in the patients before and after the treatment.

Results: Seven JSpA patients (5 males, 2 females; Median age 14 (12 to 20)) are included in this study. The median time from onset to diagnosis is three years. Before TNF-inhibitors treatment, inflammatory back pain, SJ tenderness, and peripheral enthesitis were present in all patients. One of the patients has HLA-B27. MRI features at diagnosis showed active inflammatory lesions of sacroiliitis such as bone mallow edema (3/7), capsulitis (0), enthesitis outside of sacroiliac joint (1/7), and structural lesions such as erosion (3/7), sclerosis (3/7), backfill (0), fat metaplasia (0) and ankylosis (0). The clinical severity of inflammatory back pain and peripheral enthesitis did not correlate with the MRI findings. MRI findings of bone marrow edema improved in all three patients 6-12 months after initiation of TNF inhibitors treatment.

Conclusion: The assessment of SpA International Society (ASAS) definition for adult has previously been reported to be less sensitive in children. In the early stages of sacroiliitis, inflammatory changes in the SJ are so subtle that they may not be detected on MRI. Since the early diagnosis of active sacroiliitis is important in terms of treatment options, a practical definition of active sacroiliitis specific to children and adolescents is required for pediatric rheumatologists.

Disclosure of Interest: None declared

Poster session: Autoinflammatory diseases

P106. First case with a possible diagnosis of haploinsufficiency of A20 in Libya

A. A. Abushhaiwia¹, Y. Elfawires²

¹Paediatric Rheumatology , Faculty of Medicine,Tripoli university, Tripoli Children’s Hospital , ²Paediatric Rheumatology , Faculty of Medicine,Tripoli university, Tripoli Children’s Hospital , Tripoli, Libya

Correspondence: Y. Elfawires

Introduction: Monogenic autoinflammatory disorders (AID) and primary immunodeficiencies can present early in life with features that may be mistaken for Behçet’s disease (BD). These disorders involve a growing multisystem inflammatory diseases associated with defects in the innate immune system. The symptoms appears to range through unprovoked inflammation (fever, rash, ulcers, and elevation of acute phase reactants ).We herein report a case under workup for Haploinsufficiency of A20 in a young Libyan female that is suffering from recurrent mouth and genital ulcers.

Objectives: to highlight the importance of considering the monogenic AID in children presenting with signs and symptoms mimicking BD

Methods: a case report

Results: A 7 yrs old Libyan female born to consanguineous parents, presented to our clinic as a referral from the GI clinic,with the complaint of having recurrent mouth and perianal ulcerations. The problem started at age of five, six months before presentation. With the appearance of the ulcerations about three/month, lasting for about a week and resolved spontaneously with no recognized trigger, the ulcers then started to involve other areas including the genitalia, behind ears, around umbilicus with discharging fluid/pus. Systemic review showed that these ulcers are not associated with fever, good general wellbeing, good appetite, no significant wt loss ( although her wt fall below 3rd centhile for age and sex) , arthralgia ( both knees/ no arthritis PGALS was normal), skin rash follicular/postular involving pressure areas initially then progressed to involve the face, no nail nor hair changes, she had H/O recurrent URTI and skin infections that were managed with local Rx as they appear, also H/O constipation initially that then progressed to altered bowel habit. F/H her grandmother know case of IDDM & RA. The girl was approached with the DD of BD, IBD, SLE, FMF, hyper IgD and Haploinsufficiency of A20. Her blood tests showed: CBC WBC 10.2 ( 5.11 neutro, 4.39 lympho, 0.58 mono, EO 0.10), Hgb 11.9 g/dl, PLT 477+. ESR 107, 70, 78 ( always high). CRP never been +ve, LDH 369, Ferretine 16.37 ( low ), urine for Pr:Cr ratio N, ALT 10, AST 23, Bil 0.3, serology : viral screen negative, Immunoglobuline assay IgA, IgE, IgD, IgG, IgM all within normal levels, ENA screen 7.3 ( > 1.2 +ve), ANA, ds DNA, p-ANCA and c-ANCA all negative, EBV serology negative, TTG negative. Vitamin B12 normal level, Zinc serum level normal, S Amyloid normal. Molecular genetic analysis of the MEFV and MVK gene came with no significant pathologic variant detected, HLA B51 positive. She had an upper and lower GI endoscopy done for her with an ilial biopsy taken all came normal with no abnormality. U/S abdomen also normal. Ophthalmological examination Normal no uveitis. Furthermore complement level ( C1-C9 &C50 levels), T cell function assessment ( CD4,CD8 level & ratio, CD 18, CD 45 & CD56 ), immunoglobuline response for vaccination ( anti tetanus and diphtheria IgG levels) neutrophils function ( DHR flow cytometry ), genetic testing ( TNF AIP3 gene mutation +/- WES), biopsy from the ulcers for histopathology but unfortunately due to lack of resources and lack of financial support these test are not done yet.she is on colchicine tab 1mg once daily, local steroids for mouth and genital ulcers and systemic steroids has been used for short courses with no much improvement, Azathioprine has been added waiting for the response, she is also on oral hygiene care and septrine as prophylactic Abx.

Conclusion: Due to the wide variety of disorders that present with symptoms that mimic BD, especially when presenting early in life, consideration of monogenic AID and immune deficiencies with early implementation of gene testing is crucial to shorten the duration of patients suffering and to come up with appropriate management plan.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P107. Successful treatment with infliximab in a child with deficiency of interleukin-36 receptor antagonist (DITRA)

A. A. Abushhaiwia¹, Y. Elfawires²

¹Paediatric Rheumatology , Faculty of Medicine,Tripoli university, Tripoli chlidren’s hospital , ²Paediatric Rheumatology, Faculty of Medicine, Tripoli university, Tripoli Children’s hospital , Tripoli , Libya

Correspondence: A. A. Abushhaiwia

Introduction: General pustular psoriasis (GPP) is a rare form of psoriasis and is clinically characterized by widespread eruptions of sterile pustules and bright erythematous skin accompanied by periods of fever, chills, neutrophilia, and elevated serum C-reactive protein. In 2011, Marrakchi et al3 reported a subgroup of GPP patients with a specific genetic defect: a deficiency of interleukin-36 receptor antagonist (DITRA). We report for the first time DITRA in a Libyan child successfully treated with infliximab.

Objectives: To report the efficacy of treatment with 5 mg/kg infliximab intravenous infusion at Weeks 0, 2, and 6, followed by a monthly regimen, was effective and in inducing complete or almost complete responses in a child with

Methods: case report is described

Results: A 4 year-old Arab Libyan boy, born from non-consanguineous parents came to our attention due to a suspicion of a systemic autoinflammatory condition. Of note, the index patient had two healthy brothers and an uncle diagnosed with psoriatic arthritis. At the age of 2 years recurrent and severe episodes of generalized pustular psoriases requiring many hospital admissions started. Initially, he was managed as of pustular psoriasis after a 6-month history of appearance. Diffuse pustules involving cheeks, perioral area associated with mouth ulcers, characterized skin lesions. A rapidly progression of his condition could be observed characterized by worsening of general condition and generalization of the rash over different body parts. Other clinical pictures frequently observed was fever; psoriatic nail changes (e.g. Pitting and onychomadesis) and ichthyosis altogether with joint involvement limiting his activity. Rash became severe with discharging pustules and failure to thrive could be observed. At his admission, widespread presence of scaly erythematous plaques with pinhead pustules involving the scalp, face, extremities, torso, and buttocks. The palms and soles were also affected. Nail pitting and onychomadesis. At his admission a complete blood count demonstrated anaemia HGB 8.1 g\dl and leukocytosis. However, during febrile episodes the patient’s white blood cell count increased to 17,000/ll with neutrophilia of 92%, ESR 50mm\h, and elevated CRP 20mg\dl level. No other condition, such as infection, could be observed over the time. A skin biopsy demonstrated parakeratosis, spongiosis, and psoriasiform acanthosis; we could also observe an elevated level of vitamin B12 757.90 pg\ml (reference range). Due to a suspicion of a systemic autoinflammatory condition, a genetic sequencing was requested. A homozygous already described mutation in the IL36RN was found (c.80T>C;. pLeu27Pro), thus confirming the diagnosis of DITRA. Once neither anti-IL1 (anakinra) neither anti-Il12/23 (secukinumab) is available in Libya , high doses of systemic steroids was initiated and could achieve clinical control. In order to avoid prolonged use of steroids, the patient’s dose was gradually tapered. However, cutaneous exacerbation could be observed and a steroid spared agent, methotrexate, at a dose of 7.5 mg once per week was therefore added. Under this treatment no improvement was seen .Treating him by anti-TNF (inflixmab) 5mg\kg IV, 2 weeks after starting infliximab IV reveals near complete resolution of psoriatic skin lesions. He is in total remission, “completely cleared skin”. Since October 2021

Conclusion: DITRA is a rare disease. We demonstrate in this a child with DITRA that TNF-alpha inhibition with infliximab dramatically improved the dermal changes and could normalize the skin within 2 weeks and his quality of life clearly improved after the use of infliximab treatment.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P108. A two-year-old libyan boy with recurrent abdominal pain and fever: familial mediterranean fever

A. A. Abushhaiwia¹, Y. Elfawires¹, A. Ateeq², S. Elazragh ³

¹Paediatric Rheumatology , Faculty of Medicine,Tripoli university, Tripoli Children’s Hospital , ²Paediatric Rheumatology , ³General Paediatrics , Tripoli Children’s Hospital , Tripoli , Libya

Correspondence: A. A. Abushhaiwia

Introduction: Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease, characterized by recurrent self-limited attacks of fever accompanied with peritonitis, pleuritis, or arthritis. Inherited in an autosomal recessive fashion. Occurs as a result of pathogenic variants in Mediterranean fever (MEFV) gene. Rarity of these diseases exposure during medical practice and lack of genetic testing for confirmation makes diagnosis challenging in Libya and in other middle-income countries

Objectives: To report for the first time the clinical and genetic findings of FMF in a two-year -old boy from Libya.

Methods: is a target gene panel commercially available (ISU university Germany) was requested. The results: clinical presentation was and we found a heterozygous mutation on MEFV gene (c.2177T>C p.Val726Ala

Results: A 2 year-old Libyan boy from the North Africa, born of non-consanguineous healthy parents, came to our attention because of recurrent episodes of fever since at age 4 months. That’s required him many hospitalizations and several and no specific diagnosis being made and could be achieved, recurrent attacks of fever that reached as high as 39c daily, lasting from 5-8 days, every 2-8 weeks sometimes accompanied by abdominal pain, vomiting, joint pain and diarrhea. The initial attacks were occurring as frequently as every 3 weeks. He had neither history of previous surgeries except he had undescended testes on May 2020, ultrasound scrotum&inguinal regions that showed retractile right testicle and left testicle seen within medial third of left inguinal canal and LH, testosterone both were within normal range, nor a family history of same illness or immunodeficiency. His physical examinations were unremarkable only he is under weight 10.5kg (failure to thrive). Laboratory tests during attacks revealed mild anaemia. (Haemoglobin as low as 9 -10.5g/l) during the attacks with platelets were within normal limits, white blood cells count were as high as 24,400.Remarkable leukocytosis (15,000 mm3-24, 000 mm3) mainly neutrophil 66.3%, blood film revealed mild microcytic hypochromic anemia, always with fluctuant levels of acute reactant C-reactive protein (values between 50 and 283mg/L) markers as erythrocyte sedimentation rate (ranged from 40 to 80 mm/h), all cultures included blood, urine and CSF were negative, vitamine B12 was elevated 1230pg\ml ,immune profile tests all of them were within normal range included immunoglobulin assay was normal .Evaluation of lymphocyte immunophenotyping test ( quantitation of total B cell numbers (CD19) and total T cell numbers (CD3), and quantitation of T cell subsets (CD4, CD8) and natural killer (NK) cells (CD16), total CH50,C3,C4 all were within normal range, serum amyloid was normal <3mg\dl , With normal laboratory work-up during wellbeing was a constant finding. Chest radiography, echocardiography and abdominal ultrasound were always normal. Based on his clinical background, physical examinations and his above some lab tests he is most likely the diagnosis of FMF or MVK. Molecular analysis for FMF (MEFV) revealed heterozygous c.2177T> p. V726A. Therefore the clinical and diagnosis of FMF was established for the child. The patient responded well to colchicine therapy started at a dose of 0.5 mg/day

Conclusion: FMF is frequent in many Mediterranean countries, Libya is one of the Mediterranean countries but rarely reported in Libya or delay in diagnosis due to we don’t have those particular tests in public hospitals, it is one of the greatest challenges that these diseases require so many investigations that people can’t afford it. Furthermore; the prevalence of hereditary autoinflammatory diseases particular FMF remains unknown in Libya.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P109. Plasma MIR-520B overexpression in patients with rheumatoid arthritis

Y. Achour, S. Chaabane, L. Keskes

Laboratory of Human Molecular Genetics, Faculty of Medecine of Sfax, Sfax, Tunisia

Correspondence: Y. Achour

Introduction: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disorder, affecting 0.5 to 1% of the population worldwide. It is characterized by unknown etiology in which genetics, environmental, and epigenetics aspects are considered as the main risk factors that contribute to the development of this chronic disease. MicroRNAs are endogenous small noncoding sequences of single-stranded RNA, which cause alteration of gene expression by post-transcriptional modifications, destabilize target mRNAs to inhibit protein synthesis and regulate crucial pathways and cellular processes, such as cell growth, differentiation, proliferation, and cell death. Some microRNAs have been associated with a higher risk and progressionto RA, as well as with clinical variables of RA (tender joint and disease activity score (DAS28) -erythrocyte sedimentation rate (ESR)). Moreover, miRs such miR-520b is recognized as a critical regulator by suppressing endothelial cell inflammation and might serve as a potential therapeutic target for atherosclerosis.

Objectives: The current study aimed to investigate the expression levels of circulating plasma miR-520b in Tunisian RA patients and to determine possible correlations between expression levels and clinical and immunological features.

Methods: Total RNA was isolated from plasma of 40 RA patients and 10 age-gender-matched healthy controls. Expression of miR-520b was measured using quantitative real-time PCR methods by TaqMan qRT-PCR. Correlation analyses was performed using Mann-Whitney U test and Spearman’s coefficient test.

Results: The results shows that the expression level of miR-520b was considerably increased in RA patients compared to the control group (p-value = 0.0005). A positive correlation was observed with high activity disease (DAS28 > 5,1) (p-value = 0.008) and overall C-reactive Protein (p-value = 0.031). Moreover, a significant association of the expression of miR-520b with high CRP levels ( CRP > 10mg/L) was revealed. There was no significant correlation of miR-520b overexpression and seropositivity to anti-CCP and RF patients.

Conclusion: To the best of our knowledge, this is the first report of miR-520b expression in RA. Our study demonstrates that plasma miR-520b is associated with the pathogenesis of RA and it may act as a novel diagnostic marker for disease.

Disclosure of Interest: None declared

P110. DADA2 in Malaysian children - novel mutations and “heterozygous presentation”

S. A. Affendi¹, S. P. Tang¹, S. C. Lim², B. S. Koay¹, S. K. Ng¹, P. Nadarajah¹, S. Y. Lee¹, L. R. Sangaran¹

¹Paediatric Rheumatology, Selayang Hospital, ²Paediatric Rheumatology, MARA University of Technology Malaysia (UITM), Selangor, Malaysia

Correspondence: S. A. Affendi

Introduction: Deficiency of adenosine deaminase 2 is a recently described monogenic autoinflammatory condition characterised by multi-system vasculopathy that often presents in early childhood. It has a wide heterogenous presentation which poses a diagnostic challenge to treating clinician. The aim of this case series is to highlight novel mutation associated with DADA2, the clinical spectrum and treatment outcome at our centre.

Objectives: We describe here a case series of children with proven DADA2.

Methods: Five children with DADA2 presenting with various forms of vasculopathy and immunodeficiency were identified in a single cetre tertiary hospital over 6 years follow-up duration. Their clinical data and treatment outcomes were analysed.

Results: this case series we share our experience in managing children with DADA2 in the only paediatric rheumatology centre in Malaysia. 5 DADA2 patients were reported in 6 years follow-up duration period since 2016. Their age range from 2 months to 9 years old. There are 3 males and 2 females (with a pair of siblings) within this case series and all of them are of Malay ethnicity. 3 children were diagnosed within less than a year, whilst 2 other children took more than a year highlighting the diagnostic challenge posed by this condition. Neurological symptoms namely stroke was the dominant clinical picture (n=4) and 1 patient presented with right retinal artery occlusive vasculitis at 2 months of age. 2 children had skin manifestations (1 with livedo reticularis whilst 1 had morphea-like skin condition). Recurrent fever (n=3) and orchitis (n=1) with abdominal pain (n=1) are other clinical symptoms that were reported. 1 child went on to developed low IgM with recurrent CMV infection. Of note, haematological involvement were not observed in our case series The diagnosis of DADA2 were made via genetic panel for autoinflammatory (Invitae panel) . Via this genetic panel, the pair of siblings showed homozygous novel mutation in ADA2 gene leading to their clinical symptoms. The novel mutation c.369G>T (p.Trp123Cys) has not been reported in the literature, highlighting the potential genomic heterogeneity of DADA2 . All of the children in this case series has ADA2 plasma level activity of 0 mU/g protein and 1 child had level of 5.6 mU/g protein. All 4 children were treated with anti-TNF except for 1 child who is on MMF whilst awaiting for funding approval for anti-TNF. 3 of these children have shown good inflammatory control with anti-TNF recovery whilst 1 patient has non-sustainable respond to anti-TNF. 4 of these children has had significant morbidities due to uncontrolled inflammation, steroid toxicity and sequelae from the recurrent stroke.

Conclusion: The spectrum of clinical presentation in DADA2 continues to expand in tandem with discoveries of novel mutation in ADA2 gene. More studies are needed in the future to highlight genotype-phenotype correlation and this will perhaps help to tailor a more target therapy for these children, High index of suspicion amongst clinician is vital in order to clinch the diagnosis and to prevent accrued organ damage.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P111. Chronic non-bacterial osteomyelitis in children: a multi-center cohort from Saudi Arabia

L. Alahmadi^1,2,3, J. Almasoud^1,2,3, W. Alsuwairi^1,2,3, A. Alrasheed^1,2,3, S. Al-Mayouf⁴, F. Alkhars⁴, A. Asiri⁵, D. Alwakeel⁵, A. Alenazi⁶, S. Alenazi⁶, R. Bakry⁷, K. Alsufyani⁸, O. Aldibasi², J. Alqanatish^1,2,3

¹Pediatric Rheumatology, King Saud bin Abdulaziz University for Health Sciences, ²King Abdullah International Medical Research Center (KAIMRC), ³King Abdullah Specialist Children’s Hospital,National Guard Health Affairs, ⁴Pediatric Rheumatology, King Faisal Specialist Hospital and Research Center, ⁵Pediatric Rheumatology, Prince Sultan Military Medical City, ⁶Pediatric Rheumatology, King Fahad Medical City, Riyadh, ⁷Pediatric Rheumatology, East Jeddah Hospital, Jeddah, ⁸Pediatric Rheumatology, Maternity and Children’s Hospital, Mecca, Saudi Arabia

Correspondence: L. Alahmadi

Introduction: Chronic non-bacterial osteomyelitis (CNO) is an auto-inflammatory disorder that mainly affects the bone and occurs in children and adolescents. It is a chronic condition with a spectrum of presentation ranging from a mild self-limiting mono-focal disease to a sever chronic recurrent multifocal or so called Chronic Recurrent Multifocal Osteomyelitis (CRMO).

Objectives: The objective of the study was to evaluate demographic, clinical, laboratory, imaging,histopathology characteristics, and treatment responses of pediatric CNO patients seen in Saudi children.

Methods: The clinical records of 58 patients diagnosed with CNO between 2015 and 2021 at 6 centers in 3 major cities in Saudi Arabia were reviewed.

Results: We reviewed a total of 58 children (n=36, 62% females), with median age of 8 years at diagnosis of CNO. The most common clinical manifestation was bone pain (n=51, 88%) followed by bone swelling (n=32, 55%). Fever was the most frequent systemic manifestation (n=8, 13%), followed by skin rash (n=6, 10%) and GI symptoms (n=5, 9%). Eighty five percent (n=49) of patients had elevated ESR while CRP was positive in (n=24, 41%). X-ray was the most frequent imaging modality (n=49, 85%) followed by Regional-MRI (n=41, 71%), bone scan (n=33, 57%), CT-scan (n=24, 41%), whilst a whole body MRI was the least used modality. The most common sites of bony lesions were lower limb (n=37, 64%), and bone biopsy was done in 34/58 (59%) patients. The pelvis and clavicle were involved in 18/58 (31%) in our cohort. NSAIDs were the most used medications (n=51, 86%), followed by Bisphosphonate and Anti-TNF in 55% (n=32), and Methotrexate and systemic steroids in 36% (n=21) of patients. Clinical remission was achieved in 44/58 (83%) of CNO patients.

Conclusion: This study describes the phenotype of a large-scale sample of CNO in our pediatric population and the practice of our pediatric rheumatologist in treating these patients. It is a step forward towards developing a local consensus in treating this rare entity in our Saudi patients.

Patient Consent: Not applicable (there are no patient data)

Disclosure of Interest: None declared

P112. Colchicine response in TRAPS – a molecular enigma

S. Balan, S. Raj, M. CB

Rheumatology & Clinical Immunology, Amrita Vishwavidyapeetham, Kochi, India

Correspondence: S. Balan

Introduction: TNF receptor associated Periodic Fever Syndrome (TRAPS) is an autosomal dominant, monogenic, autoinflammatory disease, characterized by mutations in TNFRSF1A gene coding for TNFR1 , which results in aberrant downstream signalling, resulting in widespread systemic inflammation and increased risk of reactive amyloidosis. Lack of response to colchicine is one of the defining features of TRAPS.

Objectives: To present a child and a family with a TRAPS mutation who are responsive to Colchicine, an unusual observation in patients with this illness

Methods: We present here a case of 9 year old female child, who presented with recurrent episodes of fever lasting for 7 to 12 days, associated with abdominal pain, maculo-papular rash, arthralgia, conjunctivitis every 3-4 months once since the age of 9 months, with strong family history. She was noted to have neutrophilic leucocytosis, grossly elevated inflammatory markers during febrile episodes. She was previously treated elsewhere with NSAIDs and glucocorticoids during flares with some response. As genetic testing was not a viable option when she first presented ,she was subsequently started on colchicine at a dose of 1mg/day with excellent clinical response. Genetic testing finally performed 4 years after the initial presentation ,revealed pathogenic TNFRSF1A variant. Her aunt ,also in the pediatric age group as well as her father, uncle and grandfather have the same mutation and all of them are currently responsive to Colchicine. She continues to be under our follow up since 3 years and is doing well on colchicine

Results: Following commencement of Colchicine, she went down from 3-4 episodes/year to none and from 40-60 days of symptomatology a year to about 6-8 days of minor symptoms/year

Inflammatory markers have stayed in the normal range.

Her 17 year old aunt, father and great uncle with the same gene have shown similar clincial response with Colchicine

The mutation this family carries-TNFRS1A Exon3 c.236C>T, Heterozygous and pathogenic .

Conclusion: In resource limited settings, Colchicine can be considered as a therapeutic option in patients with TRAPS in those patients who show good clincial response

Trial registration identifying number: none

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P113. DADA2 with 2 different phenotypes - our first experience

B. Balažiová¹, P. Čižnár¹, D. Moravčíková², I. Hulínková¹, T. Freiberger³, E. Froňková⁴, T. Dallos¹

¹Department of Paediatrics, Comenius University Medical School in Bratislava, Bratislava, ²2nd Department of Paediatrics, Slovak Medical University, Banská Bystrica, Slovakia, ³Genetic laboratory, Centre for Cardiovascular and Transplant Surgery, Brno, ⁴Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University, Prague, Czech Republic

Correspondence: B. Balažiová

Introduction: Deficiency of ADA2 (DADA2) is a rare multisystem monogenic autoinflammatory disease with a constantly increasing spectrum of clinical phenotypes and disease-causing mutations in the ADA2 gene (formerly CECR1).

Objectives: To analyse the phenotypes of our first two Slovak patients with DADA2.

Methods: Demographics and clinical phenotype of 2 patients with DADA2 were analysed in retrospect by review of their medical records.

Results: Patient 1 is a Caucasian boy of unrelated parents, who presented acutely with diplopia and ataxia due to a mesencephalic brain lesion at the age of 4.5 years. Soon after neurological restoration, he developed intermittent fever, livedo racemosa, bilateral hand thrombophlebitis after cannulation, splenomegaly with multiple focal lesions considered to be due to embolism and generalized lymphadenopathy. Persistently increased inflammatory markers (CRP 50-60 mg/l), B-lymphopenia, hypogammaglobulinemia with low post-vaccination antibodies were noted. Inflammation responded promptly to corticosteroids (CS); he was substituted with immunoglobulins regularly. Two heterozygous mutations in the ADA2 gene were confirmed at the age of 5.3 years (pathogenic missense mutation c.506G>A;p.Arg169Gln(1) and a missense variant of uncertain significance c.505C>T;p.Arg169Trp(2)). Biologic therapy with etanercept resulted in control of inflammation, the immunological disorder persists.

Patient 2 is a Caucasian girl of unrelated parents, treated for autoimmune haemolytic anaemia (AIHA) at 8 months of age, who developed persistent firm maculopapular lesions after CS discontinuation (11 months). She developed arthralgias without apparent arthritis and intermittent fever (up to 38.5°C) at 21 and 23 months, respectively, splenomegaly and permanently increased inflammatory parameters (CRP 50-110 mg/l) were noted and the patient was treated for suspected systemic JIA with pulse CS and methotrexate and later cyclosporine A. With CS tapering intermittent fever and joint pain recurred, livedo racemosa was noted and a defect in B-cell differentiation without hypogammaglobulinaemia was identified (28 months). NGS analysis revealed two heterozygous mutations in the ADA2 gene (pathogenic missense mutation c.140G>C;p.Gly47Ala(3) and a new variant c.881+1G>C predicted to considerably reduce the efficacy of gene splicing), each inherited from one parent. Treatment with etanercept was recommended.

Conclusion: Even in our limited experience, our first two Slovak patients with DADA2 presented with highly variable phenotypes and with two novel, likely pathogenic mutations identified in each patient. A high degree of suspicion is required to identify DADA2 among patients with persistent inflammation, immunological and/or haematological disorders, as well as neurologic manifestations.

References:

1. National Center for Biotechnology Information. ClinVar; [VCV000120303.32] [Internet]. [cited 2022 May 24]. Available from: https://www.ncbi.nlm.nih.gov/clinvar/variation/120303/

2. National Center for Biotechnology Information. ClinVar; [VCV000956376.3] [Internet]. [cited 2022 May 23]. Available from: https://www.ncbi.nlm.nih.gov/clinvar/variation/956376/

3. National Center for Biotechnology Information. ClinVar; [VCV000120301.14] [Internet]. [cited 2022 May 24]. Available from: https://www.ncbi.nlm.nih.gov/clinvar/variation/120301/

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P114. Efficacy and safety of anti-interleukin-1 treatment in large colchicine resistant familial Mediterranean fever cohort: single center experience

K. Barut, I. Ulkersoy, N. Gucuyener, F. Haslak, M. Yildiz, A. Gunalp, G. Yalcin, S. Sahin, A. Adrovic, O. Kasapcopur

Department of Pediatric Rheumatology, Istanbul University Cerrahpasa, Istanbul, Turkey

Correspondence: K. Barut

Introduction: Familial Mediterranean fever (FMF) is the most common hereditary autoinflammatory disease, characterized recurrent episodes of fever peritonitis, pleuritis, arthritis and rash, Colchicine is the mainstay of FMF treatment, although colchicine is the first line treatment in FMF, 5-10% of patients do not respond, another 2–5% do not tolerate the drug well. Interleukin (IL)-1 antagonists are the treatment of choice in resistant or intolerant cases. The FMF50 score is used in evaluation of disease activity, defined as 50% improvement in all of 6 criteria. Complete clinical and laboratory response is characterized with absence of clinical features and normal laboratory findings

Objectives: We aimed to evaluate anti IL-1 effect (anakinra and canakinumab) on colchicine resistant FMF cases by comparing the FMF50 score and complete clinic and laboratory response.

Methods: In this study all FMF patients followed up at tertiary pediatric rheumatology clinic assessed by examining patients’ files and network information, among these cases who met definition of resistant FMF were included in the study. in the first step colchicine dosage increased to maximum tolerated dose, after maximum dosage colchicine, if still had considered Cr FMF, then started other colchicine form (opacalcium colchicine OC) anti-IL1 treatment was started in the patients who were resistant despite receiving the OC. The FMF50 response of the resistant FMF patients under colchicine or other treatment modalities for at least 6 months has been determinates retrospectively by using data from the patients’ records. Complete clinical and laboratory remission has been evaluated for all resistant FMF patients.

Results: A total 74 FMF patients has been considered colchicine resistant FMF(Cr FMF).FMF 50 response has been obtained in only 5/74(6.7%) patients under colchicine treatment. Among patients under other treatment options, FMF 50 response has been obtained in 23/48(48%) patients under OC, in 13/18(72.2%) patients treated with anakinra and in 26/28(93%) patients under canakinumab treatment. There was a statistically significant difference in FMF50 response according to treatment modality (p<0,05). Clinical remission has been achieved in 18/48(37,7%) patients under Opacalcium colchicine, 12/18(66,7%) patients under anakinra and in 25/28(89,3%) patients under Canakinumab. There was a statistically significant difference between patients treated with OC and those with anti-IL-1 according to complete clinical remission (p<0,05).

Laboratory remission has been obtained in 19/48(39.6%), 11/18(61,1%) and 23/28(82,1%) patients treated with OC, anakinra and canakinumab, respectively. The laboratory remission was significantly different between patients treated with OC and anti-IL-1 agents (p<0,001). In patients treated with maximum dosage of colchicine (1,7±0,4 mg/day, max 2 mg/day), the most seen adverse effect was diarrhea in 18/74(24,3%), transaminase elevation in 4/74(5.4%) patients and leukopenia only in 2 patient. Diarrhea was seen in 10/48(20.8%) patients under opacalcium colchicine treatment, which is lower comparing to previously mentioned colchicine form. There was no serious adverse event with Anti- IL 1 treated patients.

Conclusion: Despite the regular and maximum dose of colchicine use, Cr FMF cases are seen at a substantial rate. In these CrFMF cases, FMF50 response was higher in both canakinumab and anakinra, and clinical and laboratory remission found more than other colchicine form. In this study found that, the both of anti IL-1 agents were safe and effective in colchicine resistant FMF patients.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P115. A score for predicting colchicine resistance at the time of diagnosis in Familial Mediterranean Fever (FMF): data from the TURPAID registry

E. D. Batu¹, S. Şener¹, E. Arslanoglu Aydin², E. Aliyev¹, I. Bagrul², S. Türkmen³, O. Akgün⁴, Z. Balık¹, A. Tanatar⁴, Y. Bayındır¹, Z. Kızıldağ⁵, R. Torun⁵, A. Günalp⁶, T. Coskuner³, R. İşgüder⁵, T. Aydın⁵, F. Haşlak⁶, M. Kasap Cuceoglu¹, E. Esen⁷, U. Akçay³, Ö. Başaran¹, A. Pac Kisaarslan⁷, F. Akal⁸, S. Özdel², M. Bülbül², Y. Bilginer¹, N. Aktay Ayaz⁴, B. Sözeri³, O. Kasapcopur⁶, E. Unsal⁵, S. Ozen¹

¹Hacettepe University Faculty of Medicine, ²Dr. Sami Ulus Maternity and Child Health and Diseases Research and Training Hospital, Ankara, ³Umraniye Research and Training Hospital, ⁴Istanbul University Faculty of Medicine, Istanbul, ⁵Dokuz Eylül University Faculty of Medicine, Izmir, ⁶Istanbul University Cerrahpasa Faculty of Medicine, Istanbul, ⁷Erciyes University Faculty of Medicine, Kayseri, ⁸Department of Computer Engineering, Hacettepe University, Ankara, Turkey

Correspondence: E. D. Batu

Introduction: Familial Mediterranean fever (FMF) is the most common monogenic systemic autoinflammatory disease. Colchicine forms the mainstay of FMF treatment. Around 5-10% of FMF patients are colchicine resistant and require anti-interleukin 1 (IL-1) drugs.

Objectives: To compare the characteristics of colchicine resistant and colchicine responsive patients and to develop a score for predicting colchicine resistance at the time of FMF diagnosis.

Methods: FMF patients enrolled in the TURPAID (Turkish Pediatric Autoinflammatory Diseases) registry were included. All patients met the Eurofever FMF criteria and had confirmatory MEFV genotype. Colchicine resistance was defined as having one or more attacks per month or presence of subclinical inflammation despite receiving maximum tolerated dose of colchicine. The predictive score for colchicine resistance in FMF was developed by using univariate/multivariate regression and ROC analyses.

Results: A total of 2944 FMF patients (297 colchicine resistant and 2687 colchicine responsive) were included (F/M=1.02, mean age at diagnosis 78.3±47.7 months). In colchicine resistant patients, the age of symptom onset and diagnosis was younger (39.1±33.9 vs. 55.4±43.8; p<0.001 and 64.2±43.1 vs. 79.7±48.0 months; p<0.001, respectively) the mean duration of attacks (2.8±1.0 vs. 2.6±1.0 days, p=0.009) and the number of attacks in the one year before diagnosis (16.7±12.9 vs. 11.3±10.4, p<0.001) were higher than colchicine responsive patients. Considering the clinical findings, fever (91.4% vs. 82%), malaise (5.4% vs. 2.8%), erysipelas-like erythema (12.5% vs. 5.7%), arthralgia (50.8% vs. 44.3%), arthritis (34.9% vs. 18.1%), myalgia (16.1% vs. 10.1%), abdominal pain (91.4% vs. 84.2%), diarrhea (10.1% vs. 5.6%), and chest pain (31.9% vs. 16.3%) were significantly more prevalent among colchicine resistant patients compared to colchicine responsive patients (p<0.05). Also, comorbidity (28.4% vs. 14.5%), parental consanguinity (24.9% vs. 15.4%), and homozygosity or compound heterozygosity for exon 10 MEFV mutations (90.3% vs. 62.3%) were more frequent in colchicine resistant than responsive patients (p<0.05). With univariate and multivariate regression and ROC analyses, a score for predicting colchicine resistance in FMF was developed (Table 1). The cut-off value that discriminated best between colchicine resistant and colchicine responsive FMF patients was ≥6. Its sensitivity was 78% while its specificity was 60%.

Conclusion: The strongest predictors of colchicine resistance at the time of FMF diagnosis were the presence of arthritis, chest pain, homozygosity/compound heterozygosity for exon 10 mutations, and ≥1 attack/month. This predictive score could help us to identify FMF patients with a higher risk of severe disease.

Funding: This study was supported by the Science Academy’s Young Scientist Awards Program (BAGEP) of Turkey.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

Table 1 (abstract P115). Score for predicting colchicine resistant disease course in FMF patients

P116. Menstruation-triggered attacks in adolescent girls with Familial Mediterranean Fever (FMF)

E. D. Batu, Y. Bayındır, Z. Balık, S. Sener, E. Aliyev, M. Kasap Cuceoglu, U. Kaya Akca, O. Basaran, Y. Bilginer, S. Ozen

Hacettepe University Faculty of Medicine, Ankara, Turkey

Correspondence: E. D. Batu

Introduction: Familial Mediterranean fever is a monogenic autoinflammatory disease characterized by febrile episodes of serositis. In some FMF patients, attacks are triggered by menstruation. There are no studies analyzing peri-menstrual FMF attacks focused on adolescent girls with FMF.

Objectives: To analyze the characteristics and treatment in adolescent FMF patients with menstruation-triggered attacks compared to FMF patients who did not have any menstruation-triggered FMF attacks.

Methods: Post-pubertal girls (12-18 years of age) with FMF were included. All patients met the Eurofever criteria for FMF and had confirmatory MEFV genotypes.

Results: A total of 153 adolescent girls with FMF were included. FMF attacks were triggered by menstruation in 37 (24.2%). In these patients, the median number of attacks within one year increased from 4 to 10 after menarche (p=0.005). The median age at disease onset and diagnosis were younger and both pre-menarche and post-menarche attack frequency were higher in FMF patients with menstruation-triggered attacks compared to the rest of the group (Table). Dismenorrhea was more common among these patients, as well (Table). Regarding the characteristics of non-menstruation associated FMF attacks, the features were similar between two groups (Table). Also, the frequency of patients with exon 10/exon 10 MEFV mutations was similar among two groups. 17 out of 37 patients did not receive any treatment addressing their menstruation-triggered attacks. Colchicine dose was increased or a different preparation of colchicine was initiated in 14 patients and 11 of them benefit from this change. On demand anakinra or corticosteroid use was prescribed to two and one patients. Two patients were receiving NSAIDs during the first 3 days of their menstruation which prevented menstruation-triggered attacks.

Conclusion: Menstruation-triggered FMF attacks are probably more common among adolescents. These patients often have earlier disease onset and higher attack frequency in the pre-menarche period, as well. Raising awareness about these patients would help us to improve effective management strategies.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

Table 1 (abstract P116). See text for description

P117. The performance of a gene panel analysis among patients with systemic autoinflammatory diseases

Y. Bayındır¹, E. D. Batu¹, O. Bölük², C. Koşukcu³, E. Sağ², A. Özcan², M. Kasap Cüceoğlu¹, Z. Balık¹, S. Şener¹, E. Aliyev¹, H. Ö. Başaran¹, Y. Bilginer¹, S. Özen¹

¹Hacettepe University Faculty of Medicine, ²Ankara Research and Training Hospital, ³Hacettepe University, Department of Bioinformatics, Institute of Health Sciences, Ankara, Turkey

Correspondence: Y. Bayındır

Introduction: Systemic autoinflammatory diseases (AIDs) are usually associated with disturbances of innate immune system. Although clinical phenotypes may suggest a specific SAID, most of these diseases are diagnosed with genetic tests.

Objectives: To determine the diagnostic yield of our autoinflammatory gene panel (mainly covering inflammasomopathies) in a cohort of AID patients and analyze and compare the characteristics of gene panel positive versus negative patients.

Methods: Patients with features of AIDs were included in this study followed in the Department of Pediatric Rheumatology at Hacettepe University, all initially screened for the common MEFV mutations. They were screened with a gene panel including IL1RN, ADA2, IL10RA, IL10RB, NOD2, PSMB8, LPIN2, MEFV, MVK, NLRP3, PSTPIP1, TNFRSF1A, NLRP12, NLRP7, CARD14, TNFRSF11A, ELANE genes. Patients with a definite or probable disease-causing variant were classified as being ‘panel positive’. ROC analysis was used to determine best performing cut-off value for C-reactive protein (CRP).

Results: In our cohort, we enrolled 122 (40.2% female) patients suspected of AID. The median age at symptom onset was 23 months (range 0.1-180). Gene panel provided a definite or probable disease-causing variant in 26 of 122 patients (21.3%). These patients were diagnosed with: FMF (n=12), HIDS (n=8), CAPS (n=1), TRAPS (n=1), Blau syndrome (n=1), PAPA (n=1), DADA-2 (n=1), NLRC3-related disease (n=1). Of the panel negative patients, 14 were fulfilling Eurofever criteria for autoinflammatory recurrent fevers. Male gender (76.9% vs. 55.2%; p=0.046) and diarrhea (38.5% vs. 19.8%; p=0.048) were more prevalent and the median CRP levels during disease flares were higher (12.8 vs. 6.39 mg/dl; p=0.009) among panel positive patients than panel negative patients (Table 1). The cut-off CRP value that discriminated best between panel positive and panel negative patients was >6 mg/dl (sensitivity 72%; specificity 50%).

Conclusion: In our cohort, the aforementioned panel offered diagnosis in 21.3% of the patients. Urticarial rash and arthralgia/arthritis were more frequent among panel positive patients and a higher CRP predicted gene panel positivity. The reason for this could be due to the fact that the gene panel used was mainly directed to genes associated with IL-1.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

Table 1 (abstract P117). The characteristics of gene panel positive and negative patients who had features of systemic autoinflammatory diseases

P118. A novel missense mutation in NLRP3 causing inflammasome hyperactivation and subsequent sensorineural hearing loss as a part of atypical CAPS

M. Birk-Bachar¹, H. Cohen², E. Sofrin-Dr^1,2, N. Kropach-Gilad^2,3, N. Orenstein¹, L. Kornreich^2,3, R. Tal^1,2, G. Amarilyo^2,3, Y. Levinsky^2,3, M. Sokolov^2,3, E. Raveh^1,2, M. Gerlic², L. Harel^1,2

¹Schneider Children’s Medical Center of Israel, Petach Tikvah, ²Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, ³Schneider Children’s Medical Center of Israel, Petach Tikva, Israel

Correspondence: M. Birk-Bachar

Introduction: Gain-of-function mutations in the NLRP3 gene, lead to hyperactivation of the NLRP3 inflammasome, resulting in the inappropriate release of inflammatory cytokines including IL-1β, and cause a spectrum of autosomal-dominant systemic autoinflammatory diseases called cryopyrin-associated periodic syndromes (CAPS). Many of these patients also develop progressive sensorineural hearing loss (SNL) due cochlear autoinflammation, which in rare cases may be the primary finding. ^(1-4) A Jewish Ashkenazi family, presented at our clinic with: autosomal dominant progressive sensorineural hearing loss, without clinical features consistent with typical CAPS, and a novel missense variant in the NLRP3 gene (NM 001079821:c.1790G>A, p.Ser597Asn).

Objectives: The combination of this unique clinical presentation spanning 3 generations, alongside the novel variant in NLRP3, led us to explore whether carriers of the novel variant indeed show evidence of NLRP3 inflammasome hyper-activity.

Methods: We conducted a prospective study in 15 family members (10 known carriers, 5 age-group matched non-carriers), which included clinical and hearing assessment along with functional measurement of the NLRP3 inflammasome activity. Peripheral blood mononuclear cells (PBMCs) were isolated from peripheral blood. IL-1 levels secreted by PBMCS were measured under 3 main conditions: basal state, exposure to IL-1 stimulant (lipopolysaccharide, LPS) and exposure to LPS + MCC950 (specific inflammasome inhibitor). Quantitative in-vitro measurement of secreted IL-1 in supernatants of carriers and controls was conducted using ELISA (Enzyme-Linked Immunosorbent Assay).

Results: Of 10 known carriers, 6 family members from 3 generations, suffered from progressive SNL, varying from isolated high frequency impairment to severe hearing loss and cochlear implant. All family members with hearing impairment were variant carriers, and carriers who had normal hearing function were all under the age of 13. 6 carriers reported occasional episodes of fever/arthralgia, 3 of which reported past episodes of monoarthritis. Functional assessment of the inflammasome in carriers vs. non carriers (controls) revealed that although basal levels of secreted IL-1 were not significantly different in both groups, the fold of change (FC) of secreted IL-1 in response to LPS stimulation was at least 2 times higher among carrier vs. control group (2 way Anova, P-value < 0.05, sidak multiple comparison). Addition of MCC950 inhibited IL-1β secretion after stimulation with LPS+CaCl2, in both groups.

Conclusion: The suggestive clinical presentation, genotype-phenotype correlation, and evidence of inflammasome hyperactivation, as seen in functional inflammasome stimulation tests, are proof that the novel variant 001079821:c.1790G>A p.Ser597Asn is a pathogenic gain of function mutation. This hyperactivation state leads to atypical CAPS phenotype, with predominant non-syndromic and syndromic bilateral progressive SNL that initially affects ultra-high frequency ranges.

Trial registration identifying number: Study was approved by the local Helsinki Comittee (RMC-0941-20)

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P119. A family with pulmonary deficiency, polyarthritis, glomerulonephritis and vasculopathy: diagnosis in 3rd generation

L. Malz¹, M. A. Lee-Kirsch^1,2, C. Wolf¹, B. Mayer¹, C. Günther³, K. Stamos¹, C. Schütz^1,2, R. Berner^1,2, N. Brück¹

¹Department of Pediatrics, ²UniversitätsCentrum für Seltene Erkrankungen, ³Department of Dermatology, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

Correspondence: N. Brück

Introduction: History and main symptoms

We report on a family with an unusual clustering of interstitial lung disease as well as acral vasculopathy and polyarthritis. The index patient – a 10-year-old boy - was referred to us with progressive pulmonary deterioration, chilblain lesions and anemia. He presented with severe growth retardation, arterial hypertension and glomerulonephritis. Laboratory investigations showed increased inflammation, strongly positive values for RF, ANA and cANCA. The child’s father had bluish-discolored acral skin lesions and suffered from fibrosing interstitial lung disease since the age of 11 years. Additionally he reported night sweats, pulmonary hypertension, and right ventricular failure. Due to respiratory failure, he had been treated with cyclophosphamide, azathioprine and corticosteroids in adolescence.

The family history revealed similar clinical abnormalities in the paternal grandmother and aunt. The grandmother who had suffered from severe rheumatoid arthritis died at the age of 35 years from lung disease. The paternal aunt presented with recurrent pneumonia at the age of 1 year, followed by diagnosis of interstitial pulmonary fibrosis at 11 years, and onset of severe polyarthritis, anemia and accompanying glomerulonephritis at the age of 12. Her pulmonary deterioration was only temporarily controlled with cyclophosphamide and corticosteroids. She died at the age of 20 due to acute respiratory failure.

Objectives: Diagnosis

In view of the suggestive family history, and high clinical suspicion of STING-associated vasculopathy with onset in infancy (SAVI), genetic testing was initiated revealing the following pathogenic variant in the TMEM173 gene (c.463G>A [p.Val155Met; V155M] heterozygous) within a few days. The child’s father is also carrier of the mutation.

SAVI is a rare autoinflammatory disease with autosomal dominant inheritance, caused by gain-of-function variants in the TMEM173 gene (prevalence 1:1 M births). The V155M variant is located in the dimer interface of the STING protein (stimulator of interferon genes), and causes hyperactivation of the type 1 interferon axis. Systemic inflammation and small-vessel-vasculopathy start in infancy. Patients later present with interstitial lung disease and failure to thrive, acral dermatoses, and elevated acute-phase proteins and interferon signature. More rarely, anemia, polyarthritis and chronic glomerulonephritis with nephrotic syndrome are the presenting features.

Methods: Case report

Results: Therapy and prognosis

After confirming the diagnosis, therapy with the Januskinase (JAK) inhibitor Ruxolitinib was initiated, which interrupts the positive interferon feedback loop. Treatment led to normalization of the initially pronounced type 1 interferon activation (score: 8907.36) within 28 days. Clinically, there was a striking improvement in respiratory (FVC 59% to 79%) and renal functions.

The index patient’s father is being treated with the JAK inhibitors Baricitinib and Nintedanib

Conclusion: Discussion

Chilblain lesions and interstitial lung disease in combination with other autoimmune phenomena are suggestive for rare monogenic diseases such as SAVI. Genetic testing is essential for rapid initiation of targeted therapies.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P120. Experience with IL-1 inhibitors in patients with monogenic autoinflammatory diseases in a tertiary hospital’s pediatric rheumatology unit

I. Burgos Berjillos¹, M. Gonzalez Fernandez², B. Lopez Montesinos¹, L. Lacruz Pérez¹, M. Martí Masanet^1,2, I. Calvo Penadés¹

¹Pediatric Rheumatology Unit, Hospital Universitario y Politécnico La Fe, Valencia, ²Pediatric Rheumatology Unit, Medical Research Institute Hospital La Fe, Valencia, Spain

Correspondence: I. Burgos Berjillos

Introduction: IL-1 plays a pivotal role in the pathogenesis of some monogenic autoinflammatory diseases (AID) in which IL-1 inhibitors have been shown to be effective.

Objectives: To describe the experience with IL-1 inhibitors in patients with a monogenic AID in a pediatric rheumatology unit in a tertiary hospital.

Methods: Clinical and demographical data, efficacy, dose and adverse events were collected from patients with a monogenic AID who received treatment with IL-1 inhibitors (anakinra and/or canakinumab), followed in our pediatric rheumatology unit from January 2007 until December 2021.

Results: 31 patients were identified with a monogenic AID diagnosis and treatment with IL-1 blockers (table 1), 16 anakinra treatment courses (3 FMF, 7 HIDS, 5 TRAPS, 1 APLAID) and 26 canakinumab treatment courses (9 FMF, 9 HIDS, 4 TRAPS, 2 CAPS, 2 PAPA). Median (Q1;Q3) treatment time with anakinra and canakinumab was: 1,98 (1,04 ; 3,70) and 5,61 (2,30 ; 7,16) years, respectively.

We assessed treatment response: 81,3% of patients treated with anakinra achieved disease control, 25% complete response (3 FMF, 1 HIDS) and 56,3% partial response (6 HIDS, 2 TRAPS, 1 APLAID); for canakinumab courses, 92,3% of patients responded, 73,1% with complete response (6 FMF, 6 HIDS, 3 TRAPS, 2 CAPS, 2 PAPA) and 19,2% with partial response (3 FMF, 2 HIDS).

Related to dose management, 4/7 HIDS patients and 2/5 TRAPS patients needed anakinra dose increase (>2mg/kg/day or >100mg/day). 8/9 HIDS patients, 2/4 TRAPS and 1/2 CAPS patients needed canakinumab dose increase (4mg/kg/4 week or 300mg/4 week).

During the follow-up, it was possible to decrease the dose (interval increase) in 12/26 (46,2%) patients treated with canakinumab (5 FMF, 3 TRAPS, 2 HIDS and 2 PAPA).

Reported severe or of interest adverse events were 2 pneumonia in 2 patients and 2 generalized skin reaction in 2 patients while on anakinra and 5 pneumonia in 4 patients, 2 appendicitis, soft tissue infections in 2 patients and 2 varicella-zoster virus primoinfection while on canakinumab. One patient with HIDS developed hidradenitis during the follow-up. No death was reported.

Conclusion: We describe our experience with IL-1 inhibitors in a cohort of patients with monogenic AID. About one third (39%) of our patients with a monogenic AID were treated with IL-1 blockers, leading them to a better disease control. Globally, 67,7% of patients achieved remission. In our cohort, 89% of HIDS patients, and around 50% of TRAPS and CAPS patients needed higher dose of IL-1 inhibitors to achieve disease control. These findings highlight the importance of IL-1 blockade, with an accurate dose adjustment, in monogenic AID.

Disclosure of Interest: I. Burgos Berjillos: None declared, M. Gonzalez Fernandez: None declared, B. Lopez Montesinos: None declared, L. Lacruz Pérez: None declared, M. Martí Masanet: None declared, I. Calvo Penadés Consultant with: Novartis, Speaker Bureau with: Novartis, Sobi

Table 1 (abstract P120). See text for description

P121. Acute febrile neutrophilic dermatosis -sweet syndrome- case presentation

A. Calin, C. Scurtu, D. Sfrijan, R. Vidlescu

Pediatrics, M.S. Curie Hospital, Bucuresti, Romania

Correspondence: A. Calin

Introduction: In most cases, the cause of Sweet’s syndrome isn’t known. Acute febrile neutrophilic dermatosis is an uncommon skin condition characterised by fever and inflamed or blistered skin and mucosal lesions.

Objectives: Sweet’s syndrome can present in several clinical settings: classical (or idiopathic) Sweet’s syndrome, malignancy-associated Sweet’s syndrome (leukemia or solid tumors, such as breast or colon cancer) and drug-induced Sweet’s syndrome (most commonly a type of drug that boosts production of white blood cells). Classical Sweet’s syndrome usually presents in women between the age of 30 to 50 years, it is often preceded by an upper respiratory tract infection. We present ca case of a 9 years old boy with malignancy-associated SS.

Methods: The authors present a case of a 9 years old boy that was admitted to our oncology departement for acute leukemia. He developed a painful skin rash (plaques and nodules), fever resistent to antibiotics, arthralgia, elevated ESR and CRP. Clinical, laboratory and histopatological (oedema of the dermis and a diffuse infiltrate of numerous neutrophils with leukocytoclasis without vasculitis in the superficial and the deep dermis) findings established the diagnostis.

Diagnostic criteria for classic acute febrile neutrophilic dermatosis have been proposed.

Results: Sweet syndrome, although rare, it can be present in children. This is why pediatricians with rheumatology concerns and beyond, need to know about it and to take it into consideration when needed.

Conclusion: Early recognition and treatment of malignancy-associated Sweet syndrome is imperative to limit patient morbidity and provide anti-cancer therapy.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P122. Effects of unopposed IL-18 in mixed inflammatory environments

V. Dang¹, E. Landy², J. Varghese¹, L. Van Der Kraak², L. Huang¹, A. Frank-Kamenetskii¹, S. Canna¹

¹The Children’s Hospital of Philadelphia, Philadelphia, ²University of Pittsburgh, Pittsburgh, United States

Correspondence: S. Canna

Introduction: Interleukin 18 (IL-18) is an inflammasome-activated, IL-1 family cytokine that canonically induces interferon-gamma (IFNg). IL-18 activity is potently inhibited by a soluble, IFNg-inducible antagonist, IL-18 Binding Protein (IL-18BP). IFNg appears central to the pathogenesis of rare, hyperinflammatory states like Hemophagocytic Lymphohistiocytosis (HLH) and Macrophage Activation Syndrome (MAS), and IL-18 is both a biomarker of MAS and may be central to its pathogenesis. In some patients, MAS may compete with IFNg-independent features like arthritis, and IL-18 may contribute to both. More recently, patients with PSTPIP1 mutations causing neutrophilic skin rashes and arthritis were found to have chronic elevation of IL-18. These observations reinforce abundant evidence from model systems that IL-18 is also capable of amplifying Type 2 and 17 inflammatory responses.

Objectives: We hypothesized that excess IL-18 will amplify the dominant inflammatory T-cell paradigm and exaggerate models of mixed inflammation regardless of their prevailing type of inflammation (e.g. Type 1, Type 2, Type 17, etc.).

Methods: C57BL/6 WT and transgenic mice underwent experimental autoimmune encephalomyelitis (EAE) and inhaled house dust mite (HDM), which are models Type 1/17 and Type 1/2 competition, respectively.

Results: Without stimulation, Il18bp^-/- mice show no baseline skew towards Type1 responses except in intestinal epithelium. By contrast, Il18tg mice show a mild increase in serum IFNg and IFNg-producing cells in multiple tissues, most notably liver and spleen. Upon induction of EAE, Il18bp^-/- mice were profoundly protected from weight loss, clinical score, and CNS infiltration of T-cells. This protection was lost upon systemic neutralization of IFNg, suggesting unopposed IL-18 was protective via induction of IFNg. Intestinal immune responses have been shown to affect EAE. However, mice with an Nlrc4 inflammasome mutation causing Th1-expansion and excess IL-18 restricted to the intestines were not protected from EAE. Notably, CD4 T-cell infiltration into spinal cords was not significantly different during EAE in WT and Il18bp^-/- mice, but only Il18bp^-/- mice showed significant infiltration of CD8 T-cells.

Excess IL-18 protected against airway eosinophilia and Th2 differentiation in HDM in Il18tg but not Il18bp^-/- mice, possibly due to minimal induction of IL-18 in the latter.

Conclusion: Despite IL-18’s ability to amplify Type 2 and 17 responses in some circumstances, in models where T-cell differentiation states actively compete with each other, excess IL-18 prevents against non Type 1 immunopathology. This likely occurs indirectly, via the products of preferential-enhancement of type 1 responses. This may be relevant to therapeutics aimed at blocking pathogenic Th2 or 17 responses or in predicting the consequences of IL-18 blockade in complex inflammatory states.

Patient Consent: Not applicable (there are no patient data)

Disclosure of Interest: V. Dang: None declared, E. Landy: None declared, J. Varghese: None declared, L. Van Der Kraak Employee with: Bluesphere Bio, L. Huang: None declared, A. Frank-Kamenetskii: None declared, S. Canna Grant / Research Support with: AB2Bio, Novartis, SOBI, IMMvention Therapeutix, Consultant with: Simcha Therapeutics, Paid Instructor with: Clinical Viewpoints

P123. DNA methylation and gene expression signatures in CD14+ monocytes separate cno patients from healthy controls

E. Carlsson¹, A. Charras¹, G. Duffy¹, M. W. Beresford¹, H. J. Girschick², H. Morbach³, C. M. Hedrich¹

¹Department of Women’s and Children’s Health, University of Liverpool, Liverpool, United Kingdom, ²Department of Paediatrics, Vivantes Klinikum im Friedrichshain, Berlin, ³Pediatric Immunology and Rheumatology, Children’s Hospital, University of Würzburg, Würzburg, Germany

Correspondence: E. Carlsson

Introduction: Chronic non-bacterial osteomyelitis (CNO), and its severe form chronic recurrent multifocal osteomyelitis (CRMO), is an autoinflammatory bone disease typically affecting children and adolescents. While the underlying pathophysiological molecular mechanisms are not well understood, dysregulation of monocyte-derived pro- and anti-inflammatory cytokines has been reported in previous studies.

Objectives: This study aimed at identifying CNO/CRMO disease-specific gene expression and DNA methylation signatures in monocytes that may be used as biomarkers or therapeutic targets.

Methods: Peripheral blood mononuclear cells (PBMCs) from healthy controls (n=12) and CNO/CRMO patients (n=12) were collected at diagnosis and 6-12 months after treatment initiation with naproxen. Cells were immunostained against CD14 and CD16 to identify and characterise monocytes, which were isolated via FACS. Monocyte RNA and DNA were then extracted using a Qiagen AllPrep DNA/RNA Kit. Isolated RNA was subjected to rRNA depletion and RNAseq analysis to identify differentially expressed genes, while isolated DNA was analysed by Illumina Infinium Methylation EPIC Arrays to identify DNA methylation signatures. Gene Ontology (GO) and KEGG pathway analyses was performed for differentially expressed genes and genes presenting at least one promoter differentially methylated position (TSS1500, TSS200, 5’UTR).

Results: CNO/CRMO patients exhibited an increased proportion of classical monocytes compared to age- and sex-matched healthy controls (98% vs 93%, p<0.05), which did not significantly change following treatment with naproxen (98% vs 98%, ns). This was associated with altered gene expression and DNA methylation profiles. A total of 54 differentially expressed genes were identified when comparing CNO/CRMO patients at baseline with healthy controls, including IL17RC. Furthermore, 6 genes were found to be differentially expressed when comparing CNO/CRMO patients at baseline with patients at 6-12 months after treatment with naproxen, including PTGES and CXCR5. Differentially methylated positions (n=1176) were identified in promoter regions comparing monocytes from CNO/CRMO patients with healthy controls. These included genomic regions associated with genes encoding pro- or anti-inflammatory cytokines, or their receptors, including IL10RA and IL10RB, and enrichment of genes associated with TGF-beta activated receptor activity. No DMPs were identified comparing CNO/CRMO patients at baseline with follow-up.

Conclusion: Gene expression and DNA methylation signatures in CD14+ monocytes differentiate CNO/CRMO patients from matched healthy controls. As molecular signatures largely do not change in response to treatment with naproxen, they may represent early events in the pathophysiology rather than effects secondary to ongoing inflammation. The exact clinical relevance, and whether these may be exploited for therapeutic purposes need to be validated in further studies.

Disclosure of Interest: None declared

P124. Evaluation of activity and performance using Canada occupational performance measure in children with Familial Mediterrenian Fever

S. Y. Cetin¹, O. Kaya Kara¹, D. S. Kara², S. Yardım², E. Comak³, S. Akman³, M. Koyun³, G. Kaya Aksoy³

¹Faculty of Health Sciences, Department of Physiotherapy and Rehabilitation, ²Institue of Health Sciences, Department of Physiotherapy and Rehabilitation, ³Faculty of Medicine, Department of Child Health and Diseases, Akdeniz University, Antalya, Turkey

Correspondence: S. Y. Cetin

Introduction: Familial Mediterranean Fever (FMF) is an autoinflammatory disease that typically begins in childhood and more common among Mediterranean populations. The primary symptoms experienced by the patients are usually fever and pain with inflammatory attacks, which may cause obstacles in the individual’s role and functions in daily living activities. The Canadian Occupational Performance Scale (COPM) is an individualized measure designed to detect a person’s self-reported activity performance in daily life and can be used among children at least aged 8 years. Practicing COPM helps children to identify their own ideas about the supports required in their daily living activities. The activity and performance of children with FMF has not been questioned in the literature.

Objectives: The aim of this study was to determine the activity and performance of children with FMF by using COPM.

Methods: The study was included 42 children (22 girls, 20 boys between the ages of 8-17 years) with a mean age of 11.14±3.62 years. COPM was used to determine children’s activity and performance. The assessment was carried out face-to-face with the children by a physiotherapist. During this interview, the children identified up to five key activities they would like to tackle first. Then, the children determine the activities they want to do, should do or are expected to do; however, they determined the activities that they could not do or had difficulty and were not satisfied with because of their rheumatic diseases. Children identified activities for 3 different areas of COPM: self-care, productivity, leisure. For each of these activities, they gave performance and satisfaction scores between 1-10 (1 point indicates that he/she cannot do/’not at all satisfied; 10 points indicates that he/she is able/extremely satisfied).

Results: Children with FMF determined 20 different activities that they have difficulty in daily living activities. Children with FMF had most difficulties in three activities including running (64.1%), writing (41%), and climbing stairs (33.3%).

Conclusion: According to the results of our study, it was observed that children with FMF had difficulties with a wide variety of activities. It can be thought that COPM may be a useful tool to identify activity performance problems, can be used by clinicians in routine evaluation, and may also be useful in determining goals of rehabilitation programs for children with FMF.

References

1- Verkerk GJQ, van der Molen-Meulmeester L, Alsem MW. How children and their parents value using the Canadian Occupational Performance Measure (COPM) with children themselves. J Pediatr Rehabil Med 2021;14 (1):7-17

2- Ben-Chetrit E, Touitou I. Familial Mediterranean fever in the world. Arthritis Care Res 2009;61(10):1447–1453

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P125. Determination of participation in children with Familial Mediterrenian Fever

O. Kaya Kara¹, S. Y. Cetin¹, S. Karademir², E. Comak³, S. Akman³, M. Koyun³, G. Kaya Aksoy³

¹Faculty of Health Sciences, Department of Physiotherapy and Rehabilitation, ²Instıtue of Health Sciences, Department of Physiotherapy and Rehabilitation, ³Faculty of Medicine, Department of Child Health and Diseases, Akdeniz University, Antalya, Turkey

Correspondence: S. Y. Cetin

Introduction: Familial Mediterranean Fever (FMF) is a genetic disease characterized by recurrent episodes of fever accompanied by pain in the abdomen or joints. It is most common in individuals of Mediterranean and Middle Eastern descent, and the first attacks typically begin in childhood. In addition, musculoskeletal findings such as arthritis, arthralgia or myalgia can often be seen in patients younger than 18 years of age in children with FMF. The quality of life and psychosocial status of these children may also be adversely affected. These symptoms and negative experiences by children can adversely affect children’s participation of activities in home, school and community settings. The participation of these children has not been evaluated so far and there is no relevant evidence in the literature. Participation and Environment Measure - Children and Youth (PEM-CY) is the most comprehensive measurement based on International Classification of Functioning (ICF) components to evaluate participation of children and adolescents with or without disabilities at aged of 5 to 17 years-old, in home, school, and community settings, alongside environmental factors.

Objectives: This aim of this study was determine the participation of children with FMF and compared them with aged matched healthy peers.

Methods: The study was included 94 children (57 children with FMF and 37 healthy children between the ages of 7-17) with a mean age of 10.76 ±2.82 years. PEMC-Y was used to assess children’s participation according to ICF. The questions in the scale were answered by the families of children in face-to-face interviews. Student t test and chi-square test was used to compare the groups.

Results: When the groups compared in terms of participation at home, a significant difference was found in favor of the healthy group in the involvement, barriers, helpfullness and overall support scores (p:0.00). At school, a significant difference was found in favor of the healthy group in the participation frequency, involvement, barriers, helpfullness and overall support scores (p:0.00). In the community, a significant difference was found in favor of the healthy group in the all of subdomain scores (p:0.00-0.03).

Conclusion: According to our study, the participation of children with FMF in home, school and community settings was found to be lower than healthy children. Especially, it was observed that the participation of activities in community setting was lower in every field. The participation of these children should also be taken into account when planning rehabilitation programs and goals, and it should be target to ensure maximum participation at home, school and community settings.

References

1-Kaya Kara O, Turker D, Kara K, Yardimci-Lokmanoglu B. Psychometric properties of the Turkish version of Participation and Environment Measure for Children and Youth. Child Care Health Dev. 2020;46:711–722.

Trial registration identifying number:

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P126. Damaging variants in P2X7R associate with chronic nonbacterial osteomyelitis (CNO)

A. Charras¹, S. R. Hofmann², A. Cox³, F. Schulze², S. Russ², H. Hartmann⁴, S. Haldenby⁵, X. Liu⁵, H. Morbach⁶, H. Wittkowski⁷, P. J. Ferguson³, C. Hedrich^1,8

¹Department of Women’s and Children’s Health, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, United Kingdom, ²Klinik und Poliklinik für Kinder- und Jugendmedizin, Universitätsklinikum Carl Gustav Carus, TU Dresden, Dresden, Germany, ³Stead Family Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, United States, ⁴Centre for Molecular and Cellular Bioengineering, TU Dresden, Dresden, Germany, ⁵Centre for Genomic Research, Institute of Infection, Veterinary & Ecological Sciences, University of Liverpool, Liverpool, United Kingdom, ⁶Pediatric Immunology and Rheumatology, Children’s Hospital, University of Würzburg, Würzburg, ⁷Klinik für Pädiatrische Rheumatologie und Immunologie, Universitätsklinikum Münster, Münster, Germany, ⁸Pediatric Immunology and Rheumatology, Children’s Hospital, University of Würzburg, Liverpool, United Kingdom

Correspondence: A. Charras

Introduction: Chronic Nonbacterial Osteomyelitis (CNO) is an autoinflammatory bone disease primarily affecting children. It can cause pain, hyperostosis and fractures, thereby affecting quality-of-life and psychomotor development. While increased inflammasome activation has been reported, the exact molecular pathophysiology of CNO is unknown.

Objectives: To identify disease mechanisms in CNO to allow patient stratification and individualized treatment.

Methods: Whole exome sequencing in families with CNO, and target sequencing of P2X7R in a large German CNO cohort. Findings were integrated with demographic and clinical datasets. Genetically modified THP-1 cells were used to investigate altered potassium flux, inflammasome assembly (ASC specks), cytokine release and pyroptosis.

Results: In 8 families with a history of CNO in 2 generations, damaging mutations in P2X7R, a regulator of inflammasome assembly, were identified. Targeted sequencing in 196 unrelated patients identified rare damaging heterozygous variants in 5. In the remaining cohort, common variants were over-represented when compared to the healthy population. Patients with rare variants were younger, more frequently exhibited multifocal disease, and required more aggressive treatment with 2^nd-line agents when compared to the remaining cohort. THP-1 cells expressing variant P2X7 exhibited altered potassium flux, inflammasome assembly, IL-1 and IL-18 release, and pyroptosis.

Conclusion: Rare damaging variants in P2X7R account for approximately 2.5% of CNO cases. Common P2X7R variants were present in all remaining (97.5%) patients and may represent a risk allele underscoring the key role of inflammasome dysregulation in CNO. Observations will aid in future patient stratification and individualized care.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P127. Type 1 interferon pathway and Aicardi-Goutieres syndrome: a case report

A. Cilona, R. Asaro, C. Martorana, C. Alizzi, M. C. Maggio, G. Corsello

A.O.U.P. Paolo Giaccone- Università degli studi di Palermo, Palermo, Italy

Correspondence: A. Cilona

Introduction: Interferonopathies are a new class of Mendelian inherited disorders, belonging to the group of systemic autoinflammatory diseases(SADs); they are characterized by a constitutive yet anomalous activation of the type I interferon pathway (IFN I). They are clinically heterogeneous; the first identified interferonopathy, the Aicardi-Goutieres syndrome (AGS) , mainly determines neurological and cutaneous involvement. At the beginning, AGS was originally defined as pseudo-TORCH syndrome, identifying a group of serologically negative disorders that mimic congenital TORCH infections, suggesting a similar pathogenetic mechanism. The underlying genetic mutations induce an accumulation of DNA and RNA fragments, generated during the genomic repair process, which act as a trigger for the production of IFN I. Other pathologies, such as systemic lupus erythematosus (SLE) have in common with the interferonopathies the overproduction of IFN and skin involvement. It has been suggested that the accumulation of nucleic acids may lead to the same pathways involved in interferonopathies, with over-production of IFN, suggesting an overlap between interferonopathies and SLE. Recent evidence suggests that interferonopathies should be considered in differential diagnosis in cases of early onset or atypical presentation of rheumatological diseases in the pediatric setting, especially if lipodystrophy, lupus pernio, vascular disease and arthralgia are found among the signs of the disease.

Objectives: Our objective is to report a case which shows a possible correlation between a specific mutation and a well known autoimmune pathology such as the Aicardi-Goutieres.

Methods: F., 16 years old, comes to our observation complaining of arthralgia, nodular dermatitis affecting lower limbs and Her laboratory evaluation showed positivity of ANA, hypocomplementemia and proteinuria. Adaptive SLE was initially suspected, and the patient was treated accordingly with hydroxychloroquine and corticosteroids, and a rheumatological follow-up was initiated. Despite therapy, there was no regression of the vasculitic lesions, nor normalization of the values ​​of complementemia and proteinuria. The patient was therefore subjected genetic investigation with NGS technique for Interferonopathies.

Results: Despite therapy, there was no regression of the vasculitic lesions, nor normalization of the values ​​of complementemia and proteinuria. The patient was therefore subjected genetic investigation with NGS technique for Interferonopathies.

Conclusion: The variant c.2893G> A, found in the patient and in her father, is currently classified as a variant of uncertain significance (VUS). However, considering that literature reports cases of interferonopathies with vasculitis as only clinical presentation, and that genetic correlation is subject to periodic review, to this day an univocal diagnosis has not been made yet the patient. We hope that further observations may help us to define her diagnosis more precisely.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P128. Effect of the janus kinase inhibitor baricitinib in the treatment of COPA syndrome

F. Corona¹, C. Matucci-Cerinic², S. Pastore³, P. Bocca⁴, A. Ravelli⁴, R. Caorsi^4,5, M. Gattorno^4,5, S. Volpi^2,4,5, A. Tommasini^1,3

¹Università degli Studi di Trieste, Trieste, ²DINOGMI, Università degli Studi di Genova, Genova, ³IRCCS Institute Burlo Garofolo, Trieste, ⁴Center for Autoinflammatory diseases, IRCCS Institute Gaslini, ⁵Clinica pediatrica e Reumatologia, IRCCS Istituto Gaslini, Genova, Italy

Correspondence: C. Matucci-Cerinic

Introduction: COPA syndrome is a rare primary immunodeficiency, characterized by features of autoinflammation, immune dysregulation and autoimmunity caused by heterozygous mutations with incomplete penetrance of the COPA gene. Clinically, the disease is characterized by lung, kidney and joint involvement. No therapeutic guidelines exist for the treatment of COPA syndrome, even if the use of JAK-inhibitors has been reported in some patients.

Objectives: to evaluate the efficacy of the JAK 1/2 inhibitor baricitinib in controlling and preventing disease progression in paediatric COPA patients.

Methods: the data of 3 COPA patients treated with Baricitinib were retrospectively reviewed. Clinical, serological, immunological and radiological data were collected.

Results: all patients were females and had a disease onset before 3 years of age. One patient (P1) carried the p.Arg233His mutation, while the 2 other unrelated patients (P2 and P3) carried the p.Arg281Trp mutation. P1 and P2 mother’s were asymptomatic carriers. P2 has a brother and a sister affected: the brother has an articular and pulmonary involvement, the sister died at 23 years of heart failure. P3’s mother is actually diagnosed with Still disease but no COPA mutation was found in the family. Clinically, all patients presented with arthritis, which was deforming in 2 cases (P1 and P2), and with pulmonary involvement, characterized by interstitial lung disease and by multiple pulmonary cysts on the CT scan. P1 and P3 presented also ground glass opacities and bronchiectasis. No pulmonary haemorrhages were reported. All patients have a normal renal function. P3 has congenital bilateral renal dysplasia. At diagnosis, spirometry in P1 showed a severe reduction of the FVC and of the DLCO, the 6minute walking test (6MWT) was pathologic with a minimal SaO2 of 85%. Spirometry and 6MWT were not performed in the other 2 patients because of the young age. All the patients presented a positive IFN signature at disease onset and were ANA and rheumatoid factor positive. P1 had also positive anti-citrullinated peptide antibodies. P1 had a disease onset 7 years before the first description of COPA disease and underwent several immunosuppressive and biologic therapies before the diagnosis (oral and intraarticular steroids, abatacept, methotrexate, mofetil mycophenolate MMF, rituximab). P2 was diagnosed one year after the disease onset and was previously treated with steroids, MMF and hydroxychloroquine. P3 was started on baricitinib at disease onset. After baricitinib was started, in all the patients a reduction of the inflammatory biomarkers was evident and steroids could be stopped in P1 and P2 (while never used in P3). In P1 a dramatic improvement of the 6MWT was achieved (minimal SaO2 during the test at last f-up 96%), CT scan and spirometry showed no disease progression over the years, and no articular injections were needed in the last 36 months (1-2 intra-articular injections/year before baricitinib start). Both P1 and P2 have a current follow-up of 36 months, P3 of 3 months on baricitinib and didn’t experience any disease relapse since the start of the therapy.

Conclusion: baricitinib seems to block lung disease progression in medium term follow-up, controlling arthritis and reducing systemic inflammation in COPA disease. Larger cohorts of patients are needed to confirm these results.

Disclosure of Interest: None declared

P129. Characterization of AR-CGD female patient with novel homozygous deletion in CYBC1 gene presenting with unusual clinical phenotype

A. De Matteis¹, M. F. Natale¹, M. Chiriaco², C. Cifaldi³, S. Di Cesare^2,3, C. Passarelli⁴, A. Novelli⁴, G. Di Matteo^2,3, A. Finocchi^2,3, F. De Benedetti⁵, A. Insalaco⁵

¹Division of Rheumatology, ERN-RITA center, IRCCS Ospedale Pediatrico Bambino Gesù, Roma, Italy, ²Department of Systems Medicine, University of Rome Tor Vergata, ³Academic Department of Paediatrics, Immune- Infectivology Unit, ⁴Translational Cytogenomics Research Unit, ⁵Division of Rheumatology, ERN-RITA center, IRCCS Ospedale Pediatrico Bambino Gesù, Roma, Italy

Correspondence: M. F. Natale

Introduction: Mutations in EROS/CYBC1 gene cause a rare form of autosomal recessive (AR) chronic granulomatous disease (CGD), characterized by severe life-threatening infections, hyperinflammation and immune-dysregulation.

Objectives: We described an AR-CGD patient with a novel homozygous deletion in CYBC1 gene leading to absent EROS/CYBC1 protein and presenting with a clinical phenotype almost exclusively characterized by inflammatory manifestations.

Methods: Whole Exome Sequencing (WES), Flow Cytometry Studies (phenotype, DHR assay, protein expression), Western Blot (protein expression

Results: The clinical history of a previously well-being two years old female child was predominantly characterized by autoinflammatory phenotype. At onset she presented with recurrent episodes of fever of unknown origin responsive to glucocorticoids. Subsequently she developed inflammatory bowel disease treated with mesalazine. NBT test was negative. At the age of 9 years old she presented with pancytopenia, hepatosplenomegaly, bowel inflammation and granulomatous lung disease. Laboratory tests showedincreased levels of chitotriosidase (> 10 times normal value) and angiotensin converting enzyme (> 2 times normal value). In the suspicion of sarcoidosis immunosuppressive treatment with high dose of glucocorticoids, methotrexate and adalimumab was started. WES identified a novel homozygous deletion c. 8_7del CTCTCGGGATGTACC in the CYBC1 gene leading to absent CYBC1/EROS protein in PBMC and EBVB cells. Patient’s parents, heterozygous for the mutation, expressed about half of the protein. The gp91phox protein expression/function was impaired in patient’s neutrophils and monocytes (about 50%), but severely compromised in B cells (gp91phox<15%; DHR+ < 4%).

Conclusion: This patient’s case emphasize the importance to consider a diagnosis of CGD even in absence of classical clinical presentation and negative NBT test.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P130. The preferential use of anti-interleukin 1 therapies in various pediatric rheumatic disorders: outcomes of treat-to-target approach

F. G. Demİrkan¹, Ö. Akgün², V. Guliyeva², N. Aktay Ayaz¹

¹Pediatric Rheumatology, ²İstanbul School of Medicine, İstanbul, Turkey

Correspondence: F. G. Demİrkan

Introduction: Interleukin-1 inhibitors are proven treatment options for autoinflammatory disorders. Anakinra and canakinumab are the most commonly used anti-interleukin 1 agents in the field of pediatric rheumatology.

Objectives: The aim of this study was to evaluate the broader effectiveness and safety of anakinra and canakinumab in a ‘real world’ pediatric population.

Methods: Patients with colchicine-resistant familial Mediterranean fever (crFMF), systemic juvenile idiopathic arthritis (sJIA), or polyarticular JIA treated with anakinra and canakinumab in any order were identified using the database of İstanbul Faculty of Medicine between January 2020-May 2022.Background characteristics of the patients, reason for switching to IL-1 inhibitor, and the side effects observed during the treatment were extracted form the patient files recorded at every 3 month visits.

Results: Forty-eight pediatric patients(65%female) were enrolled in this study. The median age was 11 years (4-17 years), and the median disease duration was 37 months (14-59 months). The median (IQR) duration of treatment with anti-IL-1 agents was 16 (12-36) months. Forty-three patients were treated with canakinumab (150 mg/4 week) and 48 patients with anakinra (100 mg/day).Six (12.5%) patients receiving anakinra were diagnosed with sJIA, 1(2%) with polyarticular JIA and 41(85.4%) with crFMF in, and . In the canakinumab group diagnoses were sJIA in 2 (4.6%) and crFMF in 41 (95.3%) patients. The patients with crFMF were first treated with colchicine alone for a median duration of 12.5(8-38) months. Canakinumab was prescribed for crFMF after previous anakinra treatment, whereas no patients who switched treatment from canakinumab to anakinra were identified. According to the current guidelines for the treatment of FMF, colchicine was continued along with the IL-1 inhibitors. The autoinflammatory diseases activity and attacks decreased with both anakinra and canakinumab. However, 18/41(43.9%) patients with crFMF discontinued anakinra due to inadequate response (4 of them with secondary failure after a good initial response) and switched to canakinumab. In 9(21.9%) children anakinra was switched to canakinumab due to patient preference regarding refuse of daily injection. Frequency of flares and the median duration of flares were significantly decreased following switching to canakinumab from anakinra treatment (p<0.01). Anakinra was effective in decreasing proteinuria and canakinumab was also successful in decreasing proteinuria in anakinra unresponsive patients. The modified FMF score was achieved in 76.2% of anakinra and 88.9% of canakinumab group. Anakinra could be stopped due to complete remission in 4 children with sJIA. However, in 2/6 patients, anakinra was switched to canakinumab due to resistant disease course. Injection site reactions (ISRs, n:13) was the most common reason for the discontinuation of anakinra and most of ISRs developed in the first month of treatment. Two severe skin rashes and one significant elevation of transaminases were observed with anakinra. No severe side effects or side effect-related discontinuation of canakinumab was observed. No serious infections were detected in both anakinra and canakinumab group.

Conclusion: While canakinumab, a human monoclonal anti-IL-1 beta antibody, for the convenience of its use, became the preferred IL-1 blocker in FMF, anakinra has its own benefits in certain circumstances of FMF. Canakinumab had a favorable safety/tolerability profile. Anakinra is also generally safe with side effects that may be observed in the short and long-term use should be taken into account. Large series and extended follow-up studies are required for establishing the long-term effects of these treatments.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P131. Predict-CRFMF score: a novel model for predicting colchicine resistance in children with Familial Mediterranean Fever

N. Aktay Ayaz¹, F. G. Demİrkan¹, T. Coşkuner², F. Demir³, A. Tanatar¹, M. Çakan², S. G. Karadağ⁴, G. Otar Yener⁵, K. Öztürk⁶, E. Bağlan⁷, F. Çakmak¹, S. Çağlayan², S. Özdel⁷, K. Ulu², B. Sözeri², H. E. Sönmez⁸

¹Pediatric Rheumatology, İstanbul School of Medicine, ²Pediatric Rheumatology, Umraniye Research and Training Hospital, ³Pediatric Rheumatology, Acıbadem Healthcare Group, ⁴Pediatric Rheumatology, Çam ve Sakura City Hospital, İstanbul, ⁵Pediatric Rheumatology, Sanliurfa Mehmet Akif Inan Training and Research Hospital, Sanlıurfa, ⁶Pediatric Rheumatology, Istanbul Medeniyet University, School of Medicine, Goztepe Research and Training Hospital, İstanbul, ⁷Pediatric Rheumatology, Dr. Sami Ulus Obstetrics and Gynecology, Pediatric Health and Disease Training and Research Hospital, Ankara, ⁸Pediatric Rheumatology, Kocaeli School of Medicine, Kocaeli, Turkey

Correspondence: F. G. Demİrkan

Introduction: As none of the previous scoring systems have a power of estimating the refractory disease course at the initiation of the colchicine treatment in familial Mediterranean fever (FMF) cases, a predictive model appear to be beneficial for achieving early control of disease in colchicine resistant FMF (cr-FMF) patients.

Objectives: We intended to develop a novel scoring system based on the initial clinical features and laboratory findings for predicting colchicine resistance in FMF, thus providing a reliable and easy tool for pediatric rheumatologists while evaluating patients at diagnosis.

Methods: The medical records including baseline clinical and laboratory findings of patients prior to initiation of colchicine were analyzed. After generating a predictive score in the initial cohort, it was applied to an independent cohort for external validation of effectiveness and reliability.

Results: Between June 2020 and December 2021, 1464 patients were admitted to the pediatric rheumatology outpatient clinic with the diagnosis of FMF. Forty-six patients were excluded from the analysis due to short follow-up period (less than 6 months). Among 1418 patients with FMF, 56 (3.9%) were colchicine resistant (cr) and 1312 (96.1%) were colchicine responsive. According to the logistic regression analysis, recurrent arthritis (4-points), protracted febrile myalgia (8-points), presence of ELE (2-points), exertional leg pain (2-points), and carrying M694V homozygous mutation (4-points) were determined as the scoring parameters for predicting patients with cr-FMF. Scores were assigned according to β coefficients in the final model. (Table 1)

Conclusion: Intolerance/resistance in a definite portion of patients with FMF is posing a dilemma for pediatric rheumatologists and uncontrolled inflammation resulting in amyloid deposition in organ systems is detrimental for the patients as well. By constructing this novel reliable predictor tool, we enunciate that predicting colchicine resistance in children with FMF at the initiation of the disease and interfering timely before the emergence of complications during the disease course will be possible.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

Table 1 (abstract P131). See text for description

P132. Can the diagnosis of PFAPA syndrome be confirmed? data from the long-term follow-up of a single-centre cohort

A. Doležalová, P. Šeferna, A. Zahornadský, Š. Fingerhutová, P. Doležalová

Department of Paediatrics and Inherited Metabolic Disorders, General University Hospital in Prague, Prague, Czech Republic

Correspondence: A. Doležalová

Introduction: Diagnosis of Periodic Fever, Aphtae, Pharyngitis and Adenitis syndrome (PFAPA) is based on its typical clinical picture and exclusion of other conditions. It has been postulated that it is a self-limited disease with spontaneous remission occurring by puberty in majority of patients.

Objectives: We aimed at supporting the presumption that diagnosis of PFAPA based on the combination of systematic clinical evaluation using modified diagnostic criteria (1) and standardized follow-up is ultimately confirmed only by its complete resolution.

Methods: A structured phone call interview was carried out during May 2022 with patients born between 1999-2008 from our PFAPA cohort described in 2013 (2) that have not been seen at our fever clinic for more than 5 years. Questions covered current health status including existence of any unexplained periodic symptoms, date of the last typical PFAPA episode, tonsillectomy (TE) date. In combination with the hospital electronic record the disease characteristics were derived.

Results: During the period of 2004-2011 diagnosis of PFAPA syndrome was confirmed in 125 children (all Czech origin Caucasians) with the median age at onset of 23 months (2). In 60 patients who answered the call the current age was 16.1 (SD 2.3) years (response rate 48%). Mean follow-up (F/U) duration (from the 1^st visit until the call) was 12.7 (SD 1.7) years. In 3/60 (5%) patients recurrence of typical PFAPA was reported after the prolonged (>1year) asymptomatic interval before they entered sustained remission. Only 4/60 (6.7%) patients reported ongoing periodic problems different from the original PFAPA episodes. In 56 patients in remission (93.3%) the total disease duration (from the first to the last reported typical PFAPA episode) was 4.1(SD 2.8) years with the mean age of the last PFAPA episode of 5.9(SD 3) years. Mean asymptomatic interval (from the last reported episode until the interview) was 9.5 years (SD 2.9). 16/60(26.7%) patients reported TE at mean age of 4.8 (SD 2.1) years that was followed by full resolution of PFAPA in 14 cases (87.5%). In one patient there was a short recurrence of typical episodes followed by remission, in the other one typical PFAPA ended post-TE but short febrile episodes with no other symptoms have been recuring until now in 3-monthly intervals.

Conclusion: Using a diagnostic approach described previously (2) the original diagnosis of PFAPA was confirmed by its longstanding remission (>9 years) in the majority (93.3%) of cases with symptom resolution occurring during the early school years. TE was a potent remission inductor in almost 90% of cases. Recurrence of symptoms after prolonged afebrile interval was uncommon. Persistence of periodic complaints in 4 patients discovered by the interview will lead to the clinical and genetic re-evaluation of their diagnosis.

References:

1. Hofer M, Cochard M, Anton J et al.: PFAPA (periodic fever, oral aphtae, pharyngitis and cervical adenitis) syndrome: a new consensus on diagnostic criteria. Ann Rheum Dis 2009; 68 (Suppl.3): 705

2. Król P, Böhm M, Sula V, et al.: PFAPA syndrome: clinical characteristics and treatment outcomes in a large single-centre cohort. Clin Exp Rheumatol 2013;31(6):980-987

Trial registration identifying number:

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P133. Long-term efficacy and safety of canakinumab in patients with Familial Mediterranean Fever (FMF) - interim analysis of the reliance registry

F. Dressler¹, J. Henes², N. Blank³, T. Krickau⁴, T. Kallinich⁵, G. Horneff⁶, F. M. Meier^7,8, I. Foeldvari⁹, F. Weller-Heinemann¹⁰, B. Kortus-Goetze¹¹, M. Hufnagel¹², J. Rech¹³, P. T. Oommen¹⁴, J. Weber-Arden¹⁵, J. B. Kuemmerle-Deschner¹⁶

¹Division of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, ²Center of Interdisciplinary Rheumatology, Immunology and autoimmune diseases (INDIRA), University Hospital Tuebingen, Tuebingen, ³Rheumatology, University Hospital Heidelberg, Heidelberg, ⁴Pediatrics, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Erlangen, ⁵Department of Pediatrics, Division of Pulmonology, Immunology and Critical Care Medicine, Charité University Medicine Berlin, Berlin, ⁶Asklepios Clinic Sankt Augustin, Sankt Augustin, ⁷Project Group Translational Medicine and Pharmacology TMP, Fraunhofer Institute for Molecular Biology and Applied Ecology IME, ⁸Division of Rheumatology, University Hospital Frankfurt, Goethe University, Frankfurt am Main, ⁹Centre for Pediatric and Adolescence Rheumatology Hamburg, Hamburg, ¹⁰Prof. Hess Kinderklinik, Klinikum Bremen-Mitte, Bremen, ¹¹Division of Nephrology, University of Marburg, Marburg, ¹²Division of Pediatric Infectious Diseases and Rheumatology, Department of Pediatrics and Adolescent Medicine, University Hospital Medical Center Freiburg, Medical Faculty, University of Freiburg, Freiburg, ¹³Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander University (FAU) Erlangen-Nuernberg and Universitaetsklinikum Erlangen, Erlangen, ¹⁴Clinic of Pediatric Hematology, Oncology and Clinical Immunology, Heinrich-Heine-University Duesseldorf, Duesseldorf, ¹⁵NOVARTIS, Nuernberg, ¹⁶Department of Pediatrics, Division of Pediatric Rheumatology, University Hospital Tuebingen, Tuebingen, Germany

Correspondence: F. Dressler

Introduction: Familial Mediterranean fever (FMF) is a chronic disease characterized by recurrent episodes of fever and serositis, with a risk of severe complications (e. g. amyloidosis). Treatment of FMF according to EULAR recommendations aims to control acute relapses and subclinical inflammation and improve patients’ quality of life.

Objectives: The present study investigates the long-term efficacy and safety of CAN in routine clinical practice in pediatric (age ≥2 years) and adult FMF patients.

Methods: RELIANCE is a prospective, non-interventional, multicenter observational study in Germany with a follow-up period of up to seven years. Patients with a clinically confirmed diagnosis of FMF who routinely receive CAN will be enrolled in the study. Disease parameters will be recorded at the time of study inclusion and six-month intervals.

[1]AIDAI: Auto-Inflammatory Diseases Activity Index

Results:

This interim analysis of FMF patients (N=74) enrolled through December 2021 includes data from baseline through the 24-month visit. The mean age in this cohort was 25 years (2-61 years). The proportion of female patients was 51% (N=38). At baseline, the median duration of prior CAN treatment was 1.0 years (0-6 years). At month 24, approximately 63% of patients were in disease remission by physician assessment, and 67% of patients documented inactive disease in the AIDAI[1] score (Table 1).

Mutations were documented in a total of N=57 patients, including M694V (9 homozygous, 10 compound heterozygous, 12 heterozygous), V726A (1 hom., 6 comp. het., 1 het.), and M680I (1 hom., 6 comp. het., 1 het.).

At baseline, N=16 FMF patients were CAN-naive and received a starting dose of median 150 mg CAN (40 mg/kg - 150 mg every 4 weeks). In this subgroup, a total of 12 dose adjustments were made over time (9 dose increases, 3 dose reductions).

A total of 18 SAE[2] were reported, of which 2 (tonsillectomy and tachycardia) were classified as drug-related.

[1]AIDAI: Auto-Inflammatory Diseases Activity Index

[2]SAE: Serious Adverse Event

[1]SAE: Serious Adverse Event

Conclusion: Interim data from FMF patients in the RELIANCE study, the longest running canakinumab registry, confirm the efficacy and safety of long-term treatment with canakinumab.

Disclosure of Interest: F. Dressler Grant / Research Support with: Novartis, Consultant with: Abbvie, Mylan, Novartis, Pfizer, J. Henes Grant / Research Support with: Novartis, Roche, Consultant with: Novartis, AbbVie, Sobi, Roche, Janssen, Boehringer-Ingelheim, N. Blank Grant / Research Support with: Novartis, Sobi, Consultant with: Novartis, Sobi, Lilly, Pfizer, Abbvie, BMS, MSD, Actelion, UCB, Boehringer-Ingelheim, Roche, T. Krickau Grant / Research Support with: Novartis, Consultant with: Novartis, Speaker Bureau with: Novartis, T. Kallinich Speaker Bureau with: Roche, G. Horneff Grant / Research Support with: AbbVie, Chugai, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Speaker Bureau with: AbbVie, Bayer, Chugai, Merck Sharp & Dohme, Novartis, Pfizer, Roche, F. M. Meier Speaker Bureau with: Novartis, I. Foeldvari Consultant with: Novartis, F. Weller-Heinemann: None declared, B. Kortus-Goetze Consultant with: Novartis, M. Hufnagel Grant / Research Support with: Novartis, J. Rech Grant / Research Support with: Novartis, Sobi, Consultant with: AbbVie, Biogen, BMS, Chugai, GSK, Janssen, Lilly, MSD; Mylan, Novartis, Roche, Sanofi, Sobi, UCB, Speaker Bureau with: AbbVie, Biogen, BMS, Chugai, GSK, Janssen, Lilly, MSD; Mylan, Novartis, Roche, Sanofi, Sobi, UCB, P. T. Oommen Grant / Research Support with: Novartis, J. Weber-Arden Employee with: Novartis, J. B. Kuemmerle-Deschner Grant / Research Support with: Novartis, AbbVie, Sobi, Consultant with: Novartis, AbbVie, Sobi

Table 1 (abstract P133). Evaluation of clinical disease activity and safety aspects of patients with FMF

P134. Impact of coronavirus outbreak restrictions on behaviors of patients with Familial Mediterranean Fever

S. Ertem, Z. B. Ozcakar, F. Aydin, N. Cakar, F. F. Yalcinkaya

Pediatric Rheumatology, Ankara University, School of Medicine, Ankara, Turkey

Correspondence: S. Ertem

Introduction: Familial Mediterranean fever (FMF) is the most common systemic autoinflammatory disease characterised by recurrent, self-limiting attacks of fever and serositis. The pandemic caused by novel coronavirus-2 (SARS-CoV-2), known as coronavirus disease 2019 (COVID-19), is a global public health problem leading to significant mortality and morbidity worldwide. To prevent the spread of COVID-19, state and local governments enacted numerous restrictions on human movement and physical interactions. The effect of COVID-19 pandemic and the implemented restrictions on the frequency of attacks and the course of pediatric FMF remains unknown.

Objectives: The aim of this study was to investigate the impact of COVID-19 restrictions on clinical status of FMF patients.

Methods: We have enrolled patients with FMF, diagnosed according to Turkish pediatric FMF criteria, who were admitted to outpatient clinic of pediatric rheumatology department between June 2021 and December 2021.

Medical records of the patients were evaluated retrospectively. Demographic data, family history, genetic results, clinical findings before and after FMF diagnosis, and the treatment modalities were recorded. Patients were also questioned about the pandemic days, information about school attendance, clinical findings of FMF, frequency of respiratory infections, colchicine dosages were noted. The clinical and laboratory findings of the patients before and during the pandemic were compared. The schools were closed for three semesters and children received online education during this period.

Parameters were expressed as mean ± standard deviation (SD), median [interquartile range (IQR)], and number (percentage). The Cochran Q test was used to compare categorical variables between dependent groups. McNemar test was used to determine which of the categorical variables caused the difference between the three groups (post-hoc analysis), and Bonferroni corrected alpha values were presented. A p<0.05 was considered to be significant.

Results: A total of 201 patients ( 97 male, 48% ) with a median age of 13 years ( 2-19 years ) and median follow up of 6 years (3-8.5 years) were included. Major clinical findings of FMF including abdominal pain, fever, arthritis, artralgia, leg pain, heel pain, and frequency of FMF attacks were significantly reduced in pandemic era compared with prepandemic era (Table 1). Moreover, the frequency of upper respiratory tract infections were also reduced during pandemic period. Attack free white blood cell (WBC) count and sedimentation rate levels were significantly decreased in pandemic era, compared to prepandemic era (p<0.05).

Conclusion: Attacks of FMF can be triggered by various factors including infections, lack of sleep or stress. During COVID-19 restrictions, patients with FMF had reduced attack frequency in childhood period. Together with online education; the rate of respiratory tract infections decreased, possibly resulting in decreased disease activity. This showed us once again the role of environmental factors in autoinflammatory disease activity.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

Table 1 (abstract P134). Comparison of clinical findings before FMF diagnosis, after FMF diagnosis before pandemic (after treatment), during pandemic

P135. Blood levels of interleukin-18 (IL-18) in patients with systemic juvenile arthritis and monogenic autoinflammatory diseases (FMF, CAPS, TRAPS)

E. S. Fedorov¹, S. S. Salugina¹, M. Kaleda¹, M. Cherkasova², Z. Kolkhidova¹

¹Pediatrics, ²1 Immunology and Molecular Biology of Rheumatic Diseases, V.A. Nasonova Research Institute of Rheumatology, Moscow, Russian Federation

Correspondence: E. S. Fedorov

Introduction: Interleukin1 plays a leading role in the pathogenesis of autoinflammatory diseases (AIDs), to which systemic juvenile arthritis (sJA) also belongs.

Objectives: IL 18 is a member of the interleukin-1 superfamily with a range of special properties; that is why it is of interest to estimate its level in patients with monogenic and polygenic AIDs.

Methods: 147 patients with sJA and monogenic AIDs (FMF, CAPS, TRAPS) participated in the study. The diagnosis in all patients with monogenic AIDs was confirmed basing on detection of pathogenic alleles of corresponding genes. IL18 was detected in blood serum through ELISA method using Invitrogen kits (Bender MedSystems GmbH, Austria): reference parameter 0-732.7 ng/ml. Statistical processing was performed using the program “Jamovi”. The reliability of differences between the FMF, CAPS, TRAPS and JA groups was assessed under the Mann-Whitney criterion.

Results: The study including 61 patients with sJA: male/female 23/38; age of inclusion into the study 3-19 years; of them ≥ 18 years - 2 (3%), FMF 40 patients; male/female 22/18; age 3-37 years, of them ≥ 18 years - 8 (20%), CAPS 30 patients; male/female 19/11; age 1-51 years, of which ≥ 18 years - 13 (43%), TRAPS 16 patients; age 4-38 years, of which ≥ 18 years - 4 (25%). In the group of patients with sJA, the Median (Me) of IL18 concentration amounted to 4 245.51 ng/ml, 1st quartile 1 136.94 ng/ml, 3rd quartile 4 324.6 ng/ml, interquartile range (IQR) 3,187.6 ng/ml. In patients with FMF Me 657.08 ng/ml, 1st quartile 180.96 ng/ml, 3rd quartile 1 815.51 ng/ml, IQR 1 634.55 ng/ml. In patients with CAPS Me 207.6 ng/ml, 1st quartile 89.0 ng/ml, 3rd quartile 291.0 ng/ml, IQR 202.0 ng/ml. In patients with TRAPS Me 338.6 ng/ml, 1st quartile 159.04 ng/ml, 3rd quartile 1 924.08 ng/ml, IQR 1 765.4 ng/ml. Differences between patients with sJA and patients with FMF, CAPS and TRAPS were reliable: sJA - FMF, sJA - CAPS p<0.001; sJA – TRAPS p<0.009.

Conclusion: The maximum concentrations of IL18 are observed in patients with multifactorial AID - sJA, which exceed the concentrations in patients with monogenic AIDs (FMF, CAPS, TRAPS). This fact may explain the greater predisposition to development of macrophage activation syndrome in patients with sJA compared to the above-stated monogenic AIDs. Among patients with monogenic AIDs, the maximum concentrations of IL18 are in patients with FMF, and the minimum concentrations - in patients with CAPS.

Patient Consent: Not applicable (there are no patient data)

Disclosure of Interest: None declared

P136. Renal involvement and amyloidosis in autoinflammatory diseases: data from the Eurofever registry

Š. Fingerhutová¹, H. Lachmann², E. Papadopoulou-Alataki³, J. Frenkel⁴, L. Cantarini⁵, L. Obici⁶, G. Fabio⁷, G. Fabio⁷, I. Koné-Paut⁸, G. Amaryan⁹, W. Armbrust¹⁰, E. Hoppenreijs¹¹, J. Kuemmerle-Deschner¹², E. Moreno¹³, M. Alessio¹⁴, N. Ruperto¹⁵, M. Gattorno¹⁶, P. Dolezalova¹ on behalf of for the Paediatric Rheumatology International Trials Organisation (PRINTO) and the Eurofever Registry

¹General University Hospital in Prague, Centre for Paediatric Rheumatology and Autoinflammatory Diseases, Prague, Czech Republic, ²Royal Free Campus, National Amyloidosis Centre, London, United Kingdom, ³Papageorgiou General Hospital, Fourth Department of Pediatrics, Aristotle University of Thessaloniki, School of Medicine, Faculty of Health Sciences , Thessaloniki, Greece, ⁴Wilhelmina Kinderziekenhuis, Department of Pediatric Immunology and Rheumatology, Utrecht, Netherlands, ⁵University of Siena, Department of Medical Sciences, Surgery and Neurosciences, Rheumatology Unit, Siena, ⁶Fondazione IRCCS Policlinico San Matteo, Centro per lo Studio e la Cura delle Amiloidosi Sistemiche, Pavia, ⁷Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Dipartimento di Medicina Interna, UOS Malattie Rare, Milano, Italy, ⁸National Referral Centre of Auto-Inflammatory Diseases and inflammatory amyloidosis, CEREMAIA, CHU de Biĉetre, APHP, University of Paris Sud, Department of Pediatric Rheumatology, Le Kremlin Biĉetre, France, ⁹Arabkir Medical Complex - Institute of Child and Adolescent Health, National Pediatric Centre for Familial Mediterranean Fever; Yerevan State Medical University, Yerevan, Armenia, ¹⁰Beatrix Kinderkliniek, University Medical Center, Department of Pediatric Rheumatology, Groningen, ¹¹Radboud UMC, Paediatric Rheumatology , CUKZ 435, Nijmegen, Netherlands, ¹²University Hospital Tuebingen, Department of Pediatrics, Division of Pediatric Rheumatology and Autoinflammation Reference Center, Tuebingen, Germany, ¹³University Hospital Valle de Hebron, Rheumatology Unit, Barcelona, Spain, ¹⁴Universita’ di Napoli Federico II, Dipartimento di Pediatria, Napoli, ¹⁵IRCCS Istituto Giannina Gaslini, UOSID Centro Trial, PRINTO, ¹⁶IRCCS Istituto Giannina Gaslini, UOSD Centro Malattie Autoinfiammatorie e Immunodeficienze, Genoa, Italy

Correspondence: Š. Fingerhutová

Introduction: Despite estimates of the rate of AA amyloidosis complicating autoinflammatory diseases (AID), its true incidence especially in children is not known. It is anticipated that kidney involvement manifesting as proteinuria can be the first detectable marker of organ amyloid A deposition.

Objectives: To assess the frequency of renal pathology in a large cohort of patients with AID reported to the Eurofever registry.

Methods: Clinical and genetic data were extracted from the Eurofever registry based on optional responses. Data from the registration form submitted until July 2021 were analysed.

Results: From the total of 6628 patients enrolled in the Eurofever registry to date, in 229 (3.46%; 114 females) abnormal value of proteinuria (PU) and/or microalbuminuria (miALBU) was reported. Mean age at the time of registration was 23.1 years (SD 17.1), 123 (53.7%, 62 females) were children. Disease duration from symptom onset was 14.9 (SD 14.1) years. The most common diagnosis was Familial Mediterranean Fever (FMF) (n=89, 38.9%), undefined AID (uAID) (n=35, 15.3%), Syndrome of Undifferentiated Recurrent Fever (SURF) (n=26, 11.4%), cryopyrinopathy (CAPS) (n=26, 11.4%), Mevalonate Kinase Deficiency (MKD) (n=14, 6.1%) and Tumor Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS) (n=13, 5.7%). Chronic nonbacterial osteomyelitis (CNO), DADA2, PFAPA, Behcet disease, PAPA syndrome, Blau syndrome, CANDLE and TNFAIP3-associated autoinflammatory syndrome were less common (2.6%, 2.2%, 2.2%, 1.8%, 0.9%, 0.9%, 0.4% and 0.4%) respectively. Presence of amyloidosis was confirmed in 47/6628 patients (0.7%; 25 females, mean age 39.8 years, SD 17.2), 6 of them were children (12.8%, 4 girls, mean age 11 years, SD 4.1). Majority of patients had TRAPS (n=19, 40.4%) and FMF (n=16, 34%) followed by CAPS (n=6, 12.8%), MKD (n=4, 8.5%), PAPA and Blau syndrome (n=2, 4.3%). Amyloidosis in paediatric patients was associated with FMF (4 cases), TRAPS and MKD (1 case each).

Conclusion: The data suggest that despite low numbers children are at risk of developing amyloidosis. High proportion of children with proteinuria warrants further analysis of follow-up data. As these have been available for minority of patients only this should alert physicians to keep submitting these data into the registry.

This study was supported by the Czech Health Research Council (AZV CR) grant NU21-05-00522

Disclosure of Interest: None declared

P137. Bisphosphonates in chronic recurrent multifocal osteomyelitis: pamidronate vs zoledronate

R. Galindo Zavala¹, L. G. Martín-Pedraz¹, G. Díaz-Cordovés Rego², E. Núñez-Cuadros¹

¹Pediatrics, ²Rheumatology, Hospital Regional Universitario de Málaga, Malaga, Spain

Correspondence: R. Galindo Zavala

Introduction: Pamidronate showed to be an effective and secure treatment for chronic recurrent multifocal osteomyelitis (CMRO). Nevertheless, there are very few reports about other bisphosphonates.

Objectives: To compare pamidronate vs zoledronate’s effectivity and safety in children suffering from CMRO.

Methods: Prospective, descriptive, and analytical research on children younger than 16 suffering from CMRO (diagnosed according to Jansson criteria) and treated with bisphosphonates between January 2013 and December 2020. Flares treated with pamidronate (0,5 mg/kg day 1; 1 mg/kg day 2; 1 mg/kg day 3 followed by 1 mg/kg/month) were compared to those treated with zoledronate (0,025 mg/kg/3 months).

Results: We identified 16 bisphosphonates treated flares, 6 with pamidronate and 10 with zoledronate, in 12 patients. Average length of pamidronate and zoledronate courses were 3,67 and 12,3 months (p < 0,01), respectively. Epidemiological and clinical data are shown in table 1. There were no significative differences in sex, age or clinical features in patients treated with pamidronate vs zoledronate.

50% of patients treated with pamidronate received corticosteroids simultaneously vs 40% of patients treated with zoledronate (p =0,696). There were no differences in the highest corticosteroid dose (0,33 vs 0,72mg/kg/day; p=0,095) or the corticosteroids’ treatment length (1,67 vs 1,85 months; p=0,879)

66,7% of pamidronate treated patients reached full response vs 80% of patients who were treated with zoledronate (p=0,474). There were no differences in the clinical response time (2 months vs 0 months; p =0,524), the remission time after discontinuing bisphosphonate (9,25 vs 10 months; p=0,877) or the recurrences rate while on treatment (1 vs 0; p=0,298). 33,3% of patients on pamidronate and 40% of patients on zoledronate needed switching to anti-TNFa (p=0,790).

Flu-like syndrome was the only reported adverse event. It was recorded in 16,7% of patients treated with pamidronate, and 40% of patients who received zoledronate (p=0,588).

Conclusion: Pamidronate’s and zoledronate’s effectivity and security in children suffering from CMRO seem to be similar. Zoledronate permits a more comfortable dosage schedule and reduces hospital stay, improving the quality of life of these patients. Therefore, it may be selected as treatment of choice in children suffering from CMRO resistant to NSAIDs.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

Table 1 (abstract P137). Clinical and analytical data comparative study

P138. Use of canakinumab in children with cryopyrin-associated periodic syndrome: a single center study

A. Gunalp, M. Deveci, F. Haslak, M. Yildiz, A. Aliyeva, O. Koker Turan, S. Sahin, A. Adrovic, K. Barut, O. Kasapcopur

Pediatric Rheumatology, Istanbul University-Cerrahpasa, Cerrahpasa Medical Faculty, Istanbul, Turkey

Correspondence: A. Gunalp

Introduction: Cryopyrin-Associated Periodic Syndrome (CAPS) is a rare inherited autoinflammatory disease with uncontrolled inflammatory symptoms due to excessive secretion of IL-1β caused by a mutation in the NLRP3 gene.

Objectives: The aim of this study is to evaluate the efficacy and safety of canakunimab in a large patient cohort.

Methods: 24 patients who were diagnosed with CAPS according to the Eurofever/PReS diagnostic criteria were included. The frequency of attacks and acute phase reactants before and after canakinumab treatment in 2 year follow up were evaluated.

Results: A total of 24 (%54 female, %46 male) patients with 5.18 mean age (11-13) were included. 19 of patients were diagnosed with FCAS, 1 Muckle Wells Syndrome and 1 was CINCA. Pathogenic mutation was found in NLRP3 gene in 21 of the patients. 3 of patients had no mutation. The clinical symptoms of our patients were; all of them had urticeria-like skin rash, 21 had fever, 13 had arthritis, 9 had abdominal pain, same 6 patients had oculer findings and convulsions, 4 patients had hearing loss, 1 had bone deformity and 1 had myalgia. 4 of the patients had central nervous system involvement with pathological MRI findings. The main reason to iniate canakinumab treatment was unresponsiveness and non-compliance to the current treatment (anakinra). The frequency of the attacks in the prior year of canakinumab treatment was median 17. 3 (5-30) and it decreased to median 1.17 (0-5) following 1 year use of canakinumab (p<0.01). Statistically significant difference was found between repeated measures of ESR levels when compared prior and following 1, 6, 12, 24 months of canakinumab treatment (p:0.01, p:0.013, p: 0.21, respectively). Mean canakinumab treatment duration was 4.2 (2-8,7) years. In the follow up one of our patients had MAS attacks and SLE-like autoimmune disease developed in the 5th year of canakinumab treatment in the same patient. One of the patient with CINCA syndrome died in the 15th month of treatment at the age of 39 months. No significant side effects were observed in our patients.

Conclusion: Cryopryrinoyrin-Associated Periodic Syndrome is a rare childhood disease with urticaria-like rash, fever and arthritis. Canakinumab is a safe and effective agent to control the inflammation of the disease.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P139. A20 haploinsufficiency identified in a girl initially diagnosed with systemic juvenile idiopathic arthritis

W. J. Jang¹, J. W. Rhim², S. Y. Lee³, H. Y. Choi⁴, S. J. Lee⁵, M. Kim⁶, D.-C. Jeong¹

¹Pediatrics, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, ²Pediatrics, Daejeon St. Mary;s Hospital, College of Medicine, The Catholic University of Korea, Daejeon, ³Pediatrics, Bucheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Bucehon, ⁴Pediatrics, Seoul St. Marys’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, ⁵Pediatrics, International St. Mary’s Hospital, Catholic Kwandong University , Incheon, ⁶Laboratory Medicine, Catholic Genetic Center, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea, Republic Of

Correspondence: W. J. Jang

Introduction: Haploinsufficiency of A20 (HA20) is a newly described autoinflammatory disease caused by mutations in tumor necrosis factor-α-induced protein 3 (TNFAIP3) gene. Patients present wide spectrum of manifestations with early-onset systemic inflammation like Behcet’s disease or other autoimmune features.

Objectives: To investigate the clinical course and immunologic characterization in HA20 patient.

Methods: We report the case of HA20 initially diagnosed with systemic juvenile idiopathic arthritis (sJIA).

An 11-year-old girl has presented recurrent episodes of fever with vomiting, diarrhea since 11-month of age. She was diagnosed with sJIA presenting fever with skin rash, lymphadenopathy and arthritis with pericardial effusion at 27-month-old. She improved after high dose steroid, but developed fever with gastrointestinal symptoms including abdominal pain and vomiting about five times per year in spite of disease-modifying anti-rheumatic drugs therapy. Acute phase reactants were markedly increased during the period of her symptoms and decreased by conservative treatment with hydration, but still showed elevated levels when she was well-being state. She was shown as growth retardation, and microcytic hypochromic anemia in spite of iron supplement.

Results: At the age of 11, she admitted due to the recurrent gastrointestinal symptoms with high acute phase reactants. Colonoscopy showed multiple ulcers on intestinal mucosa compatible with Crohn’s disease. The next generation sequencing identified the pathogenic heterozygous mutation (c.427C>T) at TNFAIP3 gene, leading to HA20. This genetic mutation presents to fail to the negative feedback mechanism for nuclear factor kappa B (NF-κB) activation, developing autoinflammatory features such as fever and systemic inflammation. Immunologic study showed high expression of IL-17 and IFN-γ in CD4 and CD8 T cells independent on zinc, and elevated level of regulatory T cells. Also, IL-1β and TNF-α in plasma were shown high level than healthy control.

Conclusion: HA20 should be considered in the patient with recurrent inflammatory disease that presented with fever and gastrointestinal symptoms which might be regarded as respective episodes of acute infections.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P140. Evaluation of gastrointestinal system complaints in pediatric Familial Mediterranean Fever patients

H. D. Karakas, Z. B. Ozcakar, F. Aydin, N. Cakar, F. Yalcinkaya

Pediatric Rheumatology, Ankara University, Ankara, Turkey

Correspondence: H. D. Karakas

Introduction: Familial Mediterranean fever (FMF) is the most prevelant hereditary autoinflammatory disease among children, manifesting with recurrent attacks of serositis accompanied by fever, usually lasting 12-72 hours. Abdominal pain and various gastrointestinal system (GIS) manifestations may arise directly from FMF or from other causes independent of primary disease.

Objectives: The aim of this study was to evaluate gastrointestinal complaints other than classical peritonitis attacks in patients with FMF and to interpret laboratory, endoscopic and histopathological findings of GIS manifestations.

Methods: The medical records of the cases with FMF, who attended to the Ankara University Pediatric Rheumatology outpatient clinic, were evaluated retrospectively from December 2011 to December 2021. Demographic data, anthropometric measures, main clinical symptoms of the episodes, treatment modalities, genetic mutations, family history, gastrointestinal system complaints, endoscopic and histologic data, serum aminotransferase levels (alanine aminotransferase [ALT], aspartate aminotransferase [AST]) were recorded. Descriptive statistics were used. All statistical analyses were carried out using SPSS 25.0.

Results: A total of 576 pediatric patients (female 301, 52.3%), diagnosed with FMF since 2011 to 2021, were included. Majority of the patients (n=416, 72.2%) were found to have at least one exon 10 mutations. All of the patients were treated with colchicine, and almost 90.3% uses colchicine regularly. Functional gastrointestinal symptoms were reported by 106 patients (18.4%). Among these, abdominal pain (65.1%) and diarrhea (42.5%) were the most common complaints, followed by dyspepsia (33%), nausea and vomiting (27.4%). Malnutrition was observed in 42 patients (7.3%). Appendectomy was notified in 40 patients (6.9%). High serum aminotransferase levels were detected in 105 FMF patients (18.2%) at any visits, only 38 patient had hypertransaminasemia (AST x 3 unv; ALT x 3 unv). The most common cause of hypertransaminasemia was viral infections (31.6%). Only three patients’ elevated enzymes were associated with colchicine usage and stopped only the longest period of a month. Gastroenterology referral was done in 144 patients (25%) during follow-up. A total of 174 patients was monitored by abdominal ultrasonography for any reason. Upper GIS endoscopy was performed in 61 patients (10.6%), and colonoscopy in 30 (5.2%) patients. Accompanying GIS diseases were detected in 78 patients (13.5%). Upper gastrointestinal tract diseases (gastroesophageal reflux disease, gastritis, duodenitis, peptic ulcer) (6.1%), inflammatory bowel disease (2.6%), and irritable bowel syndrome (1%) were the most common coexisting GIS diseases.

Conclusion: Patients with FMF could have frequent GIS complaints other than classical abdominal attacks. Taking a good medical history, clinical evaluation and gastroenterology consultation will result in early diagnosis and treatment of coexisting or associated diseases in these patients.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P141. Chronic nonbacterial osteomyelitis and immune checkpoint molecules

U. Kaya Akca¹, B. Aydın², E. Sag^2,3, Y. Bayındır¹, Y. Bilginer¹, S. Ozen^1,2

¹Pediatric Rheumatology, ²Pediatric Rheumatology Unit, Translational Medicine Laboratories, Hacettepe University, ³Pediatric Rheumatology Clinic, Ankara Training and Research Hospital, Ankara, Turkey

Correspondence: U. Kaya Akca

Introduction: Varying levels of immune checkpoint molecules have been reported in inflammatory and autoimmune diseases. Chronic nonbacterial osteomyelitis (CNO) is a rare autoinflammatory bone disease characterized by sterile bone inflammation.

Objectives: This study aimed to investigate the levels of checkpoint molecules in pediatric patients with CNO.

Methods: Plasma samples were collected from CNO patients at diagnosis or during treatment with a biologic agent. Plasma levels of PD-1 (programmed cell death protein 1) and TIM3 (T cell immunoglobulin and mucin domain-containing protein 3), which are immune checkpoint molecules, were measured using the sandwich enzyme-linked immunosorbent assay (ELISA) method. Plasma samples of healthy controls were used as the control group.

Results: Plasma samples were obtained from 18 CNO patients at the time of diagnosis and from nine patients after receiving biologic treatment. A total of 27 CNO patients (51.8% male) and six healthy controls (50.0% male) were included in the study. The median age of the patient and control groups was 14.5 years and 13.5 years, respectively (p=0.762). Plasma TIM3 levels were within the normal range in both the patient and control groups, and no significant difference was found between the two groups (p=0.981). Median plasma PD-1 levels were significantly lower in the total CNO group (treated and at diagnosis) compared to healthy controls (998.7 vs 8263.1, p=0.011). Plasma PD-1 levels of CNO patients at diagnosis were also lower compared to the healthy controls (p=0.023).

There was no difference in plasma TIM3 and PD-1 levels between diagnosis and after treatment with a biologic agent (p=0.136 and p=0.735, respectively). Also, the plasma TIM3 and PD-1 levels of CNO patients were not different between those with and without spinal lesions (p=0.072 and p=0.621, respectively).

Conclusion: Plasma PD-1 levels were significantly lower in CNO patients compared to healthy controls. This may reflect the low contribution of adaptive immunity in the pathogenesis of the disease since CNO is an autoinflammatory disease.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P142. Familial case of PSTPIP1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome

Y. Y. Choi¹, S. H. Kim²

¹Pediatrics, ²Department of Pediatrics, Seoul National University Children’s Hospital, Seoul, Korea, Republic Of

Correspondence: S. H. Kim

Introduction: In recent years, the phenotype of PSTPIP1 associated autoinflammatory syndrome has expanded. Classic phenotype is PAPA syndrome (Pyogenic Arthritis, Pyoderma gangrenosum, and severe nodulocytic Acne) and a newly identified PSTPIP1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome has some unique features including very early onset severe chronic systemic inflammation, lymphadenopathy, hepatosplenomegaly and pancytopenia.

Objectives: I would like to share our experience on familial PAMI syndrome, one of the familial autoinflammatory syndromes.

Methods: We described our first 1^st case of familial PAMI syndrome in Korea.

Results: A 14-month-old male patient presented with fever for 11 days, diarrhea, cervical lymphadenitis, and cyclic rash. Despite prolonged antibiotics treatment, fever continued for 12 days, and subsided spontaneously from 13th day. Fever usually spiked at night, but sometimes presented during daytime. CSF study confirmed sterile. Abdominal CT-scan showed mild hepatomegaly and several mesenteric lymph node enlargement. Peripheral blood smear showed mild leukopenia with a few plasmacytoid lymphocytes (2%). Laboratory work up showed LDH(Lactate dehydrogenase), CRP(C-reactive protein), ESR(erythrocyte sediment rate) elevation. At his 15-month of age, he experienced prolonged fever for 10 days again and subsided spontaneously. At his 16th month of age, he visited again with rhinorrhea, voice change, cervical lymphadenitis, erythematous rash, and fever. Laboratory work up showed elevated LDH, CRP, ESR and mild leukopenia. Immunoglobulin profile (IgG,A,M,D,E) showed mild IgG elevation, and ANA appeared positive (1:80). Echocardiogram revealed no cardiac anomaly. From medical history of unexplained recurrent fever with persistently increased inflammatory markers, we suspected autoinflammatory syndrome and performed targeted exome sequencing, which revealed pathogenic known mutation on his PSTPIP1 gene, which caused protein change (E275K). The same point mutation was found in his father as well and detailed history taking revealed his father had similar symptom throughout his life. The patient’s father was treated for lymphadenitis when he was four years of age, and he has been treated for periodic fever and JIA from his high school period since now. Recently, he is experiencing recurrent abdominal pain, diarrhea and oral ulcers which is thought to be symptoms of this disease.

Conclusion: Here, we present the 1^st case of familial PAMI syndrome in Korea.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P143. Withdrawn

P144. Long-term safety and efficacy of canakinumab in cryopyrin-associated periodic syndromes (CAPS) – 36-month data from the reliance registry

J. B. Kuemmerle-Deschner¹, B. Kortus-Goetze², P. T. Oommen³, A. Janda⁴, J. Rech⁵, C. Schuetz⁶, T. Kallinich⁷, F. Weller-Heinemann⁸, G. Horneff⁹, I. Foeldvari¹⁰, F. M. Meier^11,12, M. Borte¹³, T. Krickau¹⁴, J. Weber-Arden¹⁵, N. Blank¹⁶

¹Department of Pediatrics, Division of Pediatric Rheumatology, University Hospital Tuebingen, Tuebingen, ²Division of Nephrology, University of Marburg, Marburg, ³Clinic of Pediatric Hematology, Oncology and Clinical Immunology, Heinrich-Heine-University Duesseldorf, Duesseldorf, ⁴Department of Pediatrics, University Hospital Ulm, Ulm, ⁵Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander University (FAU) Erlangen-Nuernberg and Universitaetsklinikum Erlangen, Erlangen, ⁶Pediatrics, Medizinische Fakultaet Carl Gustav Carus, Technische Universitaet Dresden, Dresden, ⁷Department of Pediatrics, Division of Pulmonology, Immunology and Critical Care Medicine, Charité University Medicine Berlin, Berlin, ⁸Prof. Hess Kinderklinik, Klinikum Bremen-Mitte, Bremen, ⁹Asklepios Clinic Sankt Augustin, Sankt Augustin, ¹⁰Centre for Pediatric and Adolescence Rheumatology Hamburg, Hamburg, ¹¹Division of Rheumatology, University Hospital Frankfurt, Goethe University, Frankfurt am Main, ¹²Project Group Translational Medicine and Pharmacology TMP, Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Frankfurt am Main, ¹³ImmunoDeficiencyCenter Leipzig (IDCL), Hospital St. Georg gGmbH Leipzig, Leipzig, ¹⁴Pediatrics, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Erlangen, ¹⁵Novartis, Nuernberg, ¹⁶Rheumatology, University Hospital Heidelberg, Heidelberg, Germany

Correspondence: A. Janda

Introduction: Cryopyrin-associated periodic syndromes (CAPS) are monogenic autoinflammatory diseases with severe systemic inflammation. The IL-1β inhibitor canakinumab (CAN) leads to a rapid remission of CAPS symptoms in clinical trials as well as in practice.

Objectives: The RELIANCE registry investigates the long-term safety and efficacy of CAN under routine clinical conditions in pediatric (≥2 years) and adult patients with CAPS, including MWS, FCAS, and NOMID/CINCA[1].

[1]CINCA: chronic infantile neurologic cutaneous articular syndrome, FCAS: familial cold-induced autoinflammatory syndrome, MWS: muckle-wells syndrome, NOMID: neonatal multisystem inflammatory syndrome

Methods: This prospective, non-interventional, observational study enrolls patients with a clinically confirmed diagnosis of CAPS who routinely receive CAN. Clinical data, physician assessments, and patient-reported outcomes will be collected at baseline and at 6-monthly visits.

Results:

98 CAPS patients (52% female; median age 20 years) were enrolled through December 2021. At the 36-month visit, both physicians and patients of all ages rated current disease activity as absent or mild/moderate (Table 1). The proportion of patients without disease activity was highest in <12-year-old patients (78%). More pediatric compared to adult CAPS patients received higher than standard CAN (<12 years: 76%, 12-17 years: 43%, ≥18 years: 35%). Proportionate, more AE, SAE, and presumably drug-related SAE occurred in the pediatric cohort.

Pathogenic mutations were documented for a total of N=38 patients, including R260W: N=15, A439V: N=9, T348M: N=9, D303N: N=3, and E627G, G755R, and G569R: N=1 each. N=27 patients with pathogenic mutations received standard dose CAN and N=9 patients received higher dose.

Conclusion: The 36-month interim analysis of the RELIANCE study shows that long-term treatment with CAN is safe and effective in patients with CAPS regardless of the underlying mutation. Pediatric patients tend to have a higher infection rate with a better response rate.

Patient Consent: Yes, I received consent

Disclosure of Interest: J. B. Kuemmerle-Deschner: None declared, B. Kortus-Goetze Consultant with: Novartis, P. T. Oommen Grant / Research Support with: Novartis, A. Janda: None declared, J. Rech Grant / Research Support with: Novartis, Sobi, Consultant with: AbbVie, Biogen, BMS, Chugai, GSK, Janssen, Lilly, MSD, Mylan, Novartis, Roche, Sanofi, Sobi, UCB, Speaker Bureau with: AbbVie, Biogen, BMS, Chugai, GSK, Janssen, Lilly, MSD; Mylan, Novartis, Roche, Sanofi, Sobi, UCB, C. Schuetz: None declared, T. Kallinich Speaker Bureau with: Roche, F. Weller-Heinemann: None declared, G. Horneff Grant / Research Support with: AbbVie, Chugai, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Speaker Bureau with: AbbVie, Bayer, Chugai, Merck Sharp & Dohme, Novartis, Pfizer, Roche, I. Foeldvari Consultant with: Novartis, F. M. Meier Speaker Bureau with: Novartis, M. Borte Grant / Research Support with: Pfizer, Shire, T. Krickau Grant / Research Support with: Novartis, Consultant with: Novartis, Speaker Bureau with: Novartis, J. Weber-Arden Grant / Research Support with: Novartis, AbbVie, Sobi, Consultant with: Novartis, AbbVie, Sobi, N. Blank Grant / Research Support with: Novartis, Sobi, Consultant with: Novartis, Sobi, Lilly, Pfizer, Abbvie, BMS, MSD, Actelion, UCB, Boehringer-Ingelheim, Roche

Table 1 (abstract P144). Age-dependent assessment of clinical disease activity and incidence of infection

P145. Gene expression analysis of pro-inflammatory cytokines and associated transcription factors in patients with blau syndrome from India

R. Kumrah, R. Rikhi, D. Suri, A. Rawat, S. Singh

Advanced Pediatrics Centre, PGIMER, Chandigarh, India

Correspondence: R. Kumrah

Introduction: Blau syndrome (BS) is a rare monogenic form of autoinflammatory disease caused by gain-offunction mutation in NOD2 gene and is characterized by granulomatous arthritis, dermatitis, and uveitis since early childhood.

Objectives: To perform gene expression analysis of pro-inflammatory cytokines and associated transcription factors in patients with Blau syndrome

Methods: Confirmation of genetic diagnosis in patients suspected with Blau syndrome was carried out. Complementary DNA (cDNA) converted from extracted whole blood RNA was used to perform real-time PCR analysis. Genes for pro-inflammatory cytokines and associated transcription factors were selected. Comparison of fold change [2^(-ΔΔCT) method] between patients and controls were performed.

Results: BS was genetically confirmed in 6 patients (3 males, 3 females from 5 families). Missense heterozygous mutation involving amino acid change from arginine to tryptophan at position 334 (hotspot) was identified in the nucleotide-binding domain of NOD2 gene in all. All the patients were on treatment in clinic with methotrexate, corticosteroids and adalimumab. Real-time PCR analysis revealed reduced NOD2 gene expression in patients as compared to control. Expression of Eomes, IL-1B, FOXP3 was also found to be less in patients with Blau syndrome. Reduced expression of transcription regulators of inflammation (NFĸβ1 and NFĸβ2) was noted in patients as compared to healthy control. Elevated expression of pro-inflammatory (TNF- ) and master regulator for T cells (T-bet) was noted in patients. Other genes (ROR-γT, GATA3, IL-6, IL18) were comparable in patients and healthy controls.

Conclusion: R334W variant was identified in all patients with clinically suspected BS. We found altered expression of various cytokines and transcription factors in patients with Blau syndrome.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P146. Multiple autoinflammatory and autoimmune features in families with haploinsufficiency of A20

L. Levantino¹, S. Pastore², F. Biscaro³, M. Girardelli², A. Tesser², S. Martelossi³, A. Zabotti⁴, A. Tommasini^1,2

¹Department of Medical, Surgical and Health Sciences, University of Trieste, ²Department of Pediatrics, IRCCS Burlo Garofolo, Trieste, ³Department of Pediatrics, Santa Maria di Ca’ Foncello Hospital, Treviso, ⁴Department of Rheumatology, AOU Santa Maria della Misericordia, Udine, Italy

Correspondence: L. Levantino

Introduction: Haploinsufficiency of A20 (HA20) is an immune dysregulation disease due to heterozygous loss-of-function mutations in TNFAIP3, encoding A20 protein, a crucial negative regulator of the NF-kB/TRAF6 pathway. HA20 leads to an imbalance in both innate and adaptive immunity, with high penetrance but variable expressivity. As a result, the phenotype of HA20 may feature both autoinflammatory and autoimmunity disorders.

Objectives: To describe phenotypic features, response to treatments, and natural history of HA20 in children and adults.

Methods: We performed a retrospective analysis of a case series with HA20, currently cared for at three rheumatologic centres in North-eastern Italy.

Results: Overall seven patients from three unrelated Italian families with a genetic diagnosis of HA20 were included in the study. Four were female (57%) and the median age was 10 years (range 1-62). All patients were symptomatic, showing clinical manifestations with an early onset and a relapsing-remitting course. Previous diagnoses included PFAPA, Behçet’s disease, Hashimoto’s disease, celiac disease, autoimmune hepatitis, IBD, psoriatic arthritis, rheumatoid arthritis, Sjogren syndrome, and SLE. In all cases, a history of recurrent aphthous was present since infancy. Other clinical features were recurrent fever (4/7), recurrent upper respiratory infections (4/7), gastrointestinal symptoms (3/7), arthritis/arthralgia (4/7), skin involvement (2/7), psychiatric complaints (4/7), and autoimmune disorders (3/7, including celiac disease, thyroiditis, hepatitis). About laboratory findings, acute-phase reactants were elevated in 100% of patients and ANA/ENA autoantibodies were positive in one; IFN-score was high in 85% of cases and in two cases it increased during anti-TNF treatment. All patients had been received corticosteroids; six of them needed other immunosuppressive treatments.

Conclusion: HA20 is an heterogenous immune disorder characterized by both autoinflammation, tending to develop in early childhood, and autoimmunity, usually appearing from late childhood/adolescence. The “amplifier” role of A20 deficiency on distinct pathways in the lifetime may challenge therapeutic and preventive approaches.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

Table 1 (abstract P146). See text for description

P147. Do Familial Mediterranean Fever (FMF) patients treated with interleukin-1 inhibitors adhere to colchicine treatment? A population-based study

Y. Levinsky, L. Harel, R. Tal, G. Amarylio

Schneider children medical center of Israel, Petah Tikva, Israel

Correspondence: Y. Levinsky

Introduction: Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease. Despite the progress research since the discovery of the MEFV gene, colchicine treatment is still considered a main treatment for FMF patients. It reduces the frequency of attacks and effectively prevents the complication of secondary amyloidosis. Therefore, it is currently recommended to continue colchicine prophylaxis during the treatment with IL-1 inhibitors, despite clinical remission.

Objectives: Our aims where to evaluate the rate of adherence to colchicine prophylaxis among patients with FMF under IL-1 Inhibitors treatment and to examine different risk factors for low adherence among that group.

Methods: The databases of Maccabi Health Services (MHS), a 2.6 million member state-mandated health provider in Israel was searched for patients with FMF diagnosis. Patients under treatment with IL-1 inhibitors were matched to themselves – before and after starting the treatment. A sub-analysis was done among patients without amyloidosis or chronic renal failure. In the second phase, patients treated with IL-1 inhibitors were matched in a ratio of 1:4 to patients on colchicine only. Medication possession ratio (MPR) was used as main outcome measure.

Results: The final cohort included 4526 patients. Among them, 108 patients were treated with IL-1 inhibitors. The MPR was higher after starting IL-inhibitors among the total population (19.7±13.1 before versus 32.2±14.5 after, p<0.01), and among patients without amyloidosis or chronic renal failure (21.6±15.07 before versus 32.8±15.3 after, p<0.01). In the second phase, patients treated with IL-1 inhibitors were matched in 1:4 ratio to 432 “colchicine only” patients. The total MPR in each groups was similar (78.9 ±41.4 versus 82.5 ± 80.6, P=0.5). In the sub-analyses, females treated with IL-1 inhibitors had less MPR than in the matched group (81.4 ± 33.2 versus 85.1 ± 91, P=0.03).

Conclusion: Contrary to initial concerns, the adherence to colchicine increases among the same patients after starting IL-1 inhibitors, which may reflect the improvement in disease perception following the need to start the biological treatment. Moreover, the adherence is similar to the general FMF population after matching. Physicians who take care of FMF patients can consider treatment with IL-1 inhibitors when indicated without fear of decline in adherence to colchicine. Education regarding the importance of colchicine treatment is important among all FMF patients.

Disclosure of Interest: None declared

Table 1 (abstract P147). Comparison of medication possession ratio (MPR) of colchicine between FMF patients treated with IL-1 inhibitors Versus patients without IL-1 inhibitors treatment

P148. IL-1antagonist treatment in recurrent aseptic meningitis related to Familial Mediterranean Fever

R. Livny¹, Y. Bitterman², Y. Butbul Aviel²

¹Pediatric Rheumatology, Schneider’s childrens hospital, Petach Tikva, ²Rambam medical center, Haifa, Israel

Correspondence: R. Livny

Introduction: Familial Mediterranean fever (FMF) is an autosomal recessive, auto-inflammatory disease, presenting with recurrent bouts of fever and polyserositis. FMF has been associated with central nervous system (CNS) manifestations and recurrent aseptic meningitis (RAM) is a rare described one. There are only few case reports of aseptic meningitis due to FMF.

Objectives: In this case-based review, we present a pediatric patient with FMF, who suffered from proven episodes of RAM while on colchicine and responded dramatically to treatment with anakinra. We compare this patient to previously described patients with FMF who contracted aseptic meningitis.

Methods: A systematic search of the literature was performed retrieving English-language original case reports, case series, case-based reviews, and review articles on aseptic meningitis in FMF patients, up to may 2022. Articles involving patients with FMF suffering from aspetic meningitis, recurrent or single episode – were included.

Results: In addition to our case, we identified seven cases describing aseptic meningitis in patients with underlying proven FMF; 6 of 7 cases were described in the adult population, with patient age ranging from 32 to 64 years of age, two (including our case) were in the pediatric population (13 and 14 years old). All cases in the literature responded well to colchicine treatment and aseptic meningitis episodes were diminished. Our case report is the first to document a resistance to colchicine and complete response to anti IL-1 treatment of RAM due to FMF.

Conclusion: Central nervous system (CNS) manifestations of FMF are rare and under debate. Primary headaches are common among FMF patients, and may develop due to the autoinflammation. There are several reports of headaches due to recurrent episodes of RAM presumed to be related to FMF, mainly in adults. In most cases, events subsided or resolved following colchicine treatment. however, reports are scarce and vary significantly in criteria for FMF diagnosis (with or without genetic proof).

According to Capron et al. Current diagnostic criteria for RAM related to FMF are: (a) RAM episodes due to FMF should be accompanied by other clinical or biological features of FMF attacks; (b) Colchicine prevents or lessens episodes; and (c) other classical causes of RAM (drugs, HSV2 infection, systemic diseases and cystic brain lesions) should be excluded. Our patient fulfilled both criteria for FMF and at least two of the criteria for RAM related to FMF. Only seven confirmed cases investigating association between FMF and RAM were found in the systemic review.

Colchicine is the main therapeutic modality for reducing inflammatory attacks and preventing amyloidosis due to FMF. Nevertheless, 30-40 percent of FMF patients continue to suffer from recurrent attacks despite therapy, and 5-10 percent are considered resistant to colchicine. Until recently there was no other known effective treatment for FMF.

Based on the role of pyrin in the regulation of interleukin (IL)-1β activation, the efficacy of IL-1 inhibitors has been assessed and well established in FMF patients who were resistant or intolerant of colchicine.

Our study is the first report of RAM due to FMF that is responsive to anakinra. The immediate response strongly suggests there was a relationship between FMF and RAM in this patient. Our experience also offers a novel therapeutic option for colchicine resistant RAM and maybe even other CNS manifestations of FMF.

Patient Consent: Not applicable (there are no patient data)

Disclosure of Interest: None declared

P149. Music for CAPS: the experience of the centre for paediatric rheumatic diseases of Palermo

M. C. Maggio¹, C. Scalisi¹, F. Benfratello², S. Amato³, G. Corsello¹

¹University Department PROMISE “G. D’Alessandro”, ²University of Palermo, University of Palermo, ³Children Hospital “G. Di Cristina”, Arnas Palermo, Palermo, Italy

Correspondence: M. C. Maggio

Introduction: Noise is an environmental factor that can influence human health status. Any sound that causes stress, irritability or disorder on the normal course life can be defined as noise. The WHO, in 2011 defined noise pollution as the most important environmental public health risk factor after air pollution. On the contrary, music is universally recognized as an anti-stressor method, and can be used as a therapeutic strategy. Children with autoinflammatory diseases (AIDs), especially with CAPS, need to wait in the hospital during the days of day hospital for blood sampling and biological drugs parenteral administration, sometimes for many hours, waiting the results of blood sampling. Many patients refer malaise and fatigue the afternoon and the evening of the day hospital, as possible effect of tiredness and stress.

Objectives: To evaluate the music impact on wellness of patients with AIDs during the days of day hospital for blood sampling and biological drugs parenteral administration.

To empower the nurse’s role in the global care of patients with AIDs, as main actor of alternative strategies to improve the treatment compliance.

Methods: We engaged a musician nurse for the care of our patients with AIDs, especially with CAPS. The nurse played piano, involving patients to contribute with other instruments. In fact, in the following meetings, some patients chose to play music with the nurse in the waiting room in front of other patients.

Results: We collected the records of the effects of music therapy on their wellness perception, both during the hours of day hospital and after coming back home. Most of the patients referred a positive impact of music on the personal patient journey.

Conclusion: Patients with CAPS and generally with AIDs experience stress as a trigger for further attacks. Programs that improve care and support children and their families, through the complex way of AIDs, significantly improve the quality of life of patients with AIDs and their families. Healthcare providers should be aware of the impact of the long diagnostic journey on families and must work to create an environment of trust and collaboration facing a prolonged and difficult diagnostic process. Music can be considered as a winning strategy for supportive care, especially in children with CAPS or other AIDs, who experience stress as a trigger of disease attacks.

Disclosure of Interest: None declared

P150. FMF or SURF: a diagnostic dilemma in children with recurrent febrile episodes

M. C. Maggio, M. Liuzzo Scorpo, R. Panzeca, G. Corsello

University Department PROMISE “G. D’Alessandro”, University of Palermo, Palermo, Italy

Correspondence: M. C. Maggio

Introduction: Familial Mediterranean Fever (FMF) is an inherited auto-inflammatory disorder and is still extremely underdiagnosed in the Mediterranean area.

Objectives: We collected a retrospective case series of children with recurrent febrile or inflammatory episodes and referred to the Children Hospital of Palermo.

Methods: We divided all the patients with a diagnosis of FMF of our centre in 2 groups.

Group A: 16 families with 24 children (15 M; 9 F) with the polymorphism R202Q (heterozygous in 14), (homozygous in 2), that show elevated inflammatory markers during the attacks, do not fulfil the PFAPA criteria, but respond to colchicine. They show the classical symptoms of FMF, fulfilling the Eurofever/PRINTO FMF classification criteria (fever, arthralgia, abdominal pain, rash, aphthous stomatitis, thoracic pain, with attacks induced by triggers as stress, fatigue, menses, etc). The children were treated with colchicine, 4 stopped colchicine after 4 years or more for the remission of clinical presentation and are still in remission. 2 children (8%) showed a partial response to colchicine, with the reduction but not the complete resolution of recurrent attacks. Parents were frequently symptomatic in childhood and in the 13% of the families, symptoms persisted in adulthood.

Group B: 16 families with 36 children (19 M; 17 F) carrying MEFV gene mutations (M694V: heterozygous in 2, heterozygous associated with R202Q in 2, homozygous in 1; A289V: heterozygous in 3; A744S: heterozygous in 2, heterozygous associated with P369S, R408Q in 1; V796T: heterozygous in 2; I591T, P369S, R408Q: heterozygous in 1; F479D, E167D, R202Q: heterozygous in 3; R348H, R202Q: heterozygous in 3; E148Q: heterozygous in 10; R408Q, P369S: heterozygous in 2; R716H: heterozygous in 1; P369S, R408Q, R202Q: heterozygous in 1; R716H: heterozygous in 2) were included.

Results: In group A, the children were treated with colchicine, 4 stopped colchicine after 4 years or more for the remission of clinical presentation and are still in remission. 2 children (8%) showed a partial response to colchicine, with the reduction but not the complete resolution of recurrent attacks. Parents were frequently symptomatic in childhood and in the 13% of the families, symptoms persisted in adulthood.

In group B, 7 children were asymptomatic; 29 were symptomatic before treatment, and treated with colchicine (27) or colchicine plus anakinra (1), or colchicine plus canakinumab (2). 4 patients stopped colchicine for the resolution of symptoms and a good control of the disease without treatment. They are still in follow-up. Their parents showed a different clinical presentation, and, in all the cases, the diagnosis was done after the genetic study of their children. In the 16 families, all the parents, except 1, did not show fever. Most of them, however, had anamnestic records of recurrent fever in childhood. Most of the parents had recurrent abdominal pain, arthralgia at the limbs, headache, fatigue. In children, the clinical presentation was typically characterized by recurrent attacks of fever, arthralgia, abdominal pain, rash, aphthous stomatitis, thoracic pain, with attacks induced by triggers as stress, fatigue, menses, etc, with no significant differences with the children of group A.

Conclusion: We can speculate that children in group A, carrying R202Q mutation, are patients with SURF (Syndrome of undifferentiated recurrent fever, as proposed by M. Gattorno and coll.). 92% responded to colchicine. The clinical presentation of the parents diverged from A to group B: most of the patients of group A do not refer a family history of recurrent fever and/or symptoms of SURF. Most of the patients of group B have a family history of recurrent fever in siblings and parents, and actual records of abdominal pain, arthralgia at the limbs, headache, fatigue.

Disclosure of Interest: None declared

P151. Pediatric SAPHO syndrome: single entity or different diseases?

C. Matucci Cerinic^1,2, G. Viglizzo³, R. Caorsi^2,4, S. Volpi^1,2, C. Malattia^1,4, M. Gattorno^2,4

¹DINOGMI, Università degli studi di Genova, ²Centro malattie autoinfiammatorie e immunodeficienze, ³UO Dermatologia, ⁴Clinica pediatrica e reumatologia, Istituto Giannina Gaslini, Genova, Italy

Correspondence: C. Matucci Cerinic

Introduction: SAPHO is a heterogeneous autoinflammatory disease, characterized by bone and joint involvement and by a wide variety of dermatologic manifestations, including palmo-plantar pustulosis (PPP), acne, hidradenitis suppurativa (HS), pyoderma gangrenosum (PG), psoriasis, Snedd-Wilkinson disease and Sweet syndrome. The SAPHO treatment still today is a challenge, and no therapeutic guidelines are available in children: NSAIDs are frequently used as first line treatment for CRMO lesions, followed by bisphosphonates, methotrexate and biologic therapies. In the literature there are many case reports but only a few case series, of which the present one is the largest in Europe (29 cases reported in China).

Objectives: to report the clinical and radiological features and the response to therapy of a cohort of SAPHO children

Methods: the clinical data (serological, imaging and therapy) of 13 SAPHO patients, followed between 2001 and 2021 at the Unit for Autoinflammatory diseases at the Gaslini Hospital were reviewed. Patients were divided into 2 groups according to their cutaneous manifestations in an acne-HS and in a PPP group.

Results: 8 patients presented an acne-HS while 5 patients had a PPP. In the former group, 7/8 patients were male, while in the latter group 5/5 patients were females. At disease onset, in the acne-HS group, skin manifestations were the first symptom, while in the PPP group were concomitant or subsequent to bone manifestations. In the PPP group, the cutaneous involvement was mild and responded well to topical treatments, while the bone involvement required a therapy with methotrexate or salazopirin, that induced remission in 4/5 patients. 1 PPP patient showed a refractory bone disease and underwent several biological therapies. The acne-HS skin involvement was characterized as follows: 7 patients presented with severe acneiform eruptions (pustular, nodular, cystic, comedonic and ulcerative lesions), of these, the 3 patients with comedonic acne presented also HS, and 1 PG. In the acne-HS group, the osteoarticular involvement responded well to conventional DMARDS, but the skin manifestations required a therapeutic upgrade on biologics. Etanercept obtained only a partial result in 5 patients, Adalimumab had an optimal response in 6 patients, in 1 obtained a partial response even if requiring an increased dose (80 mg per week) and 1 was swapped to dapsone. Anakinra (3), ustekinumab and secukinumab (2) were not efficacious. The 3 patients with comedonic acne were refractory to all treatments and needed therapy cycling, which achieved a partial remission only.

When comparing the 2 groups, sternal and axial involvement were more frequent in the acne-HS group (75% and 87,5% versus 40 and 60% respectively) while clavicular and mandibular involvement were more frequent in the PPP group (60% and 40% vs 25% and 0% respectively). An involvement of the metaphysis of the long bones was present in both groups, however in PPP a major involvement of the tibia and fibula was present (100 and 80% vs 62,5 and 50% respectively)

Conclusion: All our patients were characterized by well-known SAPHO clinical features. For what concerns skin involvement, all patients with comedonic acne were refractory to treatments while PPP and nodulo-cystic acne achieved remission. Interestingly, a difference in the bone manifestations was found in the 2 groups. Our observation may suggest that in SAPHO two different phenotypes exist. In fact, skin involvement may have a different response to the treatment, and comedonic acne seems to belong to a separate cluster of patients that poorly respond to treatments.

Patient Consent: Not applicable (there are no patient data)

Disclosure of Interest: None declared

P152. Validation of the pediatric Behçet disease criteria (PEDBD): a consensus-based approach

C. Matucci-Cerinic^1,2, H. Palluy³, S. Al-Mayouf⁴, P. Brogan⁵, L. Cantarini⁶, A. Gul⁷, O. Kasapcopur⁸, J. Kuemmerle-Deschner ⁹, S. Ozen¹⁰, D. Saadoun¹¹, F. Shahram¹², N. Ruperto¹³, M. Gattorno^14,15, I. Kone-Paut¹⁶

¹Center for Autoinflammatory Diseases, IRCCS Istituto Giannina Gaslini, ²DINOGMI, Università degli studi di Genova, Genova, Italy, ³Pediatric rheumatology and CEREMAIA, Bicêtre hospital, APHP, Paris, France, ⁴Department of Pediatrics, King Faisal Specialist Hospital and Research Center; College of Medicine, Alfaisal University, Riyadh, Saudi Arabia, ⁵University College London Great Ormond Inst of Child Health, and Great Ormond Street Hospital NHS Foundation Trust, London, United Kingdom, ⁶Rheumatology Unit, Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Siena, Italy, ⁷Division of Rheumatology, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, ⁸Cerrahpasa Medical School, Istanbul University-Cerrahpasa Turkey, Istanbul, Turkey, ⁹Division of Pediatric Rheumatology, Department of Pediatrics and autoinflammation reference center Tuebingen, University Hospital Tuebingen, Tuebingen, Germany, ¹⁰Department of Pediatric Rheumatology, Hacettepe University, Ankara, Turkey, ¹¹Sorbonne Universités, Department of Internal Medicine and Clinical Immunology, CEREMAIA, AP-HP, Groupe Hospitalier Pitié-Salpêtrière., Paris, France, ¹²Rheumatology Research Center, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran, Islamic Republic Of, ¹³UOSID Centro Trial, IRCCS Istituto Giannina Gaslini , ¹⁴Center for Autoinflammatory Diseases, IRCCS Istituto Giannina Gaslini, ¹⁵Pediatrics and Rheumatology Clinic, IRCCS Istituto Giannina Gaslini, Genova, Italy, ¹⁶Pediatric rheumatology and CEREMAIA, Bicêtre hospital, APHP; University of Paris Saclay, Paris, France

Correspondence: C. Matucci-Cerinic

Introduction: Behçet disease (BD) is an autoinflammatory disease characterized by a variable vessel vasculitis. In children, the first BD symptoms may start early in life, mimicking other autoinflammatory diseases and making the diagnosis a real challenge in the paediatric population. While many criteria exist for the diagnosis or classification of BD in adults in children only classification criteria exist, the PEDBD criteria (2015), created by international Expert consensus.

Objectives: to perform an external validation of the PEDBD criteria and attempt to improve their sensitivity and specificity with respect to other autoinflammatory diseases.

Methods: 210 patients were randomly selected from the Eurofever Registry: patients were included if enrolled after 2010 with a diagnosis of BD, PFAPA, FMF, MKD, TRAPS, SURF and undefined autoinflammatory diseases (UND); patients were excluded if they participated in the first PEDBD study. A set of 11 Experts blinded to the original diagnosis, were chosen to evaluate the patients, and reach a consensus defined as > 80% for the following diagnosis: BD, PFAPA, FMF, MKD, TRAPS, SURF, UND. In the 1^st round only clinical and serological data were shown; in the 2^nd round genetic data were added; and in the 3^rd round the other Experts’ votes and comments were shared with all experts. Using the expert consensus as gold standard, the PEDBD, the ISG and the ICBD criteria were applied to BD patients and to the confounding diseases in order to define the sensitivity and specificity.

Results: In the 1^st round a consensus was reached in 45/210 (21%) of patients (22/70 BD, 5/35 FMF, 2/26 MKD, 11/40 PFAPA, 2/22 TRAPS, 2/12 SURF, 1/5 UND). While in the 2^nd round a consensus was reached in another 58/163 (35%) of patients, for a total consensus on 103/210 patients (49%): 31/70 BD, 17/35 FMF, 21/26 MKD, 15/40 PFAPA, 14/22 TRAPS, 3/12 SURF, 2/5 UND. The 3^rd round is now ongoing, and the data are not yet available. The next step will consist on the application of the PEDBD, the ISG and the ICBD criteria to the cohort of classified BD, and to the other diseases in order to see their performance on BD and confounding diseases.

Conclusion: the classification of Behçet disease showed a wide range of opinions among Experts. The heterogeneity of the disease is a challenge but a more robust classification can at least allow homogeneous groups of patients for research purpose.

Patient Consent: Not applicable (there are no patient data)

Disclosure of Interest: None declared

P153. Pericarditis in children: systemic and isolated recurrent pericarditis

A. Mauro¹, E. Bizzi², A. M. Pisacreta², V. Ansuini¹, C. Carollo², A. Pedroli², F. Casini³, F. Savoia⁴, A. Brucato⁵, L. Bernardo⁶

¹Pediatric Rheumatology Unit, ²Department of Medicin, Rheumatology Unit, ASST Fatebenefratelli-Sacco, ³Department of pediatrics, Vittore Buzzi Children’s Hospital, Milan, ⁴Childhood Cancer registra of campania, Santobono-Pausilipon Children’s Hospital, Naples, ⁵Department of Medicin, ⁶Department of Pediatrics, ASST Fatebenefratelli Sacco, Milan, Italy

Correspondence: A. Mauro

Introduction: Pericarditis is a clinical syndrome characterized by inflammation of the pericardium with or without pericardial effusion. The course can be acute, recurrent or chronic. Recurrent pericarditis (PR) is defined as the recurrence of pericarditis after the first attack, with a symptom-free interval greater than 4-6 weeks. Etiopathogenesis of RP is idiopathic in 70% of pediatric cases, more rarely, it can be secondary to autoinflammatory, autoimmune diseases, tumors, metabolic diseases or infections. PR can occur isolated or in the context of a polyserositis with characteristics of systemic inflammation (fever, leukocytosis, pleural effusion and more rarely peritoneal).

Objectives: The aim of the study is to assess the differences in laboratory parameters between two groups of patient affected respectively by systemic recurrent pericarditis (PRs) and isolated recurrent pericarditis (PRi).

Methods: Patients diagnosed with PRs and PRi aged <18 years were included. Inclusion criterion was the presence of fever and pleural effusion, in patients with PRs. Demographics, clinical characteristics, and blood tests were collected and compared.

Results: We prospectively enrolled 42 patients (14 RPs and 28 RPi). The distribution by gender and age was similar in the two groups (M / F 1: 1; age of onset: 15 years (IQR 13-17). The PRs compared to the PRi had significantly higher levels of leukocytes, neutrophils and CRP (p < 0.01). In addition, patients with PRs performed pericardiocentesis more frequently (p <0.01)

Conclusion: Our study showed that in patients with PRs mechanisms of autoinflammation, probably mediated by IL1, which manifest themselves with elevated levels of CRP and neutrophilia, seem to play a fundamental pathogenetic role, compared to the PRi forms.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P154. Idiopathic chronic pericardial effusion in pediatric age: the occasional finding in an asymptomatic patient

A. Mauro¹, E. Bizzi², L. Trotta², M. Pancrazi², F. Casarin², V. Ansuini², S. lassainato³, A. Brucato⁴, L. Bernardo⁵

¹Departments of Pediatrics, Rheumatology Unit, ²Departments of Medicin, Rheumatology Unit, ASST Fatebenefratelli-Sacco, ³Departments of Pediatrics, Vittore Buzzi Children’s Hospital, ⁴Department of Medicin, ⁵Department of Pediatrics, ASST Fatebenefratelli sacco, Milan, Italy

Correspondence: A. Mauro

Introduction: Chronic pericardial effusion of unknown etiology is a very rare event in pediatric age. The autoinflammatory etiology of acute and recurrent pericarditis often causes acute pericarditis and simultaneous pericardial effusion as an inflammatory epiphenomenon. Idiopathic pericardial effusions not associated with acute pericarditis in children is not reported in literature.

Objectives: We describe a case of pediatric patients with an Idiopathic, chronic and large pericardial effusion

Methods: Male patient, 9 years old, hospitalized for persistent fever and pharyngotonsillitis. On chest x-ray he presented cardiomegaly then confirmed by echocardiography which showed abundant circumferential pericardial effusion, with heart oscillating in the pericardial cavity, without signs of cardiac tamponade and normal inferior vena cava (VCI). He had no symptoms due to pericardial effusion.

Results: Pericardiocentesis was carried out with the withdrawal of 650 ml of citrine liquid. In suspicion of acute pericarditis, prednisone therapy (25 mg / day) was initiated without any benefit. Blood tests showed: PCR 147 mg / L, GB 20,000 / mm3, anti-Mycoplasma IgM positive.

Throat swab for SBEGA, autoimmunity, thyroid functions, troponin and Mantoux intradermal reaction were negative.

Discharged in good general conditions, he began therapy with indomethacin (50 mg / day).

After 7 days, for the finding of pericardial effusion of 1 cm, he combined therapy with Prednisone (37.5 mg / day) with little benefit on the extent of the effusion. For this reason he added Colchicine (1 mg / day), and made a slow decalage of the steroid.

Over the years he performed numerous echocardiographic exam that showed a slow increase in effusion of about 0.5-1 cm per year with non-dilated and normocollassing VCI, well tolerated.

At the last visit, about 7 years after onset, the patient reported full well-being. On physical examination, PA 100/70 mmHg, HR 60 bpm. Non turgor of the jugular, cardio-thoracic and abdominal examination were negative. Not organomegaly.

Echocardiography showed slightly dilated, normocollassing VCI; circumferential massive pericardial effusion, with the heart oscillating in the pericardial cavity. At the moment he does not perform any therapy.

Conclusion: It was not possible to clarify whether patient presented an effusion secondary to acute pericarditis, possibly autoinflammatory and / or due to mycoplasma infection, or an occasional finding of idiopathic pericardial effusion in the course of acute pharyngotonsillitis. Generally, acute pericarditis and related effusion respond to anti-inflammatory therapy, while occasional pericardial effusion does not respond to anti-inflammatory therapy and is often well tolerated. To our knowledge, this is the first case of idiopathic, asymptomatic, pericardial effusions not associated with acute pericarditis in pediatric age.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P155. A case of recurrent pericarditis in a patient with Bardet-Biedl syndrome

A. Mauro¹, S. Lassainato², F. Casini², E. Chittano Congedo², V. Ansuini¹, C. Carollo³, A. Pedroli³, F. Casarin³, A. Brucato³, L. Bernardo⁴

¹Department of Pediatrics, Rheumatology Unit, ASST Fatebenefratelli-Sacco, ²Department of Pediatrics, , Vittore Buzzi Childrem Hospital, ³Department of Medicin, ⁴Department of Pediatrics, ASST Fatebenefratelli-Sacco, Milan, Italy

Correspondence: A. Mauro

Introduction: Recurrent pericarditis (RP) is defined as the recurrence of pericarditis after the first attack, with a symptom-free interval greater than 4-6 weeks. Very often RP is idiopathic in pediatric age and more rarely, it can be secondary to autoinflammatory, autoimmune diseases, tumors, metabolic diseases or infection.

Objectives: We describe a case of Bardet-Biedl syndrome associate to RP

Methods: A. is a 9-year-old boy with Bardet-Biedl syndrome characterized by retinitis pigmentosa, polydactyly of the left foot, kidney cysts and learning difficulties.

He presented the first episode of pericarditis at the age of 12, successfully treated with colchicine. He also presented three further recurrences of pericarditis at a distance of 1 year each other.

During the last episode, due to the presence of large pericardial effusion, he performed pericardiocentesis with evacuation of 900 ml of serum-hematic liquid. Culture and cytological examinations of the pericardial fluid were negative.

The patient came to our attention at age 16 for retrosternal pain. At the visit he showed BP 130/90 mmHg, cardio-thoracic and abdominal physical examination negative. He performed blood tests (complete blood count, ESR, PCR, troponin, liver and kidney function, electrolytes) which were in normal range. Echocardiography showed the presence of a minimal effusion of the free pericardium wall (5 mm) with the presence of fibrin. Colchicine therapy (1 mg / day) was started.

Results: After two months he returned to our department with chest pain which worsened with movement. On physical examination the patient was in fairly good general conditions, BP 150/90 mmHg, HR 110 beats/minute. Negative cardio-thoracic and abdominal physical examination.

Blood tests were carried out and showed an increase of inflammation index (CRP 170 mg / L, ESR 80 mmHg) and white blood cells count (WBC) 10750 / mm3, Neutrophils 7920 / mm3. Anti-nucleus antibodies, ENA antibodies, anti-phospholipid antibodies and Mantoux test were performed and all were negative.

Chest X-ray and electrocardiogram were negative and Echocardiography revealed the presence of pericardial effusion (20 mm).

He started therapy with Indomethacin (50 mg / day), Prednisone (25 mg / day), Anakinra (100 mg / day).

Progressively, the patient showed an improvement of the clinical, laboratory and instrumental conditions and, gradually reduced steroid treatment.

Conclusion: To our Knowledge, this is the first case reported the association between Bardet-Biedl Syndrome and recurrent pericarditis. Given the brilliant response to therapy with Anakinra, an autoinflammatory etiology has been hypothesized for pericarditis.

Are Pericarditis there a new manifestation of Bardet-Biedl syndrome or a form of autoinflammatory pericarditis associated with it?

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P156. Current practice and research priorities in chronic non-bacterial osteomyelitis – an international survey directed to patients, families, and clinicians

M. Mohanna¹, E. Roberts ², L. Whitty¹, J. Gritzfeld¹, A. Theos³, P. Ferguson⁴, J. Preston¹, C. Hedrich^1,2

¹University of Liverpool, ²Alder Hey Children’s Hospital, Liverpool, United Kingdom, ³Georgetown University, Washington, DC, ⁴University of Iowa Stead Family Children’s Hospital, Iowa City, United States

Correspondence: M. Mohanna

Introduction: Chronic non-bacterial osteomyelitis (CNO) is a rare autoinflammatory bone disease that mainly affects children and young people. It is characterised by bone pain and reduced function (1). The pathophysiology of CNO is incompletely understood and there are no licensed treatments, diagnostic criteria, or outcome measures (2).

Objectives: The aim of this study was to explore and compare the experience of patients, their families, and clinicians with CNO, its diagnosis and treatment. Furthermore, opinions on research priorities were explored.

Methods: Questionnaires were designed in 2020 to capture patient (20 items) and clinician (24 items) experience with the diagnosis and treatment of CNO and to explore research priorities. Questionnaires were circulated internationally in 2021 (Google Form) among patients and families through the CNO Facebook group, shared by other patient groups on twitter including fight_CRMO, and mailing list from the CRMO Foundation, and among clinicians historically involved in CNO research and participating in international working groups on diagnostic and therapeutic approaches.

Results: We received 93 responses to the patient questionnaire; 23% were from young people affected by CNO, and 77% were from parents or carers on behalf of the young person they care for. There were 21 responses (27 contacted) from clinicians. The median time taken for the patient group to receive a diagnosis was 6 months (mean: 14 months). This matched the clinician perspective that estimated a diagnosis after 6 months. 56% of patients/families reported to have received alternative diagnoses before they received a CNO or CRMO diagnosis, most commonly infection (29%). The most common medications taken for CNO amongst the patient group were NSAIDs (34%), followed by bisphosphonates (28%). The most frequently prescribed by clinicians were NSAIDs, followed by bisphosphonates. Research priorities showed strong alignment between patients and clinicians. Pathophysiology was the most commonly mentioned research priority in both patient (45%) and clinician (34%) groups, followed by medication trials (18%, 33% respectively). Based on this survey, four topics were identified for further discussion between clinicians and patients/families at the inaugural “International conference on CNO and autoinflammatory bone disease”, held in Liverpool, UK in May 2022: pathophysiology, nomenclature, clinical trials, and psychosocial aspects and psychological support.

Conclusion: This survey compared clinician and patient/family experience with CNO to identify unmet need and research priorities. Results will inform roundtable discussions to guide future research and provide ongoing support and information for patients and their families.

References:

1. Zhao DY, McCann L, Hahn G, Hedrich CM. Chronic nonbacterial osteomyelitis (CNO) and chronic recurrent multifocal osteomyelitis (CRMO). Vol. 4, Journal of Translational Autoimmunity. 2021.

2. Hedrich CM, Morbach H, Reiser C, Girschick HJ. New Insights into Adult and Paediatric Chronic Non-bacterial Osteomyelitis CNO. Curr Rheumatol Rep. 2020.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P157. Sacroiliitis as a presenting symptoms in a young patient with FMF

M. Nashawi¹, A. Sabo², F. Blankenburg², A. Heinkele³, P. Müller-Abt⁴, T. Hospach³

¹Pediatric Rheumatology, King Abdulaziz University, Jeddah, Saudi Arabia, ²Klinikum Stuttgart, Stuttgart, Germany, ³Pediatric Rheumatology, ⁴Pediatric Radiology, Klinikum Stuttgart, Stuttgart, Germany

Correspondence: M. Nashawi

Introduction: Growing pains (GP) are frequent in children. They usually encompass mostly bilateral, nocturnal pains, with changing localization, especially in the lower extremities, which respond well to symptomatic therapy and resolve until the next day. It is however a diagnosis of exclusion, and selected cases warrant further investigation.

Objectives: Our objective is to point out that growing pain is a diagnosis of exclusion by presenting a case that had been falsely diagnosed as a growing pain in the beginning.

Methods: we present a case report.

Results: We present a 3-yo girl with recurrent pain of the lower extremities which was initially diagnosed with growing pains. Upon further investigation, we found severe bilateral sacroiliitis. Considering the mediterranean origin of the family we sought to investigate the MEFV Gene and found a homozygous single nucleotide mutation strongly associated with familial mediterranean fever (FMF).

Conclusion: Especially in the pediatric population, sacroiliitis (SI) is a rare and uncommon localization for FMF-associated arthritis. In this case, the patient was very young and nocturnal pains were the only manifestation of this disorder. In the population with a susceptible genetic background, we recommend further investigation of limb and lower back pains, to rule out FMF-associated arthritis.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P158. A case of adenosine deaminase 2 deficiency (DADA2) with an uncommon complex phenotype: a diagnostic challenge

M. F. Natale¹, C. Celani², S. Federici², F. De Benedetti², A. Insalaco²

¹Rheumatology, Bambino Gesu Children’s Hospital, ²Rheumatology, Bambino Gesù Children’s Hospital, Rome, Italy

Correspondence: M. F. Natale

Introduction: Deficiency of adenosine deaminase type 2 (DADA2) is an autosomal recessive disease caused by loss-of-function mutations of the ADA2/CECR1 gene which encodes adenosine deaminase type 2 (ADA2). The disease is associated with a highly variable clinical presentation, such as vasculitis of small- and medium-sized arteries, systemic inflammation, skin involvement, hematologic manifestations, immunodysregulation and neurological ischemic or hemorrhagic stroke. It is important to arrive at an early diagnosis in order to start an effective therapy to control clinical manifestations and reduce risk of complications.

Objectives: We described a 16 years old male patient with a genetically confirmed DADA2 characterized by a complex clinical phenotype.

Methods: Next generation sequencing

Results: The patient was first seen at our center at age 16 with a clinical history, started about 1 year earlier, characterized by intermittent fever (mainly serotin), persistent increase of inflammatory markers, splenomegaly (14cm) and diffuse lymph-node enlargement. At home, empiric antibiotic and glucocorticoid therapy was attempted without benefit. In family history, an older brother died when he was 12 years old with an undefined hyperinflammatory syndrome.

In our unit we performed extended microbiological tests resulted negative. Circulating autoantibodies were absent. Radiological exams confirmed splenomegaly and enlarged lymph-nodes in supra and subdiaphragmatic areas with 18F-FDG enhancement at PET-TC. In the suspicion of lymphoproliferative disease a lymphonode biopsy was performed (resulting in reactive lymphadenopathy) and bone marrow aspiration did not reveal atypic cells. Immunological exams revealed an immunodisregulation with a low level of circulating immunoglobulins (IgG 861 mg / dl; IgA 54 mg / dl, IgM 30 mg / dl) and a reduction of total count of memory B cells.

Given the complex clinical picture and the family history, a large NGS diagnostic panel for autoinflammatory diseases and immunodeficiencies was performed revealing the homozygous c.1358A>G mutation in ADA2 (CECR1) gene described in literature as pathogenetic.

We performed a brain MRI to exclude neurological involvement and then started biological therapy with Anti-TNF alfa (Etanercept) with a rapid and brilliant clinical and instrumental response.

Conclusion: This case emphasize the importance to consider a diagnosis of DADA2 in complex clinical cases characterized by systemic inflammation and/or immunedysregulation

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P159. Treatment of hematologic manifestations in a group of patients with monogenic autoinflammatory diseases (AID): single center experience

Z. Nesterenko¹, A. Kozlova¹, V. Burlakov¹, A. Laberko¹, Y. Rodina¹, E. Viktorova¹, E. Deordieva¹, A. Moiseeva¹, A. Mukhina¹, N. Kuzmenko¹, D. Bogdanova¹, A. Khoreva¹, D. Yukhacheva¹, V. Bludova¹, N. Kan¹, D. Balashov², A. Shcherbina¹

¹Immunology, ²Hematopoietic Stem Cell Transplantation , Dmitry Rogachev National Medical Research Center Of Pediatric Hematology, Oncology and Immunology, Moscow, Russian Federation

Correspondence: Z. Nesterenko

Introduction: AIDs are a group of diseases caused by dysregulation of mechanisms controlling innate immune response and characterized by systemic inflammation and a plethora of manifestations, including hematological symptoms.

Objectives: To analyze hematological manifestations and their response to treatment in a group of monogenic AIDs.

Methods: We retrospectively analyzed data of 31 patients (12- females, 19- males) in whom persistent hematological symptoms were part of their AID phenotype.

Results: The forms of AIDs with hematological symptoms included: PSTPIP1-associated syndrome (PAID) - 8, adenosine deaminase 2 deficiency (DADA2) - 8, type I Interferonopathies - 8, mevalonate kinase deficiency (MKD) - 4, A20 haploinsufficiency (HA20) - 1, POMP-related autoinflammation and immune dysregulation (PRAID) – 1, NLRC4-associated autoinflammatory disorder – 1 (AIFEC).

Median age of onset of any disease symptoms was 2 months (range 0–16 years). Median age of onset of hematologic manifestations was 2.5 years (range 0–33 years). Hematological manifestations as the first symptom of AID were seen in 23/31 patients. Median age at diagnosis was 8 years (range 0.5-33), with the mean diagnostic delay of 4 years (range 0.5-32).

9/31 patients had three-lineage cytopenia, 12/31 – two-lineage cytopenia and 5/31 - single lineage cytopenia. Also myelodysplastic syndrome was seen in 1/31 and hemophagocytic lymphohistiocytosis in 4/31.

Jak-inhibitors monotherapy were effective in 3/11 cases with interferonopathies, in 1/11- with DADA2, and in 1/11 - with HA20. Combination of an IL-6 inhibitor and JAK-inhibitor had effect in 1 patient with DADA2 (Tabl.1).

Anti-IL1 therapy was successful in 3 patients with MKD and 1 patient with AIFEC.

Immunosuppressive therapy (steroids, high-dose IVIG, mycophenolate mofetil, cyclosporine A, methotrexat) were not effective in any of the patients treated.

Hematopoietic stem cell transplantation (HSCT) was performed in 5 patients (3 – with PAID, 2- with MKD), the median follow-up time after HSCT is 2.16 years (1,08–4,58).

Four patients are alive, with predominantly donor chimerism, good immune function and complete absence of the disease symptoms.

Conclusion: The hematological manifestation of AIDs represent a therapeutic challenge. HSCT might be a viable treatment option.

Disclosure of Interest: None declared

Table 1 (abstract P159). Treatment of patients with monogenic AIDs with hematological symptoms

P160. Long-term efficacy and safety of canakinumab in patients with hids (Hyper-IGD Syndrome) - interim analysis of the reliance registry

P. T. Oommen¹, T. Kallinich², J. Rech³, N. Blank⁴, J. Weber-Arden⁵, J. B. Kuemmerle-Deschner⁶

¹Clinic of Pediatric Hematology, Oncology and Clinical Immunology, Heinrich-Heine-University Duesseldorf, Duesseldorf, ²Department of Pediatrics, Division of Pulmonology, Immunology and Critical Care Medicine, Charité University Medicine Berlin, Berlin, ³Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander University (FAU) Erlangen-Nuernberg and Universitaetsklinikum Erlangen, Erlangen, ⁴Rheumatology, University Hospital Heidelberg, Heidelberg, ⁵NOVARTIS, Nuernberg, ⁶Department of Pediatrics, Division of Pediatric Rheumatology, University Hospital Tuebingen, Tuebingen, Germany

Correspondence: J. Weber-Arden

Introduction: Hyper-IgD Syndrome/Mevalonate Kinase Deficiency (HIDS/MKD) is a rare autoinflammatory disease caused by a defect in the gene encoding mevalonate kinase. Treatment with the interleukin-1β inhibitor canakinumab (CAN), which since 2017 has been approved for use in HIDS/MKD patients, resulted in rapid remission in most patients, both in clinical trials and in practice.

Objectives: The present study investigates the long-term efficacy and safety of CAN under routine clinical conditions in pediatric (age ≥2 years) and adult HIDS/MKD patients.

Methods: RELIANCE is a prospective, non-interventional, multicenter observational study based in Germany with a follow-up period of up to 7 years. Patients with clinically confirmed HIDS/MKD diagnosis who routinely receive CAN will be enrolled in the study and followed at 6-month intervals.

Results: The present interim analysis includes baseline data from 8 HIDS/MKD patients enrolled in the study through December 2021 and preliminary 18-month data. Of these patients, N=5 (63%) were female and the median age at study entry was 8 years (2-39 years). The median duration of prior CAN treatment at study entry was 1.5 years (0-5 years). Standard, low-dose, and high-dose CAN treatment was evenly distributed at each interval.

Preliminary results indicate stable remission and disease control (as assessed by physicians and patients as well as laboratory parameters; Table 1). Overall, adverse drug reactions occurred in N=4 patients, but none were considered serious. During the study, N=4 patients underwent vaccinations, with one vaccination reaction classified as non-therapeutic occurring after a DTP (diphtheria, tetanus, pertussis) vaccination.

According to mutational analysis, pathogenic or likely pathogenic mutations (some homozygous) were present in N=7 patients. In no patient disease activity was considered to be severe.

Conclusion: Baseline characteristics and preliminary data from HIDS/MKD patients in the RELIANCE study suggest good disease control. In addition, interim analysis at 18 months revealed no unexpected safety concerns. In relation to vaccinations, vaccination reactions unrelated to CAN therapy occurred in only one case.

Disclosure of Interest: P. T. Oommen Grant / Research Support with: Novartis, T. Kallinich Speaker Bureau with: Roche, J. Rech Grant / Research Support with: Novartis, Sobi, Consultant with: AbbVie, Biogen, BMS, Chugai, GSK, Janssen, Lilly, MSD; Mylan, Novartis, Roche, Sanofi, Sobi, UCB, Speaker Bureau with: AbbVie, Biogen, BMS, Chugai, GSK, Janssen, Lilly, MSD; Mylan, Novartis, Roche, Sanofi, Sobi, UCB, N. Blank Grant / Research Support with: Novartis, Sobi, Consultant with: Novartis, Sobi, Lilly, Pfizer, Abbvie, BMS, MSD, Actelion, UCB, Boehringer-Ingelheim, Roche, J. Weber-Arden Employee with: Novartis, J. B. Kuemmerle-Deschner Grant / Research Support with: Novartis, AbbVie, Sobi, Consultant with: Novartis, AbbVie, Sobi

Table 1 (abstract P160). Baseline characteristics and interim analysis data of patients with HIDS

P161. The usefulness of the genetic study in the clinical practice of monogenic autoinflammatory diseases: from diagnosis to the application of precision medicine

J. M. Garcia Aznar ¹, N. Palmou Fontana², N. P. Gandeaga³, J. G. Ocejo-Viñals⁴, M. A. Gonzalez-gay²

¹Inmunology, Health in code, A Coruña, ²Rheumatology, ³IGENETISTA, ⁴Inmunology, Universitary Marques De Valdecilla Hospital, Santander, Spain

Correspondence: N. Palmou Fontana

Introduction: The monogenic autoinflammatory disease accounts for at least 10% of cases with the suspected autoinflammatory syndrome. inflammasome complex, overproduction of IL-1β and IL-18. Different inflammasomes have been described in which genetic defects have been identified in their protein components, resulting in the development of Pyrin-associated inflammasopathy (MEFV), Cryopyrin (NLRP3), NLRP1, NLRC4, PSTPIP1, WDR1, LPIN2, IL1RN, and IL36RN. Another group is the interferonopathies, which include three types depending on the class of interferon involved in the dysregulation: IFNα, IFNβ, IFNγ, and IFNλ. The genes involved have JAK1/2, TYK2, nucleic acid degradation-associated genes such as TREX1, IFIH1, DNASE1/2/L3, and proteasome genes (POMP, PSMA3, PSMB8/9/10, PSMG2), among others. Genes associated with deregulation of the NF-kB/TNF pathway (NF-kBopathies) also result in autoinflammatory disorders characterized by aberrant activation of NF-kB (NFkbopathies), including TNFAIP3, TNFRSF1A, OTULIN, LUBAC complex genes, NOD2, ADA2, or RIPK1 among others. Additionally, other genetic factors not included in any of the above categories can affect both intrinsic and adaptive immunity genes with an autoinflammatory component (COPA, PLCG2, LRBA, C2).

Objectives: Defining and identifying the phenotypic spectrum associated with these diseases is challenging for clinical practice. The clinical manifestations, although heterogeneous, allow defining criteria for the categorization of autoinflammatory disease.

Methods: Ninety-nine patients with suspected autoinflammatory diseases were included in the cohort, with a panel containing more than 270 genes. According to the genetic result, the subjects were categorized into five groups: inflammasome disorders, interferon disorders, NFkB/TNF alteration, unfavorable genetics, and other pathologies. A group of patients phenotype divided into eight categories.

Results: The study results revealed that 48% of the studies performed with suspected autoinflammatory disease presented relevant genetic findings. The genetic variants identified were distributed in the following genes from higher to lower frequency: MEFV (21%), NOD2 (9%), PSTPIP1 (9%), NLRP12 (9%), TNFRSF1A (6%), TNFAIP3 (6% ), NLRC4 (4%), JAK1 (4%), NLRP3 (4%), TNFRSF1A (2%), ADA2 (2%), OTULIN (2%), TNFRSF11A (2%), BANK1 (2%), C2 (2%), PLCG2 (2%), PSMB8 (2%), LRBA (2%), NLRP1 (2%), POMP (2%), RNF31 (2%). 23% contained genes associated with inflammasome disorders, 4% interferon disorders, 16% NF-kb disorders, and 3% genes from other metabolic pathways. The mean age of disease onset was lower in patients with NF-kb-pathway disorder. Overall was lower in all categories than the studies that did not have relevant genetic variants.

Among patients with the autoinflammatory genetic disease, febrile and gastrointestinal manifestations were more frequent in 0-11 years. In contrast, rash and joint manifestations appeared more frequently in patients with 36 years old

Conclusion: The genetic study turned out to be a helpful tool for identifying the altered inflammatory pathway, which is an essential element for selecting treatment. Knowledge of the clinical presentation of each age and group of diseases adds value to selecting patients with the suspected autoinflammatory disease.

Disclosure of Interest: None declared

P162. Adenosine deaminase 2(DADA2) deficiency in five indian children : a single center experience

D. B. Pandya, M. Agarwal, S. Sawhney

Pediatric Rheumatology Department, Sir Gangaram Hospital, New Delhi , India

Correspondence: D. B. Pandya

Introduction:

Deficiency of ADA2(DADA2) is the first molecularly described monogenic vasculitis syndrome which is caused by autosommal recessive loss of function mutations in the ADA2 gene(CERC1). Deficiency of ADA2 has been linked to an imbalance in differentiation of monocytes towards proinflammatory M1 macrophages, neutrophil extracellular traps(NETosis) dysregulation and endothelial dysfunction. DADA2 can present with Vasculitis or Vasculopathy , Bone marrow failure , Lymphoproliferation , Immunodeficiency and Type 1 interferonopathy.¹

Objectives:

We aim to unveal Characteristics of DADA2 deficiency in five children at Our Center.

Methods:

This is a retrospective analysis of five children who were treated at our unit between August 2013 & August 2021 for severe systemic polyarteritis nodosa. In view of resistent disease in these children , ADA2 gene analysis was ordered and returned Positive.

Results:

Conclusion:

Early age of onset, female sex, severe disease activity mainly affecting gastrointestinal system , recurrent and resistant course in polyarteritis nodosa may suggest monogenic vasculitis syndrome - DADA2 deficiency.

Trial registration identifying number:

1. J Clin Immunol. 2018, Published online 2018 Jun 27. doi: 10.1007/s10875-018-0525-8

Deficiency of Adenosine Deaminase 2 (DADA2): Updates on the Phenotype, Genetics, Pathogenesis, and Treatment

Isabelle Meyts and Ivona Aksentijevich

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

Table 1 (abstract P162). See text for description

P163. Chronic non-bacterial osteomyelitis (CNO): a study from a single center in India

D. Patro¹, A. Abraham¹, J. Raghuram^2,3, A. P. Rao^1,3

¹Pediatric Rheumatology, Manipal Hospital, ²Pediatric Rheumatology, Aster Whitefield Hospital, ³Pediatric Rheumatology, Indira Gandhi Institute of Child Health, Bengaluru, India

Correspondence: D. Patro

Introduction: First described in 1972 by Giedion et al, Chronic nonbacterial osteomyelitis (CNO) is a rare autoinflammatory bone disorder that presents as recurrent bone pain in one or multiple sites.

Objectives: 1. To understand the clinical profile of CNO patients from Indian subcontinent

2. To elucidate the clinical outcomes of the children affected with CNO.

Methods: We retrospective reviewed 38 cases diagnosed as CNO as per Bristol Diagnostic criteria in the Pediatric rheumatology clinic in Manipal hospital, Bengaluru, India after obtaining ethical approval.

Results: The findings are summarized in the table below. Of the 164 multifocal lesions detected by WB- MRI in 33 cases, tibial lesions (26%) were the commonest. LPIN2 deficiency was also reported in two cases. All cases were initiated with naproxen. 27 patients were started on methotrexate of which 2 cases each responded to Bisphosphonates and TNF inhibitor respectively. 4 out of 25 cases required additional TNF inhibitor after pamidronate and methotrexate therapy. 2 cases responded well to pamidronate infusion alone. 8 children had frequent flares. 14 children are in remission on drugs and 12 children are in remission off drugs. 2 cases are lost to follow up.

Conclusion: With increasing knowledge and timely referral to a rheumatology center may bridge the gap to delay diagnosis. WB- MRI can detect bone lesions and prevents unnecessary invasive procedures. In a resource-limited setting, methotrexate and pamidronate have helped in achieving remission. TNF inhibitors are helpful in resistant cases with good response.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

Table 1 (abstract P163). See text for description

P164. Pyoderma gangrenosum- mirror of active autoimmune disease

A.-M. Ramazan¹, A. Apostol², S. Mehdi³

¹Rheumatology Department, ²Paediatric Onco-Hematology , ³Dermatology Department, Emergency County Clinical Hospital “Sf Apostol Andrei”, Constanta, Romania

Correspondence: A.-M. Ramazan

Introduction: Pyoderma gangrenosum (PG) is a rare neutrophilic dermatosis that presents with rapidly developing, painful skin ulcers hallmarked by undermined borders and peripheral erythema. The cause of PG is not well understood, but PG is generally considered an autoinflammatory disorder. Children hospitalized in US for PG were found to have higher odds of thyroid disease, inflammatory bowel disease, hematologic malignancy, and other autoimmune disorders.

Objectives: To report a rare autoinflammatory and autoimmune condition with therapeutical difficulties

Methods: A 13-year-old girl without any past medical history was sent to our clinic for consultation and treatment of refractory pyoderma gangrenosum (PG) of bilateral lower extremities.

Results: Our patient had incomplete therapeutical response with high doses of prednisone indicated by our dermatologist. We tried to add Cyclosporine (CsA), accordingly to the first line of therapy in PG, followed by a significant flare of dermatological and biliary involvements (only hepatic cytolysis), as our best option remained Azathioprine with progressive increasing doses. The abnormal liver tests were obviously under CsA when they had a peak, a clear sign of worsening and an autoimmune involvement.

Conclusion: PG could be more than a dermatological disease and the rheumatologist must look for the underlying autoimmune disease, a required diagnosis for the adjustment of therapy.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

Table 1 (abstract P164). See text for description

P165. Criteria of remission and risk factors for disease severity in long-term follow-up of children with chronic non-bacterial osteomyelitis

C. Reiser¹, J. Klotsche^2,3, T. Hospach⁴, G. Heubner⁵, D. Windschall^6,7, R. Trauzeddel⁸, N. Grösch², M. Niewerth², K. Minden^2,3, H. Girschick⁹

¹Department of Pediatrics, LKH Bregenz, Bregenz, Austria, ²Deutsches Rheuma-Forschungszentrum Berlin, ein Institut der Leibniz-Gemeinschaft, ³Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, ⁴Department of Pediatrics, Olgahospital, Klinikum Stuttgart, Stuttgart, ⁵Städtisches Klinikum Dresden-Neustadt, Klinik für Kinder- und Jugendmedizin, Dresden, ⁶Clinic for Pediatric and adolescent Rheumatology, St. Josef-Stift, Sendenhorst, ⁷University of Halle –Wittenberg, Halle, ⁸Fachambulanz Kinderrheumatologie, Helios Klinikum Berlin-Buch, Klinik für Kinder- und Jugendmedizin, ⁹Vivantes Klinikum Friedrichshain, Children’s Hospital, Berlin, Germany

Correspondence: C. Reiser

Introduction: Chronic non-bacterial osteomyelitis (CNO) is an autoinflammatory bone disease of unknown origin. A 5 year longitudinal analysis of patients in the German National Pediatric Rheumatologic Database (NPRD) with CNO was performed.

Objectives: To document the long term course and to assess risk factors for severe disease and items defining remission of patients with CNO.

Methods: From 2015-2020 all patients with a confirmed diagnosis of CNO, who were registered in the NPRD during their first year of disease course and at least one follow-up visit, were included in this analysis.

Results: Additional to the previously reported cross-sectional analysis of almost 800 CNO patients, a data set of 314 eligible patients including up to 5 years of follow-up visits was analysed. Selected patients’ characteristics are as follows: 64% of the patients were female; the medium age was 11.2 years. 10.8% of patients were HLA-B27 positive. The mean number of clinical lesions was 2.2; using whole-body MRI imaging, the mean number was 2.9 lesions per patient at diagnosis. Co-manifestation of the skin was present in 17%. MRI-scans (whole-body) were performed in 255 patients, and most of them (86%) showed a positive TIRM/STIR signal.

The analysis of the location of the lesions showed that the distribution changed over the years. Whereas in the first year of disease course sites like vertebrae or mandibula were inflamed (8% and 2% of all affected sites), these sites completely resolved over time, while other sites like pelvis or tibia (18%/20%) remained affected after 5 years. Initially, patients were mainly treated with non-steroidal anti-rheumatic drugs (NSAIDs). During disease course the proportion of patients treated with conventional or biological disease modifying anti-rheumatic drugs (DMARDs) raised during these five years from 37% to 54%, or 5% to 12.5% respectively. Inflammation of pelvis or femur at baseline posed an elevated risk for long term severe disease (OR 1.51/1.61, each p=0.0001). Other risk factors for severe disease (defined as physician reported disease activity (PRDA) ≥4 (Visual Analogue Scale 0-10)) were raising numbers of lesions, elevated ESR (erythrocyte sedimentation rate) and multifocal disease (defined as more than one lesion). The risk for arthritis increased with the initially higher number of lesions. Items defining remission best were PRDA <1, patient reported pain score and number of radiologically defined inflammatory bone lesions. The composite Childhood health assessment score (C-HAQ) and patient reported overall well-being did not correlate with inactive disease.

Conclusion: The NPRD long-term cohort documents a large number of children and adolescents with CNO. Most of the patients were treated effectively with non-steroidal anti-inflammatory drugs, second-line treatment are disease-modifying agents, steroids or bisphosphonates. An improvement of patient-, physician- and imaging-defined disease activity measures was documented, suggesting CNO generally as benigne disease with a modest number of complicated disease course. Remission defining items and risk factors for severe disease course were defined.

Patient Consent: Yes, I received consent

Disclosure of Interest: C. Reiser Grant / Research Support with: Pfizer, Speaker Bureau with: Novartis, J. Klotsche: None declared, T. Hospach: None declared, G. Heubner: None declared, D. Windschall: None declared, R. Trauzeddel: None declared, N. Grösch: None declared, M. Niewerth: None declared, K. Minden Speaker Bureau with: Pfizer, Novartis, and Medac, H. Girschick: None declared

P166. Alone we can diagnose so little; together we can diagnose so much! when multispecialty collaboration spotlights PFIT and autoinflammation

A. Remy¹, W. Abou Chahla ², G. Boursier³, M. Le Coniac ⁴, B. Catteau⁵, H. Reumaux⁶

¹General pediatrics, ²Hematology, CHU Lille, Lille, ³Rare and Autoinflammatory diseases laboratory, Molecular Genetics and cytogenomics , CHU de Montpellier, Montpellier, ⁴General pediatrics, CH Valenciennes, Valenciennes, ⁵Dermatology, ⁶Rheumatology, CHU Lille, Lille, France

Correspondence: A. Remy

Introduction:

Auto-inflammatory diseases have a broad range of symptoms and thus are difficult to diagnose.

Objectives:

To underline the significance of multispecialty collaboration in the diagnosis of rare inflammatory disease. To describe the phenotype of a patient with undescribed mutations of WDR1 gene.

Methods:

We report a case of a child where multispecialty collaboration led to a diagnosis of Periodic Fever Immunodeficiency and Thrombocytopenia (PFIT).

Results:

The girl was born to unrelated Caucasian parents. From infancy, she presented with recurrent purulent conjunctivitis and unexplained severe mouth ulcers. The case was found atypical to her general pediatrician that sought the help of a dermatologist. Indeed, on top of mucous involvement, the patient had recurrent pustulosis on different parts of her body. Rheumatologist help was also sought because of recurrent stereotyped attacks, with or without fever, associated to high blood inflammation in and in between outbreaks (Orosomucoide: 5 g/L). Joints have never been involved and the patient had no hepatomegaly.

Immunohematologist joined the discussion when the patient presented with mild diarrhea. The hypothesis of an underlying primary immunodeficiency was confirmed with lymphocyte immunophenotyping revealing B cell lymphopenia (40/mm³ CD19+ cells) and inadequate postvaccination antitetanus immune response, along with history of recurrent infections. The hematologist point of view also gave a significant breakthrough: the patient had relative thrombopenia with lower platelets than expected regarding inflammation (157-222 × 10⁹/L).

When pediatrician, dermatologist, hematologist, rheumatologist met around this case, all agree to say that the atypical symptoms were suggestive of an autoinflammatory disease. Behcet disease was unlikely due to uncommon skin lesions. PFIT was hypothesized and confirmed by molecular analysis revealing compound heterozygosity of WDR1 gene for 2 likely pathogenic variants: NM_017491.5:c.1264G>A p.(Val422Met) and c.1790C>T p.(Ala597Val).

Conclusion: PFIT is caused by mutations in the WDR1 gene leading to actin accumulation, pyrin activation and IL-18 release.(1) Impaired cytosqueleton homeostasis impacts hematopoietic cells especially leukocytes (resulting in immunodeficiency) and platelets (resulting in microthrombocytopenia).

PFIT is a new entity first described by Standing et al in 2017.(2) Our patient has a milder phenotype than the previously described patients with no pathological scarring or microstomia to date. She had a good clinical response to colchicine, a cytosqueleton targeted therapy that has shown partial efficacy in PFIT. Should the treatment be unsuccessful, IL-18 targeted blockade might be effective, if available.

To conclude, routine blood tests and patient history as seen by a multidisciplinary team prevail extended genetics. Diagnosis and understanding of rare auto-inflammatory diseases such as PFIT require a collaboration between specialists. With respect of precision medicine, the functional consequences of those newly described WDR1 mutations need to be clarified to optimize targeted therapy.

REFERENCES:

(1) Pfajfer L, Mair NK, Jiménez-Heredia R, et al. Mutations affecting the actin regulator WD repeat-containing protein 1 lead to aberrant lymphoid immunity. J Allergy Clin Immunol. 2018;142(5):1589-1604.e11.

(2) Standing AS, Malinova D, Hong Y, et al. Autoinflammatory periodic fever, immunodeficiency, and thrombocytopenia (PFIT) caused by mutation in actin-regulatory gene WDR1. J Exp Med. 2017;214(1):59-71.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P167. Human type I interferonopathy with mutations in CTNNA3

J. Riedl¹, C. Eide², J. Tolar¹, A. Kwiatkowski³, J. Heier³, A. Almeida de Jesus⁴, R. Goldbach-Mansky⁴, B. Binstadt¹

¹Medical School, Pediatrics, ²Medical School, University of Minnesota, Minneapolis, ³Cell Biology, University of Pittsburgh, Pittsburgh, ⁴Translational Autoinflammatory Diseases Section, National Institutes of Health (NIH), Bethesda, United States

Correspondence: J. Riedl

Introduction: The interferonopathies are a group of monogenic disorders defined by persistent type 1 interferon (IFNα,β,k) signaling and upregulation of interferon-stimulated gene (ISG) expression. They are highly heterogeneous, and approximately 20 genes have been implicated in driving ISG expression and pathogenesis in these autoinflammatory disorders. The full spectrum of clinical presentation and mechanisms of disease are not fully described, and treatment remains challenging.

Objectives: We identified an 11-year-old male patient with a high IFN score in skin (1000x normal) and peripheral blood (200x normal). The patient has severe inflammatory skin lesions, conjunctivitis, mucositis and joint contractures: symptoms akin to described monogenic interferonopathies

Methods: Whole exome sequencing revealed compound heterozygous mutations in CTNNA3 encoding the protein αT-catenin, which localizes to adherens junctions of a subset of cells, where it links the cadherin complex to filamentous actin, providing cell-cell attachment.

Results: The CTNNA3 mutations encoded a premature stop codon (R208*) and an amino acid substitution (R378C). ClinVar suggests that these are pathogenic mutations. The R378C mutation is located in an intramolecular salt bridge that regulates protein conformation. Mechanical force breaks the salt bridge to induce conformational change and reveal a cryptic binding site for the protein vinculin (important for both cadherin- and integrin-mediated adhesion to the actin cytoskeleton).

The patient also had mutations in NOD2, a gene linked to Blau and Yao syndromes, This patient’s NOD2 variants included IVS8⁺¹⁵⁸ and R702W in linkage disequilibrium; both parents have the same NOD2 mutations and are unaffected. We therefore propose a possible link between CTNNA3 and an inflammatory disease with an interferon signature.

Conclusion: There are no prior reported associations of CTNNA3 mutations in inflammatory disorders. It is possible that the combination of the CTNNA3 and NOD2 gene mutations together drives patient’s phenotype. Further study is needed to investigate the potential role of CTNNA3 in in interferon-associated autoinflammatory disease.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P168. Chronic Recurrent Multifocal Osteomyelitis (CRMO): new insights into extra-osseous manifestations

M. Robert, C. Guillemin, L. Rossi-Semerano, C. Galeotti, I. Koné-Paut, P. Dusser

Rhumatologie pédiatrique, Hôpital Bicêtre, Le Kremlin Bicêtre, France

Correspondence: M. Robert

Introduction: Chronic recurrent multifocal osteomyelitis (CRMO) is a rare auto-inflammatory disease. Clinical manifestations include skeletal symptoms that are well described. Whole body magnetic resonance imaging (MRI) is the gold standard for the diagnosis. Sometimes, skin or digestive manifestations occur. Treatment relies on non-steroidal anti-inflammatory drugs (NSAIDs), bisphosphonates are used as second-line treatments. To date, the focus has been set on bone involvement and few data are available on extra-osseous manifestations in CRMO.

Objectives: This study aims to further describe these extra-osseous manifestations in CRMO.

Methods: A historical cohort was designed with patients followed at the Pediatric Rheumatology Department in a tertiary university hospital. All patients fulfilled Jansson’s criteria. Skeletal and extra-osseous manifestations were characterized. Treatments used were recorded.

Results: Forty-one patients were included, with 31 females (75.6%). The mean age at onset was 79.1 months, with a delay at diagnosis of 6.71 months. Twenty-one patients had a familial history of inflammatory diseases (n=21/41, 51.2%). At diagnosis, pain level was 5.71/10. Eleven patients (42.3%) had blood inflammation. The mean number of bone lesions, assessed thanks to MRI, was 6.65. Twenty-seven patients had extra-osseous symptoms (65.9%), with 7 patients with fever (17.1%), 24 patients had skin manifestations (58.5%) including palmoplantar lesions (n=3, 12.5%), acne (n=6, 25.0%), psoriasis (n=5, 20.8%) and aphthous (n=10, 41.7%). Four patients (9.76%) had gastro-intestinal symptoms and 7 (17.1%) had enthesitis. One patient had uveitis. A patient had a vasculitis which mimicked Behçet’s disease. Almost all patients received NSAIDs (n=39/41, 95.1%), 51.2% (n=21/41) of the cohort was treated with bisphosphonates. Nine patients (22.0%) received biologics. Subgroup analysis between CRMO with and without extra-osseous manifestations revealed significant differences for age at diagnosis (126 vs 20.5 months, p=0.03), blood inflammation (87% vs 46.2%, p=0.018) and the use of biologics (33.3% vs 0%, p=0.017).

Conclusion: Extra-osseous manifestations have to be carefully searched in CRMO and integrated in the therapeutic strategy.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P170. The Russian cohort of patients with TRAPS according to the federal rheumatology center

S. Salugina¹, E. Fedorov¹, M. Kaleda¹, E. Kamenets², E. Zakharova²

¹Pediatrics, V.A. Nasonova Research Institute of Rheumatology, ²Selective Screening, Research Center of Medical Genetics, Moscow, Russian Federation

Correspondence: S. Salugina

Introduction: TRAPS (TNF-receptor-associated periodic syndrome) is a rare autosomal dominant disease associated with a mutation of the TNFRSF1A gene. It belongs to the group of monogenic autoinflammatory diseases (mAIDs) characterized by repeated prolonged episodes of fever, skin rashes, musculoskeletal, ophthalmological symptoms, and an increase in the level of acute phase markers. The main targeted therapy is IL1 inhibitors (iIL–1).

Objectives: to present the Russian cohort of patients (pts) with TRAPS according to the Federal Rheumatology Center

Methods: For the period from 2013 to 2021, 28 pts with TRAPS were included in the study, 17 of them female, aged 2.5 to 65 years, Me 9.0 [IQR 7.9;14.5] y.o., 7 adults, 21 children. All pts underwent rheumatological examination. Molecular genetic analysis for mutations in the TNFRSF1A gene was made to all pts.

Results: Among mAIDs (162 pts), TRAPS was diagnosed in 28 (17.3%). The age of the onset ranged from 1 month of life to 28 years, Me 4.0 [IQR 1.0;7.1] y.o. The majority of pts started to hurt before the age of 10 (89.3%), of them up to a year - 8 (28.6%), from 1 to 5 years – 25%, older than 18 years – 2 (7.1%), at the age of 21 and 28. At the time of the study the duration of the disease and the delay in diagnosis ranged from 3 months to 59 years. The diagnosis was made within 1 year of the disease in 4 (14.3%), ranging from 1 to 10 years in 18 (64.3%), a delay in diagnosis of more than 10 years was in 8 (28.6%), more than 20 years in 4 (14.3%). The duration of attacks ranged from 10 to 30 days, the intervals between seizures ranged from 2 weeks to 6 months. Clinical manifestations included most often: fever – 96.4% of pts, skin rashes - 71.4% (annular in 9, erythema in 6, urticaria in 2), musculoskeletal symptoms - 64.3% (among them oligoarthritis in 9, polyarthritis in 2), gastrointestinal symptoms - 64.3% (more often abdominal pain), lymphadenopathy of various groups (cervical, intra-thoracic, mesenteric lymph nodes) - 35.7%, ophthalmological manifestations - 28.6% (more often periorbital edema-5 and eye redness-5). Less frequently observed: manifestations from the nervous system (headaches, dizziness, fatigue, convulsions) in 6 pts, pharyngitis - in 4, stomatitis - in 2. An increase in ESR was noted in 82.1% pts, CRP-71.4%, leukocytosis - 39.3%. The diagnosis in all pts was confirmed genetically. 10 pts had a low-penetrant mutation R92Q (p. Arg121Gln). 5 family cases were identified, the total number of sick family members was 12, from 2 to 4 in each family, 3 cases of amyloidosis, all adults. Treatment included: GC-19 (67.9%), cyclosporine A - 1, colchicine-5. IL-1 inhibitor (canakinumab) was prescribed to 10 pts (35.7%), duration of administration was from 1 to 9 years; etanercept-1, adalimumab-1, tocilizumab-3.

Conclusion: A cohort of pts with TRAPS in the practice of a rheumatologist is presented. The majority of pts had an early onset of the disease (before the age of 10), the delay in diagnosis was 10 years or more in a third of pts. Most pts had a typical inflammatory phenotype, the diagnosis in all was confirmed genetically. About a third of the pts needed the appointment of biological drugs, mainly iIL-1. There was a complete response to the therapy in most pts and good tolerability of the treatment.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P171. Long-term efficacy and safety of canakinumab in patients with tumor necrosis factor receptor-associated periodic syndrome (TRAPS) - interim analysis of the reliance registry

C. Schuetz¹, N. Blank², J. Henes³, T. Kallinich⁴, P. T. Oommen⁵, M. Borte⁶, M. Hufnagel⁷, A. Janda⁸, J. Weber-Arden⁹, J. B. Kuemmerle-Deschner¹⁰

¹Catharina.Schuetz@uniklinikum-dresden.de, Medizinische Fakultaet Carl Gustav Carus, Technische Universitaet Dresden, Dresden, ²Rheumatology, University Hospital Heidelberg, Heidelberg, ³Center of Interdisciplinary Rheumatology, Immunology and autoimmune diseases (INDIRA), University Hospital Tuebingen, Tuebingen, ⁴Department of Pediatrics, Division of Pulmonology, Immunology and Critical Care Medicine, Charité University Medicine Berlin, Berlin, ⁵Clinic of Pediatric Hematology, Oncology and Clinical Immunology, Heinrich-Heine-University Duesseldorf, Duesseldorf, ⁶ImmunoDeficiencyCenter Leipzig (IDCL), Hospital St. Georg gGmbH Leipzig, Leipzig, ⁷Division of Pediatric Infectious Diseases and Rheumatology, Department of Pediatrics and Adolescent Medicine, University Hospital Medical Center Freiburg, Medical Faculty, University of Freiburg, Freiburg, ⁸Department of Pediatrics, University Hospital Ulm, Ulm, ⁹NOVARTIS, Nuernberg, ¹⁰Department of Pediatrics, Division of Pediatric Rheumatology, University Hospital Tuebingen, Tuebingen, Germany

Correspondence: C. Schuetz

Introduction: TRAPS[1] is a rare hereditary autoinflammatory disease characterized by periodic fever and severe systemic and organ inflammation. Successful treatment was achieved with the interleukin-1β inhibitor canakinumab (CAN) in a pivotal phase 3 study, in which 45% of patients achieved clinical remission. CAN has been approved for the treatment of TRAPS patients since 2017.

1TRAPS: Tumor necrosis factor receptor-associated periodic syndrome

Objectives: The present study investigates the long-term efficacy and safety of CAN under routine clinical practice conditions in pediatric (age ≥2 years) and adult TRAPS patients.

Methods: RELIANCE is a prospective, non-interventional, multicenter observational study in Germany. Patients with a clinically confirmed diagnosis of TRAPS who routinely receive CAN will be enrolled in the study to evaluate the efficacy and safety of CAN under standard clinical conditions at baseline and at six-month intervals.

Results:

The interim analysis of TRAPS patients enrolled through December 2021 included baseline data (N=19) and preliminary 24-month data. Of these patients, N=12 (63%) were female and the median age at baseline was 16 years (3-43 years).

Mutation information was provided for a total of N=13 patients, all of whom were pathogenic or likely pathogenic (Table 1).

N=4 patients had dose adjustments (↑ dose increase, ↓ dose reduction): patient 1: ↑, patient 2: ↑↓, patient 3: ↑↑, patient 4: ↑↑↓↑.

Preliminary results at baseline, 12 months and 24 months indicate stable disease control by remission according to physician assessment (47, 73 and 50% of patients), laboratory parameters (CRP 0.2, 0.1, 0.2 mg/dl and Serum Amyloid A (0.5, 0.4, 0.4 mg/dl median) and disease control according to patient assessment (1.5, 1.0, 0.0). Of N=9 serious adverse events, none occurred in association with therapy. A total of N=7 adverse drug events were observed, none of which were considered serious.

Conclusion: Baseline and interim data from the RELIANCE trial for TRAPS patients indicate continued good efficacy and safety of various CAN doses.

Disclosure of Interest: C. Schuetz: None declared, N. Blank Grant / Research Support with: Novartis, Sobi, Consultant with: Novartis, Sobi, Lilly, Pfizer, Abbvie, BMS, MSD, Actelion, UCB, Boehringer-Ingelheim, Roche, J. Henes Grant / Research Support with: Novartis, Roche, Consultant with: Novartis, AbbVie, Sobi, Roche, Janssen, Boehringer-Ingelheim, T. Kallinich Speaker Bureau with: Roche, P. T. Oommen Grant / Research Support with: Novartis, M. Borte Grant / Research Support with: Pfizer, Shire, M. Hufnagel Grant / Research Support with: Novartis, A. Janda: None declared, J. Weber-Arden Employee with: Novartis, J. B. Kuemmerle-Deschner Grant / Research Support with: Novartis, AbbVie, Sobi, Consultant with: Novartis, AbbVie, Sobi

Table 1 (abstract P171). Mutation in relation to disease activity and dosage

P172. Outcomes and post-acute sequelae of COVID-19 in patients with systemic autoinflammatory diseases

S. Nazzar¹, L. Moorthy², S. Lapidus³, G. Schulert⁴, J. Tousseau⁵, M. Correia Marques^6,7, L. Mansfield^8,9, M. Twilt¹⁰, M. Gutierrez¹¹, S. Angevare¹², F. Dedeoglu¹³, K. Durrant⁵

¹UCLA, Los Angeles, ²Rutgers-RWJMS, New Brunswick, ³The Joseph M. Sanzari Children’s Hosp., Hackensack, NJ, ⁴Cincinnati Children’s Hosp., Cincinnati, ⁵Autoinflammatory Alliance, San Francisco, ⁶NIAMS, NIH, Bethesda, ⁷Children’s Nat’l Hosp., Washington DC, ⁸Hosp. for Special Surgery, ⁹Weill Cornell, NY, United States, ¹⁰Alberta Children’s Hospital, Calgary, Canada, ¹¹Johns Hopkins Hosp., Baltimore, United States, ¹²KAISZ, Amsterdam, Netherlands, ¹³Boston Children’s Hosp., Boston, United States

Correspondence: G. Schulert

Introduction: The exaggerated inflammatory responses to SARS-CoV-2 infection and the paucity of data on the risks for patients with Systemic Autoinflammatory Disease (SAID) patients is concerning.

Objectives: To assess the outcomes of SAID patients with COVID-19.

Methods: The CARRA Autoinflammatory Working Group and the Autoinflammatory Alliance conducted an anonymous online survey that was distributed to SAID patients through social media between January and March of 2021 about their experiences with COVID-19 in 2020.

Results: We analyzed data from 593 individuals with SAID including Cryopirin-associated Periodic Syndromes (CAPS) (18%, n=108), Undifferentiated Systemic Autoinflammatory Disease (USAID) (12%, n=70), Periodic Fever Aphthous Stomatitis Pharyngitis and Cervical Adenitis (PFAPA) (11%, n=64) and others. Seventy four percent of the patients were from the United States, US territories and Canada and 26% from other countries. Fifty-two subjects had COVID-19. Of these, 12% (n=6) were asymptomatic, 81% (n=42) had mild or moderate symptoms managed at home and four were hospitalized. Thirty-three percent (n=17) had a flare of their underlying SAID concurrently (n=10) or after recovering from COVID-19 (n=7). Half of the patients who were hospitalized (n=2/4) noted increased frequency of flares during the pandemic, whereas the ones who had asymptomatic infection had decreased or unchanged flare frequency. Twenty-one (40%) of patients reported post-COVID manifestations (Table 1), which were seen more often after moderate illness and hospitalized patients (60%, n=15/25), compared to mild and asymptomatic cases (22%, n=6/27). Thirty three percent (n=7) of the SAID patients who had post-COVID symptoms did not have a specific SAID diagnosis listed, 14% (n=3) had USAID, and 9.5% (n=2) for each diagnosis had CAPS, PFAPA or Familial Mediterranean Fever.

Conclusion: These data reflect the largest known global cohort of SAID patients’ experiences with COVID-19. Most of the SAID patients who had COVID-19 reported mild to moderate symptoms managed at home with a third presenting an exacerbation of their baseline SAID and lingering symptoms. The severity of acute COVID-19 was associated with reported changes in the frequency of flares during the pandemic and with the likelihood of post-COVID symptoms.

Patient Consent: Not applicable (there are no patient data)

Disclosure of Interest: S. Nazzar: None declared, L. Moorthy Grant / Research Support with: Brystol Myers Squibb, S. Lapidus: None declared, G. Schulert Consultant with: Novartis, J. Tousseau: None declared, M. Correia Marques: None declared, L. Mansfield: None declared, M. Twilt: None declared, M. Gutierrez: None declared, S. Angevare: None declared, F. Dedeoglu: None declared, K. Durrant: None declared

Table 1 (abstract P172). Post-COVID Symptoms in SAID Patients

P173. Genotypes and phenotypes patterns in patients with NLRP3 gene variants

E. Krekhova¹, E. Alexeeva¹, M. Shingarova¹, T. Dvoryakovskaya², K. Isaeva², R. Denisova², A. Chomakhidze², O. Lomakina², A. Mamutova², A. Fetisova ², M. Gautier ², C. Chibisova ², I. Kriulin ², I. Tsulukia ², A. Pushkov³, K. Savostyanov³

¹Pediatric, Sechenov First Moscow State Medical University, Pediatric, Moscow, Russian Federation, ²Rheumatology, ³Molecular genetic, National Medical Research Center of Children’s Health, Moscow, Russian Federation

Correspondence: M. Shingarova

Introduction: Cryopyrine-associated periodic syndromes (CAPS) are a group of rare congenital auto-inflammatory diseases (AID) in an autosomal dominate manner and caused by variants in NLRP3 gene. The main difficulties in diagnosing CAPS are the similarity of their clinical manifestations with other rheumatic diseases.

Objectives: To reveal genotype and phenotype characteristics in patients with NLRP3 gene variants at the National Medical Research Center of Children’s health, Moscow, Russia.

Methods: Retrospective study included 60 patients (37 females, 62%) with NLRP3 gene variants revealed by molecular genetic analysis and classified according ACMG criteria. Median age of debut was 6,3 (interquartile range (IQR) 0,1:13,7) years. The diagnosis of CAPS was founded according Eurofever/PRINTO criteria.

Results: 5/60 (8,3%) patients had NLRP3 pathogenic variants: two had c.943A>G variant, and one each with c.2173C>A, c.1991T>C and c.214G>A respectively. Likely pathogenic variants had 5/60 patients (8,3%)/ Among them two had c.1085T>A, two - c.410G>A, and one - c.796C>T; all heterozygous. Clinical manifestations 10/60 (16,7%): rash in 7 (70%), fever in 7 (70%) patients, hepatomegaly in 9 (90%), splenomegaly in 6 (60%) patients, lymphadenopathy in 8 (80%), and serositis in 4 (40%) patients. Аrthritis was observed in 10/10 (100%) patients, affection eyes in 4/10 (40%), сentral nervous impairment observed in 6(60%), sensorineural hearing loss was in 2 (20%) patients. The criteria of CAPS accorded 9/10 (90%) children. One patients with pathogenic variants was sibling child with CAPS (asymptomatic carrier). Variant with variant with conflicting pathogenicity c.598G>A was observed in 10/60 (16,7%). Clinical manifestations 10/60 (16,7%): rash in 3 (30%), fever in 7 (70%) patients, hepatomegaly in 5 (50%), splenomegaly in 3 (30%) patients, lymphadenopathy in 4 (40%), serositis in 1 (10%) patients, arthritis was observed in 9/10 (90%) patients, affection eyes in 4/10 (40%), сentral nervous impairment observed in 2(20%), and sensorineural hearing loss was in 1 (10%) patients. The criteria of CAPS accorded 4/10 (40%) children, juvenile polyarthritis (RF-) - 4/10 (40%), persistent oligoarthritis – 1/10(10%) and 1/10 with DADA2 . Among the remaining patients, 30/60 (50%) had polymorphism c.2113C>A, 8/60 had VUS c.2861C>T, c.584C>T, c.585G>A, c.459C>G and 2/60 patients - probably benign variants : c.2664-26G>C and c.1050G>A, respectively.

Conclusion: The criteria of CAPS accorded 14 patients. The most frequent clinical manifestations were in musculoskeletal involvement 93%, fever 86 % and rash 79 % of children. Central nervous impairment observed in 7/14(60%), sensorineural hearing loss was in 3/14(21,4%) and affection eyes in 4/14(29%). The number of identified causal variants of the NLRP3 gene in these 14 patients showed high diversity, while the high frequency of polymorphism c.2113C>A in the studied sample was consistent with data obtained in other populations.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P174. Netosis dysregulation in adenosine deaminase 2 deficiency

S. Signa¹, A. Bertoni¹, G. Del Zotto², M. Bonacini ³, A. Corcione¹, M. Bartolucci⁴, M. Bruschi⁵, A. Petretto⁴, R. Bertelli⁶, S. Croci³, S. Della Bella⁷, M. Gattorno¹, F. Schena¹

¹Centro per le malattie autoinfiammatorie e immunodeficienze, ²Core Facilities Flow Cytometry and Cell imaging Lab, IRCCS, Giannina Gaslini Institute, Genova, ³Clinical Immunology, Allergy and Advanced Biotechnologies Unit, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Reggio Emilia, ⁴Core Facilities-Clinical Proteomics and Metabolomics, ⁵Laboratory of Molecular Nephrology, ⁶Laboratory of Human Genetics, IRCCS, Giannina Gaslini Institute, Genova, ⁷Lab of Clinical and Experimental Immunology, IRCCS Humanitas Research Hospital, Milano, Italy

Correspondence: S. Signa

Introduction: Deficiency of Adenosine deaminase 2 (DADA2) is a monogenic autoinflammatory disorder presenting a broad spectrum of clinical manifestations, including vasculitis, immunodeficiency and hematologic disease. Biallelic mutations in ADA2 gene have been associated to an insufficient ADA2 activity and a consequent accumulation of extracellular adenosine. Recently a chronic neutrophil activation and a dysregulation of NETosis triggered by extracellular Adenosine and inducing TNF-α secretion from macrophages, has been implicated in the pathogenesis of DADA2.

Objectives: The aim of the project is to analyze NETosis in DADA2 and healthy neutrophils, quantifying suicidal and vital NETosis induced by several stimuli and by analyzing NETs remnants. Moreover, we investigated the mechanisms of NETs removal, evaluating DNAse activity. To determine if NET epitopes can change depending from the inflammatory microenvironment and if protein composition of NETs is disease specific, we used quantitative proteomics approach to characterize DADA2 patients’ NET proteins. To investigate the cross-talk between neutrophils and Dendritic cells (mDCs), we performed DCs immune-phenotype analysis in DADA2 patients and analyzed in vitro moDC maturation and cytokine production in presence of NETs.

Methods: We analyzed NETosis by Imaging Flow Citometry. We evaluated NETs remnants and DNAse in the plasma samples by ELISA assay whereas DNAse activity by DNA digestion. We used quantitative proteomics approach to characterize NET proteins. We isolated monocytes from peripheral blood with microbeads and we generated moDC after culture stimulation with LPS/NETs. On the 7th day we analyzed by flow cytometry the phenotype and the markers of differentiation. Quantification of cytokines was performed by flow cytometry bead array.

Results: Neutrophils from DADA2 patients show a significant increased suicidal NETosis, and we found an increased vital NETosis. Accordingly, plasmatic levels of circulating nucleosomes were elevated in patients; DNAse levels were normal but its activity was reduced, possibly due to presence of inhibitors. We set up experimental conditions for proteomic analysis of NETs, induced by PMA, Adenosine and TNF-α, testing two patients, two HDs and two patients with non-genetic vasculitis: in total we identified 1770 proteins among which a hundred of proteins were significantly up or down-modulated in DADA2 NETs compared to controls NETs. DC phenotype in DADA2 patients result normal, as well as moDCs cytokine production after LPS stimulation. We observed a stimulatory effect of patients’ NETs towards induction of TNF-α , IL-6 production and IP-10 from moDCs in both HD and DADA2.

Conclusion: Our findings confirm a dysregulation in NETosis process in DADA2 patients. An increase of vital NETosis was also identified. Proteomic profile of NETs isolated from DADA2 is different from HD and PAN patients: NETs are qualitatively different between HD and DADA2. NETs in DADA2 may therefore interact differently with innate immunity compartment, stimulating DCs to produce cytokines, contributing to the typical inflammatory phenotype.

Patient Consent: Yes, I received consent

Disclosure of Interest: None declared

P175. Type I interferon signature: a standardized method for clinical application

P. Bocca¹, A. Tesser², D. Cangelosi³, M. Ulivi⁴, F. Candotti⁵, A. Tommasini^2,6, M. Gattorno¹, S. Volpi

¹Clinica Pediatrica e Reumatologia, IRCCS Istituto G. Gaslini, Genova, ²Pediatric Department, Institute for Maternal and Child Health - IRCCS “Burlo Garofolo”, Trieste, ³Unità di Bioinformatica Clinica, IRCCS Istituto G. Gaslini, ⁴Centro Biotecnologie Avanzate, TIB Molbiol, Genova, Italy, ⁵Laboratory of Inherited Immune Disorders, Division of Immunology and Allergy, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland, ⁶University of Trieste, Trieste, Italy

Correspondence: M. Gattorno

Introduction: Type I interferon (IFN) signature analysis is extensively used to identify pathological conditions characterized by a type I IFN dysregulation (i.e. monogenic interferonopathies, dermatomyositis, systemic lupus erythematosus), and to direct therapy approaches. IFN signature is used to discriminate patients with IFN-related inflammation from conditions predominantly mediated by other cytokines (i.e. periodic fevers), through the calculation of an IFN score (IS). However, no standardized method is yet available for the clinical practice, and comparing values at different time points or between different centers remains a challenge.

Objectives: To implement a standardized method for IFN signature detection with the use of a synthetic control, and to evaluate the concordance of IFN signature results obtained with this method among the laboratories of two Italian Hospitals.

Methods: Peripheral blood expression analysis of the six IFN Stimulated Genes (ISGs) IFI27, IFI44L, IFIT1, ISG15, RSAD2 and SIGLEC1 was detected by Real Time PCR. A synthetic control was used to determine copy numbers of the selected genes.

The IS for each subject was calculated as the geometric mean of the genes’ copy numbers normalized using an endogenous reference gene. IS cut-off value was obtained as the mean + 2SD of 20 healthy donors’ IS.

The method was validated by analyzing the IS of 89 patients with different inflammatory, autoimmune and infectious disorders driven by type I IFN or other inflammatory pathways.

To assess inter-laboratory variability, 12 patients with different degrees of type I IFN inflammation were run in parallel in two different centers.

Results: As expected, our test confirmed a positive IFN score for inflammatory diseases such as systemic lupus erythematosus, type I interferonopathies, dermatomyositis and Sjögren syndrome.

The test demonstrated a high reproducibility as assessed by multiple analyses of the same sample. Furthermore, IS obtained from the samples shared by two different laboratories resulted in comparable values.

Conclusion: The proposed method represents a quantitative, standardized and easy to perform assay for the evaluation of type I IFN signature in IFN-driven inflammatory conditions.

The reproducibility of the synthetic control minimized the inter-assay and inter-laboratory variability. The application of a standardized method for type I IFN signature detection greatly improves the test interpretation, patient follow up and clinical discussion among centers promoting the use of type I IFN signature in clinical practice.

Disclosure of Interest: None declared

P176. Recurrent fever without molecular diagnosis: lessons from autoinflammatory disease registries

Y. Vyzhga¹, V. Hentgen², R. Papa³, H. Wittkowski⁴, N. Ruperto³, E. Lainka⁵, K. Theodoropoulou⁶, R. Caorsi³, S. Fuehner⁴, D. Foell⁴, M. Gattorno³