Proceedings of the 27th European Paediatric Rheumatology Congress (PReS 2021)

Lightning talks: Autoinflammatory diseases, Disease outcome and transition, New diseases, Patient/parent organisation initiatives

O1 Long-term efficacy and safety of canakinumab in patients with mevalonate kinase deficiency: results from the randomized phase 3 cluster trial

J. Jeyaratnam¹, A. Simon², I. Calvo³, T. Constantin⁴, A. Shcherbina⁵, M. Hofer⁶, M. Gattorno⁷, A. Martini⁸, B. Bader-Meunier⁹, B. Vastert¹⁰, J. Levy¹¹, E. Dekker¹¹, F. de Benedetti¹², J. Frenkel¹

¹Department of Pediatrics, University Medical Center Utrecht, Utrecht; ²Department of Internal Medicine, Radboud University Medical Center, Radboudumc Expertise Center for Immunodeficiency and Autoinflammation (REIA), Nijmegen, Netherlands; ³Pediatric Rheumatology Unit, Hospital Universitario y Politécnico La Fe, Valencia, Spain; ⁴2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary; ⁵Department of Immunology, Dmitry Rogachev National Medical Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russian Federation; ⁶Unité Centre Multisite Romande d'Immuno-e Rhumatologie Pediatrique, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland; ⁷Center for Autoinflammatory Diseases and Immunodeficiencies, IRCCS, G. Gaslini, Genova; ⁸University of Genoa, Genoa, Italy; ⁹Department of Pediatric Immunology, Hematology and Rheumatology, Universite de Paris, Institut des Maladies Genetiques (IMAGINE Institute), Reference Centre for Rheumatic, AutoImmune, and Systemic Diseases in Children (RAISE), Necker Hospital, Assistance Publique-Hopitaux de Paris, Paris, France; ¹⁰Department of Pediatric Immunology, University Medical Center Utrecht, Netherlands; ¹¹Novartis Pharma AG, Basel, Switzerland; ¹²Division of Rheumatology, Ospedale Pediatrico Bambino Gesù, Roma, Italy

Correspondence: J. Jeyaratnam

Introduction: Mevalonate Kinase Deficiency (MKD) is a a rare monogenic autoinflammatory disease characterized by fever and generalized inflammation. Evidence-based therapy has become available since canakinumab proved effective to control disease activity and prevent flares.

Objectives: In this study we evaluated the long-term efficacy and safety of canakinumab in patients with MKD during the open label extension period (Epoch 4, weeks 41 to 113) of the randomized controlled CLUSTER trial.

Methods: Patients received open label canakinumab 150 or 300mg every 4 or 8 (q4 or q8) weeks during the study period of 72 weeks. A stepwise dose increase was maintained if patients experienced a flare. Down-titration was not allowed in Epoch 4.

The disease activity was evaluated every 8 weeks using physician global assessment (PGA) and counting the number of flares. Measurement of C reactive protein (CRP) and serum amyloid A (SAA) protein concentrations were performed. The safety was studied by determination and classification of observed adverse events. The safety and efficacy were analyzed separately in three subgroups of patients receiving a cumulative dose of less than <2700 mg, >=2700-5400mg or >5400 mg

Results: Of the 74 MKD patients who started the CLUSTER study, 66 entered Epoch 4 and 65 completed it. Overall, 18 patients received a cumulative dose <2700 mg and 34 patients received 2700-5400 mg, while 14 patients received a cumulative dose of >5400 mg.

At the start of Epoch 4, 19 patients (29%) were receiving the lowest dose regimen (150mg q8) and in 12 (18%) this dose was sufficient to control the disease throughout epoch 4. Another 20 patients (30%) received intermediate doses (150mg q4 and 300mg q8) at the end of the study. However, the highest dose (300mg q4) was required in 32 patients (49%) at the end of Epoch 4, while this regimen was only used to treat 18 patients (27%) at the start.

During the 72-week period, 42 (64%) patients experienced no flares, while 13 (20%) had one flare, as compared with a median of 12 flares per year reported at baseline. At baseline, all patients had mild to severe disease activity according to PGA score. Low PGA scores were seen at the end of the study for all groups with >90% reporting minimal disease activity or none at all. Median CRP concentrations were consistently equal or lower than 10 mg/L. These CRP levels seemed slightly lower in patients receiving the highest cumulative dose (>5400mg). Median SAA concentrations remained only slightly above the normal range of 10mg/L.

The exposure-adjusted rate of adverse events was 2.72 per 100 day. Infection was the most frequently reported class. Twenty-seven serious adverse events were reported in fourteen patients. Some of these serious adverse events were considered to be caused by MKD flares. Eleven serious infections were reported in nine patients (pneumonia (n=3), one each: anal abscess, appendicitis, bronchitis, herpes virus infection, influenza, orchitis, pyelonephritis and tonsillitis).

Conclusion: Canakinumab proved effective to control disease activity and prevent flares in MKD during the 72-week study period. Individual dose adjustments may be required to maintain the therapeutic effect of canakinumab. No new or unexpected safety concerns were reported.

Trial registration identifying number: NCT02059291

Patient Consent Received

Yes

Disclosure of Interest

None declared

O2 Long-term safety of canakinumab in patients with autoinflammatory periodic fever syndromes − interim analysis of the reliance registry

J. B. Kuemmerle-Deschner¹, N. Blank², J. Henes¹, B. Kortus-Goetze³, P. T. Oommen⁴, J. Rech⁵, F. Weller-Heinemann⁶, G. Horneff⁷, A. Janda⁸, I. Foeldvari⁹, C. Schuetz¹⁰, F. Dressler¹¹, M. Borte¹², M. Hufnagel¹³, A. Braner¹⁴, F. Meier¹⁴, M. Fiene¹⁵, J. Weber-Arden¹⁶, T. Kallinich¹⁷

¹University Hospital, Tuebingen; ²University Hospital, Heidelberg; ³University Hospital, Marburg; ⁴University Hospital, Duesseldorf; ⁵University Hospital, Erlangen; ⁶Prof. Hess Kinderklinik, Bremen; ⁷Asklepios Clinic, Sankt Augustin; ⁸University Hospital, Ulm; ⁹Centre for Pediatric Rheumatology, Hamburg; ¹⁰University Hospital, Dresden; ¹¹Hannover Medical School, Hannover; ¹²Hospital St. Georg gGmbH, Leipzig; ¹³University Hospital, Freiburg; ¹⁴University Hospital, Frankfurt; ¹⁵District Hospital, Demmin; ¹⁶Novartis, Nuernberg; ¹⁷Charite University Medicine, Berlin, Germany

Correspondence: J. B. Kuemmerle-Deschner

Introduction: Autoinflammatory periodic fever syndromes (PFS) are characterized by severe systemic and organ inflammation. In clinical trials, successful treatment was achieved with the interleukin-1β inhibitor canakinumab (CAN).

Objectives: The present study explores the long-term efficacy and safety of CAN in routine clinical practice conditions in pediatric (age ≥2 years) and adult patients with CAPS (cryopyrin-associated periodic syndromes), FMF (familial Mediterranean fever), TRAPS (tumor necrosis factor receptor-associated periodic syndrome) and HIDS/MKD (hyperimmunoglobulinemia D syndrome/mevalonate kinase deficiency).

Methods: RELIANCE is a prospective, non-interventional, observational study based in Germany. Patients with clinically confirmed diagnoses of PFS routinely receiving CAN are enrolled. Besides efficacy parameters regarding disease activity and remission, safety parameters were recorded at baseline and assessed at 6-monthly intervals.

Results: Here we present the interim analysis of 168 patients with PFS enrolled in the RELIANCE Registry between October 2017 and December 2020. Mean age in this cohort was 24.7 years (2-79 years) and the proportion of female patients was 51 %. At baseline, median duration of prior CAN treatment was 3 years (0-12 years).

A total of 101 patients (60%) experienced any AE and 22 patients (13%) were affected by SAE. In 9 patients (5%) SAE were classified as drug related. Of 489 AE, 53 were severe and a total of 21 SAE were classified as treatment-related (table 1). Overall, 13 AE comprised upper respiratory tract infections (ARI).

Conclusion: The interim data from the RELIANCE study, the longest running real-life canakinumab registry for, confirm safety of long-term canakinumab treatment across the entire study population.

Disclosure of Interest

J. B. Kuemmerle-Deschner Consultant for: Novartis, AbbVie, Sobi, N. Blank Consultant for: Novartis, Sobi, Lilly, Pfizer, Abbvie, BMS, MSD, Actelion, UCB, Boehringer-Ingelheim, Roche, J. Henes Consultant for: Novartis, AbbVie, Sobi, Roche, Janssen, Boehringer-Ingelheim, B. Kortus-Goetze Consultant for: Novartis, P. T. Oommen: None declared, J. Rech Consultant for: Abbvie, Biogen, BMS, Chugai, GSK, Janssen, Lilly, MSD, Mylan, Novartis, Roche, Sanofi, Sobi, UCB, Speaker Bureau of: Abbvie, Biogen, BMS, Chugai, GSK, Janssen, Lilly, MSD; Mylan, Novartis, Roche, Sanofi, Sobi, UCB, F. Weller-Heinemann: None declared, G. Horneff Speaker Bureau of: AbbVie, Bayer, Chugai, Merck Sharp & Dohme, Novartis, Pfizer, Roche, A. Janda: None declared, I. Foeldvari Consultant for: Novartis, C. Schuetz: None declared, F. Dressler Consultant for: Abbvie, Mylan, Novartis, Pfizer, M. Borte: None declared, M. Hufnagel: None declared, A. Braner Consultant for: Novartis and SOBI, F. Meier Speaker Bureau of: Novartis, M. Fiene: None declared, J. Weber-Arden Employee of: Novartis, T. Kallinich Consultant for: Sobi, Novartis, Roche

Table 1 (abstract O2). Overview of the CAN safety data of the RELIANCE study across all study indications (N=168 patients)

O3 NLRP3 splice variants inactivate caps phenotype in vitro

K. Theodoropoulou^1,2, L. Spel¹, L. Zaffalon¹, F. Martinon¹

¹Department of Biochemistry, University of Lausanne (UNIL); ²Department of Pediatrics, Univerity Hospital of Lausanne (CHUV), Lausanne, Switzerland

Correspondence: K. Theodoropoulou

Introduction: NLRP3 inflammasomes has been associated to the development of autoinflammatory diseases such as Cryopyrin-associated periodic syndromes (CAPS). CAPS comprise a group of rare autoinflammatory diseases, which has recently served as a pure model of IL-1β-driven diseases. However, the mechanisms of inflammasome regulation in these diseases remain unclear. Interestingly, NLRP3 contains Leucine-rich repeats (LRR) domains which are predicted to undergo extensive alternative splicing which is likely to affect the ligand recognition capability.

Objectives: The aim of this project is to elucidate the impact of NLRP3 LRR alternative splicing in both physiological state and in systemic autoinflammatory diseases such as CAPS.

Methods: N-terminally FLAG-tagged NLRP3 plasmids for every possible LRR skipped exon were generated and subcloned in a doxycyclin inducible vector using Gateway Recombination Cloning technology. All the plasmids were created in 2 different human models: NLRP3 wild type (WT) and NLRP3 CAPS with the R260W mutation. Silencing of NLRP3 in U937 cells, a laboratory monocytic cell line, was performed using CRISPR-Cas9 technique and reconstitution was perfomed with all inducible NLRP3 splice variants by lentiviral transduction. NLRP3 expression and the competence for inflammasome activation (cleavage of IL-1β) were assessed by Western-Blot, in PMA differentiated cells. ASC specks were quantified by ImageStream flow cytometric analysis.

Results: Our data show that Δ4, Δ5, Δ7 and Δ9 NLRP3 splice variants lose the competence for inflammasome activation in both physiological and CAPS in vitro models. However, endogenous NLRP3-driven cleavage of IL-1β, GSDMD and Caspase-1 is not affected in unfunctional variants (Δ4, Δ5, Δ7, Δ9), indicating the absence of a dominant negative role of the variants. Moreover, the absence of significant ASC speck formation in unfunctional variants, suggest a functional role of the LRR domain upstream of ASC oligomerization.

Conclusion: At this point, our research shows a functional implication of the LRR alternative splicing in NLRP3 inflammasome activation, with some of the LRR exon skipping variants being completely inactive, suggesting a potential regulatory role. However, the exact function of the LRR domain in the cascade of inflammasome activation and how some of its splice variants impairs this process, remain to be elucidated.

Disclosure of Interest

None declared

O4 pGALSplus: a tool to facilitate the identification and assessment of children with serious musculoskeletal disease

V. Mercer^1,2, N. Smith¹, S. Jandial^3,4, H. E. Foster⁵

¹Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne; ²Children’s Physiotherapy, South Tyneside and Sunderland NHS Foundation Trust, South Shields; ³School of Medical Education, Newcastle University; ⁴Paediatric Rheumatology, Great North Children’s Hospital; ⁵Population Health Institute, Newcastle University, Newcastle upon Tyne, United Kingdom

Correspondence: V. Mercer

Introduction: Musculoskeletal (MSK) problems are common, often benign and self-limiting and present to healthcare professionals (HCPs) in the community who may not be MSK specialists; it can therefore be challenging to identify those with serious disease. pGALS (paediatric Gait, Arms, Legs and Spine) is a simple, quick MSK clinical assessment and has been shown to detect joint and functional problems in various MSK conditions including inflammatory arthritis. We aimed to develop an extended pGALS assessment, called pGALSplus, to facilitate identification of children with MSK disease who require onward referral to specialist services.

Objectives: To pilot the pGALSplus assessment in CYP with Juvenile Idiopathic Arthritis (JIA), Mucopolysaccharidoses (MPS), Muscular Dystrophy (MD) or Developmental Coordination Disorder (DCD) as exemplar MSK conditions and compare feasibility and acceptability with healthy controls (HC).

Methods: A 3-phase mixed methods approach; Phase 1 included a scoping review of the literature and qualitative interviews with expert HCPs within paediatric practice to identify key clinical assessments that inform diagnosis and progress. These results informed the initial ‘pGALSplus’ assessment which underwent iterative development in Phase 2 with an expert working group (including paediatric rheumatologists, expert MSK paediatric physiotherapists and neuromuscular specialists). Phase 3 focused on testing pGALSplus in the exemplar disease groups with feedback from HCPs, patients and carers. Patients; n=37 (JIA;n=10, DCD;n=10, MD;n=9, HC;n=8), age range 2-10 years).

Results: Phase 1 data identified key components of pGALSplus to include: The pGALS assessment (‘top to toe’ approach), a questionnaire to identify further indicators of DCD, components of the North Star Ambulatory Assessment (NSAA) to identify early stages of neuromuscular disease (MD), and an assessment of static balance (found to be significantly worse in children with DCD).

In Phase 2 pGALSplus was further expanded to include clinical assessment aiming to identify pain or restriction of range of movement (JIA or MPS), underlying weakness (MD) or issues with motor planning and co-ordination (DCD). The additional tests included; testing reflexes (to assess underlying neurology); leg lengths (which may indicate lower limb joint pathology); activity-based skills including standing from the floor and squatting (MD), hopping, jumping and catching a ball (DCD). Expert consensus derived a colour-coded approach to pGALSplus sequencing to facilitate identification of exemplar MSK conditions.

Phase 3 demonstrated pGALSplus to be quick to complete (mean 12.6 minutes (9 - 20), with high satisfaction from patients and carers (100% ‘about right’ time taken). The assessment was deemed ‘very easy or easy’ for HCPs (35/37, 95%) and patients (32/37, 86%). Parents and children reported high acceptability (32/37, 86% reported it to be ‘very comfortable or with minimal discomfort’).

Conclusion: pGALSplus is an evidence and consensus-based tool to discriminate between MSK conditions with high acceptability and feasibility. pGALSplus includes resources to aid HCPs to undertake the assessment. Our aim is that pGALSplus is implemented amongst HCPs in the community who are likely to encounter children early in the clinical pathway and are integral to diagnosis and specialist referral.

Disclosure of Interest

None declared

O5 OAS1 GOF causes a novel autoinflammatory disease characterized by persistently elevated IFN signature, hypogammaglobulinemia, and alveolar proteinosis

F. Licciardi¹, R. Mulatero¹, M. Dellepiane¹, C. Covizzi¹, R. Mogni¹, L. Baldini¹, M. Proietti², A. Caballero-Oteyza², A.-L. Lanz³, T. Magg³, D. Montin¹, F. Hauck ³

¹Department of Pediatrics and Public Health, Ospedale Infantile Regina Margherita, Turin, Italy; ²Institute for Immunodeficiency, University Hospital of Freiburg, Freiburg; ³Department of Pediatrics, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany

Correspondence: F. Licciardi

Introduction: Monogenic autoinflammatory diseases (AIDs) are a group of diseases characterized by dysregulation of innate immune responses. Here we describe a peculiar overlap phenotype of autoinflammation and immunodeficiency in a patient with a gain of function (GOF) mutation of oligoadenylate synthetase1 (OAS1). OAS1 is a type I interferon-induced, intracellular dsRNA sensor involved in antiviral defence. Recently OAS1 mutations have been linked with hereditary pulmonary alveolar proteinosis (PAP) and hypogammaglobulinemia but association with autoinflammation has never been reported.

Objectives: To describe the clinical phenotype of a patient affected by a novel AID due to monoallelic OAS1 GOF.

Methods: The patient, a 13-months old boy, was admitted, 3 weeks after MMR vaccine, for severe cutaneous vasculitis involving cheeks, lips, and nose, acute encephalopathy, and nephrotic syndrome. He had severe hypogammaglobulinemia (IgG 50mg/dl) with absent IgA and IgM. Blood exams ruled out X-linked agammaglobulinemia and severe combined immunodeficiency. He was treated with a IVIG (2g/kg, single dose) plus steroid (dexamethasone 0,6mg/kg/d than shifted to prednisone 2mg/kg); encephalopathy, vasculitis, and nephrotic syndrome slowly regressed.

Three months later, he had a severe acute respiratory insufficiency during Influenza A infection. CT scan showed an ARDS picture with interstitial disease, and areas of consolidation of both lungs. The patient was treated with high dose pulse methylprednisolone (15mg/kg daily for 3 days), followed by oral prednisone with good response. Interferon (IFN) type 1 signature was constantly elevated but NGS panel for interferonopathies failed to show a known mutation. In the following months, IVIG substitution therapy was started due to progressive IgG reduction. Clinical exome revealed a previously published de novo monoallelic mutation (c.326G>A, C109Y) in OAS1. The patient recently received a matched unrelated donor hematopoietic stem cell transplantation (HSCT) and during the pre-HSCT evaluation a bronchoalveolar lavage was performed and was suggestive for PAP.

Results: Biochemical and functional studies showed that monocytes, macrophages, and B-cells of the patients displayed dsRNA-independent OAS1 GOF that upon IFN-induced expression led to RNase L-mediated RNA-cleavage, translational arrest, and apoptosis. (Magg et al. Science Immunology, accepted).

Clinically, the patient exhibited features reminiscent of SAVI (STING-associated vasculopathy with onset in infancy) such as severe lung involvement, cutaneous vasculitis, and persistently elevated type 1 IFN signature. In contrast to SAVI, he had progressive hypogammaglobulinemia.

Conclusion: Monoallelic OAS1 GOF causes a novel AID. The key features of the disease are severe inflammatory flares after virus exposure, persistently elevated IFN signature, progressive PAP, and hypogammaglobulinemia. The deleterious effect of OAS1 GOF mainly affects monocytes, macrophages, and B-cells. HSCT has been already performed with success in other OAS1 GOF patients and at present is the only curative approach (Magg et al. Science Immunology, accepted). Steroids can be a valuable bridging therapy while waiting for HSCT because they might interrupt the vicious cycle induced by IFN-mediated OAS1 upregulation and ensuing IFN production.

Patient Consent Received

Yes

Disclosure of Interest

None declared

O6 While looking for one, you may find another: Tin Soldiers and the search for undiagnosed individuals with fibrodysplasia ossificans progressiva (FOP)

C. Scott¹, F. Kaplan², C. Friedman³, P. Delai⁴, M. Al Mukaddam², A. Cali⁵, V. Harries⁶, N. Ezra⁶, O. Schwegler^6,7

¹Paediatric Rheumatology, University of Cape Town, Cape Town, South Africa; ²Departments of Orthopaedic Surgery & Medicine And The Center for Research in FOP & Related Disorders, The Perelman School of Medicine, The University of Pennsylvania, Philadelphia, United States; ³Pediatric Oral Health and Dentistry, Schulich School of Medicine and Dentistry, Ontario, Canada; ⁴Instituto de Ensino e Pesquisa, Hospital Israelita Albert Einstein, Sau Paula, Brazil; ⁵Tin Soldiers Global FOP Patient Search, New Jersey, United States; ⁶Tin Soldiers Global FOP Patient Search; ⁷Blink Pictures, Johannesburg, South Africa

Correspondence: C. Scott

Introduction: FOP is an ultra-rare condition where heterozygous, gain-of-function missense mutations in the ACVR1 gene result in progressive heterotopic bone formation in ligaments, tendons and muscles and result in severe disability.¹ FOP has an estimated incidence of 0.6-1.3 per million individuals ^2,3 suggesting that currently there are approximately 8,000 patients living with FOP worldwide, however only about 900 patients are currently diagnosed world-wide The diagnosis is made clinically by identification of typical malformations of the great toes as well as inflammatory swellings (flare-ups) that result in progressive and episodic ossification of soft connective tissues, often triggered by trauma.⁴ Muscle biopsies, though contraindicated, are often performed mistakenly during the course of diagnosis, as FOP is not well known. There is a need to identify people with FOP in order to avoid harmful biopsies and provide a pathway to care.

Tin Soldiers is a global FOP patient search program utilizing multimedia campaign. The mission is to identify every person with FOP who is currently undiagnosed, as well as to deliver education and support to those living with a diagnosis, but not connected to support networks. Once found, all people living with FOP are connected to pathways to care.

Objectives: To describe the Tin Soldiers global FOP patient search program approach and report early results of the program.

Methods: Tin Soldiers creates multimedia campaigns to create awareness and to educate medical professionals, healthcare workers, general public and local communities on FOP. At the heart of the communication program is story-telling of people living with FOP, from a feature-length documentary to public service announcements, animated short films and an 8-part Global Master Series - all designed to bring attention to FOP in order to find patients and provide a pathway to diagnosis and care.

Results: Since March 2020, Tin Soldiers has trained 535 medical professionals; established an African Clinicians Council of 10 doctors with the intention of mentoring others across the continent; increased the number of African patients with a diagnosis from 25 patients in December 2020 to 32 in April 2021. Connected previously diagnosed (but not connected) patients to a robust support network and held the first African FOP Family Gathering with clinicians from both South Africa and Nigeria.

On the journey, patients with other conditions have been discovered including Juvenile Idiopathic Arthritis (JIA), Progressive Osseus Heteroplasia (POH) and Multiple Osteochondromas (MO). These patients have been diagnosed and connected to both medical care and patient support. Another important outcome is the continued education of doctors globally with the uptake of the CME Master Series in Russia and planned rollouts in Algeria, Nigeria, Kenya, Namibia, Sweden (in partnership with the national patient organization) and Brazil (under the First Lady’s patronage).

Conclusion: Tin Soldiers offers an innovative model of patient identification, diagnosis, support and education at all levels of care, using the power of story-telling and multi-media marketing. Such a model could be considered for raising the profile of other musculoskeletal or rare conditions and connecting patients to a functioning pathway to care

Patient Consent Received

No

Disclosure of Interest

None declared

Lightning talks: COVID-19 (Coronavirus), Immunodeficiency and infection related arthritis

O7 Nailfold capillaroscopy: a sensitive method for evaluating microvascular involvement in children with SARS-COV-2 infection

F. Çakmak¹, A. Demirbuğa², D. Demirkol³, S. Gümüş⁴, S. Hançerli Torun², G. Kavrul Kayaalp¹, R. Eker Ömeroğlu¹, A. Somer², M. Uysalol⁴, R. Yıldız⁴, N. Aktay Ayaz¹

¹Pediatric Rheumatology; ²Pediatric Infectious Diseases; ³Pediatric Intensive Care Unit; ⁴Pediatric Emergency Unit, Istanbul Faculty of Medicine, Istanbul, Turkey

Correspondence: F. Çakmak

Introduction: The coronavirus (SARS-CoV-2) pandemic, known as COVID-19 has spread all over the world in a short period of time and caused the death of more than 2 million people to date. Although in severe cases, it mainly progresses as a serious lung disease such as pneumonia or acute respiratory distress syndrome (ARDS), numerous extrapulmonary manifestations due to systemic hyperinflammation associated with COVID-19 have been described. The hyperinflammatory state and the viral invasion may result in endothelial dysfunction and capillaroscopic examination of the nailfold may be a feasible method for monitoring the microvascular circulation in SARS-CoV-2 infection.

Objectives: With this study, we aimed to investigate the microvascular circulation in patients diagnosed with COVID-19 and multisystem inflammatory syndrome in children (MIS-C) by nailfold videocapillaroscopy (NVC).

Methods: Thirty-one patients with SARS-CoV-2 infection, 26 of whom were diagnosed with COVID-19 and 6 with MIS-C, and 58 healthy peers were included in the study. All fingers except the thumbs were examined paying greater attention to the ring finger of the non-dominant hand for the presence of any abnormality bilaterally and two images from eight fingers were obtained from both the study and control groups. Sixteen images were examined for the morphology of capillaries, presence of pericapillary edema, microhemorrhage, avascular area, and neoangiogenesis. These parameters were assessed as present or absent, and the presence of signs in at least two fingers was recorded as capillary abnormality in both groups. Capillary length, capillary width, apical loop, arterial and venous width, and intercapillary distance were measured from three consecutive capillaries from the ring finger of the non-dominant hand.

Results: COVID-19 patients showed significantly more capillary ramification (p<0.001), capillary meandering (p=0.04), microhemorrhage (p<0.001), neoangiogenesis (p<0.001), capillary tortuosity (p=0.003). Capillary density (p=0.002) and capillary length (p=0.002) were significantly lower in the patient group while intercapillary distance (p=0.01) was significantly longer compared with healthy volunteers. Morphologically, patients with MIS-C had a higher frequency of capillary ramification and neoangiogenesis compared with COVID-19 patients (p=0.04). Patients with capillary abnormalities had significantly higher levels of C-reactive protein (CRP) and D-dimer (CRP; 16.4 vs 2.2, p=0.04 and D-dimer; 900 vs 340, p=0.04).

Conclusion: Children diagnosed with COVID-19 and MIS-C present with several microvascular abnormalities on NVC examination. MIS-C is an emergency phenomenon in which evidence suggests activation of ECs as the key determinant in the pathogenesis of the disease, and NVC may be a useful non-invasive, valid method for assessing the microcirculatory status of children with MIS-C. As a preliminary one, our study may take attention to the use of NVC for follow-up of patients with SARS-CoV-2 infection during clinical course and management.

Patient Consent Received

Yes

Disclosure of Interest

None declared

O8 Outcomes of COVID-19 infection among children and young people with pre-existing rheumatic and musculoskeletal diseases

L. Kearsley-Fleet¹, S. Lawson-Tovey¹, R. E. Costello¹, A. Belot², F. Aeschlimann³, I. Melki⁴, I. Kone-Paut⁵, S. Eulert⁶, N. Švestková⁷, Š. Fingerhutová⁷, D. Clemente⁸, Y. Berkun⁹, Y. Uziel^10,11, N. M. Wulffraat¹², B. Raffeiner¹³, F. Oliveira-Ramos¹⁴, C. Dackhammar¹⁵, A. Strangfeld⁶, E. F. Mateua¹⁶, P. M. Machado¹⁷, K. L. Hyrich¹

¹The University of Manchester, Manchester, United Kingdom; ²Hospices Civils de Lyon, Lyon; ³Hôpital Necker-Enfants Malades; ⁴Hôpital Robert-Debré; ⁵Bicêtre Hospital, Paris, France; ⁶German Rheumatism Research Center, Berlin, Germany; ⁷General University Hospital, Prague, Czech Republic; ⁸Hospital Niño Jesús, Madrid, Spain; ⁹Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem; ¹⁰Tel Aviv University, Tel Aviv, Israel; ¹¹Pediatric Rheumatology European Society; ¹²University Medical Center, Utrecht, Netherlands; ¹³Central Hospital of Bolzano, Bolzano, Italy; ¹⁴Centro Hospitalar Universitário Lisboa, Lisbon, Portugal; ¹⁵Sahlgrenska University Hospital, Sahlgrenska, Sweden; ¹⁶Portuguese League Against Rheumatic Diseases, Lisbon, Portugal; ¹⁷University College London, London, United Kingdom

Correspondence: L. Kearsley-Fleet

Introduction: It remains unknown whether children and young people with rheumatic and musculoskeletal diseases (RMD) who acquire COVID-19 infection have a more severe COVID-19 course, due to either underlying disease or immunosuppressive treatments.

Objectives: To describe outcomes among children and young people with underlying RMD who acquire COVID-19 infection.

Methods: All children and young people <19 years of age with COVID-19 (presumptive or confirmed) reported to the EULAR COVID-19 Database, which collects details regarding RMD diagnosis and treatment, COVID infection and outcomes, between 27 March 2020 and 9 April 2021 (cut-off date for this analysis) were included. Patient characteristics and COVID-19 outcomes are presented.

Results: A total of 364 children and young people (age range 2-18 years; table) have been reported to the database from 17 countries; mostly France (N=71), Germany (N=71), Czechia (N=59), Spain (N=50), Israel (N=60), and UK (N=25). Most patients had a diagnosis of juvenile idiopathic arthritis (JIA; N=244; 67%). There were 20 (5%) hospitalisations and 1 death reported due to COVID-19. The most commonly reported symptoms were fever (40%) and cough (30%). Only 42 (12%) patients reported glucocorticoid use. Any DMARD therapy was used by 251 (69%) patients; 161 (44%) were on csDMARDs, 119 (33%) on anti-TNF. 40% were in remission at time of COVID-19 infection, 28% in low, and 9% in moderate/high disease activity. Among those with hospitalisation data [N=290], patients on any DMARD therapy (cs/b/tsDMARDs) had similar odds for hospitalisation compared with those not on therapy, adjusted for age, sex, rheumatic disease, and disease severity (odds ratio 1.3; 95% CI 0.3, 4.6).

Conclusion: These initial data on outcomes of COVID-19 infection in paediatric RMDs are very reassuring, only one-in-twenty patients were reported to be hospitalised. Due to the database design and inherent reporting bias, this is likely an overestimate, suggesting that overall outcomes among this population appear to be generally good, with mild infection. Increasing case reports to the database will allow further exploration of drug- and disease-specific outcomes.

Disclosure of Interest

L. Kearsley-Fleet: None declared, S. Lawson-Tovey: None declared, R. Costello: None declared, A. Belot: None declared, F. Aeschlimann: None declared, I. Melki: None declared, I. Kone-Paut: None declared, S. Eulert: None declared, N. Švestková: None declared, Š. Fingerhutová: None declared, D. Clemente: None declared, Y. Berkun: None declared, Y. Uziel: None declared, N. Wulffraat: None declared, B. Raffeiner: None declared, F. Oliveira-Ramos: None declared, C. Dackhammar: None declared, A. Strangfeld: None declared, E. Mateua: None declared, P. Machado: None declared, K. Hyrich Consultant for: Abbvie

Table 1 (abstract O8). See text for description

O9 Benchmark analysis for congruencies and discrepancies of multisystem inflammatory syndrome in children, Kawasaki disease and macrophage activating syndrome due to systemic juvenile idiopathic arthritis

G. Otar Yener¹, A. Paç Kısaarslan ², K. Ulu³, E. Atalay⁴, F. Haşlak⁵, S. Özdel⁶, B. Bozkaya Yücel⁷, D. Gezgin Yıldırım⁸, F. Çakmak⁹, K. Öztürk¹⁰, M. Çakan¹¹, Z. Balık⁴, C. Hasbal¹², M. Yıldız⁵, T. Erat¹³, B. S. Çetin¹⁴, M. Yılmaz¹⁵, E. Bağlan⁶, S. Laçinel Gürlevik¹⁶, V. Atasayan¹⁷, S. G. Karadağ¹⁸, E. D. Batu⁴, A. Adrovic⁵, S. Çağlayan³, A. Tanatar⁹, F. Demirkan⁹, T. Coşkuner³, Ö. Akgün⁹, M. Kasap Cüceoğlu⁴, G. Kavrul Kayaalp⁹, S. Şahin⁵, Ö. Başaran⁴, F. Demir³, K. Barut⁵, D. Gürses¹⁵, A. Baykan¹⁹, Y. Özsürekçi¹⁶, H. E. Sönmez²⁰, Y. Bilginer⁴, N. Aktay Ayaz⁹, Ö. Aydoğ⁷, S. Yüksel²¹, B. Sözeri³, Ö. Kasapçopur⁵, S. Özen⁴

¹Pediatric Rheumatology, Şanlıurfa Research and Training Hospital, Şanlıurfa; ²Pediatric Rheumatology, Erciyes University, Faculty of Medicine, Kayseri; ³Pediatric Rheumatology, University of Health Sciences, Ümraniye Research and Training Hospital, İstanbul; ⁴Pediatric Rheumatology, Hacettepe University, Faculty of Medicine, Ankara; ⁵Pediatric Rheumatology, Istanbul University-Cerrahpaşa, Cerrahpaşa Faculty of Medicine, Istanbul; ⁶Pediatric Rheumatology, University of Health Sciences, Dr. Sami Ulus Maternity and Child Health and Diseases Research and Training Hospital, Ankara; ⁷Pediatric Rheumatology, Ondokuz Mayis University, Faculty of Medicine, Samsun; ⁸Pediatric Rheumatology, Diyarbakır Training and Research Hospital, Diyarbakır; ⁹Pediatric Rheumatology, Istanbul University, Faculty of Medicine; ¹⁰Pediatric Rheumatology, Istanbul Medeniyet University, Göztepe Prof. Dr. Süleyman Yalçın City Hospital; ¹¹Pediatric Rheumatology, University of Health Sciences, Zeynep Kamil Women and Children’s Diseases Training and Research Hospital; ¹²Pediatrics, University of Health Sciences, Ümraniye Research and Training Hospital, Istanbul; ¹³Pediatric Infectious Diseases, Şanlıurfa Research and Training Hospital, Şanlıurfa; ¹⁴Pediatric Infectious Diseases, Erciyes University, Faculty of Medicine, Kayseri; ¹⁵Pediatric Cardiology, Pamukkale University, Faculty of Medicine, Denizli; ¹⁶Pediatric Infectious Diseases, Hacettepe University, Faculty of Medicine, Ankara; ¹⁷Pediatric Cardiology, University of Health Sciences, Ümraniye Research and Training Hospital, Istanbul; ¹⁸Pediatric Rheumatology, Erzurum Regional Research and Training Hospital, Erzurum; ¹⁹Pediatric Cardiology, Erciyes University, Faculty of Medicine, Kayseri; ²⁰Pediatric Rheumatology, Kocaeli University, Faculty of Medicine, Kocaeli; ²¹Pediatric Rheumatology, Pamukkale University, Faculty of Medicine, Denizli, Turkey

Correspondence: G. Otar Yener

Introduction: Fever and certain manifestations are comparable in patients with Multisystem inflammatory syndrome in children (MIS-C) and Kawasaki disease (KD), whereas the cytokine storm reflected in the laboratory findings of patients with MIS-C resemble macrophage activating syndrome (MAS).

Objectives: The aim of the study was to compare the clinical and laboratory findings of multisystem inflammatory syndrome in children (MIS-C) patients with Kawasaki disease (KD) and with macrophage activating syndrome due to systemic juvenile idiopathic arthritis (sJIA-MAS) on real-life data.

Methods: Patients diagnosed with MIS-C, KD, and sJIA-MAS from 12 different centers in Turkey were included in the study.

Results: A total of 154 MIS-C, 59 KD, and 31 sJIA-MAS patients were included in the study. The median age of patients with MIS-C were higher than those with KD while lower than those with sJIA-MAS (p < 0.001). Myalgia, cardiac, gastrointestinal, and neurological involvements were more common in patients with MIS-C compared to others. Arthritis, hepatomegaly and splenomegaly were more common in patients with sJIA-MAS compared to MIS-C. Myocarditis was a distinctive feature in patients with MIS-C (n=39) compared to patients with KD (n=0) and sJIA-MAS (n=4) (p < 0.001). MIS-C patients had lower levels of lymphocyte and thrombocyte counts and higher pro-BNP levels than those with KD. The median level of CRP was higher in patients with MIS-C but ferritin levels were higher in patients with sJIA-MAS. However, patients with MIS-C had higher levels of ferritin compared to patients with KD. Patients with MIS-C had a shorter duration of hospitalization than sJIA-MAS while they required intensive care unit admission more frequently due to myocarditis.

Conclusion: MIS-C patients displayed certain differences in clinical and laboratory features when compared to KD and MAS due to sJIA. Correct diagnosis with a multidisciplinary approach and appropriate management will suppress systemic inflammation and may prevent morbidity and mortality in MIS-C patients.

Disclosure of Interest

None declared

O10 SARS-COV2 antibody phenotype and immune gene expression in MIS-C

K. Webb^1,2, T. Moyo-Gwete^3,4, S. C. Mendelsohn⁵, C. Butters¹, S. Richardson^3,4, H. Facey-Thomas¹, D. Abrahams¹, M. Madzivhandila^3,4, Z. Makhado^3,4, N. Manamela^3,4, F. Ayres^3,4, R. Baguma⁵, S. Kimbung Mbandi⁵, M. Erasmus⁵, L. Zühlke⁶, T. J. Scriba⁵, P. L. Moore^3,4,7, G. Kassiotis², C. Scott¹

¹Paediatric Rheumatology, University of Cape Town, Cape Town, South Africa; ²Retroviral Immunology, Francis Crick Institute, London, United Kingdom, ³National Institute for Communicable Diseases; ⁴Antibody Immunity Research Unit, University of the Witwatersrand, Johannesburg; ⁵South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine; ⁶Paediatric Cardiology, University of Cape Town, Cape Town; ⁷Centre for the AIDS Programme of Research in South Africa (CAPRISA), Durban, South Africa

Correspondence: K. Webb

Introduction: Multisystem Inflammatory Syndrome in Children (MIS-C) is a severe disease that affects a small proportion of children exposed to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Differences in SARS-CoV-2 antibody responses and immune gene expression between SARS-CoV-2-infected children who develop MIS-C and those who do not may provide insight into the mechanism of MIS-C.

Objectives: To determine the difference in SARS-CoV2 antibody responses and immune gene expression in children with MIS-C and healthy children with evidence of previous SARS-CoV2 infection.

Methods: Healthy children presenting for elective surgery and those with MIS-C were recruited between 22 June 2020 and 5 November 2020 from a single paediatric hospital during the first wave of SARS-CoV-2 in the region. Clinical data, whole blood RNA and serum were collected. Titres of SARS-CoV-2 spike-specific antibody (SAb) and their capacity to perform neutralization, antibody-dependent cellular phagocytosis (ADCP) and antibody dependant cellular cytotoxicity (ADCC) were measured. Whole blood RNA gene expression was measured using multiplex Fluidigm quantitative Polymerase Chain Reaction (qPCR) with a panel of 84 immune genes. Principal component analysis was performed to assess for differences in gene expression. A linear regression model was developed with a forward stepwise model selection method to assess which genes associated with C-reactive protein (CRP) in MIS-C after controlling for the neutrophil to lymphocyte ratio (NLR).

Results: Twenty-three children with MIS-C and 25 healthy children were recruited. Nine healthy children had detectable SARS-CoV-2 serum antibodies (healthy exposed). No children had preceding clinical disease related to SARS-CoV-2 infection. Comparing children with MIS-C and healthy exposed children showed no difference in SAb binding responses (p=0.372) or ADCC (p=0.992). Increased neutralisation titre (p=0.084) and ADCP (p=0.086) in children with MIS-C was observed although was non-significant. Antibody function or titre did not change over time or with treatment in MIS-C. There was a clear distinction in immune gene expression between healthy children and those with MIS-C. Immune gene expression in MIS-C resolved to become indistinct from healthy children with time. Whole blood immune gene expression associated with an abundance of neutrophils in MIS-C. In a model that accounted for 66% of the variance in CRP (adjusted R² = 0.66) the expression of IL27 accounted for 64% of the model effect (B=35; p<0.001) followed by NLR (15%, B=6.6, p=0.002) and the expression of MCP2 (11%, B=-14.59, p=0.008).

Conclusion: Comparing children infected with SARS-COV-2 from the same time period and region with or without MIS-C provides unique mechanistic insight into the disease. A trend towards higher SAb titres and ADCP implies a distinct humoral immune response to SARS-COV-2 in children with MIS-C, although further studies are required to validate this observation. The resolution of the abnormal immune gene expression in MIS-C implies a monophasic immune perturbation. The association of IL27 and MCP2 with CRP suggests that these may be important targets in future studies for possible pathogenicity and as potential biomarkers in MIS-C.

Patient Consent Received

Yes

Disclosure of Interest

None declared

O11 22Q11.2 deletion (DI George) syndrome and chronic arthritis. An international case series of 21 cases

C. Freychet¹, T. Giani², M. Jelusic³, B. Bader Meunier¹, J. L. Stephan⁴, I. Lemelle⁵, D. Montin⁶, L. Mc Cann⁷, D. McDonald-McGinn⁸, T. B. Crowley⁹, R. Cimaz¹⁰, E. Liebling⁹

¹Department of Immunology, hematology and rheumatology, Necker-Enfants Malades university hospital, Paris, France; ²Department of Medical Biotechnology, University of Siena, Siena, Italy; ³Department of Paediatrics, University of Zagreb School of Medicine, Zagreb, Croatia; ⁴Department of Paediatrics, University Hospital, Saint-Etienne; ⁵Department of Pediatric Hemato-Oncology, University hospital of Nancy, Nancy, France; ⁶Department of Public Health Sciences and Pediatrics, University of Torino, Torino, Italy; ⁷Alderhey Children’s NHS Foundation Trust, Liverpool, United Kingdom; ⁸Perelman School of Medicine, University of Pennsylvania; ⁹The Children's Hospital of Philadelphia, Philadelphia, United States; ¹⁰Department of Clinical Sciences and Community Health, University of Milano, Milano, Italy

Correspondence: R. Cimaz

Introduction: 22q11.2 deletion syndrome (22q11.2 DS), the most common cause of Di George syndrome, is associated with autoimmunity in approximately 10% of cases. Arthritis can be chronic but its characteristics and treatment tolerance are not well known.

Objectives: We describe the first international series of such patients.

Methods: We gathered retrospectively 21 patients from 7 centers. Demographic, laboratory, and clinical data focused on arthritis were collected and entered into a dedicated database.

Results:Of the 21 patients, 13 were females. Family history of Di George syndrome was present in 3 cases. Dysmorphic features were recorded in all patients, developmental delay in 19/21, cardiac defects in 17/21, palatal abnormalities in 15/21, skeletal abnormalities in 13/21, hypoparathyroidism in 8/21, ophtalmologic abnormalities in 7/21, hypoplastic thymus in 5/21. Associated autoimmunity (except arthritis) was present in 5/21 (ITP, celiac disease, psoriasis, Evans syndrome, Hashimoto: 1 case each). T and B cell numbers were within normal limits in all but one patient.

Mean age at diagnosis of arthritis was 4.9 years, with a mean number of seven involved joints at onset. Most patients (n=18) had knee involvement, followed by ankle (n=15), MCP/IP (n=11), wrist (n=10), elbow (n=5), hip (n=2). Synovial fluid analysis, when performed, was uninformative. Uveitis was never noted during the disease course. ANA was positive in 15/21 cases, while RF was never detected. An increase of inflammatory markers was detected in 15 cases for ESR and 12 for CRP. Treatment received included systemic glucocorticoids in 10 cases, intraarticular joint injections in 13, DMARDs in 14 (mostly methotrexate), and biologics 12 (Etanercept 10, Adalimumab 2, Abatacept 3, Rituximab 1). Prior to immunosuppression, infections were noted in 12 cases, 5 requiring admission. Of note, following immunosuppression infections were recorded in only two patients (one required no admission, the second was admitted for severe Evans syndrome and MAS requiring intensive immunosuppression complicated by disseminated aspergillosis and subsequently died). No patient developed neoplasia.

At last follow-up visit (mean age 13 years), arthritis was active in 9 cases, in partial remission in 2, in remission on medication in 8, and in remission off medication in only 2. Median number of active joints was 3, ESR was increased 7/12, CRP in 2/12. Eight patients had articular damage, and erosions were noted in four.

Conclusion: 22q11.2 DS can be associated with chronic arthritis, which is often polyarticular and progressive. Other autoimmune disorders are common in this series. DMARDS and biologics are possible treatment options, and in our series we did not observe more infections after the beginning of immunosuppression for arthritis.

Disclosure of Interest

None declared

O12 Clonally expanded peripheral t helper cells with distinct tcr vβ repertoire characterize synovial inflammation in children with antibiotic-refractory Lyme arthritis

J. Dirks¹, J. Klaussner¹, A. Almamy¹, J. Fischer¹, G. Haase¹, U. Fischer¹, A. Holl-Wieden², C. Hofmann², H. Girschick³, H. Morbach^1,2

¹Pediatric Immunology; ²Pediatric Rheumatology and Osteology, University Hospital Julius-Maximilians University Würzburg, Würzburg; ³Children's Hospital, Vivantes Klinikum im Friedrichshain, Berlin, Germany

Correspondence: J. Dirks

Introduction: Antibiotic-refractory Lyme arthritis (ARLA) is defined by persistent arthritis after sufficient antibiotic treatment of acute Lyme arthritis and is seen in approximately 10 % of patients with Lyme arthritis. Although some clinical and genetic risk markers for ARLA have been elucidated, the disease pathogenesis is still inadequately understood. In detail, whether chronic inflammation is sustained by persistent borrelial antigens or triggered by autoantigens is not elucidated yet.

Objectives: Identifying the cellular correlate of ongoing immune responses in the inflamed joints of children with ARLA to elucidate antigen targets and disease specific pathomechanisms.

Methods: Flow cytometric analysis of T and B cell populations in synovial fluid (SF) samples of children with ARLA and juvenile idiopathic arthritis (JIA). High-throughput sequencing of the T cell receptor β (TCR Vβ) repertoire of SF T cells and single cell immunoglobulin expression cloning of SF B cells in children with ARLA and JIA.

Results: Multidimensional flow-cytometric analysis revealed a striking expansion of an IL-21 and IFN-γ co-expressing PD-1^hiCXCR5^-HLA-DR⁺ CD4⁺ T cell population resembling peripheral T helper (T_PH) cells in the joints of pediatric ARLA patients compared to JIA patients. Indeed, ARLA patients display the highest frequencies of T_PH cells, which could separate this group of patients from JIA. Accumulating T_PH cells exhibited signs of clonal expansion with restricted TCR clonotypes. Those clonotypes showed an overlap between different ARLA patients but not to JIA patients. Furthermore, distinct molecular patterns within the TCR Vβ repertoires diverged in ARLA and JIA patients. Paralleling the observations made in the T cell compartment, accumulating SF B cells showed oligoclonal expansion and almost exclusively displayed the phenotype of CD21^lo/-CD11c⁺ double-negative (DN) B cells.

Conclusion: The inflamed joints of children with ARLA are characterized by a striking expansion of oligoclonal T_PH cells and DN B cells. The distinct features of the TCR Vβ repertoire of T_PH from ARLA patients suggest that disease specific immune response may sustain chronic inflammation in ARLA. Having defined the cellular subsets of an ongoing immune response in the joints of children with ARLA, current experiments are ongoing to dissect whether this maladaptive immune response targets persisting Borrelial antigens or rather autoantigens.

Disclosure of Interest

None declared

Lightning talks: JIA (oligo, poly, psoriatic), Imaging, Psycho-social aspects and rehabilitation

O13 Can musculoskeletal ultrasound and serum biomarkers predict disease flare in JIA patients in clinical remission?

M. Mazzoni¹, S. Merlo², C. Morreale³, A. Pistorio⁴, S. Viola³, F. Magnaguagno⁵, A. Corcione⁶, P. Bocca⁶, M. Gattorno⁷, A. Consolaro³, A. Ravelli³, C. Malattia^2,3

¹Dipartimento di Neuroscienze, Riabilitazione, Oftalmologia, Genetica e Scienze Materno-Infantili, Università degli Studi di Genova, Genova; ²Dipartimento di Neuroscienze, Riabilitazione, Oftalmologia, Genetica e Scienze Materno-Infantili, Università degli Studi di Genova; ³Clinica Pediatrica e Reumatologia; ⁴Epidemiologia e Biostatistica; ⁵Radiologia; ⁶Centro Malattie Autoinfiammatorie e Immunodeficienze; ⁷Clinica Pediatrica e Reumatologia - Centro Malattie Autoinfiammatorie e Immunodeficienze, IRCCS Istituto Giannina Gaslini, Genoa, Italy

Correspondence: M. Mazzoni

Introduction: Clinical remission (CR) is regarded as the ideal therapeutic target in JIA because its achievement helps to prevent physical disability. Recently the question has been raised whether current measures used to define CR truly reflect the absence of synovial inflammation. In fact, musculoskeletal ultrasound (MSUS) studies have demonstrated subclinical synovitis in a sizeable proportion of JIA patients despite “clinical inactive disease”. In addition, serum biomarkers such as S100A12 and MRP8/14 may identify patients with unstable remission and increased risk of relapse.

Objectives: 1) to investigate the prevalence of MSUS-detected subclinical synovitis in JIA patients in CR; 2) to evaluate the persistence of subclinical synovitis over the time; 4) to investigate whether subclinical synovitis predicts disease flare and whether it should affect the therapeutic strategy; 5) to integrate MSUS data with serum biomarkers to develop a multidimensional measure of remission status.

Methods: 135 consecutive JIA patients who met the Wallace criteria for CR were included in this 3-years prospective study. All patients underwent MSUS assessment of 56 joints at study entry and at 6 months follow-up visit. Joints were scanned for synovial hyperplasia, joint effusion and Power Doppler (PD) signal by two independent ultrasonographers. At inclusion serum levels of the following cytokines were determined with cytofluorometry: ILR-1, G-CSF, GM-CSF, IL-6, IL-10, IL-12, CXCL9, CXCL10, MIP-1α, TNFRI, TNFRII, RANTES, VEGF. Patients were followed clinically for 3 years. A flare of synovitis was defined as a recurrence of clinically active arthritis that required a major therapeutic intervention. The association between clinical and MSUS variables with flare, was evaluated by adjusted logistic regression models.

Results: 135 patients (78.5% F; median age 11.3 y; median disease duration 5.7 y; median CR duration 1.4 y) were included. Seventy-eight/135 (57.7%) patients were in CR on medication. Subclinical synovitis was detected in 82/135 (60.7%) patients. Subclinical tenosynovitis was present in 20/135 (14.8%) patients. 58.6% of patients showed persistent subclinical synovitis at 6 month follow up MSUS examination. During the 3-year follow up 45/135 (33.3%) patients experienced a disease flare (median survival time 2.2 y). PD positivity in tendons was the strongest independent risk factor of flare on multivariable regression analysis (HR: 4.8; P=0.04). Other predictors of flare were the JIA subtype (oligo-extended form: HR: 2.3; P=0.031) and the status of CR on medication (HR: 3.7; P=0.002). Serum levels of G-CSF, TNFRII and CXCL10 significant differed between patients and healthy controls (P=0.010; P=0.025; P<0.0001, respectively). However serum cytokine levels were not associated with disease relapse.

Conclusion: our results confirm that MSUS is more sensitive than clinical evaluation in the assessment of persistent synovial inflammation in JIA patients in CR. Subclinical tenosynovitis was the best predictor of disease flare, with important therapeutic implications. To date, the role of tenosynovitis in the diagnosis and prognosis of JIA has been poorly investigated. Our results further support the role of MSUS in monitoring JIA patients in CR and to identify patients with higher risk of disease flare.

Disclosure of Interest

None declared

O14 Determinants of physician global assessment in juvenile idiopathic arthritis patients without active joints

A. Alongi¹, G. Giancane², N. Ruperto², A. Consolaro², A. Ravelli²

¹ARNAS Civico, Palermo; ²Giannina Gaslini Institute, Genoa, Italy

Correspondence: A. Alongi

Introduction: Physician global assessment (PGA) is an essential outcome measure in Juvenile Idiopathic Arthritis (JIA), used alone or as part of composite scores and criteria for inactive disease (ID) to summarize providers’ appraisal of disease activity. Some evidence suggests a lack of standardization of PGA, demonstrated by a tendency among physicians to assign values above zero despite no apparent signs of active disease, and little attention to the impact of factors contributing to PGA scoring.

Objectives: To identify the determinants of the PGA in patients with JIA without active joints, and to evaluate the relative importance of their contributions to PGA.

Methods: 7265 complete visit records from two multinational (the EtICA study, n = 422, and the EPOCA study, n = 9081) and one national (the Gaslini dataset, n = 669) cross-sectional cohorts were examined. Rheumatologic assessment data included active (AJC), painful (PJC), limited (LJC) and swollen joint counts. Patients with AJC = 0 were selected for the analysis. PGA was measured with a 21-numbered circle VAS (0 = best; 10 = worse) and dichotomized as equal to or above zero. Presence of pain in axial (TMJ, sacroiliac and spinal joints), large (shoulders and hips), medium (elbows, wrists, knees, foot-ankles) and small (distal interphalangeal, proximal interphalangeal, metacarpophalangeal and metatarsophalangeal) joints was coded as a dummy variable for each pattern. Multivariate logistic regression models were fitted to explain the probability of a PGA > 0 in patients without active joints, based on erythrocyte sedimentation rate (ESR) values, systemic features, active uveitis, morning stiffness, axial, large, medium, and small painful joints, VAS-measured overall pain, total PJC, LJC and ILAR category. We used dominance analysis to compare the relative importance of predictors.

Results: Among 7265 patients, 4108 (56.5%) had negative AJC; within this subgroup, PGA was marked above zero in 32.4% (median 0, IQR 0.0 - 0.5). In 14.2% PGA was the only not-met criteria for ID among the ACR 2011 set, making it the single most frequent reason for not reaching ID. ESR, systemic features, uveitis, stiffness, large joint pain, axial joint pain, overall pain, PJC, LJC and ILAR subtype were independent predictors of a PGA > 0. Large joint pain showed the highest impact on PGA (OR=9.18; CI 2.35 - 61.05, p 0.005), followed by axial joint pain (OR=6.39; CI 2.11 - 23.84, p 0.002), systemic features (OR=3.70; CI 1.75 - 8.26, p<0.001), uveitis (OR=3.77; CI 2.49 - 5.70, p<0.001), PJC (OR=2.78; CI 1.68 - 5.04, p<0.001). ERA patients showed higher odds of PGA > 0 (OR=1.42; CI 1.03 - 1.95, p 0.032), while oligoarthritis was associated with lower odds (OR=0.75; CI 0.58 - 0.97, p 0.028). The model’s explanatory power was substantial (R_M² = 0.27). As shown in the table, dominance analysis revealed pain in the large joints as the most important variable to explain PGA variability (average R_M² 0.073), followed by PJC (0.051) and axial joints pain (0.050).

Conclusion: A substantial proportion of patients received a PGA above zero despite the absence of active joints. Large and axial joint pain, uveitis, systemic features and PJC were the main determinants of PGA. Painful joint patterns and PJC accounted for most of the variability in PGA scoring. Further research is needed to investigate factors driving PGA and their impact on classification and response assessment in JIA.

Disclosure of Interest

None declared

Table 1 (abstract O14). See text for description

O15 Assessing the causal role of the human gut microbiome on JIA risk: a mendelian randomisation study

S. L. Clarke^1,2,3, D. A. Hughes^1,3, G. C. Sharp^1,3, A. V. Ramanan^2,4, C. L. Relton^1,3, K. H. Wade^1,3

¹MRC Integrative Epidemiology Unit, University of Bristol; ²Department of Paediatric Rheumatology, Bristol Royal Hospital For Children; ³Population Health Sciences; ⁴Translational Health Sciences, University of Bristol, Bristol, United Kingdom

Correspondence: S. L. Clarke

Introduction: There is growing interest in the role of the microbiome in human health and increasing evidence of associations between components of the human gut microbiome and juvenile idiopathic arthritis (JIA). However, few findings have been replicated across studies, and robust evidence of a causal association is lacking. Most microbiomic studies are of cross-sectional or case-control design and are thus subject to confounding, reverse causation, and other biases. An alternative approach to examine the association between the human gut microbiome and JIA is using Mendelian Randomisation (MR), a method of causal inference which has recently been applied in the context of microbiome research. The reliance of MR on human genetic variation, assigned at the point of conception, makes it less susceptible to reverse causation and confounding, provided key assumptions are met.

Objectives: To use MR to examine the evidence for a causal association between the human gut microbiome, as measured by faecal samples, and JIA risk.

Methods: Genetic variants strongly associated with human faecal microbial taxa have recently been reported in a genome wide association study (GWAS) meta-analysis of three European cohorts (sample size 3,890), using a presence/absence and/or an abundance model. We combined this data with summary data from the most recent JIA GWAS (sample size 12,501) to examine the causal effect of 13 microbial taxa on JIA risk. We also examined this association in reverse (i.e. whether JIA has a causal effect on microbial taxa) using genetic variants associated with JIA from an Immunochip study (sample size 15,872) and summary data from the Flemish Gut Flora Project (sample size 2,223). We undertook these analyses using the MR-Base platform. Additional sensitivity analyses were performed to assess the robustness of the MR estimates and identify potential violations of the core MR assumptions.

Results: Of the 13 microbial taxa examined, we found strong evidence for a causal effect of a higher abundance of bacteria within the Firmicutes phylum on JIA risk (OR 1.75, 95% CI 1.12-2.72 per standard deviation (SD) higher abundance). This finding is supported by weaker evidence of a causal effect of two further taxa on JIA risk; the presence of bacteria within the Firmicutes phylum (OR 1.15, 95% CI 0.99-1.34 per doubling in genetic liability to bacteria within the Firmicutes phylum) and a higher abundance of bacteria within the Butyricicoccus genus (OR 1.50, 95% CI 0.94-2.38 per SD higher abundance). We found no evidence of a causal association in reverse; increased genetic liability to JIA was not causally associated with alterations in these microbial taxa. There was no strong evidence that there were violations of the core MR assumptions.

Conclusion: Whilst our findings are inconsistent with much of the observational human literature (which suggests an inverse association between JIA and Firmicutes bacteria), these cross-sectional and case-control studies may reflect a post-disease or treatment-related association. Accordingly, current murine data suggests that arthritis is preceded by an increase in Firmicutes bacteria during the pre-clinical disease phase, as is found in our study. Further work to explore these putative causal relationships and to understand the dynamics of the microbiomic composition in disease is warranted.

Patient Consent Received

No

Disclosure of Interest

None declared

O16 Twenty years experience with etanercept in treatment of juvenile idiopathic arthritis

A. Klein^1,2, D. Windschall³, A. Hospach⁴, K. Minden⁵, F. Weller-Heinemann⁶, F. Dressler⁷, G. Horneff⁸, on behalf of BIKER

¹Pediatric rheumatology, Asklepios Klinik Sankt Augustin, Sankt Augustin; ²Universitiy Cologne, Cologne; ³Pediatric rheumatology, St. Josef Stift, Sendenhorst; ⁴Olga Hospital, Stuttgart; ⁵Charité Universitätsmedizin, Berlin; ⁶Prof Hess Kinderklinik, Bremen; ⁷Medizinische Hochschule Hannover, Hannover; ⁸Asklepios Klinik Sankt Augustin, Sankt Augustin, Germany

Correspondence: A. Klein

Introduction: Etanercept (ETA) is the most commonly prescribed biologic for treatment off juvenile idiopathic arthritis (JIA). The German biologics in JIA register - BIKER monitors long-term safety and effectiveness of ETA in the treatment of JIA in routine clinical practice.

Objectives: To assess long-term safety and tolerability of ETA treatment in a large cohort of JIA patients in comparison to a biologic-naïve cohort treated with methotrexate (MTX). To assess effectiveness of ETA treatment and reasons for discontinuation.

Methods: Patient assessment was performed at baseline, after 3 and 6 months, and every 6 months thereafter. Baseline demographics and disease activity parameters have been documented. Efficacy was determined using the JADAS10. Safety assessments were based on adverse events reports (AE) processed according to MedDRA

Results: Altogether, 2885 JIA patients covering 6560.3 patient years (PY) of exposure to ETA for up to eight years of continuous treatment, and 1517 biologic-naïve patients accumulating 3893.6 PY of exposure to MTX were enrolled.

A higher percentage of patients in the ETA cohort had a polyarticular course (extended oligoarthritis [20.9%], RF-negative- [33.2%] and positive [8.1%] polyarthritis) than the MTX cohort (13.5%, 27.3%, and 3.4%). Mean age at treatment start and disease duration was higher in the ETA cohort (12.1 +/- 4.4 years; 4.1 +/- 3.7 years) compared to the MTX cohort (9.8 +/-4.8 years; 2.1 +/- 2.8 years). In all, 2531 AEs were reported during ETA exposure or up to 90 days of follow-up (38.5/100 PY [95% CI 37.1-40.1]). In the MTX cohort, 1354 AEs were reported (34 /100 PY [95% CI 32.9-36.6]). More SAEs (RR=2.88, 95% CI 2.12-3.9) and serious infections (RR=4.8, 95% CI 2.2-10.6) were observed in the ETA cohort. Also, more patients experienced herpes zoster reactivation (RR=3.7, 95% CI 1.3-10.6; 0.8% versus 0.3%, p=0.027) and inflammatory bowel disease (RR=13.6, 95% CI 1.8-10.1; 0.8% versus 0.07%; p=0.0008). There was no statistical difference in the rates of malignancies in patients ever exposed to ETA or MTX. During treatment, a marked clinical response was documented with JIA-ACR 30/50/70/90 scores in 68%/61%/48%/34%. JADAS minimal disease activity/JADAS remission was achieved in 60%/38% at last follow-up on ETA. Reasons for discontinuation of ETA were remission in 40% of patients, inadequate efficacy in 35% and intolerance in 12% of all discontinuations

Conclusion: This registry cohort represents the largest cohort of ETA-treated JIA patients studied. A rapid improvement upon ETA treatment was observed and could be maintained up to eight years of continuous drug use. More AEs, SAE and serious infections were observed in the ETA cohort. In all, paediatric patients demonstrated a safety profile consistent with observations in adults. he benefit-risk profile of ETA remains unchanged for the approved paediatric Tindication JIA.

Patient Consent Received

No

Disclosure of Interest

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Table 1 (abstract O16). Patient characteristics, adverse events and JADAS at baseline and last follow-up in ETAt and MTX cohort

O17 Innovative methods for biomarker discovery in oligoarticular juvenile idiopathic arthritis

F. Raggi¹, C. Rossi¹, S. Pelassa¹, 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 Giannina Gaslini, Genova; ⁵Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milano; ⁶University of Genova, Genova, Italy

Correspondence: F. Raggi

Introduction: New biomarkers for early prediction of disease progression are demanded for the management of Oligoarticular Juvenile Idiopathic Arthritis (OJIA), the most common chronic pediatric rheumatic arthritis in Western countries. Since cells causing inflammation and tissue-destructive effects release extracellular vesicles (EV) both in plasma and synovial fluid of the inflamed joints, the characterization of EV content at disease onset may be valuable for the identification of early predictive biomarkers.

Objectives: This study was aimed at identifying new candidate biomarkers able to predict disease progression and response to treatment. We developed an integrated strategy that combines classical approaches for the study of inflammatory cells in liquid biopsies and system biology–driven omics methods (miRNomic, proteomic) for the analysis of EV released by these cells

Methods: 30 OJIA patients were enrolled in the study at disease onset and followed up for 12 months after diagnosis and initiation of therapy. EV miRNA (EV-miR) and EV-protein (EV-Prot) expression profiling were carried out in PL and SF samples using TaqMan Array RT-PCR and mass spectrometry. PL from 25 age-matched healthy children was used as control. Macrophages and T cells from 10 patients of the same cohort were isolated from SF aspirates and characterized by cytofluorimetry using Kaluza software

Results: Principal Component Analysis showed a separation among different biological groups on the basis of Exo-miR expression profiles. Differential expression analysis identified 16 and 34 EV-miRs significantly up- and down-regulated, respectively, in SF vs both paired and control PL. Pathway analysis of these EV-miRs identified significantly enriched processes related to inflammatory responses, cartilage/bone homeostasis, and hypoxia, including TNF, NF-kappa B, mTOR, JAK-STAT, cytokine, chemokine, TGFb, HIF-1, and VEGF signaling pathways. Macrophage and T cell derivation of these EV-miR was suggested by in vitro experiments with mononuclear cells cultured for 48h. Five candidate miRNAs with differential expression were validated by qRT-PCR and selected as disease-specific, suggesting their implication in inflammatory condition at both local and systemic level. Unsupervised K-means Clustering analysis identified a few of these EV-miRs as able to discriminate subgroups of patients within the OJIA cohort, suggesting their potential predictive value. EV-Prot analysis demonstrated mean expression of about 1000 protein in both SF and PL samples, with a specific representativeness of the tissue of origin. Proteins with potential to modulate inflammatory and immunological processes were identified. The potential correlation between EV-miR and EV-Prot expression levels and patient clinical data is under study. The analysis of SF cells revealed different ratio of M1/M2 macrophages expressing the immunostimolatory hypoxic receptor TREM1 and activated CD4/CD8 T cells among outcome groups

Conclusion: We provide the first database containing EV-miR, EV-Prot, and cell phenotypic data of new-onset OJIA patients. The predictive value of these results could be instrumental for a better understanding of disease molecular pathogenetic mechanisms and the definition of novel early candidate diagnostic biomarkers with potential for the development of personalized therapeutic strategy

Patient Consent Received

Yes

Disclosure of Interest

None declared

O18

Withdrawn

Lightning talks: Systemic lupus erythematosus and antiphospholipid syndrome

O19 Disease-causing gene variants account for a minimum OF 5.5% OF juvenile-onset sle patients in the UK

A. Charras¹, S. Haldenby², E. M. D. Smith³, C. Roberts¹, M. W. Beresford³, C. M. Hedrich¹, on behalf of the UK JSLE Cohort Study

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

Correspondence: A. Charras

Introduction: Systemic Lupus Erythematosus (SLE) is a complex autoimmune/inflammatory disease. Juvenile-onset (j)SLE affects 15-20% of lupus patients and is characterized by increased organ involvement and damage, and higher need for immune suppressive treatment. Clinical heterogeneity between ethnicities, age groups and individual patients suggest variable pathophysiology.

Objectives: This study aimed at the definition of patient sub-cohorts with “genetic” vs. “classical” SLE to allow individualized care.

Methods: Applying target enrichment and new generation sequencing, jSLE patients (N=348) from the UK JSLE Cohort Study were screened for disease-causing mutations. Findings were integrated with demographic information and clinical datasets, including SLEDAI, pBILAG organ domain and SLICC damage scores.

Results: Approximately 5.5% of jSLE patients carried disease-causing mutations, primarily affecting nucleic acid sensing and metabolism (68%), immune complex clearance (11%), their combination (11%), immune cell signalling (5%) and NFκB signalling (5%). Patients with “genetic SLE” were younger, and exhibited less organ involvement and damage at diagnosis (neuropsychiatric, haematological, gastrointestinal), while neuropsychiatric involvement developed over time. When compared to the remaining cohort, “genetic SLE” associated with anti-dsDNA antibody positivity at diagnosis, and reduced ANA, anti-LA and anti-Sm antibody positivity at last visit which may explain reduced renal and haematological involvement.

Conclusion: Genetic disease accounts for ≥5.5% of jSLE cases. It associates with peri-pubertal onset, and distinct immunological and clinical pictures. As less commonly present after treatment induction, in “genetic SLE”, autoantibodies may be the result of tissue damage. Routine sequencing will allow for patient stratification, risk assessment, and target-directed treatment with reduced toxicity and increased efficacy.

Patient Consent Received

Yes

Disclosure of Interest

None declared

O20 Induction therapy for pediatric onset lupus nephritis : mycophenolate mofetil versus cyclophosphamide

M. Chbihi¹, L.-A. Eveillard², Q. Riller³, N. Garcelon⁴, O. Boyer², B. Bader-Meunier¹

¹Immunology, Hematology and Rheumatology; ²Nephrology, Necker Hospital for Sick Children; ³INSERM UMR1163, immunogenetics of Pediatric Autoimmune Diseases; ⁴Data Science Platform, Imagine Institute, Paris, France

Correspondence: M. Chbihi

Introduction: Class IV lupus nephritis (LN) is one of the most severe involvements in systemic lupus erythematosus and is particularly frequent in case of pediatric onset. The gold standard induction treatment consists of intravenous (IV) pulses of Cyclophosphamide (CYC) in association with corticosteroids. It has considerably improved the renal prognosis but has potential short and long-term toxic effects. Recent studies in adults have shown similar efficacy of oral Mycophenolate Mofetil (MMF) as induction therapy with a lower toxicity. However, the pediatric literature is scarce and current treatment guidelines are extrapolated from the adult population.

Objectives: The aim of the study was to compare the efficacy and tolerance of CYC and MMF as induction treatment of a first episode of class IV LN in children.

Methods: We conducted a monocentric retrospective study including all consecutive children (<18 years) with at least 4 American college of rhumatology criteria for lupus, and biopsy-proven class IV LN according to the IRS/RPS classification, and who had not received any prior immunosuppressive treatment.

Results: Among the 33 patients, 17 had been treated with oral MMF (51%) and 16 with IV CYC. The basic characteristics were similar in both groups except for more neurological involvement in the CYC group (6/17 vs. 0/16). There was a non-significant trend for more severity in the CYC group with higher grade proteinuria, lower albuminuria, and more frequent acute kidney injury. At one year, 53% of the patients from the MMF group and 77% from the CYC group had achieved remission (p=0.25). 59% of the patients from the MMF group had relapsed, versus 50% of patients from the CYC group (p=0.87), respectively at 3.4 years and 4.7 years after beginning of treatment (p=0.41). The severe and mild complication rates were not significantly different between the two groups.

Conclusion: In conclusion, we found no difference in the kidney outcome and side effects in children receiving either MMF or CYC as induction therapy of class IV LN. However, in this retrospective study, no patient from the MMF group had neurological involvement, and there was a trend for more severity in the CYC group. Further studies are needed to confirm these results with stratification of children by disease severity.

Disclosure of Interest

None declared

O21 Treatment of juvenile-onset systemic lupus erythematosus – “real world” data from the UK JSLE cohort study

N. Egbivwie^1,2, A. L. Jorgensen³, M. W. Beresford^1,2, C. M. Hedrich^1,2, E. M. D. Smith^1,2, on behalf of UK JSLE Study group

¹Department of Women’s and Children’s Health, Institute of Life Course and Medical Sciences, University of Liverpool; ²Department of Paediatric Rheumatology, Alder Hey Children’s NHS Foundation Trust, ³Department of Biostatistics, University of Liverpool, Liverpool, United Kingdom

Correspondence: N. Egbivwie

Introduction: In the absence of paediatric clinical trials, treatment and care plans vary significantly in Juvenile-onset systemic lupus erythematosus (JSLE). Aiming at harmonized treatment and collection of response data, collaborative efforts from leading experts delivered consensus treatment plans (Childhood Arthritis and Rheumatology Research Alliance) and recommendations (Single Hub and Access point for paediatric Rheumatology in Europe)[1, 2].

Objectives: The study explored how clinical manifestations impact on choice and sequence of immunosuppressants used for the treatment of JSLE.

Methods: ‘Real world’ treatment data from the UK JSLE Cohort Study (01/2010-05/2020) was accessed. The choice and sequence of immunomodulating drugs used in clinical management of JSLE (1^st, 2^nd and 3^rd-line) was explored from diagnosis to last visit. Paediatric British Isles Lupus Assessment Grade (pBILAG) organ domain disease activity scores were used to explore how different clinical manifestations guide treatment choice. Logistic regression was used to determine how treatment choice associated with organ domains.

Results: 349 patients were included with 290 females (83%). Data from 3266 visits were assessed (median: 9 visits/patient IQR=9), median age at diagnosis was 13 (IQR=4) and median follow up was 4 years (IQR=4). Immunomodulating treatments in addition to hydroxychloroquine (HCQ) and/or corticosteroids were considered. To capture the sequence of immunosuppressants used from diagnosis, this analysis focused on 197/349 patients diagnosed within the study dates. Overall, 10/197 (5%) were treated solely with HCQ, 73/197 (37%) received a single immunomodulator, 75/197 (38%) received two and 40/197 patients (20%) received three or more during follow-up. The most common 1^st-line immunomodulating treatment was mycophenolate mofetil (MMF) (72/197, 37%) followed by azathioprine (56/197, 28%) and methotrexate (43/197, 22%). MMF was the most common 2^nd-line treatment (40/197, 20%) followed by rituximab (RTX) (23/197, 12%). RTX was the most commonly chosen 3^rd-line treatment (15/197, 8%).

Across most organ domains, MMF was the most common treatment (except for gastrointestinal and ophthalmic). Patients with renal disease were most likely to receive MMF (OR 1.99 95% CI: 1.65-2.41; p=0.004). Treatment with RTX was significantly more likely in patients with neuropsychiatric (OR 1.84 95% CI: 1.05-3.21), renal (OR 1.50 95% CI: 1.12-2.00) and cardiorespiratory disease (OR 2.57 95% CI: 1.40-4.74) compared to patients with other organ involvement (p<0.05). Patients with neuropsychiatric (OR 3.10 95% CI: 1.80-5.33), renal (OR 1.61 95% CI: 1.16-2.23), cardiorespiratory (OR 5.05 95% CI: 2.82-9.04), haematological (OR 2.82 95% CI: 1.92-4.16) and mucocutaneous (OR 1.95 95% CI: 1.39-2.74) involvement were more likely to receive cyclophosphamide (CPM) compared to patients with other organ involvements (p<0.01).

Conclusion: Most patients were treated with two immunomodulators in addition to HCQ and/or corticosteroids. Notably, MMF was the most common immunomodulator, with RTX and CPM used in more resistant disease, particular for renal, neuropsychiatric and cardiorespiratory involvement. Observations will inform subsequent treat to target study algorithms as part of the TARGET LUPUS research programme.

1 Mina R, von Scheven E, Ardoin SP et al. Consensus treatment plans for induction therapy of newly diagnosed proliferative LN in JSLE. Arthritis Care Res 2012;64(3):375-83

2 Groot N, de Graeff N, Marks SD et al. European evidence-based recommendations for the diagnosis and treatment of childhood-onset LN:the SHARE initiative. Ann Rheum Dis 2017;76(12):1965-73

Disclosure of Interest

None declared

O22 Excessive production of interferon-γ drives the expansion of T-bet+ B cells in patients with systemic lupus erythematosus

E. Marasco¹, G. M. Moneta¹, C. Bracaglia¹, I. Caiello¹, C. Farroni², R. Carsetti², F. De Benedetti¹

¹Division of Rheumatology; ²B Cell Physiopathology Unit, Ospedale Pediatrico Bambin Gesù, Roma, Italy

Correspondence: E. Marasco

Introduction: Paediatric systemic lupus erythematosus (pSLE) is an autoimmune disorder of childhood characterized by the production of autoantibodies against nuclear antigens. In the last decade, several studies showed an up-regulation of genes induced by type I interferons (IFNα) in peripheral blood and tissues of pSLE patients². More recently, also the type II interferon (IFNγ) has been implicated in pSLE; however, its precise role has not been clarified yet³.

Objectives: To investigate the role of IFNγ in the pathogenesis of pSLE evaluating: 1) the expression levels of IFNγ-related genes in the peripheral blood of pSLE patients followed longitudinally; 2) the expression of T-bet in B cells of pSLE patients; the induction of T-bet in B cells by IFNγ.

Methods: Expression levels of IFNα-induced genes (IFI27, IFI44L, IFIT1, RSAD2, ISG15, SIGLEC1), IFNγ and IFNγ-induced genes (CXCL9, CXCL10, IDO1) were analysed by qPCR in whole blood of pSLE patients and healthy donors(HD). We developed a type II IFN score similarly to the type I IFN score described by Crow⁴. Expression of T-bet in B cells was evaluated by flow cytometry. Peripheral blood mononuclear cells (PBMCs) from 5 HD were stimulated in vitro with recombinant human IFNγ and IFNα. Serum levels of CXCL9 were evaluated by ELISA. For each patient, SLEDAI was calculated.

Results: Expression levels of both IFNα and IFNγ-induced genes was upregulated in patients with pSLE (n=39). The type II IFN score weakly correlated with the SLEDAI (r=0.33, P=0.03). As previously reported, the type I IFN score significantly correlated with SLEDAI (r=0.50, P<0.01). We found increased serum levels of CXCL9 in pSLE patients compared to HD (mean±SD: HD 333±117pg/mL, SLE 2125±4885pg/mL, P=0.0003). Eight patients were enrolled at disease onset before any treatment was administered: type I score decreased with initiation of immunosuppressive treatment; on the other hand, type II score and levels of CXCL9 were not significantly affected by treatment. Interestingly, type II score (mean±SD: No LN 3.3±3, LN 6.7±11, P=0.045) and CXCL9 (mean±SD: No LN 816±1225pg/mL, LN 2427±5436pg/mL, P=0.031) were significantly higher in patients with lupus nephritis(LN). Thus, patients with pSLE have increased activity of IFNγ, and this particularly evident in patients with LN.

B cells play a crucial role in the pathogenesis of SLE. In murine models of SLE, IFNγ was shown to activate B cells to make autoantibodies⁴. We evaluated the expression of T-bet (a transcription factor induced specifically by IFNγ) in B cells: we observed a population of B cells expressing T-bet in the naïve compartment in patients with pSLE. The frequency of T-bet⁺ naïve B cells correlated with SLEDAI. To confirm the induction of T-bet in B cells by IFNγ, we stimulated PBMCs of HD with either IFNγ or IFNα: both chemokines induced the expression of T-bet in naïve B cells. Since it is known that IFNα can induce the expression of IFNγ, we stimulated cells with IFNα and an antibody blocking IFNγ: in this setting IFNα did not upregulate the expression of T-bet in B cells.

Conclusion: Our data suggest a potential role of IFNγ in the pathogenesis of pSLE. IFNγ-induced genes in whole blood and CXCL9 in serum were increased in patients with pSLE, especially in patients with LN. We observed an expansion of T-bet+ naïve B cells in patients with pSLE. IFNγ specifically induced the expression of T-bet in naïve B cells. Thus, IFNγ is hyperactiaved in SLE, inducing the aberrant expression of T-bet in naïve B cells. Further research is needed to dissect the role of IFNγ-activated B cells in pSLE.

References

Petri M, et al. Lupus. 2009

Munroe M, et al. Ann Rheum Dis 2016

Rice GI, et al. Lancet Neurol 2013

Jackson SW, J Ex Med. 2016

Patient Consent Received

Yes

Disclosure of Interest

None declared

O23 Low disease activity state and clinical remission are achievable targets in JSLE, leading to a significant reduction in severe flare and new damage

E. M. Smith^1,2, K. Tharmaratnam³, C. M. Hedrich¹, A. L. Jorgensen³, M. W. Beresford¹, on behalf of on behalf of the UK JSLE Cohort Study

¹Institute of Life Course and Medical Sciences, University of Liverpool; ²Department of Paediatric Rheumatology, Alder Hey Children's NHS Foundation Trust; ³Department of Health Data Science, Institute of Population Health, University of Liverpool, Liverpool, United Kingdom

Correspondence: E. M. Smith

Introduction: A treat-to-target approach (T2T), where treatment is escalated until a specific target is achieved, with re-escalation if attainment of the target is lost, has been proposed as a strategy to improve adult-SLE outcomes. An international task force of experts has developed adult-onset SLE T2T guidance, to underpin development of the T2T approach. These recommendations highlight that lack of validated remission and low disease activity target state definitions (known as LDA, LDAS or LLDAS) is a fundamental knowledge gap limiting progress towards a T2T approach [1]. The TARGET LUPUS research programme: ‘Targeting disease, Agreeing Recommendations and reducing Glucocorticoids through Effective Treatment, in LUPUS’ has been established in order to develop a Juvenile-onset Systemic Lupus Erythematosus (JSLE) T2T study.

Objectives: To assess the achievability and impact of attaining LDAS or remission in JSLE.

Methods: Achievement of three adult-SLE derived definitions of LDAS (APLC-LLDAS [2], adapted-APLC LLDAS [3, 4], Toronto-LDA [5]), and four definitions of remission (in accordance with the recommendations of the DORIS international task force remission guidance, including cSLEDAI-defined remission on/off treatment, pBILAG-defined remission on/off treatment)[6], were assessed in UK JSLE Cohort Study patients [7]. The required duration for remission to be achieved was not pre-specified. Prentice-Williams-Petersen-GAP recurrent event models assessed the impact of LDAS/remission achievement on severe disease flare (pBILAG of A or B in any organ domain) and new damage (increase in total SLICC-SDI damage score by at least one unit).

Results: 430 UK JSLE Cohort Study patients were included (359 female, 83%), diagnosed with JSLE at a median of 12.8 years [IQR 10.4, 14.6]. Data from 4,738 visits were analysed, median of 10 visits [5, 15] per patient, over a median of 2.0 years [0.7, 4.0]. APLC-LDAS was achieved by 286/430 (67%) of patients, adapt-APLC definition in 314/430 (73%), and Toronto-LDA in 136/430 (32%). Remission on treatment was more common (61% cSLEDAI-defined, 42% pBILAG-defined) than remission off treatment (31% cSLEDAI-defined, 21% pBILAG-defined). Achievement of each LDAS/remission target state, and disease duration (>1 year) significantly reduced the hazard of severe flare (p<0.001). Increasing SLICC-SDI damage score during follow-up increased the hazard of severe flare (p<0.001). For all targets, as cumulative time in target increased, hazard of severe flare reduced. APLC-LLDAS target achievement reduced hazard of severe flare more than adapt-APLC LDAS (p<0.001). Achievement of APLC-LDAS target had a comparable impact on severe flare, to the attainment of remission definitions (p>0.05). Achievement of all targets LDAS/remission reduced the hazards of new damage (p<0.05).

Conclusion: This is the first study to demonstrate that adult-derived definitions of LDAS/remission are achievable in JSLE, significantly reducing risk of severe flare and new damage. Balancing achievability and impact, the APLC-LLDAS definition performed best, demonstrating comparable effect on severe flare to the achievement of clinical remission. Paediatric-specific adaptations of these targets should be considered.

Patient Consent Received

Yes

Disclosure of Interest

None declared

O24 BCAP as a modulator of LPS-induced interferon production in relevance to the pathogenesis of systemic lupus erythematosus

A. Tesser¹, G. M. Piperno², A. Pin¹, E. Piscianz¹, E. Valencic¹, V. Boz³, F. Benvenuti², A. Tommasini^1,3

¹Department of Pediatrics, Institute for Maternal and Child Health - IRCCS “Burlo Garofolo”; ²International Centre for Genetic Engineering and Biotechnology; ³Department of Medicine, Surgery, and Health Sciences, University of Trieste, Trieste, Italy

Correspondence: A. Tesser

Introduction: PI3K kinases cover crucial roles in maturation, proliferation and survival of immune cells. The signaling of PI3Ks is fine-tuned by BCAP protein (encoded by PIK3AP1 gene), which connects TLRs activation and determines the signaling of NF-kB or interferon (IFN) pathway. Moreover, the role of BCAP in promoting IFN-producing macrophages and autoimmune B cells suggests its possible involvement in the pathogenesis of SLE, along with TLR stimulation by bacterial LPS (1-5).

Previous studies on a monogenic form of SLE (DNase2 interferonopathy, D2I) demonstrated that the “priming” of type I IFN pathway make cells hyper-responsive to LPS-induced production of IFNs (6) and that BCAP could play a key role in the crosstalk LPS-IFN.

Objectives: By studying D2I, we aim to unravel the role of BCAP and PI3K in regulating the synergy LPS-IFN in SLE models.

Methods: D2I fibroblasts were pre-treated for 2h with STING inhibitor H-151 (10μM) and PI3Kδ inhibitor Leniolisib (10μM, 50μM), both in single and combined treatment, and after challenged for 1h with LPS (0.5μg/mL). Phosphorylated-TBK1 was measured by intracellular staining with specific antibodies in flow-cytometry.

D2I fibroblasts were also stimulated for a longer time (48h) with H-151 (10μM) and Leniolisib (10μM, 50μM), both in single and combined treatment, for RNA extraction and retro-transcription. PIK3AP1 relative quantification was conducted by Real-Time PCR with specific probes and two housekeeping genes in relation to un-stimulated control fibroblasts.

Results: The IFN pathway activation in D2I fibroblasts after stimulation with LPS could be reduced by the combined inhibition of STING and PI3Kδ.

Moreover, in the “naturally-IFN-primed” D2I fibroblasts, PIK3AP1 is hyper-expressed compared to control, and is down-regulated by either single or combined inhibition of STING and PI3Kδ.

Conclusion: Further studies to investigate the potential of STING and PI3Kδ inhibition for the reduction of LPS-induced IFN-production and for PIK3AP1 regulation in SLE models will improve understand the clinical relevance of LPS-IFN pathways crosstalk in SLE pathogenesis, paving the way for novel therapeutic approaches.

References

1. Ruse M, Knaus UG. New players in TLR-mediated innate immunity: PI3K and small Rho GTPases. Immunol Res. 2006;34(1):33-48.

2. Troutman TD, Hu W, Fulenchek S, Yamazaki T, Kurosaki T, Bazan JF, et al. Role for B-cell adapter for PI3K (BCAP) as a signaling adapter linking Toll-like receptors (TLRs) to serine/threonine kinases PI3K/Akt. Proc Natl Acad Sci U S A. 2012;109(1):273-8.

3. Chu T, Ni M, Chen C, Akilesh S, Hamerman JA. Cutting Edge: BCAP Promotes Lupus-like Disease and TLR-Mediated Type I IFN Induction in Plasmacytoid Dendritic Cells. J Immunol. 2019;202(9):2529-34.

4. Ma Y, Xu X, Li M, Cai J, Wei Q, Niu H. Gut microbiota promote the inflammatory response in the pathogenesis of systemic lupus erythematosus. Mol Med. 2019;25(1):35.

5. Azzouz D, Omarbekova A, Heguy A, Schwudke D, Gisch N, Rovin BH, et al. Lupus nephritis is linked to disease-activity associated expansions and immunity to a gut commensal. Ann Rheum Dis. 2019;78(7):947-56.

6. Tesser A, Piperno GM, Pin A, Piscianz E, Boz V, Benvenuti F, et al. Priming of the cGAS-STING-TBK1 Pathway Enhances LPS-Induced Release of Type I Interferons. Cells. 2021;10(4).

Patient Consent Received

No

Disclosure of Interest

None declared

Lightning talks: Macrophage activation syndrome and Systemic JIA

O25 Mortality and clinical response to treatment in children with secondary hemophagocytic lymphohistiocytosis (SHLH)

C. Bracaglia, R. Pecoraro, D. Pires Marafon, A. De Matteis, G. Marucci, M. Pardeo, F. De Benedetti

Division of Rheumatology, IRCCS Ospedale Pediatrico Bambino Gesù, Roma, Italy

Correspondence: C. Bracaglia

Introduction: sHLH is a life-threatening condition associated with several disorders, such as infections, malignancies and rheumatologic/inflammatory diseases. In a significant number of cases an apparent underlying disease cannot be found. Data on mortality rate and on clinical response to treatments (CRT) are lacking or limited to small series.

Objectives: To evaluate mortality rate and CRT in a cohort of sHLH patients.

Methods: A retrospective chart review of sHLH patients followed at Ospedale Pediatrico Bambino Gesù from April 2006 through September 2020 was performed. Patients with sHLH in the context of sJIA and secondary to malignancy were excluded. Clinical, laboratory features and treatment data were collected at onset, at 1, 3 and 6 months in order to assess CRT. The last follow-up was used to evaluate mortality. To evaluate CRT we divided the cohort in responders and non-responders. Responders were those who achieved the criteria for CRT in the emapalumab trial for pHLH [1] after conventional therapy. Conventional therapy was defined as glucocorticoids, cyclosporine-A, intravenous Ig and/or anakinra at the dose of ≤ 5mg/kg/day. Non-responders were those who died, those who did not achieve CRT and those who required additional or prolonged (more than 1 month) treatment.

Results: 82 sHLH patients, 49 males, with a median age at disease onset of 5.9 years, were included. 21 patients had HLH secondary to rheumatic/inflammatory diseases (other than sJIA), 4 secondary to SLE, 2 to JDM, 1 to systemic vasculitis, 1 to Crohn’s disease, 1 to Sjögren syndrome, 1 to antiphospholipid antibody syndrome and 11 to other rheumatic/inflammatory diseases. 39 were secondary to infections, 8 to other conditions, such as metabolic disorders or immunodeficiencies and 14 had no evidence of underlining disease (unknown). The mortality rate of the entire cohort was 27% (Table 1). To analyse CRT, 9 patients, who did not receive immunosuppressive therapy, as they responded rapidly to the treatment of the HLH trigger, were excluded from this analysis. There were 32 (44%) responders: of those 7 had HLH secondary to rheumatic/inflammatory diseases, 22 to infections, 3 of unknown origin and none secondary to other conditions. 24/32 patients achieved CRT at 3 months. 41 (56%) were non-responders, included those who died (n=22), 14 of whom had HLH secondary to rheumatic/inflammatory diseases (3 to SLE), 11 to infections, 7 to other conditions and 9 of unknown. In the entire cohort only 7 patients received anakinra, 4 of them subcutaneously at the dose of 3 to 5 mg/kg/day and 3 received intravenous anakinra up to 10 mg/kg/day to treat the sHLH episode. Of the 3 patients treated with high-dose anakinra, 2 died.

Conclusion: The mortality rate of this cohort is high (27%) similar to those reported in smaller series. The percent of patients achieving complete response at 3 months is less than 50%, underlying the severity of the disease and the poor response to unspecific immunosuppression. Even though the use of anakinra is reported to be effective in some cases of sHLH, particularly in sHLH with an underlying rheumatic disease, in our cohort only few patients with a very severe disease were treated with anakinra.

Reference

[1] Locatelli F. et al N Engl J Med. 2020 May 7;382(19):1811-1822.

Disclosure of Interest

C. Bracaglia Consultant for: Sobi, Novartis, R. Pecoraro: None declared, D. Pires Marafon: None declared, A. De Matteis: None declared, G. Marucci: None declared, M. Pardeo: None declared, F. De Benedetti Consultant for: Abbvie, SOBI, Novimmune, Novartis, Roche, Pfizer

Table 1 (abstract O25). Mortality rate of sHLH patients

O26 Activated CD8+ T cells discriminates patients with macrophage activation syndrome from patients with active systemic juvenile idiopathic arthritis

G. Prencipe¹, A. De Matteis², M. Colucci³, M. N. Rossi¹, I. Caiello¹, M. Pardeo², C. Bracaglia², F. De Benedetti²

¹Laboratory of Immuno-Rheumatology; ²Division of Rheumatology; ³Renal Diseases Research Unit, Bambino Gesù Children's Hospital, ROMA, Italy

Correspondence: G. Prencipe

Introduction: T cell activation profiling has been recently demonstrated to be able to distinguish patients with primary and infection-associated hemophagocytic lymphohistiocytosis (HLH) from patients with sepsis (1).

Objectives: In this study, we aimed to evaluate whether activated CD8⁺ T cell profile also characterizes patients with macrophage activation syndrome (MAS) in the context of systemic juvenile idiopathic arthritis (sJIA) and whether it is able to distinguish patients with MAS from those with active sJIA.

Methods: Flow cytometric analyses were performed on peripheral blood mononuclear cells isolated from children with inactive sJIA (n=17), active sJIA (n=27), MAS (n=14) and with HLH secondary to infection (n=7).

Results: To assess the activation status of CD8+ T lymphocytes, we evaluated the expression of the activation markers HLA-DR and CD38. In patients with MAS, the frequency of CD38^high/HLA-DR⁺_, gated on CD8⁺ CD3⁺ cells, was significantly higher compared to those observed in patients with active and inactive sJIA (mean ± SD: 38.4 ± 21.1 % vs 6.9 ± 7.6 % and 2.6 ± 4.2 %, respectively). Receiver operating characteristic (ROC) curve analysis demonstrated that frequency of CD38^high/HLA-DR⁺ CD8⁺ T cells was able to reliably discriminate patients with MAS from those with active sJIA [area under the curve (AUC) of 0.96 (95%CI 0.90-1.00, p<0.001)]. No statistically significant differences in the frequency of CD38^high/HLA-DR⁺ CD8⁺ T cells between MAS and HLH secondary to infection were observed. In addition, CD38^high expressing cells represented the major source of IFNγ among CD8⁺ T cells. The percentage of CD38^high/HLA-DR⁺ CD8⁺ T cells detected in MAS patients correlated with laboratory parameters of disease severity, including haemoglobin, lactate dehydrogenase and ferritin.

Conclusion: We found that CD8⁺ T cell activation status also characterizes patients with MAS in the context of sJIA, demonstrating that T cell activation status in HLH does not vary depending on the underlying condition/trigger. Moreover, assessment of percentage of CD38^high/HLA-DR⁺ CD8⁺ T cells represents a valid tool for an accurate identification of patients with MAS. The correlation, in MAS patients, between the increased number of IFNγ-producing CD38^high/HLA-DR⁺ CD8⁺ T cells and the laboratory parameters of the disease, further confirms the pathogenic role of IFNγ in HLH.

1. Chaturvedi V, Marsh RA, Zoref-Lorenz A, Owsley E, Chaturvedi V, Nguyen TC, Goldman JR, Henry MM, Greenberg JN, Ladisch S, Hermiston ML, Jeng M, Naqvi A, Allen CE, Wong HR, Jordan MB. T-cell activation profiles distinguish hemophagocytic lymphohistiocytosis and early sepsis. Blood. 2021 Apr 29;137(17):2337-2346. doi: 10.1182/blood.2020009499.

Disclosure of Interest

G. Prencipe: None declared, A. De Matteis: None declared, M. Colucci: None declared, M. Rossi: None declared, I. Caiello: None declared, M. Pardeo: None declared, C. Bracaglia Consultant for: SOBI, Novartis, F. De Benedetti Consultant for: Abbvie, SOBI, Novimmune, Novartis, Roche, Pfizer

O27 Development of clinical definitions of refractory disease trajectories in systemic JIA

R. Erkens¹, A. Grom², R. Sinha ³, Y. Kimura⁴, C. Towe ², A. Consolaro⁵, S. W. Canna⁶, C. Bracaglia⁷, F. De Benedetti⁷, C. Wouters⁸, K. Tenbrock⁹, A. Horne¹⁰, R. Yeung¹¹, D. Föll¹², N. Wulffraat¹, G. Schulert², B. Vastert¹

¹Wilhelmina kinderziekenhuis, UMC Utrecht, Utrecht, Netherlands; ²Cincinnati Children’s Hospital; ³Systemic JIA Foundation, Cincinnati; ⁴Hackensack UMC, Hackensack, United States; ⁵IRCCS Istituto Giannina Gaslini, Genova, Italy; ⁶The Children’s Hospital of Philadelphia, Philadelphia, United States; ⁷Ospedale Pediatrico Bambino Gesù, Rome, Italy; ⁸UZ Leuven, Leuven, Belgium; ⁹RWTH Aachen University, Aachen, Germany; ¹⁰Karolinska Institutet, Stockholm, Sweden; ¹¹The Hospital for Sick Children, University of Toronto, Toronto, Canada; ¹²University of Münster, Münster, Germany

Correspondence: R. Erkens

Introduction: Systemic Juvenile Idiopathic Arthritis (sJIA) is a distinct and heterogeneous disease presently classified under the umbrella of JIA, with some patients following a monophasic remitting course, while others have persistent disease with chronic organ- and life-threatening complications. Though biologic therapies have revolutionized treatment and improved outcomes, recent long-term follow-up studies report significant numbers of children with persistently active disease. Even in 2020, a significant number of sJIA patients show incomplete responses to targeted biological therapies and need to try multiple sequential treatments. Treatment-refractory sJIA patients often face severe and life-threatening complications including macrophage activation syndrome (MAS), sJIA associated lung disease (sJIA-LD), and destructive arthritis. Due to a lack of clinical trials, there is little evidence to guide treatment, making treatment of refractory sJIA patients challenging. Developing a broadly accepted consensus on the definitions of refractory sJIA will be an important first step towards collaborative international research.

Objectives: To develop widely accepted definitions of refractory sJIA to enable international collaborative studies of refractory sJIA patients.

Methods: During the 2019 NextGen Meeting of the Systemic JIA Foundation (Canna et al. Pediatr Rheumatol. 2020), a group of sJIA experts discussed preliminary definitions of refractory disease trajectories (table 1). There is overlap in these disease states, with a strong association between MAS and sJIA-LD, and active sJIA is a risk factor for developing MAS. Currently, we are performing a systematic literature review in preparation for consensus processes including an international Delphi survey followed by a consensus meeting of experts to develop broadly acceptable definitions of refractory sJIA.

Results:

Conclusion: There is an unmet need for a better understanding and definition of refractory disease in sJIA. A consensus based definition is being developed together with patients and caregivers (incl. the Systemic JIA Foundation). Accepted definitions will then enable collaborative research aimed at understanding the disease mechanisms in sJIA patients fitting these definitions. This knowledge can then be translated into targeted therapeutic strategies, which are urgently needed to improve the outcomes and daily life of these patients.

Disclosure of Interest

R. Erkens: None declared, A. Grom: None declared, R. Sinha : None declared, Y. Kimura Grant / Research Support from: Genentech, C. Towe Consultant for: Pediatric ILD Advisory Board for Boehringer Ingelheim, A. Consolaro Grant / Research Support from: Pfizer and AlfaSigma, Speaker Bureau of: AbbVie and Pfizer, S. Canna Grant / Research Support from: Immvention Therapeutix, AB2Bio and Novartis, Consultant for: Simcha Therapeutics, C. Bracaglia Speaker Bureau of: SOBI and Novartis, F. De Benedetti: None declared, C. Wouters Grant / Research Support from: GSK immune-inflammation, Pfizer, Novartis and Roche, Consultant for: advisory board Sobi and Novartis, K. Tenbrock Grant / Research Support from: Pfizer and Novartis, Consultant for: BMS, Pfizer and Novartis, A. Horne Speaker Bureau of: Sobi and Novartis, R. Yeung: None declared, D. Föll Speaker Bureau of: Novartis and Sobi, N. Wulffraat Grant / Research Support from: Sobi, Consultant for: UCB and Pfizer, G. Schulert Speaker Bureau of: Novartis, B. Vastert Grant / Research Support from: Sobi, Consultant for: Sobi and Novartis

Table 1 (abstract O27). Preliminary definitions of refractory disease courses in sJIA

O28 Naive CD4+ t cell differentiation in systemic juvenile idiopathic arthritis is skewed towards a peripheral t helper cell phenotype

J. Kuehn, S. Schleifenbaum, A. Hellige, C. Hinze, H. Wittkowski, D. Foell, C. Kessel

Pediatric Rheumatology & Immunology, University Children's Hospital, Muenster, Germany

Correspondence: J. Kuehn

Introduction: In terms of pathogenesis, systemic juvenile idiopathic arthritis (sJIA) is a unique JIA entity in that it is thought to feature characteristics of both autoinflammatory and autoimmune diseases. A bi-phasic model of disease progression has been proposed, where initial systemic inflammation may develop to chronic destructive arthritis¹.

Objectives: Our previous work indicated low interferon gamma (IFNg) expression by CD4^pos T helper (Th) cells in sJIA², which echoed earlier findings on low IFNg immune cell exposure in disease³ but is in sharp contrast to sJIA-associated macrophage activation syndrome (MAS) with IFNg as a central driver of cytokine storm and anemia⁴. Thus, appart from MAS we hypothesized that due to the likely lack of cognate sJIA-associated T cell antigens in an in vivo environment of proinflammatory mediators with the power to drive T cell polarization in different directions, CD4^pos T cells in sJIA may suffer from aberrant or incomplete polarization, which may translate into insufficient IFNg expression.

Methods: Naïve Th cells were isolated from pediatric healthy controls (HC, n = 12) and active (excluding MAS) and inactive sJIA patients (n = 21) and were cultured under various Th1, Th17 and Tfh polarizing conditions. Following super-stimulation with PMA/ionomycin, cell surface marker, transcription factor and cytokine expression was analyzed by flow cytometry, cyto-/chemokine release was quantified by multiplexed bead array assay or ELISA. For ex vivo studies, PBMCs were stimulated with PMA/ionomycin and analyzed by flow cytometry.

Results: Among naive peripheral CD4^pos T cells obtained from sJIA patients, we found an impaired IFNg expression and Th1 differentiation compared to healthy controls, when exposed to respective polarizing cytokines. Low IFNg production was linked to suboptimal Eomes expression. Surprisingly, we found a substantially increased release of IL-21, which was particularly pronounced under Th1 differentiation conditions and correlated to low IFNg and Eomes expression levels. Therefore, we tested a skewing of naive sJIA T cell differentiation towards T follicular helper (Tfh) cells (PD-1^posICOS^posCXCR5^pos) as a major source of IL-21 in the Th cell compartment. Under Th1 and Tfh differentiating conditions, we observed a strong up-regulation of the Tfh markers PD-1 and ICOS as well as the hallmark cyto-/chemokines IL-21 and CXCL13. PD-1 and ICOS expression levels were tightly correlated to high IL-21 expression and particularly evident in inactive disease patients‘ cells. Throughout, we only observed marginal expression of CXCR5. Ex vivo, we observed an expanded Tfh cell compartment and IL-21 expression among inactive disease sJIA patients, whereas active disease patients CD4^pos cells rather revealed signs of exhaustion (PD-1^hiICOS^neg).

Conclusion: In sJIA, naïve T helper cell differentiation appears skewed towards a peripheral T helper phenotype (PD-1^hiICOS^posCXCR5^neg), which has been described to occur in context of chronic inflammation^5,6. In sJIA pathogenesis this may represent an echo of autoimmunity, which could shed light on the mechanisms driving the progression towards chronic destructive arthritis.

References

(1) Nigrovic PA, Arthritis Rheumatol, 2014

(2) Kessel C et al., Arthritis Rheumatol, 2017

(3) Sikora K et al., Arthritis Rheum, 2012

(4) Crayne et al., Front Immunol, 2019

(5) Rao et al., Nature, 2017

(6) Bocharnikov et al., JCI Insight, 2019

Disclosure of Interest

None declared

O29 Efficacy and safety of secukinumab in enthesitis-related arthritis and juvenile psoriatic arthritis in a randomised, double-blind, placebo-controlled, treatment withdrawal, phase 3 study (Junipera)

N. Ruperto¹, I. Foeldvari², E. Alexeeva³, N. A. Ayaz⁴, I. Calvo⁵, O. Kasapcopur⁴, V. Chasnyk⁶, M. Hufnagel⁷, Z. Zuber⁸, G. Schulert⁹, S. Ozen¹⁰, A. Popov¹¹, A. Ramanan¹², C. Scott¹³, B. Sozeri¹⁴, E. Zholobova¹⁵, X. Zhu¹⁶, S. Whelan¹⁷, L. Pricop¹⁶, A. Ravelli¹⁸, A. Martini¹, D. J. Lovell¹⁹, H. Brunner¹⁹, on behalf of PRINTO and PRCSG

¹IRCCS Istituto G. Gaslini, Genova, Italy; ²Hamburger Zentrum fuer Kinder und Jugendrheumatologie, Hamburg, Germany; ³National Scientific and Practical Center of Children's Health, Moscow, Russian Federation; ⁴Istanbul University, Istanbul, Turkey; ⁵Hospital Universitario i Politecnic La Fe Valencia, Valencia, Spain; ⁶St. Petersburg State Pediatric Medical Academy, St. Petersburg, Russian Federation; ⁷University of Freiburg, Freiburg, Germany; ⁸Wojewodzki Specjalistyczny Szpital Dzieciecy im Sw Ludwika, Krakow, Poland; ⁹Universtiy of Cincinnati, Ohio, United States; ¹⁰Hacettepe University, Ankara, Turkey; ¹¹Ural State Medical University, Yekaterinburg, Russian Federation; ¹²University of Bristol, Bristol, United Kingdom; ¹³University of Cape Town, Cape Town, South Africa; ¹⁴Health Sciences University, Istanbul, Turkey; ¹⁵First Moscow State Medical University, Moscow, Russian Federation; ¹⁶Novartis Pharmaceutical Corporation, East Hanover, United States; ¹⁷Novartis Ireland Ltd, Dublin, Ireland; ¹⁸Istituto Giannina Gaslini, Genova, Italy; ¹⁹University of Cincinnati, Cincinnati, United States

Correspondence: N. Ruperto

Introduction: Enthesitis-related arthritis (ERA) and juvenile psoriatic arthritis (JPsA) are two ILAR categories of juvenile idiopathic arthritis (JIA) with adult correlates of axial spondyloarthritis (axSpA) and adult psoriatic arthritis (PsA), respectively.^1,2 Secukinumab (SEC) improved signs and symptoms of axSpA, PsA and non-radiographic axSpA.^3-5

Objectives: Evaluate efficacy and safety of SEC in patients (pts) with active ERA and JPsA

Methods: In open label (OL) treatment period (TP) 1 (12 weeks), pts (2 to <18 years) were administered SEC (s.c., 75 mg in pts <50 kg and 150 mg in ≥50 kg) at baseline (BL), and at Weeks 1–4, 8 and 12. Responders (pts who achieved at least JIA ACR 30 in TP1) were randomised to double-blinded SEC or placebo (PBO) treatment q4w until experiencing a disease flare or up to Week 104 in TP2. Primary endpoint was time to flare in TP2 and key secondary endpoints were JIA ACR 30/50/70/90/100 responses, inactive disease status, Juvenile Arthritis Disease Activity Score (JADAS), enthesitis count and safety. Data are as observed.

Results: In TP1, 86/97 (89%; ERA, n=52; JPsA, n=34, mean age: 13.1 years, females: 33.7%) of pts received OL SEC treatment. BL mean JADAS-27 score and enthesitis count were 15.1 and 2.6, respectively. JIA ACR 30/50 responses were 90.4% and 86.7%, respectively at the end of TP1 (Table). In TP2, 10 flares in SEC and 21 flares in PBO were observed. SEC vs PBO treated pts had a significantly (P<0.001) longer time to flare (HR: 0.28; 95% CI: 0.13–0.63) with a 72% risk of flare reduction in TP2. SEC safety profile was similar to adults with no new safety signals.

Conclusion: In pts with active ERA and JPsA, efficacy of SEC was demonstrated with a significantly longer time to flare vs PBO with sustained improvement of signs and symptoms up to Week 104 and a favourable safety profile.

References

1. Colbert RA. Nat Rev Rheumatol. 2010;6:477–85

2. Martini A, et al. J Rheumatol. 2019;46:190–7

3. McInnes IB, et al. Lancet. 2015;386:1137–46

4. Baeten D, et al. N Engl J Med. 2015;373:2534–48

5. Deodhar A, et al. Arthritis Rheumatol. 2021;73:110–20

Trial registration identifying number: NCT03031782

Patient Consent Received

No

Disclosure of Interest

N. Ruperto Consultant for: Ablynx, Astrazeneca-Medimmune, Bayer, Biogen, Boehringer, Bristol Myers and Squibb, Celgene, Eli-Lilly, EMD Serono, Glaxo Smith and Kline, Hoffmann-La Roche, Janssen, Merck, Novartis, Pfizer, R-Pharma, Sinergie, Sobi and UCB, Speaker Bureau of: Ablynx, Astrazeneca-Medimmune, Bayer, Biogen, Boehringer, Bristol Myers and Squibb, Celgene, Eli-Lilly, EMD Serono, Glaxo Smith and Kline, Hoffmann-La Roche, Janssen, Merck, Novartis, Pfizer, R-Pharma, Sinergie, Sobi and UCB, I. Foeldvari Consultant for: Novartis, Speaker Bureau of: Novartis, E. Alexeeva Speaker Bureau of: Novartis, Pfizer, Sanofi, MSD, AMGEN, Eli Lilly, Roche, N. Ayaz: None declared, I. Calvo Consultant for: Sobi, Novartis, Abbvie, GlaxoSmithKline, Pfizer, Amgen, Clementia, Speaker Bureau of: Sobi, Novartis, Abbvie, GlaxoSmithKline, Pfizer, Amgen, Clementia, O. Kasapcopur: None declared, V. Chasnyk: None declared, M. Hufnagel: None declared, Z. Zuber: None declared, G. Schulert Consultant for: Sobi, Novartis, S. Ozen: None declared, A. Popov: None declared, A. Ramanan Speaker Bureau of: Roche, Sobi, Eli Lilly, UCB, Novartis, C. Scott: None declared, B. Sozeri: None declared, E. Zholobova Speaker Bureau of: Abbvie, Pfizer, Roche, X. Zhu Employee of: Novartis, S. Whelan Shareholder of: Novartis, Employee of: Novartis, L. Pricop Shareholder of: Novartis, Employee of: Novartis, A. Ravelli Consultant for: Abbvie, Bristol-Myers Squibb, Pfizer, Hoffmann-LaRoche, Novartis, Centocor, Angelini Holding, Reckitt Benckiser, Speaker Bureau of: Abbvie, Bristol-Myers Squibb, Pfizer, Hoffmann-LaRoche, Novartis, Centocor, Angelini Holding, Reckitt Benckiser, A. Martini Consultant for: Eli Lilly, EMD Serono, Janssen, Novartis, Pfizer, Abbvie, Speaker Bureau of: Eli Lilly, EMD Serono, Janssen, Novartis, Pfizer, Abbvie, D. Lovell Consultant for: AstraZeneca, Wyeth, Amgen, Abbott, Pfizer, Hoffmann-La Roche, Novartis, UBC, Takeda, Janssen, GlaxoSmithKline, Boehringer Ingelheim, Celgene, Bristol Myers Squibb, AbbVie, Forest Research, Speaker Bureau of: AstraZeneca, Wyeth, Amgen, Abbott, Pfizer, Hoffmann-La Roche, Novartis, UBC, Takeda, Janssen, GlaxoSmithKline, Boehringer Ingelheim, Celgene, Bristol Myers Squibb, AbbVie, Forest Research, H. Brunner Consultant for: Aurina, AbbVie, Astra Zeneca-Medimmune, Biogen, Boehringer, Bristol-Myers Squibb, Celgene, Eli Lilly, EMD Serono, GlaxoSmithKline, F. Hoffmann-La Roche, Merck, Novartis, R-Pharm, Sanofi, Pfizer

Table 1 (abstract O29). Efficacy of secukinumab in Treatment Periods 1 and 2 (Key secondary endpoints)

O30 Single-cell genomics reveals a shared monocyte interferon program in a subset of patients with systemic juvenile idiopathic arthritis, macrophage activation syndrome and lung disease

E. L. Verweyen¹, K. Thakkar^2,3, K. Chetal², S. Dhakal¹, A. A. Grom^1,4, N. Salomonis², G. S. Schulert^1,4

¹Division of Rheumatology; ²Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center; ³Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine; ⁴Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, United States

Correspondence: E. L. Verweyen

Introduction: Systemic juvenile idiopathic arthritis (SJIA) is a clinically heterogenous disease and can be complicated by macrophage activation syndrome (MAS) and lung disease (LD) thought to be driven by interferon signaling, though the contributing cell populations and distinctions between IFNγ and IFNα/β are undefined.

Objectives: To identify novel prognostic transcripts and potential patient subtypes, we aimed to characterize single-cell heterogeneity and patient-specific transcriptomics responses from the peripheral blood of children with SJIA, MAS and LD.

Methods: 10x Genomics single-cell RNA Sequencing (scRNA-Seq) was performed on PBMCs from 7 active SJIA and 5 inactive SJIA patients, 2 SJIA-MAS and 6 SJIA-LD patients and 5 healthy controls. Integration analyses were performed with the software Seurat 3 to identify discrete cell populations while correcting for donor and disease-level differences. To identify subsets of patients with cell-type specific signatures, we developed a new hybrid supervised/unsupervised computational pipeline in the software AltAnalyze, called cellHarmony 2.0, designed specifically for large cohort single-cell genomic studies.

Results: scRNA-Seq analysis was performed on a total of 234,128 individual cells (ranging from 6,662-12,647 cells/patient), with a mean number of 21,637 genes detected per sample. To assess cell-population level differences, we identified and annotated based on marker genes 34 discrete cell populations across all submitted samples. This indicated a consistent increase in Natural Killer (NK) cells and decrease in naïve and regulatory T cells in SJIA-LD, with the distribution of cells from inactive SJIA patients similar to that of controls. To exploit anticipated heterogeneity within this cohort, we applied our new cell-type aware patient subtype discovery algorithm cellHarmony 2.0. We computed an aggregate cell signature for all cell populations or pseudo-bulks (n=34) for each patient and their associated fold differences relative to matched control cell clusters, and performed unsupervised clustering of the pseudo-bulks to identify patient subtypes associated within one or more cell types. This analysis uncovered 11 pseudo-clusters of cell type gene expression differences, both shared and unique across the patients. Specifically, pseudo-cluster 4 was defined by IL-2 mediated signaling genes, composed of mostly NK cells from all SJIA subtypes except MAS. SJIA-MAS PBMCs were almost exclusively represented in three separate pseudo-clusters that contained genes mediating T-cell receptor activation, immune response and interferon signaling. Finally, pseudo-cluster 8 was composed of mainly monocytes/macrophages with specific upregulation of IFNα/β induced genes IFITM3, IFI6 and ISG15, only in active SJIA, SJIA-MAS and SJIA-LD.

Conclusion: Unsupervised single-cell cohort analysis provides new opportunities to uncover novel disease molecular programs and pathways in clinically heterogenous patient groups. Here, we found active SJIA, SJIA-MAS and SJIA-LD PBMCs have distinct monocytic responses characterized by upregulation of interferon-induced genes, highlighting the role for both IFNγ and IFNα/β in driving disease pathogenesis.

Patient Consent Received

No

Disclosure of Interest

E. Verweyen: None declared, K. Thakkar: None declared, K. Chetal: None declared, S. Dhakal: None declared, A. Grom Consultant for: Novartis, Sobi, AB2Bio, Cerecor, N. Salomonis: None declared, G. Schulert Speaker Bureau of: Novartis

Lightning talks: Juvenile dermatomyositis, Scleroderma and related syndromes, Systemic lupus erythematosus and antiphospholipid syndrome, Uveitis

O31 Investigating novel mechanisms of t cells in the pathogenesis of juvenile dermatomyositis

L. R. Marshall¹, E. C. Rosser², C. T. Deakin¹, D. Eleftheriou¹, E. J. Sumner¹, B. Jebson¹, K. O'Brien¹, Q. Wu¹, L. R. Wedderburn¹, on behalf of JDRG

¹IR, UCL Great Ormond Street Institute of Child Health; ²UCL Centre for Adolescent Rheumatology Versus Arthritis, London, United Kingdom

Correspondence: L. R. Marshall

Introduction: Juvenile Dermatomyositis (JDM) is a rare autoimmune disease causing skin and muscle inflammation with an average onset of 7 years old. At present, JDM aetiology is poorly understood and current treatment options are not evidence based. This highlights the need for research investigating underlying disease pathogenesis. A skewed T helper (Th)17 phenotype in CD4+ T cells resulting in a Th1/17 imbalance has been observed in both child and adult-onset immune-mediated diseases including rheumatoid arthritis, and multiple sclerosis.

Objectives: The aim of this project is to investigate whether a Th1/17 imbalance can be observed in patients with JDM compared to age/sex-matched child healthy controls (CHC).

Methods: Expression of IL-17 and IFNγ in CD4+ T cells within peripheral blood mononuclear cells (PBMC) from JDM pre-treatment (JDM Pre, n=7), JDM on-treatment (JDM On, n=28) and CHC (n=22) was assessed by flow cytometry after stimulation with PMA/Ionomycin/Brefeldin A (P/I/B) for 4 hours. For secreted cytokine production, isolated CD4+ T cells were isolated by magnetic separation and stimulated with anti-CD3 or anti-CD3/anti-CD28 for 36 hours in the presence of IL-2. Supernatants were analysed for secreted IL-17 and IFNγ and measured by cytokine bead array. In parallel, extracellular Th1 (CD3+CD4+CXCR3+CCR6-), Th17 (CD3+CD4+CXCR3-CCR6+) and Treg (CD3+CD4+CD127-CD25hi) subsetting was carried out using flow cytometry and proliferative capacity of T cells was assessed following stimulation using Ki67.

Results: Both intracellular cytokine staining and stimulation experiments to assess secreted cytokine revealed a decreased trend of IFN-γ production in JDM compared to CHC within CD4+ T cells, regardless of treatment status. Ratio analysis of CD4+IFNγ+ to CD4+IL-17+ cells within peripheral blood after PMA/Ionomycin stimulation demonstrated that the JDM CD4+ T-cell phenotype is significantly skewed towards Th17 cells (p=<0.001) compared to CHC. A Th17 skew was also seen when analysing surface markers for Th1 and Th17 on JDM pre CD4+ T cells compared to controls (p=<0.0001). Central and Effector Memory compartments within CD4+ T cells were reduced in JDM Pre patients compared to controls (p=0.02, p=<0.001 respectively).

Conclusion: To summarise, our novel findings show a lack of Th1 response, via IFNγ, in JDM CD4+ T cells compared to CHC. Whilst results show promising avenues for further investigation there are no definitive explanations for this low Th1 response at present. Future work aims to investigate memory and naive compartments within JDM Pre CD4+ T cells in addition to testing of Th1 markers within the muscle. Additionally, other immune and metabolic pathways that may explain this Th17 skew could be targeted to restore IFNγ loss in JDM patients.

Disclosure of Interest

None declared

O32 Oxidised mitochondrial DNA induces an interferon response in JDM: a new therapeutic target

M. Wilkinson^1,2,3, E. C. Rosser^2,4, M. Orford⁵, C. Wincup^2,4, T. C. R. McDonnell⁶, G. Otto^3,7, D. Kelberman^3,7, S. Castellano^3,7, L. R. Wedderburn^1,2,3, S. Eaton⁵, C. T. Deakin^1,2,3

¹Infection, Immunity and Inflammation Programme Research and Teaching Department, UCL Gosh Institute of Child Health; ²Centre for Adolescent Rheumatology Versus Arthritis at UCL UCLH and GOSH, University College London; ³NIHR Biomedical Research Centre at GOSH, GOSH; ⁴Centre for Rheumatology Research, University College London; ⁵Developmental Biology and Cancer Programme; ⁶Centre for Rheumatology Research; ⁷Genetics and Genomic Medicine Programme, UCL Gosh Institute of Child Health, 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. A key pathological feature of JDM is a strong type 1 interferon (IFN1) signature, identifying and understanding the mechanisms up-stream is important for the development of new therapeutics.

Objectives: This study aimed to identify dysregulated biological processes up-stream of IFN1 by RNA-sequencing in JDM and develop functional assays to confirm these pathways.

Methods: Peripheral blood samples were obtained from JDM patients [pre-n=10 on-n=12 treatment] and age/sex-matched child healthy controls (CHC) [n=8]. CD4⁺, CD8⁺, CD14⁺ and CD19⁺ cells were sorted by flow-cytometry from PBMC, and RNA was extracted and RNA-sequenced. Mitochondrial superoxide was assessed in CD14+ monocytes by flow cytometry using MitoSox quantified by median fluorescence intensity (MFI), JDM pre-treatment [n=5], on-treatment [n=6] and CHC [n=3]. Oxidised mitochondrial DNA (oxmtDNA) from CD14+ monocyte isolated mitochondria was measured by western dot-blot quantified using densitometry, JDM [n=10] and CHC [n=11]. Plasma cell-free mtDNA was quantified as copy number of the mitochondrial gene MT-CO3per ml of plasma for CHC [n=16] and JDM pre-treatment [n=45] using standard curve qPCR. HC PBMC samples [n=6] were cultured with IFN-α or oxmtDNA (+ LL37) with or without TLR-9 antagonist or the anti-oxidant n-acetyl cysteine (NAC). Post-culture, IFN1 gene expression was measured by qPCR.

Results: RNA-seq confirmed a strong IFN1 signature pre-treatment, and demonstrated that genes involved in mitochondrial function were abnormally expressed in both pre- and on-treatment CD14+ cells compared to controls, suggesting that mitochondrial dysfunction is not corrected by current treatment strategies. Validation of RNAseq using flow cytometry and western dot-blot showed that there was an increase in mitochondrial superoxide and oxmtDNA in CD14+ monocytes, JDM pre-treatment vs. CHC (p=0.034) and JDM Vs. CHC (p=0.061). This was complimented by increased plasma cell-free mtDNA was increased in JDM pre-treatment compared to controls (p=0.0076). 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 IFN1 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: This study establishes that in JDM, monocytes have an increased production of mitochondrial superoxide and oxmtDNA. There is also an increased amount of plasma cell free mtDNA. We have established a mechanism of oxmtDNA induction of IFN1 signature and the potential to block this pathway with TLR-9 antagonist and NAC, identifying these pathways as novel treatment targets. Further work will investigate the mechanistic relationship between IFN1 driven inflammation and altered mitochondrial metabolism in monocytes.

Patient Consent Received

Yes

Disclosure of Interest

None declared

O33 Long-term follow-up of juvenile localized scleroderma patients treated with methotrexate-based standardized regimens (consensus treatment plans)

S. Li¹, A. Thammavongxay², M. Ibarra³, K. Torok⁴, P. Ferguson⁵, C. E. Rabinovich⁶, R. Fuhlbrigge⁷, K. Stewart⁸, E. Pope⁹, R. Laxer¹⁰, S. Hong⁵, T. Mason¹¹, M. Becker⁶, G. Higgins¹², F. Dedeoglu¹³, F. the CARRA Legacy Registry Investigators¹⁴

¹Pediatrics, Joseph M Sanzari Children's Hospital, Hackensack Meridian School of Medicine; ²Bergen Academies, Hackensack; ³Children's Mercy Hospital, Kansas City; ⁴Children’s Hospital of Pittsburgh, Pittsburgh; ⁵University of Iowa, Iowa City; ⁶Duke University, Durham; ⁷University of Colorado, Denver; ⁸Texas Scottish Rite, Dallas, United States; ⁹Hospital for Sick Kids; ¹⁰Hospital for Sick Children, Toronto, Canada; ¹¹Mayo Clinic, Rochester; ¹²The Ohio State University, Columbus; ¹³Boston Children's Hospital, Boston; ¹⁴CARRA, Milwaukee, United States

Correspondence: S. Li

Introduction: Juvenile localized scleroderma (jLS) is a rare chronic inflammatory and fibrosing disease associated with a high risk for morbidity in children. Methotrexate (MTX) has been identified as effective treatment, but data is limited as to the optimal duration, and need for corticosteroid (CS) treatment. The LS group of the Childhood Arthritis and Rheumatology Research Alliance (CARRA) developed standardized regimens (consensus treatment plans, CTPs) for comparative effectiveness studies. The results of a 1-year follow-up of a pilot multi-center study of the MTX-based CTPs were previously reported. Of the 50 patients enrolled, 44 (88%) completed 1 year of follow-up, with 33 (66%) of the patients rated as responders and 11 (22%) as non-responders. We now report on long-term follow-up of these patients.

Objectives: To determine the long-term response of jLS patients treated with MTX-based CTPs.

Methods: Patients enrolled in the pilot CTP study were eligible to enroll in the long-term extension, with study visits completed at 24 and 36 months. Each patient was evaluated by the same investigator for all 3 years of the study. Treatments and adverse events that occurred since the last study visit were collected. Descriptive analysis was performed, with p values calculated by Z-score or Mann Whitney U test. Inactive disease was defined as physician global assessment of activity (PGA-A) = 0, remission off medicine as PGA-A = 0 with the patient off treatment.

Results: Most patients were female (70%), had linear scleroderma (28/44), with a median age of onset 9.4 years. Thirty-seven (74%) of patients completed 3 years of follow-up (Table). PGA-A and skin activity scores (mLoSSI, LSCAM) declined by 12 months and were then stable. Over time, more patients achieved inactive disease, with 20% able to achieve remission off methotrexate. Disease flares were most common in years 1 and 2 when ~20% of patients flared. In addition to 11 non-responders in year 1, 5 additional patients were non-responders in years 2 and 3. Non-responders most commonly received CS and mycophenolate mofetil. The frequency of adverse events decreased 3-fold by year 3.

Conclusion: JLS patients treated with MTX-based standardized regimens were found to achieve further improvement in years 2 and 3 with continued treatment, with 20% able to achieve remission off medicine in year 3. Disease flares occurred in each year and overall, 16 (32%) patients were non-responders, requiring additional treatment for disease control. More work is needed to identify the at-risk patients and determine their optimal therapy.

Disclosure of Interest

None declared

Table 1 (abstract O33). See text for description

O34 Genetics of age at systemic lupus erythematosus diagnosis

R. Carlomagno¹, F. Liao¹, J. Cao², D. Dominguez¹, D. D. Gladman³, N. Groot⁴, M. Ishimori⁵, C. Jefferies⁵, D. L. Kamen⁶, S. Kamphuis⁴, M. S. Klein-Gitelman⁷, A. M. Knight¹, C.-C. J. Lee⁵, D. M. Levy¹, K. B. Onel⁸, A. Paterson², C. A. Peschken⁹, J. E. Pope¹⁰, Z. Touma³, M. B. Urowitz³, D. J. Wallace⁵, J. E. Wither³, D. Webber¹, E. D. Silverman^1,11, L. T. Hiraki^1,2

¹Division of Rheumatology; ²Genetics & Genome Biology, Research Institute, The Hospital for Sick Children; ³Schroeder Arthritis Institute, Krembil Research Institute, Toronto Western Hospital, Toronto, Canada; ⁴Department of Pediatric Rheumatology, Sophia Children’s Hospital, Erasmus University Medical Center, Rotterdam, Netherlands; ⁵Division of Rheumatology, Department of Medicine, Cedars Sinai Medical Center, Los Angeles; ⁶Division of Rheumatology and Immunology, Medical University of South Carolina, Charleston; ⁷Division of Rheumatology, Department of Pediatrics, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago; ⁸Pediatric Rheumatology, Hospital for Special Surgery, New York, United States; ⁹Departments of Medicine and Community Health Sciences, University of Manitoba, Winnipeg; ¹⁰Department of Medicine, University of Western Ontario, St. Joseph's Health Centre, London; ¹¹Division of Translational Medicine Research Institute, The Hospital for Sick Children, Toronto, Canada

Correspondence: R. Carlomagno

Introduction: Genome wide association studies (GWAS) have identified >100 SNPs associated with systemic lupus erythematosus (SLE) risk. There may be additional loci impacting the age of diagnosis.

Objectives: The purpose of this study was to identify genetic variants associated with age of SLE diagnosis.

Methods: Our cohort included patients who met ACR and/or SLICC classification criteria for SLE, followed at tertiary care centres. We censored patients with missing data on age at diagnosis. Patients were genotyped on the Illumina Multiethnic Array (MEGA) and Illumina Global Screen Array (GSA). Ungenotyped SNPs were imputed using the TopMed reference. We restricted to SNPs with a minor allele frequency (MAF) ≥ 0.01 and imputation quality R²≥ 0.3. Ancestry was genetically inferred from principal components (PCs) and ADMIXTURE in reference to 1000 Genome Project. We completed genome-wide linear regression of log-transformed age at SLE diagnosis with GENESIS (genome-wide significance P<5x10^-8). Multivariate models were adjusted for sex and 5 PCs. We also conducted a GWAS of childhood-onset SLE (cSLE) patients, defined as diagnosis <18 years of age, vs. adult-onset SLE (aSLE), using logistic regression, and adjusted for the same covariates. We conducted sensitivity analyses where we stratified GWAS by cSLE and aSLE, then meta-analyzed results using inverse variance weighting, as well as ancestry-stratified analyses (Europeans, East Asians, Africans, Amerindians and Admixed).

Results: Our cohort included 1489 patients, 761 (51%) with cSLE, 1306 (88%) female. The median age at diagnosis was 17.7 years (IQR 14, 31) in the total cohort, 14.1 years (IQR 11.8, 15.8) in the cSLE, and 31.2 years (IQR 24.7, 42) in the aSLE groups. In the total cohort, 576 (39%) were of European ancestry, 278 (19%) East Asian, and 253 (17%) Admixed. We included 11.7M SNPs in GWAS. In the age of SLE diagnosis GWAS, 2 loci on chr16 were genome-wide significant associated to a younger age at diagnosis (top SNP rs11641349, Beta -0.03y, SE 0.15y, P=4.33x10^-8, MAF 0.2). Both SNPs were intronic to CCDC113, a component of centriolar satellites. These loci were also the most significant in the GWAS of cSLE (top SNP rs16959933, OR 1.75 [95% CI: 1.43, 2.14, P=5.45 x10^-8]). Sensitivity analyses showed similar results, yet they did not reach genome-wide significance with top SNPs rs11641349 (P=3.84x10^-7) and rs16959933 (P=4.50x10^-7) in the age group model, and rs11641349 (P=3.52x10^-7) and rs16959933 (P=4.22x10^-7) in the ancestry model.

Conclusion: In our multiethnic cSLE and aSLE cohort, we identified genome-wide significant loci associated with age at diagnosis and cSLE risk, both intronic to CCDC113 (chr16). Our study requires independent validation.

Disclosure of Interest

None declared

O35 Gene signature fingerprints divide sle patients in subgroups with similar biological disease profiles: a multicenter longitudinal study

M. J. Wahadat^1,2, D. Schonenberg-Meinema³, C. van Helden-Meeuwsen¹, S. van Tilburg¹, N. Groot², E. Schatorjé^4,5, E. Hoppenreijs^4,5, P. Hissink Muller⁶, D. Brinkman⁶, D. Dvorak⁷, M. Verkaaik², K. Bouchalova⁷, M. van den Berg³, S. Kamphuis², M. Versnel¹

¹Immunology; ²Paediatric Rheumatology, University Medical Center Rotterdam, Rotterdam; ³Paediatric Immunology, Rheumatology and Infectious Diseases, Amsterdam University Medical Centre, Amsterdam; ⁴Paediatric Rheumatology, st. Maartenskliniek; ⁵Paediatric Rheumatology, Radboud University Medical Center, Nijmegen; ⁶Pediatrics, Division of Pediatric Rheumatology, Leiden University Medical Center, Leiden, Netherlands; ⁷Paediatric Rheumatology,Department of Paediatrics, Faculty of Medicine and Dentistry, Palacky University Olomouc and University Hospital, Olomouc, Czech Republic

Correspondence: M. J. Wahadat

Introduction: Clinical phenotyping and predicting treatment responses in Systemic Lupus Erythematosus (SLE) patients is challenging. Extensive blood transcriptional profiling has identified various gene modules that are promising for stratification of SLE patients based upon aberrantly activated immunological pathways. Yet the feasibility to implement these complicated and expensive tests for use in daily clinical practice of routine clinical laboratories is challenging if not impossible.

Objectives: This study aims to translate transcriptomic data into gene signatures suitable for introduction into clinical practice and to associate these signatures with disease activity.

Methods: RT-PCR of multiple genes from the Interferon M1.2, Interferon M5.12, neutrophil (NPh)- and plasma cell (PLC) modules, followed by a principle component analysis was used to identify indicator genes per gene signature. Gene signatures were measured in longitudinal samples from two childhood onset SLE cohorts (n=101 and n=34, respectively) and associated with clinical features. Disease activity was measured using SELENA-SLEDAI. Cluster analysis subdivided patients into three fingerprint groups termed 1) all-signatures-low, 2) only IFN high (M1.2 and/or M5.12) and 3) high NPh and/or PLC.

Results: All gene signatures were significantly associated with disease activity in cross-sectionally collected samples. The PLC signature showed the highest association with disease activity. Also, in longitudinally collected samples, the PLC signature was associated with disease activity and showed a decrease over time. When patients were divided into the three fingerprints, the highest disease activity was observed in fingerprint-3, the high NPh and/or PLC group. The lowest disease activity was observed in fingerprint-1, the all-signatures-low group. The same distribution could be reproduced in samples from an independent SLE cohort.

Conclusion: Gene signatures are associated with disease activity and can be suitable tools to sub-classify patients into groups with similar pathogenically activated immunological pathways.

Patient Consent Received

Yes

Disclosure of Interest

None declared

O36 Frequency of uveitis in craniofacial juvenile scleroderma

M. K. Osminina, N. S. Podchernyaeva, M. S. Petrova, O. V. Shpitonkova, M. N. Nkcolaeva, T. V. Zubareva

Pediatric Department, I. M. Sechenov First Moscow State Medical University, Moscow, Russian Federation

Correspondence: M. K. Osminina

Introduction: Eye involvement in craniofacial juvenile scleroderma (CFJS) reported to present with sclerotic skin changes of eyelids and eyelashes, keratoconjunctivitis sicca and uveitis (anterior segment inflammation), the latter could result in reducing of the visual acuity

Objectives: To analyze the frequency of uveitis in CFJS, specifity of its clinical presentation,

and prognosis.

Methods: Retrospective analysis of clinical and instrumental observation, including brain magnetic resonance imaging (MRI), electroencephalography (EEG), ophthalmologic examination in particular with slit-lamp was done

Results: We observed 105 children with CFJS, aged from 3 to 17 years, the mean age was 10,2 years (M ±2,52), 62 girls and 43 (girls\ boys

boys = 1.4: 1). The majority patients (pts) – 95 have linear skin lesions only on face and head ( linear scleroderma “en coupe de sabre”type - LSCD group), 10 pts have unilateral skin damage of trunk, extremities - (UlSl) affecting face and head.

Uveitis was detected in 12 pts (11,4% ), among them 11 girls and 1 boy. Anterior uveitis was unilateral on the side of skin lesions in 10 pts, bilateral in 2.

In 2 pts uveitis was accompanied by episcleritis, in one-by chorioretinitis. In group UlSl -there were 3 uveitis, detected after 3-5 year of disease duration, while in Lubricant eye drops group -uveitis appeared during this first year of disease outburst, in most cases simultaneously with appearance of skin lesions. In 4 girls uveitis was accompanied by focal seizures, with EEG epileptic pattern and brain foci on MRI on the side of skin damage.90% of uveitis pts were ANF positive.

Pts with uveitis have no specific complains or overt symptoms of eye involvement. It was detected only by ophthalmologic examination screening with slit-lamp we use as a matter of routine in all scleroderma children .Mean follow up period for uveitis children was 5,5 (M ±0.3) years. All of 12 patients achieved remission of uveitis. Significant decrease of activity was seen in 1 month (mo) of therapy, remission in 6 mo. In 2 children uveitis relapsed, after systemic disease modifying antirheumatic therapy (BMART) was stopped by parents. In both cases it was uveitis in LSCD, in 18 and 36 mo after initiation of BMART and in 4-6 weeks (wk) of its discontinuation,the relapses of uveitis were diagnosed after exacerbation of skin lesions. BMART in all uveitis pts includes corticosteroids(CS) orally 1mg\kilo- 12 wk, followed by taping and withdrawal, methotrexate(MTX) 12-15 mg\b.sw. parenterally 30-36 mo; in some cases of severe LSCD MTX in combination with mycophenolate mofetil (600 mg\b.sq. twice a day)-Local treatment - CS and non steroid anti-inflammatory drops, and lubricant eye drops for cornea protection

Conclusion: Frequency of uveitis in our cohort of CFJS pts was 11,4%. In all the cases children did not have ocular complains –so called “white uveitis”, but more than 30% uveitis pts had concomitant central nervous system involvement- seizures, brain foci on MRI on the side of skin damage. The prognosis of uveitis in our pts was benign. Pts with CFJS must be regularly ( every 3 mo) checked by ophthalmologist, with obligatory slit-lamp evaluation, compulsorily at the disease debut and before discontinuation of BMART in remission.

Patient Consent Received

Yes

Disclosure of Interest

None declared

e-Poster viewing: JIA (oligo, poly, psoriatic)

P1 A Problem-oriented approach to assessment hand-related problems in patients with juvenile idiopathic arthritis: ICF perspective

N. Arman¹, E. Tarakci¹, O. Kasapcopur²

¹Department of Physiotherapy and Rehabilitation, Istanbul University-Cerrahpasa, Faculty of Health Science; ²Department of Pediatric Rheumatology, Cerrahpasa Medical School, Istanbul University-Cerrahpasa, Istanbul, Turkey

Correspondence: N. Arman

Introduction: A problem-oriented approach (POA) is suggested that the best way to assess and management in patients with chronic disease. POA provides to set a meaningful and purposeful goal for treatment. Creating a problem-oriented assessment algorithm specific to disease provides practical and efficient results in the clinic. There is no defined algorithm for POA in patients with JIA in the literature. So, our team has firstly defined an algorithm of POA in patients with JIA and use it in the clinic. Assessment and management of the hands and wrist that are the most included joints in JIA are also complex. There is little information about the prevalence of hand- and wrist-related symptoms (i.e. pain or stiffness) and impairments (i.e. problems in body function or structure, such as limitation of the range of motion (ROM)), and their resulting activity limitations (i.e. difficulties in dressing) and participation restrictions (i.e. problems with involvement in life situations, such as attending school) in JIA.

Objectives: The aim of this study was to use the POA for assessing hand-related problems in patients with JIA.

Methods: 216 patients were evaluated for eligibility, 44 patients with JIA who have bilaterally affected wrist joints were included in the study. The POA with three steps was used to evaluate the patients. In the first step in which the problems are determined, hand-related problems of the patients were questioned in 5 categories: pain, limitation of ROM, fatigue, weakness and functional incompetence. The patients were asked to rank these five problems as follows: the most important problem and the least important problem for them. In the second stage of POA, in which body structure and functions are assessed, pain and fatigue were evaluated with the Numeric Rating Scale (NRS). ROM of hand was assessed with a universal goniometer. Muscular strength was estimated at maximal isometric force for the wrist muscles by using a portable handheld dynamometer. Grip and pinch strengths were evaluated by a dynamometer. In the third stage of POA, in which activity and limitations were evaluated, activity performance was evaluated with the Jebsen Taylor Hand Function Test (JTHFT), activity limitation was performed with the Childhood Health Assessment Questionnaire (CHAQ) and Duruoz Hand Index (DHI).

Results: 45.5% of the patients reported that their primary problem was functional incompetence, 34.1% of weakness, 13.6% of limitation, 4.5% of fatigue and 2.3% of pain. The score of NRS-pain was five and above in 54.5 % of the patients. Also, the score of NRS-fatigue was five and above in 75 % of the patients. The ROMs of wrist flexion and extension were decreased in 72% of the patients. Also, all scores of the wrist muscle strengths and grip and pinch strengths of all patients were low according to the strength norms of healthy children. In the various grade of scores (1-3 points) according to CHAQ, 79.5% of the patients reported difficulty in dressing activities, 93.2% gripping, 70.5% arising and 51.1% eating. Significant relationships were found in the scores of JTHFT and all grip and pinch strengths, the strength of wrist extension, DHI and CHAQ-total (p<0.05). Pinch strength was also a significant predictor of fatigue severity (p<0.05).

Conclusion: We believe that POA is a useful method for a comprehensive evaluation in patients with JIA who hand involvement. We found that functional problems were the most critical problems reported by patients. Factors affecting functional abilities can be evaluated systematically through the POA by choosing the eligible assessment scale. Also, setting a short and long-term functional ability-oriented goal with POA will be provided with practical and systematic strategies for JIA treatment.

Patient Consent Received

Yes

Disclosure of Interest

None declared

P2 several rare autoimmune diseases in one patient

L. Augunaite, M. Jakineviciute, A. Snipaitiene, L. Jankauskaite

Academy of Medicine, Lithuanian University of Health Sciences, Kaunas, Lithuania

Correspondence: L. Augunaite

Introduction: Patients diagnosed with an autoimmune disease have a substantially increased risk for another autoimmune disease, e.g, psoriasis patients can develop multiple sclerosis [1].

Objectives: We present a patient with several rare autoimmune diseases.

Methods: Case presentation.

Results: A 15 y/o girl referred to a pediatric rheumatologist regarding pain of the left knee, increasingly prominent limping and clumsiness. The left wrist movements were painful and limited, and the left knee was slightly swollen, painful during flexion. There were a severe skin psoriasis seen in the head, that was bothering patient already a few years. Also granuloma annulare signs were seen in the armpits and on the ankle area. Ultrasound examination (UG) of the joints showed an effusion in the left knee and signs of a ganglion-specific cyst in the left wrist joint with synovitis signs. Psoriatic juvenile idiopathic arthritis (psJIA) was suspected. Medical anamnesis revealed that the patient was diagnosed with multiple sclerosis (MS) a year ago and received treatment with methylprednisolone pulse therapy. At that time additional studies for infectious and autoimmune disease were done. There were signs of previous citomegalovirus (CMV), Epstein – Barr virus (EBV) and Herpes Simplex virus (HSV) infections (positive IgG for CMV, HSV and EBV). Immunological tests (anti-dsDNA, ANCA, ANA) were in normal range. However, because of the relapsing-remitting course of the neurological disease immunomodulatory treatment with interferon β-1α subcutaneously was initiated. Unfortunately, treatment had to be changed regarding adverse reactions. As MS progressed with new symptoms, new foci in brain MRI and poor prognosis criteria were met, the patient was prescribed second-line treatment with Fingolimoda. During treatment with Fingolimoda, the patient's neurological status remains stable for 2 years. Although there is constant slight leukopenia and lymphopenia (LY: 0,9 x 10 ^9/l, norm: 1,2 -3,34 x 10 ^9/l) seen in complete blood count (CBC). Also episodic exacerbations of psoriasis, subsequent pain of joints and signs of inflammation in the left wrist are observed every 2-3 months. Episodic treatment with NSAIDs for 2-3 weeks for psJIA improves the patient's condition. Additionally, for the left wrist severe inflammation Kenalog injection was done according to the oligoarticular course of psJIA. For now treatment with disease modifying antirheumatic drugs (DMARDs) like methotrexate or others was resisted regarding lymphopenia constantly seen in the CBC.

Conclusion: We present a complex patient with several rare autoimmune diseases from different organ systems (skin, joints and neurology) and remind specialists that in the presence of one autoimmune disease, other autoimmune diseases are also possible. In children psoriasis may be associated with multiple sclerosis and progress to psJIA. There are data that the development of different autoimmune diseases can be caused by certain viral infections, which in our case could be the EBV and CMV [2]. Treatment of these patients can be challenging as there is no experience with drug-drug interactions between Fingolimoda and DMARDs.

References

1. Egeberg A, Mallbris L, Gislason GH, Skov L, Hansen PR. Risk of Multiple Sclerosis in Patients with Psoriasis: A Danish Nationwide Cohort Study. J Invest Dermatol. 2016 Jan;136(1):93-8. doi: 10.1038/JID.2015.350. PMID: 26763428.

2. Langer-Gould A, Wu J, Lucas R, Smith J, Gonzales E, Amezcua L, Haraszti S, Chen LH, Quach H, James JA, Barcellos LF, Xiang AH. Epstein-Barr virus, cytomegalovirus, and multiple sclerosis susceptibility: A multiethnic study. Neurology. 2017 Sep 26;89(13):1330-1337. doi: 10.1212/WNL.0000000000004412. Epub 2017 Aug 30. PMID: 28855411; PMCID: PMC5649756.

Patient Consent Received

Yes

Disclosure of Interest

None declared

P3 Do we all score the physician global assessment in the same way? Results from a large international survey

C. Trincianti¹, M. Backström^2,3, M. Tarkiainen⁴, N. Ruperto⁵, A. Consolaro^1,5, P. Vähäsalo^3,6

¹University of Genova, Genova, Italy; ²LAVA, Vaasa Central Hospital, Vaasa; ³Medical Research Center Oulu, PEDEGO Research Unit, University of Oulu, Oulu; ⁴New Children’s Hospital, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland; ⁵Pediatric Rheumatology Unit, IRCCS Istituto G.Gaslini, Genova, Italy; ⁶Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland

Correspondence: M. Backström

Introduction: The physician global assessment (PGA) of the level of disease activity plays a central role in monitoring the disease course of juvenile idiopathic arthritis (JIA) patients and the response to therapy in clinical practice and in clinical trials as endorsed by the FDA and EMA for the so called ACR JIA coreset. However, it has not been investigated which factors influence the physicians when scoring the PGA.

Objectives: Aim of the study is to assess on a global scale the heterogeneity in PGA scoring and to clarify the factors having an impact on the PGA through a web-based survey.

Methods: A questionnaire regarding factors affecting PGA was sent electronically to all 2640 PRINTO members. The responders were asked to rate from 0 to 100 the relevance of 17 factors possibly affecting PGA scoring. The factors were chosen based on consensus of the study panel. The questionnaire also included 17 detailed patient cases selected to represent a diverse spectrum of clinical situations. The responders were asked to indicate the PGA for each patient on a 0 to 100 scale. Results were compared also after grouping for the level of experience of the assessor in the field of pediatric rheumatology (<5 years, 5-10 years, or >10 years). The heterogeneity in the PGA scoring in the 17 cases was measured through the coefficient of variation (CV). The difference between groups was analysed by Kruskal-Wallis one-way analysis of variance.

Results: Of the 708 health care providers who responded to the survey, 431 delivered a complete answer regarding the factors affecting PGA and 376 indicated the PGA for all the patients. There was a large individual variation in the impact of different factors on PGA (Table). The smallest variation was seen in the number of swollen joints and tender joints. PGA was scored heterogeneously in most patient cases. The median PGA of the cases did not differ between physicians divided in groups based on experience in pediatric rheumatology. The CV of PGA was >50 in 12 and >100 in 3 out of 17 patient cases. 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?” 209 physicians replied “no” and 219 “yes”.

Conclusion: The PGA is scored heterogeneously throughout the world. Shared guidelines for scoring the PGA are needed to obtain consistent patient assessment in clinical trials and routine practice. In particular the weight of the patient clinical history (e.g. oligoarthritis versus polyarthritis), the presence of extra-articular manifestations and patient reported outcome measures should be discussed.

Patient Consent Received

No

Disclosure of Interest

None declared

Table 1 (abstract P3). Factors affecting physician´s global assessment (mean, standard deviation (SD) and coefficient of variation (CV)) in non-systemic JIA. N = 431

P4 The juvenile arthritis damage index: how well does this index reflect damage in patients with juvenile idiopathic arthritis?

R. Bax, J. van Straalen, N. M. Wulffraat, S. de Roock, J. F. Swart

UMC Utrecht, Utrecht, Netherlands

Correspondence: R. Bax

Introduction: The Juvenile Arthritis Damage Index (JADI) is used to assess articular and extraarticular damage caused by long-term inflammation in patients with Juvenile Idiopathic Arthritis (JIA)¹. Virtually no research has been conducted about the quality of the JADI and the knowledge the index provides to us.

Objectives: The aim of this study is to gain insight into the characteristics of JIA patients who scored positively on the articular part of the JADI (JADI-A) and to examine whether the JADI-A is a representative index for damage.

Methods: This is a retrospective cohort study in which data were analyzed from patients with JIA in the Wilhelmina Children’s Hospital in Utrecht, the Netherlands. The JADI-A score is expected to increase or remain the same but not to decrease over time. To evaluate this expectation, it was examined if ever-positive JADI-A scores have flipped into a zero on their last reported cumulative JADI-A score.

To evaluate if the JADI-A identified all joints with damage, the results of the JADI-A in the included patients were compared to the limited joint count in the last joint assessment and to radiographic damage. On the other hand, the number of inactive limited joints during the last joint assessment of patients with a never-positive JADI-A was determined to examine if there are patients with inactive limited joints and a negative JADI-A score, whereas they could be expected to have a positive JADI-A score. Finally, the results of the JADI-A of a selection of patients known to have radiographic damage were evaluated to examine the assumption that the JADI-A reflects (radiographic) damage when present.

Results: 375 of the 914 patients (41.0%) in the database had an ever-completed JADI-A. Of these 375 patients 53 (14.1%) had an ever-positive JADI-A with a total amount of 158 ever-positive joints. 14 of these 53 patients (26.4%) had a negative JADI-A at the last time the JADI-A was assessed.

Only 29.7% of the ever-positive joints was also limited in the last joint assessment and 69.2% of all ever-positive joints did show radiographic damage on the last X-ray.

14.6% of the 322 patients with a never-positive JADI-A did have inactive limited joint(s) in their last joint assessment. Only 50.0% of the 18 selected patients known to have radiographic damage and with an ever-completed JADI-A had an ever-positive JADI-A.

Conclusion: A considerable discrepancy was seen between the results of the JADI-A on the one hand and the inactive limited joint count in the last joint assessment as well as radiographic damage on the other hand. Furthermore several positive JADI-A scores flipped to negative, suggesting either that rheumatologists did not complete the index correctly and/or that the JADI-A is not successful in detecting (lasting) damage in patients with JIA. Further research on this remarkable discrepancy is needed, because in the end we want to identify all children with damage as expeditiously as possible and to not unnecessarily burden children without joint damage with repeated radiographs.

Disclosure of Interest

None declared

P5 Prospective study on MMR booster vaccine in children with rheumatic diseases treated with DMARDS and/or biologics

M. Bizjak, F. Dasoula², B. Balaziova³, A. Adrovic⁴, D. Maritsi², T. Dallos³, O. Kasapcopur⁴, N. Toplak^1,5, on behalf of PReS Vaccination WP

¹Department of Allergology, Rheumatology and Clinical Immunology, UCH Ljubljana, Ljubljana, Slovenia; ²Second Department of Pediatrics, “P.&A. Kyriakou” Children’s Hospital, National and Kapodestrian University of Athens, Athens, Greece; ³Department of Paediatrics, Comenius University Medical School in Bratislava, National Institute of Children’s Diseases, Bratislava, Slovakia; ⁴Department of Pediatric Rheumatology, Istanbul University-Cerrahpasa, Istanbul, Turkey; ⁵MF Ljubljana, Ljubljana, Slovenia

Correspondence: M. Bizjak

Introduction: Live attenuated vaccines are not usually recommended in children with rheumatic diseases (RD) treated with immunosuppressive (IS) therapy (1). However, a retrospective study which included 234 children with RD who received live attenuated booster measles-mumps-rubella (MMR) vaccine during treatment with IS therapy showed that the booster dose was safe (2).

Objectives: To evaluate safety and long-term immunogenicity of the MMR booster vaccine in children with RD treated with IS therapy in a prospective study.

Methods: This is an ongoing multinational, multicentre prospective study. Patients with immune-mediated diseases treated with DMARDs and/or biologic therapy with stable disease were included if they were scheduled, according to their national vaccination program, to receive 2^nd (booster or “catch-up”) dose of MMR vaccine. Safety was monitored by tracking infection with vaccine or wild-type viruses after vaccination, possible adverse events of the MMR vaccine and by monitoring disease activity before and after vaccination. Immunogenicity was monitored by measuring protective antibodies before vaccination and then at predetermined time points after vaccination.

Results: By the end of May 2021, 22 patients from 4 centres were included (Greece, Slovakia, Slovenia and Turkey). One patient had localized scleroderma and all others had juvenile idiopathic arthritis (JIA) (12 oligoarticular JIA, 4 polyarticular JIA, 2 systemic JIA, 2 enthesitis-related arthritis, 1 psoriatic JIA) Median age at diagnosis was 3.8 years (range 1.4-10.5 years), median age at 1^st dose of MMR vaccine was 1.27 years (range 0.58-4.36 years) and median age at 2^nd dose of MMR vaccine was 8.05 years (range 2.8-14.3 years). At the time of 2^nd vaccination, 13 patients were treated with TNF-α inhibitors, 9 of them received methotrexate (MTX) concomitantly, 1 patient was on IL-1 inhibitor and corticosteroids (CS), 1 patient on IL-6 inhibitor and CS and 7 patients were on MTX. Regarding safety, there were no increase in disease activity, vaccine strain infection or serious adverse events after vaccination. Six patients reported mild local or systemic reactions (fever, fatigue, arthralgia, headache, cough) in the 6 weeks following vaccination. Protective antibodies against measles and mumps were measured in 9 patients, they were positive in 7/8 patients 2-3 months after 2^nd dose.

Conclusion: These preliminary results of prospective study corroborate the findings of recently published retrospective study (2). However, the number of included children is currently too small to draw any firm conclusions and long-term immunogenicity remains to be determined in the future. This is an ongoing project and we expect that other countries and centres will join this effort soon.

References

1 Heijstek MW, et al. Ann Rheum Dis. 2011; 70: 1704-12.

2 Uziel Y, et al. Vaccine. 2020; 38: 2198-201.

Patient Consent Received

Yes

Disclosure of Interest

None declared

P6 M-ficolin: a valuable biomarker to identify leukemia from juvenile idiopathic arthritis

N. Brix^1,2, M. Glerup¹, S. Thiel³, C. E. Mistegaard³, R. G. Skals⁴, L. Berntson⁵, A. Fasth⁶, S. Nielsen⁷, E. Nordal⁸, M. Rygg^9,10, H. Hasle¹, B. K. Albertsen¹, 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; ³Department of Biomedicine, Aarhus University Hospital, Aarhus; ⁴Department of Clinical Biostatistics, Aalborg University Hospital, Aalborg, Denmark; ⁵Department of Women’s and Children’s Health, Uppsala University, Uppsala University; ⁶Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; ⁷Department of Pediatrics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; ⁸Department of Pediatrics, University Hospital of North Norway and Department of Clinical Medicine, UiT The Arctic University of Norway, Tromsø; ⁹Department of Clinical and Molecular Medicine, NTNU - Norwegian University of Science and Technology; ¹⁰Department of Pediatrics, St. Olavs Hospital, Trondheim, Norway

Correspondence: N. Brix

Introduction: Distinction on clinical grounds between acute lymphoblastic leukemia presenting with arthropathy (ALL_arthropathy) and juvenile idiopathic arthritis (JIA) is difficult, as the clinical and paraclinical signs of leukemia may be vague. As the only study of lectin pathway in children with ALL indicate low serum M-ficolin levels and M-ficolin has proven to be a marker of disease activity in JIA, we hypothesized that it would be possible to differentiate ALL from JIA by M-ficolin.

Objectives: The primary aim was to examine the use of lectin complement pathway proteins as markers to differentiate ALL_arthropathyfrom JIA. The secondary aims were to compare the protein levels at baseline and follow-up in a paired number of children with ALL and to examine the correlation with hematology counts, ESR, CRP, blasts, relapse, and death.

Methods: In this observational study, we measured M-ficolin, CL-K1 and MASP-3 in children with ALL (n = 151) and JIA (n = 238) by time-resolved immunofluorometric assays in serum. Logistic regression was used for the predictions, considering risk of ALL as the outcome. We performed internal validation using repeated “10-fold cross-validation” with 100 repetitions computing the optimized corrected Area Under the ROC curve (AUC) as well as positive and negative predictive values in order to evaluate the predictive performance.

Results: The level of M-ficolin was more than 4-fold higher in JIA than in ALL_total and the ALL_arthropathy subgroup_: 0.65 μg/mL (IQR 0.32-1.21) versus 3.01 μg/mL (IQR 2.43-3.85)μg/mL, p <0.001. The M-ficolin level normalized after remission of ALL to 1.57 μg/mL ( IQR 0.83-2.24), p <0.001. M-ficolin could differentiate ALL from JIA with an AUC of 94% and positive predictive value (PPV) of 95%, exceeding CRP and hemoglobin. In a dichotomy predictive model with optimal cut-offs for M-ficolin, platelets and hemoglobin AUC was 99% and PPV 98% in detecting ALL from JIA.

Conclusion: M-ficolin is a valuable marker to differentiate the child with ALL from JIA.

Patient Consent Received

Yes

Disclosure of Interest

None declared

P7 Nationwide Israeli study: obstacles in early diagnosis of children with juvenile idiopathic arthritis (JIA) - a retrospective study

Y. Butbul Aviel, Y. Frenkel², I. Kraushar³, M. H. Saied⁴, R. Haviv⁵, Y. Uziell⁵, Y. Berkun⁶, M. Heshin-Bekenstein⁷, I. Tirosh⁸, I. Tirosh⁹, G. Amerilio¹⁰, L. Harel¹¹, E. Ling¹²

¹Pediatric Rheumatology unit, Ruth Rappaport Children's Hospital, Rambam Medical Center, Haifa, Israel; ²Rambam Medical Center Haifa Israel, Haifa, Israel; ³Pediatric Rheumatology Service, Rambam Medical Center Haifa Israel; ⁴Pediatric Rheumatology Service, Carmel Medical center, Haifa; ⁵Pediatric Rheumatology Service, Department of Pediatrics, Meir Medical Center, Kfar Saba; ⁶Pediatric Rheumatology Service, Hadassah-Hebrew University Medical Center, Mount Scopus, Jerusalem, Jerusalem; ⁷Pediatric Rheumatology Service, Dana-Dwek Children’s Hospital Tel Aviv; ⁸Pediatric Rheumatology Service, Edmond and Lily Safra Children's Hospital, Sheba Medical Center; ⁹Israel Pediatric Rheumatology service, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Tel Aviv; ¹⁰Pediatric Rheumatology Unit, Schneider Children's Medical Center of Israel; ¹¹Pediatric Rheumatology Unit, Schneider Children's Medical Center of Israel, Petach Tikva; ¹²Pediatric Rheumatology Unit, Saban Pediatric Medical Center for Israel Soroka University Medical Center, Be'er Sheva, Israel

Correspondence: Y. Butbul Aviel

Introduction: Juvenile idiopathic arthritis (JIA) is the leading cause of chronic arthritis in children. A delay in the diagnosis may lead to long term damage.

Objectives: Characterization of the stages that patients with JIA pass until diagnosis and analysis of the different outcome measures that lead to a delay in the diagnosis of JIA in Israel.

Methods: We conduct a retrospective cohort study in 8 pediatric rheumatology centers in Israel. All patients that were diagnosed with JIA between 2017 and 2019 included in the study. Demographic, clinical and data regarding the referral’s doctors were collected.

Results: 207 patients included in the study (69% female). Patients were evaluated by primary care physicians (62%), ER physicians (13%), and orthopedists (11%) prior to diagnosis. The median time until diagnosis was 56 days (1-2451 days). Patients diagnosed with ERA/SPA and psoriatic arthritis had the longest period until diagnosis (351 and 213 days respectively). A younger age was correlated with a later diagnosis (r=0.3, P<0.0001). Females were diagnosed earlier compared to males (median 48 vs 84 days respectively). The distance to the rheumatology center with regards to time until diagnosis was not significant (P=0.19). Fever at presentation, significantly shortened the time to diagnosis (P<0.0001), whereas involvement of the small joints/sacroiliac joints significantly lengthened the time (P<0.05).

Conclusion: This is the first nationwide multicenter study that analyzes the obstacles in the diagnosis of JIA in Israel. Raising awareness of JIA, especially of patients with SPA, is crucial in order to avoid delays in diagnosis and treatment.

Patient Consent Received

No

Disclosure of Interest

None declared

P8 Juvenile idiopathic arthritis: assessment of the general knowledge of the different medical professionals involved

L. Charlène, D. Alexandra

Calvados, CHU de Caen, Caen, France

Correspondence: L. Charlène

Introduction: Juvenile idiopathic arthritis is one of the most common chronic pediatric diseases. However, it remains little known by 1st line doctors to evoke the diagnosis. This results in a diagnostic delay, sometimes several months, potentially responsible for disabilities. The associated anterior uveitis is also unknown. This is probably related to a lack of teaching, but studies on this subject are scares.

Objectives: The main objective is to establish an inventory of the knowledge of medical professionals of Lower Normandy, but also to sensitize them to this pathology, to make better known its network of care, and its management.

Methods: We carried out a cross-sectional descriptive study whose data were collected using a questionnaire addressed to the various medical professionals concerned by the AJI in the three departments of the former Basse-Normandie region: pediatricians, rheumatologists, pediatric orthopaedic surgeons, ophthalmologists, general practitioners and internal physicians of these different specialties. Three hundred and eleven questionnaires were collected out of the 178 sent out.

Results: The response rate was 17.4%. Juvenile idiopathic arthritis is known to 89% of professionals. Dedicated rare disease reference and skills centers are known by 31% and 32% of them; the national diagnostic and care protocol (PNDS) by 20.5%. Amalgamation with inflammatory pathologies of the digestive tract (10%) and autoimmune pathologies (9%) is common. The anti-nuclear factors are performed by 19% of professionals. Systemic corticosteroids are prescribed in 23% of cases in 1st intention. Anterior uveitis is recognized in 76% of cases as a complication (ophthalmology). Quarterly eye monitoring is carried out by 35% of professionals, 45% of whom are ophthalmologists.

Conclusion: Our results show that, although the majority of health professionals who responded to this questionnaire are aware of the AJI, there is a lack of education during initial training of physicians. Specific training seems necessary in order to improve the management of this chronic pathology and thus avoid sequelae. These data must be confirmed by other studies of national scope in order to determine whether the lack of knowledge about this pathology is related to a lack of communication and local or national education.

Patient Consent Received

Yes

Disclosure of Interest

None declared

P9 Vitamin D levels and risk of juvenile idiopathic arthritis: a mendelian randomization study

S. L. Clarke^1,2,3, R. E. Mitchell^1,2, G. C. Sharp^1,2, A. V. Ramanan^3,4, C. L. Relton^1,2

¹MRC Integrative Epidemiology Unit; ²Population Health Sciences, University of Bristol; ³Department of Paediatric Rheumatology, Bristol Royal Hospital for Children; ⁴Translational Health Sciences, University of Bristol, Bristol, United Kingdom

Correspondence: S. L. Clarke

Introduction: Evidence for the role of vitamin D in juvenile idiopathic arthritis (JIA) risk is mixed across epidemiological studies, however such studies are challenging to undertake and are susceptible to considerable bias. Low vitamin D levels are common within the general population and easily corrected, therefore there is considerable potential public health benefit if a causal association between vitamin insufficiency and JIA is established. Mendelian randomisation (MR) is a method of causal inference which relies on the use of genetic variation, assigned at conception, as a proxy of the exposure of interest and thus limits bias due to confounding and reverse causation, subject to core assumptions being met.

Objectives: To use MR to test whether vitamin D levels are causally associated with JIA risk.

Methods: Since 25-hydroxy-vitamin D (25OHD) is the major circulating form of vitamin D we used summary level data from the largest and most recent genome wide association study of 25OHD levels (sample size 443,734), alongside summary data from two JIA genome wide association studies (sample sizes 15,872 and 12,501), all from European populations. To test and account for potential bias due to violations of the core MR assumptions we employed multiple different MR methods and sensitivity analyses.

Results: Using a genetic instrument for 25OHD, comprising 69 25OHD-associated single nucleotide polymorphisms, we show there is no evidence of a causal association between genetically predicted 25OHD levels and JIA risk (OR 1.00, 95% CI 0.76-1.33 per standard deviation increase in standardised natural-log transformed 25OHD levels). This estimate was consistent across all methods tested. There was also no evidence of reverse causation when assessing the causal effect of genetically predicted JIA on 25OHD levels (0.004 standard deviation decrease in standardised natural-log transformed 25OHD levels per doubling odds in genetically predicted JIA, 95% CI -0.009-0.002).

Conclusion: In this study we found no evidence that genetically increased 25OHD levels confers protection from JIA and that population level vitamin D supplementation is unlikely to contribute to a reduction in JIA incidence.

Patient Consent Received

No

Disclosure of Interest

None declared

P10 Achievement of controlled disease and normal physical function in patients with polyarticular course juvenile idiopathic arthritis receiving tofacitinib: a post hoc analysis of data from a phase 3, randomised, withdrawal trial

A. Consolaro¹, D. J. Lovell², O. Synoverska¹, C. Abud Mendoza¹, A. Spindler¹, Y. Vyzhga¹, E. Alexeeva¹, J. Chaitow¹, P. Chiraseveenupraprund², H. Shi³, L. Stockert³, G. Sawyerr⁴, A. Diehl³, N. Ruperto¹, H. I. Brunner², on behalf of for PRINTO and PRCSG

¹PRINTO, IRCCS Istituto Giannina Gaslini, Genova, Italy; ²PRCSG, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH; ³Pfizer Inc, Collegeville, PA; ⁴Pfizer Inc, New York, NY, United States

Correspondence: A. Consolaro

Introduction: Tofacitinib is an oral JAK inhibitor that is being investigated for several forms of JIA. The efficacy and safety of tofacitinib in patients (pts) with polyarticular course (pc)JIA were demonstrated in a Phase 3 trial.

Objectives: To evaluate the frequency of controlled disease, measured by achievement of low disease activity (LDA) status per the Juvenile Arthritis Disease Activity Score (JADAS), and normal physical function, measured by the Childhood Health Assessment Questionnaire-Disability Index (CHAQ-DI), in tofacitinib-treated pts with pcJIA.

Methods: Data were analysed post hoc from pts with pcJIA aged 2−<18 years in a Phase 3, randomised, double-blind, placebo (PBO)-controlled withdrawal trial, where all pts received open-label tofacitinib 5 mg BID or body weight-based lower equivalent dose until Week (W)18 (end of Part 1). Pts with ≥JIA/ACR30 response at W18 were randomised 1:1 to continue tofacitinib or switch to PBO in the double-blind phase (Part 2, W18−44). Pts with JIA flare were discontinued from the trial. pcJIA disease control was assessed using: clinical JADAS in 10 joints (cJADAS10; no CRP/ESR laboratory measure), JADAS10-CRP and CHAQ-DI. LDA for cJADAS10 was defined as a score of ≤2.5 and for JADAS10-CRP as a score of ≤3.8. Normal function was defined as a CHAQ-DI score of 0.

Results: 184 pts with pcJIA entered Part 1 and 142 were randomised in Part 2 to continue tofacitinib (N=72) or switch to PBO (N=70). At Part 1 baseline, pcJIA control was absent, per mean (SD) values of: cJADAS10, 18.9 (4.7); JADAS10-CRP, 20.3 (5.5); and CHAQ-DI, 1.0 (0.7). At W18, disease control was improved, per mean (SD) values of: cJADAS10, 5.4 (4.8); JADAS10-CRP, 6.2 (4.9); and CHAQ-DI, 0.5 (0.6). cJADAS10 LDA and JADAS10-CRP LDA were achieved at the end of Part 1 by 42.9% and 44.2% of pts (N=154), respectively, while 24.0% achieved cJADAS10 LDA + normal function and 24.0% achieved JADAS10-CRP LDA + normal function. In Part 2, LDA ± normal function frequency remained stable in pts who continued tofacitinib, while in pts who switched to PBO, LDA ± normal function frequency decreased over time (Table). At the end of Part 2 (W44), in pts who continued tofacitinib vs pts who switched to PBO, cJADAS10 LDA was achieved in 47.2% vs 31.4% and JADAS10-CRP LDA in 47.2% vs 32.9%, respectively.

Pts who discontinued treatment for any reason, except while in clinical remission, were counted as non-responders as of their discontinuation visit through W44

Conclusion: Tofacitinib reduced disease activity in a rapid and sustained fashion and improved function in pts with pcJIA. A large proportion of pts achieved LDA, a current pcJIA treatment target, at W18 and thereafter. LDA prevalence estimates were comparable using cJADAS10 vs JADAS10-CRP, suggesting that cJADAS10 may suffice to assess treatment targets in pts with pcJIA.

Trial registration identifying number: ClinicalTrials.gov (NCT02592434)

Patient Consent Received

No

Disclosure of Interest

A. Consolaro: None declared, D. Lovell Consultant for: AstraZeneca, Boehringer Ingelheim, GSK, Roche, Novartis, Pfizer Inc, Takeda and UBC, and DSMB chairperson for NIH, O. Synoverska Speaker Bureau of: Sanofi, C. Abud Mendoza: None declared, A. Spindler Speaker Bureau of: Eli Lilly, Y. Vyzhga: None declared, E. Alexeeva: None declared, J. Chaitow: None declared, P. Chiraseveenupraprund Consultant for: CARRA and Novartis, H. Shi Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, L. Stockert Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, G. Sawyerr Consultant for: Pfizer Inc, Employee of: Syneos Health Inc, A. Diehl Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, N. Ruperto Consultant for: Ablynx, AstraZeneca/MedImmune, Biogen, BMS, Boehringer Ingelheim, 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 of: Ablynx, AstraZeneca/MedImmune, Biogen, BMS, Boehringer Ingelheim, Eli Lilly, EMD Serono, F. Hoffmann-La Roche, GSK, Janssen, Merck Sharp & Dohme, Novartis, Pfizer Inc, R-Pharm, Sanofi, Servier, Sinergie and Sobi, H. Brunner Consultant for: AbbVie, AstraZeneca/MedImmune, Bayer, Biocon, BMS, Boehringer Ingelheim, Eli Lilly, Janssen, Novartis, Pfizer Inc, Roche and R Pharm, Employee of: Cincinnati Children’s Hospital Medical Center, Speaker Bureau of: GSK, Novartis and Roche

Table 1 (abstract P10). Number (%) of pts with pcJIA achieving JADAS LDA ± normal function with tofacitinib vs PBO in Part 2

P11 Usefulness of synovial biopsy in the differential diagnosis and as predictor of clinical course in juvenile idiopathic arthritis: a monocentric study on 100 patients

S. Costi¹, F. Pregnolato¹, A. Parafioriti², E. Armiraglio², T. Giani³, R. Cimaz^4,5

¹Pediatric Rheumatology, University of Milan, G. Pini Hospital; ²Department of Pathology, G. Pini Hospital, Milan; ³Department of Medical Biotechnology, University of Siena, Siena; ⁴Department of Clinical Sciences and Community Health, and Research Center for Adult and Pediatric Rheumatic Diseases, University of Milan; ⁵Pediatric Rheumatology, G. Pini Hospital, Milan, Italy

Correspondence: S. Costi

Introduction: While synovial biopsy is an invasive procedure and is not required for the diagnosis of juvenile idiopathic arthritis (JIA), it may be useful in doubtful cases. Histopathologic characterization with regard to future course of disease has not been well studied.

Objectives: Aims of this study were i. to investigate the usefulness of synovial biopsy for diagnostic purposes, and ii. to review histological specimens in order to evaluate possible associations between pathology features and JIA clinical outcome.

Methods: We reviewed data from medical records of patients under the age of 18 years who underwent a synovial biopsy requested by our Pediatric Rheumatology Unit over the last 15 years. We collected information on clinical (remission criteria, number of disease flares, number of cDMARDs/bDMARDS used) and histological characteristic (number of layers of synovial lining, inflammatory infiltrate, elementary lesions of the subsynovia). Differences in numerical variable between groups were assessed by Mann-Whitney test while associations between categorical predictors and outcomes by Chi-square or Fisher’s exact test. A logistic multivariable model with outcome as dependent variable was applied in order to measure the strength of and adjust for potential confounders.

Results: We identified 100 patients who underwent a synovial biopsy during the study period. Of those, 99 (65% female) had complete data. Median age at onset of 8.5 years (range 1-17), median follow-up time was 161 months (range 8-1160). We recognized two groups: patients with known/suspected JIA (44/99) and patients with unknown diagnosis (55/99). In the first group, 10 patients underwent synovial biopsy as a result as diagnostic doubt, while 34 had an orthopedic procedure. In all these 34 patients the biopsy results were consistent with JIA. Among the second group, 31/55 results were consistent with a chronic synovitis (final JIA diagnosis), while in others the histologic results led to a final diagnosis of other conditions (e.g. Giant cell tumor of the synovium and tendon sheat n=6, foreign body n=2, osteomyelitis n=1, sarcoidosis n=1). Between the two groups we identified 75 patients with JIA diagnosis. At the last follow-up visit 47 of them of patients were in clinical remission or had low disease activity, while 23 patients had a severe course of disease. In 43 cases the correlation between status at clinical outcome and histological score could be assessed. Subjects who had more than 4 flares during follow-up showed a significantly higher number of layers of synovial lining (4.5 [3.0 to 6.0] vs 3.0 [2.0 to 4.5], p = 0.035). The number of layers remained significantly predictive after adjusting for age at diagnosis and observation time (OR [95% CI]: 2.2 [1.3 - 3.9], p = 0.007). Subjects who had switched more than two bDMARDs had a higher prevalence of elementary lesions of the subsynovia (55.6% vs 10.3%, p = 0.005) and a higher prevalence of fibrin deposits at the level of the synovial lining (60.0% vs 22.6%, p = 0.04). Fibrin deposits remained significant predictors even after adjustment for observation time and age at diagnosis (OR [95% CI]: 8.1 [1.03 - 64.2, p = 0.047]). Krenn score and infiltrate pathotype were assessed but no statistically significant association was found.

Conclusion: Synovial biopsy may be useful in those patients whose diagnosis is unclear and in complicated cases it may allow diagnoses of rare conditions. We found statistically significant correlations between histological features of synovial membrane and the clinical phenotype.

Patient Consent Received

No

Disclosure of Interest

None declared

P12 Influenza vaccine uptake among JIA patients in COVID-19 era: a multi-centre cross-sectional study

F. Dasoula¹, D. Maritsi¹, N. Alpert², M. Bizjak³, M. Heshin-Bekenstein⁴, A. Ziv⁵, B. Balaziova⁶, M. Yildiz⁷, A. Gagro⁸, M. Sestan⁹, A. Khabirova¹⁰, B. Sozeri¹¹, S. Caglayan¹¹, M. Jelusic⁹, V. Opoka-Winiarska¹², M. Kostik¹⁰, C. Bracaglia¹³, F. Minoia¹⁴, T. Dallos⁶, O. Kasapcopur⁷, N. Toplak³, Y. Uziel², on behalf of Vaccination WP & MAS/sJIA WP

¹Infectious Diseases, Immunology and Rheumatology Unit, Second Dpt of Pediatrics, Athens Medical School, Athens, Greece; ²Pediatric Rheumatology Unit, Dpt of Pediatrics, Meir Medical Center, Kfar Saba, Israel; ³Dpt. of allergy, rheumatol, immunol UCH Ljubljana. MF Ljubljana, Ljubljana, Slovenia; ⁴Dana Children’s Hospital of Tel Aviv Medical Center; ⁵Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; ⁶Dpt of Paediatrics, Comenius University Medical School in Bratislava, National Institute of Children’s Diseases, Bratislava, Slovakia; ⁷Dpt of Pediatric Rheumatology, Istanbul University, Cerrahpasa, Turkey; ⁸Dpt of Pediatrics, Children's Hospital Zagreb; ⁹Dpt of Paediatrics, University of Zagreb School of Medicine, Zagreb, Croatia; ¹⁰Saint-Petersburg State Pediatric Medical University, Saint-Petersburg, Russian Federation; ¹¹University of health sciences, Umraniye Training and Research Hospital, Istanbul, Turkey; ¹²Dpt of Paediatric Pulmonology and Rheumatology, Medical University of Lublin, Lublin, Poland; ¹³Division of Rheumatology, IRCCS Ospedale Pediatrico Bambino Gesù, Roma; ¹⁴Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy

Correspondence: F. Dasoula

Introduction: JIA patients are targeted for vaccination as a population at risk of severe influenza disease. Recent COVID-19 pandemic is an additional challenge; nonetheless, their influenza vaccine coverage remains uncertain.

Objectives: To assess the flu vaccination rate in JIA patients & investigate family’s attitudes towards it; to identify how COVID-19 pandemic has affected caregivers’ decision on flu vaccine administration.

Methods: A multi-center cross-sectional study was conducted across 9 countries. Participants completed a questionnaire about the flu vaccination uptake history including the year of 2020-21, sociodemographics and data regarding the disease. Analysis was conducted using SPSSv.20.

Results: 655 JIA caregivers were surveyed across 9 countries (Table). The majority was employed (61.2%), married (78.5%) & held a tertiary education (43.1%). Patients’ median age was 11y (IQR: 7-15). Principal diagnosis was oligoJIA (34%) & most patients were treated systemically (81%). 21.7% had received influenza vaccine in the past & 18.6% in 2019-20 season; 85% were fully vaccinated.

152 children (23.2%) were vaccinated against flu the current season. The majority was informed by their ped rheumatologist (33.5%). Highest uptake was recorded in Greece (79.3%) while lowest in Turkey (1.1%) (p<0.01) (Table). Employed & self-employed and those with tertiary education were more likely to vaccinate their children compared to unemployed & those with elementary education (28.2% & 29.9% vs 13.6%, 28% vs 9.7% respectively, p<0.01). Children with psoriatic & polyJIA had the highest uptake (both 30%) while patients with undifferentiated reported the lowest (7.4%, p<0.01). Among vaccinators, 92.4% were fully vaccinated, 64.6% had been vaccinated in the past & 57.6% in 2019-20 season (p<0.05). An increase was reported in uptake between 2019-20 & 2020-21 seasons (18.6% vs 23.2%, p<0.01).

Among non-vaccinators, 52% did not have the chance to discuss their concerns. Major reason for non-vaccination was unawareness of the need (36%); 13% reported it was a doctor’s advice. Caregivers suggested that informing in advance (67%) may improve uptake.

Most of caregivers expressed their concerns regarding their children’s vulnerability to SARS-COV-2 due to JIA (51.3%) & their risk of COVID-19 (85.3%); 51.3% of them were pro COVID-19 vaccine administration to their children (Table). Those who vaccinated their children against flu in the 2019-20 & 2020-21 seasons were more likely to vaccinate them against SARS-COV-2 (79.5% & 73.4% respectively, p<0.01).

Conclusion: Despite variations among countries, flu vaccine uptake remains low in JIA patients. Higher education, thorough informative discussion and notifying families in advance may lead to universal vaccine coverage in children with RDs.

Disclosure of Interest

None declared

Table 1 (abstract P12). See text for description

P13 Identification of pathogenic B cells in JIA by the oxysterol receptor GPR183

N. M. de Gruijter^1,2, C. Brown³, L. R. Wedderburn¹, E. C. Rosser^1,2

¹Centre for Adolescent Rheumatology Versus Arthritis at UCL, UCLH and GOSH; ²Centre for Rheumatology Research, University College London, London, United Kingdom; ³Memorial Sloan Kettering Cancer Center, New York City, United States

Correspondence: N. M. de Gruijter

Introduction: Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease of childhood and causes significant suffering. Oligoarthritis (oJIA) – the most common JIA subtype – is characterized by autoantibody production and the differentiation of autoreactive T cells. B cells produce these autoantibodies, but also contribute to pathology by secreting cytokines and presenting antigen. Case studies have shown some positive effects of B cell-depleting drugs, but B cell depletion also reduces immunoregulatory B cells. Treatment strategies specifically targeting pathogenic B cells are necessary, especially for patients that do not respond well to conventional treatments.

Objectives: To identify a marker for pathogenic memory B cells in JIA synovial fluid (SF) and peripheral blood (PB).

Methods: Single-cell RNA sequencing was used to measure gene expression in JIA B cells from SF and PB. Flow cytometry was used for in-depth phenotyping of B cells in the SF and/or PB of 31 patients with oJIA, and the PB of 5 healthy children. Mann-Whitney U test was used to compare significance of difference between groups. All numbers are portrayed as median (interquartile range), unless otherwise specified.

Results: Through single cell RNA sequencing we found that memory B cell subsets can be defined by the expression of oxysterol receptor GPR183. When plotting the expression of GPR183 against that of activation marker CD27, we saw a clear population co-expressing both markers. GPR183⁺CD27⁺ memory B cells are found in oJIA synovial fluid (SF), oJIA peripheral blood (PB), and healthy child and adult PB. GPR183⁺CD27⁺ memory B cells are expanded in oJIA SF compared to PB: 23.8% (19.5%-29.5%) of oJIA SF B cells are GPR183⁺CD27⁺, compared 7.2% (4.8%-9.5%) in oJIA PB (p<0.0001, U=8), and 8.8% (6.5%-11.4%) in healthy child PB (p=0.0004, U=3.5). GPR183⁺CD27⁺ memory B cells in oJIA SF have an atypical, activated phenotype, expressing high levels of CD86, HLA-DR, CD11c and FcRL4 (Table 1) compared to oJIA PB (expression did not differ between healthy child and oJIA PB; data not shown). Depletion of GPR183⁺ B cells from total oJIA synovial fluid mononuclear cells reduced T cell proliferation in vitro. Blocking the production of GPR183’s endogenous ligand 7α,25-dihydroxycholesterol with the anti-fungal drug clotrimazole reduced inflammation in a mouse model of experimental arthritis. These functional experiments suggest that GPR183⁺ memory B cells have a pro-inflammatory role in joint inflammation.

Conclusion: Our data identify GPR183 as an important, therapeutically relevant molecule for the definition of memory B cells in juvenile idiopathic arthritis.

Rerences

1. Yeo L, Lom H, Juarez M, Snow M, Buckley CD, Filer A, et al. Expression of FcRL4 defines a pro-inflammatory, RANKL-producing B cell subset in rheumatoid arthritis. Ann Rheum Dis. 2015;74(5):928–35.

Patient Consent Received

Yes

Disclosure of Interest

None declared

Table 1 (abstract P13). Expression of phenotypic markers on oJIA SF and PB B cells

P14 Lubricin concentration of synovial fluid and blood serum in two diseases: juvenile idiopathic arthritis and camptodactyly, arthropathy, coxa-vara and pericarditis syndrome

G. Dobson^1,2,3, M. Wilkinson^1,2,4, L. Marshall^1,2,4, L. Wedderburn^1,2,3,4

¹Infection, Immunity and Inflammation Programme Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, University College London; ²Centre for Adolescent Rheumatology Versus Arthritis at UCL UCLH and GOSH, at UCL UCLH and GOSH, University College London; ³Rheumatology, Great Ormond Street Hospital; ⁴NIHR Biomedical Research Centre at GOSH, London, United Kingdom

Correspondence: G. Dobson

Introduction: Lubricin (coded for by the gene PRG4) is a mucinous glycoprotein, which provides mechanical lubrication and may also function as an inflammation modulator [1]. Lubricin protein is highly expressed in synovial fluid, blood and many other organs [1,2]. In a rare, autosomal recessive condition, lubricin is absent or non-functioning causing disabling manifestations associated with the disease: camptodactyly, arthropathy, coxa-vara and pericarditis (CACP) [3]. There are limited treatment options for CACP patients as understanding the role of lubricin in normal and diseased states is still being defined [3]. To date, synovial fluid of adult Rheumatoid Arthritis and Osteoarthritis patients have shown reduced lubricin concentrations compared to healthy adult controls [4]. Concentrations in paediatric cohorts have never been described.

Objectives: To define the concentration of lubricin protein in blood and synovial fluid of juvenile idiopathic arthritis (JIA) patients, CACP patients, and blood serum of healthy child controls.

Methods: The mean age was 7 years (range 1-13 years). Lubricin concentrations in venous blood serum (VBS) and synovial fluid (SFS) were measured by sandwich ELISA (Mybiosource). Samples were from the following patient groups: rheumatoid factor negative polyarticular and oligoarticular JIA patients’ blood (n=15) and synovial fluid (n=13), CACP blood (n=1) and synovial fluid (n=2) and child healthy control blood (n=10). Lubricin concentrations in JIA paired VBS and SFS samples (n=11) were analysed on SPSS by Spearman’s Rank Order Coefficient. Lubricin concentrations in VBS from JIA and CACP patients were compared to data from child healthy controls by Kruskal Wallis ANOVA analysis.

Results: The median concentrations of lubricin were 3280ng/ml (IQR: 2640-3491ng/ml) in JIA synovial fluid, 3240ng/ml (IQR: 3085-3394ng/ml) in CACP synovial fluid, 341ng/ml (IQR: 182-645ng/ml) in JIA blood serum, 105ng/ml in CACP blood serum, and 115ng/ml (IQR: 106-195ng/ml) in healthy child control blood serum. The blood serum concentrations variation was significantly different between JIA, CACP and healthy child controls, p=0.008. The relationship of lubricin concentration between JIA paired blood and synovial fluid serum had a correlation coefficient 0.545 (p=0.083).

Conclusion: This study is the first to show measure of lubricin in both blood and synovial fluid of paediatric patients. The data suggest that lubricin concentration in JIA blood was significantly higher compared to CACP and healthy child controls, but there was no correlation between levels in VBS compared to SFS. Lubricin measured from the synovial space of CACP patients could be non-functioning lubricin, given the positive phenotype and confirmed PRG4 mutations in these patients. Further work will investigate the functionality of lubricin in patients.

Disclosure of Interest

None declared

P15 Proof-of-concept study of accelerometry to quantify knee joint movement to assist with juvenile idiopathic arthritis diagnosis

A. Garner¹, R. Saatchi², D. Hawley³, O. Ward³

¹University of Sheffield Medical School; ²Industry and Innovation Research Institute, Sheffield Hallam University; ³Department of Paediatric Rheumatology, Sheffield Children's Hospital, Sheffield, United Kingdom

Correspondence: A. Garner

Introduction: Body-worn accelerometers can accurately quantify joint movements, and could potentially assist with the diagnosis of juvenile idiopathic arthritis (JIA) as joint movement restriction is a feature of the condition.

Objectives: This proof-of-concept study aimed to evaluate the use of accelerometry to objectively quantify knee joint movements in children with clinically active JIA. Restriction in joint movement can be observed in JIA, so an accurate, cost effective, and portable tool that objectively measures restriction could aid diagnosis.

Methods: Seven participants (age: 11.7 (2.7) years) with suspected active arthritis of a single knee joint were recruited. Participants had established diagnoses of oligoarticular (n = 2) and polyarticular JIA (n = 5) and were recruited just prior to planned appointments for steroid joint injections. paediatric Gait, Arms, Legs and Spine (pGALS) examination¹ was performed by an experienced practitioner on the day of data collection, to confirm the suspicion of active arthritis. The contralateral knee joint acted as reference. An accelerometer is a miniature sensor for measuring movements in three perpendicular dimensions. Four tri-axial accelerometers were integrated individually in soft elastic bands. The data from the accelerometers were collected using a microprocessor and stored on a computer. Accelerometers were placed above and below each knee and participants were asked to perform ten consecutive flexion and extension movements of each knee joint while lying, followed by walking ten meters. Accelerometry data were processed using a data analysis package called Matlab^© to quantify knee movement according to range of movement, maximum velocity, maximum acceleration, angular displacement, and period of movement. A participant questionnaire was used to establish procedural acceptability.

Results: The accelerometry results were concordant with pGALS examinations in 86% (n = 6) of cases. In all variables measured, the extent of movement was reduced in the knee joint with active JIA, this was most pronounced during flexion and extension movements compared to walking. Joint range of movement had a greater standard deviation (16.6 degrees) and interquartile range (29.1 degrees) in the knees with active JIA compared to the healthy knees during flexion and extension movements, demonstrating inconsistency of movement in the joints with active JIA. There were statistically significant differences between the range of movement (p = 0.032) and angular displacement (p = 0.030) of the knees with active JIA and the healthy contralateral knee joints during flexion and extension. No statistically significant differences were identified between knee joints with active JIA and the healthy knee joints during walking. The questionnaire indicated one participant suggested future improvement in the accelerometer's band design due to discomfort, and the remaining participants found the procedure acceptable.

Conclusion: The study demonstrated proof-of-concept for the use of accelerometry to quantify knee joint movement in JIA. It examined accelerometry variables that suitably represented joint movement. It was found that accelerometry has potential for differentiating between joints with active arthritis and unaffected joints, particularly through assessment of flexion and extension movements. Further research is required to confirm these findings and refine the use of this novel technology in children with JIA.

Reference

1. Foster HE et al. Musculoskeletal screening examination (pGALS) for school-age children based on the adult GALS screen. Arthritis Rheum. 2006 Oct 15;55(5):709-16.

Disclosure of Interest

None declared

P16 The influence of BMI on JIA course in children

M. F. Gicchino, A. Di Sessa, R. Melone, S. Zarrilli, P. Marzuillo, E. Miraglia del Giudice, A. N. Olivieri

Department of Woman, Child and General and Specialistic Surgery, University of the Study of Campania Luigi Vanvitelli, Naples, Italy

Correspondence: M. F. Gicchino

Introduction: Juvenile Idiopathic Arthritis (JIA) represents the most common chronic rheumatic disease in childhood affecting joints and other structures. According to International League of Association for Rheumatology (ILAR), seven subtypes of arthritis can be defined in relation with the number of joints and the extra-articular involvement occurring in the first six months of disease. In the last years, greater improvements in long-term outcomes have been provided by new therapeutic options. Growing evidence has supported the role of obesity as a risk factor for severity disease both in adults and children, but recent studies have also showed a potential effect of underweight in this context. To date, the influence of Body mass index (BMI) on JIA course is poorly studied, in particular in children.

Objectives: To evaluate the influence of BMI on disease course in children with JIA.

Methods: We retrospectively examined 113 children with JIA classified according to ILAR criteria attending our Rheumatology Clinic. At the time of the first visit, anthropometric and laboratory data were assessed. Age at disease onset, disease duration, joint involvements, presence of comorbidities, and medications were also collected. Disease activity was assessed by JADAS-10. According to BMI Z-score, our cohort was divided into five groups: underweight, normal weight, overweight (OW), obesity (OB), and severe obesity. Differences for continuous variables were analysed with the independent-sample t test for normally distributed variables and with the Mann-Whitney test in case of non-normality. Qualitative variables were compared using the chi-squared test. Linear regression was used to investigate the association of JADAS-10 with BMI categories.

Results: The mean age was 7.43±4.03 years. Forty-one percent were persistent oligoarticular, 9.1% extended oligoarticular, 23.6% RF- polyarticular, 8.2% RF+ polyarticular, 7.3% systemic, 8.2% enthesitis-related arthritis, and 2.7% psoriatic arthritis. The prevalence of underweight, normal weight, overweight, obesity, and severe obesity was 7.2%, 54.1%,10.8%,17.1%, and 10.8%, respectively. Ferritin levels, erythrocyte sedimentation rate values, and disease duration were significantly higher in patients with severe obesity and in those underweight compared to subjects belonging to normal weight, OW, and OB groups (p=0.02, p=0.03, and p=0.04, respectively). Similarly, underweight patients and those with severe obesity showed the greater JADAS-10 than other groups (p=0.013). Obese patients presented with the greater number of affected joints (p=0.04). More, a major involvement of lower limbs was observed in patients with obesity and severe obesity, including sacroiliac and midfoot joints (p=0.004 and p= 0.005, respectively). These patients had also an increased number of relapses compared to other groups (p=0.025).

Conclusion: BMI seems to influence JIA course in children through different mechanisms. In addition to the mechanical role of obesity and its potential pro-inflammatory effect, underweight seems also to affect the course of the disease. This could be explained by hypothesising an impairment on weight gain by active disease, but further studies are needed to a better understanding. In addition to the arthritis control, these findings underscore the need to maintain an adequate BMI through dietary and lifestyle intervention in order to avoid a more unfavourable JIA course.

Patient Consent Received

Yes

Disclosure of Interest

None declared

P17 The metabolic perspective in children with JIA

A. Di Sessa, M. F. Gicchino, S. Zarrilli, R. Melone, S. Guarino, E. Miraglia del Giudice, A. N. Olivieri

Department of Woman, Child and General and Specialistic Surgery, University of the Study of Campania Luigi Vanvitelli, Naples, Italy

Correspondence: M. F. Gicchino

Introduction: Juvenile Idiopathic Arthritis (JIA) is the most common inflammatory chronic disease in childhood. According to International League of Association for Rheumatology (ILAR) seven subtypes of arthritis can be defined in relation with the number of joints and the extra-articular involvement occurring in the first six months of disease. Although it has been largely recognized that these patients are at risk for disease-specific complications and for metabolic syndrome (MetS) in adulthood, very limited data are available on metabolic risk at this age. Robust evidence demonstrates that high acid uric (UA) levels represent a risk factor for cardiometabolic diseases such as MetS, cardiovascular disease, and type 2 diabetes in adults. In children, serum UA levels increased in youth with obesity and metabolic abnormalities.

Objectives: To investigate the metabolic risk in children with JIA.

Methods: We retrospectively evaluated 113 children affected by JIA classified according to ILAR criteria attending our Rheumatology Clinic. Both clinical and biochemical assessments were performed. Participants were stratified in four groups according to sex-specific quartiles of UA. Disease activity was calculated by Juvenile Arthritis Disease Activity Score 10 (JADAS-10). Differences for continuous variables were analysed with the independent-sample t test for normally distributed variables and with the Mann-Whitney test in case of non-normality. Qualitative variables were compared using the chi-squared test.

Results: The mean age of our cohort was 7.43±4.03 years. Systolic blood pressure levels and BMI-Z score significantly increased across quartiles (p= 0.002 and p=0.003, respectively). Patients belonging to the highest UA quartile also showed higher triglycerides and total cholesterol (p=0.01 and p=0.025, respectively) and lower HDL cholesterol levels (p<0.0001) than subjects belonging to the lowest quartiles. JADAS-10 score, ferritin and erythrocyte sedimentation rate levels, and age at disease onset did not significantly differ across UA quartiles (all p >0.05), but a trend for JADAS-10 score was observed (p=0.06). With regard to treatment, the prevalence of the use of biological drugs significantly increased across UA quartiles (p=0.04).

Conclusion: A worse cardiometabolic profile across UA quartiles has been observed in children with JIA. Our preliminary data suggest that in clinical practice UA might represent a useful marker of cardiometabolic risk in children with JIA. Taking into account the increased MetS development risk later in life in these patients, a careful global management is highly recommended, by paying attention not only to disease-specific comorbidities (e.g. uveitis, etc) but also to both metabolic and cardiovascular derangements at an earlier stage of JIA. Further studies are needed to better clarify the early cardiometabolic risk in JIA patients and its potential influence on treatment response.

Patient Consent Received

Yes

Disclosure of Interest

None declared

P18 Relapse rate and associated factors after discontinuation of biologic dmards in non-systemic JIA patients

J. Gieling¹, B. van den Bemt², E. Hoppenreijs³, E. Schatorjé³

¹Department of Pediatric Rheumatology, Pediatrics, Radboud University Medical Center; ²Departments of Pharmacy; ³Department of Pediatric Rheumatology, Pediatrics, Sint Maartenskliniek / Radboud University Medical Center, Nijmegen, Netherlands

Correspondence: J. Gieling

Introduction: Biologic disease-modifying antirheumatic drugs (bDMARDs) have changed the treatment of juvenile idiopathic arthritis (JIA) patients notably, as nowadays substantially more patients achieve remission. Research has proven their safety and resulted in guidelines upon how and when to start bDMARDs. When sustained remission is achieved, tapering or even discontinuation of the bDMARD is advocated to reduce side effects and costs. However, when and how to discontinue bDMARD therapy once remission is attained and what happens afterwards, is less known.

Objectives: With this scoping review we aim to collect available data in the current literature on relapse rate (RR), time to relapse (TTR) and possible flare associated variables (such as time spent in remission and method of discontinuation) after discontinuing bDMARDs in non-systemic JIA patients.

Methods: We performed a literature search using the Pubmed database and found 607 articles related to JIA and bDMARDs available for non-systemic JIA treatment. Based on title/abstract and full text screening we obtained 27 articles reporting RR, TTR or factors associated with flare after tapering and/or stopping of bDMARDs.

Results: The 27 selected articles included in total 605 non-systemic JIA patients who tapered and/or stopped bDMARD therapy. RR after discontinuation of bDMARDs, either abruptly or following tapering, were 25-48%, 36.8-46.2% and 60-78% at 6, 8 and 12 months respectively. Other studies did not report RR per month but noted a total RR ranging from 26.3-83.3% with a either a mean TTR of 2-8.4 months or a median TTR of 3-8.4 months. All studies stated a good response after restart of therapy after flare. Not all studies reported RR and/or TTR. Results of the largest studies reporting RR are shown in table 1.

JIA subtype, type of bDMARD, concomitant methotrexate use, treatment duration, tapering method, age, sex and time in remission could not conclusively be related to RR or TTR. However, some studies reported a positive association of RR or TTR with ANA-positivity, younger age at disease onset, male sex, disease duration and delayed remission, which were not confirmed in other studies.

Conclusion: Flares seem to be common after bDMARD discontinuation, but little is known about which factors influence these flares in JIA patients. Follow up after discontinuation with careful registration of patient variables, information about tapering methods and flare rates are required to better guide tapering and/or stopping of bDMARDs in JIA patients in the future.

Disclosure of Interest

None declared

Table 1 (abstract P18). Relapse rate in non-systemic JIA patients after withdrawal of bDMARD

P19 Clinical features of juvenile idiopathic arthritis in Batna -Algeria-

D. Hadef¹, S. Slimani², M. C. Khamari³, W. Mekaoussi³, S. Brahmi¹, A. Belot⁴, P. Quartier⁵

¹Department of Pediatrics, University Hospital Center of Batna, Faculty of Medicine, Batna 2 University; ²Atlas Clinic of Rheumatology; ³Private Clinic of Rheumatology, Batna, Algeria; ⁴Pediatric Nephrology, Rheumatology, Dermatology Unit, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, National Referee Centre for Rheumatic and AutoImmune and Systemic Diseases in Children (RAISE), Lyon; ⁵Pediatric Immunology-Hematology and Rheumatology Unit Necker Hospital, Assistance Publique Hôpitaux de Paris, National Referee Centre for Rheumatic and AutoImmune and Systemic Diseases in Children (RAISE), Paris, France

Correspondence: D. Hadef

Introduction: Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in childhood. There is a disparity in the prevalence of Juvenile idiopathic arthritis (JIA) subsets between different geographical areas or ethnic groups. In Arabic and African populations, data describing JIA are scarce. However, the epidemiological studies remain the best tool to understand the disease and to improve its management.

Objectives: The aim of this study was to determine subtype frequencies, demographic and clinical features of JIA in Batna -Algeria- and to compare the findings with other JIA populations worldwide.

Methods: A multicenter retrospective descriptive study was conducted in Batna health centers (public and private sectors), over a seven-year period from January 2013 to December 2019, based on data collected on JIA patients. As public sector source, we referred to the department of pediatrics of the university hospital center (CHU Benflis Touhami Batna), and as private sector source, we referred to private adult rheumatologists based in Batna. The studied variables were: gender, age at the initial symptoms, age at diagnosis, JIA subtype based on International League of Associations for Rheumatology (ILAR) criteria, symptoms at onset, disease duration at the latest follow up, uveitis presence, auto antibodies (antinuclear antibodies, Rheumatoid Factor and anti-CCP) pattern, joint imaging results, JIA medications, JIA status at the time of enrollment and the latest follow-up. The study was approved by local ethics committee of University hospital center of Batna.

Results: The study included a total of 69 cases of JIA that were being followed in Batna health centers over the study period. The female to male ratio was 1.83. The median age at diagnosis was 9 years (range 1-16). Forty-six patients (72%) were diagnosed within the first year after disease onset. At the latest follow-up, the median disease duration onset was 1year (range 1-8 years). There were 34 oligoarthritis (49.3%), 9 polyarthritis rheumatoid factor (RF) negative (13%), 8 polyarthritis (RF) positive (11.6%), 6 systemic arthrits (8.7%), 6 enthesitis-related arthritis (8.7%), 3 psoriatic arthritis (4.3%), and 3 undifferentiated arthritis (4.3%). Nine patients (18.7%) were anti-nuclear antibody (ANA) positive, and 21 patients (30.4%) had indeterminate ANA status. Sixty-three patients (91.3%) had benefited from a slit lamp examination, uveitis was found in 7.9% of cases. The used medications included non steroidal anti-inflammatory drugs (NSAIDs) in 54 patients (79.4%), steroids in 37 (54.4 %), intra articular steroid injections in 17 (24.6 %), conventional disease-modifying anti-rheumatic drug (c DMARDs) in 51 (72.5 %), and biologic agents in 11 patients (15.9%).

Conclusion: Oligoarthritis was the most common JIA subtype in our study with cases of uveitis at diagnosis. The RF positive polyarthritis frequency was higher than in literature. The use of c DMARDs was common whilst few patients received biologics. Prospective multicenter studies are necessary to better identify the JIA particularities in our country.

Disclosure of Interest

None declared

P20 The consistency of the physician global assessment: a single centre study

L. Hussen¹, M. J. H. Doeleman^1,2, N. M. Wulffraat^1,2, M. H. A. Jansen^1,2, A. van Royen^1,2, B. J. Prakken^1,2, B. J. Vastert^1,2, S. de Roock^1,2, J. F. Swart^1,2

¹Faculty of Medicine, Utrecht University; ²Pediatric Rheumatology and Immunology, Wilhelmina Children’s Hospital, Utrecht, Netherlands

Correspondence: L. Hussen

Introduction: With the Juvenile Arthritis Disease Activity Score (JADAS), the disease activity in Juvenile Idiopathic Arthritis (JIA) can be monitored. The JADAS consists of 4 aspects: Physician Global Assessment (PGA), active joint count (AJC), parent of patient Visual Analogue Scale (VAS) of overall wellbeing and the erythrocyte sedimentation rate (ESR). The ESR can be left out in clinical settings, resulting in the clinical Juvenile Disease Activity Score (cJADAS). The overall impact on daily life does not only depend on the number or location of joints, but also on the amount of pain and limitation every separate involved joint causes. These differences are supposed to be reflected by the PGA ^1,2

Objectives: To determine the differences of PGA scores for similar AJC across paediatric rheumatologists in the Wilhelmina Children’s Hospital (WCH) as a part of the (c)JADAS.

Methods: This is a monocentric retrospective cohort study with pseudonymized data from the WCH, gathered since 2011. 4 criteria were required for inclusion: (1) have visited a currently active physician, (2) have any subtype of JIA, (3) have a documented PGA, and (4) have an available joint assessment of the visit.[MD1] 972 patients met the inclusion criteria, of which 9704 visits have been observed by 1 of 6 paediatric rheumatologists.

Correlations of PGA scoring across physicians with AJC and weighted active joint count (wAJC) were established with Spearman’s Rank correlation (with 95% CI) for three subcategories of the cohort. The subcategories are based on the number of active joints; (1) an AJC equal to zero, (2) an AJC of 1 to 4 or (3) an AJC of 5 or more. With the Kruskall-Wallis test, and Bonferroni corrections for multiple comparisons, differences were determined in PGA scoring (median, IQR) between physicians considering a single active joint. The joints of the knee, ankle, hip, wrist, jaw and DIP/PIP of the fingers were investigated. A difference of 30 points in PGA scoring was considered clinically relevant as it could make the difference between low, moderate or high disease activity.^3,4

Results: Spearman’s Rank of the PGA and AJC or wAJC for the total cohort showed a high correlation of 0.858 (95% CI 0.850 - 0.865) (p<0.001) and 0,861 (0.854 to 0.869) (p<0.001), respectively. In table 1, Spearman’s Rank correlation coefficients (with 95% CI) for the categories is shown below.

Due to the constant value of the AJC (0), the correlation rank could not be computed for category 1. Spearman’s Rank is noticeably without consideration of category 1, suggesting high consistency of physicians when scoring the PGA without any active joints.

Single joint analysis shows a statistically significant difference in PGA scoring among physicians for the joints of the knee (max. 15, P<0.001), hip (max. 20, P<0.001), ankle (max. 15, P<0.001), wrist (max. 23 P<0.001) and DIP/PIP (max. 5, P=0.005), but not for the jaw (max. 8, P=0.735). The difference in PGA scoring did not exceed 30 points, thus had no clinical relevance.

Conclusion: Despite statistically significant differences in PGA scoring for the same median AJC across paediatric rheumatologists in the WCH, the clinical relevance of the difference is negligible. Linear mixed models could give more insight in which patient and disease characteristics contribute to the difference in PGA scoring across paediatric rheumatologists.

Trial registration identifying number:

References

1. Backström M, Tynjälä P, Ylijoki H, et al. Finding specific 10-joint juvenile arthritis disease activity score (JADAS10) and clinical JADAS10 cut-off values for disease activity levels in non-systemic juvenile idiopathic arthritis: A finnish multicentre study. Rheumatology (Oxford, England). 2016;55(4):615-623.

2. Consolaro A, Ravelli A. Defining criteria for disease activity states in juvenile idiopathic arthritis: what are the optimal JADAS cut-offs? Rheumatology (Oxford, England). 2016;55(4):595-596.

3. Consolaro A, Bracciolini G, Ruperto N, et al. Remission, minimal disease activity, and acceptable symptom state in juvenile idiopathic arthritis: Defining criteria based on the juvenile arthritis disease activity score. Arthritis Rheum. 2012;64(7):2366-2374.

4. Consolaro A, Ruperto N, Bracciolini G, et al. Defining criteria for high disease activity in juvenile idiopathic arthritis based on the juvenile arthritis disease activity score. Ann Rheum Dis. 2014;73(7):1380-1383.

Patient Consent Received

No

Disclosure of Interest

None declared

Table 1 (abstract P20). Spearman's Rank for the categories

P21 Neutrophil count, platelet indices, CRP and their association with the disease activity of juvenile idiopathic arthritis (JIA) patients: a study from Bangladesh

M. I. Islam, S. Parvin Sonia, S. A. Rahman

Department of Paediatrics, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh

Correspondence: M. I. Islam

Introduction: Chronic inflammation of the joints in JIA patients are associated with raised levels of serum inflammatory biomarkers that vary according to disease activity. Neutrophil Count, Platelet count, Mean Platelet Volume (MPV), Platelet Distribution Width (PDW), ESR and CRP are the essential inflammatory markers to evaluate JIA patients' disease activity status.

Objectives: To assess Neutrophil Count, Platelet count, Mean Platelet Volume (MPV), Platelet Distribution Width (PDW), CRP and Juvenile Arthritis Disease Activity Score (JADAS) in JIA patients and determine the association between them at the initial visit and at six months of follow up after treatment.

Methods: This prospective observational study was conducted from March 2019 to December 2020 in the department of Paediatrics, Bangabandhu Sheikh Mujib Medical University,Dhaka, Bangladesh. Fifty newly diagnosed JIA cases who fulfilled the ILAR classification criteria were included in the study. Disease activity was assessed by JADAS 27. A predesigned questionnaire was completed for each patient which included socio-demographic, clinical and laboratory parameters. JADAS 27 and inflammatory biomarkers were evaluated at the initial visit and at follow-up after six months of treatment. Statistical analysis of data was done by using SPSS version 22.

Results: Mean neutrophil count, platelet count, and CRP significantly decreased at follow-up after six months of treatment. MPV and PDW were increased at follow-up after six months compared to the initial visit, but PDW change was significant. Mean JADAS 27 also decreased significantly at follow-up compared to initial visit. Neutrophil count, Platelet indices and CRP were significantly associated with JADAS 27.

Conclusion: In this study, neutrophil count, platelet indices, and CRP at follow-up after six months of treatment were improved. Significant association of JADAS 27 was found with platelet indices, neutrophil count and CRP

Trial registration identifying number: No BSMMU/2019/1431 Date : 12-02-2019

Disclosure of Interest

None declared

Table 1 (abstract P21). Changes of Leukocyte count, Platelet Indices at initial visit and at follow up

P22 Anti-TNF agents impair seroprotection in paediatric patients with juvenile idiopathic arthritis and inflammatory bowel disease vaccinated with the meningococcal ACWY vaccin

M. Jansen¹, A. J. J. Sellies¹, M. Ohm², M. Zijlstra³, J. F. Swart¹, S. J. Vastert¹, J. Montfrans van¹, G. C. Joode de¹, M. Bartels⁴, A. Royen-Kerkhof van¹, J. G. Wildenbeest⁵, C. A. Lindemans⁶, V. Wolters³, R. A. Wennink⁷, F. M. Verduyn-Lunel⁸, J. H. de Boer⁷, M. W. Heijstek⁹, G. A. Berbers², N. M. Wulffraat¹, on behalf of PRES Vaccination Working Group

¹Pediatric Immunology and Rheumatology, University Medical Center Utrecht, Utrecht; ²Centre for Infectious Disease Control, National Institute for Public Health and the Environment, RIVM, Bilthoven; ³Pediatric gastroenterology; ⁴Pediatric Hematology; ⁵Pediatric Infectiology-immunology, University Medical Center Utrecht; ⁶Stem Cell Transplantation, Princess Maxima Centre; ⁷Ophthalmology; ⁸Microbiology and Virology; ⁹Rheumatology and Immunology, University Medical Center Utrecht, Utrecht, Netherlands

Correspondence: M. Jansen

Introduction: In 2018, the Meningococcal C vaccination was replaced by the Meningococcal ACWY (MenACWY) vaccination in the Dutch Immunisation Programme, due to rising numbers of meningococcal W. We investigated the immunogenicity and safety of this vaccine in paediatric patients with (auto)immune disease, here focussing on Juvenile Idiopathic Arthritis (JIA) and Inflammatory Bowel Disease (IBD).

Objectives: The primary objective was to assess the immunogenicity of the MenACWY vaccine in paediatric patients with JIA or IBD, compared to the healthy control population. Within the patient cohort we studied the effect of biological DMARDs on seroprotection. The secondary objective was to assess safety of the MenACWY vaccine in patients.

Methods: A prospective study was set up in the Wilhelmina Childrens Hospital Utrecht in patients with immune disorders. Immunogenicity measures for meningococcal serotypes A, C, W-135 and Y were performed by the Centre for Infectious Disease Control, National Institute for Public Health and the Environment, using the Fluorescent bead-based Multiplex ImmunoAssay (FMIA). Immunogenicity is reached at titre levels above the cut-off of 2 μg/ml for each meningococcal serotype. Patient were sampled at baseline and 3, 12 and 24 months post-vaccination. Safety was measured by asking for adverse events during the first hospital visit after vaccine administration. Alterations in disease activity were measured by the Clinical Juvenile Arthritis Disease Activity Score-27 (cJADAS-27) in JIA patients, the Paediatric Crohn’s Disease Activity Index (PCDAI) in Crohn’s Disease patients and the Paediatric Ulcerative Colitis Activity Index (PUCAI) in Ulcerative Colitis patients.

Results: 222 patients were included (41% male). Median age was 16 years (range 15-19). 80% of the patients was using immunosuppressive drugs of which 47% biologicals, which were all anti TNF-inhibitors. Protected proportions for MenACWY 12 months post-vaccination were respectively 45% for A, 91% for C, 36% for W and 48% for Y compared to 94% for MenACWY in healthy controls. There was a significant difference in seroprotection rates in patients using anti TNF versus no TNF agents at 12 months post-vaccination: for MenC 100 versus 90%, MenW 61% versus 21%, and MenY 77% versus 31%. The MenACWY vaccine did not aggravate JIA or IBD disease and no severe adverse events were observed.

Conclusion: The MenACWY vaccine is well tolerated in JIA and IBD patients but less immunogenic compared to healthy controls. Seroprotection rates at 12 months-post vaccination are significantly lower in patients treated with anti-TNF agents. We therefore advice to measure antibodies in patients on anti-TNF 12 months post-vaccination and to consider a booster vaccination accordingly.

Patient Consent Received

Yes

Disclosure of Interest

None declared

P23 JIA-uveitis: a B-cell-driven disease?

B. Jebson^1,2, N. de Gruijter^2,3, A. L. Solebo^1,4, L. Wedderburn^1,2,4, E. Rosser^2,3

¹UCL GOS Institute of Child Health; ²Centre for Adolescent Rheumatology Versus Arthritis; ³Centre for Rheumatology, Division of Medicine, UCL; ⁴Great Ormond Street Hospital for Children, NHS, London, United Kingdom

Correspondence: B. Jebson

Introduction: Approximately one third of patients with poly- and oligo-articular juvenile idiopathic arthritis (JIA) are susceptible to developing the comorbidity uveitis (JIA-Uveitis). JIA-Uveitis is commonly asymptomatic and if not detected early, can cause disabling vision loss. At present, all JIA patients are screened for uveitis- often for many years following diagnosis. Given two thirds will never develop eye disease, this wastes both NHS and patient time. There is an unmet need for a clinical test which can identify JIA patients that are at risk of developing JIA-Uveitis. Although a lack of evidence surrounds the connection between JIA & JIA-Uveitis, risk factors such as anti-nuclear antibody (ANA) presence and B-cell infiltrates in JIA-Uveitis eye tissue suggest B-cells may be involved in development of eye disease.

Objectives: To explore whether B-cell signatures in the peripheral blood can be used to distinguish JIA-Uveitis patients versus JIA patients with no eye disease.

Methods: We performed multi-parameter flow cytometry analysis on peripheral blood mononuclear cells (PBMC) of JIA (no uveitis) n=31 and n=15 JIA-Uveitis patients to explore phenotypic differences in the B-cell compartment (based on expression of CD19, CD24 & CD38). JIA-Uveitis patients included those with current or historical uveitis diagnosed by a paediatric ophthalmologist. Flow cytometry was also used to assess the class switched antibody profiles of B-cells in JIA patients with (n=9) and without eye disease (n=8). For patients to be included as JIA (arthritis only), all previous ophthalmology screenings must have been negative.

Results: JIA-U patients showed a significant increase in ‘atypical’ memory B-cells (CD19posCD24loCD38lo, p=0.0029) and a decrease in immature B-cells (CD19posCD24hiCD38hi, p=0.0078) compared to those with no uveitis. JIA-U patients also displayed a higher proportion of class switched B-cells expressing IgG (p=0.0061) and higher levels of potentially anergic IgD+, IgM- B-cells (p=0.0633) when compared with JIA patients.

Conclusion: The differences in B-cell proportions in JIA-Uveitis compared with JIA suggest a skew towards a more inflammatory B-cell phenotype. An increase in atypical memory B-cells has shown to be inflammatory in autoimmune conditions such as JIA, while a reduction of immature B-cells suggests a lack of regulatory cell presence. In addition, the increase in IgG producing B-cells and anergic B-cell levels may be contributing to the autoimmune and hyperreactive pathology of JIA-Uveitis. By developing a clinical assay to test the B-cell profile of all JIA patients, we may be able to detect JIA-Uveitis before any eye damage occurs.

Disclosure of Interest

B. Jebson: None declared, N. de Gruijter: None declared, A. Solebo: None declared, L. Wedderburn Paid Instructor for: The CLUSTER consortium PI, Prof. Lucy Wedderburn, has partnerships with industrial partners currently: GSK, Abbvie, UCB, sobi & Pfizer. None of these were directly involved in the data analysis or interpretation of this work, E. Rosser: None declared

P24 CACP syndrome and juvenile polyarthritis – is it a single disease or separate conditions. a familial case

Z. Kolkhidova¹, S. Salugina¹, A. Shapovalenko¹, M. Kostik², I. Nikishina¹, V. Matkava¹

¹Pediatric Department, V. A. Nasonova Research Institute of Rheumatology, Moscow; ²St-Petersburg Pediatric Medical University, Saint-Petersburg, Russian Federation

Correspondence: V. Matkava

Introduction:

Camptodactyly-arthropathy-coxa vara-pericarditis syndrome (CACP) is a rare autosomal recessive genetic disorder caused by a mutation in the PRG4 gene. It is characterized by congenital or early-onset camptodactyly and symmetric polyarticular non-inflammatory arthropathy of large joints with synovial hyperplasia, coxa vara, non-inflammatory pericarditis / pleurisy, and the absence of inflammatory markers. Symptoms appear from birth and do not differ by sex or race. This condition more common among children of blood related couples. Currently, there is no pathogenetic therapy. NSAIDs are used for symptomatic treatment and hip arthroplasty is used as surgical treatment of coxa vara. Therapy used for juvenile idiopathic arthritis (JIA) is ineffective.

Objectives:

To report a case of CACP in 2 siblings (sister and brother) in rheumatological practice.

Methods:

The patients were examined in the rheumatology department. Both patients were diagnosed with the CACP using genetic analysis - Sanger sequencing. Two PRG4 mutations were identified on chromosome 1q25-q31 (pathogenic p.K918fs * 10 and probably pathogenic p.T1161Hfs * 2).

Results:

Case report: Girl and boy born in 2014 and 2017, respectively. Parents are not blood related. Table 1 shows the clinical and demographic characteristics of patients. From the moment of birth, both had contractures of the metacarpophalangeal joints of the hands with further rapid formation of symmetric exudative total polyarthritis without signs of significant inflammatory, including laboratory activity. Type 6 mucopolysaccharidosis and Blau's syndrome were excluded in the girl. Both were diagnosed with JIA and treated with methotrexate subcutaneously, GC per os, intra-articular steroid injections with insufficient effect. During the one year, the girl received the TNF-inhibitor etanercept with a partial response. Patients receive the IL-6 inhibitor tocilizumab with an 30% of ACR response. Nevertheless, both pts currently have polyarthritis with joints effusion and moderate functional impairments, flexion contractures in the small joints of the hands.

Conclusion:

Due to the polyarthropathy pts with CACP syndrome can meet in the practice of rheumatologist under the mask of JIA. Both our pts had polyarthritis, no laboratory activity, they received antirheumatic therapy, including biologics with insufficient effect, but partial respond. The question of whether arthritis in our patients belongs to the CACP manifestation or is a separate disease has not been answered yet. Further study requires

Patient Consent Received

Yes

Disclosure of Interest

None declared

Table 1 (abstract P24). Clinical and demographic characteristics of patients and in compare to literature data

P25 Joints involvement in two diseases: mucopolysaccharidosis and juvenile idiopathic arthritis or how do not confuse them up with each other

N. Buchinskaya¹, N. Vashakmadze^2,3, L. Sorokina⁴, M. Kostik⁴

¹Saint-Petersburg State Medical Diagnostic Center (Genetic medical center), Saint-Petersburg; ²Pirogov Medical University; ³Central Clinical Hospital RAS, Moscow; ⁴Saint-Petersburg State Pediatric Medical University, Saint-Petersburg, Russian Federation

Correspondence: M. Kostik

Introduction: Mucopolysaccharidosis (MPS) is an inherited metabolic disease which can involve joints and be close resemble to juvenile idiopathic arthritis (JIA).

Objectives: To evaluate discriminative features between MPS and JIA.

Methods: In the retrospective study we included 255 children with RF-negative polyarthicular JIA and 155 patients with MPS with joints involvement. MPS patients were I type (n=42), II type (n=67), III type (n=27), IV type (n=9), VI type (n=10). We calculated involved joints, hematology, biochemistry markers, patient’s demographics.

Results:

Conclusion: MPS and JIA have similar inflammatory parameters. Early onset age, growth delay and predominantly involvement of upper arm joints can help to discriminate two diseases.

This work supported by the Russian Foundation for Basic Research (grant № 18-515-57001)

Patient Consent Received

No

Disclosure of Interest

None declared

Table 1 (abstract P25). See text for description

P26 evaluation of the safety and effectiveness of vaccination of children against measles, rubella, mumps and diphtheria with juvenile idiopathic arthritis: data from a cross-sectional study

N. Lyubimova¹, I. Fridman², O. Goleva², S. Kharit^2,3, M. Kostik^1,3

¹Almazov National Medical Research Centre, Russian Federation; ²Pediatric Research and Clinical Center for Infection Diseases; ³Saint Petersburg State Pediatric Medical University, Saint Petersburg, Russian Federation

Correspondence: M. Kostik

Introduction: Patients with juvenile idiopathic arthritis (JIA) often stop vaccination after the onset of the disease for fear of relapse or worsening of the course, although international experience shows the effectiveness and safety of vaccination in patients with immunocompromised diseases.

Objectives: To evaluate the efficacy and safety of vaccination against measles, rubella, mumps, and diphtheria in patients with JIA who continued to be vaccinated after the onset of JIA.

Methods: In a cross-sectional study, from a database containing information on 170 patients with JIA aged 2 to 17 years, who were identified with antibodies against measles, rubella, mumps and diphtheria, patients were selected who continued to be vaccinated against measles, rubella and mumps (n=19) and diphtheria (n=25) or refused to be vaccinated against MMR (n=39) and diphtheria (n=51), due to the development of JIA. The decision on vaccination was entirely voluntary, made by the legal representatives of the patient together with the district pediatrician or the rheumatologist together with the immunologist of the child health center. All legal representatives signed an informed consent for revaccination. The study selected patients whose age corresponded to the terms of revaccination, according to the National Schedule of Vaccinations of the Russian Federation. The diagnosis of JIA was established based on the ILAR criteria. In all patients, the levels of antibodies (IgG) against vaccines were determined using ELISA. The data is presented with a median and 25%>75%.

Results: Children with the oligoarticular variant of JIA were more often subjected to revaccination against measles, rubella, and mumps. There were no significant differences in antibody levels and the proportion of patients who did not have protective antibodies against measles, rubella and mumps between the compared groups, as well as differences in the characteristics of the course of JIA and the therapy. Patients with less severe JIA, less frequently treated with methotrexate, and less likely to need both primary administration of biologics and switching between biologics were more likely to be revaccinated against diphtheria. Vaccination against diphtheria was effective, as evidenced by an almost twofold prevalence of patients with a protective antibody titer compared to those who refused revaccination. Methotrexate (OR = 9.5 [95%CI: 1,004; 90.3]) and biologics (OR=4.4 [95%CI: 1.6; 12.1]) were predictors of failure to revaccinate against diphtheria. Serious adverse events, as well as JIA flares in the 3-month period after vaccination were not recorded.

Conclusion: Vaccination of children with juvenile idiopathic arthritis against measles, rubella, mumps and diphtheria is effective and safe. Further research is needed to increase physicians' confidence in vaccinating children with rheumatic diseases.

This work supported by the Russian Foundation for Basic Research (grant № 18-515-57001)

Disclosure of Interest

None declared

Table 1 (abstract P26). See text for description

P27 Investigation of the immunoregulatory role of the PD-1 pathway in juvenile idiopathic arthritis - preliminary results

A. Koutsonikoli, A. Taparkou, P. Pratsidou-Gertsi, V. Sgouropoulou, M. Trachana

Pediatric Immunology and Rheumatology Referral Centre, 1st Pediatric Dept, Aristotle University of Thessaloniki, Hippokrateio General Hospital, Thessaloniki, Greece

Correspondence: A. Koutsonikoli

Introduction: The Programmed cell Death protein-1 (PD-1) pathway promotes self-tolerance, by inhibiting immune responses. The soluble form of PD-1 (sPD-1) may antagonize the binding of the membrane-bound PD-1 with its ligands, leading to the blocking of the pathway’s functions. Data regarding the role of the PD-1 pathway in Juvenile Idiopathic Arthritis (JIA) are still limited.

Objectives: To investigate the immunoregulatory role of the PD-1 pathway in JIA patients.

Methods: A. Determination of sPD-1 levels in serum and synovial fluid (SF) samples using ELISA. B. Analysis of the PD-1 expression on T-helper and T-cytotoxic cells in the peripheral blood (PB) and SF, by applying flow cytometry. C. Search for an association between the above biomarkers, as well as their relation with JIA activity. Inactive disease was defined according to Wallace criteria.

Results: Fifty-six Caucasian patients (39 female) participated in this study, with a median (range) age of 13 (2-19) years, with oligoarthritic (33%), polyarthritic (29%), psoriatic (9%), enthesitis-related (14%), systemic (11%) and undifferentiated (4%) JIA. There was no correlation between the sPD-1 levels and the PD-1 cellular surface expression (n=16 PB/serum, n=11 SF). The median sPD-1 was statistically significantly higher in the SF [1104.4pg/ml (560.4-1419)] than in the serum [773.4pg/ml (215.4-980.4)] (n=7) (p=0.028). The median serum sPD-1 was statistically significantly higher in patients with active JIA [218.3pg/ml (149.8-980.4)] (n=22) than in those with an inactive disease [186.7pg/ml (46.8-340.4)] (n=10) (p=0.035). The median percentage of positive for PD-1 T-helper cells in PB was statistically significantly higher in patients with active JIA [1.79% (0.14-19.1)] (n=26) than in those with inactive disease [0.16% (0.1-2.43)] (n=6) (p=0.006). The median percentage of positive for PD-1 T-cytotoxic cells in PB was statistically significantly higher in patients with active JIA [2.65% (0.73-12.93)] (n=26) than in those with inactive disease [0.55% (0.26-4.2)] (n=6) (p=0.014).

Conclusion: These preliminary results indicate that the sPD-1 levels rise in active JIA, more prominently in the inflamed joint than in the PB. Also, in active JIA a higher number of T-helper and T-cytotoxic cells expressing PD-1 were detected. Further investigation in a larger sample of JIA patients may verify these observations and contribute to unraveling the precise role of the PD-1 pathway in the pathogenesis and maintenance of the joint inflammation.

Disclosure of Interest

None declared

P28 Multifactorial aspects of IGA nephropathy onset in a 13 year-old boy affected by oligoarticular juvenile idiopathic arthritis (JIA) with ongoing adalimumab treatment

B. Lattanzi¹, A. Omenetti¹, A. Ranghino², L. Caponi³, S. Cazzato¹

¹Pediatric Unit, Salesi Children's Hospital; ²Nephrology, Dialysis and Transplantation Unit, AOU Ospedali Riuniti; ³Department of Pediatria, Polytechnic University of Marche, Ancona, Italy

Correspondence: B. Lattanzi

Introduction: According to anecdotal reports, renal involvement due to uncontrolled inflammation or long exposure to anti-rheumatic drugs, may rarely occur during juvenile idiopathic arthritis (JIA). Most of these cases refer to systemic JIA, associated with inflammation and, eventually, renal amyloidosis. Little is known about oligoarticular JIA. Biological agents, such as adalimumab, can induce IgA nephropathy but this usually resolves following cessation of therapy.

Objectives: To highlight potential aetiology of renal involvement in oligoarticular JIA.

Methods: We herein report a case of a 13 years old boy affected by JIA and uveitis, who developed proteinuria and haematuria during adalimumab treatment.

Results: The patient was diagnosed by ANA positive oligoarticular JIA at the age of 3. He was initially treated with intra-articular steroid injections and methotrexate, with subsequent switch to etanercept due to frequent articular relapses. Despite complete remission, he later presented relapsing uveitis for which adalimumab was started in Oct 2017. Complete remission was successfully obtained and maintained with ongoing treatment. However, on Nov 2020, unforeseen proteinuria and haematuria occurred regardless persistent JIA remission. Drug-induced renal damage was considered and adalimumab promptly discontinued. Infectious triggers were ruled out. Autoimmune profiling was unremarkable (i.e. negative ENA, dsDNA, p-ANCA, c-ANCA, p anti-phospholipase A2 receptor and glomerular basal membrane antibodies antibodies, anti-thyroid antibodies) except for known ANA positivity (1:160). Complement fractions were in normal range whereas IgA levels were slightly elevated (330 mg/dl, normal values 61-301). Intriguingly, laboratory tests unveiled the presence of HLA-DQ2/DQ8 positivity and IgA-class tissue transglutaminase antibodies (tTGA), which were persistently negative at previous yearly screening. Coeliac disease may actually elicit IgA nephropathy with consequent beneficial effect of gluten-free diet. However, tTGA levels remained in borderline ranges at following assessments, not allowing a definitive serological diagnosis. Meanwhile, given worsening course of proteinuria and haematuria, renal biopsy was performed, and unveiled findings consistent with mesangial IgA nephropathy. Unfortunately, discontinuation of biological therapy resulted in both ocular and articular disease relapse. In order to rapidly target either kidney and JIA disease manifestations, systemic corticosteroids regimen according to “Pozzi protocol” was started with prompt improvement of both proteinuria and haematuria, and resolution of articular and ocular relapse.

Conclusion: The case herein presented addresses the multifactorial putative causes underlying onset of an IgA nephropathy in oligoarticular JIA. In particular, this report rises several considerations: 1) the patient developed IgA nephropathy during adalimumab therapy, with worsening proteinuria and haematuria despite drug discontinuation, weaking the drug-induced hypothesis; 3) several evidence indicate a role for gut-renal connection in IgA nephropathy onset and celiac disease is part of the autoimmune clinical spectrum including JIA. In conclusion, due to rarity of reports demonstrating safety of other anti-TNFα agents, once renal remission will be achieved by the ongoing steroid regimen, JIA maintaining therapy with different biologic drug (i.e. abatacept) will be considered. In addition, the ongoing suspicious celiac disease onset will need to be confirmed or excluded by small bowel biopsy as soon as the high dose steroid regimen will be concluded in other to avoid potential relapse of IgA nephropathy.

Patient Consent Received

Yes

Disclosure of Interest

None declared

P29 Evaluation of the immunological profile and vacinal status of patients with juvenile idiophatic arthritis

M. Lopes¹, L. A. C. Cronemberger², C. F. C. Valença², F. S. Tavares², A. G. Islabão¹

¹Rheumatology; ²Immunology, Hospital da Criança de Brasília José Alencar, Brasília, Brazil

Correspondence: M. Lopes

Introduction: Children and adolescents with Juvenile Idiopathic Arthritis (JIA) suffer a great impact on quality of life, due to changes caused by the disease and association with the treatment, which increase the susceptibility to infections. Thus, a safe and effective vaccination is important. B cells have an important role in immune responses with antibodies production against pathogens and response to vaccines.

Objectives: Due to the scarce literature on this topic, the main objective of this study was to trace the immunological profile including lymphocytes subsets and vaccine response of patients with JIA being followed up at the pediatric rheumatology outpatient reference clinic.

Methods: An observational, analytical, cross-sectional study was carried out, obtaining data through the collection of laboratory tests and charts in the period from April to December 2020. Consecutive patients diagnosed with JIA according to the International League of Associations for Rheumatology (ILAR) were included.

The evaluated subtypes of JIA were oligoarticular, polyarticular, systemic, enthesitis-related arthritis and undifferentiated. Each patient underwent a single laboratory collection. The tests used were blood count, immunoglobulins (IgM, IgG, IgA and IgE), lymphocyte profile by flow cytometry (CD3, CD4, CD8, CD19 and CD56), serology IgG for measles and rubella and anti-HBs for hepatitis B.

Results: Sixty patients, out of the eighty-nine diagnosed with JIA, were included. Median age was 11 years and 3 months and the most prevalent gender was female 44/60 (73.3%).

Among the patients studied, 37/60 (62.7%) had positive Anti-Nuclear Antibodies Hep-2 (ANA) and 10/60 (16.6%) positive Rheumatoid Factor (RF). The most prevalent JIA subtype was the oligoarticular 28/60 (46.6%) and polyarticular 24/60 (40%). The main hematological alteration found was lymphopenia, in 14/60 (23.3%) patients. The number of patients with reduced IgA levels corresponded to 12/60 (20%), with no emphasis on the reduction of IgM, IgG or IgE. Among the evaluated patients, 37/60 (63.7%) presented serology that was not reactive to hepatitis B, 10/60 (17.8%) to measles and 6/10 (10.3%) to rubella. Regarding to lymphocytes subsets, one patient did not collected the exam. Observed that 11/59 (18.6%) had CD3 below the 10th percentile (p10), 8/59 (13.5%) CD4 below the p10, 12/59 (20.3%) CD8 below p10, 40/59 (67.8%) CD19 below p10, 27 (45%) CD56 below p10.

Conclusion: In conclusion, our study demonstrated an important reduction in lymphocytes subsets, mainly CD19 and CD56, and protection against hepatitis B. We also evidenced JIA association with IgA deficiency.

Disclosure of Interest

None declared

P30 Effects of Humira in children with juvenile idiopathic arthritis (JIA) and polymorphic manifestations of uveitis- in example of one rheumatology center in Georgia

M. Lekishvili¹, K. Mamamtavrishvili², M. Ioseliani¹

¹Rheumatology; ²New Hospitals, Tbilisi, Georgia

Correspondence: K. Mamamtavrishvili

Introduction: JIA is the most prevalent rheumatologic disease among children and is commonly associated with chronic uveitis. Without adequate control of ocular inflammation, patients may develop complications leading to permanent visual loss.

Objectives: 4 female patients starting from 4 to 20 years of age, length of JIA varies between the months and 15 years.

Methods: Patient presented with various ophthalmic complications such as:

Case #1: Cataract, peripheral corneal dystrophy, Iritis, cystoid macular edema of right eye, glaukoma and artiphakia of left eye (20 y/o female)

Treatment Humira 40 mg per 2 weeks.

Case #2: Artiphakia and vitritis of both eyes, (8 y/o female)

Treatment Humira 20 mg per 2 weeks.

Case# 3. Uveitis and vitritis of both eyes (5 y/o female)

Treatment Humira 20 mg per 2 weeks, Methothrexate, 5 mg orally once a week

Case # 4 Unilateral uveal cataract (5 y/o female)

Treatment Humira 20 mg per 2 weeks, Methothrexate, 7,5 mg orally once a week, Methilprednizolone 2 mg orally daily

In all this cases methothrexate treatment alone was not enough for ocular complication.

Results: : visual acuity was improved in all 4 cases due to this treatment.

Case #1 Cystoid macular edema reduced

Case # 2 Vitreous body is partially transparent

Case # 3 Condition of both eyes is markedly improved

Case #4 Cataract surgery was performed without postoperative complication

Conclusion: Humira was successful in all 4 cases.

Humira was proven to be effective and should be considered in treatment in JAI complicated with the various ophthalmic problems.

Disclosure of Interest

None declared

P31 TNF-α inhibition pre and post-rituximab in JIA: what shall we expect? A pilot study

A. Marino¹, F. Pregnolato², F. Orsini³, I. Pontikaki¹, M. V. Gattinara¹, R. Cimaz²

¹ASST G.PINI-CTO; ²Department of Clinical Sciences and Community Health, and Research Center for Adult and Pediatric Rheumatic Diseases; ³University of Milan, Milan, Italy

Correspondence: A. Marino

Introduction: Biologic agents have revolutionized the treatment of Juvenile idiopathic arthritis (JIA). However, difficult to treat patients need several biological swaps. In this context, it is important to improve the effectiveness of available drugs and to spare our weapons with a lifespan perspective. The resetting of peripheral B cells promoted by rituximab (RTX), a chimeric monoclonal antibody against B-cell antigen CD20, represents a quite interesting option in autoimmune diseases such as JIA not only for the immediate advantage but also for the possible future use of subsequent therapies that might be necessary to achieve disease control.

Objectives: To evaluate whether TNF-α inhibition, which had already been used could be repurposed after RTX therapy.

Methods: This is a retrospective pilot study involving JIA patients who took a TNF-α inhibitior before and after having been treated with RTX. Clinical and laboratory data were collected and statistically analyzed. Clinical status, number of flares, and retention on treatment were then evaluated at different time points. Confidence intervals (CI) lower than 95% were used to estimate a probabilistic range of pre and post-RTX variations and trend was considered relevant when at least one of CI excluded the reference value of “no change”. As the sample size was limited, a bootstrapping procedure (i.e. a statistical procedure that resamples a single dataset to create many simulated samples) was used to estimate disease activity parameters and related CI.

Results: Eight patients (6 girls) were identified: 4 patients with oligoarticular JIA, 2 with psoriatic JIA, 1 with systemic JIA and 1 with RF-negative polyarticular JIA. 6/8 patients were ANA positive. The median (range) age at disease onset, at the selected biologic agent pre-RTX (SB pre-RTX), at RTX onset, at the SB post-RTX were 2.1 years (1.2-15.8), 17.8 years (9.6-49.9), 21.6 years (15.3-51.6), and 23.2 years (17.4-52.5), respectively.

Clinical remission was achieved in 7 patients on SB pre-RTX and in 8 patients on SB post-RTX; furthermore, the median time to achieve clinical remission was shorter (2 months vs 3 months) before and after RTX. Both the remission duration and the retention time of the TNF-α inhibitor were longer (3.9 years vs 2.2 years) on the SB post-RTX.

After adjustment for the exposition time, the median number of flares was 1.03 (0.29 to 3.02) during the treatment with TNF-α inhibitor pre-RTX and decreases post-RTX to 0.64 (0.0 to 2.09).

The bootstrapped differences of remission time, TNF-α inhibitor retention rate and flare rate ratio of post- versus pre-RTX are shown in Table 1. As the reference value of no change (0 or 1 according to the effect measure used) does not fall within the 95% and 90% CI, our findings highlight a trend towards a substantial variation.

Conclusion: This pilot study documented a possible amelioration of disease response to TNF-α inhibition after treatment with RTX. A larger cohort is advisable in order to verify this opportunity in the context of a chronic disease starting in early childhood.

Disclosure of Interest

None declared

Table 1 (abstract P31). Bootstrapped estimates of measures of effect and related CI post- vs pre-RTX

P32 Toll-like receptor 4 expression on peripheral blood mononuclear cells in juvenile idiopathic arthritis

O. Mukvich, A. Matskevych

Department of Pediatric Rheumatology and Autoinflammatory Diseases, State Institution “Institute of Pediatrics, Obstetrics and Gynecology of NAMS of Ukraine”, Kyiv, Ukraine

Correspondence: O. Mukvich

Introduction: Juvenile idiopathic arthritis (JIA) is currently considered a heterogeneous group of inflammatory arthritis of unknown etiology (ACR, 2019). The formation of its pathological mechanisms is due to dysregulation of both adaptive and innate immunity, the key ligands of which are toll-like receptors (TLR). TLR4 play an important role in the recognition of inflammation caused by bacterial lipopolysaccharides (LPS), activation of the nuclear factor-κB (NF-κB) and other intracellular signaling pathways with subsequent expression of pro-inflammatory cytokine genes. An increased expression of endogenous TLR4 ligands (heat shock proteins, fibronectin, fibrinogen, HSP, EDA, etc.) has been found in the tissue synoviocytes and peripheral blood monocytes, which are recruited to the site of inflammation and participate in the pathogenesis of synovial inflammation, which is believed to be an important mechanism in the pathogenesis of rheumatoid arthritis. To clarify the pathogenetic role of TLR4, the levels of its stimulation in different subtypes of JIA are of interest.

Objectives: To determine the levels of TLR4 expression on CD14+ monocytes in the heparinized whole blood in children with different subtypes of JIA.

Methods: 62 children from 10 to 17 years old were examined, including 42 children diagnosed with JIA and 20 healthy children. Patients with JIA were stratified by subtypes: systemic - 6, polyarthritis -17, oligoarthritis - 19 children. The intensity of TLR4 expression on CD14+ monocytes was determined in the heparinized whole blood during incubation with a cocktail of CD14-FITC/TLR4-PE monoclonal antibodies (Biolegend, USA) using flow cytometry. The Student's t-test was used to assess the differences between the groups in cases of normal distribution. The difference with p<0.05 was considered significant.

Results: Patients diagnosed with JIA had an increased expression of TLR4 - (51.51±6.18)%, which showed a statistical difference (t=3.01, α=0.05, p=0.0033), compared to the control group of healthy children (23.47±6.68)%. The level of its expression was (54.43±12.10)% (t=2.24, α=0.05, p=0.033) in children with oligoarthritis and (52.86±7.14)% (t=3.01, α=0.05, p=0.005) in children with polyarthritis. The highest level of stimulation was determined in children with oligoarthritis, which was 2.3 times higher, compared to the control group. In systemic JIA, TLR4 expression was lower (38.48±10.32)% and showed no statistical differences compared to healthy children (t=2.12, p>0.05).

Conclusion: High expression of TLR4 on CD14+ blood monocytes, which are able to migrate to synovial membranes and increase the synthesis of pro-inflammatory cytokines and chemokines, determines the role of innate immunity, and the TLR signaling pathway in particular, in the formation and persistence of chronic inflammation induced by microbial ligands. The obtained data indicates the possibility of differences in the formation of inflammatory mechanisms in articular and systemic JIA. The implementation of the TLR4 signaling pathway orientation in the clinical practice has a therapeutic potential in JIA

Patient Consent Received

Yes

Disclosure of Interest

None declared

P33 Predictive factors of uveitis and its complications in a cohort of 302 JIA patients

A. T. Melo^1,2, J. M. Martinho^1,2, P. Martins^1,2, R. Ferreira³, P. José³, S. Mano³, I. Leal³, P. C. Reis^2,4,5, F. O. Ramos^1,2,4, J. E. Fonseca^1,2, R. C. Marques^1,2,4

¹Serviço de Reumatologia e Doenças Ósseas Metabólicas, Hospital de Santa Maria, Chuln; ²Unidade de Investigação em Reumatologia, Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa; ³Serviço de Oftalmologia; ⁴Unidade de Reumatologia Pediátrica; ⁵Serviço de Pediatria, Hospital de Santa Maria, Chuln, Lisbon, Portugal

Correspondence: A. T. Melo

Introduction: Screening and prompt diagnosis are essential to avoid complications, such as cataracts and glaucoma in uveitis.

Objectives: To identify clinical or laboratorial predictive factors of uveitis complications in patients with juvenile idiopathic arthritis (JIA).

Methods: A retrospective observational study of patients with JIA, registered at the Portuguese Rheumatic Diseases Register (Reuma.pt) was performed. Demographic variables, data on presence of uveitis and its complications (synechiae, band keratopathy, glaucoma, cataracts, macular edema), clinical features and treatment were collected and complemented with hospital clinical data. Statistical analysis was done using SPSS 26.0, with a significance of p<0.05. Univariate analysis was performed using Fisher’s exact test, Mann-Whitney U test or Chi-Square. Multivariate analysis was also performed.

Results: We included 302 JIA patients, 59.6% females, with a mean age at JIA onset of 8.4±4.8 years and a mean disease duration of 12.8±11.1 years. Uveitis was identified in 52 of the 302 patients (17.2%), with a mean age at uveitis onset of 11.3± 9.4 years. The mean time since JIA diagnosis until uveitis onset was 5.4± 8.3 years. Only in 2 cases uveitis started before JIA. Uveitis developed only in adulthood in 11 of those patients.

Younger age at JIA diagnosis was associated with uveitis (6.2 [4.5] vs 8.9 [4.7], p=0.01). Oligoarticular persistent (opJIA) (23.7% vs 14.1%, p=0.040) and extended form (oeJIA) (39.3% vs 15.0%, p=0.003) were also positively correlated with the presence of uveitis. On the other hand, polyarticular JIA had a lower frequency of uveitis (7.9% vs 20.4%, p=0.013). First uveitis episode at adulthood was more common in JIA ERA patients (15.4% vs 62.5%, p=0.011), whereas uveitis onset <18years old was associated with an opJIA form (36.0% vs 9.0%, p=0.03).

Uveitis was more frequent in patients with positive antinuclear antibodies (ANA) (25.8% vs 13.6%, p=0.012), however, there were no significant differences between the ANA title (≤1/160 vs > 1/160) or pattern. We found no association between the development of uveitis and positivity to rheumatoid factor, anticyclic citrullinated peptides, human leukocyte antigen B27 or with inflammatory markers. Multivariate analyses showed that opJIA and oeJIA were independent predictors of uveitis (OR 2.9 95%CI: 1.3-6.6; OR 6.1 95% CI: 2.3-16.2; respectively)

Ocular complications occurred in 15 patients out of the 52 patients (28.3%): synechiae occurred in 28.3%, band keratopathy in 22.7%, cataracts in 17%, glaucoma in 15.1%, macular edema in 7.6%. We found an association between oeJIA form and the development of glaucoma (80% vs 22%, p=0.033) and with the need for ocular surgical procedures (75.0% vs 14.8%, p=0.028). Multivariate analyses showed that oeJIA form was an independent predictor of ocular surgical procedures (OR 14.9 95% CI: 1.2-193.4).

Conclusion: Uveitis was more frequent in opJIA and oeJIA patients and was related to ANA positivity, which is consistent with the literature. The need of ocular surgeries and prevalence of glaucoma seems to correlate with oeJIA.

Disclosure of Interest

None declared

P34 Self-reported physical activity in children and adolescents with juvenile idiopathic arthritis (JIA): correlates and comparison with the general population

F. Milatz¹, S. Hansmann², M. Niewerth¹, J. Klotsche¹, J. Hörstermann¹, J.-P. Haas³, D. Windschall⁴, J. Peitz⁵, T. Kallinich⁶, R. Trauzeddel⁷, H. Girschick⁸, K. Minden^1,9

¹Epidemiology and Health Care Research, German Rheumatism Research Centre, Berlin; ²Center for Pediatric Rheumatology, autoinflammation reference centre Tuebingen (arcT), University Children's Hospital Tuebingen, Tuebingen; ³German Center for Paediatric and Adolescent Rheumatology, Garmisch-Partenkirchen; ⁴Clinic for Paediatric and Adolescent Rheumatology, Northwest German Center for Rheumatology, St. Josef-Stift Hospital, Sendenhorst; ⁵Paediatric Rheumatology Centre, Asklepios Clinic, Sankt Augustin; ⁶Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, University Medicine Charité Berlin; ⁷Department of Paediatrics, Helios Klinik Berlin-Buch; ⁸Children's Hospital, Vivantes Hospital im Friedrichshain; ⁹Department of Rheumatology and Clinical Immunology, University Medicine Charité Berlin, Berlin, Germany

Correspondence: F. Milatz

Introduction: Physical activity (PA) is essential throughout growth and maturation to ensure optimal physical function and fitness, especially for those suffering from chronic conditions such as JIA [1].

Objectives: This study aimed i) to estimate the proportion of JIA patients meeting the recommended minimum level of PA compared with general population controls and ii) to identify clinical parameters associated with physical (in)activity.

Methods: Patients’ (≥12 years) or parents’ (≤11 years) self-reported data on PA were considered from the German Paediatric Rheumatologic Database. In accordance with the methodology used in the general population survey [2], achievement of WHO recommendations on PA of at least 60 minutes per day was determined among 3-17-year-olds. For comparability reasons with the general population, 2017 served as the year for which sex- and age-matched pairs were formed. Multinomial logistic regression was used to analyze the association between physical (in)activity and clinical as well as self-reported outcomes.

Results: Data from 6.297 matched-pairs (mean age 11.2 ± 4.2 years, female 67%, patients’ disease duration 4.5 ± 3.7 years, persistent oligoarthritis 43%) were eligible for analysis. Almost 36% of patients aged 3 to 17 years met the recommended PA amount (72% aged 3 to 6; 48% aged 7 to 10; 28% aged 11 to 13; 16% aged 14 to 17). In matched controls, 21% fulfilled the WHO recommendations on PA (42% aged 3 to 6; 25% aged 7 to 10; 17% aged 11 to 13; 10% aged 14 to 17). While no relevant sex differences were found in JIA, considerable variation between categories could be identified (e.g. 42% persistent oligoarthritis vs. 22% enthesitis-related arthritis). Older age (OR = 0.79, 95% CI = 0.78-0.80), longer disease duration (OR = 0.88, 95% CI = 0.86-0.89), higher BMI (OR = 0.96, 95% CI = 0.93-1.00) and more frequent use of biologics (OR = 0.74, 95% CI = 0.65-0.85) were associated with a lower likelihood of achieving the PA recommendations. According to patient-reported data (adolescents ≥12 years), the proportion of physically inactive (PA <2 days/week) was highest (15%, n=493). Among them, female sex (OR = 0.74, 95% CI = 0.60-0.92), age (OR = 1.08, 95% CI = 1.02-1.15), cJadas-10 (OR = 1.08, 95% CI = 1.06-1.10), CHAQ (OR = 2.16, 95% CI = 1.77-2.63), and treatment with glucocorticoids (OR = 3.19, 95% CI = 1.35-7.5) were associated with physical inactivity.

Conclusion: Although children and adolescents with JIA meet the WHO recommendation on PA more often than general population controls, a remarkable decline towards physical inactivity is observed with increasing age. Because this cannot be explained by disease- or symptom-related factors alone, overprotective attitudes should be avoided and social, emotional, cultural, and environmental barriers to PA considered.

References

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

[2] Finger JD et al. Körperliche Aktivität von Kindern und Jugendlichen in Deutschland - Querschnittergebnisse aus KiGGS Welle 2 und Trends. Journal of Health Monitoring 2018;3:24-31.

The National Paediatric Rheumatological Database has been funded by AbbVie, Chugai, Novartis and GSK.

Trial registration identifying number:

Disclosure of Interest

None declared

P35 PD-1+ CD8+ T lymphocytes as a potential molecular marker of JIA activity – preliminary results

V. Opoka-Winiarska¹, I. Morawska², S. Mertowski², J. Ludian², I. Korona-Głowniak³, E. Grywalska², J. Roliński²

¹Department of Paediatric Pulmonology and Rheumatology; ²Chair and Department of Clinical Immunology; ³Chair and Department of Pharmaceutical Microbiology, Medical University of Lublin, Lublin, Poland

Correspondence: I. Morawska

Introduction: Juvenile idiopathic arthritis (JIA) is a chronic inflammatory disease in which immune-related mechanisms involved in the pathogenesis still remains unclear. Similarly, immunological markers of disease activity require explanation.

Objectives: The aim of the study was to assess the expression of programmed-death cell receptor 1 (PD-1) on lymphocytes in patients diagnosed with JIA and determine whether those results correlates with the type of the disease, chosen laboratory parameters, as well as disease activity.

Methods: The study included 34 children, 18 patients with newly diagnosed JIA prior to any therapy and 16 healthy volunteers (HV) with a similar age distribution. 9 patients were diagnosed with the enthesitis-related (ERA) JIA type, 7 the oligo- and 2 poly-arthritis. Disease activity was assessed by the Juvenile Arthritis Disease Activity Score 71 (JADAS 71) calculated on the following parameters: parent global assessment of well-being, physician’s global assessment of disease activity, number of active joints and erythrocyte sedimentation rate (ESR).

After obtaining the appropriate consents, blood samples were taken from the patients and HV’s. Samples after preparation according to the protocol were stained using anti-human antibodies (BD Biosciences, USA) and analyzed using FACSCaliburTM flow cytometer (BD Biosciences) and CellQuest Pro Software. Results were statistically analyzed using Statistica 12. Kruskal-Wallis test and Spearman rank correlation were used to determine statistical significance.

Results: Data analysis showed no significant differences in the percentages of PD-1⁺CD4⁺, PD-1⁺CD8⁺ and PD-1⁺CD19⁺ cells between the JIA patients and the control group. A higher level of PD-1⁺ lymphocytes was observed in patients with polyarthritis form, but this relationship was not statistically significant. Preliminary results indicated that there was no correlation between the percentage of PD-1 receptor and other laboratory and clinical parameters. However, there was a strong statistically significant correlation (p=0.0057) between the percentage of CD8⁺PD-1⁺ lymphocytes and the disease activity measured by the JADAS 71 (Tab.1.)

Conclusion: Our research showed a correlation between the percentage of PD-1+CD8+ T lymphocytes and the disease activity. The search for a molecular markers of the disease activity is extremely important in the process of choosing proper treatment strategies and preventing the disability of children diagnosed with JIA. Flow cytometry is a cheap, quick and clinically available method. The role of the PD-1+CD8+ cells in chronic inflammation is also interesting. More research is needed to assess whether the PD-1+CD8+ lymphocytes may be used as a marker of disease activity or the potential target of therapy.

Bioethics Committee approval number KE-0254/93/2021.

Disclosure of Interest

None declared

Table 1 (abstract P35). Correlation of % lymphocyte (PD-1⁺CD4⁺, PD-1⁺CD8⁺ and PD-1⁺CD19⁺) and JADAS 71

P36 Psychological symptoms during COVID-19 pandemic in a cohort of patients with juvenile idiopathic arthritis

C. Traverso, R. Naddei, T. Lastella, F. Aversano, M. Alessio

Pediatric Rheumatology Unit, Mother and Child Department, University of Naples Federico II, Naples, Italy

Correspondence: R. Naddei

Introduction: Juvenile idiopathic arthritis (JIA) is the most common pediatric chronic rheumatic disease. Since SARS-CoV-2 outbreak, patients with JIA had to cope with some challenges which may have impacted not only their routine disease management but also their mental health.

Objectives: Aim of our study was to evaluate psychological status of children and adolescents affected by JIA during COVID-19 pandemic.

Methods: A web-based survey, consisting in two questionnaires, was conducted through the Google-Forms platform. Between November 11 and December 4, 2020, the links to access the online survey pages were sent out to the parents of patients with JIA, aged 7-18 years, followed at the Pediatric Rheumatology Unit of the University of Naples Federico II. The survey included the Children's Depression Inventory (CDI) and the Anxiety Questionnaire for Developmental Age. A CDI score of 19 was used as threshold to discriminate children at risk of depression from nondepressed children. Anxiety questionnaire scores equal or higher than the 80° centile were considered suggestive of anxiety symptoms. Univariate statistical analysis was performed.

Results: 83 patients (mean age 12,9 years, SD 3) answered the survey. 54 out of 83 patients were on-medication (65.15%); the most frequent JIA subtype was the oligoarticular one (63.8%), followed by the RF-negative polyarticular (25.3%) and the systemic ones (8.4%). 6 patients scored more or equal to 19 at CDI, resulting in a prevalence of depressive symptoms of 7.2% in our cohort. CDI scores resulted significantly higher in children on medication compared to patients off-therapy (median CDI 7 [IQR 4-9.5] vs 4 [2-7.50], p=0.046) and in females compared to male patients (6 [3-11] vs 4.5 [2-6.75], p=0.046). CDI levels were not associated with JIA subtype, age or presence of uveitis, meanwhile a weak correlation was found between CDI score and disease duration (Spearman's ρ 0.244, p=0.026). Anxiety symptoms were present in 12 out of 83 patients (14.5%). Females presented higher score at the anxiety test compared to males (33 [IQR 26-42) vs 26 [IQR 20.2-33], p=0.019). No association was found between the scores of Anxiety Questionnaire for Developmental Age and patient age, JIA subtype, treatment for JIA, presence of uveitis or disease duration. A moderate correlation was detected between depressive and anxiety symptoms (Spearman's ρ 0.486, p<0.0005).

Conclusion: About 7% and 14.5% of our patients with JIA resulted at risk of depression and anxiety, respectively. SARS-CoV-2 pandemic may have impacted their psychological status; therefore, a screening evaluation should be performed in patients with JIA, especially in females on-medication, in order to provide psychological support to children experiencing depressive or anxiety symptoms, which may have been triggered and worsened by COVID-19 pandemic.

Disclosure of Interest

None declared

P37 Lipoma arborescens in childhood: a rare condition mimicking oligoarticular juvenile idiopathic arthritis (JIA) at onset

A. Omenetti¹, B. Lattanzi¹, V. Galeazzi², M. Marinelli³, S. Cazzato¹

¹Pediatric Unit, Salesi Children's Hospital; ²Clinical Radiology, Departments of Radiologic Science; ³Clinical of Adult and Paediatric Orthopedic, AOU Ospedali Riuniti, Ancona, Italy

Correspondence: A. Omenetti

Introduction: Mild painful knee swelling with functional limitation is one of the most common clinical picture at onset of monoarticular juvenile idiopathic arthritis (JIA).

Objectives: To present an unusual condition featured by overlapping clinical signs typical of monoarticular JIA, which may need to be reminded during differential diagnosis.

Methods: Diagnostic work up including routine and immunological blood test combined to imaging assessments (i.e. knee ultrasound and magnetic resonance imaging, MRI) and synovial biopsy was carried out. Literature revision of similar case reports was performed to confirm significance of the findings.

Results: A 12 year-old female presented with left knee swelling, mild pain and functional limitation, persisting for 8 weeks without history of recent trauma nor infections. Morning stiffness was not referred. Physical examination was unremarkable except for local mild painful swelling in the absence of calor, rubor nor significant joint effusion, and associated to functional limitation at squatting. General condition were good except for obesity, in the absence of constitutional symptoms. By investigating her personal and medical history, a similar episode, occurring on the same joint 18 months earlier and resolved following evacuative arthrocentesis, was described. The procedure had been performed in emergency room with no further measures due to referred serosal synovial fluid and unremarkable routine blood tests with negative knee X-ray. Persistent well-being was referred until the ongoing relapse. Given the disease history and the presence of autoimmunity in the family (i.e. psoriasis and autoimmune thyroiditis in father and sibling, respectively), onset of JIA was suspected. Routine tests were normal with negative ERS, CRP and anti-streptococcal titer antibodies. Autoimmune profiling was unremarkable (i.e. negative ENA, dsDNA, rheumatoid factor, anticitrullinated antibodies, and eye examination ruled out signs of uveitis. Knee ultrasound reported a prominent diffuse synovial thickening with mamillated aspects, associated with mild corpuscolated joint effusion, without certain signs of hypervascularization. Pigmented villonodular hyperplasia was thus considered, and bilateral knee MRI performed. Surprisingly, MRI findings were consistent with lipoma arborescens, a benign intra-articular tumor featured by villous synovial hypertrophy and lipomatous infiltration of the subsynovial tissue. Namely, the MRI reported bilateral villous proliferation of the synovia with lipomatous features. Synovial biopsy eventually confirmed the diagnosis of lipoma arborescens and the patient was referred to orthopedics for therapeutical synovectomy. Patient lost at follow up.

Conclusion: Lipoma arborescens usually affects the knee (mostly but not exclusively in monoarticular pattern) although every joint can be involved. Although rare in children, we revised the available literature in order to assess the significance of this finding. Actually, to date only 15 cases have been described in pediatric age, affecting one knee (N=9), bilateral knees (N=4), one ankle (N=1) and one knee and one elbow (N=1). Due to the rarity of this condition, delayed diagnosis (in terms of months-years) usually occurred. Interestingly, in at least 3 cases patients had been previously diagnosed with JIA and treated accordingly, mostly for years. In one case the patient also obtained diagnosis and treatment for rheumatic fever, before receiving JIA misdiagnosis. In conclusion, although rare, lipoma arborescens should be considered in differential diagnosis of oligoarticular JIA at onset, in order to avoid misdiagnosis and overtreatment.

Patient Consent Received

No

Disclosure of Interest

None declared

P38 Juvenile idiopathic arthritis damage index articular and extraarticular: single-center report

S. Asadova¹, A. Paç Kisaarslan², S. Özdemir Çiçek³, N. Şahin⁴, S. N. Taşkın², S. Doğantan², M. H. Poyrazoğlu²

¹Pediatrics; ²Pediatric Rheumatology, Erciyes University School of Medicine; ³Pediatric Rheumatology, Kayseri City Hospital, Kayseri; ⁴Pediatric Rheumatology, Bursa City Hospital, Bursa, Turkey

Correspondence: A. Paç Kisaarslan

Introduction: After biological treatment options, quality of life and articular functions in patients with Juvenile Idiopathic Arthritis (JIA) have been maintained close to normal. The damages have decreased considerably compared to the past.

Objectives: We aimed to evaluate the damage status of the patients with JIA following in our center.

Methods: 202 JIA patients who had been followed up for two years or more were included. The data of the patients were collected retrospectively. Demographic data, comorbid diseases, laboratory data (at baseline and during follow-up), disease activity during the follow-up period, and treatments were evaluated. Disease activities, quality of life and Juvenile Arthritis Damage Index articular (JADI-A) and extraarticular (E) were evaluated at the final examination. Factors affecting JADI-A and E were assessed by univariate and multivariate logistic regression analysis.

Results: Two hundered two patients with disease duration of more than two years and still being followed up were included in the study. 127 (62.6%) of the patients were female and 75 (36.9%) were male. Their median age was 13 (IQR: 11-16), and age at diagnosis was 7 (IQR: 4-10) years. The median follow-up time was 5 (IQR: 4-8) years. 17(8%) in systemic, 82(40,5%) in oligo, 41(20%) in poly, 54(26%) in enthesitis-related arthritis, 5(2,4%) in psöriatic, 3 (1,5%) in undifferentiated arthritis were involved. Ninety-two (45.3%) patients had comorbid diseases. The median age at diagnosis was 8(IQR: 4-11) years and the follow-up period was 5(IQR: 2-9) years in patients with at least a single comorbid disease. A fifty-four(26.6%) patients had a family history of rheumatologic disease. There was no statistical difference between the disease subgroups in terms of demographic data (p> 0.05).

JADI-A scores were median:0(min-max: 0-24), JADI-E scores were median:0(min-max:0-4) in whole study population. In multivariate analysis, the mean annual attacks number [OR: 1,759 (CI: 1,300-2,379], p: 0,000), mean annual eritrocyte sedimantation rate (ESR) [OR: 1,072 (CI: 1,021-1,125), p: 0.005], duration of metotrexate usage [OR: 1.029 (CI: 1.013-1.046, p: 0.001] and biological drug usage [OR: 5.810 (CI: 1.296-26.054), p: 0.022) were effective on JADI-A scores. The CRP value at the first admission [OR: 1.007 (CI: 1,000-1,014), p: 0.037], the mean annual ESR value [OR: 1,051 (CI: 1,008-1,095), p: 0.019] were found to be effective on the JADI-E scores. The ideal cut-off point of the annual attacks number was detected 1.38 [AUC: 0.734 (0.641-0.828) / p: 0.001], the ideal cut-off point for mean annual ESR was detected 14.32 [AUC: 0.617 (0.514-0.7121) / p: 0.027] affecting JADI-A scores. The ideal cut-off point of the CRP value at the first admission was detected 13,25 [AUC: 0,662 (0,541-0,782) / p: 0,009], the ideal cut-off point for the mean annual ESR value was detected 15,10 [AUC: 0.674(0.567-0.780) / p: 0.002] affecting JADI-E scores.

Conclusion: In this study, JIA damages were evaluated after a period of biological treatment usage. Both JADI-A and E scores were very low in our cohort. This study showed that the importance of timely and effective suppression of inflammation. The parameters used in routine clinical practice can help to predict damage.

Disclosure of Interest

None declared

P39 NRF2 regulates redox metabolism of CD4+T cells in chronic inflammatory conditions

A. Rajendiran, P. Klemm, K. Tenbrock, K. Ohl

Clinic for Pediatrics and Adolescent Medicine, University Hospital RWTH Aachen, Aachen, Germany

Correspondence: A. Rajendiran

Introduction: By entering inflamed tissues, T cells adapt to low levels of oxygen, lack of key nutrients and oxidative stress conditions. To study how this environment affects T cells, we analyzed T cell metabolism and function in synovial fluid cells from Juvenile Idiopathic Arthritis (JIA) patients.

Objectives: We aimed to investigate how oxidative stress regulates T cell responses within inflamed joints of JIA patients and analyzed Nrf2-the key regulator of the antioxidative stress response- and it’s signaling pathways.

Methods: Flow cytometry analyses were performed to determine oxidative status and metabolic characteristics in the mononuclear cells from arthritic joint and peripheral blood of JIA patients. Seahorse assay were performed to analyze their metabolic activity. qRT-PCR were performed to analyze expression of genes involved in glucose and fatty acid metabolism.

Results: We identified high ROS levels in CD4+ T cells from synovial fluid (SF). Nrf2 and its target gene Nqo1 were less expressed in SF compared to blood CD4+ T cells. SF CD4+ T cells expressed high levels of mitochondrial mass, high glucose uptake and ECAR levels and high fatty acid uptake. Vice versa, Nrf2 activation of SF T cells yielded in downregulation of ROS, ECAR and fatty acid uptake and also reduced secretion of IFN-g.

Conclusion: These findings suggest that Nrf2 signaling regulates the metabolism of SF T cells and its dysregulation in T cells during chronic inflammation could contribute to disease progression.

Patient Consent Received

Yes

Disclosure of Interest

None declared

P40 Impact of concomitant methotrexate use and prior bdmard exposure on tofacitinib efficacy and safety in patients with polyarticular course juvenile idiopathic arthritis: post hoc analysis of a phase 3 withdrawal study

N. Ruperto¹, D. J. Lovell², O. Synoverska¹, C. Abud Mendoza¹, A. Spindler¹, Y. Vyzhga¹, I. Tirosh¹, L. Imundo², E. Alexeeva¹, P. Chiraseveenuprapund², H. Shi³, G. Sawyerr⁴, A. Blum⁵, P. Klaus⁵, A. Shapiro⁶, A. Diehl³, A. Ebrahim³, A. Martini¹, H. I. Brunner², on behalf of for PRINTO and PRCSG

¹PRINTO, IRCCS Istituto Giannina Gaslini, Genova, Italy; ²PRCSG, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH; ³Pfizer Inc, Collegeville, PA; ⁴Pfizer Inc, New York, NY, United States; ⁵Pfizer Pharma GmbH, Berlin, Germany; ⁶Pfizer Inc, Peapack, NJ, United States

Correspondence: N. Ruperto

Introduction: Tofacitinib is an oral JAK inhibitor that is being investigated for several forms of JIA. The efficacy and safety of tofacitinib in patients (pts) with polyarticular course (pc)JIA were demonstrated in a Phase 3 trial.

Objectives: To assess tofacitinib efficacy/safety in pts with pcJIA, stratified by concomitant methotrexate (MTX) use and prior exposure to biologic (b)DMARDs.

Methods: This post hoc analysis included data from pts with pcJIA aged 2–<18 years in a Phase 3, randomised, double-blind, placebo (PBO)-controlled withdrawal study. Pts received tofacitinib 5 mg BID or body weight-based lower equivalent dose. Pts achieving ≥JIA/ACR30 response at Week (W)18 were randomised 1:1 to continue tofacitinib or switch to PBO to W44. Here, pts were analysed in subgroups: concomitant MTX use on study Day 1 (yes/no) and prior bDMARD exposure (yes/no). Efficacy for tofacitinib vs PBO was assessed to W44, by subgroup: JIA flare rate; JIA/ACR50/70/90 response and JIA/ACR inactive disease (ID) rates; and least squares mean (LSM) change from W18 (∆) in JADAS27-CRP. Safety with tofacitinib was assessed throughout, by subgroup.

Results: 184 pts with pcJIA received tofacitinib to W18, when pts were randomised to receive tofacitinib (n=72) or PBO (n=70). Of these pts, 106 received concomitant MTX and 43 had prior bDMARD exposure. Across subgroups, most pts were female and white, and mean age ranged from 10.9–12.9 years. JIA flare rate was lower and JIA/ACR50/70/90 response and JIA/ACR-ID rates were higher with tofacitinib vs PBO at W44 across subgroups (Table). The greatest differences between treatments were in pts who did not use concomitant MTX and those with prior bDMARD exposure. Across subgroups, JADAS27-CRP improved or was stable at W44 vs W18 in pts receiving tofacitinib; scores worsened with PBO, most evidently in pts with prior bDMARD exposure (Table). AEs and serious AEs, respectively, occurred in: 72.9% and 3.0% (+MTX); 88.2% and 3.9% (-MTX); 80.3% and 4.5% (prior bDMARDs); and 75.4% and 2.5% (no prior bDMARDs) of pts. The most common AEs, by system organ class, were infections in all subgroups (43.6–58.8% of pts). AEs of special interest occurred at a low frequency across subgroups; overall, 1.6% had hepatic events, 1.1% had herpes zoster (all events non-serious) and 1.6% had serious infections. No pts died, nor had opportunistic infections (including TB), malignancies, macrophage activation syndrome, MACE, GI perforations, interstitial lung disease or thrombotic events.

Conclusion: In pts with pcJIA, tofacitinib was efficacious irrespective of concomitant MTX use or prior bDMARD exposure. Tofacitinib safety in all subgroups was generally consistent with the overall Phase 3 study population. The analysis is limited by the small sample size in the subgroups.

Trial registration identifying number: ClinicalTrials.gov (NCT02592434)

Patient Consent Received

No

Disclosure of Interest

N. Ruperto Consultant for: Ablynx, AstraZeneca/MedImmune, Biogen, BMS, Boehringer Ingelheim, 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 of: Ablynx, AstraZeneca/MedImmune, Biogen, BMS, Boehringer Ingelheim, Eli Lilly, EMD Serono, F. Hoffmann-La Roche, GSK, Janssen, Merck Sharp & Dohme, Novartis, Pfizer Inc, R-Pharm, Sanofi, Servier, Sinergie and Sobi, D. Lovell Consultant for: AstraZeneca, Boehringer Ingelheim, GSK, Novartis, Pfizer Inc, Roche, Takeda and UBC, and DSMB chairperson for Forest Research and NIH, O. Synoverska Speaker Bureau of: Alpen Pharma AG, Nestlé, Sanofi and SPERCO, C. Abud Mendoza: None declared, A. Spindler Speaker Bureau of: Eli Lilly, Y. Vyzhga: None declared, I. Tirosh: None declared, L. Imundo: None declared, E. Alexeeva: None declared, P. Chiraseveenuprapund Consultant for: CARRA and Novartis, H. Shi Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, G. Sawyerr Consultant for: Pfizer Inc, Employee of: Syneos Health Inc, A. Blum Shareholder of: Pfizer Pharma GmbH, Employee of: Pfizer Pharma GmbH, P. Klaus Shareholder of: Pfizer Pharma GmbH, Employee of: Pfizer Pharma GmbH, A. Shapiro Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, A. Diehl Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, A. Ebrahim Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, A. Martini Consultant for: Aurinia, BMS, Eli Lilly, EMD Serono, Janssen and Pfizer Inc, H. Brunner Consultant for: AbbVie, AstraZeneca/MedImmune, Bayer, Biocon, BMS, Boehringer Ingelheim, Eli Lilly, Janssen, Novartis, Pfizer Inc, Roche and R-Pharm, Employee of: Cincinnati Children’s Hospital Medical Center, Speaker Bureau of: GSK, Novartis and Roche

Table 1 (abstract P40). Efficacy in pts with pcJIA at W44

P41 Review of the worldwide epidemiological data of juvenile idiopathic arthritis

V. Sevostyanov¹, I. Razumov¹, E. Zholobova²

¹I.M. Sechenov First Moscow State Medical University (Sechenov University); ²I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation

Correspondence: V. Sevostyanov

Introduction: Juvenile idiopathic arthritis (JIA) is a chronic, systemic autoimmune disorder that is characterized by joint inflammation of unclear etiology. The study of the epidemiology of JIA is one of the important areas of pediatrics, knowledge of the prevalence allows planning the necessary resources for the diagnosis and treatment of patient.

Objectives: A Review of new epidemiological data of the worldwide incidence and prevalence of rheumatic diseases in children.

Methods: Studies searched in the electronic database PubMed.

Results: 125 studies were screened, 11 epidemiological studies of JIA since 2010 were undertaken, 11 countries included in the review. Prevalence. Europe: Germany - prevalence was 73.4 to 101.5; The Russian Federation - 65.7; Spain - prevalence was 39.7; France - prevalence was 15.7. Asia: Bangladesh - prevalence was 60.5, India - prevalence was 48, Singapore - prevalence 19.2. Africa: Egypt - prevalence was 3.43. South America: Brazil - prevalence was 196. North America: USA - prevalence was 44.7 per 100,000 children. Incident. Europe: Germany - incidence was 16.6, Sweden - incidence was 12.8, Spain - incidence was 6.9. North America: USA - incidence was 11.9 per 100,000 children.

Conclusion: An analysis was made of articles on morbidity. Data is heterogeneous across countries, requiring further in-depth study. There was a lack of updated data on the incidence of JIA worldwide.

Patient Consent Received

No

Disclosure of Interest

None declared

P42 factors that cause ineffective supplementation of vitamin D in patients with JIA

N. S. Shevchenko^1,2, I. Khadzhynova^1,2, L. Bohmat^1,2

¹Department of pediatrics № 2, V. N. Karazin Kharkiv National University; ²Department of rheumatology and comorbid states, SI Institute for Children and Adolescents Health Care of NAMS of Ukraine, Kharkiv, Ukraine

Correspondence: N. S. Shevchenko

Introduction: Modern publications discuss the role that vitamin D plays in the onset, development and course of rheumatic diseases. The question of additional supplementation with calciferol and dosage in persons with chronic inflammatory diseases remains open.

Objectives: To determinate the tendency of changes of VD status in children with juvenal idiopathic arthritis JIA after its 3-months supplementation based on characteristics of JIA and methotrexate (MTX) therapy.

Methods: 40 children with JIA (23 females, 10 males) were included to the study. The average age of patients was 10.8±4.6 years. The results were analyzed depending on physical development of children, taking into account body mass index (BMI), variant of the disease (oligoarthritis (n=17), polyarthritis (n=13), undifferentiated (n=10) arthritis), disease activity on a scale JADAS-27 and mode of application of basic therapy (the presence of methotrexate or its absence, duration, doses). The study was conducted twice: the first one- in the absence of additional intake of vitamin D, the second one - after its 3 months supplementation in a dose of 2000 IU. Serum 25-hydroxyvitamin D [25(OH)D] levels were measured using chemiluminescent method (Cobas 6000, Roche Diagnostics, Switzerland).

Results: The average primary level of vitamin D was 21,40±1,97 ng/ml. The re-examination found 28,89±2,11 ng/ml of vitamin D (p<0,05). Positive dynamic was observed, but the optimal level of VD was not reached by patients. Analysis of the changes of vitamin D level in the blood showed the following regularities (Table). Its increase was not determined in overweight children. The oligoarticular variant of JIA was more favorable with respect to both the initial and the repeated level of vitamin D. Children with achieved remission of the disease and a low degree of JIA activity did not show a significant increase in the level of vitamin D. There was no positive dynamics of vitamin D status in children who received MTX monotherapy for more than six months at a MTX dose of less than 10 mg / m².

Conclusion: Children with JIA have an impaired vitamin D status, its decrease. The effectiveness of additional supplementation with cholecalciferol is higher in children with low and normal body weight, with oligoarticular JIA. In order to achieve an optimal response to additional intake of vitamin D, its early prescription is necessary, especially against the background of high JIA activity. Rational prescription of basic therapy and its intensification after 6 months of use is one of the links in the prevention of vitamin D deficiency in children with JIA.

Disclosure of Interest

None declared

Table 1 (abstract P42). Dynamics of vitamin D levels in children with JIA after its 3-months supplementation М±m, ng/ml

P43 Trajectories of response to etanercept identified in four UK juvenile idiopathic arthritis cohorts

S. J. W. Shoop-Worrall^1,2, K. L. Hyrich^1,3, L. R. Wedderburn^4,5,6, W. Thomson^3,7, N. Geifman², on behalf of BSPAR-ETN Study, BCRD Study, CAPS, CHARMS, CLUSTER

¹Centre for Epidemiology Versus Arthritis; ²Centre for Health Informatics, 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, London; ⁷Centre for Genetics and Genomics Versus Arthritis, UNIVERSITY OF MANCHESTER, Manchester, United Kingdom

Correspondence: S. J. W. Shoop-Worrall

Introduction: In children and young people (CYP) with JIA, we have previously identified clusters with different patterns of disease impact following methotrexate (MTX) initiation. It is unclear whether clusters of treatment response following etanercept (ETN) therapy exist and whether, in a group of CYP who have responded inadequately to or had adverse events on methotrexate, similar treatment response patterns exist. Novel response patterns would aid stratified treatment approaches through better understanding and potential forecasting of more specific response patterns across multiple domains of disease.

Objectives: To identify and characterise trajectories of juvenile arthritis disease activity score (JADAS) components following ETN initiation for JIA.

Methods: ETN-naïve CYP with non-systemic JIA were selected if enrolled prior to January 2019 in at least one of four CLUSTER consortium studies: the UK BSPAR Etanercept Register, the Biologics for Children with Rheumatic Diseases Study, the Childhood Arthritis Prospective Study and the Childhood Arthritis Response to Medication Study at point of starting ETN as their first biological therapy. JADAS components (active joint count, physician’s global assessment (0-100mm), parental global evaluation (0-100mm) and ESR (mm/hr) were collected at ETN initiation and during the following year.

Multivariate group-based trajectory models, that identify clusters of CYP with similar patterns of change over time, were used to explore ETN response clusters across the different JADAS components. Censored-normal (global scores, ESR) and zero-inflated Poisson (active joint count) models were used, adjusting for year of ETN initiation. Optimal models were selected based on a combination of model fit (BIC), parsimony, and clinical plausibility.

Results: Of the 1003 CYP included, the majority were female (70%) and of white ethnicity (90%), with rheumatoid factor-negative JIA the most common disease category (39%).

The optimal model identified five trajectory clusters of disease activity following initiation of ETN. Clusters following ETN were similar and covered similar proportions of CYP to those previously identified following MTX: Fast (Group 1: 13%) and Slow (Group 2: 10%) response, active joint count improves but either physician (Group 3: 6%) or parent global scores (Group 4: 34%) remain persistently raised and a group with persistent raised scores across all JADAS components (Group 5: 36%). Compared to the persistent disease cluster, those with greater improvement had lower age and higher functional ability at ETN initiation and those with persistent raised parent global scores had lower ESR levels and were less likely to be RF-positive at ETN initiation.

Conclusion: This study has identified that within CYP initiating ETN, similar response clusters are evident to those previously identified following MTX. This commonality suggests a new framework for understanding treatment response, beyond a simple responder/non-responder analysis at a set point, which applies across multiple drugs despite different mechanisms of action and previous unfavourable treatment outcomes. Understanding both clinical factors associated with, and biological mechanisms underpinning, these clusters would aid stratified medicine in JIA.

Patient Consent Received

Yes

Disclosure of Interest

None declared

P44 Treatment to target reduced pain significantly in children with juvenile idiopathic arthritis participating in the best for kids study

K. Spekking¹, P. de Boer¹, S. A. Bergstra², J. M. van den Berg³, D. Schonenberg-Meinema³, L. W. van Suijlekom-Smit⁴, M. A. van Rossum^5,6, Y. Koopman-Keemink⁷, R. ten Cate¹, C. F. Allaart², D. M. Brinkman¹, P. C. E. Hissink Muller¹

¹Department of Pediatrics, division of Pediatric Rheumatology, Willem Alexander Children’s Hospital, Leiden University Medical Center; ²Department of Rheumatology, Leiden University Medical Center, Leiden; ³Department of Pediatric Immunology, Rheumatology and Infectious Diseases, Emma Children’s Hospital, Amsterdam University Medical Center, Amsterdam; ⁴Department of Pediatrics/Pediatric Rheumatology, Sophia Children's Hospital Erasmus Medical Center, Rotterdam; ⁵Department of Pediatrics, Emma Children's Hospital, Amsterdam University Medical Centers; ⁶Department of Pediatric Rheumatology, Amsterdam Rheumatology and Immunology Center | Reade, Amsterdam; ⁷Department of Pediatrics, Hagaziekenhuis Juliana Children’s Hospital, The Hague, Netherlands

Correspondence: K. Spekking

Introduction: In Juvenile Idiopathic Arthritis (JIA), a treat-to-target (T2T) strategy is recommended to improve clinical outcomes and was proven effective in suppression of disease activity in the BeSt for Kids study. Does this approach also help to reduce pain in children with JIA?..

Objectives: To compare pain in three T2T strategies in JIA patients participating in the BeSt for Kids study and to identify baseline characteristics predicting high pain levels during follow up.

Methods: DMARD naïve children who participated in the BeSt for kids study with oligoarticular JIA, RF-negative polyarticular JIA and juvenile psoriatic arthritis were treated with a T2T strategy aiming at (drug free) inactive disease in 1 of 3 initial treatment groups;

• 1) Initial sequential DMARD monotherapy (Methotrexate (MTX) or Sulphasalazine)

• 2) Initial MTX with 6 weeks of prednisolone bridging

• 3) Initial MTX with etanercept.

Pain intensity was measured using a 100 mm Visual Analogue Scale during 24 months of follow-up with 3-monthly intervals. Potential differences in VAS pain scores over time between treatment arms were compared using linear mixed models. A similar multivariable mixed model was used to assess the ability of several baseline characteristics to predict high pain levels during follow-up and to determine the effect of inactive disease on pain.

Results:

92 patients were randomized.

Overall, pain scores over time reduced from mean 55.3 (SD 21.7) mm at baseline to 19.5 (SD 25.3) mm after 24 months. When comparing pain over time per arm, pain scores decreased significantly β -1.37 (95% CI -1.73; -1.02). No significant difference was found in pain over time between initial treatment groups. Correction for sex and symptom duration as possible confounders yielded similar results. Inactive disease contributed to pain reduction by -11.36 mm (95% CI -13.80; -8.93). However, 7 children still experienced pain during inactive disease.

Several baseline characteristics demonstrated a significant predictive value for pain over time when tested in a multivariable model. A higher baseline VAS pain and number of active joints at baseline were predictive of higher pain over time. VAS of the patient/parent, symptom duration and NSAID use were not predictive for pain over time.

Conclusion: In children with JIA participating in the BeSt for Kids study treatment to target (drug free) remission is effective in reducing pain irrespective of initial treatment. However, some children still experience pain despite reaching inactive disease. This emphasizes the necessity of patient related outcomes for targeted treatment. High VAS pain and many active joints at baseline can help to identify non-systemic JIA patients with a high risk of pain over time despite applying a treat-to-target strategy.

Trial registration identifying number: Trial NL1504 (NTR1574)

Disclosure of Interest

None declared

Table 1 (abstract P44). Baseline Characteristics

P45 Evaluation of factors for predicting risk of uveitis in juvenile idiopathic arthritis

N. Tekgoz, E. Celikel, F. Aydın, Z. Tekin, T. Kurt, M. Sezer, B. Acar

Department of Pediatric Rheumatology, University of Health Science, Ankara City Hospital, Ankara, Turkey

Correspondence: N. Tekgoz

Introduction: Juvenile idiopathic arthritis (JIA) is the most common chronic inflammatory arthritis in childhood and causes much disability. Uveitis developed during the disease course due to uveal inflammation. The most common form of JIA-U is chronic anterior uveitis which has frequently seen in the oligoarticular subtype. It often has a silent and insidious onset, which results in severe ocular complications. Therefore screening becomes more critical in JIA patients. It is very difficult to distinguish the treatment of JIA from JIA-U.

Objectives: The aim of this study is to evaluate the risk factors that play a role in the development and recurrence of uveitis and determine the relationship between arthritis and uveitis activity.

Methods: Patients who were diagnosed juvenile idiopathic arthritis (JIA) with and without uveitis between April 2005 and May 2020, were retrospectively reviewed. The Juvenile Arthritis Disease Activity Score (JADAS-27) was used to evaluate the disease activity. JADAS-27 was calculated separately at the onset of arthritis and uveitis.

Results: Uveitis developed in 26 (13.3%) of 195 JIA patients. Of 26 JIA-U patients, 19 (73%) had oligoarticular subtype. The age at the onset of JIA was lower in patients with uveitis than those without uveitis (p=0.015). MTX and biological DMARDs treatments were significantly higher in patients with JIA-U than JIA without uveitis (p<0.001, p=0.038). Oligoarticular JIA was found to be associated with recurrence of uveitis (p=0.021). Patients with the recurrent course had a significantly earlier onset of arthritis and uveitis than the none-recurrent group (p=0.041, p=0.002, respectively). The median JADAS27 score at the onset of uveitis was lower in the recurrent group (p=0.038). MTX treatment's median duration and the median time interval between MTX and biologic DMARDs were significantly longer in the recurrent group (p=0.013, p=0.045).

Conclusion: In conclusion, “early age” is a significant risk factor for developing and recurrence of uveitis. It is important to keep in mind patients with low disease activity may also develop uveitis. Therefore, treatment and follow-up should be planned with a multi-disciplinary approach.

Patient Consent Received

No

Disclosure of Interest

None declared

P46 Children with juvenile idiopathic arthritis have alterations in B and T follicular cell subsets in peripheral blood

C. Tomé¹, F. Oliveira-Ramos^1,2, R. Campanilho-Marques^1,2, A. F. Mourão³, S. Sousa⁴, A. P. Martins⁵, P. C. Reis^1,6, A. T. Melo^1,2, R. L. Teixeira^1,2, M. Gonçalves⁵, M. J. Santos^1,4, L. Graca^1,7, J. E. Fonseca^1,2, R. A. Moura¹

¹Instituto Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa; ²Rheumatology Department, Hospital de Santa Maria; ³Rheumatology Department, Centro Hospitalar Lisboa Ocidental, Lisbon; ⁴Rheumatology Department, Hospital Garcia de Orta, Almada; ⁵Pediatric Surgery Department; ⁶Pediatric Department, Hospital de Santa Maria, Lisbon; ⁷Instituto Gulbenkian de Ciência, Oeiras, Portugal

Correspondence: C. Tomé

Introduction: Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in children. Our group has recently demonstrated that extended oligoarticular (eoJIA) and polyarticular JIA (pJIA) mostly evolve to a rheumatoid arthritis (RA) like phenotype in adulthood. Disturbances in B cells, T follicular helper (Tfh) and T follicular regulatory (Tfr) cell immune responses are associated with the pathogenesis of RA, but their exact role in JIA development is not entirely known.

Objectives: The main goal of this study was to characterize the frequency and phenotype of B, Tfh and Tfr cells in peripheral blood of children with eoJIA and pJIA when compared to healthy controls and children with persistent oligoarticular JIA (poJIA).

Methods: Blood samples were collected from children with eoJIA (n=5), pJIA (n=11) and poJIA (n=19) treated with disease modifying anti-rheumatic drugs. A group of age-matched healthy children (n=8) was used as control. Peripheral blood mononuclear cells were isolated and the frequency and phenotype of B, Tfh and Tfr cells were evaluated by flow cytometry.

Results: The frequency of B, Tfh and Tfr cells was similar between JIA patients and controls. Children with eoJIA and pJIA, but not poJIA, had higher levels of naïve B cells and lower frequencies of post-switch memory B cells and plasmablasts when compared to controls. Th17-like Tfh cells were significantly increased in all JIA patients when compared to controls. B cell phenotype was similar between JIA patients and controls, but a reduced activated phenotype of Tfh cells was observed in JIA patients in comparison to controls.

Conclusion: Changes in B and Tfh cell subpopulations, but not in Tfr cells, were found in peripheral blood of children with JIA when compared to controls. The increased frequencies of Th17-like Tfh cells detected in JIA when compared to controls suggests a potential role of these cells in JIA pathogenesis. A treatment effect on the activation state of B, Tfh and Tfr cells cannot be excluded.

Patient Consent Received

No

Disclosure of Interest

None declared

P47 Duration of remission in non-systemic juvenile idiopathic arthritis after termination of tumor necrosis factor inhibitors

I. Tsulukiya¹, E. Alexeeva^1,2, T. Dvoryakovskaya^1,2, R. Denisova¹, K. Isaeva¹, O. Lomakina¹, A. Mamutova¹, A. Chomakhidze¹, A. Fetisova¹, M. Gautier¹, I. Kriulin^1,2, E. Krekhova^1,2

¹Rheumatology, National Medical Research Center of Children's Health; ²Pediatric, Sechenov First Moscow State Medical University, Moscow, Russian Federation

Correspondence: E. Alexeeva

Introduction: Currently, little is known about when or how to stop tumor necrosis factor inhibitors (TNFi) in non-systemic juvenile idiopathic arthritis (JIA) when a good clinical response is achieved.

Objectives: To evaluate the rate of flare during the first 24 months following TNFi withdrawal in patients with non-systemic JIA who have achieved remission while taking the medication.

Methods: 85 patients (27—male, 58—female) with JIA and a mean age at diagnosis of 4 years (range 1–18 years) were analyzed retrospectively.

All of them had been receiving TNFi for more than 24 months and discontinued TNFi due to a long-term remission on treatment. Inactive disease was defined according to the criteria of Wallace et al. [1].

Results: The clinical subtypes of JIA were persistent oligoarthritis – 39 (46%), RF-negative polyarthritis– 34 (40%), extended oligoarthritis—9 (10,5%), enthesitis-related arthritis—3 (3,5%). 22 (26%) patients have been diagnosed with JIA-associated uveitis.

TNFi were discontinued after 46 (range 10–114) months after initiation of therapy. Duration of remission prior to discontinuing TNFi was 41 (range 6 – 121) months.

In 60 (71%) patients TNFi had been withdrawn after long-term remission was achieved, in 17 (20%) patients as a result of side effects, in 4 (4,5%) patients had been discontinued because of organization problem, and in 4 (4,5%) patients had been stopped biologic therapy by parents. All of them had remission prior to discontinuing TNFi more than 24 months.

The mean duration of remission after TNFi discontinuation was 29 (range 1–92) months.

14 (16%) of patients had flares after less than 6 months after discontinuing of TNFi, 33 (39%) had flares after 6 – 24 months, 38 (45%) had not flares and had remission due to 24 months after discontinuation TNFi.

In 47/85 (55%) patients flares had been appeared, 37/47 (79%) of patients flared with active arthritis, while 10/47 (21%) flared with uveitis.

Disease was successfully controlled in 7/47 (15%) patients with non-biological DMARDs, 40/47 (89%) patients restarted TNFi after flares, due to lack of improvement after non-biological DMARDs.

Conclusion: The mean duration of TNFi therapy was 46 months, duration of remission prior to discontinuing TNFi was 41 months. The mean time of remission after discontinuation of TNFi was 29 months, although it should be noted that in as many as 38 children (45 %), flares occurred in more than 24 months.

Data from our experience with TNFi in the treatment of JIA suggest that 45% of patients can be successfully withdrawn from TNFi for at least 24 months.

Disclosure of Interest

None declared

P48 No significantly different effect of etanercept and adalimumab on well-being in non-systemic JIA

J. W. van Straalen¹, S. de Roock¹, G. Giancane^2,3, M. Rygg⁴, E. B. Nordal^5,6, N. Rubio-Perez⁷, M. Jelusic⁸, J. de Inocencio⁹, J. Vojinovic¹⁰, N. M. Wulffraat¹, P. C. J. L. Bruijning-Verhagen¹¹, J. F. Swart¹, N. Ruperto², on behalf of Paediatric Rheumatology International Trials Organisation (PRINTO)

¹Department of Pediatric Immunology and Rheumatology, Wilhelmina Children's Hospital, Utrecht, Netherlands; ²Clinica Pediatrica e Reumatologia, IRCCS Istituto Giannina Gaslini; ³Dipartimento di Neuroscienze, Riabilitazione, Oftalmologia, Genetica e Scienze Materno-Infantili (DiNOGMI), Università degli Studi di Genova, Genoa, Italy; ⁴Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, NTNU - Norwegian University of Science and Technology; ⁵Department of Pediatrics, University Hospital of North Norway; ⁶Department of Clinical Medicine, UiT the Arctic University of Norway, Tromsø, Norway; ⁷Departamento de Pediatria, Hospital Universitario "Dr. J. E. González", Facultad de Medicina, Universidad Autónoma de Nuevo León, Monterrey, Mexico; ⁸Division of Rheumatology and Immunology, University School of Medicine, University Hospital Centre Zagreb, Zagreb, Croatia; ⁹Department of Pediatric Rheumatology, 12 de Octubre University Hospital, Madrid, Spain; ¹⁰Department of Pediatric Immunology and Rheumatology, Faculty of Medicine, University of Nis, Nis, Serbia; ¹¹Julius Centre for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht, Netherlands

Correspondence: J. W. van Straalen

Introduction: Current treatment guidelines consider adalimumab (ADA) and etanercept (ETN) equally effective in treating arthritis in JIA (1) and in practice the choice between the two drugs is based on patient and physician preferences (2).

Objectives: To compare the effects of ADA and ETN on well-being in non-systemic JIA.

Methods: Biologic therapy naïve non-systemic JIA patients without a history of uveitis were selected from the international observational Pharmachild registry. Patients who started ETN were matched 1:1 to patients who started ADA based on propensity score, i.e. the probability of receiving one of the two drugs. Outcomes were collected around therapy initiation and 3-12 months afterwards. Primary outcome at follow-up was the change in VAS well-being score from the Juvenile Arthritis Multidimensional Assessment Report (JAMAR). Secondary outcomes were the change in active joint count, number of adverse events and uveitis events. Outcomes were analyzed using linear and logistic mixed model analyses.

Results: 46 ADA and ETN starters were matched (Table 1). The estimated change in VAS well-being was lower for ADA compared to ETN, but not clinically and statistically significant (-0.81, 95% CI: -1.72 – 0.08). Similarly, no significant differences were observed for the change in active joint count and number of adverse events. One event of uveitis occurred in the ETN group.

Conclusion: No clinically and statistically significant different effect of ADA and ETN on well-being was observed in non-systemic JIA patients.

References

1. Beukelman T, Patkar NM, Saag KG, Tolleson-Rinehart S, Cron RQ, DeWitt EM, et al. 2011 American College of Rheumatology recommendations for the treatment of juvenile idiopathic arthritis: initiation and safety monitoring of therapeutic agents for the treatment of arthritis and systemic features. Arthritis Care Res (Hoboken). 2011 Apr;63(4):465–82.

2. Anink J, Otten MH, Gorter SL, Prince FHM, van Rossum MAJ, van den Berg JM, et al. Treatment choices of paediatric rheumatologists for juvenile idiopathic arthritis: etanercept or adalimumab? Rheumatology. 2013 Sep 1;52(9):1674–9.

Patient Consent Received

No

Disclosure of Interest

None declared

Table 1 (abstract P48). Outcomes at follow-up

P49 Clinico-epidemiological profile of juvenile idiopathic arthritis (JIA) from a single centre in North-West India

S. Verma, A. Rafi, A. Sharma

Pediatrics, Dr Rajendra Prasad Govt .Medical College,Tanda, Kangra, HP,India-176001, Kangra, India

Correspondence: S. Verma

Introduction: Juvenile idiopathic arthritis is the most common chronic arthritis affecting the children leading to long-term disability. Its incidence and prevalence varies according to ethnicity and environmental influences and each sub type of JIA has distinct age of presentation and gender predilection.

Objectives: To evaluate the clinical, laboratory and treatment profile of children with JIA.

Methods: This retrospective study was done at a tertiary-care centre in North-India in a government run, tertiary-care medical institute. Demographic data, clinical manifestations, laboratory findings and treatment of patients registered in Pediatric Rheumatology Clinic (PRC) of the institute over last three and half years was analysed. JIA was classified according to the ILAR criteria.

Results: We analysed the records of 191 children who were enrolled in PRC, 96(50%) had joint involvement. JIA was the most common rheumatological disorder observed in 61(63.5%) out of 96 children who had arthritis as their predominant presenting manifestation. Thirty two (52.5%) were boys with M:F ratio of 1.1:1. In twenty five (42%) children oligoarthritis was identified, making it the most common subtype of JIA. Enthesitis related arthritis (ERA) was found in 16(26%) patients, predominantly in boys with M:F ratio of 5:1. Eight (13%) and 11(18%) children had systemic JIA (sJIA) and polyarthritis JIA with M:F ratios being 1:1.6 and 1:4.5 respectively. In polyarthritis more children were RF positive 6(55%). Only one case, 15 years old male adolescent had psoriatic arthritis with history of psoriasis in mother. Mean age at disease onset was 7.78 years, 4.75 years, 14.8 years and 14.4 years in oJIA, sJIA, polyarthritis and ERA, respectively. Minimum age of presentation was 13 months, a male child diagnosed with sJIA. Knee joint was the most common joint involved with bilateral involvement in polyarthritis and unilateral in rest of JIA. Hip joint, 6(37.5%) and axial skeleton, 1(6.25%) involvement was found exclusively in ERA while small joints of hands, were involved in all the patients of RF positive polyarthritis 6(100%). None of the patients had temporomandibular joint and cervical spine involvement. Five (62.5%) out of 8 patients of sJIA developed macrophage activation syndrome (MAS) with 50% mortality, may be due to late presentation to our institute. Antinuclear antibodies (ANA) was found positive in 65% cases of polyarthritis and 56% cases of oJIA while 94% (15 out of 16) cases of ERA had HLA B-27 positive. Only 2(3.3%) patients of oJIA had uveitis, both were ANA positive. After enrolment, 75% children were given nonsteroidal anti-inflammatory drugs (NSAIDs). Forty percent of sJIA patients required methylprednisolone pulse therapy and intravenous immunoglobulin (IVIg) for the management of MAS. Intra-articular corticosteroid injections (IACI) were used in 5(20%) patients of oligoarthritis and 4(25%) patients of ERA to alleviate inflammatory symptoms. Oral corticosteroids was given in 4(50%), 5(20%) and 4(25%) patients of sJIA, oJIA and ERA to relieve extra-articular manifestations in sJIA and to bridge the effect of disease modifying anti rheumatic drugs (DMARDs) in oJIA and ERA. Methotrexate (MTX) was the most commonly used DMARD, mainly in polyarthritis RF positive (83%) children. Sulfasalazine was used in 9(56%) children with ERA. Biological agents were not used in any of our patients.

Conclusion: The clinical and epidemiological profile of children in our study with JIA was different from the Western countries with almost equal frequency of JIA in boys and girls and high prevalence of ERA. Uveitis was uncommon. Majority of Patients are doing well on follow-up and thus use of biological agents has not been considered in some whereas cost is the limiting factor in others.

Disclosure of Interest

None declared

P50 MS Developed on a JIA background drug induced side effect or autoimmune prone patients?

S. Karamichalou¹, A. Stamati¹, M. Chondrogianni², G. Vartzelis¹, V. Konstantinos², O. Vougiouka¹

¹2nd Department of Pediatrics, ‘P&A Kyriakou’ Children’s Hospital, National and Kapodistrian University of Athens; ²2nd Department of Neurology, Attikon Hospital, National and Kapodistrian University of Athens, Athens, Greece

Correspondence: O. Vougiouka

Introduction: Tumor necrosis factor antagonists (anti-TNFa) have been paramount in the management of several autoimmune diseases. Despite their clinical effectiveness, there are reports documenting their potential role in the induction or aggravation of demyelination of the central nervous system (CNS) [1, 2]. Or it may be only a coincidence due to the underlying genetic susceptibility of these patients to disturbed autoimmune reactivity [3].

Objectives: We report two new cases of demyelinating events of the CNS, following treatment with anti-TNFa for two and nine years respectively, in two girls with polyarticular type of Juvenile idiopathic arthritis background, firstly diagnosed at the age of seven and twelve years old respectively.

Methods: We investigated these cases of demyelination with laboratory examinations (screening for auto-antibodies, viral infection), lumbar puncture and magnetic resonance imaging (MRI) of the brain and spinal cord.

Results:

Conclusion: Inflammatory demyelination of the CNS may be associated with the use of anti-TNFa. Thus, all patients should, before and throughout the treatment, be monitored for any neurological complication, indicative of demyelination and evaluate appropriate treatment interventions [1]. However, we should not forget the co-occurrence of MS with other autoimmune disorders because of immunologic predisposition [4].

REFERENCES

1. Atzeni, F., et al., Concerns about the safety of anti-TNF agents when treating rheumatic diseases. Expert Opinion on Drug Safety, 2020. 19(6): p. 695-705.

2. Seror, R., et al., Pattern of demyelination occurring during anti-TNF-α therapy: a French national survey. Rheumatology, 2013. 52(5): p. 868-874.

3. Andreadou, E., et al., Demyelinating Disease following Anti-TNFa Treatment: A Causal or Coincidental Association? Report of Four Cases and Review of the Literature. Case Reports in Neurological Medicine, 2013. 2013: p. 671935.

4. Kaouther, B.A., et al., Concurrence of Juvenile Idiopathic Arthritis and Multiple Sclerosis. Case Reports in Rheumatology, 2011. 2011: p. 162857.

Patient Consent Received

No

Disclosure of Interest

None declared

Table 1 (abstract P50). See text for description

P51 Down syndrome associated arthritis or JIA: clinical case

Y. Vyzhga, N. Tokarchuk

National Pirogov Memorial Medical University, Vinnytsya, Vinnitsya, Ukraine

Correspondence: Y. Vyzhga

Introduction: In abstract presented clinical case of arthritis in 9 yr. patient with Down syndrome. In the literature it’s still doubtful, if patients with Downs syndrome may present clear JIA or its some other type of the arthritis associated with genetic pathology.

Objectives: Our goal is to check and evaluate possibility of the JIA development in patient with Down syndrome.

Methods: To evaluate clinical importance, we examined patient with Down syndrome who was presenting signs of arthralgia for a time frame more than 6 weeks and who was admitted to pediatric rheumatologist with suspicion of arthritis onset.

Results: Patient D., 9 yr. came to the center 6 months ago. Patient became sick approximately 8 months ago, but due to difficulties associated with mental and behavior development, mother didn’t concern about joint pain. Acute episode of the disease started with limping gait, child wasn’t able to move at the morning, that was associated with pain syndrome in both knees. Before this episode of the disease child was healthy. The baby was delivered from the 1st pregnancy, in term, didn’t have any complicated family or epidemiological anamnesis. Mom went to the family doctor; symptomatic treatment was started together with systemic antibacterial drugs. Within 14-day condition wasn’t significantly improved, child still presented pain, less intense than at the onset of the disease, and as well limping gait. General practitioner diagnosed reactive arthritis and continued NSAIDs. The child was followed with complete blood count that showed mild inflammation, X-ray of the joints didn’t show any pathological changes. General duration of the disease was longer than 6 weeks, but general practitioner ensured mom, that they don’t require consultation of any other specialist. When the child was sick for 2 months mother by herself admitted him to the pediatric rheumatologist. During first investigation child showed signs of the arthritis of both knee joints, with typical swelling, mild to moderate pain, movements limitation, morning stiffness up to 1 hour. Other joints were not involved to the process, laboratory results showed mild increased ESR (21 mm/h), negative CRP, signs of the synovitis of both knee joints. Aspiration of the synovial fluid was presented with following intraarticular injection of the steroid. During detailed investigation child performed ANA 1:320, aCCP – 34 IU/ml (N – up to 8 IU/ml). After the intraarticular injection situation much more improved, resolved pain syndrome, movement limitation. In 2-month, child returned back with the same complains on pain and movement limitation in both knee joints, but with minimal synovitis. Laboratory activity was mild, but taking into account previous disease anamnesis, results of additional investigations, diagnose of JIA was estimated and started treatment with methotrexate. By this time child was taking methotrexate for 3,5 months, JADAS-27 – 5 was achieved (compare with initial JADAS-27 - 9).

Conclusion: By this time a lot of discussions are opened in arthritis associated with Down syndrome. Classical presentation has small joints involvement without autoimmune markers. Our patient showed other clinical signs so diagnose of the JIA is more adequate in this particular case.

Disclosure of Interest

None declared

P52 Knowledge of juvenile idiopathic arthritis among Israeli pediatricians might improve early referral and disease outcomes

A. Ziv¹, M. H. Bekenstein², D. Schujovitzky³, S. Eylon⁴, P. J. Hashkes⁵, Y. Uziel⁶, R. Haviv⁶, Z. Grossman⁷

¹1Pediatric Rheumatology Unit, Department of Pediatrics, Meir Medical Center, Kfar Saba, Israel., Meir Medical Center, kfar saba; ²pediatrics, 3Pediatric Rheumatology Clinic, Department of Pediatrics, Dana-Dwek Children’s Hospital, Tel Aviv, Tel Aviv; ³Pediatrics, Meir Hospital, Kfar Saba, Israel, kfar saba; ⁴Pediatric Orthopedic Service, Alyn Rehabilitation for Children & Adolescents, Jerusalem, Israel, Chair of the Israel Pediatric Orthopedic Society, Alyn Rehabilitation for Children & Adolescents; ⁵Paediatric Rheumatology Unit, Shaare Zedek Medical Centre, Jerusalem, Israel, Shaare Zedek Medical Center, Jerusalem; ⁶1Pediatric Rheumatology Unit, Department of Pediatrics, Meir Medical Center, Kfar Saba, Israel., Meir Medical Center, kfar saba; ⁷5Adelson School of Medicine, Ariel University, Ariel, Israel and Maccabi Healthcare Services, Tel Aviv, Israel, Israel and Maccabi Healthcare Services, Tel Aviv, Israel

Correspondence: A. Ziv

Introduction: Approximately 1 child in 1,000 is affected by chronic juvenile idiopathic arthritis (JIA). Persistent, undiagnosed JIA with high disease activity interferes with daily life and carries a risk of irreversible physical and psychosocial damage. Due to its relative rarity, primary physicians often do not recognize it; thus, diagnosis and referral to pediatric rheumatologists are delayed.

Objectives: To evaluate the knowledge of Israeli pediatricians and pediatric-orthopedic surgeons regarding epidemiology, clinical manifestations, laboratory parameters and treatment of JIA.

Methods: An 11-item online questionnaire regarding JIA sent to the lists of Israeli Society of Pediatrics and Pediatric Orthopedics, was completed by 274 pediatricians and 27 pediatric-orthopedic surgeons.

Results: Average score was 67.8% overall participants. Several groups were associated with better overall scores: hospital physicians compared to community physicians; pediatric residents (especially after board exams) compared to seniors; exposure to rheumatology during residency; and more JIA patients during the last 5 years. No significant difference was found between pediatricians and pediatric-orthopedic surgeons. 40% of participants underestimated the true incidence of JIA; 30-45% were not familiar with its clinical presentation (age of onset, pain characteristics, chronic uveitis symptoms), and up to 65% were not familiar with up-to-date treatments.

Conclusion: Israeli pediatricians and pediatric-orthopedic surgeons have misconceptions regarding JIA. This could result in delayed referral and treatment, which might affect outcomes. The results of this study highlight the need for better education and exposure to a rheumatologist, leading to the goals of better health and quality of life for JIA patients by improving knowledge.

Patient Consent Received

No

Disclosure of Interest

None declared

e-Poster viewing: Systemic JIA

P53 Systemic juvenile idiopathic arthritis associated lung disease in Europe

C. Bracaglia¹, on behalf of MAS/sJIA Working Party, F. Minoia², C. Kessel³, S. Vastert⁴, M. Pardeo¹, A. Arduini¹, O. Basaran⁵, N. Kiper⁶, M. Kostik⁷, M. Glerup⁸, S. Fingerhutova⁹, R. Caorsi¹⁰, A. Horne¹¹, G. Filocamo², H. Wittkowski³, M. Jelusic¹², P. Dolezalova⁹, A. Ravelli¹³, 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), Muenster, 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; ⁹Paediatric Rheumatology and Autoinflammatory Diseases Unit, General University Hospital, Prague, Czech Republic; ¹⁰Department of Pediatrics and Rheumatology, IRRCS Istituto Giannina 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, Zagreb, Croatia; ¹³IRCCS 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 it is 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 26 sJIA-LD patients, diagnosed in 10 European paediatric rheumatology centres between 2006 and 2020, were collected. 25 patients were Caucasian and 1 African-American, 16 were female, the median age at sJIA onset was 6.4 years and LD onset occurred after a median time of 2.7 years. 15 patients had a chronic persistent sJIA disease course, 10 had a polycyclic course and only 1 patient had a monocyclic course; 24 (92%) had active sJIA at time of LD diagnosis. During the disease course, 21 (81%) patients developed MAS, 9 (34%) of whom had MAS at sJIA onset and 15 (57%) had full-blown MAS at time of LD diagnosis; 21 (80%) patients had >1 MAS episode. 19 (73%) patients were treated with at least one IL-1 or IL-6 inhibitor before LD diagnosis: 12 with canakinumab, 17 with anakinra and 10 with tocilizumab. 10 (38%) patients experienced drug adverse reaction to a cytokine inhibitor: 8 to tocilizumab and 2 to anakinra. 20 (77%) patients developed ILD, 4 (15%) PAP and 3 (11%) PAH. 13 (50%) patients presented acute digital clubbing; 10 (38%) patients developed hypoxia and 6 (23%) developed pulmonary hypertension. A chest CT scan was performed in all patients with evidence of septal thickening and peri-bronchovascular thickening in the majority of patients (22 and 14 respectively). In 12 patients a bronchoalveolar lavage was performed and 9 underwent a lung biopsy. The histopathological pattern was alveolar proteinosis in 4 patients, endogenous lipoid pneumonia in 3, vasculitis in 1 and fibrosis in 1. Twelve (46%) patients required ICU admission and 3 (11%) died. All patients were treated with glucocorticoids (GCs) at time of diagnosis, and 22 received IL-1 or IL-6 inhibitor after the diagnosis (12 canakinumab, 15 anakinra, 13 tocilizumab).

Conclusion: Lung involvement is an emerging life-threatening complication of sJIA in Europe, especially in patients with a history of MAS, and a prompt recognition is crucial. New strategies are needed to reduce the risk and improve outcome of this complication.

Disclosure of Interest

C. Bracaglia Consultant for: Sobi, Novartis, F. Minoia Consultant for: SOBI, C. Kessel Consultant for: SOBI, Novartis, S. Vastert Consultant for: SOBI, Novartis, M. Pardeo: None declared, A. Arduini: None declared, O. Basaran: None declared, N. Kiper: None declared, M. Kostik: None declared, M. Glerup: None declared, S. Fingerhutova: None declared, R. Caorsi Consultant for: Novartis, Lilly, Speaker Bureau of: SOBI, A. Horne: None declared, G. Filocamo Consultant for: SOBI, H. Wittkowski: None declared, M. Jelusic: None declared, P. Dolezalova: None declared, A. Ravelli Consultant for: AbbVie, Novartis, Pfizer, Angelini, Reckitt Benkiser, S. Ozen Consultant for: Novartis, Pfizer, and Sobi, F. De Benedetti Consultant for: Abbvie, SOBI, Novimmune, Novartis, Roche, Pfizer

P54 Comparison of potential biomarkers differentiating systemic juvenile idiopathic arthritis from other causes of fever of unknown origin in children

P. R. Chickermane¹, S. Krishnan², A. Tiwari¹, H. Hari³, S. Balan¹

¹Department of Clinical Immunology and Rheumatology; ²Department of Biochemistry; ³Department of Biostatistics, Amrita Institute of Medical Sciences, Kochi, India, Kochi, India

Correspondence: P. R. Chickermane

Introduction: Systemic juvenile idiopathic arthritis (sJIA), a prototype of systemic rheumatic diseases in children is one of the common conditions presenting as fever of unknown origin (FUO) in the pediatric age group. Children with sJIA often prsent initially with FUO with systemic features preceding the onset of arthritis by weeks, months or even years. Diagnosing sJIA in these cases is challenging and highlights the need for a diagnostic biomarker to facilitate an early diagnosis and treatment. Dysregulation of innate immune response with overproduction of macrophage derived cytokines IL-1, IL-6, IL-18, S100 calcium-binding proteins S100A8 and S100A9 (calprotectin) is implicated in the pathogenesis of sJIA. A few studies have assessed potential biomarkers for sJIA in the recent years, however no such study has been conducted in the Indian population.

Objectives: To evaluate serum IL-1, IL-6, IL-18, S100A8 and S100A9 as potential diagnostic markers to distinguish sJIA from other conditions presenting as FUO in children.

Methods: A prospective cross-sectional study was conducted at a 1500-bedded tertiary care centre in Kerala, southern India between May 2019 and October 2020. Children under 16 years of age who presented with FUO defined as "fever > 38.0°C (100.4°F) lasting for at least 8 days without a clear source" were enrolled on the study. Patients who had already received glucocorticoids and/or immunosuppressive therapy were excluded. Serum concentrations of IL-1, IL-6, IL-18, S100A9 and S100A8 were determined using enzyme-linked immunosorbent assay (ELISA) kits. Receiver operating curve (ROC) analysis was used to determine the cut-off values for IL-1, IL-6, IL-18, S100A8 and S100A9 for differentiating sJIA from other causes of fever.

Results: Forty-seven children (females- 27) who presented with FUO were enrolled. Nineteen of them were eventually diagnosed with sJIA according to the International League of Associations for Rheumatology (ILAR) classification. In the other 28 children, fever was attributed to conditions other than sJIA (non-sJIA). The non-sJIA group comprised of children with acute lymphoblastic leukemia (n=6), hemophagocytic histiocytosis (n=5), systemic lupus erythematosus (n=4), systemic infections (n=4), Kawasaki disease(n=2), Kikuchi disease (n=2) and inflammatory bowel disease (n=2). This group also included one child each diagnosed with Sweet syndrome with polyarthritis, drug rash with eosinophilia and systemic symptoms (DRESS) syndrome and post-infection multisystem inflammatory disease. Serum levels of IL-18, S100A8 and S100A9 were significantly higher in patients with sJIA compared to the non- sJIA group (p<0.05) (Table-1). ROC analysis showed that the area under the curve (AUC) was significant for IL-18 (77.9%), S100A8 (74.9%) and S100A9 (71.2%). A serum IL-18 cut-off level of > 2030.45 pg/ml was useful for differentiating between sJIA and other diseases with a sensitivity of 66.67% and specificity 75.86% for the diagnosis of sJIA.

Conclusion: Serum IL-18, S100A8 and S100A9 can be useful in differentiating sJIA from other causes of FUO in children.

Patient Consent Received

Yes

Disclosure of Interest

None declared

Table 1 (abstract P54). Comparison of candidate biomarkers in patients with sJIA and other causes of FUO in children (non- sJIA)

P55 Fatty acid uptake is increased in monocytes of patients with systemic juvenile idiopathic arthritis and blockade regulates IL8 and TNFΑ production

R. Erkens¹, K. Ohl², R. Scholman¹, J. Van Loosdregt¹, K. Tenbrock², B. Vastert¹

¹Wilhelmina kinderziekenhuis, UMC Utrecht, Utrecht, Netherlands; ²RWTH Aachen University, Aachen, Germany

Correspondence: R. Erkens

Introduction: Fatty acids (FA) are key players in cellular homeostasis. Interestingly changes in FA metabolism can influence inflammation by controlling transcriptional and posttranscriptional events that are central to immune activation. FA metabolism might also play an important role in JIA inflammation. Indeed, levels of polyunsaturated FA are associated with JIA disease course and active disease shows decreased arachidonic acid levels(1). Monocytes are essential cellular components of the innate immune system and in systemic idiopathic arthritis (sJIA) monocytes play a central role(2). In a glucose deprived milieu monocytes shift to increased FA metabolism so cytokine secretion, migration, and phagocytosis remain intact(3). This is also the case in a low oxygen environment such at the synovium(4). Therefore FA uptake and metabolism might play a role in monocyte inflammation in sJIA. We hypothesize that investigating the effects of FA uptake inhibition on monocyte metabolism and inflammation can contribute to a better understanding of sJIA pathogenesis, the identification of cellular pathways contributing to disease and possibly to new therapeutic targets.

Objectives: To investigate the effects of fatty acid uptake inhibition on monocyte metabolism and phenotype, assessed by changes in cytokine production.

Methods: We used the monomac 6 cell line, as well as primary monocytes from healthy control and SJIA patients in active disease. We measured the uptake of FA analog C₁-BODIPY-C₁₂ using flow cytometry and studied the effects of inhibition of FA uptake by pre-incubation with FA uptake inhibitors, lipofermata and grassofermata. In addition, we studied the effects of FA uptake inhibition on monocyte cytokine and prostaglandin production and metabolism using FACS and qPCR.

Results: Monomac 6, a cell line for human monocytes, show increased uptake of FA after LPS stimulation compared to unstimulated cells. The uptake of the FA can be inhibited with lipofermata and grassofermata in a dose depend way. FA uptake inhibition decreases IL 8 and TNFα production in these cells upon LPS stimulation. Preliminary results from experiments using primary cells show an increased uptake of FA in monocytes from active SJIA synovium compared to monocytes derived from healthy donor blood and a decreased inhibition of FA uptake with lipofermata.

Conclusion: The analysis of FA uptake and metabolism offers new insights in immune regulation. Our preliminary results in a monocyte cell line and sJIA patient monocytes suggest that this might play a role as well in monocytes in the inflammatory cascade in active sJIA. Targeting FA immunometabolism could potentially be exploited for the treatment of autoimmune diseases in the future.

References

1. Gorczyca D, Postępski J, Czajkowska A, Paściak M, Prescha A, Olesińska E, et al. The profile of polyunsaturated fatty acids in juvenile idiopathic arthritis and association with disease activity. Clin Rheumatol. 2017;

2. Leong JY, Guan YJ, Albani S, Arkachaisri T. Recent advances in our understanding of the pathogenesis of juvenile idiopathic arthritis and their potential clinical implications. Expert Review of Clinical Immunology. 2018.

3. Raulien N, Friedrich K, Strobel S, Rubner S, Baumann S, von Bergen M, et al. Fatty acid oxidation compensates for lipopolysaccharide-induced Warburg effect in glucose-deprived monocytes. Front Immunol. 2017;

4. Rodgers LC, Cole J, Rattigan KM, Barrett MP, Kurian N, McInnes IB, et al. The rheumatoid synovial environment alters fatty acid metabolism in human monocytes and enhances CCL20 secretion. Rheumatol (United Kingdom). 2020;

Disclosure of Interest

R. Erkens: None declared, K. Ohl: None declared, R. Scholman: None declared, J. Van Loosdregt: None declared, K. Tenbrock Grant / Research Support from: Pfizer and Novartis, Consultant for: BMS, Pfizer and Novartis, B. Vastert Grant / Research Support from: Sobi, Consultant for: Sobi and Novartis

P56 Systemic onset juvenile idiopathic arthritis, experience of one center

S. S. Hashad, H. M. Etayari, M. N. Etfil, E. A. Almsallati, A. A. Altawati, Z. O. Awhaidah, S. Alhadi Mohamed, M. S. MOUJRANI

Pediatric Rheumatology, Tripoli Children Hospital, Tripoli, Libya

Correspondence: H. M. Etayari

Introduction: Systemic onset Juvenile idiopathic arthritis (sJIA), differs from other JIA subtypes in its clinical manifestations and pathogenesis. It is characterized by a severe course and has the highest rate of mortality and morbidities.

Objectives: To study initial manifestations, laboratory findings, course, outcome and complications of patients of sJIA in pediatric rheumatology clinic in Tripoli Children Hospital, Which is one of two referral clinic covering the western and southern part of Libya

Methods: The files of the patients diagnosed with sJIA from 5/2000 t0 5/2021 were reviewed and data was retrospectively collected regarding the presenting symptoms, initial investigations, disease course, complications and treatment used. Patients who followed up for less than 6 months were excluded.

Results:

There were 38 patients with sJIA diagnosed according to the International League Against Rheumatism (ILAR) criteria were included. 47.4% of them were males and 52.6% were females. They were followed up for a period of 6.3±4.4y.

The mean period from appearance of symptoms to first follow up in rheumatology clinic 5±6 months.

The following table summarizes the most common presenting symptoms among the patients:

Symptom	percentage
Fever	100%
Rash	78.9%
Lymphademopathy	55.3%
Hepato and/or splenomegally	15.8%
Pericarditis	18.4%
Myocarditis	2.6%
Pleuritis	2.6%
Arthralgia without arthritis initially	7.9%
Arthritis	92.1%

There is one patient presented with MAS and required ICU management.

The most frequently affected joints are the knees (76.3%) followed by the ankles (73.7%) then the wrists (55.3%) and the elbows (39.5%).

The disease course was monocyclic in 39.5%, polycyclic in 28.9% and persistent in 31.6% of the patients. and in 65.8% the disease has polyarticular pattern while in the rest of the patients it followed an oligoarticular pattern.

The number of patients who achieved remission is 30 (78.9%), 16 (53.3%) of them were in remission on treatment while 14 (46.7%) of them were in remission off treatment

Oral steroids, NSAIDs and MTX were used as a first line treatment to control the disease in the patients. Also intraarticular injections were used in 21.1% of the patients. In 55.3% of the patients switching to biologics was necessary to control the disease, Etanercept was sufficient in controlling the disease in only 2 patients (5.2%) while Anakinira was sufficient in controlling the disease in 5 patients (13.2%) and Tocilizumab was sufficient in controlling the disease in 6 patients (15.8%). More than one biologic used in 8 patients.

Joint deformities were present in 10 (26.3%) of the patients, and evidence of extra-articular damage is present in 12 (31.6%). MAS occured in 4 (10%) of the patients and one patient experienced 3 mas episodes

Conclusion: There is a high rate of disease remission on and off treatment and high rate of disease related articular and extra-articular damage because alot of patients started biologics late after disease onset.

Patient Consent Received

No

Disclosure of Interest

None declared

P57 Thalidomide in 30 patients with refractory systemic juvenile idiopathic arthritis

A. Khan¹, D. Ramadoss¹, P. Pimpale Chavan^2,3, K. Tiwari⁴, R. Khubchandani¹

¹Pediatric Rheumatology; ²Former Pediatric Rheumatologist, NH SRCC Childrens Hospital, Mumbai, India; ³Current: Inflammatory Disease Section, National Human Genome Research Institutes,National Institutes of Health, Bethesda, United States; ⁴Former Pediatric Subspeciality Fellow, Jaslok Hospital and Research Centre, Mumbai, India

Correspondence: A. Khan

Introduction: Thalidomide made a comeback at the turn of century for use in Erythema nodosum leprosum (anti TNF) and multiple myeloma (anti angiogenic). It has also been used in various pediatric autoinflammatory conditions notably sJIA. We report the largest experience with this drug in sJIA, adding to our earlier reported series.

Objectives: Share our experience with thalidomide in 30 patients of sJIA refractory to cDMARDs with /without biologicals.

Methods: Thalidomide was commenced in 30 patients beyond 4 years of age (children who could vocalize pain and paraesthesia) who failed to achieve disease control with NSAIDs,steroids,cDMARDs like methotrexate (n=3) or combination of methotrexate and leflunomide (n=24). 23/30 refused step up treatment to biologics due to cost constraints. 7 had also received biologicals in combination with methotrexate (etanercept- 4, tocilizumab-3) but were shifted to thalidomide due to poor response (6) and cost constraints (1). Before initiating thalidomide,families were educated in their preferred language about thalidomide,its adverse effects and limited evidence in medical literature for use in children and sJIA. After consent, thalidomide available as capsules of 50 /100 mg was commenced as a single night dose (2-3mg/kg/day) along with high fibre diet. Thalidomide was started along with at least one cDMARD. On 8-12 weekly follow up,disease activity was assessed based on systemic features, active joint counts, acute phase reactants and reduction of steroid dose. Complete response was defined as no active joints or systemic features, ESR < 25mmhr, dose of prednisolone < 0.3mg/kg/day and no response as no reduction in joint counts with persistent systemic features, ESR > 40mm/hr and prednisolone dose > 0.5mg/kg/day. Others were deemed partial responders. At every visit specific enquiry about features of peripheral neuropathy (tingling,numbness and paraesthesia), neurological examination (nerve conduction study if needed ), complete hemogram and liver function were studied.

Results: The age range of our patients was 4-17 years. Thalidomide was discontinued in 2/30 patients due to rash and thrombocytopenia respectively within a month of starting treatment and 1 patient was lost to follow up. 27/30 patients were followed up over 970 patient – months with a range of 2-96 months (Median= 26.5). 16/27 (59.2%) showed complete response. In 1/16 of responders’ thalidomide was discontinued after 22 months due to peripheral neuropathy and 1 patient with constipation was managed with diet modification and stool softeners. 6/27 (22.2 %) patients had no response. 4/6 were shifted over to biologics of whom 3 have responded to tocilizumab and 1 to etanercept biosimilar.2/6 were lost to follow up. They had no adverse effects related to thalidomide while being followed on drug. 5/27 (18.5 %) patients showed partial response with no side effects. 7/30 patients were on biologicals before being shifted to thalidomide. 4/7 had shown no response to etanercept biosimilar tried in a dose of 0.8 mg/kg/week for 8 - 48 weeks. 1 of these patients failed to show response to thalidomide but eventually responded to tocilizumab. 3/7 patients received tocilizumab in a dose of 8-12 mg/kg fortnightly intravenously for duration ranging 16 weeks to 28 weeks. All 3/7 patients who showed no response to tocilizumab responded well to thalidomide.

Conclusion: In resource challenged situations cost of biologics is high. Thalidomide offers an alternative in patients failing cDMARDs and/or biologics (after due parent information through a regulated drug availability program). 10% of our patients had major adverse effects necessitating stoppage emphasizing the need for close supervision.

Patient Consent Received

No

Disclosure of Interest

None declared

P58 Experience of tocilizumab use for systemic juvenile idiopathic arthritis in children under 2 years

E. Krekhova^1,2, E. Alexeeva^1,2, T. Dvoryakovskaya^1,2, R. Denisova², K. Isaeva², O. Lomakina², A. Mamutova², A. Chomakhidze², A. Fetisova², M. Gautier², I. Kriulin^1,2, I. Tsulukiya²

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) was approved in the treatment of patients with systemic juvenile idiopathic arthritis (sJIA) aged 2 to 17 years. Currently, one open-label phase 1 clinical trial has been carried out on the use of TOC under the age of 2 years.

Objectives: To evaluate the drug efficacy and safety of TOC in patients younger than 2 years with sJIA treated at the National Medical Research Center of Children`s health, Moscow, Russia.

Methods: We analyzed retrospectively the medical records of 23 patients younger than 2 years with sJIA which were prescribed to TOC. Informed consent of the patient's parents and approval of the medical commission for the prescription of off-label drugs was obtained. Inactive disease was defined according to the criteria of Wallace et al.

Results: 23 patients (11 — male, 12 — female) were initiated on TOC therapy (8-12 mg/kg IV every 2 weeks). The average age of onset of sJIA was 1.15 year (IQR 0.79-1.5), the average age at initiation - 1.4 year (IQR 1.2-1.7). At initiation, systemic features were noted in all patients, arthritis was present in 5/23 patients. All patients underwent exclusion of autoinflammatory syndromes due to the early age of onset of sJIA. At TOC initiation 16/23 patients received glucocorticosteroids (GCS), 6/23 patients received methotrexate. AE was noted in 7 patients at TOC initiation (6 - neutropenia; 1 - severe allergic reaction).

After 1 month of therapy, 30/50/70/90% improvement according to the ACR criteria was noted in 86/86/82/70% of 23 patients, and 57% of patients achieved remission according to C. Wallace. The lack of disease activity according to the JADAS-71 index was noted in 65% (13/23) of patients.

By the 6th month of therapy, 30/50/70/90% improvement according to the ACR criteria was noted in 78/78/78/74% of 23 patients, 70% (16/23) of patients achieved remission according to C. Wallace. 74% (17/23) of patients achieved JADAS-71 remission.

After 12 months of therapy, 30/50/70/90% improvement according to ACR criteria was noted in 81/81/76/76% of 21 patients (2 patients were follow-up for less than 1 year), remission according to C. Wallace and JADAS-71 index was reached by 71% (15/21) of patients.

TOC was discontinued in 11/23 patients. 3 patients had primary inefficiency, so we changed the therapy. 1 patient had a severe allergic reaction to the first infusion of TOC, but the stage of remission was achieved after infusion, today he continues to receive methotrexate. 1 patient developed secondary inefficiency. 6/23 (26%) patients achieved drug-off remission.

AE was noted in 15/23 patients in our observation. The most common AE was neutropenia (in 11/23 patients), especially at the beginning of TOC therapy. 4 patients were infected with tuberculosis without signs of an active process. 4 episodes of pneumonia were recorded and 2 cases of chickenpox. 2 (8.7%) patients had severe allergic reactions on TOC therapy.

Only 2/20 patients had a flare of sJIA during TOC therapy after achieving remission. 1 patient was switched to other biological drug. 1 patient received GCS pulse therapy due to a temporary delay of TOC administration.

Conclusion: The mean duration of TOC therapy was 27 months (IQR 9-40). The mean time of remission at TOC therapy was 29 months (IQR 9.5-56). Data from our experience suggest that TOC provided efficacy in sJIA patients younger than 2 years comparable to those in patients aged 2 to 17 years and also has an acceptable safety profile.

Disclosure of Interest

None declared

P59 Lung functioning and inflammation in a mouse model of systemic juvenile idiopathic arthritis

B. Malengier Devlies¹, T. Decaesteker², K. Dekoster³, A. Vanstapel², K. Ahmadzadeh¹, F. Poosti⁴, T. Mitera¹, L. Seldeslachts³, E. Verbeken⁵, C. Wouters^1,6,7, G. Vande Velde³, J. Vanoirbeek², P. Matthys¹

¹Laboratory of Immunobiology, Department of Microbiology and Immunology, Rega Institute KU Leuven; ²Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic Diseases and Metabolism; ³Biomedical MRI, Department of Imaging & Pathology, KU Leuven; ⁴Laboratory of Molecular Immunology, Department of Microbiology and Immunology, Rega Institute KU Leuven; ⁵Morphology and Molecular Pathology Section; ⁶Division of Pediatric Rheumatology; ⁷European Reference Network for Rare Immunodeficiency, Autoinflammatory and Autoimmune Diseases (RITA), University Hospitals Leuven, Leuven, Belgium

Correspondence: B. Malengier Devlies

Introduction: Systemic juvenile idiopathic arthritis (sJIA) is an immune disorder characterized by fever, skin rash, arthritis and splenomegaly. Recently, increasing number of sJIA patients were reported having lung disease.

Objectives: We explored lung abnormalities in a mouse model for sJIA relying on injection of IFN-γ deficient (IFN-γ KO) mice with complete Freund's adjuvant (CFA).

Methods: Lung abnormalities were assessed using microcomputer tomography, lung functionality tests, histology, flow cytometry and quantitative PCR.

Results: Monitoring of lung changes during development of sJIA using microcomputer tomography revealed a moderate enlargement of lungs, a decrease in aerated and increase in non-aerated lung density. When lung function and airway reactivity to methacholine was assessed, gender differences were seen. While male mice showed an increased tissue hysteresivity, female animals were characterized by an increased airway hyperactivity, mirroring ongoing inflammation. Histologically, lungs of sJIA-like mice showed subpleural and parenchymal cellular infiltrates and formation of small granulomas. Flow cytometric analysis identified immature and mature neutrophils, and activated macrophages as major cell infiltrates. Lung inflammation in sJIA-like mice was accompanied by augmented expression of IL-1β and IL-6, two target cytokines in the treatment of sJIA. The increased expression of granulocyte colony stimulating factor, a potent inducer of granulopoiesis, in lungs of mice was striking considering the observed neutrophilia in patients.

Conclusion: We conclude that development of sJIA in a mouse model is associated with lung inflammation which is distinct to the lung manifestations seen in sJIA patients. Our observations however underscore the importance of monitoring lung disease during systemic inflammation and the model provides a tool to explore the underlying mechanism of lung pathology in an autoinflammatory disease context.

Patient Consent Received

No

Disclosure of Interest

None declared

P60 Lenalidomide- an effective drug for refractory systemic onset juvenile idiopathic arthritis

A. P. Rao¹, A. Girdhar¹, J. Raghuram²

¹Pediatric Rheumatology, Manipal Hospital; ²Pediatric Rheumatology, Indira Gandhi Institute of Child Health, Bangalore, India

Correspondence: A. P. Rao

Introduction: A small subset of Systemic onset Juvenile Idiopathic arthritis (SJIA) patients, remain refractory to first line treatment including NSIADs/steroids/methotrexate. Biologic response modifiers like IL6 or IL1 antagonists are either expensive or are unavailable to many patients in Indian subcontinent. There is a felt need for drugs which are affordable and available to treat these patients.

Objectives: The objective of the study was to determine the efficacy, tolerability and safety of lenalidomide in patients with refractory SJIA and in whom biologics were not a plausible option either due to lack of affordability or non-availability.

Methods: 9 SJIA patients who were refractory to steroids and methotrexate were started on lenalidomide after informed consent and followed up for a period of 6 months at least. Patients were monitored for clinical improvement in the form of subsidence of fever, joint symptoms and laboratory markers in the form of hemoglobin (Hb), WBC count, ESR and platelet count. All the subjects were also closely monitored for any adverse effects of the drug. The statistical analysis was performed by STATA 11.2 (College Station TX USA).

Results: At the end of 6 months of therapy all patients were free from systemic features and most of the patients experienced clinical improvement in articular symptoms. There was a statistically significant improvement in the Hb(p=0.045) and ESR(p=0.008) in the patients. Steroid dosage could be reduced in all the patients and marked improvement was noted in all the laboratory markers. The drug was tolerated well by all the patients and there were no major adverse events observed. The most common side effect observed was generalized hyperpigmentation of skin.

Conclusion: Lenalidomide holds the potential of being an important drug in refractory cases of SJIA in a resource poor setting wherein biologic therapies are either unaffordable or unavailable. The limitation of the study is the small sample size and the need is felt for larger studies which can further the knowledge about lenalidomide use in SJIA.

Patient Consent Received

Yes

Disclosure of Interest

None declared

P61 Natural history of disease on a systemic juvenile idiopathic arthritis case without diagnosis and treatment. A case report in a developing country

S. Rodríguez Aguayo, E. Faugier Fuentes, M. I. De La Cera Rodríguez, H. W. Bermudez Canales, A. Guzman Revilla

Paediatric Rheumatology, Hospital Infantil de México Federico Gómez, Ciudad de México, Mexico

Correspondence: S. Rodríguez Aguayo

Introduction: Juvenile idiopathic arthritis (JIA) is the most prevalent chronic rheumatic disease in children and young people, is a major cause of musculoskeletal disability. Low-income countries face a unique set of challenges, which limit the ability to deliver high-quality care to patients with JIA. These challenges include a lack of trained pediatric rheumatologists or pediatricians, inadequate healthcare funding, delay in diagnosis and restricted access to medications.

Objectives: The objective of this study is to present the case of a pediatric patient with severe sequelae of systemic JIA, who failed in the diagnosis, treatment and timely referral, to raise awareness of the importance of early diagnosis and timely referral to the pediatric rheumatologist for effective treatment and prevention of disease progression and sequelae.

Methods: We presented the case of a pediatric patient with Systemic JIA severe sequelae, that failed in diagnosis, treatment and timely referral to pediatric rheumatologists.

Results: A 9-year-old patient who lives on a low socioeconomic and cultural level, came to the emergency room for fever of unknown origin. He has a history of hospitalization for fever in a second level care center 2 years ago. He received diagnosis of community-acquired pneumonia, and was treated intravenous antibiotics, with no response. Due to the persistence of fever, an approach is initiated, infectious causes are ruled out (negative blood and urine cultures, negative serologies for Brucellosis, Ricketssiosis and Lyme disease), and oncological causes too (negative bone marrow aspirate). A computed tomography of the thorax and abdomen reported lymphadenopathy and splenomegaly. Splenectomy is performed in that center, in the abstract of reference to our hospital, they do not explain the surgical indication, however, after the procedure apparently there was fever resolution as equal to the other symptoms, so they perform the hospital egress, but the family did not follow up with the pediatrician, so the patient lost tracing for more than 1 year. Two months before his admission to our center, presented high fever (100-104 °F), arthralgia, arthritis, weight loss 8 pounds, and constitutional symptoms. Clinically patient presented cachexia, malnutrition, paleness, retrognathia, generalized adenopathy, hepatomegaly 4-4-5 cm, arthritis in more than 15 joints, including the temporomandibular joint, shoulders, elbows, wrists, knees and ankles, as well as an axial skeleton that include cervical and lumbar vertebrae with a 2cm Schober test. Presented severe functional limitation with decreased arches of mobility because of the ankylosis. Patient has microcytic anemia (8.4mg/dl), leukocytosis (14,000 cel/ml), thrombocytosis (900,000 cel/ml) and elevated acute phase reactants ESR 23 mm/seg and PCR 11mg/dl. On the radiography images can observe periarticular bone loss, juxta-articular bone erosions and ankylosis. In two years of evolution, any paediatric rheumatologist had evaluated the patient, at the time of our evaluation, the patient had not received DMARDs or other JIA treatment.

Conclusion: The early recognition of signs and symptoms suggestive of rheumatic disease is imperative to make a timely diagnosis and provide effective treatment, in order to avoid progression and sequelae. In low-income countries, we must seek strategies to solve the challenges they present, such as a lack of trained pediatricians or pediatric rheumatologists, inadequate funding, and restricted access to medications with the objective of implement a hard and early hit strategy to improve in the evolution and prognosis of the disease.

Disclosure of Interest

None declared

P62 What is hidden under the diagnosis of systemic juvenile idiopathic arthritis: lessons of real clinical practice

S. Salugina, M. Kaleda, E. Fedorov, I. Nikishina

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

Correspondence: S. Salugina

Introduction: Systemic juvenile idiopathic arthritis (sJIA) is a rare and serious autoinflammatory disease characterized by systemic inflammation (fever, typical rash, serositis, hepatosplenomegaly, lymphadenopathy, acute phase reaction) and is variously accompanied by chronic arthritis, but at the onset of the nonspecific symptoms may be similar to other diseases with a pronounced acute phase inflammatory reaction.

Objectives: According to the data of a retrospective study, to analyze in which part of patients (pts) with sJIA the diagnosis is revised, in what time frame, what distinguishes this group at onset.

Methods: A total of 104 pts (57 females) with an initial diagnosis of sJIA who underwent inpatient treatment at our center from 2012 to 2020yy were included. The diagnosis of sJIA was verified in accordance with the ILAR criteria (2001), after excluding infectious, neoplastic or autoimmune diseases in regional hospitals. The median age at the onset was 4.5 years [interquartile range (IQR) 2.0; 8.0]. Molecular genetic testing for mutations in the NLRP3, MVK and TNFRSF1A genes was carried out in 101 pts.

Results: The diagnosis was changed in 27 pts (25.9%). The median duration of the disease at the time of the revision of the diagnosis was 3.5 [1.5; 6.25] years. Monogenic autoinflammatory diseases (mAIDs) were diagnosed in 22 pts (CAPS – 13, TRAPS – 7, HIDS – 1, FMF – 1). Diagnoses of mAIDs were confirmed by the detection of pathogenic mutations of causal genes. Also polymorphisms NLRP3 was revealed in 74.7% pts in the group who retained the diagnosis of sJIA, but they were clinical insignificant. In 2 pts verified inflammatory bowel disease, 1 – Behcet’s disease, 1 – PFAPA, 1 – neuroblastoma. The median age at the onset and gender were not statistically different between the groups (sJIA and non sJIA). Erythematous rash, typical for sJIA, and arthritis were significantly less common in pts in whom the diagnosis was changed (p=0.048 and p=0.0043, respectively) without difference between groups by other criteria sJIA at onset (p>0.05).

Conclusion: According to our data, about a quarter of pts with an inflammatory phenotype similar to the manifestations of sJIA suffer from mAIDS. Typical erythematous rash and arthritis are more likely to indicate the onset of sJIA, but the diagnosis of sJIA should be established with great caution, these pts need a thorough and critical assessment of all symptoms, anamnesis data and mandatory molecular genetic testing for the most common mAIDs. Identification of polymorphisms NLRP3 in pts with sJIA requires a dynamic assessment for a more correct interpretation of its clinical significance.

Disclosure of Interest

None declared

P63 Retrospective analysis evaluating clinical outcomes in Turkish SJIA patients with biological therapeutic agents - tursis study

B. Sozeri¹, K. Barut², E. Atalay³, A. Pac Kisaarslan⁴, S. Ozdel⁵, O. Altug Gucenmez⁶, F. Demir¹, B. Makay⁷, N. Aktay Ayaz⁸, E. Acar⁹, F. Haslak², E. Sag³, M. Yıldız², U. Kaya Akca³, A. Adrovic², Y. Bilginer³, H. Poyrazoglu⁴, E. Unsal⁷, O. Kasapcopur², S. Ozen³

¹Pediatric Rheumatology, University of Health Sciences, Istanbul, Umraniye Training and Research Hospital; ²Pediatric Rheumatology, Istanbul University-Cerrahpasa, Istanbul; ³Pediatric Rheumatology, Hacettepe University Faculty of Medicine, Ankara; ⁴Pediatric Rheumatology, Erciyes University Faculty of Medicine, Kayseri; ⁵Pediatric Rheumatology, Health Sciences University, Sami Ulus Training and Research Hospital, Ankara; ⁶Pediatric Rheumatology, Health Sciences University, Dr Behcet Uz Children's Hospital; ⁷Pediatric Rheumatology, Dokuz Eylul University Faculty of Medicine, Izmir; ⁸Pediatric Rheumatology, Istanbul University, Faculty of Medicine; ⁹Senior Medical Manager, Novartis, Istanbul, Turkey

Correspondencec: B. Sozeri

Introduction: Systemic Juvenile Idiopathic Arthritis (SJIA) is the most acute and severe form of JIA. Despite the substantial evidence supporting the effectiveness of biologic drugs in the treatment of SIA, the clinical response to these treatment options has not been largely investigated in Turkey.

Objectives: TURSIS, the 24-month, multicenter, retrospective, non-interventional study aimed to assess the clinical response to biological treatments for SJIA in Turkey and provide real life data that might help improve the disease outcomes.

Methods: This was a retrospective and multicenter study in patients with SJIA for whom a biological treatment had been initiated during the index period. The data collection from medical records of patients evaluated at the 8 Pediatric Rheumatology Clinics in Turkey from July 2019 till December 2020. Patients’ characteristics, clinical inactivity, and safety related variables and ACR70 response were assessed.

Results: The study population of 147 patients consisted of 76 females (51.7%). The mean age (SD) at diagnosis and baseline were 4.25 (2.91) and 8.00 (4.99) years, respectively. The percentage of patients without corticosteroids were 27.9% at baseline and gradually increased up to Month 24 (p<0.001 for all visits). The proportion of patients with no articular involvement gradually increased from baseline to Month 6. The median (min-max; IQR) VAS was 0 (0-90;20) at Month 3. The overall functional ability of patients was good. The median (min-max) global assessment score was 7.00 (0.00- 10.00). The scores differed significantly across biologics (p=0.026). The only significant difference between the drug pairs was observed between anakinra and etanercept (mean [SD]: 6.70 [2.69] vs 5.04 [2.87]; p=0.007). During the 2-year study period, 51.0% of patients (n=75) remained on the same biologic. Sixty-two patients (42.2%) had experienced 1 switch in biologic treatment, and 10 patients (6.8%) switched twice. In patients who required switching, canakinumab was the first alternative for patients treated with anakinra (44.9%) followed by tocilizumab (14.5%). A total of 22 adverse events were observed in 12 patients (8.2%) and included one death. Thirty-two patients (22.4%) had experienced a MAS attack between the diagnosis of SJIA and baseline. Nine patients experienced MAS after baseline. At Month 3, 73.5% of patients were clinically inactive. The proportion of clinically inactive patients was highest at Month 18 (84.69%), and 45.5% of patients were reported to have ACR70 response at Month 3. ACR30, 50 and 70 responses could be achieved in 95.5%, 50% and 45.5% of patients, respectively.

Conclusion: This study described the patient characteristics and the impact of biologics on disease activity in a real-life study of patients with SJIA in Turkey. Overall biological therapies resulted in improvement in clinical activity early after initiation. There was a decrease in the frequency of MAS after a biological drug initiation compared to the period to the start of biological therapy. Biologics were well tolerated. Further studies with larger study size can reveal the differences between the biologics on disease outcomes and guide treatment decisions, thereby improving patient management.

Patient Consent Received

Yes

Disclosure of Interest

None declared

e-Poster viewing: Spondyloarthritis (SpA) and enthesitis related arthritis (ERA)

P64 Comparing patient reported outcome measures in patients with enthesitis related arthritis and ankylosing spondylitis: a single-centre study

R. Amarnani, M. Leandro, D. Sen, C. Fisher

Rheumatology, University College London Hospitals NHS Foundation Trust, London, United Kingdom

Correspondence: R. Amarnani

Introduction: Enthesitis related arthritis (ERA) and ankylosing spondylitis (AS) can present with similar clinical symptoms but have a distinct age of onset. Peripheral arthritis is more common in ERA, whereas axial arthritis is more common in AS. Although validated in ERA, it is not fully understood how patient reported outcome measures (PROMs) for AS such as the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Bath Ankylosing Spondylitis Functional Index (BASFI) perform in patients with ERA.

Objectives: To compare the differences in commonly used PROMs including BASDAI and BASFI in patients with a diagnosis of ERA and AS.

Methods: Adult patients with a diagnosis of AS or ERA under the care of the rheumatology department at University College London Hospital were included in this study. Data was collected over a 3 month period. Patients were asked to complete questionnaires of different PROMs as part of their routine clinical care. These included BASDAI, BASFI and also Global and Spinal Visual Analogue Scale (VAS), Jenkins Sleep Score (JSS), AS quality of life score (ASQOL) and the Mood & Feelings Questionnaire (MFQ). Baseline patient demographics were extracted manually from our electronic healthcare database. Data analysis was completed using IBM SPSS v26 and tested for significance using a Mann Whitney U test.

Results: A total of 44 patients with ERA (n=29) and AS (n=15) were included. 23% of patients were female (n=10, AS=5/15 (33.3%), ERA=5/29 (17.2%)). Those with a diagnosis of ERA were significantly younger (p<0.0001) with a median age of 21 (range 18-30) compared to 40 (range 23-65) in the AS group. A similar proportion of patients in each group were on biologic treatment (ERA 15/29 (51.7%), AS 7/15 (46.7%)), although a higher proportion of patients with ERA were treated with conventional DMARDs (ERA 23/29 (79.3%), AS 2/15 (13.3%)). There was no significant difference between total mean BASDAI in the AS group compared to the ERA group (4.4 vs 3.18, p= 0.13). Interestingly, a significant difference was found for question 2 of the BASDAI which focuses on neck, back and hip pain and patients with AS recorded higher median scores (5 vs 3, p=0.01). The mean BASFI was significantly higher in patients with AS compared to patients with ERA (3.94 vs 1.78, p=0.005). In all other PROMs, patients with AS scored significantly higher including mean scores for global VAS (5.35 vs 2.93, p=0.009), spinal VAS (5.0 vs 2.58, p=0.013), JSS (10.6 vs 4.72, p=0.003), ASQOL (9.26 vs 4.34, p=0.003) and the MFQ (6.92 vs 2.79, p=0.015).

Conclusion: Our results show that patients with a diagnosis of AS reported significantly worse PROMs in a wide range of domains compared to patients with ERA. Total BASDAI was the only PROM where no significant difference was found, although the higher score for question 2 in patients with AS may reflect the prominence of axial disease compared to ERA. Questions in the BASFI are also weighted towards spinal disease and may underestimate enthesitis and peripheral arthritis, resulting in lower scores in patients with ERA. However, poor levels of sleep, quality of life and low mood in patients with AS compared to those with ERA are not explained by this and need further investigation. Possible explanations include differences in disease duration and age of onset, patient age, HLA-B27 status, disease activity, early treatment with biologic medication and pattern of joint involvement. Although this study is limited to a single centre and a small cohort of patients, it identifies important differences between ERA and AS and may indicate PROMs for AS are not as sensitive in patients with ERA.

Disclosure of Interest

None declared

P65 Looking beyond joints: gastrointestinal involvement in children and adolescents with juvenile idiopathic arthritis

F. Civitelli¹, F. Ardenti Morini¹, F. Soscia¹, G. Bruno², F. Ferrari¹, V. D'Ovidio², M. E. Bazuro², G. Santeusanio³, E. Cortis¹

¹Department of gender diseases, children and adolescents, Pediatric Unit, Sant'Eugenio Hospital; ²Sant'Eugenio Hospital, Endoscopy Unit; ³Department od Diagnostic Services, UOC of Pathology, Sant'Eugenio Hospital, Rome, Italy

Correspondence: F. Civitelli

Introduction: Gastrointestinal (GI) symptoms are frequent in patients (pts) with chronic disease such as juvenile idiopathic arthritis (JIA). Disease-related drugs, psychological issues due to the chronic condition should be considered as possible causes. However, gut inflammation has been described in some forms of JIA and inflammatory bowel disease (IBD) occur in 7-10 % of pts with sponidloarthropaty (SpA). Accurate assessment of GI symptoms in JIA pts with is necessary to identify those requiring a further invasive diagnostic work-up with endoscopy.

Objectives: To describe the presence and type of GI involvement in a population of children and adolescents with different subtypes of JIA. The secondary aim was to assess the accuracy of non-invasive tests, such as fecal calprotectin (FC) and bowel ultrasonography (BWUS), in identifying pts requiring a further diagnostic work-up with endoscopy.

Methods: Consecutive JIA pts complaining of GI symptoms for at least 12 weeks were prospectively enrolled during a twelve-month period. All underwent a complete clinical assessment, including evaluation by a pediatric gastroenterologist, blood inflammatory markers, FC (Calprest®, Eurospital), and BWUS with Colour-Doppler examination (Esaote equipment, 3.5 MHz convex and 12 MHz linear transducers). US assessed parameters were: Bowel Wall Thickness (BWT) > 3 mm, presence of BW vascularity, presence of enlarged mesenteric nodes and mesenteric fat hypertrophy (MFH). In pts with high clinical suspicion of IBD upper and lower endoscopy with multiple biopsies was performed. Pts who received NSAID in the 14 days before enrolment were excluded to avoid any possible effect on symptoms and FC levels. Sensitivity (SE), specificity (SP), positive and negative predictive value (PPV and NPV) of laboratory and US parameters were analysed according to the final diagnosis of gut inflammation.

Results: 32 pts (16 female) aged 5-16 years (median 11) were enrolled: 11 with oligoarthritis, 6 polyarthritis, 2 systemic, 10 SpA, 3 undefined. Eight pts were receiving methotrexate, 7 sulfasalazine, 10 anti-TNFα therapy, 1 canakinumab, 1 tocilizumab. All pts presented abdominal pain, 12 complained of diarrhoea, 7 also with blood in the stools, 2 failure-to-thrive and 2 recurrent oral aphthosis. 14 pts (43%) showed a first-degree relative with Rheumatoid Arthritis (8) or IBD (6). The mean time between the diagnosis of JIA and clinical evaluation (months) was 20.5 ± 19.4. BWUS revealed increased BWT of the terminal ileum in 17 pts, increased BW vascularity in 13, enlarged mesenteric nodes and MFH in 8. Sixteen pts underwent endoscopy: 14 showed gut inflammation, 5 had a final diagnosis of IBD, 9 showed chronic aspecific inflammation at histology requiring a further GI follow-up. One pt had celiac disease, 15 were finally diagnosed as irritable bowel syndrome based on Rome IV criteria. Pts with gut inflammation at histology had higher FC levels (200 ± 190 ug/g vs 48 ± 25, p<0.001) and higher BWT at US (4 ± 0.5 vs 3.2 ± 0.7, p< 0.05 ) and a more frequent family history (10 vs 4, p=0.4). SE, SP, PPV, NPV of BWT and FC > 50 ug/g vs the final diagnosis of gut inflammation were (%): 92.8, 85.7, 81.2, 94.3, and 86.7, 81.2, 76.5, 90, respectively

Conclusion: Pts with JIA and GI symptoms should be managed together by the pediatric rheumatologist and the pediatric gastroenterologist. FC and BWUS may be useful non-invasive tests to identify pts requiring a additional diagnostic workup with endoscopy. Further studies with larger number of pts are needed to assess the usefulness of non-invasive test in detecting sub-clinical gut inflammation also in asymptomatic pts with JIA.

Patient Consent Received

No

Disclosure of Interest

None declared

P66 The challenge of classification in juvenile spondyloarthritis

M. Katsicas, M. Bertinotti, G. Villarreal

Immnulogy& Rheumatology, Hospital De Pediatría Garrahan, Buenos Aires, Argentina

Correspondence: M. Katsicas

Introduction: Juvenile spondyloarthropathies (JSpA) are a group of rheumatic diseases that involves sacroiliitis and spondylitis, peripheral large joints, and enthesitis. JSpA are represented by enthesitis related arthritis (ERA), juvenile psoriatic arthritis and undifferentiated arthritis (UA) in the ILAR criteria. The proposed PRINTO classification criteria for JIA introduced a new approach of axial imaging changed ERA by enthesitis/spondylitis-related JIA (ESRA).

Objectives: To assess the sensibility and specificity of the provisional new PRINTO JIA classification criteria ESRA for identification of patients with JSpA To compare the performance of ESRA and ASAS classification criteria.

Methods: Consecutive patients with JSpA (defined as ERA, or UA according to ILAR) followed in our center with complete records were included. Randomly selected patients with oligoarthritis, systemic arthritis and polyarthritis RF negative served as controls. Variables recorded were: arthritis, enthesitis, tarsitis, inflammatory back pain, sacroiliac joint tenderness, presence of HLA-B27 antigen, acute anterior uveitis, history of SpA in a first-degree relative. Imaging on sacroiliac joints. Summary statistics included overall sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), positive Likelihood ratio (+LR).

Results: 103 patients with JSpA (84 ERA, 19 UA) were included (M:89), median age at onset: 10(1-15) years, disease duration at time of first visit 10 (1-48) months, follow-up time 6 (1-15) years. Controls: 69 patients with JIA (25 oligoarthritis, 24 polyarthritis RF negative, 20 systemic) (M:27). At first visit cases showed: 100 (97%) arthritis, 64(62%) elevated CRP, 52 (50%) limitation of lumbar spine motion, 52 (50 %) HLA-B27, 46 (45%) enthesitis, 40(39%) tarsitis, 39(38%) low back pain, 31 (30%) sacroiliac joint tenderness, 30 (29%) good response to NSAIDS, 26 (25%) positive family history, 13 (13%) dactylitis, 7(7%) uveitis,7(7%) diarrhea, 5 (5 %) infectious previous disease, 2(2%) urethritis, 2(2%) inflammatory bowel disease, 2 (2%) buttock pain. Imaging criterion for sacroiliitis: 28 (27%) on X-Ray (21 grade 2 bilateral and 7 grade 3), 26 (25%) on magnetic resonance imaging (MRI). At first visit (103 patients): 90 (87%) fulfilled ESRA criteria. During disease course (97patients): 92 (95%). Axial radiological arm allowed to classify 6 UA patients at baseline and others 7 UA patients could be reclassified during the follow-up. Table shows accuracy PRINTO and ASAS classification criteria

First Visit	Sensitivity	Specificity	PPV	NPV	+LR
PRINTO ESRA	87%	86%	90%	81%	6.31
Peripheral ASAS	74%	86%	89%	68%	5.39
Axial ASAS	24%	86%	73%	42%	1.75
Global ASAS	77%	86%	89%	70%	5.53
Disease Course
PRINTO ESRA	95%	86%	91%	92%	6.85
Peripheral ASAS	92%	86%	91%	87%	6.66
Axial ASAS	40%	86%	82%	48%	2.94
Global ASAS	92%	86%	91%	87%	6.66

Conclusion: In our cohort ESRA provides a wider clinical and imaging spectrum by adding some UA. ESRA showed better accuracy than ASAS. The validation of these provisional criteria are expected to be used in clinical practice

Disclosure of Interest

None declared

P67 The performances of the ILAR and ASAS classification criteria in JIA patients

U. Kaya Akca, E. D. Batu, S. Sener, Z. Balik, M. Kasap Cuceoglu, E. Atalay, O. Basaran, Y. Bilginer, S. Ozen

Department of Pediatrics, Division of Rheumatology, Hacettepe University Faculty of Medicine, Ankara, Turkey

Correspondence: U. Kaya Akca

Introduction: Enthesitis-related arthritis (ERA) is considered the equivalent of ankylosing spondylitis in adults albeit with certain significant differences. In our routine practice, the International League of Associations for Rheumatology (ILAR) classification criteria are used in children with ERA and the Assessment of Spondyloarthritis International Society (ASAS) classification criteria for axial and peripheral spondyloarthritis (SpA) in adults.

Objectives: We aim to evaluate the sensitivity and specificity of ILAR and ASAS classification criteria in ERA patients.

Methods: The medical records of ERA patients who were followed up in the Department of Pediatric Rheumatology at Hacettepe University between January 2005 and September 2020 have been analyzed. The control group consisted of patients with oligoarticular JIA (n=146), polyarticular JIA (n=55), and psoriatic arthritis (n=20). Patients followed up for at least 6 months were included. The diagnosis of ERA was based on expert opinion.

Results: This retrospective study included 108 ERA (26.9% female) and 221 control patients (74.2% female). The median age at diagnosis for ERA and control patients were 12.5 and 4.0 years, respectively (p<0.001). Arthritis was observed more frequently in the control group at diagnosis and follow-up (p<0.001 for both), while enthesitis, sacroiliac joint tenderness, and inflammatory back pain were more common in the ERA group both at diagnosis and follow-up (p<0.001 for all). The presence of human leukocyte antigen (HLA)-B27 and elevated C-reactive protein levels were also more frequent in the ERA group. In sacroiliac imaging, 70.1% of ERA patients had positive findings suggestive of sacroiliitis at diagnosis and 78% at follow-up. There was a low response rate to non-steroidal anti-inflammatory drugs in the ERA group compared to the control group. The sensitivities of ILAR and ASAS criteria for axial SpA, and peripheral SpA at diagnosis were 73.1%, 21.3%, and 83.3%, respectively which increased to 83.3%, 35.1%, and 92.5%, respectively at follow-up. The specificity of all three classification criteria was >90% at diagnosis and follow-up (Table 1).

Conclusion: The ASAS criteria for peripheral SpA was the most sensitive while ASAS classification criteria for axial SpA was the most specific criteria in ERA patients. The sensitivities of all three classification criteria has increased during follow-up, which is probably due to the additive nature of the disease.

Disclosure of Interest

None declared

Table 1 (abstract P67). Comparison of the sensitivity and specificity of the ILAR criteria, ASAS classification criteria for axial and peripheral SpA at diagnosis and follow-up

P68 Quality of life of patients with ankylosing spondylitis with anemic syndrome among ukrainian population

O. Zviahina, S. Shevchuk

Internal Medicine #2, National Pirogov Memorial Medical University, Vinnytsya, Ukraine, Vinnytsya, Ukraine

Correspondence: O. Zviahina

Introduction: Anemic syndrome is one of the manifestations of ankylosing spondylitis (AS). Anemia in this cohort of patients may be, on the one hand, a completely independent disease, as well as a complication of both the underlying disease and the consequence of the pharmacotherapy of AS. Anemia often complicates the course and prognosis of the disease, which in turn impairs the quality of life (QOL) of this group of patients. This topic is being researched for the first time among the Ukrainian population of AS patients.

Objectives: The purpose of this work was to evaluate QOL in patients with AS and its relationship with the presence and type of anemic syndrome.

Methods: The study included 118 patients diagnosed with ankylosing spondylitis according to the modified New York criteria. All patients were divided into three groups: 84 patients with AS without anemia, 34 patients with AS and anemia, and the control group consisting of 26 almost healthy persons. All hematologic, biochemical and enzyme-linked immunosorbent assays were performed to determine the indicators of hematopoiesis and ferrokinetics. AS activity assessment was performed using ASDAS (Ankylosing Spondylitis Disease Activity Score) and BASDAI (Bath ankylosing spondylitis disease activity index) questionnaires. QOL was evaluated using the SF-36 questionnaire. Statistical processing of the results was performed using a set of statistical programs "Microsoft Office Excel 2007".

Results: The QOL score according to the SF-36 questionnaire in the control group was equal to 96.41 ± 0.25 points, and in patients with AS – 42.2 ± 1.01 points. The mean rate of QOL in patients with AS without anemia was significantly different from patients with AS with anemia (44.65 ± 1.18 versus 36.13 ± 1.51, respectively (p <0.05). Analysis of QOL in patients with different pathogenetic types of anemia syndrome showed that the highest rate of QOL according to SF-36 was among patients with IDA and was 42,36 ± 3,39, which was significantly higher compared to the groups of patients with ACD and ACD with iron deficiency (p <0.05). SF-36 in the group of patients with ACD was 34.62 ± 1.48 points, and in persons with ACD with iron deficiency 31.98 ± 2.91 points. It should be noted that the physical component of QOL suffered more than the psychic component. In the group of patients with IDA, the physical component of health according to SF-36 was 27.71 ± 4.89 points, in the group with ACD - 22.81 ± 1.64 points, in the group with ACD and iron deficiency - 23,95 ± 3,27 points. Mental component in the group of patients with IDA was 57,04 ± 4,31 points, and was significantly higher than in the group with ACD - 46,48 ± 2,26 and ACD with iron deficiency - 40.05 ± 2.98 (p <0.05). Analysis of the subscales of the SF-36 questionnaire revealed no significant differences between the groups, except for the “Role limitations due to emotional problems” indicator, which was significantly better in the group of patients with IDA compared with patients with ACD and ACD with iron deficiency. In our opinion, this difference between the groups is explained by the fact that the significantly lower value of BASDAI and ASDAS was in particular among patients with IDA (5.40 ± 0.46 points and 3.95 ± 0.29 points, respectively), whereas ACD (7.42 ± 0.25 points and 4.44 ± 0.11 points) and ACD with iron deficiency (6.76 ± 0.38 points and 4.04 ± 0.15 points) were characterized by higher rates of disease activity (p < 0.05).

Conclusion: QOL in patients with AS is lower, compared with a relatively healthy population. Anemic syndrome in patients with AS is associated with worse QOL according to SF-36. ACD and ACD with iron deficiency are characterized by lower rates of QOL than patients with IDA.

Trial registration identifying number: ClinicalTrials.gov: NCT03926195

Patient Consent Received

Yes

Disclosure of Interest

None declared

e-Poster viewing: Autoinflammatory diseases

P69 The rare autoinflammatory disease manifesto: a key educational tool to help raise awareness and improve care

S. Angevare¹, B. Bori², A. Runov³, M. Nudel⁴, C. Normand⁵, L. Bergamini⁶, M. Jesenak⁷, L. Fagerhed⁸

¹KAISZ, Amersfoort, Netherlands; ²Novartis, Origgio, Italy; ³Sunflower Foundation, Moscow, Russian Federation; ⁴Mifrakim Tz’eirim, Haifa, Israel; ⁵ENCA, Geneva, Switzerland; ⁶Spedali Civili, Brescia, Italy; ⁷Centre for Periodic Fever Syndromes, Department of Paediatrics and Department of Pulmonology and Phthisiology, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, University Hospital in Martin, Bratislava, Slovakia; ⁸Novartis, Espoo, Finland

Correspondence: S. Angevare

Introduction: Rare autoinflammatory diseases are an emerging and rapidly evolving group of rare conditions characterised by spontaneous and disabling attacks of systemic inflammation, resulting in a broad spectrum of symptoms and consequences, including recurring fevers and severe fatigue.^1-6 The Rare Autoinflammatory Disease Manifesto was developed in collaboration with the Rare Autoinflammatory Disease Council (a group of patients, patient advocacy groups [PAGs] and healthcare professionals [HCPs]) to define how rare autoinflammatory diseases are discussed and align the community voice.

Objectives: The aim of the manifesto is to explore the unmet needs of people living with rare autoinflammatory diseases and identify a call to action for key aspects of the patient journey, in order to improve patient care.

Methods: Extensive research was conducted to gain a deeper understanding of rare autoinflammatory diseases and the patient journey, including disease burdens and unmet needs. Primary research included two virtual advisory board meetings in May and July 2020 with members of the Rare Autoinflammatory Disease Council and a physician specialising in periodic fevers to discuss their experiences. A literature review was performed to supplement the primary research.

Results: The manifesto clarifies key scientific aspects of rare autoinflammatory diseases including disease definition, categorisation and genetic background. It reports significant physical, emotional, social and financial burdens on people living with these conditions. Notably, the rarity and low awareness of disease results in substantial delays to appropriate patient care, and a lack of understanding and support from their social environment. We found that paediatric patients are especially impacted as symptoms disrupt physical, educational and social development. The transition to adult care is considered one of the most challenging times. The lifelong nature of these conditions places a substantial economic burden on healthcare systems. Early diagnosis, increasing therapy options, optimising disease management and facilitating patient engagement and empowerment were identified as key strategies to overcome the barriers to effective care. Based on these goals, the manifesto outlines actions targeted towards HCPs, policymakers, PAGs and other stakeholders to help improve care and health outcomes.

Conclusion: The Rare Autoinflammatory Disease Manifesto is an important educational resource that was published on the Periodic Fevers website (www.periodicfevers.com/about-periodic-fevers/manifesto) in March 2021 and has since been translated in six languages. A multi-channel campaign is underway to promote the manifesto internationally. Our efforts are focused on continued collaboration with PAGs to disseminate and evolve the manifesto as we uncover further insights from the rare autoinflammatory community.

References

1.Erbis G, Schmidt K, Hansmann S, Sergiichuk T, Michler C, Kuemmerle-Deschner JB, et al. Living with autoinflammatory diseases: identifying unmet needs of children, adolescents and adults. Pediatr Rheumatol Online J. 2018;16(1):81. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6302479

2.Savic S, Wood P. Does this patient have periodic fever syndrome? Clin Med. 2011;11(4):396–401. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5873756

3.Gurcay E, Akinci A. Autoinflammatory Diseases and Physical Therapy. Mediterr J Rheumatol. 2017;28(4):183–91. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7046004

4.Touitou I, Galeotti C, Rossi-Semerano L, Hentgen V, Piram M, Kone-Paut I, et al. The expanding spectrum of rare monogenic autoinflammatory diseases. Orphanet J Rare Dis. 2013;8:162. Available from: https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-8-162

5.Krainer J, Siebenhandl S, Weinhausel A. Systemic autoinflammatory diseases. J Autoimmun. 2020;109:102421. Available from: https://pubmed.ncbi.nlm.nih.gov/32019685

6.McDermott MF, Aksentijevich I, Galon J, McDermott EM, Ogunkolade BW, Centola M, et al. Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes. Cell. 1999;97(1):133–44. Available from: https://pubmed.ncbi.nlm.nih.gov/10199409

Patient Consent Received

No

Disclosure of Interest

S. Angevare: None declared, B. Bori Employee of: Novartis, A. Runov: None declared, M. Nudel: None declared, C. Normand: None declared, L. Bergamini Consultant for: Novartis, M. Jesenak Speaker Bureau of: Novartis, SOBI, Sanofi Genzyme, CSL Behring, Takeda, GlaxoSmithKline, L. Fagerhed Employee of: Novartis

P70 Assessment of physical fitness with fitnessgram® and physical activity in children and adolescents with familial mediterranean fever: a pilot study for health risk analysis

A. Albayrak¹, N. Arman², E. Tarakci², O. Kasapcopur³

¹Master Program of Physiotherapy-Rehabilitation, Graduate Education Institute, Istanbul University-Cerrahpasa; ²Department of Physiotherapy and Rehabilitation, Istanbul University-Cerrahpasa, Faculty of Health Science; ³Department of Pediatric Rheumatology, Cerrahpasa Medical School, Istanbul University-Cerrahpasa, Istanbul, Turkey

Correspondence: N. Arman

Introduction: Familial Mediterranean Fever (FMF) is the most common inherited autoinflammatory disease, which is characterized by recurrent fever attacks, inflammation of serosal membranes and arthritis mostly occurring in childhood. Although the clinical findings during attacks may vary, the most common attack type is a combination of fever, abdominal pain, and joint findings. Children and adolescents with FMF may also have symptoms not related to attacks, such as prolonged myalgia, exertional leg pain, post-exercise erythema, and sacroiliitis.

Objectives: The aim of the study was to assess physical fitness and physical activity in children and adolescents with FMF.

Methods: Eleven patients with FMF were included in the study. Health-related components of physical fitness were evaluated using the FitnessGram® Test Battery. These tests included curl-ups, push-ups, a 20-m shuttle run test (20mSRT), trunk lift test, the modified back-saver-sit-and-reach test (mBSRT) and body composition measurements. The curl-up and push-up tests were used to evaluate muscular strength and endurance. The 20mSRT was used to evaluate cardiorespiratory fitness. The trunk lift test was used to evaluate trunk extensor strength. mBSRT was used to evaluate flexibility. The percent of body fat with Bioelectrical Impedance Analysis and Body Mass Index (BMI) were used to evaluate body composition. All tests were conducted according to the FitnessGram® measurement procedures. Participants were then classified according to the age and sex-specific cut-off points of FitnessGram as Needs Improvement (NI)-health risk, NI and healthy fitness zone (HFZ). The Physical Activity Questionnaire (PAQ) was used to evaluate the physical activity levels of patients.

Results: Four of the participants were male and 7 of them were female. The mean age was 13.54±3.69 and the mean disease duration was 6±3.90 years. When the FitnessGram standards were applied, %63.6 of them were categorized in the NI and %36.4 of them in the HFZ for curl-up test, %72.7 of them in the NI and %27.3 in the HFZ for the push-up test, %90.9 of them in the NI-health risk, %9.1 of them in the NI for the 20mSRT, %72.7 of them in the NI and %27.3 of them in the HFZ for the trunk lift test, %81.8 of them in the NI and %18.2 of them in the HFZ for the mBSRT. Besides, according to FitnessGram body composition classification criteria, %27.3 of them were categorized in the NI, %27.3 of them in the very lean and %45.5 of them in the HFZ for percent body fat, %9.1 of them in the NI-health risk, %18.2 of them in the NI, %9.1 of them in the very lean and %63.6 of them in the HFZ for BMI. The physical activity level of the patients was categorized “low-active” in %81.8 of them and “sufficiently active” in %18.2 of them, according to the PAQ.

Conclusion: The results of this pilot study reveal that the physical fitness and physical activity levels in children and adolescents with FMF were considerably poor at a risk level for health. However, further research on physical fitness and physical activity in childhood FMF with larger sample sizes is required. We consider that physical activity and exercise programs should focus on improving physical fitness and increasing physical activity levels to minimize health risks in childhood FMF.

Patient Consent Received

Yes

Disclosure of Interest

None declared

P71 Pediatric chronic non-bacterial osteomyelitis: a single-center case series

P. O. Avar-Aydin¹, B. Ozcakar¹, N. Cakar¹, D. Karakas¹, 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: Chronic nonbacterial osteomyelitis (CNO) is an autoinflammatory bone disorder that most commonly affects children and adolescents and covers a wide clinical spectrum from unifocal involvement and nonrecurrent course to recurrent or persistent multifocal disease. CNO remains a diagnosis of exclusion.

Objectives: To present a single-center experience of pediatric CNO patients.

Methods: Children with a diagnosis of CNO who were followed up at the Department of Pediatric Rheumatology of Ankara University School of Medicine between 2013 and 2021 were included in this study. Patient data was documented from electronic medical records retrospectively. The clinical score by Jansson et al. was used to classify patients. Patients without remission despite treatment for 6 months were defined to have a persistent course.

Results: A total number of 24 patients with a median follow-up duration of 32.5 months (0-84) were included. Clinical and laboratory features are summarized in Table 1. Co-existing diseases were as follows: familial Mediterranean fever (n:4), psoriasis and severe acne (n: 2), Crohn’s disease (n:1), and juvenile idiopathic arthritis (n: 1). A family history of autoinflammatory diseases was present in 4 patients (16.7%).

All patients had multifocal bone lesions at diagnosis. The most affected bones were the pelvis (58.3%), femur (50%), and vertebra (50%). Long bone lesions were metaphyseal in 92.9% of the cases. Increased CRP levels were present in 70.8% and antinuclear antibody positivity in 16.7% of the patients. Patients with sacroiliitis were screened for the presence of HLA-B27 and one patient was found positive.

More than 50% of the patients with a follow-up of more than 6 months had a persistent course who experienced remission after anti-TNF agents. All patients with two mutations in the MEFV gene (n: 4) benefitted from concurrent use of colchicine and anti-TNFs.

Conclusion: Chronic nonbacterial osteomyelitis presents with a variety of clinical findings and has a variable disease course. NSAIDs are effective in treatment; however, persistent or recurrent disease activity may need biologics and other therapies.

Patient Consent Received

Yes

Disclosure of Interest

None declared

Table 1 (abstract P71). Demographic, Clinic, and Laboratory Features of Patients with CNO

P72 Probiotic use in the prophylaxis of PFAPA (Periodic fever, adenitis, pharyngitis, aphthous stomatitis) syndrome

E. D. Batu, U. Kaya Akca, M. Kasap Cuceoglu, E. Atalay, Z. Balık, S. Sener, O. Basaran, Y. Bilginer, S. Ozen

Department of Pediatrics, Division of Rheumatology, Hacettepe University Faculty of Medicine, Ankara, Turkey

Correspondence: E. D. Batu

Introduction: Periodic fever, aphthosis, pharyngitis, and adenitis (PFAPA) syndrome is an autoinflammatory recurrent fever syndrome which mainly affects children. Cimetidine, colchicine, and anti-IL-1 agents could be used to prevent attacks. Probiotics were previously reported to be beneficial in a few PFAPA patients for prevention of attacks.

Objectives: We aimed to evaluate the response to probiotics in PFAPA patients.

Methods: Patients with PFAPA syndrome who received probiotics were included in this retrospective study. Demographic and clinical features, and response to probiotics were assessed.

Results: Twenty patients with PFAPA syndrome (F/M:1) were included. All had pharyngitis during attacks while oral aphthosis (65%), lymphadenitis (50%), and fatigue (80%) were also common attack-associated features. 9 (45%) patients also had abdominal pain during attacks. Periodicity was present in 15 (75%) patients. Throat culture was performed during an attack in 16 (80%) patients and revealed normal flora in all. MEFV variant analysis (n=17) revealed heterozygosity for M680I in 3, M694V in 2, and E148Q in 3 patients. The median (min-max) ages at symptoms onset and diagnosis were 24 (3-72) and 51.5 (11-120) months, respectively. All patients received probiotics during the disease course. The probiotic they used included a combination of two lactobacilli as Lactobacillus plantarum HEAL9 (Lp HEAL9) and Lactobacillus paracasei 8700:2 (Lpa 8700:2). The median age at probiotic onset was 60 (33-192) months while duration of probiotic use was 4.5 (3-19) months. All patients except one experienced decrease in attack frequency with probiotic use. The attack frequency decreased significantly with probiotics (median number of attacks per 3 months: 3 vs. 1, respectively; p<0.001). 8 (40%) patients had no attacks during the 3-months period after probiotic initiation. And, 5 (42%) of 12 patients who had ≥1 attacks on probiotics mentioned that the attack severity (duration and the degree of fever) decreased significantly during probiotic use. Colchicine was also administered to 4 (20%) patients for a duration of 30 (6-55) months before the onset of probiotics. Two of them did not respond to colchicine and colchicine was discontinued. Other two patients experienced decrease in attack frequency with colchicine treatment; however, they were still having >1 attack/month. Probiotic was beneficial in all four of these patients.

Conclusion: Intake of the probiotic strains Lp HEAL9 and Lpa 8700:2 were previously shown to decrease the incidence and severity of common cold in randomized controlled trials. A significant reduction in pharyngeal symptoms was also noted in these studies. We may speculate that these lactobacilli might be beneficial in PFAPA syndrome by down-regulating the inflammatory response in tonsils through changes in the microbiota.

References

Bergggren et al. Randomised, double-blind, and placebo-controlled study using new probiotic lactobacilli for strengthening the body immune defence against viral infections. Eur J Nutr 2011;50:203-10.

Bush et al. Randomised, double-blind, and placebo-controlled study using a combination of two probiotic lactobacilli to alleviate symptoms and frequency of common cold. Food and Nutrition Sciences 2013;4:13-20

Francesco et al. The use of Streptococcus salivarious K12 in attenuating PFAPA syndrome; a pilot study. Altern Integr Med 2016;5:4.

Patient Consent Received

Yes

Disclosure of Interest

None declared

P73 Long term safety profile of anti IL-1 therapy in patient with autoinflammatory childhood onset disease

M. Camacho-Lovillo, L. Fernandez-Silveira, M.-I. Garcia Ruiz-Santa Quiteria, A. Capilla Miranda, O. Neth

Hospital Virgen Del Rocio, Sevilla, Spain

Correspondence: M. Camacho-Lovillo

Introduction: There are currently two IL-1 inhibitors approved for clinical use in Europe. However, long term follow-up data of five or more years regarding security and efficacy of anti IL-1 treatment in autoinflammatory diseases (AID) in children are scarce.

Objectives: A retrospective study of patients with AID diagnosed in a tertiary referral pediatric rheumatology department receiving anti IL-1 therapy for 5 years or longer was conducted. Demographic data, symptoms, treatments and adverse events (AE) were collected from clinical chart, not only from hospital but also from primary attention in order to improve information quality.

Methods: A retrospective study of patients with AID diagnosed in a tertiary referral pediatric rheumatology department receiving anti IL-1 therapy for 5 years or longer was conducted. Demographic data, symptoms, treatments and adverse events (AE) were collected.

Results:

Patient	1 male	2 male	3 male	4 male	5 female	6 male	7 male	8 male	9 female
Current Age (y.o)	19	23	21	13	18	17	12	22	11
Diagnosis	JIAs	JIAs	Recurrent pericarditis	JIAs	FMF	JIAs	Recurrent pericarditis	JIA s	CINCA
Genetic test	No mutation found	No mutation found	No mutation found	No mutation found	V267A heterozygosis in MEVF gene	No mutation found	No mutation found	pI591T heterozygosis in MEVF gene	p. E387G in NLRP3 gene
Diagnosis age (years)	6	7	12	5	4	6	7	5	4
Years with anti IL-1 treatment	13	15	9	7	11	10	5	10	7
Starting anti IL-1 therapy date	2008 May	2006 April	2009 Nov	2013 March	2007 Sept	2009 Sept	2016 May	2010 Jan	2014 Dec
Stop anti IL-1 therapy date (cause)	-	-	2018 Lost Follow-up	2020 october (remission)	2018 february (remission)	2019 september (remission)	-	2020 january (inefficacy)	-
Current Treatment	Anakinra100 mg/ 48 h	Anakinra 100 mg/ 24 h	Anakira 100 mg / 24 h	-	-	-	Anakinra 100 mg /48 h	Tocilizumab	Canakinumab150 mg/ 4 w
Adverse events during anti IL-1 therapy	Nephrolithiasis, Gastroenteritis, Flu, sinusitis	vertebral fracture	Intracraneal hypertension cataract		Varicella, pneumonia				Mild covid disease, lysteriosis

We identified a total of 9 patients, 8 who received anakinra and one canakinumab. 5 diagnosed with systemic juvenile idiopathic arthritis, 2 recurrent pericarditis, one familial Mediterranean fever with renal and skin vasculitis and one with cryopyrin-associated periodic syndromes. 7/9 were males. Patients are currently 11 to 23 years old; mean disease duration being 6.2 years (range 4-12 y) and a mean therapy duration of 9.7 years (range 5-15 y). No laboratory abnormalities were detected. No malignancy or macrophage activation syndrome was observed, no fatalities occurred. Although infections were uncommon, 4 infectious episodes required admission, importantly no opportunistic infections were diagnosed. Other side effects were a vertebral fracture, cataract and an intracranial hypertension, probably related to steroid therapy. 4 patients are currently receiving antiIL-1 therapy as mono therapy only, all 4 being in full clinical remission not needing of steroid therapy. To date only 3 patients stopped treatment due to inactive disease without occurrence of flares.

Conclusion: In our experience long-term use anti IL-1 therapy appears to be safe and effective in pediatric AID. Early treatment initiation can avoid prolonged corticoids treatment thereby reducing secondary adverse events.

Disclosure of Interest

None declared

P74 Through the development of a composite score to assess disease activity in recurrent fevers

R. Caorsi¹, V. Hentgen², I. Gueli³, C. Castellano³, C. Matucci Cerinic³, M. P. Teodoro³, A. Consolaro^1,4, A. Ravelli⁵, I. Kone-Paut⁶, M. Gattorno¹, N. Ruperto⁷

¹Clinica pediatrica e reumatologia, IRCCS Istituto Giannina Gaslini, Genova, Italy; ²National Referral Centre of Auto-Inflammatory Diseases and inflammatory amyloidosis, Versailles Hospital, Le Chesnay (Paris), France; ³Università degli studi di Genova, Genova, Italy; ⁴DiNOGMI, Università degli studi di Genova; ⁵IRCCS Istituto Giannina Gaslini, Genova, Italy; ⁶National Referral Centre of Auto-Inflammatory Diseases and inflammatory, University of Paris Sud, le Kremlin Biĉetre, France; ⁷Clinica pediatrica e reumatologia, PRINTO, IRCCS Istituto Giannina Gaslini, Genova, Italy

Correspondence: R. Caorsi

Introduction: Recurrent Fevers syndromes are autoinflammatory diseases characterized by febrile episodes associated with systemic symptoms and elevation of acute phase reactants; many of these diseases can present long-term complications, which can be avoided by an appropriate therapeutic approach. In light of this, monitoring of disease activity over time is mandatory.

Currently, the available tools to assess disease activity in recurrent fever syndrome take into account the clinical manifestations of the diseases and not the laboratory parameters, that nowadays are clearly important in the definition of disease activity.

Objectives: The purpose of the study is the creation of a composite score for the disease activity of autoinflammatory syndrome characterized by recurrent fever: FMF, TRAPS, MKD, PFAPA and systemic undefined recurrent fever (SURF).

Methods: the project is divided into two main phases: the first dedicated to the selection of variables of the score, the second intended for the validation of the latter.

In the first phase, a literature review was carried out to search for the parameters defining the disease activity. At the same time, through the Delphi method, a questionnaire was proposed to the main experts of Recurrent Fever, in which they were asked to list the variables used in the daily clinical practice to assess the disease activity of their patients. Finally, the same question was asked to the families of patients suffering from these conditions. In the second round of the Delphi Survey expert of the diseases and family representatives were ask to select and rank the 10 variables the think to be most effective for the purpose.

Results: by the review of the literature, 3005 articles were taken into consideration, of those 90 presented parameters defining the disease activity. 54 patients/families responded to the questionnaire. 114 experts were contacted, of those 95 reply to the first Delphi survey. From the three parallel searches, a list of different variables (clinical, laboratory, instrumental and other) was obtained; repetitions and redundancies were deleted and a final list of 147 parameters was obtained. The second round of the Delphi survey is actually ongoing.

Conclusion: the work lays the foundations for the creation of a composite score for the assessment of disease activity in patients with recurrent fever. We hope that this tool will be of help not only in the daily clinical practice, but also in future trials and experimental studies.

Disclosure of Interest

None declared

P75 Serum protein signatures differentiate paediatric autoimmune/inflammatory disorders

E. Carlsson¹, A. Midgley¹, S. Perkins^2,3, E. Caamano-Gutierrez^2,3, J. F. Gritzfeld¹, M. W. Beresford^1,4,5, C. M. Hedrich^1,4,5

¹Department of Women's and Children's Health, Institute of Life Course and Medical Sciences; ²Computation Biology Facility, Technology Directorate, Faculty of Health and Life Sciences; ³Department of Biochemistry and Systems Biology, Institute of Systems, Molecular and Integrative Biology, Faculty of Health and Life Sciences, University of Liverpool; ⁴Department of Rheumatology; ⁵National Institute for Health Research Alder Hey Clinical Research Facility, Alder Hey Children's NHS Foundation Trust Hospital, Liverpool, United Kingdom

Correspondence: E. Carlsson

Introduction: Because of their rarity, limited awareness among non-specialists, and significant overlaps in their clinical presentation, autoimmune/inflammatory conditions represent a diagnostic and therapeutic challenge in paediatrics. Juvenile idiopathic arthritis (JIA), with its 7 sub-forms, is the most common paediatric “rheumatic” disease. Juvenile-onset systemic lupus erythematosus (jSLE) is a severe autoimmune/inflammatory disease that can affect any organ system and shares clinical features with JIA.

Objectives: To overcome challenges around diagnostic approaches in the context of clinical overlap, we aimed to define disease sub-types through specific cytokine and chemokine profiles.

Methods: Serum samples from patients with JIA (n=77) and jSLE (n=48), as well as healthy controls (n=30), were collected. Samples were analysed using the Meso Scale Discovery (MSD) U-PLEX Biomarker Group 1 (hu) panel. The antibody-set contains biotinylated capture antibodies and corresponding detection antibodies for 71 cytokines and chemokines involved in multiple biological processes.

Results: Differential serum protein levels were investigated across disease groups and healthy controls. Significant differences were seen in several proteins, many of which have previously been implicated in the pathogenesis of JIA and/or jSLE. Partial least squares discriminant analysis (PLSDA) models of two components were trained to discriminate between samples from healthy controls, JIA or jSLE patients. This bioinformatic model allowed discrimination between the three groups with ~90% accuracy. Variable importance in projection (VIP) scores of the model detailing the contribution of each feature (i.e. protein) towards each of the components in the PLSDA model were used to predict potential biomarkers. The top VIP proteins included IL-23, MIP-1β, MCP-1 and M-CSF as most promising candidates.

To estimate the minimum number of proteins necessary to quantify in order to accurately discriminate between groups, PLSDA models with various different feature counts and selection features were produced. Reduction of proteins to approximately 27 could be done without significant impact on the accuracy of the model. Furthermore, serum IL-18, MIF, MIP-5 and YKL-40 vary between systemic JIA and other JIA subtypes, while serum IL-33 levels were elevated in jSLE patients with “very high” (SLEDAI ≥ 10) when compared to patients with ”high” (SLEDAI 5-9) or “moderate” (SLEDAI ≤ 4) disease activity.

Conclusion: Distinct cytokine/chemokine signatures, including a minimum of 27 serum proteins, associate with paediatric autoimmune/inflammatory diseases, and discern between JIA and jSLE. Some of these proteins may correlate with disease activity in jSLE (IL-33) or associate with sub-forms of JIA (IL-18, MIF, MIP-5, YKL-40). Individual proteins or their combination may therefore be used for future diagnostic approaches, assessment of disease activity or to inform treatment decisions.

Disclosure of Interest

None declared

P76 Aphtosis prevalence in autoinflammatory and multi-factorial rheumathological diseases in a population of children and adolescents

T. M. Caruso¹, M. Guida¹, S. Imparato¹, C. Alizzi², M. C. Maggio²

¹Università Degli Studi di Palermo; ²Azienda di Rilievo Nazionale ed Alta Specializzazione Ospedali "Civico Di Cristina Benfratelli", Palermo, Italy

Correspondence: T. M. Caruso

Introduction: Many patients have a recurrent aphtosis 2 to 4 times a year (single aphtosis); others may have recurrent lesions after the recovery of the previous (complex aphtosis). We also distinguish minor and major aphtosis: the latter are often in patients affected by diseases such as systemic lupus erythematosus (SLE), and Behçet disease. Recurrent aphtosis is in several diseases such as celiac disease, chronic inflammatory intestinal diseases, autoimmune disorders (Behçet disease), SLE, in recurrent fever as PFAPA and in monogenic autoinflammatory syndromes. A20 haploinsufficiency, due to the mutation of the TNFAIP3 gene, shows a clinical picture similar to Behçet disease’s.

The PFAPA and Behçet disease are both associated with the mutation of IL12A gene.

Therefore, recurrent aphtosis, PFAPA and Behçet disease are three clinical aspects of a single defect.

Objectives: The main objectives of our retrospective study are:

• to correlate the recurrent aphtosis with the most common rheumathological conditions and with defects in both innate and adaptive immunity in a paediatric population related to our Paediatric O.U.

• to detect genetic mutations related to defects of innate immunity associated with recurrent aphtosis.

Methods: We enlist 44 patients with recurrent aphtosis associated with fever or not, followed in our Pediatric Reumatology ward of Children Hospital “G. Di Cristina”, ARNAS Palermo, in the past two years.

The presence or absence of fever, complement alterations, serum amyloid increase, association with HLA, autoimmunity, ocular involvement, dermatological lesions and genetics for monogenic autoinflammatory diseases have been evaluated.

Results: Out of 44 patients enlisted, we have seen recurrent aphtosis in 28 females and 16 males, with an average age of 12 years, M:F ratio 1:1.75.

The prevalent symptom associated with aphtosis was fever (in 39/44 patients).

Skin lesions were in 15/44 patients: 1 erythema nodosum, 2 vasculitis, 3 evanescent rash, 5 urticaria/maculopapular exantema and 1 chronic urticaria.

Ocular disorders (in 6/44 patients): 2 anterior uveitis (with or without synechiae) and 4 conjunctivitis.

Laboratory abnormalities:

serum amyloid increased in 16/44 patients (very high in 5 patients and moderately high in 11). These patients had positive genetic diagnosis for FMF, cryopyrinopathy, TRAPS and A20 haploinsufficiency.

The diagnosis were: 18 FMF, 5 TRAPS, 6 CAPS, 5 SLE, 1 Behçet disease, 4 PFAPA, 1 A20 haploinsufficiency, 1 RAP, aphtosis and cyclic vomiting, 1 Behçet with isolated uveitis, 1 autoimmune thyroiditis and 1 acrocyanosis.

C3 changes were observed in three patients with SLE.

We found HLA B51 in 1 patient, HLAB57 in 1 patient and HLAB27 in 1 patient.

There were no serum amyloid increase far away from fever attacks or genetic for periodic fever syndromes in patients with PFAPA.

The genetic alterations in our patients with aphtosis were:

• -among patients with FMF, 5 heterozigosis mutation P369S and R408Q, and in 1 also the A744S and 1 R202Q mutations; 2 patients had heterozigosis E148Q. Another patient had heterozigosis mutations for R202Q, E148Q.

• -all patients with TRAPS had the R92Q mutation.

• -among patients with CAPS, 2 had a NLRP3 (VAL200MET) mutation and 1 a NLRP12mutation .

• -One patient had heterozigosis mutations for the TNFAIP3 gene with A20 haploinsufficiency.

• -among patients with PFAPA 1 had TLR9 mutation.

Conclusion: Behçet disease in Paediatric population appears incomplete. From literature evidence bringing PFAPA to Behçet disease, it could be assumed that PFAPA could be an incomplete start of Behçet; so the genetic analysis should be extended to the IL12A gene sequencing.

It is clear from our study that the recurring aphtosis is mostly associated with monogenic diseases.

Disclosure of Interest

None declared

P77 Monitoring of BK viral reactivation on JAK1/2 inhibition with baricitinib

K. Cetin Gedik¹, G. Materne¹, G. A. Montealegre Sanchez¹, A. M. Ortega-Villa², S. Alehashemi¹, A. A. de Jesus¹, R. Goldbach-Mansky¹

¹Translational Autoinflammatory Diseases Section; ²Biostatistics Research Branch, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, United States

Correspondence: K. Cetin Gedik

Introduction: Baricitinib has been used to treat pediatric patients with rare type I interferonopathies (1). Safety profile including BK viral (BKV) reactivation in urine and pharmacokinetic model have been reported (1,2).

Objectives: Given the association of BK nephropathy and BK viremia (3), we determined the prevalence of BKV reactivation [BKV load in urine/blood] in baricitinib-treated patients with rare type I interferonopathies and assessed the impact of BK viremia on renal function longitudinally.

Methods: Between October 2011 and August 2018, 25 patients [10 CANDLE (Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures), 7 SAVI (Stimulator of IFN genes–associated [STING-associated] vasculopathy with onset in infancy), 8 other interferonopathies] were enrolled in an institutional review board approved protocol and their parents gave informed consent. Safety was longitudinally assessed during study period (cut off October 2020). After detection in an index patient in June 2015, BKV load and renal function were monitored longitudinally with baseline assessments in 7 additionally enrolled patients. Summary statistics and linear mixed model were used to characterize the association of BKV load and renal function.

Results: The mean age at enrollment was 10.9 years [range 1.2-24.2]. On baricitinib, BKV loads (log₁₀ copy/mL) in blood and urine were monitored for a mean of 3.6±2.1 years [83.9 patient years] and 3.2±1.8 years [74.9 patient years] respectively. Of 23 patients monitored, 20 had BK viruria (3/20 pre-baricitinib) and 14 BK viremia (2/14 pre-baricitinib). All except one patient with BKV load in urine >7 log₁₀ copy/ml had BK viremia. Three patients with no BK viruria before treatment became positive at a mean age of 4.3 ± 1.5 years after 10.1 ± 13.2 months of baricitinib treatment. The time from achieving therapeutic doses of baricitinib to detection of BK viremia [n=12, 18.8±13.9 months] was twice as long as the time to detection of BK viruria. Of 14 patients with BK viremia, 4 had transient elevation >4 log₁₀ copy/ml. Index patient developed significant BK viremia (6 log₁₀ copy/ml) with azotemia and baricitinib was discontinued. One was on combination of baricitinib and a biologic agent at the time of transient elevation. Two were on baricitinib and BKV load in blood was associated with baricitinib dose and inversely associated with renal function. The baricitinib dose was adjusted to keep BK viremia <4 log₁₀ copy/ml and all except index patient had stable renal function over 83.9 patient years. No difference in BKV load between gender and disease groups was observed. Dermatomal herpes zoster reactivation was seen in 2 patients and resolved on antiviral treatment without holding baricitinib.

Conclusion: Overall, baricitinib was well tolerated. Prevalence of BK viruria in patients on therapeutic doses of baricitinib was 87% (20/23), and 60% (14/23) for BK viremia. Our data suggest that BKV load should be monitored in blood and urine. The presence of pre-baricitinib BK viremia/viruria suggests evaluation of BKV load in patients on other chronic immunosuppressive regimens. Dose adjustments to keep BK viremia <4 log₁₀ copy/ml preserved normal renal function over 83.9 patient years.

Acknowledgements

This baricitinib expanded access program was supported by Eli Lilly. We thank the physicians of the JAGA study network for ongoing collaboration. This research was supported by the Intramural Research Program of the NIH, Division of Intramural Research and NIAID.

References

1. Montealegre Sanchez GA, et al. J Clin Invest. 2018;128(7):3041-3052.

2. Kim H, et al. Clin Pharmacol Ther. 2018;104(2):364-373.

3. Hirsch H, et al. Transplantation. 2005;79(10):1277-1286

Trial registration identifying number: NCT01724580

Disclosure of Interest

K. Cetin Gedik: None declared, G. Materne: None declared, G. Montealegre Sanchez: None declared, A. Ortega-Villa: None declared, S. Alehashemi: None declared, A. de Jesus: None declared, R. Goldbach-Mansky Consultant for: Received study support under government CRADA from Lilly, IFM, Regeneron, SOBI and Novartis

P78 Much more than the fcas phenotype; NLRP12 related periodic syndrome, data from the uper-aid registry

F. Demir, T. Coşkuner, K. Ulu, S. Çağlayan, B. Sözeri

Department of Pediatric Rheumatology, Umraniye Training and Research Hospital, Istanbul, Turkey

Correspondence: T. Coşkuner

Introduction: NLRP12 associated periodic syndrome (NAPS12) is a rarely seen autoinflammatory disease also known as familial cold autoinflammatory syndrome 2 (FCAS2), caused by autosomal dominant inherited mutations in the NLRP12 gene. Common clinical features of recurrent NAPS12 attacks have been described as fever, fatigue and musculoskeletal symptoms that are typically activated by cold exposure. Skin manifestations can be seen during attacks in about half of the patients.

Objectives: We aimed to present our single-center NAPS12 patient experience and results.

Methods: The data of 320 patients from next generation sequencing genetic database of autoinflammatory diseases, Umraniye Training and Resarch Hospital, Department of Pediatric Rheumatology (UPER-AID registry), were included in the study. Patients with VUS-likely pathogenic or pathogenic mutations in the NLRP12 gene were collected from these patients. In at least three months of follow-up, patients with autoinflammatory disease compatible recurrent episodes (with high acute phase response) were defined as NAPS12, in which other etiological reasons (infectious, autoimmune, malignant diseases) were excluded. Demographic, clinical and laboratory data, treatments and responses of patients with a diagnosis of NAPS12 were presented.

Results: Eight patients were diagnosed with NAPS12. The F/M ratio was found as 5/3. The mean age of onset of the symptoms was 56.6 months (min-max: 7-120), and the mean age at diagnosis was 109 months (min-max: 10-122). The mean follow-up time was found 17.5 months (min-max: 3-42). The duration of the attack varied between 1-14 days. The attack findings frequency was found as follow respectively; fever (n: 7), urticarial rash (n: 6), myalgia (n: 4), arthralgia (n: 3), abdominal pain (n: 2), conjunctivitis (n: 2), diarrhea (n: 1) ranked as headache (n: 1) and pericarditis (n: 1). CRP and serum amyloid A levels were found to be elevated in all patients during the attack period. In the NGS gene panel, three patients had pathogenic, one had likely pathogenic, three had VUS, and one had novel variants. Partial response was obtained with colchicine in 3 patients and complete response in 2 patients. The other three patients that unresponsive to colchicine, were achieved to inactive disease with anti-IL 1 treatments.

Conclusion: While the clinical findings were compatible with FCAS in four patients, attacks accompained with varied clinical findings and lasting longer than 3 days were observed in the other four. It was observed that the attack duration of patients who were not compatible with the FCAS, could extend up to 14 days. NAPS12 should be considered in the differential diagnosis in patients with a clinical manifestations of autoinflammatory diseases who do not show typical findings for any monogenic SAID.

Trial registration identifying number: (Approval No/Date: B.10.1.TKH.4.34.H.GP.0.01/233/18.12.2019).

Patient Consent Received

Yes

Disclosure of Interest

None declared

P79 Cluster analysis of pediatric behçet’s disease: data from the Pediatric Rheumatology Academy (PERA)-research group

F. Demir¹, H. E. Sönmez², E. Bağlan³, Ö. Akgün⁴, T. Coşkuner⁵, G. Otar Yener⁶, K. Öztürk⁷, M. Çakan⁸, S. G. Karadağ⁹, S. Özdel³, N. Aktay Ayaz⁴, B. Sözeri¹ on behalf of The Pediatric Rheumatology Academy (PeRA)-Research Group

¹Department of Pediatric Rheumatology, University of Health Sciences, Ümraniye Research and Training Hospital, Istanbul; ²Pediatric Rheumatology, Kocaeli University, Faculty of Medicine, Kocaeli; ³Department of Pediatric Rheumatology, University of Health Sciences, Sami Ulus Maternity and Children's Diseases Training and Research Hospital, Ankara; ⁴Department of Pediatric Rheumatology, Istanbul University, Faculty of Medicine; ⁵Pediatric Rheumatology, Umraniye Training and research Hospital, Istanbul; ⁶Department of Pediatric Rheumatology, Şanlıurfa Training and Research Hospital, Sanliurfa; ⁷Department of Pediatric Rheumatology, Istanbul Medeniyet University, Göztepe Prof. Dr. Süleyman Yalçın City Hospital; ⁸Department of Pediatric Rheumatology, University of Health Sciences, Zeynep Kamil Maternity and Children's Diseases Training and Research Hospital, Istanbul; ⁹Department of Pediatric Rheumatology, Erzurum Regional Research and Training Hospital, Erzurum, Turkey

Correspondence: F. Demir

Introduction: Behçet‘s Disease (BD) is a systemic vasculitis affecting many organ systems with the involvement of all sized arteries and veins. Although recurrent oral aphthous and cutaneous lesions are the predominant features during the course of the disease, five different forms of disease have been defined previously: 1) mucocutaneous-only cluster, 2) papulopustular lesion–arthritis–enthesopathy cluster, 3) ocular cluster, 4) gastrointestinal cluster, 5) vascular cluster.

Objectives: To determine the main characteristics of pediatric BD patients and also analyze the clustering phenotype of pediatric BD in a large multicentric cohort.

Methods: Eight pediatric rheumatology centers from Turkey have participated in this study. Demographic data, clinical manifestations, laboratory features, radiological findings, treatment schedules, and disease outcomes were achieved from patient charts retrospectively. A cluster analysis was performed according to five independent clinical forms.

Results: A total of 241 patients with BD were enrolled in the study. Among them, 120 (49.7%) were male and 121 (50.3%) were female. Eighty-three (34.4%) patients had a family history of BD. The median age of diagnosis was 144 (36-216) months. The median time between onset of symptoms and diagnosis was 1 (0-196) months. Oral aphthous (83.8%) was both the most common initial symptom and the most frequent symptom (97.9%) during the disease course followed by genital ulcers (66.8%) and pseudofollicutis (33.2%). Uveitis was observed in 34 (14.1%) patients. Thirty-three (13.7%) patients had neurological involvement. Pathergy test was positive in 64 (26.6%) patients and HLA-B51 was positive in 108 (44.8%) patients. According to cluster analysis; 133 (55.1%) patients belonged to the mucocutaneous-only cluster while 37 (15.4%) patients fitted to papulopustular lesion–arthritis–enthesopathy cluster, 33 (13.7%) were in ocular cluster, 19 (7.9%) were in gastrointestinal cluster and 19 (7.9%) belonged to the vascular cluster. Ocular and vascular clusters were more common in boys (p<0.001) while girls usually presented with mucocutaneous-only cluster. The age of diagnosis were similar among the clusters. The activity scores of disease at the diagnosis and at the last control were higher in ocular and gastrointestinal clusters (p=0.001).

Conclusion: To our best of knowledge, this is the first cluster analysis in pediatric BD patients. Our analysis showed that mucocutaneous-only cluster was the common form while phenotype of the disease differed according to gender. Furthermore, ocular and gastrointestinal involvements affected disease activity not only at the diagnosis but also during the course of the disease.

Trial registration identifying number: .

Patient Consent Received

Yes

Disclosure of Interest

None declared

P80 Evaluation of childhood behçet's disease cases: a single center experience

S. Doğantan, S. N. Taşkın, A. P. Kısaarslan, H. M. Poyrazoğlu

Division of Pediatric Rheumatology, Kayseri, Erciyes University Faculty of Medicine, Kayseri, Turkey

Correspondence: S. N. Taşkın

Introduction: Behçet's disease is a multisystem vasculitis that can affect all sizes of arteries and veins. Diagnosis can be made mostly in adult ages. Evaluation of childhood findings is important for early diagnosis. Serious complications can be seen years after diagnosis in the disease, which has periods of exacerbation and recovery. Although the mortality of Behçet's disease is low, intestinal perforation and central nervous system involvement are risky in terms of morbidity and mortality. Long-term effects are related to organ involvement. Young age, male gender, early onset disease are poor prognostic factors (1,2).

Objectives: We aimed to evaluate the demographic, clinical and laboratory data of patients who were followed up with a diagnosis of Behçet's disease in our clinic.

Methods: In our study, data were collected by retrospectively examining the files of patients who were followed up with the diagnosis of Behçet's disease between 01.01.2010 and 01.01.2021 in Erciyes University Children's Hospital Pediatric Rheumatology Department. While making the diagnosis, the diagnostic criteria of the International Behçet's Disease Working Group and the Consensus Classification of pediatric Behçet's Disease-2016 were used. Patients with 2 other criteria (genital ulcers, skin lesions, uveitis, pathergy) in addition to recurrent oral ulcers according to the diagnostic criteria of the International Behçet's Disease Study Group were included in the study (3). According to the Consensus Classification of Pediatric Behçet's Disease-2016 diagnostic criteria, three of six items are required (recurrent oral aphthae, genital ulcer, skin involvement, eye involvement, neurological involvement, vascular involvement) (4)

Results: We had a total of 42 cases in the study group. 22 (52.4%) of the patients were female and 20 (47.6%) were male. The average age at the time of first application was 12.56 ± 3.34. There was first degree consanguinity among the parents of 9.5% (n = 4) of the patients. 35.7% of the patients (n = 15) had a family history of BD. Recurrent oral aphthae were present in 85.7% (n = 36) of the patients.

Genital aphthae in 28.6% (n = 12) of patients, uveitis in 26.1% (n = 11), skin lesions in 21.4% (n = 9), 14.2% (n = 6) vascular involvement, 4.8% (n = 2) central nervous system vascular involvement, 7.14% (n = 3) had GIS findings, and one patient (2.4%) had epididymoorchitis. 45.4% (n = 5) of uveitis cases had anterior uveitis, 36.3% (n = 4) posterior uveitis, 9% (n = 4) middle uveitis and 9% (n = 1) ) panuveitti. Of the cases with skin lesions, 11.1% (n = 1) erythema nodosum, 22.2% (n = 2) pseudofolliculitis, 33.3% (n = 3) acneiform lesions and 33.3% ( n = 3) livedo reticularis was present. Pathergy test was positive in 11.9% of the patients (n = 5). One patient had GIS bleeding (rectal bleeding), one patient had chronic active inflammation in the colon, and one patient had an ulcer in the terminal ileum. HLA B51 was found to be positive in 57.14% (n = 24) of the patients. Systemic steroid in 28.6% (n = 12) of patients, colchicine in 95.2% (n = 40), azathioprine in 19% (n = 8), and methotrexate in 33.3% (n = 14), 11.9% (n = 5) sulfasalacin, 4.8% (n = 2) infliximab, 4.8% (n = 2) adalimumab were given. 26.1% (n = 11) of the patients had additional disease. Two patients had familial Mediterranean fever, 1 patient had phenylketonuria, 2 patients had atrial septal defect, 1 patient had epilepsy, 1 patient had essential tremor, 1 patient had ulcerative colitis, 1 patient had Sydenham's Chorea.

Conclusion: The clinical features of childhood Behçet's patients vary widely. The clinical findings becoming evident over the years indicates the importance of follow-up.

Patient Consent Received

Yes

Disclosure of Interest

None declared

P81 Early onset of mevalonate kinase deficiency syndrome: 2 cases in the one center

M. Dubko, A. Zinchenko, E. Goltsman, I. Solodkova

Saint Petersburg Pediatric Medical University, Saint-Petersburg, Russian Federation

Correspondence: M. Dubko

Introduction: Mevalonate kinase deficiency (MKD) is an extremely rare autoinflammatory disorder with an autosomal recessive inheritance mechanism.

According to the EUROFEVER register, the age of onset of MKD is on average 6 months, and the delay in establishing the diagnosis is 6.8 years. Patients are often treated as cases with infectious diseases, primary immunodeficiency conditions, or other autoinflammatory disorders

In the clinical picture, the most important is the periodicity of fevers and associated rashes, cervical lymphadenopathy, hepatosplenomegaly and increased markers of inflammation (CRP, ESR). Early manifestation is usually associated with a severe course and poor prognosis

Objectives: Show the efficiency of therapy with the IL-1 blocker canakinumab at the example of two cases of early onset of mevalonate kinase deficiency syndrome.

Methods: Observation and description of clinical picture.

Therapy with the IL-1 blocker canakinumab.

Results: In the center, we observed 2 patients with genetically confirmed mevalonate kinase deficiency syndrome.

Both babies (girl and boy) were born prematurely: 36 and 35 weeks. The girl matched the gestational age in terms of weight and height parameters, and the boy had signs of intrauterine growth retardation (P 10). The condition of the children at birth was assessed as severe. The leading symptoms were: thrombocytopenia (31*10)^9 and (98*10)^9, anemia (hemoglobin 68 g / l and 83 g / l), significant hepatosplenomegaly, stable over the entire observation period. Both babies were treated as patients with intrauterine infection and received repeated courses of combined antibiotic therapy, IVIG, transfusion of thrombus suspension and erythrocyte mass. Both babies had no fevers until age of 4 months. Equivalent to fevers there were periodic increases in CRP and ESR. A typical clinical picture appeared only by the age of 4 months. Genetic analysis revealed in the girl the pathogenic variant c.118C> T (p.R40W) and c.206_207del (p.S69fs) in the MVK gene in a compound heterozygous state. The boy has c.939_940del (p.L315Gfs * 49) and c.1006G> A (p.G336S). Both children are successfully receiving canakinumab therapy.

Attribute	Patient 1	Patient 2
Weight at birth	2915	1910
Body length at birth	48	43
Platelets	(31*10)^9	(98*10)^9
Hb	68 g / l	83 g / l
Organomegaly	Hepato-splenomegaly	Hepato-splenomegaly since 2 month
Fever start	3 month	4 month
Course of disease	Recurrent at short intervals	Continuously relapsing
Canakinumab dose	6 mg/kg 1 per month	4 mg/kg 1 per month
Result	No exacerbations	No exacerbations

Conclusion: We described 2 cases of mevalonate kinase deficiency syndrome with onset in the neonatal period and successful therapy with the IL-1 blocker canakinumab.

Patient Consent Received

Yes

Disclosure of Interest

None declared

P82 An interesting relationship between inattention/hyperactivity and familial mediterranean fever in children and adolescents

G. Durcan¹, K. Barut², F. Haslak², M. Yildiz², H. Doktur¹, M. T. Kadak³, Z. Koyuncu³, A. Adrovic², S. Sahin², B. Dogangun³, O. Kasapcopur²

¹Department of Child and Adolescent Psychiatry, University of Health Sciences, Bakirkoy Research and Training Hospital for Psychiatry, Neurology and Neurosurgery; ²Department of Pediatric Rheumatology; ³Department of Child and Adolescent Psychiatry, Medical Faculty of Cerrahpasa, Istanbul University-Cerrahpasa, Istanbul, Turkey

Correspondence: M. Yildiz

Introduction: Although familial Mediterranean fever (FMF) progresses with attacks, its subclinical inflammation may continue in attack-free periods. To date, increased inflammatory cytokines have been reported in many psychiatric diseases.

Objectives: In this study, we aimed to evaluate the psychological symptoms, especially inattention/hyperactivity, in children and adolescents with FMF.

Methods: The study included 272 children and adolescents with FMF and 250 healthy peers as a control group. The Strengths and Difficulties Questionnaire-Parent Form was used to assess emotion, behavior and peer related problems, as well as inattention/hyperactivity and prosocial behavior in participants.

Results: The mean age of the patients was 12.35, ± 2.65 years, and the mean age of the control group was 12.08, ± 2.67. In total, 51% (n = 139) of patients with FMF and 56% (n = 140) of the control group were females. The age and gender of the children were similar across groups (p=0.265 for age; p=0.262 for gender). The emotional and behavioral problem subscale scores of patients with FMF were significantly higher than those of healthy controls. The inattention/hyperactivity scores of patients with FMF were also significantly higher than those of the control group (3.99 ± 2.34 vs 2.93± 2.26, p <0.001). The psychological scale comparisons of the patient and control groups are given in Table 1 in detail. When patients with FMF were compared according to the presence of attacks in the last year, presence of exertional leg pain as well as their mutation types, no differences were found in terms of inattention/hyperactivity scores. However, patients whose FMF symptoms were onset before the age of 6 had significantly higher inattention/hyperactivity subscale scores (4.21 ± 2.42) when compared to patients whose symptoms started after 6 years of age (3.42 ± 2.02; p =0.016).

Conclusion: This research demonstrated that FMF patients had increased inattention/hyperactivity, similar across all ages and genders, which was unaffected by FMF-related variables, except for age of onset. The FMF-inattention/hyperactivity relationship may be due to a common etiology in which proinflammatory cytokines play a role.

Patient Consent Received

Yes

Disclosure of Interest

None declared

Table 1 (abstract P82). Comparison of psychological scale scores in patient and control groups

P83 Refractory panuveitis with splenomegaly in a 14-year-old adolescent

P. Dusser¹, C. BOROCCO¹, C. Titah², G. Sarrabay³, I. Koné-Paut¹

¹Rheumatology-Pediatrics Department and CeRéMAIA (Reference Centre for Autoinflammatory Diseases and Inflammatory Amyloidosis), APHP - Bicêtre Hospital, Le Kremlin Bicêtre; ²Ophthalmology Department, Rothschild Ophthalmological Foundation, Paris; ³Laboratory of rare genetic and autoinflammatory diseases and CeRéMAIA (Reference Centre for Autoinflammatory Diseases and Inflammatory Amyloidoses), University of Montpellier, Montpellier, France

Correspondence: P. Dusser

Introduction: ROSAH syndrome is characterised by the association of retinal dystrophy, optic nerve oedema, splenomegaly, anhidrosis and migraines. It has recently been shown that this syndrome is monogenic, caused by dominant mutations in the ALPK1 gene. Up to date, 18 patients of ROSAH syndrome have been reported.

Objectives: Clinical and biological description of an atypical panuveitis.

Methods: Herein we present the case of a 14-year-old male who presented to us with an atypical bilateral posterior uveitis associated with splenomegaly and migraines.

Results: N. is a Caucasian teenager, monophthalmic, with bilateral posterior uveitis complicated by right papilledema and left anterior retinal detachment, cortico-dependent, evolving since the age of 5 years old. At the age of 8 years old, he presented with a febrile episode with splenomegaly and pancytopenia, in relation to a PVB19 infection, which resolved spontaneously. On the paternal side, there was evidence of splenectomy in the father and grandfather during an EBV infection. The grandfather also had uveitis and died at 59 years old of kidney cancer in the context of familial polycystic hepatorenal disease. Biologically, no systemic inflammation was found except for a significant synthesis of IL1β in our adolescent. Several treatment lines have been tried (anti-IL1, anti-TNF and anti-IL6) for N. without efficacy. In this context, a trio exome was performed showing a mutation in the ɑkinase gene, ALPK1 (NM_025144.4 :c.710C>T, [p.Thr237Met]) in favour of ROSAH syndrome for N. and his father.

Conclusion: ROSAH syndrome is therefore a differential diagnosis to be considered in cases of posterior uveitis with collapsed visual acuity resistant to treatment and should be investigated for a family history of splenomegaly and/or uveitis.

Patient Consent Received

Yes

Disclosure of Interest

None declared

P84 Clinical features and colchicine response in patients with undifferentiated systemic autoinflammatory disease carrying E148Q VS. other MEFV mutations

B. Egeli¹, H. Wobma², M. Marques³, J. Hausmann⁴, F. Dedeoglu¹

¹Immunology; ²IImmunology, Boston Children's Hospital, Boston; ³UPMC Children's Hospital, Pittsburgh; ⁴Boston Children's Hospital, Boston, United States

Correspondence: B. Egeli

Introduction: Undifferentiated systemic autoinflammatory diseases (uSAID) are diverse syndromes characterized by acute flares of fever and inflammation, which do not meet clinical criteria for known disorders like Familial Mediterranean Fever (FMF). As part of the uSAID workup, many patients undergo genetic testing, sometimes revealing variants of uncertain significance in genes associated with autoinflammation. E148Q is a common polymorphism in exon 2 of the MEFV gene, which is not thought to be a disease-causing variant for FMF. The contribution of E148Q mutations in patients with uSAID is poorly understood, and it is unknown how it may respond to empiric treatment with colchicine, which is first line for FMF.

Objectives: To compare the clinical characteristics and colchicine response of children with uSAID identified to have E148Q vs non-E148Q mutations in the MEFV gene.

Methods: Children with uSAID ≤18 years old at initial evaluation seen at a single-center during 2000-2019 were included if they received ≥3 months of colchicine therapy and carried at least one MEFV mutation but did not meet clinical criteria for FMF (n = 25). Data on demographics, clinical features, laboratory/genetic studies, and treatment responses were collected.

Results: Results: In our cohort of 25 children with uSAID and MEFV mutations, 8 (32%) were heterozygous for E148Q mutations. Half of these patients also carried another non- exon 10 MEFV mutation (2x 369S, 1x L110P, 1x I591T). Distribution of the remaining variants on MEFV gene is shown in Figure 1. Clinical features of children with E148Q vs. other MEFV mutations are shown in Table 1. Asian ancestry was seen in 3/8 (37%) children with E148Q mutations and in no child with other MEFV mutations. Children with E148Q mutations had longer length of febrile episodes (8.36.5 vs. 3.4 days; p=0.009) and were less likely to have a full response to colchicine (25% vs 70%; p = 0.03).

Conclusion: In our cohort of children with uSAID and MEFV mutations, E148Q was associated with longer duration of fever flares and a reduced colchicine response. Larger studies will be helpful in elucidating the unique role of these mutations in autoinflammation.

Patient Consent Received: No

Disclosure of Interest

B. Egeli: None declared, H. Wobma: None declared, M. Marques: None declared, J. Hausmann Consultant for: Novartis, Pfizer, Biogen, Rheumatology Research Foundation, CARRA, F. Dedeoglu Consultant for: Novartis

Table 1 (abstract P84). Characteristics of uSAID patients with heterozygous MEFV mutations

Figure 1 - Location of non-E148Q MEFV mutations in uSAID patients (n=17)

P85 Efficacy, safety and tolerance of anakinra in paediatric rheumatology and periodic fever clinics: real life experience

S. Fingerhutova¹, E. Jancova², P. Dolezalova¹

¹Centre for Paediatric Rheumatology and Autoinflammatory Diseases, Department of Paediatrics and Inherited Metabolic Disorders; ²Department of Nephrology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic

Correspondence: S. Fingerhutova

Introduction: Interleukin 1 (IL-1) induced proinflammatory signals were discovered as a causative aetiology in a spectrum of diseases. Efficacy and safety of the recombinant IL-1 receptor antagonist anakinra across autoinflammatory and autoimmune diseases has been demonstrated in many studies. Despite the recommended dosage in patients above 8 months and weighing more than 10 kg, use of higher doses or earlier onset of therapy have been occasionally reported.

Objectives: To an institutional review of data on efficacy, safety and tolerance of anakinra in patients with autoinflammatory diseases (AID).

Methods: A single-centre retrospective review of electronic records of patients treated with anakinra between August 2007 and May 2021.

Results: A total of 47 patients (30 children, 17 adults) were identified. The median follow-up was 35 months (range 1-165 months). Patients have been treated for diagnosis of systemic juvenile idiopathic arthritis (sJIA) (n = 18; 38%), cryopyrinopathy (CAPS) (n = 10; 21%), mevalonate-kinase deficiency (MKD) (n = 7; 15%), undifferentiated AID (uAID) (n = 6; 13%), PIMS-TS (n = 3; 6%), NLRC4-GOF (n = 1, 2%), PAPA syndrome (n = 1; 2%) and polyarticular JIA (n = 1, 2%). The most frequent indication for starting anakinra was macrophage activation syndrome (MAS) (n = 20; 42,5%) which occurred in patients with sJIA (n=14, 70%), uAID (n=3, 15%), PIMS (n=1, 5%), NLRC4-GOF (n=1, 5%) or polyarticular JIA (n=1, 5%). Fourteen patients with sJIA (78%) received anakinra due to macrophage activation syndrome. MAS was the first manifestation of sJIA in 6 patients (33%).

Recommended dosing of anakinra (1-4 mg/kg/day) was exceeded in 44,6% of patients (n=21) with the following dose range: 4-6 mg/kg (n = 8; 38%), 6-9,9mg/kg (n = 4; 19%), ≥10 mg/kg (n = 9; 43%). Paediatric cohort received anakinra in very wide dosing range of 1,4 -26,1 mg/kg (average 5,59 mg/kg, median 4,15 mg/kg). The highest dose (10-26mg/kg) was required by patients with uAID (n=1, 8 days of age), sJIA/MAS (n=2, 3 and 5 years of age), CINCA (n=1, 4 years of age) and NLRC4-GOF (n=1, 4 weeks of age). The median dose of anakinra in adult patients was 1,6 mg/kg (range 0,9-7,7mg/kg). In severely sick patients the daily dose was divided into 2-4 intravenous applications, one patient received continuous anakinra i.v. infusion. Rapid therapeutic effect (within 24-48 hours from starting anakinra) was observed in all patients.

The most frequent recorded adverse effects were already well-known injection-site reaction in 25,5% (n = 12) of patients which disappeared within one month in all of them. Persistent eosinophilia (highest values 3,6 and 2,3x10*9 cells) was documented in 2 sJIA patients. Mild asymptomatic neutropenia (ANC min 0,8 x10*9/L) and transient liver transaminase elevation (up to 3-times ULN) both occurred in 4,2% (n = 2) of patients each.

Conclusion: Use of anakinra in a wide dosing range was reported. Our observation illustrates the need as well as safety of higher anakinra dosing in younger age groups including 2 newborns. No serious adverse effects that would require discontinuation or termination of anakinra were observed at all dosing regimens.

ANC = absolute neutrophil count

This work was supported by the Ministry of Health of the Czech Republic (NU21-05-00522)

Disclosure of Interest

None declared

P86 Myositis as a deciding but late symptom of DADA2 syndrome – report of two cases

K. Palm-Beden¹, F. Gohar¹, D. Windschall^1,2

¹Clinic for Paediatric and Adolescent Rheumatology, St. Josef-Stift Hospital, Northwest German Center for Rheumatology, Sendenhorst; ²University Halle-Wittenberg, Halle, Germany

Correspondence: F. Gohar

Introduction: The recognition of adenosine deaminase-2-(ADA2)-deficiency (DADA2), a monogenic vasculitis syndrome, is important due to the significant morbidity associated with the increased risk of stroke and vasculopathy.

Objectives: DADA2 has a highly variable clinical presentation including signs of vasculopathy (e.g. livedo reticularis, vasculitis, stroke), systemic inflammation and musculoskeletal findings e.g. arthritis and myositis, which is not widely recognised to be a typical finding associated with the diagnosis.

Methods: We report the diagnostic work-up and management of two patients with DADA2, where myositis was a key symptom to reaching the diagnosis.

Results: Patient 1 and 2 (both female, Turkish-German ethnicity), presented aged 5 and 10 years respectively, with muscle and joint pain, a history of fever attacks and livedo reticularis beginning in infancy. Inflammatory markers including serum amyloid A, were persistently elevated in both patients. Diagnostic tests ruled out HIDS, Blau Syndrom (Patient 1), as well as Bechet’s Disease (negative HLA-B51 and Pathergie test), CAPS, TRAPS and FMF. However, Patient 2 was positive for the non-pathogenic FMF heterozygous mutation A744S. Initial therapy for both patients was colchicine with varying compliance and effectiveness. In patient 1, therapy was extended to include azathioprine and due to minimal effect, oral cortisone. Unfortunately, both patients attended sporadically and were non-compliant with therapy. In this time, Patient 1 was found to be a distant relative of Patient 2. Ten years after initial presentation, Patient 1 complained of muscle pains in the thighs. CK was normal, PM-Scl antibodies were positive and whole-body MRI showed muscle oedema and inflammation particularly affecting the vastus medialis and gracilis muscles. In combination with a history of trochlear nerve paralysis, the diagnosis of DADA2 was suspected. Once confirmed with genetic testing, treatment was initiated with the TNF-Inhibitor adalimumab. Fever and inflammation episodes did not reoccur, and the muscle pain resolved. Patient 2 was invited for re-evaluation after being lost to follow-up. However, before attending, she suffered a lacunar thalamus infarct. Genetic testing and etanercept were initiated after acute neurological management. The patient had first developed muscle pains in the upper and lower legs 2-3 weeks after the infarct, without elevated CK. Whole-body MRI confirmed myositis of the symptomatic muscles.

Conclusion: In patients with recurrent autoinflammation and myositis and an otherwise unclear diagnosis, DADA2 should be considered as a possible cause. Whole-body MRI can help confirm myositis. A thorough family history and genetic testing are vital to reach the diagnosis.

Patient Consent Received

Yes

Disclosure of Interest

None declared

P87 Influence of canakinumab dosing on efficacy and safety of long-term treatment in patients with familial mediterranean fever − interim analysis of the reliance registry

T. Kallinich¹, J. Henes², N. Blank³, F. Dressler⁴, I. Foeldvari⁵, M. Hufnagel⁶, G. Horneff⁷, B. Kortus-Goetze⁸, F. Weller-Heinemann⁹, F. Meier¹⁰, J. Weber-Arden¹¹, J. B. Kuemmerle-Deschner²

¹Charite University Medicine, Berlin; ²University Hospital, Tuebingen; ³University Hospital, Heidelberg; ⁴Hannover Medical School, Hannover; ⁵Centre for Pediatric and Adolescence Rheumatology, Hamburg; ⁶University Hospital, Freiburg; ⁷Asklepios Clinic, Sankt Augustin; ⁸University Hospital, Marburg; ⁹Prof. Hess Kinderklinik, Bremen; ¹⁰University Hospital, Frankfurt; ¹¹Novartis, Nuernberg, Germany

Correspondence: T. Kallinich

Introduction: Familial Mediterranean Fever (FMF) is characterized by severe systemic and organ inflammation. Successful treatment with rapid remission of symptoms and normalization of laboratory parameters was achieved in most patients with the interleukin-1β inhibitor canakinumab (CAN) in clinical trials.

Objectives: The aim of the present analysis was the evaluation of long-term efficacy and safety of CAN in pediatric (age ≥2 years) and adult patients with FMF with respect to weight-dependent CAN dosing in routine clinical practice.

Methods: RELIANCE is a prospective, non-interventional, observational study based in Germany. Patients with clinically confirmed diagnoses of autoinflammatory periodic fever syndromes routinely receiving CAN are enrolled. Efficacy- and safety-parameters, CAN dosing as well as weight were recorded at baseline and assessed at 6-monthly intervals within the 3-year observation period of the study.

Results: The interim analysis of the RELIANCE Registry comprises data of 54 FMF patients enrolled by December 2020. Of these, the % of patients reported to receive standard dose CAN (SD CAN; 150 mg or 2mg/kg respectively per 4 weeks) halved from 77% at baseline to 36% at month 18 in favor of less than SD CAN (<87.5% of SD) and higher than SD CAN (>112.5% of SD).

Patients´ and physicians´ rating of disease activity was higher in patients receiving SD CAN and higher (table 1), even though CRP was equally well controlled in all three dosing groups. A total of 11 serious adverse events was reported, of which 1 case of tonsillectomy was classified as drug-related.

The interim analysis of the RELIANCE Registry comprises data of 54 FMF patients enrolled by December 2020. Of these, the number of patients reported to receive less than standard CAN dose* (SD CAN; <87.5% of SD) / SD CAN / higher than SD CAN (>112.5% of SD) were 2/36/9 at baseline, 10/13/9 at 6 months, 11/7/8 at 12 months and 5/5/4 at 18 months.

Even though CRP was equally well controlled in all three dosing groups, disease activity was rated higher by patients and physicians in patients receiving SD CAN and higher (table 1). A total of 11 serious adverse events was reported, of which 1 case of tonsillectomy was classified as drug-related.

Conclusion: The present interim data from the RELIANCE study confirm efficacy and safety of long-term CAN treatment in clinical routine. CRP levels were well controlled in all dosing groups. Remaining disease activity was mainly observed in patients under SD CAN and higher than SD CAN.

Disclosure of Interest

T. Kallinich: None declared, J. Henes Consultant for: Novartis, AbbVie, Sobi, Roche, Janssen, Boehringer-Ingelheim;, N. Blank Consultant for: Novartis, Sobi, Lilly, Pfizer, Abbvie, BMS, MSD, Actelion, UCB, Boehringer-Ingelheim, Roche, F. Dressler Consultant for: Abbvie, Mylan, Novartis, Pfizer, I. Foeldvari Consultant for: Novartis, M. Hufnagel: None declared, G. Horneff Speaker Bureau of: AbbVie, Bayer, Chugai, Merck Sharp & Dohme, Novartis, Pfizer, Roche, B. Kortus-Goetze Consultant for: Novartis, F. Weller-Heinemann: None declared, F. Meier: None declared, J. Weber-Arden Employee of: Novartis, J. B. Kuemmerle-Deschner Consultant for: Novartis, AbbVie, Sobi

Table 1 (abstract P87). Stratification of efficacy parameters by CAN dose category and weight (N=54)^#

P88 Two siblings with Majeed syndrome and neutropenia

M. Kasap Cuceoglu¹, E. D. Batu¹, A. E. Yildiz², U. Kaya Akca¹, E. Atalay¹, S. Sener¹, Z. Balik¹, O. Basaran¹, Y. Bilginer¹, S. Ozen¹

¹Pediatric Rheumatology; ²Department of Radiology, Hacettepe University, Ankara, Turkey

Correspondence: M. Kasap Cuceoglu

Introduction: Majeed syndrome (MS) is a rare monogenic autoinflammatory disease characterized with early-onset chronic nonbacterial osteitis and hematological features; especially dyserythropoietic microcytic anemia.

Objectives: Here, we report the first sibling cases of Majeed syndrome from Turkey.

Methods: Case Report

Results: Patient 1

A seven-year-old boy presented to the local pediatrician with recurrent joint and bone pain. Bone pain started at the age of 18 months. There was no joint swelling, recurrent abdominal, chest pain or fever in his past medical history, and there were no signs of uveitis. His parents were first degree cousins. Physical examination was normal. Acute phase reactants (APRs) were high at admission (erythrocyte sedimentation rate (ESR) 50 mm, normal range 0-20, and C-reactive protein (CRP) 3 mg/dl, normal range 0-0.5). Neutropenia (1100/mm³) was detected with normal white blood cell (WBC) count. Antinuclear antibody (ANA) and extractable nuclear antigen antibodies (ENA) were negative. The local pediatrician initially started him on colchicine treatment, suspecting familial Mediterranean fever. However, MEFV gene variant analysis did not reveal any mutations. After two years of colchicine treatment, his family discontinued the drug since there was no response. The patient was then referred to our center. A periodic fever gene panel analysis (including LPIN2, MEFV, MVK, NLRP3, PSTPIP1 and TNFRSF1A genes) was performed with next generation sequencing and homozygous mutation was detected in exon 4 of the LPIN2 gene; c.589C>T (p. Arg197*). Both his parents were carriers for this variant. The whole body musculoskeletal system magnetic resonance imaging (MRI) was normal. After the diagnosis of Majeed syndrome, recombinant IL-1RA (anakinra) treatment was initiated at a dose of 2 mg/kg/day via the subcutaneous route. The patient has remained free of symptoms on anakinra treatment. However, neutropenia did not improve as of yet.

Patient 2

The sister of patient 1, presented to our department with recurrent joint and bone pain, fatigue, and anemia in the last six months. Physical examination was unremarkable. APRs were elevated at admission (ESR 120 mm and CRP 14 mg/dl). Severe neutropenia (600/mm³) with normal WBC count, microcytic anemia (Hb 8.6 mg/dl), and thrombocytosis (700x10³/mm³) were detected. She was consulted to the pediatric hematology department. Her bone marrow assessment revealed a normocellular bone marrow with megaloblastic changes. The whole body musculoskeletal system MRI demonstrated osteitis at the distal femur, proximal, and distal tibia, bilaterally. The periodic fever gene panel analysis revealed homozygote mutations in exon 4 of the LPIN2 gene; c.589C>T (p. Arg197*), like her brother. After the diagnosis of Majeed syndrome, anakinra was initiated at a dose of 2 mg/kg/day at the same time with her elder brother. Patient 2 has also remained free of symptoms with normal APRs on anakinra treatment. However, she still has neutropenia (900/mm³) four months after the diagnosis.

Conclusion: Majeed syndrome should be considered in children with joint and bone pain, anemia, and neutropenia especially in the presence of parental consanguinity or positive family history. Anti-IL-1 drugs seems to be effective in treating of Majeed syndrome-related inflammation while neutropenia seems to be unresponsive to this treatment.

References

1. El-shanti H, Ferguson P. Majeed Syndrome – Retired Chapter, For Genetic counseling Clinical Diagnosis. Published online 2021:1-11.

2. Ferguson PJ, Hedrich CM. 40 - Autoinflammatory Bone Diseases. Eighth Edi. Elsevier Inc.; 2021. doi:10.1016/B978-0-323-63652-0.00040-9

Patient Consent Received

Yes

Disclosure of Interest

None declared

P89 Amyloid arthropathy in a young girl with familial mediterranean fever

B. Kasap-Demir^1,2, F. C. Sarıoğlu³, A. Kaya⁴

¹Department of Pediatric Nephrology and Rheumatology; ²Izmir Katip Çelebi University; ³Radiology; ⁴Orthopedisc and Traumatology, Health Sciences University Tepecik Training and Research Hospital, Izmir, Turkey

Correspondence: B. Kasap-Demir

Introduction: Aymloid arthropathy is characterized by infiltrative deposition of amyloid into articular and periarticular spaces. Although it has been more commonly reported in cases with rheumatoid arthritis, multiple myeloma and in those on chronic hemodialysis programme, it has rarely been reported in cases with familial mediterranean fever (FMF).

Objectives: Here we report a case with FMF complicated with aymloid arthropathy.

Methods: An 18-year-old girl was admitted with bilateral knee swelling. Her past medical history was remarkable for recurrent fever, abdominal pain and joint pain beginning at the age of 3 and was diagnosed with FMF at the age of 6. Genetic analysis revealed M694V homozygous mutation. Renal biopsy performed at the age of 10 upon proteinuria revealed amyloidosis. She had attacks every two weeks which were resistant to colchicine, thus canacinumab was initiated. Despite canacinumab, chronic kidney disease developed and she was put on peritoneal dialysis programme at the age of 13 and two years later she received a living unrelated kidney transplant.

At admission, she had bilateral swollen knees without warmth or hyperemia. All other physical examination findings were normal.

Results: Laboratory parameters were as follows: WBC 10,500/mm³, Hb 9.7 g/dL, MCV 66.3 fL, RBC 4.68 x 10⁶, plt 412,000/mm³, urea 25 mg/dL, serum creatinine 1.06 mg/dL, CRP 0.3 mg/L, ESH 14 mm/h, serum amyloid A: 0.75 mg/L (N<6). Knee MRI revealed widespread irregularity in the bony cortex at the level of the lateral malleolus of the femur and millimetric degenerative bone cysts in the tendency to merge were observed. There were heterogeneous contrast enhancements in degenerative bony cysts. Effusion was observed in the suprapateller bursa and intraarticular area. The findings were compatible with amyloid arthropathy. Non-steroid anti-inflammatory drugs were prescribed and colchicine dose was tried to increase.

Conclusion: The typical radiological findings should suggest amyloid arthropathy in cases who have predisposition to amyloidosis. This is the first case with amyloid arthropathy associated with FMF in the literature.

Patient Consent Received

No

Disclosure of Interest

None declared

P90 Features of children with fmf and a defined variant in MEFV gene: a single center experience

S. Güneş Yılmaz¹, B. Kasap-Demir^{2,2,2,2,3,3,4,4}, E. Soyaltın¹, G. Erfidan⁵, Ö. Özdemir Şimşek⁵, S. Arslansoyu Çamlar⁵, D. Alaygut⁵, F. Mutlubas⁶

¹Pediatrics, Health Sciences University Tepecik Training and Research Hospital; ²Pediatric Nephrology and Rheumatology, Izmir Katip Çelebi University; ³Pediatric Nephrology and Rheumatology; ⁴Pediatric Rheumatology; ⁵Pediatric Nephrology, Health Sciences University Tepecik Training and Research Hospital; ⁶Pediatric Nephrology, Izmir Katip Çelebi University, Izmir, Turkey

Correspondence: B. Kasap-Demir

Introduction: Familial Mediterranean Fever (FMF) is the most common monogenic autoinflammatory disease and autosomal recessive mutations in the MEFV gene are responsible for the clinical manifestations. The phenotype-genotype correlations have not been clarified definitively yet.

Objectives: This study aimed to present the demographic, clinical, and laboratory features of children clinically diagnosed with FMF and had a defined variant in at least one allele. The secondary aim was to predict more severe mutations by evaluating clinical findings.

Methods: We enrolled cases diagnosed with FMF according to Tel-Hashomer criteria and a defined variation in at least one allele, being followed up for at least 6 months. The medical charts of the patients were reviewed retrospectively. The patients were grouped as homozygous, compound heterozygous, and simple heterozygous cases with and without M694V mutation and the data were compared between the groups.

Results: A total of 263 (M/F:109/154) cases were included. The mean age at the onset of symptoms, follow-up duration, and time to diagnosis was 81.10±47.00 (3-204), 51.78±39.31 (6-166), and 9.23±14.44 (1-132) months, respectively. The rates of parental consanguinity, positive family history, and FMF in a first-degree relative were 15%, 42%, and 31.4%, respectively. The most common symptom was abdominal pain (85%). There was no difference between the growth parameters of the cases during the initial and final control periods. The most frequent alleles were M694V, E148Q, V726A. The most common accompanying disease was IgA vasculitis (20%). Almost 90% of the cases fulfilled all the defined criteria. Hb values ​​were lower and the ESR and CRP values ​​were higher during the attack period; ESR and CRP values were higher in the attack-free period; Pras scores were higher and the use of high dose colchicine was more frequent in homozygous and compound heterozygous cases carrying M694V. The presence of FMF in a first-degree relative increases the probability of this genetic predisposition 2.63 times; and each 1 unit increase in Pras score increases this probability 1.63 times. The threshold Pras score for this possibility is 5.5 (sensitivity: 65%, specificity: 55%).

Conclusion: M694V is the most common and severe mutation in our cohort. First degree relative with the disease and Pras scores ≥5.5 may predict an M694V homozygous or a compound heterozygous mutation.

Patient Consent Received

No

Disclosure of Interest

None declared

P91 performance of Eurofever/PRINTO classification criteria to differentiate fmf from PFAPA

B. Kasap-Demir^1,2, S. Güneş Yılmaz³, A. Kanık⁴

¹Pediatric Rheumatology, Health Sciences University Tepecik Training and Research Hospital; ²Pediatric Nephrology and Rheumatology, Izmir Katip Çelebi University; ³Pediatrics, Health Sciences University Tepecik Training and Research Hospital; ⁴Pediatrics, Izmir Katip Çelebi University, Izmir, Turkey

Correspondence: B. Kasap-Demir

Introduction: Eurofever/PRINTO classification criteria has been established to differentiate autoimmune diseases from each other.

Objectives: We aimed to differentiate cases with FMF and PFAPA with this new set of crtieria.

Methods: Patients diagnosed with PFAPA syndrome and FMF and followed up at Pediatric Rheumatology and Pediatrics outpatient clinics between March 2016 and March 2021 were included in the study. Patients were diagnosed with PFAPA syndrome regarding modified Marshall’s criteria, while patients with FMF were diagnosed using Yalçınkaya-Özen criteria. Regardless of their primary diagnosis, all the patients and their primary caregivers were exposed to a questionnaire including demographic and clinical data. MEFV gene mutations of the cases with FMF were noted. Homozygous or compound heterozygous pathogenic MEFV gene variants were defined as “confirmatory” and heterozygous pathogenic MEFV mutations, or compound heterozygous for one pathogenic MEFV variant and one variant of unknown significance (VUS), or biallelic VUS were defined as “non-confirmatory” genotype. Patients with heterozygous VUS or benign variants were defined as “non-pathogenic” and were not taken into consideration for Eurofever/PRINTO “genetic and clinical (CG)” criteria. The consistency between Eurofever/PRINTO “clinical only (CO)” and (CG) criteria was established. The effectivity of the CO criteria to differentiate cases with FMF from those with PFAPA, sensitivity, specificity, negative and positive predictive values (NP and PP, respectively) and accuracy of the CO criteria were calculated.

Results: 407 patients (M/F: 200/207) were included. Of those patients, 230 were diagnosed with FMF and 177 were diagnosed with PFAPA. In patients with FMF, 80 had confirmatory, 97 had non-confirmatory, and 53 had non-pathogenic mutations. When patients with FMF and PFAPA were compared, age at disease onset and diagnosis were significantly younger, male gender, pharyngotonsillitis, aphthous stomatitis, lymphadenitis, rinorrhea, cough, and febrile convulsion were more prevalent in cases with PFAPA, while abdominal and chest pain, maculopapular rash was more prevalent in cases with FMF (p<0.01). Disagreement between CO and CG criteria was established in only 5 of 177 (3%) patients with pathogenic mutations. The sensitivity, specificity, PP, NP and accuracy levels of CO criteria to differentiate FMF cases from PFAPA were 98.26%, 63.84%, 77.93%, 96.58%, and 83.29%, respectively. When evaluated considering MEFV gene groups, the highest sensitivity, specificity, PP, NP and accuracy were found in cases with “non-confirmatory” genotype. Since not all PFAPA cases have MEFV gene analysis, these values for CG criteria could not be defined for the whole group.

Conclusion: The sensitivity is higher, whereas the specificity and accuracy was lower for CO to differentiate FMF from PFAPA in our series when compared to the values established by Eurofever/PRINTO to differentiate FMF from other autoinflammatory diseases. Also, CO shows the best performance for cases with non-confirmatory mutations, which may cause diagnostic challenge for clinicians.

Patient Consent Received

No

Disclosure of Interest

None declared

P92 Comparison of the performance of four different criteria to diagnose PFAPA

A. Kanık¹, K. Sözmen², B. Kasap-Demir^3,4

¹Pediatrics; ²Public Health; ³Pediatric Nephrology and Rheumatology, Izmir Katip Çelebi University; ⁴Pediatric Rheumatology, Health Sciences University Tepecik Training and Research Hospital, Izmir, Turkey

Correspondence: B. Kasap-Demir

Introduction: Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome is a periodic fever syndrome. No universally accepted criteria for PFAPA hasbeen developed yet. An international consensus has been established recently to define a new set of classification criteria for PFAPA syndrome.

Objectives: We aimed to evaluate the diagnostic validity of four different criteria for the diagnosis of PFAPA.

Methods: The patients diagnosed with PFAPA syndrome and Familial Mediterranean fever (FMF) and followed up at Pediatric Rheumatology and Pediatrics outpatient clinics of Tepecik Teaching Hospital, İzmir, Turkey between April 2016 and April 2021 were included in the study. Patients who fulfilled the modified Marshall’s criteria irrespective of age and responded to steroids during the follow up were recruited for PFAPA syndrome. Patients with FMF were diagnosed using Yalçınkaya-Özen criteria and were included as the control group. All the patients and their primary caregivers were exposed to a questionnaire including demographic and clinical data mentioned in the criteria sets. The agreement between the four criteria was established. In addition, the sensitivity, specificity, positive predictivity (PP), negative predictivity (NP) and accuracy levels were calculated for each criteria set.

Results: There were 418 patients (M/F: 203/215) included in the study. Of those patients, 238 were diagnosed with FMF and 180 were diagnosed with PFAPA. When evaluated according to four different sets of criteria, modified Marshall’s criteria misdiagnosed none, Vanoni criteria misdiagnosed 4, Takeuchi criteria misdiagnosed 34, and Eurofever/PRINTO classification criteria for PFAPA misdiagnosed 1 cases with FMF as PFAPA, while modified Marshall’s criteria missed 8, Vanoni criteria missed 4, Takeuchi criteria missed none, and Eurofever/PRINTO classification criteria for PFAPA missed 22 of the cases with PFAPA. The sensitivity, specificity, PP, NP and accuracy levels as % for the abovementioned criteria were as follows: 95.48, 100, 100, 96.75, 98.0 for modified Marshall’s; 97.74, 98.32, 97.74, 98.32, 98.07 for Vanoni; 100, 85.71, 83.89, 100, 91.81 for Takeuchi; and 87.57, 99.58, 99.36 91.51, 94.46 for Eurofever/PRINTO, respectively. The agreement between the four criteria set was “very good” (kappa: 0.834, CI: 0.832-0.835). The four sets of criteria agreed in 353 patients (all diagnosed 147 and ruled out PFAPA in 206 cases), while there was disagreement between the citeria in 65 cases.

Conclusion: Although all criteria sets defined for PFAPA have a high level of agreement between each other, the most recent Eurofever/PRINTO classification criteria has the lowest sensitivity in our series. Further studies in higher number of patients would be needed to verify our data.

Patient Consent Received

No

Disclosure of Interest

None declared

P93 Blood pressure, arterial stiffness and left ventricular hypertrophy in FMF patients with confirmatory mutations

B. Kasap-Demir^1,2, G. Erfidan³, T. Demircan⁴, Ö. Özdemir Şimşek³, C. Başaran³, S. Arslansoyu Çamlar³, D. Alaygut³, F. Mutlubas⁵

¹Pediatric Nephrology and Rheumatology, Izmir Katip Çelebi University; ²Pediatric Nephrology and Rheumatology; ³Pediatric Nephrology; ⁴Pediatric Cardiology, Health Sciences University Tepecik Training and Research Hospital; ⁵Pediatric Nephrology, Izmir Katip Çelebi University, Izmir, Turkey

Correspondence: B. Kasap-Demir

Introduction: Chronic inflammatory era may result in cardiovascular changes.

Objectives: We aimed to evaluate whether children with familial Mediterranean fever (FMF) have increased blood pressure (BP) values, higher arterial stiffness or left ventricular mass index (LVMI).

Methods: Patients diagnosed with FMF who have homozygous or compound heterozygous mutations in the exon 10 of the MEFV gene and being followed up between April 2020 and April 2021 were included in the study. Demographic data, office blood pressure (OBP) measurements were recorded at the first visit. Ambulatory blood pressure monitoring (ABPM), central BP (cBP), pulse wave velocity (PWV), and augmentation index (AIx@75) values recorded within the same device and LVMI calculated with echocardiographic measurements were recorded in the following visit. The same tests were performed for a sex and age-matched control group.

Results: Finally, data would be collected for 26 cases with FMF and 26 cases as the healthy controls. Body weight, height, body mass index SDS values were similar between the groups (p>0.05). Both systolic and diastolic OBP SDS values were similar as well (p>0.05). 24-hour, daytime and nighttime systolic and diastolic BPs and 24-hour mean arterial pressure (MAP) SDS and nighttime mean MAP SDS levels were similar between the groups (p>0.05). However, daytime MAP SDS was significantly higher in FMF patients (p:0.033). Both daytime systolic and diastolic loads were significantly higher in FMF cases (p=0.005 and p=0.034, respectively), whereas nighttime systolic and diastolic loads and systolic and diastolic dips were similar between the groups. 24-hour, daytime and nighttime AIx@75 and PWV levels, and systolic and diastolic central BP levels were similar between FMF patients and the control group (p>0.05).

Conclusion: The results of this preliminary study suggested that FMF cases with confirmatory mutations were prone to have higher daytime systolic BP and MAP, however negative effects of these disorders on the left ventricle and arterial stiffness could not be established. Evaluation of these parameters in larger patient groups and re-assessment of the same patients in the follow-up would be rather valuable.

Patient Consent Received

No

Disclosure of Interest

None declared

P94 And quickly there were ten: DADA2, experience from a center in Mumbai, India

R. Khubchandani¹, D. Ramadoss¹, A. Khan¹, P. Lee², P. Pimpale Chavan^3,4

¹Section of Pediatric Rheumatology, NH SRCC Children's Hospital, Mumbai, India; ²Division of Allergy, Immunology and Rheumatology, Boston Children's Hospital, Boston, United States; ³Former Pediatric Rheumatologist, NH SRCC Children's Hospital, Mumbai, India; ⁴Current : Inflammatory Disease Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, United States

Correspondence: R. Khubchandani

Introduction: The number / phenotype of DADA2 continues to expand rapidly though series from Asia are scant.

Objectives: Share experience with 10 DADA2 patients (9 unrelated families) identified over 2 years.

Methods: We diagnosed the first case in April 2019 following which we recalled and diagnosed 4 more patients on renewed suspicion. In 2, their phenotypes did not match the initial provisional diagnosis of primary CNS vasculitis and inflammatory bowel disease (IBD) respectively while 2 had been treated as classic PAN. 4 patients were diagnosed prospectively on clinical suspicion and 1in whom we suspected syndromic bone dysplasia with inflammatory features was a diagnostic surprise.

Results: 7/10 are males. Age of onset ranged from 4 months – 17 years 9 months. Referrals were by varied specialists including primary pediatrician, pediatric hematologist, ophthalmologist, adult neurologist and urosurgeon. Medium-vessel dominated disease was seen in 6 patients and in 3 we suspected a systemic autoinflammatory disease (SAID) {1-febrile relative of a previously diagnosed DADA2 patient, 1-IBD-like with cutaneous vasculitis,1- early onset prolonged fever with granulomatous mediastinal adenitis suspected Blau syndrome} and 1 patient with progressive deforming symmetric inflammatory arthropathy and acquired micrognathia.

Cutaneous features were the commonest; seen in 7 patients and stroke was seen in 3. Other systems involved were musculoskeletal (5-including the bone dysplasia mimic described above),renal (4- notable were renal artery stenosis and perinephric hematoma), gastrointestinal (2- notable was bowel perforation), while ocular involvement was seen in 2 (notable being central retinal artery occlusion and episcleritis). Hematological features were seen in 5 and included pure red cell aplasia, persistent leucopenia and thrombocytopenia in 1 patient each and anemia in 2 (notable-unexplained anemia of infancy). None of the patients had exclusive hematological disease or immunodeficiency.

5 were homozygous for p.G47R variant and 2 are compound heterozygous with p.G47R and splice mutation c.753+2T>A and p.G47R and p.H219P respectively. Of those with p.G47R variant 4 belong to Agarwal community in whom endogamy is known. 2 patients born of a first cousin marriage (and even related three generations higher) have a homozygous pathogenic variant p.G358R. The patient with symmetrical skeletal affliction has a homozygous pathogenic variant in p.R169Q. All 4 patients in whom ADA2 enzyme assay was performed were deficient.

4 patients are on etanercept originator molecule and 6 on etanercept biosimilar with treatment duration varying between 2 weeks to 116 months and no drug side effects. 9 patients are in clinical remission off steroids and growing well with no restriction of activities of daily living. 2 have residual hypertension. 1 unvaccinated patient contracted COVID 19 and recovered uneventfully.

Conclusion: Since our first case in 2019, DADA2 is now the commonest SAID in our cohort (10/44). Due to its initial presentation to varied specialists we need to spread awareness to increase diagnosis. We report an unusual phenotype mimicking a bone dysplasia and alert colleagues that the classic phenotype originally described is being overshadowed by a wide spectrum. The p.G47R mutation is the commonest in our series and seen in the endogamous Agarwal community. The disease is very responsive to etanercept and treatment is progressively affordable with etanercept biosimilar. Residual hypertension may be seen with renal involvement and 1 patient with COVID19 on etanercept recovered uneventfully.

Disclosure of Interest

None declared

P95 Long-term efficacy and safety of canakinumab in patients with hids (Hyper-igd syndrome) − interim analysis of the reliance registry

J. B. Kuemmerle-Deschner¹, T. Kallinich², J. Rech³, N. Blank⁴, J. Weber-Arden⁵, P. T. Oommen⁶

¹University Hospital, Tuebingen; ²Charite University Medicine, Berlin; ³University Hospital, Erlangen; ⁴University Hospital, Heidelberg; ⁵Novartis, Nuernberg; ⁶University Hospital, Duesseldorf, Germany

Correspondence: J. B. Kuemmerle-Deschner

Introduction: Autoinflammatory periodic fever syndromes such as the Hyper-IgD syndrome/mevalonate kinase deficiency (HIDS/MKD) are rare autoinflammatory conditions characterized by severe systemic and organ inflammation. Successful treatment with rapid remission of symptoms and normalization of laboratory parameters was achieved in most patients with the interleukin-1β inhibitor canakinumab (CAN) in clinical trials¹ and real life. CAN has been approved and applied for the treatment of HIDS/MKD patients since 2017².

¹ De Benedetti F, et al. Canakinumab for the treatment of autoinflammatory recurrent fever syndromes. N Engl J Med 2018;378:1908–19

² Ilaris, INN-canakinumab (europa.eu)

Objectives: To explore the long-term efficacy and safety of CAN under routine clinical practice conditions in pediatric (age ≥2 years) and adult HIDS/MKD patients.

Methods: RELIANCE is a prospective, non-interventional, multi-center, observational study based in Germany with a 3-year follow-up period. Patients with clinically confirmed diagnoses of TRAPS, CAPS, FMF or HIDS/MKD who routinely receive CAN are enrolled in order to evaluate efficacy and safety of CAN under standard clinical practice conditions at baseline and at 6-monthly intervals.

Results: The present interim analysis comprises baseline data of 7 HIDS/MKD patients enrolled by December 2020 as well as preliminary 12-month data. Of these patients, 4 (57%) were females and median age at baseline was 7 years (2-39 years). The median duration of prior CAN treatment at baseline was 2.0 years (0-5 years). Standard, low, and high dose CAN treatment was evenly distributed at every interval.

Preliminary results indicate stable remission and disease control by physicians´ and patients´ assessment as well as laboratory parameters (table 1). In total, 3 patients were affected by adverse drug reactions, however, none of these events was classified as serious.

Conclusion: Baseline characteristics and preliminary data of HIDS/MKD patients from the RELIANCE study indicate good clinical and laboratory disease control and no unexpected safety concerns at the 12 months interim analysis.

Disclosure of Interest

J. B. Kuemmerle-Deschner Consultant for: Novartis, AbbVie, Sobi, T. Kallinich Consultant for: Sobi, Novartis, Roche, J. Rech Consultant for: Abbvie, Biogen, BMS, Chugai, GSK, Janssen, Lilly, MSD, Mylan, Novartis, Roche, Sanofi, Sobi, UCB, Speaker Bureau of: Abbvie, Biogen, BMS, Chugai, GSK, Janssen, Lilly, MSD; Mylan, Novartis, Roche, Sanofi, Sobi, UCB, N. Blank Consultant for: Novartis, Sobi, Lilly, Pfizer, Abbvie, BMS, MSD, Actelion, UCB, Boehringer-Ingelheim, Roche, J. Weber-Arden Employee of: Novartis, P. T. Oommen: None declared

Table 1 (abstract P95). Baseline characteristics and interim analysis data of patients with HIDS

P96 Long-term efficacy and safety of canakinumab in patients with traps (Tumor necrosis factor receptor-associated periodic syndrome) − interim analysis of the reliance registry

J. B. Kuemmerle-Deschner¹, N. Blank², C. Schuetz³, M. Borte⁴, P. T. Oommen⁵, J. Henes¹, J. Weber-Arden⁶, T. Kallinich⁷

¹University Hospital, Tuebingen; ²University Hospital, Heidelberg; ³University Hospital, Dresden; ⁴Hospital St. Georg gGmbH, Leipzig; ⁵University Hospital, Duesseldorf; ⁶Novartis, Nuernberg; ⁷Charite University Medicine, Berlin, Germany

Correspondecne: J. B. Kuemmerle-Deschner

Introduction: Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is a rare autoinflammatory condition characterized by severe systemic and organ inflammation. In a phase 3 pivotal trial¹, TRAPS patients have been successfully treated with the interleukin-1β inhibitor canakinumab (CAN). 45% of patients reached clinical remission after 16 weeks (primary endpoint)¹. CAN has been approved and applied for the treatment of TRAPS patients since 2017².

¹ De Benedetti F, et al. Canakinumab for the treatment of autoinflammatory recurrent fever syndromes. N Engl J Med 2018;378:1908–19

² Ilaris, INN-canakinumab (europa.eu)

Objectives: The present study explores 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, multi-center, observational study based in Germany with a 3-year follow-up period. Patients with clinically confirmed diagnosis of TRAPS who routinely receive CAN are enrolled in order to evaluate efficacy and safety of CAN at baseline and at 6-monthly intervals.

Results: The interim analysis of TRAPS patients enrolled by December 2020 includes baseline (N=16, 1 patient with atypical TRAPS) and preliminary 18-month data. Of these patients, 11 (69%) were females and median age at baseline was 23 years (3-43 years). 10 (62.5%) patients had been pre-treated with anakinra and 1 (6.3%) with tocilizumab.

Preliminary results indicate stable remission by physicians´ assessment and laboratory parameters. Disease control by patients´ assessment showed no major changes (table 1). In total, 7 adverse drug reactions where observed, of which none was classified as severe.

Conclusion: Baseline characteristics and interim data of TRAPS patients are available from the RELIANCE study. Further interim and end-of-study data will be analyzed to assess efficacy and safety of long-term treatment as well as dosing effects in TRAPS patients.

Disclosure of Interest

J. B. Kuemmerle-Deschner Consultant for: Novartis, AbbVie, Sobi, N. Blank Consultant for: Novartis, Sobi, Lilly, Pfizer, Abbvie, BMS, MSD, Actelion, UCB, Boehringer-Ingelheim, Roche, C. Schuetz: None declared, M. Borte: None declared, P. T. Oommen: None declared, J. Henes Consultant for: Novartis, AbbVie, Sobi, Roche, Janssen, Boehringer-Ingelheim, J. Weber-Arden Employee of: Novartis, T. Kallinich Consultant for: Sobi, Novartis, Roche

Table 1 (abstract P96). Baseline characteristics and interim analysis data of patients with TRAPS

P97 Long-term safety and effectiveness of canakinumab in Cryopyrin-Associated Periodic Syndromes (CAPS) – 30-month data from the reliance registry

J. B. Kuemmerle-Deschner¹, N. Blank², B. Kortus-Goetze³, P. T. Oommen⁴, A. Janda⁵, J. Rech⁶, F. Weller-Heinemann⁷, G. Horneff⁸, I. Foeldvari⁹, C. Schuetz¹⁰, M. Borte¹¹, A. Braner¹², J. Weber-Arden¹³, T. Kallinich¹⁴

¹Pediatrics, University Hospital, Tuebingen; ²University Hospital, Heidelberg; ³University Hospital, Marburg; ⁴University Hospital, Duesseldorf; ⁵University Hospital, Ulm; ⁶University Hospital, Erlangen; ⁷Prof. Hess Kinderklinik, Bremen; ⁸Asklepios Clinic, Sankt Augustin; ⁹Centre for Pediatric and Adolescence Rheumatology, Hamburg; ¹⁰University Hospital, Dresden; ¹¹Hospital St. Georg gGmbH, Leipzig; ¹²University Hospital, Frankfurt; ¹³Novartis, Nuernberg; ¹⁴Charite University Medicine, Berlin, Germany

Correspondence: J. B. Kuemmerle-Deschner

Introduction: In clinical trials as well as in real-life, the IL-1β inhibitor canakinumab leads to rapid remission of symptoms in the treatment of CAPS, a monogenic autoinflammatory disease with severe systemic and organ inflammation.

Objectives: The RELIANCE registry is designed to explore long-term safety and effectiveness of canakinumab under routine clinical practice conditions in pediatric (≥2 years) and adult patients with CAPS, including Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), and neonatal onset multisystem inflammatory disease (NOMID)/chronic infantile neurological cutaneous and articular syndrome (CINCA).

Methods: This prospective, non-interventional, observational study with a 3-year follow-up enrolls patients with clinically confirmed diagnoses of CAPS routinely receiving canakinumab. In 6-monthly visits, clinical data, physician assessments and patient-reported outcomes are evaluated starting at baseline with last update at 30 months of follow-up in the total cohort including the cohort with severe subtypes (NOMID/CINCA).

Results: 91 CAPS patients (50% female; 14 [15%] NOMID/CINCA subtypes) were enrolled by December 2020 (table 1). At baseline, median age was 20.5 years and median duration of prior canakinumab treatment was 6 years. 20 drug related severe adverse events (11 per 100 patient years) were reported. 68% of patients reached disease remission by physicians´ assessment along with rates of 40-61% absent disease activity in PGA. CAPS was impairing social life in 50% of patients. Lab parameters were within normal limits.

Conclusion: The 30-month interim analysis of the RELIANCE study demonstrates that long-term canakinumab treatment is safe and effective in patients with any subtype of CAPS. However, impairment of social life still exists.

Disclosure of Interest

J. B. Kuemmerle-Deschner Consultant for: Novartis, AbbVie, Sobi, Speaker Bureau of: Novartis, AbbVie, Sobi, N. Blank Consultant for: Novartis, Sobi, Lilly, Pfizer, Abbvie, BMS, MSD, Actelion, UCB, Boehringer-Ingelheim, Roche, B. Kortus-Goetze Consultant for: Novartis, P. T. Oommen: None declared, A. Janda: None declared, J. Rech Consultant for: Abbvie, Biogen, BMS, Chugai, GSK, Janssen, Lilly, MSD, Mylan, Novartis, Roche, Sanofi, Sobi, UCB, Speaker Bureau of: Abbvie, Biogen, BMS, Chugai, GSK, Janssen, Lilly, MSD; Mylan, Novartis, Roche, Sanofi, Sobi, UCB, F. Weller-Heinemann: None declared, G. Horneff Speaker Bureau of: AbbVie, Bayer, Chugai, Merck Sharp & Dohme, Novartis, Pfizer, Roche, I. Foeldvari Consultant for: Novartis, C. Schuetz: None declared, M. Borte: None declared, A. Braner Consultant for: Novartis and SOBI, J. Weber-Arden Employee of: Novartis, T. Kallinich Consultant for: Sobi, Novartis, Roche

Table 1 (abstract P97). Patient and physician assessment of clinical CAPS disease activity and laboratory markers over time

P98 Cryopyrin-associated periodic syndromes: gosh and national amyloidosis centre experience

O. Kul Cinar¹, C. Papadopoulou^1,2, A. Putland¹, K. Wynne¹, H. J. Lachmann³, D. Eleftheriou^1,2, P. Brogan^1,2

¹Paediatric Rheumatology, GREAT ORMOND STREET HOSPITAL FOR CHILDREN NHS TRUST; ²Infection, Immunity & Inflammation, UCL GOS Institute of Child Health; ³National Amyloidosis Centre, UCL Medical School, Royal Free Campus, London, United Kingdom

Correspondence: O. Kul Cinar

Introduction: Cryopyrin-associated periodic syndrome (CAPS) is a rare, heterogenous inflammasomopathy associated with gain-of-function mutations in NLRP3. Mutations in NLRP3 result in excessive IL-1ß production that may underlie wide range of symptoms including skin rashes, conjunctivitis, arthritis, and sensorineural deafness. IL-1 blockade demonstrated complete responses to treatment which has been life-changing in this monogenic inflammasomopathy.

Objectives: We aimed to demonstrate the disease activity scores, inflammatory markers, genetic mutations, and MRI brain of the CAPS patients followed by GOSH and the National Amyloidosis Centre, encompassing a very large cohort of paediatric patients, including adolescents now transitioned to adult care. Data collection was carried out before and after treatment with IL-1 inhibitors.

Methods: Patients followed-up in GOSH and NAC specialist CAPS clinics from 2005 to 2021 were identified. Data on following parameters collected: disease subtype, presenting symptoms, CAPS disease activity scores, serum amyloid A (SAA) and C-reactive protein (CRP) levels, MRI brain; and treatment. Statistical analysis was performed by GraphPad Prism version 9.1.1.

Results: A total of 48 patients [female (n=20, 42%), male (n=28, 58%)] with CAPS diagnosis in childhood/adolescence were identified. Median age at disease presentation was 3.50 years (range:0.20–16.23). Disease subtypes were: CINCA (n=4), MWS (n=37), FCAS (n=6), CAPS-like disease (n=1). Two of 6 patients with FCAS harboured NLRP3 variants of unknown significance, and were discharged since they ultimately proved asymptomatic after review. Clinical symptoms were recorded and CAPS disease activity score was calculated in each clinic visit. There was a significant drop in the mean CAPS activity scores between first and last visits (8.66/20 (±2.59), 1.12/20 (±1.29), respectively). Median treatment duration was 5.83 years (range:0.17–15.83). Mutations could not be detected by sanger sequencing in 6/48 (12,5%), although clinical characteristics of CAPS were identified. Two/6 had next-generation sequencing without evidence of mosaicism. The commonest mutation was p.A439V in NLRP3 gene (19/48), followed by p.V198M (3/48), p.T348M (3/48) and p.R488K (3/48) mutations. CRP and SAA levels were checked prior to treatment and at each clinic visit. 45 of 48 patients (94%) were on anti-IL1 treatment: 42/45 (93%) canakinumab, 27 of whom were switched from anakinra; and 3/45 (7%) on anakinra. Two FCAS patients were discharged from clinic without any treatment, 1 patient with compound heterozygous IRAK4 mutations in addition to NLRP3 p.E457D was switched from canakinumab to tocilizumab, with complete clinical and serological response. Median CRP before and after treatment were 5.0 mg/L (range:1.0-83.0) and 5.0 mg/L (range:1.0–51.0). Median SAA before and after treatment were 8.5 mg/L (range: 2.4 – 680.0) and 3.50 mg/L (range: 2.0 – 222.0). Thirteen of 48 (27%) patients underwent MRI brain due to neurological involvement, mainly due to recurrent headaches, with no abnormalities identified in 9/13 (70 %); whereas 4 patients (3 with CINCA) had changes on their MRI brain. None of the patients experienced deterioration neither in their clinical symptoms nor in MRI brain scans after starting anti-IL1.

Conclusion: Anti-IL1 treatment has had a major impact in paediatric patients for the prevention and treatment of CAPS symptoms. Treatment efficacy was observed by improved CAPS clinical disease activity scores; and normalised inflammatory markers. In our cohort, neurological symptoms including sensorineural hearing problems improved and MRI brain scans have remained stable with anti-IL1 therapies.

Disclosure of Interest

None declared

P99 Serum calprotectin as a marker of disease activity in the assessment of the paediatric patient with autoinflammatory disease: a cross-sectional study

M. Marti Masanet¹, M. I. González Fernández¹, B. López Montesinos², L. Lacruz Perez², A. Alba Redondo³, B. Laiz Marro³, I. Calvo Penadés²

¹Pediatric Rheumatology Unit, Medical Research Institute Hospital La Fe; ²Pediatric Rheumatology Unit; ³HOSPITAL Universitari i Politecnic La Fe, Valencia, Spain

Correspondence: M. Marti Masanet

Introduction: Serum calprotectin (S100A8/9 or MRP8/14) is considered a good plasmatic marker for the assessment of systemic-onset JIA (sJIA) and other autoinflammatory diseases (AID).

Objectives: To evaluate the use of serum calprotectin in a paediatric population with autoinflammatory disease for assessment of disease activity and to correlate it with other blood inflammatory parameters.

Methods: Patients who fulfilled International League of Association for Rheumatology Criteria for sJIA and patients with defined genetic or clinically diagnosed AID were included. Serum calprotectin and other inflammatory markers (CRP, ESR, serum amyloid A, ferritin) were tested in a blood sample from the patients, MRP8/14 was tested by ELISA Kit sandwich of Bülmann (automated in an immunoassay analyzer DSX). Physician global assessment of disease activity and parent/patient global assessment of well-being were measured on a 0-10 Visual Analogue Scale (VAS). Sample was divided into active and inactive cases at the time of calprotectin testing: sJIA patients were considered active if they had active joint count and/or systemic symptoms (such as fever and rash) and patients with AID diagnosis were considered active if they had typical symptoms of disease activity.

Graphpad Prism Version 9.0 was used for data analyses. Between-group comparisons were done by Mann-Whitney U test. Correlations were studied with Spearman’s test. Receiver operating characteristic curve (ROC) analysis was done to assess the use of an inflammatory parameter to differentiate patients active than inactive.

Results: 84 patients were included in this study, 40% females and 60% males. Diagnosis, number of active/inactive patients and serum calprotectin levels (μg/mL) are described in table 1.

Association between MRP8/14 and disease activity status was analysed. Globally (including sJIA and AID together), active patients had higher levels of MRP8/14 than inactive patients (p=0.0031). For FMF patients, serum calprotectin levels were higher in the active group but not statistically significant (p= 0.06). For sJIA patients, levels were also higher in the active group and statistically significant (p= 0.044), but in this case the sample was very small. It should be noted that PAPA patient had by far the highest value of serum calprotectin, despite being inactive.

Low positive correlation between MRP8/14 and CRP was found (r=0.34), that was statistically significant (p=0.01), as well as between MRP8/14 and ferritin (r=0.39; p=0.0064). Low positive correlations were found between each serum calprotectin/CRP/amyloid A and physician VAS, that were statistically significant. The best correlation was with calprotectin (r=0.388; p=0.0006).

Globally, we analyzed the use of serum calprotectin to differentiate between active and inactive patients. Compared to CRP and serum amyloid A, MRP8/14 showed better ability to differentiate activity (AUC=0.69). We obtained a cut-off value of 2.26 μg/mL for serum calprotectin, with 55,56 % sensitivity and 87,18% specificity.

				Serum calprotectin (μg/mL) Median (IQR)
	N	active	inactive	active	inactive
FMF	35	13	22	3.19 (1.3-4.6)	1.31 (0.49-1.86)
TRAPS	10	6	4	2.37 (1.44-4.85)	1.49 (1.14-1.96)
HIDS-MVD	8	7	1	1.76 (0.6-2.3)	-
PFAPA	11	3	8	1.52 (0.97-5.26)	1.32 (1-2.02)
CAPS	5	3	2	4.54 (4.4-8.4)	1.75 (1.2-2.3)
PLAID	1	1	0	2.57	-
PAPA	1	0	1	-	27
Systemic-onset JIA	13	2	11	10.14 (7.7-12.57)	1.65 (0.75-2.12)

Conclusion: Although our sample is small and we need to increase the number of patients to obtain stronger evidence, our study showed the potencial role of serum calprotectin in the assessment of paediatric patients with AID and sJIA.

Patient Consent Received

Yes

Disclosure of Interest

None declared

P100 A case report of haploinsufficiency of A20 in a russian patient with Behҫet-like disease in pediatric rheumatogist practice

V. Matkava, S. Salugina, I. Nikishina, A. Shapovalenko, E. Fedorov, Z. Kolkhidova

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

Correspondence: V. Matkava

Introduction: A20 Haploinsufficiency (HA20) is a recently described autoinflammatory disease (AID) caused by a loss-of-function mutation in the TNFAIP3 gene. HA20 can be described like rare autosomal-dominant syndrome with early onset of systemic inflammation. Clinical manifestations of HA20 are similar to Behҫet’s disease (BD) and represented by periodic fever, recurrent oral aphthosis and genital ulcers, arthralgia/arthritis, uveitis. In world practice there are a few described cases of gastrointestinal involvement (abdominal pain, diarrhea, vomiting, rectorrhagia). Elevated acute-phase markers and immune reactants (ANA, anti-dsDNA, anti-Sm, RNP) and positive HLAB51 have been observed in some patients.

Objectives: To present clinical manifestations of Behҫet-like syndrome (HA20), initially diagnosed as an rheumatic disease.

Methods: Case report of patient with HA20 genetically confirmed by high-throughput DNA sequencing and detection TNFAIP3 gene mutation.

Results: An adolescent girl (16 у.о.) was examined in our Federal Rheumatologic Centre. From the age of 14, disease manifested with repeated episodes of oral and genital ulcerations, arthritis of proximal and distal interphalangeal joints (PIP, DIP), CRP was 124 g/l (Normal=0-5 mg/l). Initially diagnosis was verified as juvenile idiopathic arthritis (JIA). The treatment included subcutaneous methotrexate (MTX) 15 mg/week, NSAID courses without positive respond. Since 15 y.o., hips and ankles arthritis were developed, deformation of PIP, DIP joints were getting worse. BD, JIA were included in differential conditions. Because persistence of symmetric polyarticular damage, increased ESR, CRP - abatacept was prescribed, without any response. Gastrointestinal involvement (erosive enteritis, endocolitis), loss of 9 kg weight for 6 months and diffuse alopecia were detected after 1.5 years from the onset of the disease. A lot of laboratory disturbance including ESR-46 mm/h (N= 2,0-30,0); ANA-1/2560 (N<1/160); anti-dsDNA-23.9 IU/ml (N= 0,0-20,0); lymphopenia (0,72x109/l, N= 1,20-3,00), anemia (HGB 111 g/l, N=120-140) was preserved. Overlap-syndrome (JIA and Systemic Lupus Erythematosus) was discussed. Rituximab (RTX) 500 mg №1 and glucocorticoids (GC) 15 mg/day of methyl prednisolone have been started with improvement. Despite of reversing polyarthritis, there were relapses of ulcerations and joining a disorder of the psychoemotional state. High-throughput DNA sequencing was performed due to atypical disease course. The mutation c.591_593delTGT in the TNFAIP3 gene in a heterozygous state was detected. The treatment has been continued (MTX, GC, RTX) with quite good clinical response. At first time have been found high levels of Anti-CCP - 84,7 u/ml (N= 0,0-5,0). The girl is under long-term follow-up nowadays.

Conclusion: Rare genetic AID with early-onset systemic inflammation including HA20 can be determined in rheumatologist’s practice like common rheumatic disease.

Patient Consent Received

Yes

Disclosure of Interest

None declared

P101 Clinical characteristics of children with chronic rheumatological presentations associated with pathogenic and variants of unknown significance in the NOD2 gene: the gosh experience

K. Mclellan, K. Nott, A. Shivpuri, C. Papadopoulou, S. Compeyrot-Lacassagne

Paediatric Rheumatology, Great Ormond Street Hospital, London, London, United Kingdom

Correspondence: K. Mclellan

Introduction: Blau syndrome describes an autoinflammatory granulomatous condition comprising a triad of dermatitis, uveitis and synovitis caused by gain-of-function mutations in NOD2. Genetic testing can also identify variants of unknown significance (VUS) the role of which in pathogenesis is unknown. Recent reports suggest that some VUS in patients with Early Onset Sarcoidosis (EOS) might be pathogenic.

Objectives: To describe the phenotype of children with chronic rheumatological disorders and NOD2 mutations.

Methods: Retrospective case note review.

Results:

• 1. Three groups identified; 3 patients (Group A) with an EOS phenotype with pathogenic mutations in NOD2 gene; A334G, H603A & G498A (the latter’s affected mother also had the same mutation). 3 patients (Group B) with an EOS phenotype with VUS in NOD2 (2 sisters with mutations in P268S & 1 with A725G) and 11 patients (Group C) with a heterogeneous presentation and VUS in NOD2; 2 patients with severe uveitis, 2 with hepatic sarcoidosis (1 of whom had uveitis), 2 with severe polyarticular JIA, (1 with fever, without rash or uveitis), 2 with chronic rashes and 2 with systemic JIA.

• 2. Demographics: In Group A, median age of symptom onset 2 years (IQR,1.75-5.63), Group B median age of symptom onset 1.33 (1.08-5.25) and Group C: median age of symptom onset 4.83 (2.88-11.25). 67% in Group A Caucasian, 33% South Asian. 100% in Group B Black. Group C; 45% Caucasian, 27% Black, 18% Mixed Race and 9% Middle Eastern. 1/17 patients had a history of consanguinity; in Group A with H603A variant. Median follow-up duration 4.33 years (2.67-6.17).

• 3. Clinical features: summarised in Table 1.

  • Rash: Group A: 2/3 patients (1 erythema nodosum, 1 scaly erythematous plaques); Group B 3/3 patients (100% nodular rash)

  • Renal involvement: 100% patients in Group B (67% proteinuria, 67% raised tubulo-interstitial markers, 67% raised urine: creatinine ratio)

  • Pulmonary involvement: 2 patients in the entire cohort; both in Group B with interstitial lung disease (1 with variant P268S & 1 with A725G).

  • No patients had significant cardiac or vascular involvement or hearing loss.

  • Systemic inflammation: 100% patients in Group A had a raised erythrocyte sedimentation rate (ESR) at presentation (median 32mm/hr (IQR 22.5-46), Group B: ESR 22mm/hr (20-44) and Group C: ESR 28mm/hr (11-105). 1/3 in Group A had a raised angiotensin converting enzyme (ACE) at presentation median value 49U/L (IQR 37.5-55.5), 3/3 in Group B median 270U/L (IQR 167.5-345).

• 4. Tissue biopsy: 2/3 in Group A (skin: non-necrotising granulomatous inflammation; synovium: non- specific chronic synovitis), 3/3 in Group B (synovium, skin and lymph node showing non-necrotising granulomas).

• 5. Management: 88% received steroids, methotrexate was given to 100% in Group A received methotrexate, 67% in Group B and 55% in Group C. 100% in Group A & B received biologics (anti-TNF), with biologics used in 55% of Group C.

Group (no. patients(%))	Arthritis (clinically/radiologically)	Tenosynovitis	Rash	Fever (>380C)	Lymphadenopathy (clinically/ultrasonography)	Uveitis	Hepatic involvement (hepatomegaly/deranged liver function)	Pancreatic involvement (biochemical markers)	Splenic involvement (splenomegaly)
A(n=3)	3(100)	3(100)	2(67)	1(33)	1(33)	3(100)	2(67)	1(33)	1(33)
B(n=3)	3(100)	0(0)	3(100)	2(67)	3(100)	3(100)	3(100)	2(67)	2(67)
C(n=11)	4(36)	1(9)	5(45)	3(27)	5(45)	3(27)	4(36)	3(27)	1(9)

Conclusion: With greater availability of genetic testing, variants of unclear significance are identified. We plan to test the activity of these NOD2 variants to assess their significance. Increased genetic testing of patients with relevant phenotypes and advances in genomics may improve understanding of the role of these variants in these complex diseases.

Patient Consent Received

No

Disclosure of Interest

None declared

P102 Recurrent fevers and septal panniculitis in aicardi- goutières syndrome caused by TREX1 gene mutation with response to baricitinib

K. Mclellan, P. Brogan, D. Eleftheriou, E. Moraitis

Paediatric Rheumatology, Great Ormond Street Hospital, London, London, United Kingdom

Correspondence: K. Mclellan

Introduction: Aicardi-Goutieres syndrome (AGS) is a heterogenous disorder in terms of phenotypical expression and severity. Mutations in TREX1 are associated with early-onset encephalopathy with basal ganglia calcification, familial chilblain lupus, retinal vasculopathy with cerebral leukodystrophy.

Objectives: To describe a rare presentation of AGS TREX1 mutation with a predominantly systemic autoinflammatory phenotype and response to baricitinib.

Methods: Retrospective case notes review.

Results: A 21 month old girl presented with a 9 month history of recurrent fevers lasting 3-5 days, approximately every 14 days, associated with arthralgia, urticarial rashes, blistering panniculitic lesions on hands, legs and face and irritability. She had mild delay in gross motor skills and speech.

She had been born to Caucasian non-consanguineous parents at 35+4 weeks gestation. She developed a persistent cough from five weeks of age and and was treated for bilateral lower respiratory tract infections secondary to pseudomonas aeruginosa. Subsequently unsafe swallow was noted and she was fed via a nasogastric tube. Bronchoscopy, video fluoroscopy, bulbar EMG, and cystic fibrosis screening were performed, all with negative results. There was a family history of chilblains in father and paternal grandmother.

Laboratory parameters revealed normal full blood count and elevated inflammatory markers during the episodes with CRP 24 mg/L (reference range [RR] < 20 mg/L), erythrocyte sedimentation rate (ESR) 45 mm/hr (RR < 10), serum amyloid A 100mg/L (RR < 10), with normalisation between episodes. A skin biopsy of the rash showed features of urticaria and septal panniculitis, but no vasculitis. An extensive work up for infections, autoimmune diseases and common immunodeficiencies was negative. Ophthalmic examination was normal. Echocardiogram and magnetic resonance imaging of brain were normal, and an ultrasound of the abdomen showed a mildly coarse liver. CT scan brain showed left frontal lobe calcification.

A systemic neuro-autoinflammatory disease was suspected, leading to genetic screening with targeted next-generation sequencing. Empirical treatment with colchicine 0.5mg/kg/day was commenced and subsequently azathioprine 2 mg/kg/day pending genetic results. No benefit was observed from the treatment with colchicine or azathioprine, and oral prednisolone (1mg/kg for 3 days) was introduced with improvement in shortening duration of fever episodes. Motor skills and language remained delayed, and there was a decline in neurological function with mild spasticity in the lower limbs.

Genetic studies revealed a heterozygous c.G217A mutation (p.D73N) in TREX1 gene confirming a diagnosis of AGS. Expression of interferon-stimulated genes was found to be upregulated. Treatment with baricitinib (2 mg three times a day (0.34mg/kg/day)), a selective JAK1/2 inhibitor, was initiated at age 4 years. At 5 months follow up post initiation of baricitinib there was significant improvement in the clinical features, with only one episode of fever and mild rash which lasted 2 days over a 5 month period. The neurological function remained stable.

Conclusion: We describe a rare autoinflammatory phenotype as the predominant manifestation of AGS caused by a heterozygous mutation in TREX1 and highlight the response to baricitinib. Recognition of this phenotype and early diagnosis is of outmost importance as prompt initiation of treatment may be of greatest benefit in the early stages of the disease. The patient has shown clinical response to JAK inhibition, although we cannot comment on the long term benefits at preventing progression of neurological manifestations.

Patient Consent Received

Yes

Disclosure of Interest

None declared

P103 Chronic recurrent multifocal osteomyelitis refractory to various immunosuppressive therapy:case description

Z. Nesterenko, A. Kozlova, V. Burlakov, A. Moiseeva, S. Dibirova, J. Rodina, A. Horeva, A. Roppelt, A. Shcherbina

Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russian Federation

Correspondence: Z. Nesterenko

Introduction: Chronic recurrent multifocal osteomyelitis (CRMO) is a rare mostly multifactorial autoinflammatory disease. It is characterized by non-infectious recurrent bone lesions, usually manifesting in childhood. There is no standard and universal treatment approach that is able to control disease progression in all patients with CRMO.

Objectives: We aim to report our positive experience with treatment of a refractory CRMO case with tocilizumab.

Methods: We describe clinical, laboratory, imaging characteristics and treatment response of a CRMO patient. Known genetic defects, leading to CRMO, were excluded via whole exome sequencing. The diagnosis was confirmed histologically, bone tumors and infections were excluded.

Results: A 7-year-old girl was admitted to our hospital because of pain in the right knee and left ankle, accompanied by fever and increased laboratory inflammatory markers (C-reactive protein (CRP), erythrocyte sedimentation rate (ESR). Treatment with NAID, antimicrobial therapy was not effective. She was started on bisphosphonate therapy, with minimal reduction of the clinical symptoms. TNF-α inhibitors (adalimumab, then infliximab) were ineffective. Steroids (2 mg/kg/day) + methotrexate relived her pain, as well as led to normalization of CRP levels, yet all the symptoms relapsed with steroids tapering.

Therefore, she was started on anakinra with partial effect. Two days after cessation of anti-IL-1 therapy she relapsed with exudative and proliferative lesions in the knee, ankle joints, joints of the wrists, and palmar-plantar pustulosis (erythema) on the feet

Canakinumab 150 mg, later 300 mg every 4 weeks, was initiated and the patient's general condition improved, but increased acute phase reactants and pain persisted. Denosumab, nuclear factor kappa-B ligand (RANKL) inhibitor, had been added to the сanakinumab and MTX therapy, without. MRI and bone scintigraphy showed persistent inflammatory changes in the bones. She was then started on tocilizumab and MTX. Now the patient is 8 months on treatment, is clinically asymptomatic, has no fever and pain. Laboratory tests showed decrease inflammatory activity.

Conclusion: Our experience in treating a patient with CRMO demonstrates the insufficient effectiveness of previous therapy with bisphosphonate, TNF inhibitors, IL1 inhibitors, denosumab. Improvement of the condition was achieved on therapy with an IL6 inhibitor, which requires additional monitoring and study.

Patient Consent Received

Yes

Disclosure of Interest

None declared

P104 Long term visual outcome of blau-associated uveitis in a single centre study

A. V. Ramanan¹, S. K. Ng¹, P. Sinnappurajar¹, C. M. Guly²

¹Paediatric Rheumatology, Bristol Royal Hospital for Children; ²Bristol Eye Hospital, University Hospitals Bristol NHS foundation Trust, Bristol, United Kingdom

Correspondence: S. K. Ng

Introduction: Blau Syndrome is a rare dominantly inherited autoinflammatory disease resulting from a mutation of a pattern recognition receptor NOD2 gene and typically manifest as a triad features of arthritis, dermatitis and uveitis with a paediatric onset. Several case series have reported that ocular manifestation is a frequent presentation (70-80%) and is often a bilateral disease with progression towards panuveitis in a long run. Management of uveitis in Blau Syndrome has been particularly challenging due to the chronicity and persistent uveitis despite systemic corticosteroids and institution of immune modulatory and biologic treatments. Combination of persistent active ocular disease, with post-inflammatory ocular complications and long term topical steroids, inevitably result in progressive decrease in visual acuity. The visual burden of patients suffering from Blau-associated uveitis is essentially unknown. There is lack of a published data assessing long term visual outcomes of patients with Blau-associated uveitis and the data published so far are based on case series without a standardized follow up.

Objectives: Sight threatening complications remains as one of the major factor of long term morbidity in patients with Blau syndrome. In this review, we aim to identify and quantify the visual prognosis of Blau syndrome uveitis in a retrospective longitudinal review of a single centre study.

Methods: Clinical data were collected retrospectively from patients with a diagnosis of Blau Syndrome associated uveitis with a proven NOD2 mutations attending the regional South West of England Paediatric Rheumatology and Ocular Inflammatory Service, Bristol Eye Hospital. Patients who had at least more than 5 year review were included in this study. Data was collected at standard time intervals ; at baseline, 1,3,5,10,15,20,25 and 30 years post diagnosis. General demographics, laterality of the uveitis, age of onset, anatomical classification and course of uveitis were recorded for each patient. Ocular disease activity, ocular complications and surgical interventions required were recorded for each patient.

Results: A total of 16 eyes of 8 patients ( 4 female, 4 male) with genetic proven NOD-2 mutation Blau Syndrome associated uveitis patients who had at least more than 5 year review were included in this study. The median age of systemic symptoms (arthritis / skin manifestation) was 1.25 years and the median age of uveitis diagnosis in 7 out of 8 patients known was 4.67 years. Two (25%) out of eight patients present with unilateral eye involvement. All of the eight patients on follow-up eventually develop bilateral eye involvements with one eye presented with phthisis bulbi at first review. Mean visual acuity at the last clinic visit was 0.26 logMAR ; range -0.1-NPL]). 4 out of 16 eyes (25%) had logMAR ≥0.3 and 4 out of 16 eyes (25%) had logMAR ≥1.0 or worse.

12 eyes (75%) developed cataract, 1 patient had both eyes developed ocular hypotony, 2 eyes had glaucoma with an eye needing glaucoma tube surgery. 3 eyes in 2 patients developed ocular hypertension. 6 out of 8 patients continues to have persistent anterior chamber inflammation till last review.

Conclusion: Blau-associated uveitis confers a major long term morbidity with a quarter patient developing severe visual impairment.

Patient Consent Received

No

Disclosure of Interest

None declared

P105 Severe recurrent oral ulcers - is there a genetic cause?

M. Niemuth¹, A. Gabrielyan¹, J. Fischer², M. Laass¹, R. Berner¹, J. Roesler¹, N. DiDonato², M. A. Lee-Kirsch^1,2, C. Schuetz¹

¹Department of Paediatrics; ²Department of Genetics, Medical Faculty Carl Gustav Carus, Technische Universität, Dresden, Germany

Correspondence: M. Niemuth

Introduction: In 2016 an early-onset autoinflammatory disorder with a clinical phenotype resembling Behcet's disease was described by Zhou et al. (1) caused by heterozygous loss-of-function mutations in the TNFAIP3 gene encoding A20. Haploinsufficiency of A20 (HA20) decreases the NF-kB regulatory protein A20 and thereby amplifies action of the transcription factor NF-kB, a central mediator within inflammatory and innate immune signaling pathways.

Objectives: This review/case report is to provide additional information on clinical presentation and genetic findings in a rare, only recently, described autoinflammatory disorder.

Methods: A 10y/o girl repeatedly presented with severe oral ulcers, gingivitis, lymphadenopathy and occasional fevers. Serum levels of C-reactive protein (CrP) and erythrocyte sedimentation rate (ESR) were mildly increased, Immunglobulin E levels considerably elevated. No ulcers were found by endoscopy in stomach and colon, but few intramucous lymphoid follicles were seen. Interestingly, her mother also suffers from recurrent oral ulcers in addition to lung emphysema, autoimmune hepatitis of unknown origin, and scleroderma.

Results: Whole exome sequencing in the index patient revealed a novel heterozygous mutation in the TNFAIP3 gene (NM_006290.4:c.176_177delAG, p.Gln59fs). This variant leads to a frameshift and a premature STOP codon at the beginning of exon 2 and thereby most probably to nonsense mediated decay. Mutations in this gene can vary in location and usually lead to STOP codons or frame shift mutations.

Due to the decreased A20 levels and hence reduced inhibition of NF-kB, patients with HA20 suffer from episodes of fever, recurrent oral and genital ulcers, skin rashes, and polyarthritis, as well as from gastrointestinal and neurological symptoms. Ocular manifestations are far less frequent than in Behcet’s disease, and age at manifestation is usually earlier.

Conclusion: In patients with severe “familial” aphthosis and unexplained fever, genetic testing may guide clinical treatment decisions as exemplified in this family with unexpected monogenic disease. Our patient is presently stable under colchicine (1 mg/d) and on-demand steroid treatment. TNF-alpha-inhibitors and IL-1 antagonists may control ulcers, arthritis and sterile abscesses in patients with HA20. In the presence of systemic autoimmunity and an elevated interferon signature, JAK-inhibitors are a therapeutic option as stated by Schwartz et al. (2).

Consent for publication was signed by the patient's parents.

References

(1) Zhou Q, Wang H, Schwartz DM, Stoffels M, Park YH, Zhang Y, et al. Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset autoinflammatory disease. Nat Genet. 2016;48(1):67–73.

(2) Schwartz DM, Blackstone SA, Sampaio-Moura N, Rosenzweig S, Burma AM, Stone D, et al. Type I interferon signature predicts response to JAK inhibition in haploinsufficiency of A20. Ann Rheum Dis. 2020;79(3):429–31.

Patient Consent Received

Yes

Disclosure of Interest

None declared

P106 Expanding the autoinflammatory phenotype of sideroblastic anemia with immunodeficiency, fevers and development delay (SIFD) syndrome

F. Orlando¹, M. Tardi¹, D. De Brasi¹, R. Naddei², R. Borrelli¹, M. Alessio², L. Martemucci¹

¹Department of Pediatrics, AORN Santobono Pausilipon; ²Department of Translational Medical Sciences, Section of Pediatrics, University of Naples Federico II, Naples, Italy

Correspondence: F. Orlando

Introduction: TRNT1 is a nuclear gene encoding a ubiquitous enzyme (CCA-adding tRNA nucleotidyltransferase enzyme) necessary for aminoacylation of both mitochondrial and cytosolic tRNA. Mutations of that gene were firstly associated to SIFD but over the years phenotypic heterogeneity was described.

Objectives: To expand autoinflammatory phenotype of SIFD and to report a novel mutation of TRNT1 gene.

Methods: Case report of a 10-years-old female admitted to our Rheumatology Pediatric Unit of Santobono Children's Hospital of Naples due to febrile illness associated with vomit and diarrhoea, evolved in shock, treated with broad spectrum antibiotics and cardiovascular support in Intensive Care Unit. No infective causes were found.

Results: At the admission, the anamnesis revealed recurrent episodes of fever since the second month of life treated with antibiotics even without evidence of infection, with poor clinical response. She underwent to haematological investigations due to microcytic anaemia requiring blood transfusions. Bilateral cataract was diagnosed at the age of one years, ascribed to perinatal infection of Cytomegalovirus. Physical examination evidenced facial dysmorphisms, brittle hair, intellectual disability, failure to thrive. Laboratory assessment showed microcytic anemia (Haemoglobin 9.4 g/dl, MCV 60.9 fL, RDW 43 fL), lymphopenia (Lymphocytes 619/uL), elevated inflammatory markers (C-Reactive Protein 324 mg/L, Procalcitonin 610 ng/ml, Ferritin 2071 ng/ml). Immunological assessment was performed, showing hypogammaglobulinemia with IgA <0.22 g/l (0.5-3) and IgG 6,3 g/dl (7-15), low levels of CD3+ T cells 49% (55-78%). The clinical history plus the phenotype and the laboratory data, led us to assume mutations of TRNT1 gene. Genetic analysis was done, confirming our suspicion. Sanger sequencing was performed for genetic confirmation, resulting for TRNT1 mutations in SFID in compound heterozygous status in the proband: c.1205_1206dupAA (p.Glu403Lysfs*27) and c.1246A>G (p.Lys416Glu), the first mutation never described in literature, the second one already reported as pathogenic. She required low-dose prednisone to control a new febrile episode and then she started on anti-TNFα therapy (Etanercept), with resolution of recurrent fever and improvement of laboratory inflammation.

Conclusion: Since the first publication on SIFD, several studies have described patients with heterogeneous phenotypes and systemic involvement of variable severity and progression. Our patient presented a clinical picture characterized by several features which until the age of ten had not been considered as a part of a single disease. Currently, about 50 cases are outlined in literature. We also reported a novel mutation in the TRNT1 gene (c.1205_1206dupAA) and even if functional analysis of the protein expression was not performed, the in-silico prediction led to consider the mutation as pathogenic. Taking into account the clinical and immunological phenotype altogether with the found mutations and response to treatment, we conclude that the patient is affected by SIFD syndrome. Due to the rarity of that syndrome, diagnostic delay is observed, as in our patient. Early diagnosis of this condition would enable patients to promptly access to therapies thus allowing the opportunity of a better outcome.

Written informed consent for the publication was obtained.

Patient Consent Received

Yes

Disclosure of Interest

None declared

P107 Real-life data from the largest pediatric familial mediterranean fever cohort

K. Öztürk¹, T. Coşkuner², E. Bağlan³, H. E. Sönmez⁴, G. Otar Yener⁵, F. Çakmak⁶, F. G. Demirkan⁶, A. Tanatar⁶, S. G. Karadağ⁷, S. Özdel³, F. Demir², M. Çakan⁸, N. Aktay Ayaz⁶, B. Sözeri² on behalf of PeRA-Research Group

¹Pediatric Rheumatology, Istanbul Medeniyet University Prof. Dr. Süleyman Yalçın City Hospital; ²Pediatric Rheumatology, University of Health Sciences, Ümraniye Research and Training Hospital, Istanbul; ³Pediatric Rheumatology, University of Health Sciences, Dr. Sami Ulus Maternity and Child Health and Diseases Research and Training Hospital, Ankara; ⁴Pediatric Rheumatology, Kocaeli University, Faculty of Medicine, Kocaeli; ⁵Pediatric Rheumatology, Şanlıurfa Research and Training Hospital, Şanlıurfa; ⁶Pediatric Rheumatology, Istanbul University, Faculty of Medicine, Istanbul; ⁷Pediatric Rheumatology, Erzurum Regional Research and Training Hospital, Erzurum; ⁸Pediatric Rheumatology, University of Health Sciences, Zeynep Kamil Maternity and Children's Diseases Training and Research Hospital, Istanbul, Turkey

Correspondence: K. Öztürk

Introduction: Familial Mediterranean fever (FMF) is the most common monogenic autoinfammatory disease manifesting with phenotypic heterogeneity. It is a clinically diagnosed disease supported by MEditerranean FeVer (MEFV) gene mutation analysis. However, the phenotype–genotype correlation is not yet established clearly.

Objectives: We aimed to determine the clinical findings, phenotype-genotype correlation and treatment outcomes within a large pediatric FMF cohort.

Methods: The medical charts of children with FMF who were diagnosed and followed up at the eight pediatric rheumatology units were reviewed retrospectively. All patients in the cohort were analyzed for sequence variants in exon 2,3,5 and 10 of the MEFV gene. Patients without any mutations or with polymorphisms including R202Q were excluded.

Results: A total of 3454 children (1755 girls, 1699 boys) were involved in the study. The mean±standard deviation of current age, age at symptom onset, and age at diagnosis were 12.1±5.2, 5.1±3.8, and 7.3±4.0 years, respectively. Of 3454 patients, 88.2% had abdominal pain, 86.7% had fever, 27.7% had arthritis, 20.2% had chest pain, 23% had myalgia and 13.1% had erysipelas-like erythema. The most common MEFV mutation patterns were homozygous (32.5%) and heterozygous (29.9%) mutations of exon 10. Homozygous M694V was present in 969 patients (28.1%). Allele frequencies of common mutations were M694V (n=3373, 55.3%), M680I (n=782, 11.3%), V726A (n=529, 7.6%) and E148Q (n=503, 7.2%). Children carrying homozygous or compound heterozygous mutations had an earlier age of disease onset (4.6 vs 5.6 years, p=0.000) and a higher number of attacks per year (11.1 vs 9.6, p=0.001). Although 8% of the patients had a family history of amyloidosis, 0.3% (n=11) had presence of amyloidosis. M694V homozygosity was detected in nine patients who developed amyloidosis. Colchicine resistance was present in 4.2% (n = 145) of our patients.

Conclusion: In this largest pediatric cohort studied and presented since now, it has been demonstrated that exon 10 mutations, particularly the M694V homozygous mutation, are important in disease severity and outcome. Although E148Q is considered as a polymorphism in some populations, it was identified as a disease-causing mutation in our cohort. Secondary amyloidosis is still happening in adults however, it is extremely rare among children, presumably due to increased awareness, tight control and the availability of anti-IL1 agents in colchicine-resistant cases.

Patient Consent Received

Yes

Disclosure of Interest

None declared

P108 NLRC4-associated periodic autoinflammatory syndrome, phenotype and genotype of two clinical cases with novel variants

N. Palmou- Fontana¹, C. Alvarez², G. Ocejo-Viñals ³, J. M. Garcia-aznar⁴, B. Jimenez², A. Tejerina-Puente², D. Prieto¹, M. J. Cabero², M. A. Gonzalez-Gay¹

¹Rheumatology; ²paediatrics; ³Iinmunology, Hospital Universitario Marques De Valdecilla, Santander; ⁴Inmunology, Healthincode, A Coruña, Spain

Correspondence: N. Palmou- Fontana

Introduction: To date, fewer than 20 variants with demonstrated pathogenicity in the NLRC4 gene associated with the development of autoinflammatory syndrome due to gain-of-function (GoF) of the NLRC4 inflammasome have been described. This autosomal dominant disorder encompasses a spectrum,from cold-induced relapsing fevers (FCAS) to neonatal-onset multisystem autoinflammatory disease (NOMID), autoinflammatory syndrome with infantile enterocolitis (AIFEC) or macrophage activation syndrome (MAS). In most cases, the onset of the disease occurs during early infancy with recurrent fever, and rash Treatment varies according to the degree of presentation, being key the identification of severe forms, associated with macrophage activation and secretion of pro-inflammatory cytokines (IL-1β and IL-18) for disease control with targeted drugs.

Objectives: In this study, we report two clinical cases in which the genetic study revealed two novel variants in NLRC4

Methods:

23-year-old woman with a history of self-recurrent episodes of oral aphthous ulcers and odynophagia treated with antibiotics since the age of 4 years. At age 21, she presented mononucleosis followed by a generalized skin rash, pharyngotonsillitis, fever of 39°C, being diagnosed with scarlet fever. Currently, she refers to have recurrent episodes, usually 2 or 3 a month, of oral aphthous ulcers, abdominal pain and pharyngotonsillitis, along with increase of acute phase reactants, treated with glucocorticoids. They are mainly associated with stress.

Girl aged 2 years and 5 months, with recurrent fever every 15 days (fever up to 39-40°C for 4-5 days) with pharyngotonsillitis in the last 11 months. The febrile episodes are associated with a marked elevation of acute phase reactants. She had experienced an immediate response to methylprednisolone in two of the three episodes in which they were administered. Her father had similar symptoms during childhood that disappeared with tonsillectomy

Results: The genetic study revealed two heterozygous variants not previously described in NLRC4. Case 1 carried the p. Cys258Arg variant (Allelic Freq<0.01%), absent in her asymptomatic mother, located within the NACHT-NBD domain, in which the presence of GoF variants has not been statistically associated with mild or severe forms of the disease. Case 2 carried the p. Glu311Lys variant (Allelic Freq. unknown), inherited from the affected father during childhood and absent in her asymptomatic mother, which is located within a region of the NACHT domain (between NACHT-NBD and NACHT-WHD), in which the presence of GoF variants has been found in a more significant number of patients with severe forms of the disease (AIFEC/MAS).

Conclusion: Nowadays, these two variants remain uncertain clinical significance, although potentially associated with the development of NLRC4 inflammasomopathy. Nevertheless, the genetic study has been of prognostic utility to identify genotype-phenotype correlations in other cases in the scientific literature with variants in NLRC4, because of that, if its pathogenicity is confirmed in these two cases, its result allows us to anticipate severe forms of the disease and to evaluate targeted treatment options.

Patient Consent Received

Yes

Disclosure of Interest

None declared

P109 Focal myositis – a case series of a rare cause of hip immobility and calf Pseudotumor in children

F. Patel¹, A. Sridhar¹, A. F. Sharaf²

¹Paediatric rheumatology; ²Department of radiology, University Hospitals of Leicester NHS trust, Leicester, United Kingdom

Correspondence: F. Patel

Introduction: Case 1 -

A systemically well 7 year-old girl presented with 5-weeks of right calf tenderness and swelling following a short episode of pharyngitis and generalised maculopapular rash. There was no gait abnormality, focal neurology or restriction in activity aside from fatigability on walking distances. There were no skin rashes, joint involvement, eye changes or involvement of other muscles. She had a raised creatine kinase, plasma viscosity and lactate dehydrogenase. Her other blood results were normal including an extended autoimmune screen, immunoglobulins, complement levels, ASOT and titres of mycoplasma, EBV and CMV. MRI showed evidence of extensive inflammation of the gastrocnemius and soleus. A muscle biopsy showed heavy interstitial inflammatory cell infiltrate of predominantly lymphocytes, features of fibre necrosis including phagocytosis and hyalinisation with concurrent fibre regeneration (figures 1+2). She was initially managed with physiotherapy and anti-inflammatory medications but then developed intermittent right calf pain, restriction in activity and tiptoe walking due to gastrocnemius contractures. She was commenced on an 8-week tapering course of oral steroids and is improving with weekly methotrexate.

Case 2-

A systemically well 14-year-old presented with 6-months of left-sided hip pain, weight loss and inability to weight-bear without crutches. On examination there was painful fixed limitation of the left hip to 45^o on abduction and external rotation with bilateral mild swelling of the proximal interphalangeal (PIP) joints on both upper limbs. Otherwise, there was a full range of movement in all joints, with no rashes or other joint swelling or inflammation. Her blood tests were ANA positive 1:6000 and MRI of her hips demonstrated high T2 signal intensity in the left gluteus minimis and medius, obturator internus, obturator externus in keeping with myositis (figure 3). She received a pulse of corticosteroids followed by a course of methotrexate. There was immediate improvement in her PIP joint swellings and within a few weeks she was able to walk without crutches for the first time in 6 months. Unfortunately, 18 months after her diagnosis, she had developed anterior uveitis of her left eye with posterior synechiae; this responded well to steroid and cyclopentolate eye drops.

Objectives: .

Methods: .

Results: .

Conclusion: Summary-

Focal myositis is a rare immune-mediated pseudotumour of a single skeletal muscle group ⁽¹⁾. Only around 200 cases have been described in the literature so little is known on incidence, prevalence, patient management and outcomes ⁽²⁾. This differs and should not be confused with post-viral myalgia which bears neither the histological changes nor chronicity of focal myositis. Treatment options are centred on immunomodulation and in severe cases surgical management of contractures ⁽³⁾.

We emphasise that clinicians should bear this rare differential diagnosis for in mind for consideration of early conservative management, assessment for uveitis, immunomodulation and possibly surgical correction to improve patient outcome.

References

1. Auerbach A, Julie CFS, Wang G, Rushing EJ. Focal myositis a clinicopathologic study of 115 cases of an intramuscular mass-like reactive process. Am J Surg Pathol. 2009;33: 1016–1024.

2. Devic P, Gallay L, Streichenberger N, Petiot P. Focal myositis: a review. Neuromuscul Disord. 2016 Nov;26(11):725-733.

3. Milani GP, Mazzoni MBM, Gatti H, et al. Recurrent focal myositis in childhood: a case report and systematic review of the literature. Pediatr Neurol 2017;71:77.e1–81.e1

Trial registration identifying number: Figure 1 – Coronal magnetic resonance imaging of the calves showing hypertrophy and inflammation of the medial head of the right gastrocnemius muscle compared to the left (White asterisk).

Figure 2 – Muscle biopsy stained with H+E shown at x40 (left) and x400 magnification (right). Heavy interstitial inflammatory cell infiltrate of predominantly lymphocytes, features of fibre necrosis including phagocytosis and hyalinisation with concurrent fibre regeneration is shown.

Figure 3 - T2-weighted coronal magnetic resonance imaging of the hips showing high T2 signal intensity in the left gluteus minimis, gluteus medius, obturator internus and obturator externus in keeping with myositis (yellow arrows). Minimal T2 high signal noted in the left acetabulum, iliac bone and left femoral head (white arrow) likely secondary to patient positioning artefact rather than true marrow oedema.

Patient Consent Received

Yes

Disclosure of Interest

None declared

P110 Interferon inflammation in a case with PAMI syndrome and possible relationship with gene expression

A. Pin¹, A. Tesser¹, M. Girardelli¹, S. Federici², C. Celani², P. Tomietto³, D. Stolfo⁴, A. Taddio^1,5, A. Insalaco², A. Tommasini^1,5

¹Institute for Maternal and Child Health IRCCS "Burlo Garofolo", Trieste; ²IRCCS Ospedale Pediatrico Bambino Gesù, Roma; ³ASUGI, Rheumatology Unit; ⁴ASUGI, Department of Cardiolody; ⁵University of Trieste, Trieste, Italy

Correspondence: A. Pin

Introduction: Pathogenic heterozygous variants in PSTPIP1 lead to excessive IL1 mediated inflammation, which is the cause of rare autoinflammatory syndromes: PAPA (pyogenic arthritis, pyoderma gangrenosum, acne) and the more recently described PAMI (PSTPIP1-associated myeloid-related proteinemia inflammatory) (1).

Gene expression characterization may lead to better understand the molecular pathogenesis of these diseases.

Objectives: We investigated the gene expression pattern in two patients with familial PAPA syndrome (father and son, pt1 and pt2), two siblings with PAMI syndrome (pt3 and pt4) and a sporadic case of PAMI syndrome in a girl who presented an atypical clinical picture (pt5).

Methods: Gene expression studies of whole blood cells of patients with PAPA and PAMI syndrome compared to a group of healthy subjects and pathway over-representation analysis to investigate the main biological processes involved.

Results:

Family	Patient (pt)	PSTPIP1 mutations	Clinical symptoms	Treatment	Reference
Family-1 (PAPA)	Pt1-father	A230T	Arthritis, acne	Anakinra	(2)
	Pt2-son	A230T	Arthritis	Canakinumab
Family-2 (PAMI)	Pt3-brother	E250K	Leukopenia, neutropenia, acne	Anakinra	(3)
	Pt4-sister	E250K	Leukopenia, neutropenia	Anakinra
Family-3 (PAMI)	Pt5	E250K	Leukopenia, Atypical: SLE-like features (autoantibodies, nephritis, pulmonary arterial hypertension)	Hydroxychloroquine (HCQ)

Table above describes the analyzed families including the results of target sequencing panels and pharmacological treatments.

Gene expression analysis highlighted the heme metabolism pathway which is over-expressed among all the patients compared to controls already known to be involved in physiological and pathological processes (4). Only patients with PAMI syndrome showed among the over-represented signaling pathways the neutrophils degranulation pathway probably due to neutrophiles hyper-activation. Interestingly, only pt5 presented a high interferon signature score that recovered after therapy with HCQ.

Conclusion: The presence of lupus-like manifestations in PAMI has never reported so far. Even if only one of our patients with PAMI displayed interferon-related-inflammation, we can speculate a possible cross-talk between IL1 and interferon pathways. A possible hypothesis, which could be worth investigating, is that the increased neutrophil activation pathway found in PAMI could be associated to the release of neutrophil extracellular traps and to the activation of interferon signaling.

References

1. Holzinger D, Fassl SK, de Jager W, Lohse P, Röhrig UF, Gattorno M, et al. Single amino acid charge switch defines clinically distinct proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1)-associated inflammatory diseases. J Allergy Clin Immunol. 2015;136(5):1337-45.

2. Cortis E, De Benedetti F, Insalaco A, Cioschi S, Muratori F, D'Urbano LE, et al. Abnormal production of tumor necrosis factor (TNF) -- alpha and clinical efficacy of the TNF inhibitor etanercept in a patient with PAPA syndrome [corrected]. J Pediatr. 2004;145(6):851-5.

3. Belelli E, Passarelli C, Pardeo M, Holzinger D, De Benedetti F, Insalaco A. Haematological involvement associated with a mild autoinflammatory phenotype, in two patients carrying the E250K mutation of PSTPIP1. Clin Exp Rheumatol. 2017;35 Suppl 108(6):113-5.

4. Wu B, Wu Y, Tang W. Heme Catabolic Pathway in Inflammation and Immune Disorders. Front Pharmacol. 2019;10:825.

Patient Consent Received

Yes

Disclosure of Interest

None declared

P111 A peculiar phenotype of ADA2 deficiency

M. Rossano, F. Baldo, S. Torreggiani, L. Baselli, S. Giliani, S. Lanni, A. Petaccia, G. Filocamo, F. Minoia, C. Agostoni

Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, ²ASST Spedali Civili di Brescia, Milan, Italy

Correspondence: M. Rossano

Introduction: ADA2 deficiency (DADA2) is an autosomal recessive disease that causes a monogenic vasculitis syndrome characterized by protean manifestations, including haematological, cutaneous, articular and vascular involvement. Diagnosis is often difficult, due to the large phenotypic variability and the indolent course of the disease.

Objectives: To report an unusual case of ADA2 deficiency presenting with myositis, due to a new compound heterozygosity for a missense mutation and a novel deletion in ADA2.

Methods: A 7-year old boy was investigated for intermittent bilateral leg pain. Clinical evaluation was unremarkable, with normal strength. Blood tests revealed elevated inflammatory markers and normal lactic dehydrogenase (LDH) and creatinkinase (CK). Moderate lymphopenia was observed with low count of both CD19+ and NK cells, elevated CD3+HLA-DR+ cells, and low levels of IgM; double negative αβ T lymphocytes were normal (Table 1). MRI presented bilateral signs of myositis of the lower limbs. He subsequently developed nocturnal fever, multiple inguinal, axillary lymphadenopathy and splenomegaly. Infectious workup, the autoimmunity panel including myositis specific and associated autoantibodies, and serum markers of malignancies were all negative. PET-scan showed multiple tracer uptake in axillary, inguinal and abdominal lymph nodes (SUV max 2.2). A myogenic pattern of active denervation was confirmed by electromyography. Muscle biopsy did not reveal clear sign of vasculitis, only showed non-specific signs of inflammation with scarce macrophagic infiltration; no alteration of muscle fibres or perifascicular atrophy. Bone marrow and lymph node biopsy with flow cytometry were negative for malignancy.

Symptomatic treatment with indomethacin was started because of extremely painful musculoskeletal involvement associated to the development of recurrent infiltrative burning nodular skin lesions of both hands and feet. The result was a dramatic and prompt relief, but persistence of elevated acute phase reactants.

Genetic sequencing of ADA2 revealed compound heterozygosity for a novel frameshift deletion in the catalytic domain, c.1100_1113del:p.I367Tfs*41, inherited from the father, and a maternally inherited missense variant, c.1148G>A:p.G383D, previously described in compound heterozygosity in two patients with DADA2. ADA2 functional analysis confirmed pathological low activity of the enzyme. Brain angio-MRI was unremarkable. Etanercept treatment was deployed with rapid response of muscoloskeletal and skin involvement, normalization of inflammatory markers and regression of lymphoproliferation.

Results:

Weeks from disease onset	4	6	14	16	21	43	46	56	61
Therapy			Indomethacin start			Etanercept start
CRP (mg/dl)	2,64	3,19	5,13	2,08	0,9	2,53	0,05	0,05	0,05
ESR (mm/h)	52	63	52	40	35	44	13	4	2
Hb (g/dl)	11,1	9,9	9,9	9,4	10,2	9,5	10,3	11,3	12
WBC (cell/mm3)	5400	6100	7050	4990	5060	5540	4650	3260	4020
N (cell/mm3)	3760	4270	4760	2840	2910	3320	2210	1050	1890
L (cell/mm3)	850	750	1390	1380	1310	1470	1790	1570	1440

Conclusion: Here, we report a case of an unusual presentation of DADA2 with myositis and an optimal response to the anti-TNF α therapy. We described a new compound mutation with a novel ADA2 deletion leading to premature protein truncation in heterozygosity with the recently described c.1148G>A mutation. The pathogenic role of the latter, so far reported in only two siblings in compound heterozygosity, is supported by our data. DADA2 phenotype spectrum is constantly increasing and description of peculiar cases and new mutations could improve genotype/phenotype correlation leading to significant progresses in diagnosis, management and prognosis of these patients.

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Yes

Disclosure of Interest

None declared

P112 Family case of SAVI-syndrome in the practice of a rheumatologist and pulmonologist

S. Salugina¹, E. Fedorov¹, N. Lev ², S. Zhikrivetskaya ³, A. Shapovalenko¹, A. Torgashina⁴, O. Golovina⁴

¹Children, V. A. Nasonova Research Institute of Rheumatology; ²Veltishev Research and Clinical Institute for Pediatrics of the Pirogov Russian National Research Medical University of the Russian Ministry of Health; ³Veltishev Research and Clinical Institute for Pediatrics of the Pirogov Russian National Research Medical University of the Russian Ministry of Health; ⁴V. A. Nasonova Research Institute of Rheumatology, Moscow, Russian Federation

Correspondence: S. Salugina

Introduction: SAVI-syndrome – STING-associated vasculopathy with onset in infancy, a rare monogenic autosomal-dominant autoinflammatory disease associated with a mutation in the TMEM173 gene; belongs to type 1 interferonopathies. It is characterized by an early onset, fever, skin rashes (vasculopathy), arthritis, interstitial lung disease (ILD), increased levels of acute phase markers, and presence of autoantibodies (ANA, RF and other antibodies). The main treatment: glucocorticoids (GC), JAK inhibitors

Objectives: To present a family case of SAVI-syndrome in the practice of a rheumatologist and pulmonologist

Methods: Family case: three patients from the same family were sequentially hospitalized at the federal rheumatology center and diagnosed with SAVI-syndrome: 2 children-twins (2018 y.o.b.), the 1^st pregnancy (IVF), the 1^st cesarean operation (the girl was examined at the age of 1 year and 7 months, the boy – at the age of 2 years and 3 months), the children’s father (1980 y.o.b.) was diagnosed at the age of 41. All the three of them were revealed to have a genetic mutation in the TMEM173 gene c.463G> A, p.V155M in a heterozygous state. No mutation was found in the mother. Prior to the diagnosis, all these patients were monitored by a pulmonologist

Results: The main characteristics of the pts are presented in Table 1. Earlier than all, the manifestation of the disease was noted in the boy: shortness of breath from the birth, ILD, up from 1.5 months - skin rash, up from 2 years - ankle arthritis, changes in fingers like drumsticks and nail plates like watch glasses. The girl from the age of 1.5 years has suffered from skin rash, arthritis of the knees, ankles, small joints of the hands, fever, lymphadenopathy, enlarged liver, spleen, ILD in the absence of shortness of breath and manifestations of a respiratory failure. The father had a manifestation of a pulmonary pathology in the form of shortness of breath, decreased exercise tolerance from 9 years old, cutaneous vasculopathy up from 20 years old, arthritis of the knee, ankle, hand joints up from 24 years old, interstitial pulmonary involvement, fibrosis established at the age of 29. Treatment: prednisolone (Pr), cyclophosphamide, rituximab without any effect. The children were not treated. In all the patients during the course of the disease there was an increase in ESR, CRP; autoantibodies were detected. GC at a dose of 1 mg/kg in terms of Pr, tofacitinib - 5 mg per day were prescribed to the children; Pr - 5 mg per day, tofacitinib -10 mg / day were prescribed to the father. The children’s treatment duration lasted for 8 months, the father’s treatment - 1 month. During the treatment, the children showed positive dynamics in terms of the systemic inflammatory response. It is not yet possible to assess the changes in the lungs.

Conclusion: Pts suffering from the SAVI-syndrome can be encountered in the practice of a rheumatologist and a pulmonologist. Pts with an early onset, with systemic manifestations (fever, skin rashes, lymphadenopathy, hepatolienal syndrome), arthritis in combination with ILD, increased ESR, CRP, and the presence of autoantibodies require special attention. A family history is crucial to identify similar cases in relatives and to perform a genetic testing

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Yes

Disclosure of Interest

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Table 1 (abstract P112). Clinical and demographic characteristics of patients from the same family with SAVI- syndrome

P113 Biological therapy for monogenic autoinflammatory diseases - experience of using it in rheumatological practice

S. Salugina, E. Fedorov, M. Kaleda

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

Correspondence: S. Salugina

Introduction: Monogenic autoinflammatory diseases (MAIDS) are a heterogeneous group of rare genetically determined conditions, the main manifestations of which are episodes of fever in combination with other signs of a systemic inflammatory process: skin rash, musculoskeletal, neurological and other clinical symptoms often imitating a rheumatic pathology, acute phase markers, lack of autoantibodies. The most common and well-studied are 4 MAID: FMF, TRAPS, HIDS/MKD, CAPS. The use of a biological therapy in pts with MAIDS, especially IL-1 inhibitors, has led to a significant progress in the supervision of such patients.

Objectives: To present the experience of the Federal Rheumatology Center of using biological drugs (BD) in the treatment of pts with MAID.

Methods: For the period from 2008 to 2020 the study included 153 pts with MAID, of whom 48 were prescribed BD, among them 10 pts with FMF, 24–with CAPS (MWS-20, CINCA/NOMID - 4); TRAPS-11; HIDS/MKD - 3. The patient’s characteristics are presented in table 1. These were 20 male and 28 female pts aged from 1.5 to 38 years old, 40 children (under 18) and 8 adults. Interleukin-1 inhibitors were administered subcutaneously: canakinumab at a dose of 2-4 mg / kg or 150 mg per injection every 4-8 weeks, anakinra 1-3 mg / kg or 100 mg per day on a daily basis. TNF inhibitors were injected subcutaneously: etanercept at a dose of 0.4-0.8 mg / kg 1-2 times a week, adalimumab 20-40 mg once every 2 weeks. Tocilizumab was administered intravenously at a dose of 8-12 mg / kg once every 2-4 weeks. The disease duration at the time of the treatment beginning ranged from 1 to 44 years. The duration of treatment with BD for pts with MAID ranged from 3 months to 12 years.

Results: For 48 pts with MAID (31.4%) BD were used in the treatment, more often in pts with CAPS (47.1%), TRAPS (45.8%) and HIDS/MKD (50%), less often for pts with FMF (13.9%). Among BD IL-1 inhibitors (89.6%) were predominantly prescribed: canakinumab (33) and anakinra (10), which were used in half of pts with CAPS (50.9%), in a third of pts with TRAPS and HIDS (33.3 %), in 9.7% of patients with colchicine-resistant FMF. Against the background of treatment with IL-1 inhibitors, all the pts with MAID within the first few days showed a significant clinical improvement: normalization of well-being, significant improvement in mood, emotional uplift, relief of fever, disappearance of rash, decrease in the severity of lymphadenopathy and hepatosplenomegaly, relief of eye symptoms or significant positive dynamics, subjective improvement in hearing and audiogram with a further dynamic control in pts with CAPS, a decrease in the level of acute phase markers in all. In 7 patients with CAPS, receiving anakinra, after a significant positive response was achieved, switched to canakinumab, while maintaining the full efficiency. Less often tocilizumab (14.6%) and TNF-inhibitors (20.8%) were administered: adalimumab in 3, etanercept in 4, mainly in FMF and TRAPS pts with a positive response. The tolerability of therapy with BD was satisfactory in all the pts.

Conclusion: In pts with MAID BD are successfully used, more often for pts with CAPS, TRAPS and HIDS/MKD, less often for pts with FMF. Among them, IL-1 inhibitors predominate, which have shown high efficiency and good tolerance, especially in pts with CAPS.

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Yes

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Table 1 (abstract P113). The characteristics of patients with MAIDS

P114 The structural and functional changes of phospholipids in the biomembrains of lymphocytes and erythrocites for familial mediterranean fever and Henoch-Schonlein Purpura with children

H. Sargsyan, P. Ghazaryan

Republican Hematological Center, Yerevan, Armenia

Correspondence: H. Sargsyan

Introduction: According to some clinical feature of similarities (fever, abdominal pain, arthritis, skin manifestation, gastro-intestinal disorders and kidney diseases) Familial Mediterranean Fever (FMF) and Henoch-Schonlein Purpura (HSP) we attempt to identify membranes aspects of pathogeneses these diseases.

Objectives: The aim of our study is to identify some changes of individual phospholipids (PL), the activity of phospholipase A₂, glycerol kinase and glycerophosphate dehydrogenase in lymphocytes and erythrocyte membranes and comparative analysis of FMF and HSP patients.

Methods: The examinations have carried out in 85 non complicated 7-14 ages of FMF patients and 32 healthy volunteers. Clinical studies have carried out in the National FMF Children Center, Center “Arabkir”. Biochemical changes have studied in Hematological Center. 85 patients in erythrocyte and lymphocytes membranes by the separate individual PL are studied: phosphatidylcholines (PCH), phosphatidylethanolamines (PE), phosphatidylinosites (PI), sphingomyelins (SPM), phosphatidic acids (PA), phosphatidylserine (PS), cytotoxic - LysoPCH (LPCH), and above mentioned enzymes changes. Previously it has been investigated the changes of indicators during the HSP diseases. The fractions of separate PL in erythrocyte and lymphocytes membranes are carried out by thin-layer chromatography methods and decay their enzymes of phospholipase A₂, glycerol kinase and glycerophosphate dehydrogenase activity was determined by the microspectrophotometry method.

Results: Comparative studies are identified on the basis of membrane of erythrocyte and lymphocytes structural metabolism disorders, for the prevention and regulation some changes of FMF and HSP. Based on the results obtained by our research is an attempt to separate the membrane lipids metabolism disorder specific data which are responsible for affection of biomembranes.

Conclusion: According to our investigation we can conclude, that level of phospholipase A₂ and citotoxic-LPCH are increase, at the same time, decreases the level of processes of phosphatidogeneses in mentioned diseases.

Disclosure of Interest

None declared

P115 Assessment of clinical and genetic profile of greek patients with familial mediterranean fever using quantitative contemporary tools

V. Sgouropoulou, E. Farmaki, P. Pratsidou-Gertsi, M. Trachana

Pediatric Immunology and Rheumatology Referral Centre, 1st Dept of Pediatrics, Aristotle University, Hippocration Hospital, Thessaloniki, Greece, Aristotle University, Thessaloniki, Greece, Thessaloniki, Greece

Correspondence: V. Sgouropoulou

Introduction: Familial Mediterranean Fever (FMF) is the most common monogenic autoinflammatory disease, common in people of Mediterranean descent.

Objectives: To depict the clinical, laboratory and genetic profile in Greek patients with FMF, as well as to assess the severity, course, outcome of the disease using contemporary tools.

Methods: This is a single center, retrospective study including 94 young patients monitored at a paediatric rheumatology reference center in Northern Greece for a long time up to 30 years. Genotyping was performed with the conventional techniques PCR and NIRCA, disease severity was assessed at baseline with the ISSF, response to treatment with FMF50 at 6, 12 months post treatment initiation and at the end of follow-up and quality of life with GHQ-28 and SMILY-Illness questionnaires.

Results: The patients’ mean age at the disease onset was 3.49±3.04 years and the attack duration for 87.2% of the patients was 1-3 days. The clinical phenotype at the disease onset included fever (96.8%), abdominal pain (85.1%), arthralgia (54.3%), thoracic pain (45.7%), arthritis (21.3%), myalgia (20.2%), diarrhoea (19.1%), vomiting (19.1%), erysipelas-like rash (10.6%), lymphadenopathy (8.5%), splenomegaly (6.4%) and orchitis (2.1%). Regarding severity 36.2% had mild disease, 62.7% moderate and 1 patient had severe disease. The severity of the disease was significantly correlated with the M694V mutation (p=0.00), M694V/M694V homozygosity (p=0.001), rheumatic manifestations [arthritis (p=0.00)/arthralgia (p=0.002)], chest pain (p=0.00), erysipelas-like rash (p=0.001) and myalgia (p=0.00). No renal amyloidosis was observed in patients. All patients were treated with colchicine. Response to treatment was correlated with compliance to treatment (p=0.00). At 6 months post treatment onset an FMF50 score was observed in 67.02% of patients. At 12 months this score was achieved by 95.7%, by improving the patients’ compliance with experiential education, adjusting the colchicine dose, where needed and adding Canakinumab to the treatment of 3 patients. At the end of the patients΄ follow-up FMF50 score was achieved by 98.9%.The genetic profile of patients consisted of the following mutations: M694V (55.3%), M680I (29.8%), V726A (8.5%), E148Q (7.4%), M694I (3.2%), R761H, K695R and P369S (2.1% each). Molecular testing with NIRCA identified additionally R202Q (9.6%), E230K (2.1%), A761H and M694Q (1.1% each), that PCR does not include in its own panel. It was observed that homozygotes constituted 22.3% of the patients, heterozygotes 34%, compound heterozygotes 30.9%, while patients with complex genotype were 3.2%. Absence of mutation was observed in 9.6% of patients. The majority of patients showed a good quality of life. According to the GHQ-28 questionnaire, only 3 of the 78 patients were found to have some degree of psychological disorder, while the mean score of the SMILY-Illness questionnaire, which was 81.17 ± 11.93, proves the minor effect of the disease on patients' quality of life.

Conclusion: This study presented for the first time the long-term outcome of a large cohort of Greek pediatric patients and contributed in capture the national profile of the disease. FMF in Greece has a mild to moderate course. Compliance to treatment remains the cornerstone in taming disease activity, leading to a favorable outcome.

Patient Consent Received

No

Disclosure of Interest

None declared

P116 Familial cold auto-inflammatory syndrome type 1 – first report from the Indian subcontinent!

R. Shanbhag Mohite, S. Bhattad

Pediatric Immunology and Rheumatology, Aster CMI hospital, Bangalore, India

Correspondence: R. Shanbhag Mohite

Introduction: Familial cold autoinflammatory syndrome (FCAS), is a rare inherited inflammatory disorder, caused by mutation in NLRP3 gene which encodes a protein NLRP3.

Objectives: To describe a family with FCAS involving multiple members across 4-generations.

Methods: Retrospective review of clinical records was performed. A detailed clinical history including the age of presentation, symptoms, family history including details of affected family members, findings on physical examination, laboratory findings and details of treatment taken were recorded. Whole exome sequencing was performed on Next generation sequencing (NGS)platform.

Results: A 4-year-old boy, first born of non-consanguineous marriage, presented with skin rashes during the winter season from age of 2 years. The rashes were macular, red in color not associated with itching lasting for 12-24 hours. He complained of similar episodes on travelling to areas with low temperatures that resolved spontaneously. He had no history of any joint complaints or any other systemic involvement.

He had a strong family history involving at least 10 members across four generations of family members on the paternal side. All these family members reported rash during the winter season or on travel to areas with low temperature. The father had had macular rashes on the lower limbs and arms on exposure to low temperature during winter season followed by pain in ankles, knees, elbows, and small joints of fingers. Similar history was reported by the grandfather with rashes and joint pains during winters.

On examination, the boy was healthy looking, having multiple blanching macular rashes on his lower limbs on both flexor and extensor surfaces and on the soles of his feet. Systemic examination was normal. Inflammatory markers were slightly elevated, however immunological evaluation showed normal immunoglobulin levels.

In view of the strong family history, an autosomal dominant pattern of inheritance was suspected, and genetic evaluation was carried out. A pathogenic heterozygous mutation c.13222C>T (p.Ala441Val) was identified in exon 3 of the NLRP3 gene by whole exome sequencing. Father was also noted to have the same mutation. A diagnosis of FCAS was established and they were started on colchicine for the persisting complaints and are under close follow-up.

FCAS is characterized by early onset fever, urticarial rashes, and joint pains after 1-3 hours of generalized cold exposure. Cold sensitivity is unique to FCAS among the autoinflammatory disorders and has been shown to increase the activity of the transcription factor AP-1, which increases synthesis of secretory proteins from inflammatory cells.

Mean age of presentation in a large series, was 47 days, with a range of 2 hours to 10 years. The most consistent finding in all affected subjects included recurrent fever and chills (93%), arthralgia (96%) and recurrent conjunctivitis (84%). Amyloidosis was reported only in 2% among those affected. In the index family, none of the family members developed amyloidosis, suggesting a milder phenotype.

Hoffman et al studied the benefit of the IL-1 receptor antagonists in patients with FCAS. Unfortunately, IL-1 blockers are not readily accessible in our subcontinent. There are case reports of thalidomide being used, however, prolonged exposure to thalidomide is known to cause peripheral neuropathy. We chose colchicine as it seems to be least toxic among the choices available. As majority of patients with FCAS seem to have a milder phenotype especially in tropical countries, it is often a clinical dilemma deciphering the choice and duration of therapy.

Conclusion: Cold induced urticarial rashes, arthritis and fever must make one think of FCAS especially in the setting of a positive family history. To the best of our knowledge, this is the first Indian family to be reported with FCAS type 1.

Patient Consent Received

Yes

Disclosure of Interest

None declared

P117 Hypogammaglobulinemia and periodic fevers – think of TRNT1 deficiency!

R. Shanbhag Mohite, S. Bhattad

Pediatric Immunology and Rheumatology, Aster CMI hospital, Bangalore, India

Correspondence: R. Shanbhag Mohite

Introduction: Sideroblastic anemia associated with immunodeficiency, fevers and developmental delay (SIFD) is a newly described inborn error of immunity caused by TRNT1 deficiency. Not many cases have been described in literature.

Objectives: To describe a case of TRNT1 deficiency.

Methods: Retrospective review of clinical records was performed. A detailed clinical history including the age of presentation, symptoms, family history, findings on physical examination, laboratory findings and treatment details were recorded. Whole exome sequencing was performed on Next generation sequencing (NGS) platform.

Results: A 3-year-old boy born to a non-consanguineously married Indian couple, developmentally normal, presented with recurrent fevers from 6 months of age. Fever was intermittent, high grade; each episode lasting for 4-7 days and recurred 2-3 times a month occasionaly associated with loose stools and vomiting. He was also treated for pneumonia with intravenous antimicrobials twice in the past.

Family history was significant as the boy had lost two elder brothers within the first 2 years of life. Both had recurrent fevers from 6 months of age. While the first boy did not receive any blood transfusion, the second boy was transfused blood only while he was critically ill. No immunological or genetic studies had been performed in either of the children. Both parents and three daughters were healthy.

Systemic examination was normal. Immunological work up showed panhypogammaglobulinemia and low B cells. This in the setting of a family history suggestive of X-linked inheritance, a provisional diagnosis of X-linked agammaglobulinemia was made and he was started on monthly intravenous immunoglobulin (IVIG) transfusions. Despite which, he continued to have episodic periodic fevers and intermittent episodes of diarrhea, with no response to antibiotics. Inflammatory parameters were found to be elevated during the febrile episodes and they were normal while he was afebrile.

Genetic evaluation showed compound heterozygous mutation in TRNT1 gene: exon 2 – c.143_144insTT and exon 7- c.1043A>T on whole exome sequencing. A diagnosis of SIFD was established and the family has been counselled for bone marrow transplant.

TRNT1 is an enzyme necessary for mitochondrial and cytosolic tRNA function. A deficiency of TRNT1 disrupts the protein synthesis machinery, leading to multi-organ involvement. The death of two boys in the index family, misled us to think on the lines of a possible X-linked disease. However, occurrence of periodic aseptic febrile episodes with no respite despite regular IVIG infusions, pointed towards an alternate diagnosis such as TRNT1 deficiency.

In a recent study on TRNT1 deficiency, hypogammaglobulinemia was detected in 7/9 with persistent B-cell lymphopenia in a few patients. Index case was noted to have panhypogammaglobulinemia and was treated with regular IVIG infusions. He, however, did not have severe anaemia warranting transfusions, retinitis pigmentosa (RP) or developmental delay, highlighting the heterogeneity of mitochondrial diseases.

Of late, TNF blockers have been effectively used to treat periodic fevers in SIFD. However, bone marrow transplant offers a more definitive therapy in these patients. Long term neurological outcome in transplanted patients remains undetermined as of now.

Sensorineural hearing loss, nephrocalcinosis, panniculitis, myofascitis, hemophagocytic lymphohistiocytosis, thromboembolism have been reported in a few cases of TRNT1 deficiency. Fortunately, index case has none of the above mentioned manifestations and is under close follow-up.

Conclusion: TRNT1 deficiency must be considered as a differential diagnosis in children presenting with periodic fevers and hypogammaglobulinemia. We describe a 3-year-old boy with periodic aseptic febrile episodes, hypogammaglobulinemia and low B-cells due to TRNT1 deficiency.

Patient Consent Received

Yes

Disclosure of Interest

None declared

P118 Sjögren disease and Sjögren syndrome in children

O. Shpitonkova, N. Podchernyaeva, M. Osminina, V. Seraya, M. Nicolaeva, E. Afonina, J. Kostina

I.M.Sechenov First Moscow State Medical University, Moscow, Russian Federation

Correspondence: O. Shpitonkova

Introduction: Sjögren disease/syndrome (SD/SS) is uncommon in children. The standard clinical criteria used in diagnosis of adult Sjögren syndrome do not allow to make a diagnosis in children at an early stage. Xerostomia and xerophthalmia are the basic criteria of SD/SS more often revealed in late stage of the disease in children.

Objectives: To analyze and clarify the clinical and laboratory signs that indicates early stage of disease.

Methods: Analysis of 28 childhood cases SD/SS was done. All patients (pts) had satisfacted for disease criteria (Sjogren’s International Collaborative Clinical Alliance = SICCA, 2012г). All children carried out physical examination, salivary glands ultrasound investigation, sialometry, sialography, tests for xerophthalmia. Lab test included the measuring of CBC, total protein (TP), α-, β- and γ-globulins, IgA, IgM, IgG, rheumatoid factor (RF), ANA, ENA-profile with anti-SSA/Ro and anti-SSB/La detection.

Results: we observed 28 pts, aged from 3.5 to 17 years, the mean age 10.5 years, 24 girls and 4 boys (girls/boys = 7:1). SD was diagnosed in 13 girls. SS was diagnosed in 15 pts. Systemic lupus erythematosus (SLE) and SS – 11 pts ( 9 girls, 2 boys), systemic scleroderma (SSD) and SS – 2 girls, juvenile rheumatoid arthritis (JRA) and SS – 1 boy, juvenile dermatomyositis (JDM) and SS – 1 girl. Pts with SD (13) more often had mild course of the disease. Arthralgia, fatigue and low subfebrile temperature after acute respiratory infection was common complaints in all 13 pts (100%). Two girls had hemorrhagic nonspecific rush. Lab investigations revealed increased ESR in all pts (100%), leukopenia in 6 (46%) pts. Due to prolonged arthralgia, fatigue and subfebrile fever subsequent studies revealed hyper γ-globulinaemia (100%), ANA and RF in unexplained high titers (100%), and SSA/SSB antibodies (100%). Only two girls complained of dry mouth. And also two girls had episodes of recurrent parotitis. So the diagnosis was made on average 6-12 months after the onset by excluding other systemic diseases and by instrumental investigations. Salivary glands ultrasound investigation revealed initial stage of parotitis in all pts (100%) that was suggested by sialometry and sialography. As to xerophthalmia no one of patients complained of dry eyes. Low lacrimation was detected in 5 girls (38%). Low dose of prednisone and micophenolate mofetil (MF) have been used for treatment in all patients. In compare with SD course SS depend on associated rheumatic diseases and seems more aggressive. Strong fever up to 38C had all pts with SLE, one of with SSD and one pts with JRA. This two pts demonstrated high level of TP, significant hyper γ-globulinaemia with polyclonal secretion that required excluding lymphoma. Body weight loss had 6 children (40%). Generalized lymphoadenophaty had 8 pts (40%). Purpura and nonspecific rash registered in 9 (60%) children. Seven pts (46%) demonstrated Raynaud phenomenon. Six pts complained of dry mouth and 5 pts complained of dry eyes in disease onset. Twenty six pts (90%) with SS/SD demonstrated good response for immunosupressive treatment with reducing of clinical symptoms (fever, arthralgia, rush, function of salivary glands, lacrimation) after six month of treatment but not for lab parameters. Increased level of RF, ANA, anti-SSA/Ro and anti-SSB/La persisted in all patients for six month of follow up. In children with SS persistence of RF, ANA, anti-SSA/Ro and anti-SSB/La was strong despite more intensive immunosuppression. Two patients with SSD and JRA were not responsible for therapy.

Conclusion: SD/SS in children is characterized with late complain of xerophthalmia and xerostomia. Persistence of RF, ANA, anti-SSA/Ro and anti-SSB/La required the investigations for revealing of SD or SS.

Patient Consent Received

Yes

Disclosure of Interest

None declared

P119 Recurrent attacks of fever and serositis associated with multiple polymorphisms: a case report

E. Baskın, M. Siddiqui, K. S. Gülleroğlu, A. Ç. Yılmaz, O. Söylemezoğlu

Department of Pediatrics, Başkent University, Ankara, Turkey

Correspondence: E. Baskın

Introduction: Hereditary periodic fever syndromes (HPF) are a group of autoinflammatory diseases characterized by recurrent attacks of fever and localized or systemic inflammatory manifestations, mainly in serosal surfaces, joints, and skin. HPFs are monogenic autoinflammatory disorder with autosomal dominant or recessive transmission. The well-known HPFs are Familial Mediterranean fever (gene MEFV), mevalonate kinase deficiency (gene MVK), TNF-receptor associated periodic fever syndrome (gene TNFRSF1A) and Cryopyrin-Associated Periodic Syndrome (gene NLRP3). Since the discovery of known HPFs genes, many variants, with clear or unclear pathogenic significance have also been reported. The possible manifestations of these variations are still largely unknown and maybe associated with atypical presentation in patients.

Objectives: Here we describe a 13-year-old patient with recurrent attacks of fever, pleural effusion, and chronic periodontitis, whose genetic workup for autoinflammatory diseases revealed polymorphism in genes coding for the inflammasome proteins.

Methods: Genetic workup for autoinflammatory diseases revealed NLRP3 (c.2113 C>A, p.Q705K) heterozygous polymorphism located in axon 5, SH3BP2 (c.1429 C>T, p.R477W) heterozygous polymorphism in exon 11 and MEFV (c.605 G>A), p.R202Q) heterozygous polymorphism in exon 2.

Results: A 13-year-old male patient, with a history of chronic periodontitis, was hospitalized with fever, chest pain, shortness of breath and fatigue. A computed tomography (CT) scan of the thorax revealed atelectasis at lower lobes of the left lung and left-sided pleural effusion. Two years later, recurrent symptoms with left sided pleural effusion led to the second and third hospitalisation of the patient. On the second attack, the MEFV genetic analysis revealed c. 605 G> A (p. R202Q) (p. Arg202Gln) heterozygous polymorphism, which has not been reported so far with such severe symptoms. However, colchicine 1.5mg/day was initiated. The patient was hospitalised again with recurrent symptoms on the third month of colchicine treatment. Genetic testing for the autoinflammatory diseases revealed polymorphism in genes coding for the inflammasome proteins. Clinical symptoms such as recurrent fever, myalgia, pleural effusion, and chronic periodontitis in our patient were atypical compared to the CAPS forms described at present. Therefore, canakinumab treatment was initiated. He remains symptom-free at one year on canakinumab and colchicine treatment.

Conclusion: The relationship between clinical heterogeneity and weak genotype phenotype in CAPS has been previously reported, and it has been shown that disease expression may be affected by other factors in addition to specific gene polymorphism. It is proposed that NLRP3 variants with unknown clinical significance may be associated with atypic inflammatory presentation. In our case, we presumed that the associations of NLRP3 Q705K polymorphism with R202Q and SH3BP2 polymorphisms have aggravated the clinical presentation and caused the resistant findings.

Patient Consent Received

Yes

Disclosure of Interest

None declared

P120 Differentiation of phenotypes in patients carrying the Q705K mutation in the cryopyrin-associated periodic syndrome-data from the uper-aid registry

B. Sozeri¹, K. Ulu¹, T. Coskuner¹, S. Caglayan¹, S. Canbek², F. Demir¹

¹Pediatric Rheumatology; ²Medical Genetic, University of Health Sciences, Istanbul, Umraniye Training and Research Hospital, Istanbul, Turkey

Correspondence: B. Sozeri

Introduction: Cryopyrin-associated periodic syndrome (CAPS) is a hereditary autoinflammatory syndrome caused by mutations in NLRP3 (encoding cryopyrin), which presents with fever, fatigue and arthralgia and increased interleukin-1 (IL-1) secretion. There are three classical phenotypes observed: familiar cold autoinfammatory syndrome (FCAS), MuckleWells syndrome (MWS), and chronic infantile neurological, cutaneous articular syndrome (CINCA).

Objectives: We aim to describe NLRP3 gene mutations clinical presentation and relationship of phenotype and genotype.

Methods: The data of 320 patients from next generation sequencing genetic database of autoinflammatory diseases, Umraniye Training and Research Hospital, Department of Pediatric Rheumatology, were included in the study. Patients with VUS-likely pathogenic or pathogenic mutations in the NLRP3 gene were collected from these patients. In at least three months of follow-up, patients with autoinflammatory disease (AID) compatible recurrent episodes (with high acute phase response) were included, in which other etiological reasons (infectious, autoimmune, malignant diseases) were excluded. Demographic, clinical and laboratory data, treatments and responses of patients were presented

Results: 23 patients (16 male, 69.6%) were included in the study. The median age (IQR) at disease onset was 29 months ( 9 months – 5 years) and the median disease duration (IQR) was 33 months (14-40 months) . The mean number of febrile episodes was 11.2±7.3 per year and the mean duration of fever attacks was 4.45±2.50 days. The history of AID in family members was in 6 (26%) patients and consanguinity was in 3 patients. All patients were characterized by symptoms consistent with recurrent inflammatory syndrome. 52.2 % of patients (n= 12) presented with urticarial rash, 39% (n=9) with tonsillitis, 82.6% (n= 19) with arthralgia, 30.7 % (n=7) with conjunctivitis, 17.4 % (n=4) with headache. In 11/23 patients had worsening symptoms with cold contact. The phenotypes of PFAPA (n=5,21.7%), CAPS (FCAS and MWS) (n=11,47.8%) and undifferentiated AID (uAID) (n=7, 30.4%) were determined . There was no statistical significance between phenotypes in terms of median age at onset of attacks (>0.05). The most of patients (n=19, 82.6%) had Q705K variant in NRLP3 gene. Patients carrying the q705k variant had 26.3% PFAPA, 42% FCAS and 31.6% uAID phenotype. In 13 (59%) patients responded to colchicine treatment. Remained 9 (40.9%) patients had partial response or unresponsive to colchicine, were achieved to inactive disease with anti-IL 1 treatments.

Conclusion: We suggest that the Q705K variant causes autoinflammatory syndromes in a variety of phenotypes.

Patient Consent Received

Yes

Disclosure of Interest

None declared

P121 Recurrent fever: an epidemic in a pandemic?

S. Torreggiani¹, L. A. Baselli¹, M. Gallizzi², R. M. Dellepiane¹, F. Minoia¹

¹Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico; ²University of Milan, Milano, Italy

Correspondence: S. Torreggiani

Introduction: Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis (PFAPA) Syndrome is the most common periodic fever syndrome in children. It is a benign self-limiting multifactorial disorder with an estimated incidence of 2.3/10000 children up to 5 years of age. Year 2020 was dramatically affected by the Covid-19 pandemic, with a yet undefined impact on several aspects of child health.

Objectives: To describe the demographic and clinical features of pediatric patients with recurrent febrile episodes referred to a single centre, with a focus on cases with onset in 2020.

Methods: Patients referred to the Pediatric Immunology and Pediatric Rheumatology departments between 01/01/2015 and 01/05/2021 for recurrent fever without an infectious cause were included in the study. Demographic, clinical and laboratory features were retrospectively reviewed and compared between patients with fever onset before and after January 1st, 2020. For the classification of PFAPA, both the modified Marshall criteria and the Eurofever/PRINTO criteria were used. Resolution of PFAPA was defined in presence of a 3-month fever-free interval. For statistical analysis, Mann-Whitney U test and Fisher’s exact test were used as appropriate.

Results: 84 patients were included; 33 were female, 82 were white. Median age at onset was 3.7 years (IQR 2-4.6, range 0.3-12.9). Median length of follow-up was 1.3 years (IQR 1.1-2.3, range 0.5-6.4 years). 57/84 (68%) patients met the modified Marshall criteria, 72/82 (88%) patients met the Eurofever/PRINTO criteria for PFAPA. Thirty-nine patients had disease onset between 01/2015 and 12/19, while 45 patients in 2020. One patient with onset in 2015 and resolution in 2018, restarted presenting recurrent fever in January 2020. In 29 patients recurrent fever resolved during the follow-up, 39 in the 2015-2019 cohort and 10 in the 2020 cohort. Median follow-up since onset was 2.4 years in the 2015-2019 group and 1.1 years in the 2020 group. While median age at onset was not significantly different in the two groups (3.2 vs 3.8 years), in patients with onset in 2020 median time to referral was shorter (14.3 vs 7.5 months, p<0.0001) and recurrent fever episodes tended to resolve faster (median 2.3 vs 0.9 years, p<0.0001). Aphtous stomatitis and lymphadenitis appeared more common in patients with onset before 2020 (64% vs 32%, p=0.0062 and 84% vs 58, p=0.0322 respectively). Duration of fever episodes and intercritic interval, periodicity, prevalence of pharyngitis, abdominal pain and arthralgia were not significantly different between the two cohorts.

Onset	2015-2019 (n=39)	2020 (n=45)	p
Female	14/39 (35.9%)	19/45 (42%)	0.6556
Median age at onset (years)	3.2	3.8	0.5694
Median time to referral (months)	14.3	7.5	< 0.0001
Median time to resolution (years)	2.3 (n=19)	0.9 (n=10)	< 0.0001
Resolution within 1 year since onset*	1/39 (2.6%)	10/36 (27.8%)	0.0025
Aphtous stomatitis	23/36 (63.9%)	13/41 (31.7%)	0.0062
Lymphadenitis	26/31 (83.9%)	21/36 (58.3%)	0.0322
Modified Marshall Criteria	28/39 (71.8%)	29/45 (64.4%)	0.4933
Eurofever/PRINTO Criteria	33/37 (89.2%)	39/45 (86.7%)	1

1. * In patients with at least 1 year of follow-up

Conclusion: We observed an increase in referrals for recurrent fever with onset during 2020. Demographic and clinical features did not significantly differ between patients with onset in 2015-2019 and patients with onset in 2020, with the exception reduced occurrence of aphtous stomatitis and lymphadenitis, and faster referral and resolution for the latter. Whether an increase in parental attention and concern for fever episodes, or environmental factors, including SARS-CoV-2, contributed to the increase of referrals for recurrent fever still needs to be clarified.

Disclosure of Interest

None declared

P122 Role of Interferon Signature (IS) in children with chronic non-bacterial osteomyelitis

S. Della Paolera¹, C. Udina², M. Klanjscek², M. Giangreco¹, B. M. Feldman³, R. M. Laxer³, N. Naraidoo³, T. Duong³, A. Tesser¹, A. Taddio^1,2

¹Institute for Maternal and Child Health IRCCS Burlo Garofolo; ²University of Trieste, Trieste, Italy; ³Hospital for Sick Children, Toronto, Canada

Correspondence: C. Udina

Introduction: Chronic Nonbacterial Osteomyelitis (CNO) is a non-infectious inflammatory disease characterized by uni- or multifocal bone lytic lesions that may cause local pain and swelling. CNO pathogenesis remains unknown, but many findings suggest that CNO might be an autoinflammatory disorder. It has been demonstrated that some rare variants in genes involved in chronic sterile bone inflammation are often reported in CNO patients; moreover, an increased type I interferon (IFN)-induced gene expression has been described in a subset of patients with autoinflammatory diseases.

Objectives: To assess the IFN signature in a cohort of children affected by CNO, and to evaluate its possible correlations with disease activity, disease severity, clinical manifestations, presence of comorbidities and different response to treatment.

Methods: We performed a multicenter cohort study involving two tertiary pediatric rheumatology units (The Hospital for Sick Children Hospital, Toronto, Canada and Institute of Maternal and Child Health “Burlo Garofolo”, Trieste, Italy). From May 1^st 2018 to May 31^st 2019 all patients aged <18 years with an established diagnosis of CNO were considered eligible for the study. Clinical, laboratory and radiological findings were collected into an anonymized electronic database (REDCap). An IFN score (measure of IFN signature intensity) >2 was considered positive. Informed consent was obtained from caregivers. Categorical variables are presented as absolute numbers and percentages; continuous variables are reported as median and interquartile range (IQR); p-values <0.05 were considered statistically significant.

Results: 37 patients aged <18 years with an established diagnosis of CNO were enrolled. Sixteen of 37 patients (43%) had a positive IFN score with a median value of 7.37 (IQR 3.2-11.3). Patients with a positive score did not differ in age at onset of disease, clinical or radiological features of disease, laboratory findings or response to treatment when compared to those with a negative score. The presence of complications was detected in 10 of 37 patients; 7 showed a positive IFN score (p=0.07). Analysis of continuous variables showed a higher IFN score in subjects with active disease, but this was not statistically significant (p=0.18) (Table 1).

	Disease status	N	Min	25°pc	Median	75°pc	Max	Wilcoxon Mann Whitney P-value
IFN score	Active	23	0.45	0.89	2.07	8.43	23.65	0.18
	Inactive	14	0.53	0.80	1.07	3.52	12.89

Conclusion: Nearly half of children with CNO enrolled in our study had a positive IS thus suggesting an IFN autoinflammatory pathway may be involved in a subset of patients with CNO. However, in our study, the IS did not distinguish between different disease phenotypes or response to treatment, or clinical course. Further studies with larger samples and with repeated measures of IFN score are warranted.

Patient Consent Received

Yes

Disclosure of Interest

None declared

P123 Chronic nonbacterial osteomyelitis: clinical characteristics, therapy, and outcome in Turkish pediatric patients

K. Ulu¹, S. G. Karadağ², E. Bağlan³, G. Kavrul Kayaalp⁴, G. Otar Yener⁵, M. Çakan⁶, K. Öztürk⁷, H. E. Sönmez⁸, S. Özdel³, F. Demir¹, N. Aktay Ayaz⁴, B. Sözeri¹ on behalf of PeRA-Research Group

¹Pediatric Rheumatology, University of Health Sciences, Ümraniye Research and Training Hospital, Istanbul; ²Pediatric Rheumatology, Erzurum Regional Research and Training Hospital, Erzurum; ³Pediatric Rheumatology, University of Health Sciences, Sami Ulus Maternity and Children's Diseases Training and Research Hospital, Ankara; ⁴Pediatric Rheumatology, Istanbul University, Faculty of Medicine, Istanbul; ⁵Pediatric Rheumatology, Şanlıurfa Research and Training Hospital, Şanlıurfa; ⁶Pediatric Rheumatology, University of Health Sciences, Zeynep Kamil Maternity and Children's Diseases Training and Research Hospital; ⁷Pediatric Rheumatology, Istanbul Medeniyet University, Göztepe Prof. Dr. Süleyman Yalçın City Hospital; ⁸Pediatric Rheumatology, Kocaeli University, Faculty of Medicine, Istanbul, Turkey

Correspondence: K. Ulu

Introduction: Chronic non-bacterial osteomyelitis (CNO) and its severe form chronic recurrent multifocal osteomyelitis (CRMO) are considered as rare autoinflammatory diseases. It is a heterogeneous condition and is characterized by recurrent attacks of localized bone pain, swelling or loss of function in any area, mainly affecting the metaphysis of the long bones, clavicles, vertebrae, and pelvis. The pathophysiology of the disease is not fully understood, but it has been shown that there is unbalanced cytokine expression and increased inflammatory activation in patients' monocytes, a pro-inflammatory response contributing to osteitis.

Objectives: The aim of this study was to describe the characteristics and outcome of patients with CNO.

Methods: We retrospectively reviewed clinical, pathological, and radiological data of children with CNO at 8 pediatric rheumatology centers from Turkey.

Results: Sixty-seven patients were assessed (31 females and 36 males) with a median follow-up time of 20 months [min.-max. (3-70 mo.)]. The median age at diagnosis and median time of diagnostic delay were 12 years (3-17,4 yrs.) and 12 months (1-96 mo.), respectively. Arthralgia in various joints, especially in the ankle, and bone pain were the most common presenting symptoms (58.2%). Peripheral arthritis was detected in 30 patients (44.7%), isolated sacroiliitis in 12 patients (17.9%) and both type of involvement in 5 patients (7.4%).

The distribution of the lesions was examined by MRI (local or whole body) at the time of diagnosis and throughout the course of the disease: metaphysis of the long bones, especially lower extremities were affected most commonly (76.1%). Vertebrae and clavicles were affected in 19.4% and 16.4% of the patients, respectively. Biopsy was performed in 26 patients (38.8%). The disease course was unifocal non-recurrent in 8 patients (11.9%), unifocal recurrent in 4 patients (6%), multifocal non-recurrent in 37 patients (55.2%), and multifocal recurrent (CRMO) in 18 patients (26.9%). Patients with vertebral involvement had multifocal disease generally. All patients enrolled in the study received non-steroidal anti-inflammatory drugs (NSAIDs) as initial therapy, of which thirty (44.8%) were partially responsive, twenty-five (37.3%) were unresponsive, and eleven (16.4%) were in remission. Disease-modifying antirheumatic drugs (methotrexate or salazopyrin) were used in 56 patients (83.5%). Biological therapy was required in 22 patients (32.8%) with a median duration of 18 months. Among these patients, 5 (7.4%) had a flare under biologic therapy. Also four patients (5.9%) received bisphosphonate therapy. At the last visit evaluation, active disease findings were present in 8 patients (11.9%).

Conclusion: This large multicentric cohort gives a detailed evaluation of clinical presentation, extent of involvement, therapeutic approaches and outcomes of children with the diagnosis of CNO. Most of the patients had multifocal involvement and a third of them had a relapsing course. NSAIDs were not able to control disease activity alone but disease activity was controlled in most of the patients by addition of methotrexate/salazopyrin or a biologic agent.

Patient Consent Received

Yes

Disclosure of Interest

None declared

P124 Severe pulmonary fibrosis as the first manifestation of Sting Associated Vasculitis of Infancy (SAVI)

O. Vougiouka, S. Karamichalou, S. Oikonomou, G. Kolitsida, M. Tsolia

2nd Department of Pediatrics, ‘P&A Kyriakou’ Children’s Hospital, National and Kapodistrian University of Athens, Athens, Greece

Correspondence: O. Vougiouka

Introduction: SAVI is a rare autosomal or de novo heterozygous genetic disorder, classified under the newly discovered type I interferonopathies [1]. We present a case of a child with SAVI, without typical cutaneous vasculopathy and genotype.

Objectives: The presentation of a 14 month old girl, born to a consanguineous couple of Syrian descent, with multiple episodes of aggressive cough, tachypnea and failure to thrive, since the age of 6 months.

Methods: Whole exon sequencing was ordered and a novel homozygous mutation in the STING gene [(c.10822 C>T (p.Arg281Trp)] was confirmed, resulting in constitutive activation of STING protein. In addition, a strong interferon type I signature had been found in peripheral blood.

Results: The child attended the emergency department with difficulty in breathing (respiratory rate > 60/min, Paco2= 55mmHg), and low fever. Radiograph of lung demonstrated diffuse lung opacities and initial impression was of bacterial infection, so antibiotics were administered, without improvement. During her hospitalization, she entered a state of complete oxygen dependency, with increasing needs of high flow oxygen supply and occasionally fever spikes accompanied by elevation of acute inflammatory indexes: WBC (max 29.000/μl), CRP (130mg/L), ESR (51mmHg), Ferritin (360ng/ml) and SAA (30,7mg/L). While none of pathogen was identified by laboratory investigation, administration of corticosteroids was attempted with good treatment response (1-2 mg /kg/d). CT lung scan revealed diffuse lung disease and whole exon sequencing confirmed the cause. Until now, the identified mutation has been described in 8 children, all of whom of Arabic ethnicity [2]. Treatment with baricitinib, a JAK-1, 2 inhibitor, was commenced in increasing dose with impressive response (max dose: 10mg per day). As a result the deterioration of the disease stopped and at the same time the status of our patient improved: needs of oxygen supply decreased to 2 liters normal flow, oral steroids tampered (0,2mg/kg/d) and the respiratory status improved.

Conclusion: Interferonopathies are the newly added subject of current inflammatory syndromes uncovering decisive steps of etiological pathways and treatments [1]. One of them is SAVI, recognized in 2014. SAVI is formally presented as peripheral necrotizing vasculitis on which lung fibrosis and end stage respiratory failure develops [3]. There are a few cases in literature with initial lung involvement and vasculitis development under environmental circumstances [4]. Our patient never developed any kind of skin involvement, even if she had past exposure to cold. Diagnosis was challenging. Early diagnosis and treatment are of vital importance in order to avoid progression to pulmonary failure, which is the first cause of death in SAVI [3]. Clinical suspicion of SAVI among infants, presented with severe, intractable respiratory distress, is of prime importance in order to diagnose the disease, using whole exon sequencing test examination. ‘Chance favors the prepared mind’, Louis Pasteur.

REFERENCES

1. J. Munoz et al. Interferonopathies de type I, Elsevier Masson 2015, 142 (653-663)

2. M. A. Alghmadi et al, A Novel biallelic STING 1 Gene Variant Causing SAVI in two siblings, Frontier in immunology, Jan 2021, vol 11, article 599564.

3. F. Staels et al, Adult –onset ANCA – associated vasculitis in SAVI: Extension of the phenotypic spectrum, case report and review of literature, Frontier in Immunology, Sept 2020, vol 11, article 575219.

4. S. Cazzato et al. Lung involvement in monogenic interferonopathies, Eur Respir Rev 2020; 29: 200001.

Patient Consent Received

No

Disclosure of Interest

None declared

P125 Phenotypic overlap of (autoinflammation and) PLCG2-associated antibody deficiency and immune dysregulation: case series and literature search

T. Welzel^1,2, L. Oefelein¹, U. Holzer³, J. B. Kuemmerle-Deschner¹

¹Pediatric Rheumatology and Autoinflammation Reference Center Tuebingen (arcT), University Children`s Hospital Tuebingen, Tuebingen, Germany; <sup>2</sup>Pediatric Pharmacology and Pharmacometrics, University Children`s Hospital Basel (UKBB), University of Basel, Basel, Switzerland; ³Pediatric Hematology and Oncology, University Children`s Hospital Tuebingen, Tuebingen, Germany

Correspondence: T. Welzel

Introduction: Mutations in the phospholipase C gamma 2 (PLCG2) gene are typically associated with a spectrum of diseases ranging from allergy and immunodeficiency to autoimmunity and autoinflammation [1]. PLCG2 gene variants can cause the PLCG2-associated antibody deficiency and immune dysregulation (PLAID) and the autoinflammation and PLCG2-associated antibody deficiency and immune dysregulation (APLAID) syndrome. In recent years, awareness for monogenic syndromes with concomitant symptoms of autoinflammation and immunodeficiency has expanded. However, making a diagnosis is still challenging.

Objectives: To elaborate phenotype and genotype characteristics of five patients with suggestive history for autoinflammation and immunodeficiency.

Methods: This is a single center case series of five patients (P). P1 is a 44-year-old mother of 14 (P2) and 11 year (P3) old boys and twins (male/female) aged 4 years (P4, P5). They presented with recurrent fevers, episodes of conjunctivitis, lymphadenopathy, headaches, myalgia, abdominal pain, cold induced urticaria and upper airway infections. In P1 symptoms appeared in early adulthood. P2-P5 are affected since infancy. Family history was unremarkable. Parents were not consanguineous.

Work-up included physical and laboratory examinations (genetic panel test, flow cytometry for lymphocyte subsets, expression of Interleukin (IL-)2, IL-4, IL-17, IFNγ, and CFSE proliferation of T cells. High-frequency pure tone audiometry (HF-PTA), ophthalmology examination and skin biopsy were performed.

Results: Examination confirmed conjunctivitis (P1–5) and mild hearing loss (P1, P2). Skin biopsy in P1 indicated urticaria. Serum amyloid A and S100A8/A9 were slightly elevated during flares. Unswitched B-cells were decreased. Naive IgD⁺CD27^- B-cells and unswitched IgD⁺CD27⁺ B-cells were decreased, switched IgD^-CD27⁺ B-cells were slightly increased (P1-5). T-cell function was normal. Genetic testing revealed a new heterozygous missense variant (c.77C>T, p.Thr26Met) in the PLCG2.

A literature search in Pubmed and Infevers yielded reports on PLAID patients with cold-induced urticaria, recurrent infections, signs of autoimmunity, allergic diseases and granulomatous dermatitis along with immunologic findings (reduced immunoglobulins (Igs), low circulating class switched memory B cells, reduced NK cells). In APLAID patients, rash, granuloma, cutis laxa, eye inflammation, recurrent infections, abdominal pain/inflammatory bowel disease, musculoskeletal complaints and immunologic findings (reduced/normal Igs, reduced circulating class-switched CD27⁺ memory B-cells, decreased/normal NK-cells) were reported. P1-5 showed similarities to both, PLAID (cold-induced urticaria) and APLAID (eye inflammation, musculoskeletal complaints, no circulating antibodies). In addition, they displayed PLAID and APLAID symptoms (recurrent infections, abdominal pain/diarrhea, normal T-cell function). Sensorineural hearing loss (P1, P2) was reported in one APLAID patient [2].

Conclusion: This case series describes a new heterozygous missense PLCG2 variant (c.77C>T, p.Thr26Met) which might cause a phenotypical overlap of PLAID and APLAID disease patterns.

References

[1] Giannelou A, et al. Curr Opin Allergy Clin Immunol. 2014;14:491-500.

[2] Neves JF, et al. Front Immunol. 2018;9:2863.

Patient Consent Received

Yes

Disclosure of Interest

T. Welzel: None declared, L. Oefelein: None declared, U. Holzer: None declared, J. Kuemmerle-Deschner Consultant for: SOBI, Novartis

P126 Colchicine effectiveness in periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA)

T. Welzel^1,2, M. Ellinghaus¹, A. L. Wildermuth¹, N. Deschner³, S. M. Benseler⁴, J. B. Kuemmerle-Deschner¹

¹Pediatric Rheumatology and Autoinflammatory Reference Center, University Children`s Hospital Tuebingen, University of Tuebingen, Tuebingen, Germany; <sup>2</sup>Pediatric Pharmacology and Pharmacometrics/ Pediatric Rheumatology, University Children`s Hospital Basel (UKBB), University of Basel, Basel, Switzerland; ³Department of Anaesthesiology and Intensive Care Medicine, University Hospital Tuebingen, University of Tuebingen, Tuebingen, Germany; ⁴Rheumatology, Department of Paediatrics, Alberta Children`s Hospital, Cumming School of Medicine, Alberta Children’s Hospital Research Institute, University of Calgary, Alberta, Canada

Correspondence: T. Welzel

Introduction: Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is the most common recurrent fever syndrome in children. PFAPA has often a good prognosis, but disease activity dramatically impacts health-related quality of life, family and psychological wellbeing. Thus, disease control is imminent. Colchicine may be effective in reduction of disease activity in PFAPA.

Objectives: To evaluate the effectiveness of colchicine for PFAPA in children.

Methods: A cohort study of consecutive children diagnosed with PFAPA treated with colchicine was performed between 03/2012 and 12/2020. Patients were excluded if (i) genetic AID testing revealed any gene variant, (ii) they had elevated liver enzymes or decreased kidney function. Demographics, clinical features, inflammatory parameters and PGA/PPGA were collected. Disease activity was defined as patient/parent (PPGA) and physician (PGA) global assessment recorded on a 10 cm visual analogue scale, with 0 representing no and 10 maximal disease activity. PPGA/PGA was captured at baseline (colchicine start) and at follow-up. Primary outcome was colchicine effectiveness defined as improvement of disease activity (PPGA or PGA ≥2).

Results: A total of 30 PFAPA patients were included, 50% were female, median age was 5.2 years (1- 10.75). At baseline, the median PPGA was 4 (0 – 9) and median PGA was 3.5 (0 – 6). All patients had fever (mean 40.08 °C, ± 0.58°C). Median flare frequency was 4 weeks (1 – 6); flares lasted 3 to 6 days. Lymphadenopathy (100%), pharyngitis (97%) and aphthous stomatitis (47%) were commonly reported. During flares, serum amyloid A (mean 423 mg/l, SD ± 327) and C-reactive protein (mean 5.05 mg/dl, SD ± 4.8) were elevated. In the past, 11 patients (37%) were treated with corticosteroids (CS). CS reduced flare intensity in all, but increased frequency in 9 patients (82%). Median follow-up time was 3.9 months (2 – 10.6). Primary Outcome: colchicine was effective in 19 patients (63%). Of these, 13 patients (43%) achieved a PPGA reduction ≥2 and 14 patients (47%) a PGA improvement ≥2. No PPGA or PGA changes were seen in 4 and 3 patients, respectively. Secondary Outcome: Children with CS mediated increased flare frequency experienced on colchicine PGA (100%) and PPGA (55%) improvement. At follow-up, a total of 17 patients (57%) experienced any PPGA improvement and 25 (83%) had any PGA improvement. Median PPGA and PGA decreased to 2 (0 – 8 and 0 – 4, respectively).

Conclusion: Colchicine was effective in controlling disease activity in PFAPA patients. More than 60% of PFAPA patients had a PPGA or PGA improvement ≥2. In patients with CS mediated increased flare frequency colchicine effectively reduced disease activity. Taken together, colchicine is an effective treatment in PFAPA and a potent alternative to CS, particularly in PFAPA patients with CS mediated increased flare frequency.

Susanne M. Benseler and Jasmin B Kuemmerle-Deschner have contributed equally to this work and should be therefore be considered as co-senior authors.

Disclosure of Interest

T. Welzel: None declared, M. Ellinghaus: None declared, A. Wildermuth: None declared, N. Deschner: None declared, S. Benseler: None declared, J. Kuemmerle-Deschner Consultant for: SOBI, Novartis

P127 The development and preliminary validation of a scoring tool for monitoring disease activity in patients with iga vasculitis (HSP)

C. E. C. Williams¹, J. Murphy², T. Dowsett³, L. Oni¹

¹Department of Women’s and Children’s Health, Institute of Life Course and Medical Sciences; ²Royal Liverpool and Broadgreen University Hospitals; ³Department of Paediatric Nephrology, Alder Hey Children’s NHS Foundation Trust Hospital, Liverpool, United Kingdom

Correspondence: C. E. C. Williams

Introduction: IgA vasculitis (IgAV, Henoch-Schoenlein purpura, HSP) is the most common form of childhood vasculitis. The Paediatric Vasculitis Activity Score (PVAS) is an objective tool used for scoring all types of vasculitis in clinical trials and it includes 64 manifestations of various active vasculitides. However, the inclusion of some subsystems such as chest, cardiovascular and ENT suggest it may not be specific enough for evaluating IgAV disease activity.

Objectives: The aim of this study was to develop and perform preliminarily validation of a vasculitis activity scoring tool designed specifically for IgAV (the IgA-VAS) and compare performance to the PVAS.

Methods: A cohort of children with IgAV were retrospectively scored in February 2021 using both the IgA-VAS and the PVAS. Test validity, concurrent validity and inter-rater agreement were assessed. A randomly selected subgroup were also scored using a physician visual analogue scale as a marker of global disease activity. Any domains which scored 0 for all patients were excluded from the analysis.

Results: The IgA-VAS consists of 40 manifestations, each with a score from 0-10, divided into 5 domains: cutaneous, gastrointestinal, musculoskeletal, renal and other. For preliminary validation, retrospective scoring was performed in a single tertiary centre over a 5-year period. 196 children were identified; 153 met inclusion criteria. 54% were male with a median age of 5.7 years (range 0.6-16.7). Median total scores for the IgA-VAS were 7/125 (range 2-31) and 5/125 (range 2-29) for rater 1 and rater 2 respectively. Median PVAS scores were 6/63 (range 2-25) and 5/63 (range 2-20). Correlation between all overlapping domains of the two tools was strong (all r>0.5,p<0.001). Inter-rater reliability overall was low for both tools (0.131 and 0.225, p<0.001). For the IgA-VAS, inter-rater reliability was low for the cutaneous, renal and other domains (0.332, 0.237, 0.288 p<0.001) and high for the gastrointestinal and musculoskeletal domains (0.543 and 0.667, p<0.001). The general, cutaneous and renal subsystems in the PVAS had a low inter-rater reliability (0.347, 0.213, 0.304, p<0.001) and was better for the abdominal domain (0.579, p<0.001). The IgA-VAS moderately correlated with the visual analogue scale for both raters (r=0.482, r=0.362, p<0.05), however the PVAS strongly correlated with rater 1 (r=0.504, p=0.004) and moderately correlated with rater 2 (r=0.372, p=0.043).

Conclusion: The IgA-VAS has improved since its initial circulation however further work is needed to optimise the tool before prospective validation.

Disclosure of Interest

None declared

P128 Temporary colchicine treatment in children with heterozygous familial mediterranean fever - an analysis of aid-registry and JIRcohorte

C. Vinit¹, V. Hentgen¹, A. L. Hitzegrad², J. Klotsche³, E. Lainka⁴, T. Niehues⁵, U. Neudorf⁴, I. Kone-Paut⁶, C. Hinze⁷, E. M. Michalski⁷, S. Fuehner⁷, M. Hofer⁸, D. Foell⁷, T. Kallinich^2,9, H. Wittkowski⁷

¹Department of General Pediatrics, French reference center for autoinflammatory diseases (CEREMAIA), Versailles Hospital, Versailles, France; ²Pediatric Pneumology and Immunology, Charité University Medicine; ³Department of Epidemiology, German Rheumatism Research Centre Berlin, Berlin; ⁴Pediatric Rheumatology, University Children`s Hospital, Essen; ⁵Center of Pediatrics and Youth Medicine, Helios Klinikum Krefeld, Krefeld, Germany; ⁶Pediatric Rheumatology and CEREMAIA, Bicêtre Hospital APHP, University of Paris Sud Saclay, Le Kremlin-Bicêtre, Paris, France; ⁷Pediatric Rheumatology and Immunology, UNIVERSITY HOSPITAL MUENSTER, Muenster, Germany; ⁸Pediatric Rheumatology Unit of Western Switzerland, Lausanne University Hospital (CHUV), Lausanne, Switzerland; ⁹German Rheumatism Research Centre Berlin, Leibniz Institute, Berlin, Germany

Correspondence: H. Wittkowski

Introduction: Familial Mediterranean Fever (FMF) is a prototypic autoinflammatory disorder associated with MEFV pyrin-encoding gene mutations, characterized by unprovoked episodes of inflammation. In a substantial number of patients with familial Mediterranean fever (FMF) only one mutation within the MEFV gene (MEditerranean FeVer gene) can be found.

Objectives: To analyse whether colchicine can be terminated in a subgroup of these patients without reoccurrence of symptoms and/or inflammation.

Methods: All FMF-patients registered in the German AID-registry (Autoinflammatory Disease registry) and the international Juvenile Inflammatory Rheumatism cohort (JIRcohort) with a heterozygous MEFV-genotype and confirmed clinical FMF diagnosis, that stopped colchicine treatment during follow-up, where enrolled. Duration of colchicine withdrawal, reasons of re-introduction, and epidemiologic characteristics of the patients successfully terminating colchicine in comparison to patients re-introducing the medication where analysed.

Results: We identified 169 heterozygous pediatric FMF patients, in 44 of them colchicine therapy was discontinued. Among those, 27 stayed in colchicine-free remission during a follow-up of 2,04 ± 1,55 years after discontinuation. Compared to heterozygous FMF patients continuously taking colchicine (n=125) and patients who had to resume colchicine after temporary discontinuation (n=17), these patients were treated with lower initial colchicine dosages, 0,7 ± 0,32 mg/day vs 0,77 ± 0,38 mg/day (not significant). They were older at disease onset (4,84 ± 3,15 years vs 4,04 ±3,86 years) and in tendency they had lower initial CRP-levels during subclinical disease (15,68 ± 19, 56 mg/L vs. 19,07 ± 27,23 mg/L).

Conclusion: This study underlines previous observations of a non-chronic phenotype of heterozygous FMF, which follows a rather mild clinical course, may respond to lower colchicine dosages to control the disease and may require therapy only temporarily. Further prospective and long-term observations are warranted before formal recommendations for colchicine termination can be drawn.

Patient Consent Received

No

Disclosure of Interest

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P129 Evaluation of the medical conditions of first-degree relatives of patients with familial mediterranean fever

S. Yildirim, F. Haslak, M. Yıldız, A. Aliyeva, O. Koker, A. Adrovic, S. Sahin, K. Barut, O. Kasapcopur

Department of Pediatric Rheumatology, Istanbul University-Cerrahpasa, Istanbul, Turkey

Correspondence: M. Yıldız

Introduction: Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease. It was recently shown that the most common additional two diseases were juvenile idiopathic arthritis (JIA) and immunoglobulin (Ig) A vasculitis in children with FMF. Furthermore, it was demonstrated in the studies involving all age groups that the frequencies of spondyloarthropathies, Behçet disease, Sjögren disease, polyarteritis nodosa (PAN), inflammatory bowel diseases, multiple sclerosis (MS), and psoriasis were increased in patients with FMF.

Objectives: Given the strong genetic background of FMF, the diseases that have been previously demonstrated as co-exists in children with FMF should also be investigated in the other family members. Therefore, we aimed to examine the diseases of first-degree relatives (FDRs) of our pediatric patients with FMF in the present study.

Methods: In total, 449 patients with FMF and 147 patients with JIA who are being followed up at Istanbul University-Cerrahpasa Department of Pediatric Rheumatology and 93 healthy controls were interviewed between March 2019- November 2019 during routine outpatient visits. The medical conditions of their FDRs were asked. Among the FDRs of index cases, those with FMF were excluded from the study.

Results: The mean age of healthy children (n=93), patients with FMF (n=449), and patients with JIA (n=147) were 7.7 ± 4.6 years, 12.6 ± 4.8 years, and 11.6 ± 5.2 years, respectively. A total of 3071 FDRs (FMF:1975, JIA: 690, Healthy Children: 406) were included in the study. While the most common medical conditions reported among the FDRs of the patients with FMF were asthma (n=90, 4.5%), tonsillectomy history (n=66, 3.3%) and type 2 diabetes (n=59, 2.98%), the most common medical conditions detected among the FDRs of the patients with JIA were type 2 diabetes (n=17, 2.4%), asthma (n=15, 2.1%) and tonsillectomy history (n=13, 1.8%). Among the FDRs of the healthy children, asthma (n=15, 3.69%), tonsillectomy history (n=12, 2.95%), and type 2 diabetes (n=6, 1.47%) were the most commonly detected ones. The frequencies of acute rheumatic fever (ARF), asthma, allergic rhinitis, and appendectomy history were significantly higher among the FDRs of the patients with FMF compared to other FDRs (all <0.05).

Conclusion: This is the first study evaluating the FDRs of patients with FMF. ARF, asthma, allergic rhinitis, and appendectomy history were found to be significantly more frequent in FDRs of the patients with FMF compared to the FDRs of healthy children and the patients with JIA.

Patient Consent Received

Yes

Disclosure of Interest

None declared

P130 A Very precocious inflammatory colitis: a case of A20 haploinsufficiency (HA20)

F. Biscaro, L. Zanatta, V. Piazza, S. Martelossi

Pediatric, Ca' Foncello Hospital, Treviso, Italy

Correspondence: L. Zanatta

Introduction: We describe a case of non-specific colitis as the first manifestation of an autoinflammatory disease.

Objectives: A., 12 months old, comes to our attention for severe normocytic anemia, without signs of hemodynamic failure. From 3 months of age, A. had a history of bloody diarrhea during exclusive maternal breast-feeding. This condition was diagnosed as allergic proctitis and maternal diet free of milk and derivatives was started. The weaning was conducted in a diet free from milk too. Despite a reduction in bloody diarrhea complete resolution of the symptom never occurred. At admission to our Center, the patient performed a colonoscopy, which revealed the presence of small, eroded translucent nodules and bleeding mucosa suggestive of nodular lymphoid hyperplasia throughout the colon. Histological examination showed active colitis without signs of colitis IBD or allergic colitis. After discharge, we began oral steroid therapy and gastroenterological follow-up. Two weeks later, during steroid withdrawal, A. came to Emergency Room for acute panniculitis of the limbs for which we prescribed an anti-inflammatory therapy. After 48 h the skin condition worsened and she was febrile and suffering. Therefore, A. was hospitalized for further investigations. Blood tests showed a rise in inflammation indexes. Given the inflammatory status, intravenous steroid therapy was started with rapid response. At each attempt to stop steroid treatment, the same symptoms recurred. We also noted the presence of adverse effects related to therapy (Cushing-like aspect and irritability).

Methods: In differential diagnosis, the following hypotheses were evaluated and relative tests were performed. 1) Haematological disease: bone marrow aspirate negative for neoplastic conditions. 2) Infectious disease: swabs for viruses and bacteria, as well as serological tests all negative. No history of COVID19 or contact with COVID19 patients. 3)Immunological/inflammatory disease: family history of autoimmune conditions (father with recurrent oral aphthosis, vitiligo and thyroiditis) and unkown diseases with early-onset (paternal grandfather with liver disease started when he was young, brother of paternal grandfather died at 16 years old due to unexplained causes). Therefore, first level autoimmune tests were done, resulted all normal. Then the possibility of early-onset chronic inflammatory bowel disease (VEO-IBD) were evaluated but genetics was negative. Finally, since autoinflammatory genesis was suspected, interferon signature and molecular investigations of the main known genes responsible for auto-inflammatory diseases were performed. These tests revealed mutation in TNFAIP3, leading to the diagnosis of haploinsufficiency A20 (HA20). In view of this diagnosis, therapy with a biological drug, IL1 receptor antagonist (Anakinra), was started.

Results: HA20 is an autoinflammatory disease due to a loss of function of A20 protein, whose role is to down-regulate the pro-inflammatory pathway of NF-kb. It is autosomal dominant, with early-onset and with very heterogeneous manifestations even within the same family. This condition is often called Behcet-like, with which it shares some features (oral ulcers, gastrointestinal and skin involvement). Regarded A., the disease appeared at 3 months of age with ulcerative colitis and later skin manifestations started. Probably father and paternal grandfather have the same condition but with milder manifestations.

Conclusion: This case taught us that HA20 should be considered in patients with very early-onset inflammatory disease, characterized by colitis as the first manifestation and cutaneous involvement, often with positive family history.

Patient Consent Received

Yes

Disclosure of Interest

None declared

e-Poster viewing: Uveitis

P131 Challenging a case of intermediate uveitis in a young female

A. M. A. Abushhaiwia¹, Y. AElfawires¹, A. Ateeq², A. A. Abdullah³, A. Nuwayji², A. M. Kouklah²

¹Paediatric Rheumatology, Tripoli Children's Hospital, Faculty of Medicine, Tripoli university; ²Paediatric Rheumatology; ³Paediatric Rheumatology, Tripoli Children's Hospital, Tripoli, Libya

Correspondence: A. M. A. Abushhaiwia

Introduction: Intermediate uveitis (IU) is described as inflammation in the anterior vitreous, ciliary body and the peripheral retina. The diagnostic term pars planitis should be used only for that subset of IU where there is snow bank or snowball formation occurring in the absence of an associated infection or systemic disease (that is, “idiopathic”). It is usually bilateral and is usually asymmetric in severity. Pars planitis is a chronic condition that may reoccur for many years. Hereby, we are presenting one rare case report of a 13-year Libyan girl who was diagnosed with intermediate uveitis

Objectives: illustrating importance of not considering all types of uveitis as pars planitis, and the need to rule out sarcoidosis, multiple sclerosis and Lyme disease as possible causes.

Methods: case report study

Results: A 13-year-old Libyan, female presenting to our Rheumatology clinic, Dec/2020 with blurred vision and floating objects for one month involving her Lt > than Rt eye, not associated pain nor irritation, with history of previous episodes of bilateral uveitis in 2017 and 2018. Managed with topical steroids and mydriatics under ophthalmology care. There was no history of trauma, headaches, tick bites, fever, rash, joint pain or swelling, cough, respiratory distress, oral ulcer, no weakness, numbness, or clinical features suggestive of enthesitis or other organ system involvement. There was significant family history of autoimmune diseases (vitligio, psoriasis, her father has vaculitis churge Strauss syndrome). Neurological examination was free with pain free eye movement, no diplopia . On detailed ophthalmological evaluation, she was found to have the presence of vitreous reaction more on left eye suggesting inflammatory exudates, predominantly near pars plana region (vitritis), thereby diagnosis of bilatral intermediate uveitis (pars planitis) was established, with no retinal (no macular edema), corneal, or choroidal involvement. She was evaluated to exclude other systemic associations such as JIA, sarcoidosis, TINU and MS. Blood tests, CBC with differential, ESR, CRP, Toxocara, CMV and Toxoplasma titres, ACE level, serum creatinine, ANA, (HLA) B27, testing for syphilis, TB, hepatitis, HIV, c-ANCA, p-ANCA and RF all were within normal limits, chest X-ray and MRI brain were within normal limits, urinary β2-microglobulin also normal . Diagnosis was consistent with idiopathic pars planitis with no macular oedema and minimal visual acuity involvement. She was started on local therapy, followed by oral steroid (prednisolone) 1 mg/kg/day for 2 weeks, tappered over the next 4 weeks. Her vision improved dramatically, with V/A 10\10 bilaterally. A relapse after few months bilateral pars planitis affecting Lt eye more (moderate vitritis and minimal decreased in visual acuity of left eye 6\10). She was started a short course of repeat oral prednisolone for 4 weeks and on methotrexate injection at 15 mg/m2/week in April 2021, with consideration of Humira (40 mg/every other week) according to her response.

Conclusion: To highlight the importance of the detailed description of type of uveitis by ophthalmologists considering that they are playing a major role and can guide the rest of work up and management in such cases.

Patient Consent Received

Yes

Disclosure of Interest

None declared

P132 Visual function and quality of life: a cross-sectional study on a cohort of juvenile idiopathic arthritis-associated and idiopathic uveitis

G. B. Beretta¹, F. Minoia¹, L. Marelli², C. Mapelli¹, G. Leone¹, M. Rossano¹, T. Giani³, P. Nucci^2,4, E. Miserocchi⁵, R. Cimaz^4,6 on behalf of Pediatric Rheumatology Associated Group of the Milan Area

¹Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico; ²Ospedale San Giuseppe, IRCCS Multimedica, Milan; ³Università di Siena, Siena; ⁴Università degli Studi di Milano; ⁵San Raffaele Scientific Institute; ⁶ASST Gaetano Pini-CTO, Milan, Italy

Correspondence: G. B. Beretta

Introduction: Juvenile idiopathic arthritis (JIA) is the main cause of chronic uveitis in childhood and JIA associated uveitis (JIA-U) is the most common extraarticular complication of JIA. Despite continuous improvement in its management, pediatric uveitis still represents a serious condition with potential sight-threatening complications and a significant impact on quality of life (QoL).

Objectives: To evaluate visual function (VF) and QoL in children with JIA-U and idiopathic uveitis.

Methods: A cross-sectional study was conducted in two tertiary Pediatric Rheumatology Centres, enrolling all patients seen with JIA-U, JIA without uveitis and idiopathic uveitis. VF was assessed by a translated form of the available EYE-Q, adapted for cross-cultural feasibility into a 10-question tool, while QoL was evaluated by the Italian version of the Pediatric Rheumatology Quality of Life scale part of the Juvenile Arthritis Multidimensional Report (JAMAR), shortened for feasibility to an 8-question tool. JAMAR section on treatment compliance and school attendance was also included. Parents, and patients when appropriate, were asked to complete each patient/parent-reporting outcome measure, answering on a 4-point Likert scale, with a total score ranging from 0 to 72 (worst condition). Medical charts were reviewed regarding JIA and uveitis features and outcome. Quantitative and qualitative variables were compared by means of Mann-Whitney U test or chi-square/Fisher exact test, as appropriate; correlations among quantitative non-parametric variables were evaluated by Spearman’s test.

Results: We describe results from 170 patients enrolled (72.9% female), with a median age at study time of 12.9 (9.3-16.4) years. Seventy-seven had JIA-U, 72 JIA without uveitis and 21 idiopathic uveitis. Uveitis was active in 22/98 patients (22.4%), with a median of uveitis duration of 8.0 years (3.7-13.0). Almost all children with uveitis were on systemic treatment (89/98, 90.8%) at the time of interview; 48.0% of patients presented an ocular damage, with 7.1% having a best corrected visual acuity (BCVA) < 4/10. Total score, VF and QoL scores resulted significantly higher in JIA-U patients compared to JIA without uveitis, while no differences were noticed among children with uveitis with or without JIA (Table 1). VF was significantly worse in patients with ocular damage and BCVA < 4/10 (p 0.0242 and 0.0039, respectively). In patients with uveitis, VF and QoL showed a significant correlation (r 0.47, p <0.0001) especially in patients with idiopathic uveitis (r 0.61, p <0.0001).

Conclusion: Visual function is a crucial component of QoL in children with uveitis and it correlates with ocular damage. Since eye involvement significantly affects QoL in patients with JIA, a specific tool widely validated and cross-cultural adapted is highly demanded in the clinical care of JIA-U patients.

Patient Consent Received

No

Disclosure of Interest

None declared

Table 1 (abstract P132). See text for description

P133 The features of the articular course in JIA patients, who developed uveitis or not

M. Chakhalian, E. Gaidar, T. Nikitina, E. Isupova, I. Chikova, M. Dubko, V. Masalova, T. Likhacheva, L. Snegireva, M. Kaneva, O. Kalashnikova, V. Chasnyk, M. Kostik

Saint Petersburg State Pediatric Medical University, Saint-Petersburg, Russian Federation

Correspondence: M. Chakhalian

Introduction: juvenile idiopathic arthritis (JIA) is the commonest rheumatic disease of childhood and JIA-associated uveitis is the most frequent extra-articular manifestation [1]. There is little information on the characteristics of the articular status in JIA children with uveitis.

Objectives: our study aimed to describe joint involvement in JIA patients depending on the uveitis.

Methods: in the retrospective study 520 JIA children were included.

Results: Uveitis was in 116 (22.3%) patients. Patients with uveitis, were ANA-positive (OR=2.4 95% CI: [1.4; 4.0], p=0.001, the number of affected joints was less. The main affected joints in JIA patients with uveitis were knee (22.4%), ankle (19.1%), PIP (16.3%), foot joints (15.2%), MCP (13.5%), elbow (12.8%). The main predictors were oligoarthritis (OR= 2.5 [95%CI: 1.6; 3.9], p=0.00003) and relapsed JIA course (presence of flares) 31% vs 14.9% (OR=2.6 [95%CI: 1.6; 4.2], p=0.00008). Absence of arthritis of specific joints (table) had a protective effect against uveitis.

Parameter	OR (95%CI)	р
Arthritis of the wrist joint	0,47 (0,26; 0,83)	0,0002
Arthritis of the metacarpophalangeal joint	0,47 (0,26; 0,83)	0,012
Arthritis of the distal interphalangeal joint	0,22 (0,1; 0,7)	0,006
Arthritis of the hip joint	0,37 (0,2; 0,72)	0,003
Talocalcaneal arthritis	0,53 (0,1; 0,83)	0,015
Cervical spine	0,42 (0,2; 0,88)	0,018
Temporomandibular joint	0,11 (0,01; 0,78)	0,007
Shoulder joint	0,17 (0,04; 0,7)	0,006
Elbow joint	0,46 (0,24; 0,88)	0,016

Conclusion: relapsed course of JIA, oligoarthicular category, ANA-positivity and involvement of specific joints were predictors of uveitits in JIA patients, whom precise ocular examination required.

References

1. Ethan S. Sen, A.V. Ramanan Clinical Immunology, Vol.211, February 2020, 108322.

Trial registration identifying number: This work supported by the Russian Foundation for Basic Research (grant № 18-515-57001)

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Yes

Disclosure of Interest

None declared

P134 The profile of uveitis, required adalimumab treatment: single centre experience

M. Chakhalian¹, E. Gaidar¹, T. Nikitina¹, E. Isupova¹, I. Chikova¹, M. Dubko¹, V. Masalova¹, T. Likhacheva¹, L. Snegireva¹, M. Kaneva¹, O. Kalashnikova¹, A. Kononov², V. Chasnyk¹, M. Kostik¹

¹Saint Petersburg State Pediatric Medical University; ²North – Western State Medical University named after I.I. Mechnikov, Saint-Petersburg, Russian Federation

Correspondence: M. Kostik

Introduction: chronic autoimmune uveitis often associated with juvenile idiopathic arthritis (JIA) or could be alone. For patient whom topical corticosteroids fold, methotrexate (MTX) and subsequent adalimumab (ADA) are treatment options.

Objectives: to evaluate features and outcomes of uveitis, required treatment with adalimumamb.

Methods: in the retrospective study we used 280 charts of patients with uveitis, treated in the pediatric rheumatology department since 2008 to 2019 year, who had at least 2 years of observation period and had all necessary data for study inclusion. After selection we included 167 JIA patients with uveitis and 17 patients with chronic anterior uveitis (121 girls and 63 boys) whom metotrexate MTX (n=48) or ADA±MTX (n=136) were initiated due to failure of previous treatment. All patients initially received MTX, and ADA was added if MTX fold. Treatment with ADA±MTX might be initiated as first-line in the cases of vision-threatened complications.

Results: Uveitis types were: chronic anterior (n=149), peripheral (n=6), posterior (n=3) and panuveitis (n=26). Unilateral involvement was in 54 and 134 had bilateral involvement. JIA categories were distributed subsequently: 118 (70.7%) had oligoarthritis, 32 (19.2%) - polyarthritis, 10 (6.0%) - enthesytis-related arthritis, and 7 (4.1%) - psoriatic arthritis. In 151/167 (90.4%) arthritis preceded to uveitis and in 14 (9.6%) uveitis was before arthritis. ANA positivity was in 56/184 (30.4%) and HLAB27 was in 22/167 (13.2%). Uveitis de novo was in 11/167 (6.6%) patients after etanercept treatment. Uveitis remission achieved 140 (76.1%) in 1.5 (0.4; 4.9) years and 78/140 (55.7%) patients experienced at least one flare in 4.5 (3.2; 6.1) years. In 71 (38.6%) uveitis-related complications were detected during the first visit to our centre in 0.8 (0.2; 2.8) years after uveitis onset and following complications during the treatment developed 27 (14.7%) patients, so 98 (53.3%) patients developed at least one uveitis-related complication during the study. Eye surgery had 29 (15.8%) in 1.8 (0.4; 3.0) years. No differences in gender distribution, number of involvement eyes, ANA and HLA B27 positivity, achievement of the uveitis remission depending the ADA or MTX treatment. Prescribing of ADA was a predictor of uveitis, other than anterior (OR=4.6 [95%CI:1.3; 15.9], p=0.009) primary uveitis-related complications (OR=8.1 [95%CI: 3.0; 21.7), eye surgery (OR=5.7 [95%CI:1.3; 25.0]), oligoarthicular JIA category (OR=2.5 [95%CI:1.2; 5.1]). After ADA initiation the flare frequency, time before flares and frequency of secondary uveitis-related complications became equal.

Parameter	MTX (n=48)	ADA±MTX (n=136)	p
Uveitis subtypes, n (%)
anterior	45 (93.8)	104 (76.5)	0.062
peripheral	0 (0)	6 (4.4)
posterior	0 (0)	3 (2.2)
panuveitis	3 (6.2)	23 (16.9)
Chronic uveitis withour arthritis, n (%)	0 (0)	17 (12.5)	0.011
JIA category, n (%)
oligoarthritis	27 (56.3)	91 (76.5)	0.029
polyarthritis	16 (33.3)	16 (13.4)
entesytis-related arthritis	3 (6.2)	7 (5.9)
psoriatic arthritis	2 (4.2)	5 (4.2)
Time, before remission, years	0.7 (0.1; 3.1)	2.2 (0.6; 5.0)	0.0006
Primary uveitis-related complications, n (%)	5 (10.4)	66 (48.5)	0.000003
Eye surgery, n (%)	2 (4.2)	27 (19.9)	0.010

Conclusion: ADA treatment was associated with poor-prognostic uveitis resistant to MTX treatment. Treatment with ADA encouraged to previously non-achievement remission.

Trial registration identifying number: This work supported by the Russian Foundation for Basic Research (grant № 18-515-57001)

Patient Consent Received

Yes

Disclosure of Interest

None declared

P135 Childhood chronic idiopathic uveitis in a multicentre international cohort: a descriptive analysis

I. Maccora¹, C. Guly², C. De Libero³, A. V. Ramanan⁴, G. Simonini⁵

¹Neurofarba department, Rheumatology Unit, Meyer children’s University Hospital, Florence, Italy; ²Bristol Eye Hospital, Bristol, United Kingdom; ³Ophathalmology Unit, Meyer children's University Hospital, Florence, Italy; ⁴Paediatric Rheumatology, Bristol Royal Hospital for Children, Bristol, United Kingdom; ⁵Neurofarba department, Rheumatology Unit, Meyer Children's University Hospital, Florence, Italy

Correspondence: I. Maccora

Introduction: Nonetheless the most frequent form of uveitis in paediatric age, there is fair evidence regarding chronic idiopathic uveitis (CIU) in childhood

Objectives: To describe the demographic, clinical, laboratory and ophthalmological characteristics of children with CIU

Methods: This is a multicentre retrospective chart review observational study recruiting children affected by CIU, who attended the uveitis clinic of Bristol and Firenze Children Hospital (1^st Jan2019 - 31^st Jan 2020). Demographic, clinical and laboratory data of enrolled children were collected at disease onset, and at 3, 6, 12 months, and the last available follow-up

Results: Data of 126 (61 F) children with diagnosis of CIU were entered. The median age at diagnosis was 9.3 years (3-16 years), median time of follow-up 46 months (4-149 months). 111 (88.8%) were Caucasian, 5 (4%) African, 5 (4%) Asian, 3 (2.4%) Arab and 1 (0.8%) mixed. Uveitis was bilateral in 106 patients (84.1%). Sixty-eight patients had an anterior involvement (54%), 29 intermediate (23%), 15 anterior plus intermediate (11.9%), 13 panuveitis (10.3%) and one a posterior involvement (0.8%). Ocular signs and symptoms at onset have been reported in the 77.9% of patients (95), of whom 31.6% reported ocular pain (30), 57.9% ocular redness (50) and 55.8% blurred vision or floaters (53). The mean of ESR was 11.9 mm/h (SD ±12) and of CRP was 0.47 (SD ± 0.92). ANA positivity was reported in the 26.1% of patients, ANCA in the 5.5%. ANA positive patients were younger than ANA negative (F18.1, p<0.001), as well as ANA positivity was more frequently in female gender (χ² 3.9, p 0.04). At the onset, the 54.7% of patients (47) had normal VA, while impaired visual acuity and blindness were reported respectively in the 31.4% (27) and 14% (12). The mean value of best corrected visual acuity (BCVA) was 0.425 LogMAR (SD ± 0.63). At the last available follow-up, the 83.2% had a normal VA (99) while impaired VA and blindness were reported in the 12.6% (15) and 4.2% (6) respectively. The mean value of VA in LogMar was 0.14 (SD ± 0.42). A significant improvement in VA logmar was observed in all patients at the last available follow-up (p <0.001). The 85.6% of patients (89) showed at least one complication at onset, while 46.8% (59) at the last follow-up. Stratifying by different anatomical subtypes, anterior uveitis was more frequently in Asians (χ²: 4.5 p= 0.034). ANA were significatively more frequently positive in patients with the anterior subtype (χ²: 15.1 p= 0.002). No differences have been detected in age at onset. At the onset, panuveitis had worse BCVA (0.9, p=0.03), an increased number of complications (4, p=0.011), and was associated with the presence of retinal vasculitis (χ² 36.1, p<0.0001). Conversely, anterior uveitis presented more frequently posterior synechiae (χ² 19.1, p <0.000) and band keratopathy (χ²15.8, p =0.001). At the last available follow-up, a significative proportion of cataract were observed in panuveitis (χ² 12.3, p 0.006), whilst epiretinal membrane and multifocal choroiditis in intermediate uveitis (χ²19.5, p < 0.0001, χ² 21.3 p < 0.0001) and band keratopathy in anterior uveitis (χ² 8.7 p 0.033).

Conclusion: We report a large descriptive, retrospective cohort of idiopathic chronic uveitis in childhood. No predominance of gender was observed in idiopathic uveitis, that is in contrast with JIA associated uveitis

Disclosure of Interest

None declared

P136 Effectiveness of Humira in unilateral complicated uveal cataract treatment in juvenile idiopathic arthritis (JIA). Case report

M. Lekishvili¹, M. Gavura², K. Mamamtavrishvili², M. Ioseliani¹

¹Rheumatology; ²New Hospitals, Tbilisi, Georgia

Correspondence: K. Mamamtavrishvili

Introduction: Juvenile idiopathic arthritis ( JIA) is the most common rheumatic disease of childhood. Ocular inflammation may occur at any time in the course of JIA. JIA associated uveitis its most common extra-articular manifestation. The treatment of the uveitis in children is often unsuccessful and can result in various complications.

Objectives: We present case of patient with JIA association uveitis. The patient is a 5 years old female with the unilateral uveitis in JIA diagnosed in 2020. With intact vision in the right and markedly reduced vision in the left eye (VIS OD 20/20, VIS OS 20/2000).

Slit lamp exam shows transparent cornea, anterior uveitis complicated cataract with posterior synechia. eye fundus not visible. IOP is normal in both eyes.

B. Scan Ultrasound (US) - Vitreous body clear, within normal limits (WNL), retina attached.

Methods: For 3month the patient was treated with the combination of Methothrexate, 7,5 mg orally once a week, Methilprednizolone 2 mg orally daily and Humira 20 mg per 2 weeks. 2weeks prior the surgery Methotrexate was discontinued. The operation,

Cataract phacoemulsification and intraoccular lens implantation in the

posterior chamber was performed on 5/20/21.

Surgical intervention consisted of the opening of the posterior synechia and the anterior vitrectomy.

Results: Marked improvement in vision without exacerbation of the anterior uveitis. Visual acuity was considerably improved to 20/40 in the left eye.

Conclusion: Success of the presented case is attributed to the above combination of Used of Methotrtexate, Methilprednizolone and Humira, resulting in marked improvement of vision without postsurgical complications.

Patient Consent Received

Yes

Disclosure of Interest

None declared

P137 Predictive factors for lack of response to treatment in a long-term cohort of patients with juvenile idiopathic arthritis-associated uveitis

F. Minoia¹, L. Marelli², F. Pregnolato³, G. B. Beretta¹, C. Mapelli¹, G. Leone¹, G. Cincinelli³, T. Giani⁴, P. Nucci^2,3, R. Cimaz^3,5, E. Miserocchi⁶ on behalf of on behalf of the Pediatric Rheumatology Associated Group of the Milan Area

¹Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico; ²Ospedale San Giuseppe, IRCCS Multimedica; ³Università degli Studi di Milano, Milan; ⁴Università di Siena, Siena; ⁵ASST Gaetano Pini-CTO; ⁶San Raffaele Scientific Institute, Milan, Italy

Correspondence: F. Minoia

Introduction: Uveitis is the main extraarticular complication of juvenile idiopathic arthritis (JIA) with still a significant impact on JIA morbidity, despite continuous improvement in systemic treatment. Although antinuclear antibody positivity and early onset of JIA have been associated with a high risk of uveitis onset, no clinical features have been widely recognized as predictive factors for JIA-associated uveitis (JIA-U) lack of response to treatment, so far.

Objectives: To investigate clinical features associated with lack of response to systemic treatment in a long-term cohort of patients with JIA-U

Methods: Clinical records of patients with JIA-U were retrospectively reviewed with regard to clinical features, therapeutic choices and outcome. The role of potential predictors for lack of response to treatment has been assessed at bivariate and multivariate levels. Furthermore, a multivariable logistic model has been applied in order to estimate the strength of association between predictors and outcome, adjusting for potential confounders.

Results: Data from 152 JIA-U patients were analysed (82.2% female), with a median follow up of 12.0 years (IQR 9.9) and a median age at uveitis onset of 4.8 (4.1) years. In 72 patients (43.4%) at least one biologic DMARD (bDMARDs) to control uveitis was required. Compared to patients responsive to a monotherapy with a DMARD (n=38), children requiring a bDMARDs for uveitis had a lower median age at uveitis onset, a longer disease duration and a greater frequency of bilateral uveitis at onset (Table). No difference was observed in uveitis activity grade at onset. Despite similar frequency of ocular damage at onset, patients not responsive to DMARDs showed a higher percentage of ocular damage at last visit (66.7% vs 39.5% p=0.011). Multivariable analysis confirmed younger age at disease onset as an independent factor for lack of response to DMARDs (p 0.018). Male gender is associated with higher frequency of ocular surgery (33.3% vs 12.4%, p=0.043), and, despite the inaccuracy of the estimate due to limited sample size, acts as an independent factor in multivariable analysis with an almost 9 times higher risk to lack of response to DMARDs (p=0.049).

	Monotherapy with DMARDs (n=38)	bDMARDs for uveitis (n=72)	p-value
Gender, %M (n)	7.9 (3)	25.0 (18)	0.055
Age at uveitis onset (yr), median (IQR)	6.0 (3.3)	4.1 (4.3)	0.008
Duration of disease (yr), median (IQR)	10.4 (8.0)	13.4 (10.7)	0.047
Oligoarthritis persistent course, % (n)	84.2 (32)	72.2 (52)	0.053
ANA positive, % (n)	89.5 (34)	94.4 (68)	0.444
Positive acute phase reactants at onset, % (n)	68.2 (15)	78.4 (29)	0.575
Active arthritis at uveitis onset, % (n)	57.6 (19)	72.7 (48)	0.197
Ocular damage at onset, % (n)	18.2 (6)	26.9 (18)	0.480
Bilateral uveitis at onset % (n)	50.0 (19)	77.8 (56)	0.006

Conclusion: Younger age at uveitis onset and male gender are predictors of a worse response to DMARDs, while the length of follow-up exerts a confounding effect on bilateral uveitis. Children resistant to conventional treatment need prompt recognition and additional strategies to improve long-term outcome

Disclosure of Interest

None declared

P138 Paediatric non-infectious granulomatous uveitis: retrospective cohort study

A. T. Nguyen¹, A. Rousseau², B. Bodaghi³, P. Dusser¹, L. Rossi¹, C. Galeotti¹, E. Da Cunha², L. Eid², M. Labetoulle², E. Barreau², C. Titah⁴, I. Koné-Paut¹, C. Borocco¹

¹Department of Paediatric Rheumatology, CeReMAIA, CHU Bicêtre, Assistance Publique - Hôpitaux de Paris, Université de Paris Saclay; ²Department of Ophthalmology, OPHTARA, CHU Bicêtre, Assistance Publique - Hôpitaux de Paris, Université de Paris-Saclay, Le Kremlin-Bicêtre; ³Department of Ophthalmology, Hôpital de la Pitié-Salpêtrière, Assistance Publique - Hôpitaux de Paris; ⁴Department of Ophthalmology, Fondation Ophtalmologique de Rothschild, Paris, France

Correspondence: A. T. Nguyen

Introduction: Paediatric-onset granulomatous uveitis (PGU) is rare. In addition, the lack of awareness often leads to diagnosis delay and poor visual outcome. Determining the underlying cause is essential and challenging. In addition, the care of these patients still lies on very little data.

Objectives: To evaluate the demographics, aetiologies, complications, treatments and visual prognoses of paediatric non-infectious granulomatous uveitis

Methods: Retrospective chart review of PGU occurring in children before 16 years of age and recruited from the paediatric rheumatology department at Bicêtre Hospital, France from 2001 to 2021. Our study excluded infectious uveitis. Our definition of inactive disease and remission followed the Standardization of Uveitis Nomenclature criteria. (1)

Results: We included 43 patients with 80 affected eyes: 24 had idiopathic uveitis, 13 had sarcoidosis-associated uveitis, 3 had NOD2 mutation-associated uveitis, 2 had juvenile idiopathic arthritis-associated uveitis, and one had Vogt-Konayagi-Harada disease. The median age at diagnosis was 10.2 years. Sex-ratio M/F was 0.72. Features of PGU were mostly: panuveitis (63%), bilateral (84%), and evolving chronically (84%). Granulomatous features consisted in mutton-fat keratic precipitates (65%) in all aetiologies. Choroidal granulomas and iris nodules were present more in sarcoidosis-associated uveitis than in idiopathic uveitis (31% vs 17%, p=0.4 and 38% vs 8%, p=0.07). All but 5 patients with sarcoidosis had ocular symptoms before other manifestations, which included mainly lung damage in 38%, then liver damage (23%), lymph node involvement (23%), lymphocytic meningitis (23%), arthritis (15%), hearing loss (8%), and cutaneous lesions (8%). Features leading to diagnosis of sarcoidosis were mainly lymphopenia, hypergammaglobulinemia, elevated lysozyme and ESR. None of the investigations were relevant for the diagnosis of Blau syndrome, excepted screening for NOD2 mutation. None of the patients with NOD2 mutation exhibited neither granulomatous polyarthritis and dermatitis, nor extraocular symptom. Ocular complications at diagnosis and/or during follow-up were present in 62 eyes out of 80 (78%). The most used treatments were systemic corticosteroids (79%), methotrexate (79%), TNF-alpha monoclonal antibody (42%), and azathioprine (16%). Twenty-seven per cent of eyes were on remission at last follow-up, 67% were inactive and 5% remained active. The median duration of follow-up was 4.8 years.

Conclusion: We report herein the first significant cohort focused on paediatric non-infectious granulomatous uveitis. PGU are idiopathic in most cases. Sarcoidosis-associated uveitis are associated to laboratory tests abnormalities. A high rate of complications is associated with PGU. However, a significant proportion of uveitis became inactive or achieved remission, following the use of systemic treatments as corticosteroids, immunosuppressants and/or biologics.

1. Jabs DA, Nussenblatt RB, Rosenbaum JT, Standardization of Uveitis Nomenclature (SUN) Working Group. Standardization of uveitis nomenclature for reporting clinical data. Results of the First International Workshop. Am J Ophthalmol. sept 2005;140(3):509-16.

Patient Consent Received

Yes

Disclosure of Interest

None declared

P139 Long-term experience of biological therapy in juvenile idiopathic arthritis associated with uveitis: single center experience

S. Arsenyeva¹, I. Nikishina¹, M. Kaleda¹, A. Shapovalenko¹, E. Denisova², A. Panova²

¹Paediatric, V.A. Nasonova Scientific Research Institute of Rheumatology; ²Paediatric, Helmgoltz Moscow Research Institute of Eye Diseases, Moscow, Russian Federation

Correspondence: I. Nikishina

Introduction: Biological agents (BA) are high efficacy options for current therapy for patients (pts) with juvenile idiopathic arthritis (JIA). They are successfully used not only for the arthritis but also for JIA-associated uveitis.

Objectives: to evaluate the main clinical features of pts with JIA-associated uveitis, who needed to treat by BA, the spectrum of BA, reasons for indication and withdrawals.

Methods: retrospective cohort study included all JIA pts (1136) who were treated with BA in our clinic from 2002 to 2020. All cases of JIA-associated uveitis were collected in special study for the describing of their clinical features, JIA category, exposure to Methotrexate (MTX) and BA, presence of ANA, HLA B27.

Results: among of 1136 pts treated with different BA we identified 204 (18 %) pts (71 male/133 female; 35% and 65% respectively), included 36 (3.2%) pts (19 female /17 male) with uveitis de novo under BA. JIA subtypes were as follows: RF-neg polyarthritis 25 (12%), persistent oligoarthritis 76 (37%), extended oligoarthritis 92 (45%), enthesitis-related arthritis (ERA) - 9 (4%). Average age at JIA onset was 4.3 yrs (Me 3,0, min 0,3, max 15,3 yrs). Duration of disease before BA treatment was 5,1 yrs (Me 4,3, min 0,2 max 16,6 yrs). Average age of BA treatment start was 9,4 yrs (Me 9,4, min 1,7 max 18 yrs). 149/204 pts were ANA-positive (73%), 63/204 pts had HLA B27 (31%), including 24 pts who had the both features. 171/204 (84%) of pts received MTX. Due to high activity of arthritis and uveitis BA treatment was started, 305 treatment series in total, including 175 for Adalimumab (1^st line – 124(71%), 2^{nd -} 45, 3^rd - 6). Infliximab was indicated in 37 in 2002-2012, as a “historical cohort” (1^st line - 32, 2^{nd -} 4, 3^{rd –} 1). Abatacept was given in 31- mostly in patient without HLA B27 and not ERA subtypes, and in pts with high risk of infection, especially, tuberculosis (1^st line - 20, 2^{nd -} 9, 3^rd -1, 4^th -1). 15 pts were treated by Golimumab (1^st line - 0, 2^{nd -} 10, 3^{rd –} 4, 4^th-1), 11 – Tocilizumab, mostly in severe polyarthritis and high laboratory activity (1^st line - 2, 2^{nd -} 2, 3^{rd –} 5, 4^th – 1), 2 - Sarilumab (3^{rd –} 2). Etanercept was not indicated in pts with uveitis, but we observed 34 pts, who developed uveitis de novo (1^st line - 26, 2^{nd -} 4, 3^{rd –} 4). There were 116 cases of withdrawals. Secondary inefficacy was as the reason for withdrawals in 47/116 (41%): Infliximab 15/37 (40 %), Adalimumab 22/175 (13%), Abatacept – 8/31 (26%), Tocilizumab – 2/11(18%). Withdrawals due to AE were found in 55/116 (47%): Etanercept – 34 cases of uveitis de novo; Infliximab – 13/37 (35%); Adalimumab – 4/175 (2%), Abatacept -4/31 (13%); others – 14 (12%), basically due to non-medical reasons, including difficulties in BA access in adulthood.

Conclusion: Our experience demonstrated that Adalimumab is still the preferred alternative for the treatment of JIA-associated uveitis with the best drug survival. In case of its secondary inefficacy Golimumab may be as the next option. Abatacept and Tocilizumab were indicated if there were additional reasons.

Disclosure of Interest

None declared

P140 Demographic and clinical characteristics of children with refractory JIA-associated uveitis receiving biological therapy

E. Baranovskaya, A. Berbenyuk, L. Galstyan, E. Popova, E. Zholobova

Institute of Child's Health, Sechenov University, Moscow, Russian Federation

Correspondence: A. Berbenyuk

Introduction: Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease among children. Uveitis is the extra-articular manifestation which occurs in approximately 8-30% of patients depending on the clinical form of JIA (1). JIA-uveitis is frequently anterior, often asymptomatic and is associated with oligoarthritis and rheumatoid factor (RF) negative polyarthritis. Disease-modifying antirheumatic drugs (DMARDs) normally used for uveitis management are showing positive effect in about 70% of cases (2). Biological agents are a second-line treatment for JIA-uveitis in case of DMARDs ineffectiveness. As JIA uveitis is a sight-threatening manifestation, it is important to discover the risk factors of severe disease refractory to DMARDs to start biological treatment timely.

Objectives: To address the features of refractory to DMARDs JIA-associated uveitis by evaluating demographic and clinical characteristics of children with JIA receiving biologics.

Methods: This open-label, single-center, observational (2020–ongoing) cohort study included 43 patients (4.5–17.5 y/o) with JIA and associated rheumatoid uveitis refractory to DMARDs who required biological treatment. A percentage ratio, Chi-square test for categorical data and Me (Q1, Q3) with preceding Shapiro-Wilk test for numerical data were used.

Results:

Age, y/o	Number of patients, n	Percentage, %
Before 1	3	7
1 – 2	13	30.2
2 – 5	20	46.5
6 – 11	6	14
12 – 18	1	2.3

in this cohort of patients with JIA-associated uveitis (n=43) a median age was 11.7 (IQR 7.2, 14.3) y/o, with girl/boy ratio of 2/1. Oligoarthritis was seen in 62.8% (n=27), RF negative polyarticular – in 30.2% (n=13) of patients; 4.7% (n=2) of children were diagnosed with enthesitis-related arthritis, 2.3% (n=1) – with psoriatic arthritis. JIA manifested at the median age of 2.6 (IQR 1.6, 4.4): before 1 y/o – 7% (n=3), 1–2 y/o – 30.2% (n=13), 2–5 y/o – 46.5% (n=20), 6–11 y/o – 14% (n=6), 12–18 y/o – 2.3% (n=1) (Table 1). Articular syndrome preceded in 83.8% (n=36), uveitis – in 9,3% (n=4), and simultaneous joint and eye involvement was seen in 6.9% (n=3) of children. Uveitis OU occurred in 74.5% (n=32, girl/boy ratio 2.2/1), single-eye uveitis – in 25.5% (n=11; girl/boy ratio 1.75/1) of patients, though overall no statistically significant correlation was revealed between sex and number of eyes involved (R=0.04). Time between articular syndrome manifestation and eye involvement (and vice versa if uveitis preceded) was 23 (IQR 7, 48) months, time before biological treatment initiation – 36 (IQR 14, 60) months. Antinuclear factor (ANF) positivity prevailed (74.4 %; n=32), with no statistically significant correlation between sex and ANF positivity (R=0.066). Most patients were initiated with adalimumab (n=39), some of them – with etanercept (n=3) or abatacept (n=1).

Conclusion: The group of patients with JIA-associated uveitis refractory to DMARDs is characterized by female predominance, early manifestation of arthritis and oligoarthritis. These features could be considered as factors in favour of earlier biological therapy initiation in case of conventional therapy ineffectiveness.

References

1. Nordal E, Rypdal V, Christoffersen T, Aalto K, Berntson L, and for the Nordic Study Group of Pediatric Rheumatology (NoSPeR). Incidence and predictors of Uveitis in juvenile idiopathic arthritis in a Nordic long-term cohort study. Pediatr Rheumatol. 2017 г.;15(1):66.

2. Galstyan L.A., Zholobova E.S., Chebysheva S.N., Meleshkina A.V., Seraya V.A., Loskutova O.Yu. Uveitis associated with juvenile idiopathic arthritis. Ros Vestn Perinatol i Pediatr. 2019; 64:(2): 30–37

Patient Consent Received

Yes

Disclosure of Interest

E. Baranovskaya: None declared, A. Berbenyuk: None declared, L. Galstyan: None declared, E. Popova: None declared, E. Zholobova Speaker Bureau of: Pfizer, AbbVie, Novartis, Roche

P141 The impact of selecting different outcome measure on the results of juvenile idiopathic arthritis associated uveitis treatment - the longitudinal observational study

M. Barisic Kutija¹, M. Sestan², S. Peric¹, N. Kifer², P. K. Ivkic¹, M. Galiot Delic¹, J. Knezevic¹, M. Held², M. Frkovic², M. Jelusic², N. Vukojevic¹

¹University Hospital Centre Zagreb, Department of Ophthalmology, University of Zagreb School of Medicine; ²University Hospital Centre Zagreb, Department of Pediatrics, University of Zagreb School of Medicine, Zagreb, Croatia

Correspondence: M. Sestan

Introduction: The number of patients with juvenile idiopathic arthritis associated uveitis (JIA-U) on systemic immunomodulatory treatment (IMT) is relatively small, especially those who need IMT for disease control. Variabilities in the way patients are selected and the results presented in different studies on the effectiveness of IMT make it very difficult to compare studies with each other.

Objectives: The aim of this study was to show on the same sample of JIA-U patients how different the obtained levels of therapy efficacy are depending on the selected definitions of outcomes in the long-term management with IMT.

Methods: The longitudinal observational study with JIA-U patients treated with IMT was conducted at University Hospital Centre Zagreb in the period from 2011 to 2017.

Results: We included 38 JIA-U patients aged 2 to 15 years and 69 eyes respectively, since 7 patients had unilateral JIA-U. Median (range) time of follow up was 209 (19-381) weeks. At the first examination 46 (66.7%) eyes had grade ≤1+ of inflammation in anterior chamber (AC) according to Standardization of Uveitis Nomenclature (SUN) Working Group criteria, 11 (15.9%) had grade 2+, while 3 (4.4%) eyes had grade 3+ of inflammation. At baseline, 23 children (60.5%) had already received methotrexate (MTX) therapy and 8 (21.0%) biologics, while 4 (10.5%) children were treated with systemic glucocorticoids (GC). Topical glucocorticoids (TGC) in the form of drops were used to treat JIA-U in 61 (88.4%) eyes with a median of 4 daily doses. Most patients were treated concomitantly with GC ointment (75.4% of the eyes) with a median of 1 daily dose. Until the end of the follow-up, all children received MTX at least for some period, and 40% of patients were treated with biologics. The results of the effectiveness of IMT are presented according to the reduction of the need for TGC therapy and according to the achieved level of inflammation in AC. In the first 12 months of follow-up, among JIA-U patients treated with both biologics and MTX, in 65% of eyes there was no need for TGC therapy. Overall, in the 48th month of follow-up, in 50% of eyes there was no need for TGC therapy, and the rest required 1-2 daily doses of TGC. At the end of the first year, with MTX and biological therapy 75% of eyes had grade 0 of inflammation in AC and in 48th month 61.1% of eyes achieved grade 0 of inflammation. In the 12th month of application of biological therapy, in addition to MTX, in our study in 75% of eyes a grade 0 of inflammation was achieved with ≤2 doses of TGC, and in the 48th month in 61.1% of eyes. If the results are presented according to milder criteria, then in the 12th month of follow-up 90% of the eyes have a degree of inflammation ≤0.5+ with ≤2 doses of TGC, and in the 48th month all patients achieved a degree of inflammation ≤0.5+ with ≤2 doses of TGC.

Conclusion: It was shown that the results of treatment outcomes during follow-up largely depend on the selected outcome measures, i.e. the criteria for the effectiveness of therapy. This will be important for future research because it suggests caution that in the pursuit of better results, setting different limits can lead to a more favorable outcome.

Patient Consent Received

No

Disclosure of Interest

None declared

P142 The influence of systemic immunomodulatory treatment on the intensity of topical glucocorticoid therapy in patients with juvenile idiopathic arthritis-associated uveitis - longitudinal observational study during 7 years

M. Barisic Kutija¹, M. Sestan², S. Peric¹, N. Kifer², P. K. Ivkic¹, M. Galiot Delic¹, S. Jandrokovic¹, M. Held², M. Frkovic², M. Jelusic², N. Vukojevic¹

¹University Hospital Centre Zagreb, Department of Ophthalmology, University of Zagreb School of Medicine; ²University Hospital Centre Zagreb, Department of Pediatrics, University of Zagreb School of Medicine, Zagreb, Croatia

Correspondence: M. Sestan

Introduction: Juvenile idiopathic arthritis associated uveitis (JIA-U) is the most common and potentially most destructive extraarticular manifestation of JIA. The main goal of the treatment is to achieve complete suppression of intraocular inflammation, maintain visual acuity, prevent relapses and complications and avoid the side effects of systemic and topical medications.

Objectives: The aim of this research was to determine the need for topical glucocorticoid therapy (TGC) in patients with JIA-U on systemic biological therapy in comparison to patients treated with methotrexate (MTX) only.

Methods: We have conducted longitudinal observational study in which we included JIA-U patients in whom systemic immunomodulatory treatment (IMT: biologics and/or MTX) was introduced and who were followed at least 3 months in the period between 2011 and 2017. The data about the number of cells in the anterior chamber (AC) according to Standardization of Uveitis Nomenclature (SUN) Working Group criteria, about TGC and systemic therapy and JIA complications were collected on each examination. Generalized linear mixed models were used to analyze the relationships between treatment with biologics, MTX, TGC and the grade of inflammation in AC according to SUN criteria.

Results: 38 JIA-U patients (69 eyes) with median (range) age of 4.9 (2-15) years and follow up period of 209 (19-381) weeks were included. There were a total of 1205 examinations. At the first examination JIA-U was detected in 16 (42.1%) of patients, 59 (79.7%) of the eyes had ≤1+ cells in the AC, and in 19 (50%) of JIA-U patients complications were already present. MTX was introduced in 23 (60.5%) JIA-U patients before the inclusion in the study, 8 (21%) has already received biologics, while in 4 (10.5%) prior systemic glucocorticoids were also used. Until the end of the study, all patients received MTX and 40% JIA-U patients were treated with biologics. The average number of TGC doses decreased steadily in the first 12 months, from 3.74 doses at baseline, 0.95 doses at 12th month to 0.72 doses in the 48th month of follow-up. After Friedman and the post hoc test a statistically significant difference in the daily doses of TGC could be seen from the 12th month after application of systemic IMT. The number of daily doses of TGC per eye as well as the degree of inflammation in AC per eye decreased over time. Using generalized linear mixed models it was shown that the treatment with biologics, but not with MTX and systemic glucocorticoids, was associated with lower intensity of TGC therapy. Treatment with biologics and systemic glucocorticoids, but not with MTX, was associated with lower degree of inflammation in AC.

Conclusion: The results showed that the application of systemic biological therapy may result in less intensive TGC therapy, resulting in glucocorticoid-sparing potential, and reducing intraocular inflammation.

Patient Consent Received

No

Disclosure of Interest

None declared

P143 Adalimumab in a cohort of children with juvenile idiopathic arthritis: a single-center experience

G. Tarantino¹, D. Pires Marafon¹, G. Zinzanella², A. Uva³, A. Aquilani¹, G. Marucci¹, R. Nicolai¹, D. Rigante⁴, F. De Benedetti¹, S. Magni-Manzoni¹

¹Rheumatology; ²Ophtalmology, Ospedale Pediatrico Bambino Gesù, Rome; ³Division of Paediatrics, Ospedale di Ravenna, Ravenna; ⁴Division of Paediatrics, Policlinico Agostino Gemelli, Rome, Italy

Correspondence: G. Tarantino

Introduction: Uveitis is the most serious extra-articular complication of juvenile idiopathic arthritis (JIA). Screening at-risk patients is essential as well as prompt treatment to minimize intra-ocular inflammation and preserve visual function with steroid-sparing immunomodulatory drugs (i.e. c-DMARDs) or TNF-α inhibitors (b-DMARDs).

Objectives: To describe demographic and clinical features in a single-center cohort of children with JIA treated with adalimumab (ADA), grouped according to the presence or absence of uveitis (JIA-U), and to observe the disease course in the JIA-U group during a 36-month-period of follow-up (FU).

Methods: Records of JIA patients treated with ADA throughout 2019 were retrospectively reviewed to assess joint involvement and ophthalmological examinations. Children with FU <12 months were excluded. Uveitis was diagnosed according to the SUN Working Group criteria. Data were analyzed through descriptive statistics.

Results: Of 109 patients with JIA, only 96 were included in the study (Table 1). None of them presented RF-positive polyarthritis, nor systemic JIA (sJIA). In JIA-U cohort, 60% (35/58) presented isolated joint involvement at onset. Median time from diagnosis to uveitis was of 19 months. Articular and ocular inflammation occurred simultaneously in 19 children; uveitis preceded arthritis in 6.9%. Each uveitis episode was initially treated with topical steroids and mydriatics. Most of JIA-U patients (87.9%) were already on c-DMARDs at ADA-start. Compared to the cohort without uveitis, they were younger both at onset and at baseline and started TNF-α inhibition later. Forty-five (77.6%) experienced recurrent uveitis (median frequency of 3 episodes) before starting ADA. Among JIA-U patients, there were no differences in gender, age at disease onset, ILAR JIA subtype and ANA positivity between active disease (AD) and clinical remission on therapy (CM) cohorts at 6 and 12 months from baseline. At baseline, 32 of the JIA-U children showed ocular complications, including posterior synechiae (n=29), visual loss (n=10, BCVA 20/40), cataract (n=9), band keratopathy (n=6) and glaucoma (n=1). Uveitis flares between 12-24 months were mostly bilateral, as well as at baseline; those occurred by 6 months from ADA start and after withdrawal were more frequently unilateral.

	TOTAL (N=96)	WITH JIA-U (N=58)	WITHOUT JIA-U (N=38)
Female, n (%)	67 (69.8)	48 (82.8)	19 (50.0)
Age at disease onset (years), median (IQR)	3.7 (2.1-9.6)	2.5 (1.9-4.2)	10.0 (4.9-13.0)
Antinuclear antibody (ANA) positive, n (%)	69 (71.9)	54 (93.1)	15 (39.5)
JIA Classification (ILAR Criteria), n (%)
Persistent oligoarthritis	41 (42.7)	33 (56.9)	8 (21.1)
Extended oligoarthritis	25 (26.0)	15 (25.9)	10 (26.3)
RF-negative polyarthritis	18 (18.8)	8 (13.8)	10 (26.3)
Enthesitis-related arthritis	8 (8.3)	1 (1.7)	7 (18.4)
Psoriatic arthritis	4 (4.2)	1 (1.7)	3 (7.9)

Conclusion: Results about real-life use of ADA at our center confirm its role as first-choice option among b-DMARDs for children with refractory JIA-U, according to a traditional “step-ladder” model. A targeted risk analysis of clinical and/or laboratories parameters was not available. Further prospective studies evaluating the appropriate withdrawal timing and determining the risk factors for relapse are warranted.

Disclosure of Interest

None declared

e-Poster viewing: Immunodeficiency and infection related arthritis

P144 Parasitic rheumatism – an unusual cause of chronic polyarthritis

A. Cristóvão Ferreira¹, A. R. Claro¹, J. Gil¹, M. Cabral², H. S. Sousa³

¹Pediatrics, Centro Hospitalar Universitário Lisboa Norte; ²Pediatrics, Hospital Professor Doutor Fernando Fonseca, Lisbon; ³Pediatrics, Hospital Vila Franca de Xira, Vila Franca de Xira, Portugal

Correspondence: A. Cristóvão Ferreira

Introduction: In Europe, parasites are an exceptionally rare etiology of infection-related arthritis.

Objectives: To recall the importance of excluding parasitic infestations in a child with chronic arthritis.

Methods: Description of a case report.

Results: A 12-year-old (yo) boy, born and raised in Sub-Saharan Africa (São Tomé and Príncipe), arrived in Portugal 5 days before admission, with no past medical report. Since 5-yo he presented with chronic asymmetric migratory polyarthritis with inflammatory pain and movement limitation of the cervical spine, elbows, wrists, knees, ankles, hands and feet’ fingers. Despite fluctuating, there were no symptom-free intervals, and, since its presentation, there was no disease progression. Some episodes of self-limited fever and tonsillitis, vomiting and diarrhoea, and two hospital admissions (gastroenteritis and malaria) were reported.

The national immunization program was updated, and both growth and neurodevelopment were regular. Familiar history was unremarkable.

On examination, he was slightly pale, apyretic, prepubertal, weight 29,5Kg, height 135cm (P3, WHO), BMI 16,8Kg/m2 (P15, WHO), with a limping gait. Pain and tenderness of cervical spine and ankles. Pain, swelling and decreased range of motion of the right elbow and wrist, both knees and small joints of the hand and feet. He also had sausage-like toes. The remainder examination was normal.

Laboratory investigation revealed an erythrocyte sedimentation rate of 86mm/h, C-reactive protein 3,35mg/dL, normal leucocyte count with eosinophilia (536/μL), normocytic anaemia (hemoglobin 11,2g/dL), 404000 platelets/uL. Routine biochemical tests, urinalysis, serum immunoglobulins and complement fractions were normal. Rheumatoid factor, antinuclear antibodies and HLA-B27 were negative. ASO and DNase-B were elevated and throat culture positive for S. pyogenes. Wide serological tests (HIV, B/C hepatitis, parvovirus B19, CMV, M.pneumoniae, B.burgdorferi, B.henselae), tuberculin test, IGRA, blood and stool cultures were negative. Stool ova and parasites exam revealed many larvae and adult forms of Ascaris Lumbricoides and Trichuris trichiura and positive Giardia antigen in stool. Abdominal ultrasound revealed impressive signs of parasitic infestation in different maturation phases and with variable size. Plain x-rays of affected joints revealed soft tissue swelling. There was no joint effusion on ultrasonography of the left knee and right wrist. Ophthalmologic and cardiac evaluations were normal. He was treated with non-steroidal anti-inflammatory drugs (NSAIDs) and on day 7 metronidazole was started with impressive clinical improvement. On day 12, a single dose of intramuscular benzylpenicillin was administered. One month later, he was asymptomatic and laboratory values were normal. When re-evaluated 3 years later, the patient was still free of symptoms.

Conclusion: Parasitic rheumatism is a rare condition characterized by inflammatory aseptic joint manifestations due to a parasitic infestation. The clinical presentation of this reactive arthritis may be very heterogeneous and can mimic the clinical picture of different inflammatory rheumatic diseases making it a challenging differential diagnosis. It seems to rely on genetic predisposition, which may explain its uncommon occurrence despite the high prevalence of parasitic infestation worldwide. The failure of NSAID’s, along with the notable efficacy of specific anti-parasitic treatment in a patient with a parasitic infestation, are the main hallmarks.

When caring for a patient coming from an endemic area of parasitosis with osteoarticular complaints, even with none or mild gastrointestinal manifestations, a high index of suspicion is suggested, and when correctly treated, the prognosis is excellent.

Patient Consent Received

Yes

Disclosure of Interest

None declared

P145 Clinical features of paediatric HIV arthropathy

M. Harrison¹, N. Brice^2,3, K. Webb^2,3, W. Slamang^2,3, C. Scott^2,3

¹Department of Paediatrics, Fort Beaufort Hospital, Fort Beaufort; ²Division of Paediatric Rheumatology, Department of Paediatrics and Child Health, Red Cross War Memorial Children’s Hospital; ³Department of Paediatrics and Child Health, University of Cape Town, Cape Town, South Africa

Correspondence: M. Harrison

Introduction: Advanced HIV infection is associated with an inflammatory arthritis, however few reports have described this disorder in children.

Objectives: This study aimed to describe the clinical features of HIV arthropathy in a case series of children in South Africa and compare these with features of JIA.

Methods: Retrospective data were collected from HIV-infected children with HIV arthropathy enrolled in a Paediatric Rheumatology clinic in Cape Town, South Africa. Data from a recently described, published cohort of children with JIA enrolled in the same clinic were included for comparison. Ethical approval was granted by the Human Research Ethics Committee of the University of Cape Town, with a waiver for consent.

Results: Eleven cases of HIV arthropathy were identified. Cases predominantly affected boys (8/11), and the median age of onset was 10.3 years (IQR 6.9 – 11.6). Most cases presented in the setting of advanced immunosuppression, with a median absolute CD4+ count of 389 cells/uL (IQR 322 – 449) and median CD4+ proportion of 19.5% (IQR 14.8 – 25.0) at presentation. The clinical presentation was variable, with both oligoarthritis (6/11) and polyarthritis (5/11) being prevalent. All cases exhibited large joint involvement, which was usually asymmetrical. In addition, four children had asymmetrical small joint involvement. Associated features included enthesitis (4/11) and dactylitis (1/11). The most consistent laboratory feature was elevated acute phase reactants, and typical ultrasonographic findings were joint effusions and synovial hypertrophy. JIA and HIV arthropathy presented at a similar age, with median age at HIV arthritis onset of 10.3 years (IQR 6.9 – 11.6) versus 9.25 years (IQR 4.5 – 12.3) at arthritis onset in the JIA subgroup. HIV arthropathy cases were predominantly male (M/F ratio 3.0), whereas JIA cases had an equal sex distribution (M/F ratio 0.9). Oligo-articular disease was more frequently described in children with HIV arthropathy (55%), compared to those with JIA (38%).

Conclusion: In this series, most cases of HIV arthropathy exhibited asymmetrical large joint oligoarthritis or polyarthritis, and presented in older boys with advanced immunosuppression. HIV arthropathy appears to present at a similar age to JIA, with a comparable pattern of joint involvement to oligo-articular and poly-articular JIA subtypes.

Patient Consent Received

No

Disclosure of Interest

None declared

e-Poster viewing: Macrophage activation syndrome

P146 Efficacy of emapalumab in chronic/relapsing macrophage activation syndrome in systemic juvenile idiopathic arthritis with lung and liver involvement

A. Arduini, M. Pardeo, A. De Matteis, G. Marucci, I. Caiello, G. Prencipe, F. De Benedetti, C. Bracaglia

Division of Rheumatology, IRCCS Ospedale Pediatrico Bambino Gesù, Roma, Italy

Correspondence: A. Arduini

Introduction: MAS is a severe complication of sJIA. IFNγ is a major driver of hyperinflammation and hypercytokinemia.

Objectives: To report the response to the anti-IFNγ antibody, emapalumab, in a patient with sJIA and chronic relapsing MAS.

Methods: Serum levels of IL-18, CXCL9 and neopterin were measured by ELISA.

Results: A 6 years old Caucasian girl, presented a first episode of HLH in April 2017, with persistent fever, hepatosplenomegaly, CNS involvement with seizures, marked hyperferritinemia and high CXCL9 levels (Table). She met the HLH-2004 primary HLH criteria and she was treated with emapalumab in the context of the primary HLH trial. She had complete remission with normalization of CXCL9. In June 2018 (after 10 months from last emapalumab) she presented a progressive increase in liver enzymes (ALT 1333 UI/l, AST 851 UI/l, LDH 822 UI/l), with no other HLH features. The liver biopsy was suggestive for autoimmune hepatitis. Treatment with oral prednisone (1 mg/kg/die) was started with progressive normalization of liver enzymes and continued for 8 months up to February 2020. During these months she presented recurrent episodes of fever with thrombocytopenia, increased levels of inflammatory markers, transaminases, LDH with mild hyperferritinemia (< 1500). All these episodes were managed with transient increase in GCs. In February 2020, she developed arthritis (wrists and knee) and she was referred to our attention. At this time she met the ILAR criteria for sJIA and the EULAR/ACR MAS criteria (ferritin 3.460, PLT 64.000, triglyceride 220; fibrinogen 385, AST 100). Abdominal CT showed splenomegaly and hepatomegaly, with disseminated round lesions. Chest CT showed initial signs of interstitial lung disease. Intravenous methylprednisolone (3 pulses of 30 mg/kg) followed by oral prednisone (0.5 mg/kg) and anakinra (5 mg/kg) were started without significant improvement. She then presented a further episode of MAS with severe marrow and liver involvement. CXCL9, neopterin and IL-18 levels were persistently elevated. Emapalumab was started, on compassionate use regimen. After 5 months of emapalumab she achieved complete clinical remission with normalization of laboratory parameters. GCs were tapered to <0.2 mg/Kg after 4 months and discontinued after 7 months. After 13 months of emapalumab, CT showed complete resolution of the liver nodular lesions, of splenomegaly and of lung involvement. CXCL9 and neopterin levels normalized, while IL-18 levels decreased, but remained persistently elevated.

Conclusion: This case shows that IFNγ neutralization may represent a valid therapeutic approach in patients with chronic/relapsing MAS with liver and marrow involvement.

Patient Consent Received

Yes

Disclosure of Interest

A. Arduini: None declared, M. Pardeo: None declared, A. De Matteis: None declared, G. Marucci: None declared, I. Caiello: None declared, G. Prencipe: None declared, F. De Benedetti Consultant for: for Abbvie, SOBI, Novimmune, Novartis, Roche, Pfizer, C. Bracaglia Consultant for: SOBI, Novartis

Table 1 (abstract P146) . Laboratory parameters and cytokine levels during disease course

P147 Applicability of the hscore criteria in patients with macrophage activation syndrome

M. I. De La Cera Rodríguez, N. L. De la Rosa Encarnacion, H. F. Menchaca Aguayo, E. R. Mercedes Perez, P. P. Ramos Tiñini, R. E. Loor Chavez, S. Rodriguez Aguayo, E. Faugier Fuentes

Paediatric Rheumatology, Hospital Infantiil de México Federico Gómez, Mexico, Mexico

Correspondence: M. I. De La Cera Rodríguez

Introduction: Macrophage activation syndrome (MAS) is a secondary form of hemophagocytic lymphohistiocytosis (HLH), a potentially fatal complication of rheumatic diseases. This usually occurs in the context of systemic juvenile idiopathic arthritis (JIAs), it can also occur, although more rarely in systemic lupus erythematosus (SLE) and Kawasaki disease.

The HScore (hemophagocytic syndrome diagnostic score) was created to timely identify secondary HLH in adults. With a total of nine variables, where 3 are clinical, 5 biological and 1 cytological, each of them is given a specific score, in which a sum of 203-257 points with a mean of 230 points determines the posibility for the diagnosis of secondary hemophagocytic syndrome and a score of 125 confers negativity for it. The HScore has not yet been validated in the pediatric population, however it has been shown that a higher score cutoff >141 points provides greater sensitivity and specificity in children.

Objectives: The application of the HScore criteria in pediatric population with diagnosis of Macrophage Activation Syndrome

Methods: Retrospective, descriptive cross study

Results: A total of 17 patients were included by review of the physical and electronic medical record in a period of five years from 2016 to 2021, all of them aged between 0 to 18 years, with a distribution by female gender of 76.4% and male 23.6%. 100% of the patients have a diagnosis of underlying rheumatological disease. The main condition being Systemic Juvenile Idiopathic Arthritis (JIAs) with a total of 11 patients and Systemic Lupus Erythematosus (SLE) 6 patients.

Regarding the complete hematic biometry, the presence of cytopenias is describen in 1 line in two patients (11.7%), two cell lines in eight patients (47%) and three cell lines in seven patients (41.3%). A finding of hemophagocytes in bone marrow was evidenced in 12 patients (70.5%) The JIAs an SLE groups are compared by analyzing each of the criteria individually, finding statistical significance in the cytopenia criterion, with 100% of the patients with SLE presenting affection of three cell lines (p 0.001) codition explained by the pathophysiological bases of each of the diseases described above.

The score was given to each variable determined by de HScore with a mean of 272.9, median of 271 an mode of 297 points respectively. Concluding that it is possible to diagnose MAS with HScore variables in 100% of the studied patients.

When comparing the JIAs and SLE groups, no statistical significance is found in the final absolute value of the HScore, with which it is possible to conclude that the Hscore has no variation in terms of the associated base pathology, establishing then, that obtaining the necessary score allows to do diagnose of Macrophage Activation Syndrome and therefore its application is possible in the face of the different associated comorbidities.

Conclusion: The high mortality rate of these conditions highlights the importance of early and timely recognition to establish treatment strategies. This being the main reason why it seeks to establish new criteria that facilitate its application and that in turn have high sensitivity an specificity for the diagnosis. The objective of applying these criteria is to simplyfy laboratory tools using more widely available markers.

Considering that at this time, the HScore criteria have not yet been validated in the pediatric population, however, the study and application of them in our population establishes the possibility of diagnosing Macrophage Activation Syndrome from the initial or early stages, a situatioin that allows to implement early and aggressive treatment of the underlying disease.

Patient Consent Received

No

Disclosure of Interest

None declared

P148 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, C. Alizzi⁶, G. Prencipe¹, F. De Benedetti¹, C. Bracaglia¹

¹Division of Rheumatology, IRCCS Ospedale Pediatrico Bambino Gesù, Rome; ²Pediatric Rheumatology, Fondazione IRCCS Ca’ Grande Ospedale Maggiore Policlinico, Milan; ³Department of Pediatrics and Infectious Diseases, School of Medicine, University of Turin, Regina Margherita Children’s Hospital, Turin; ⁴Department of Pediatrics, University of Bologna, S. Orsola-Malpighi Hospital, Bologna; ⁵Pediatric Rheumatology Unit, Meyer Children's University Hospital, Florence; ⁶University Department Pro.Sa.M.I. “G. D’Alessandro”, University of Palermo, Palermo, Italy

Correspondence: A. De Matteis

Introduction: Macrophage Activation Syndrome (MAS) and Secondary Hemophagocytic Lymphohistiocytosis (sHLH) are cytokine storm syndromes, in which IFNγ plays a pivotal role.

Objectives: Routine laboratory parameters of disease activity and severity were collected from 103 patients, 41 sHLH, 40 MAS in the context of sJIA, and 22 sJIA without MAS, from 6 Italian centers.

Methods: 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). Serum levels of the IFN-γ related biomarkers (CXCL9, CXCL10, Neopterin) and IL-18 were measured by ELISA.

Results: 367 samples were collected. Laboratory characteristics at T0 are detailed in table. Using the 2016 classification criteria for MAS, we can confirm that platelet count is a specific parameter, only 4 patients with sJIA had a value <181x10⁹/liter; while ferritin is a sensitive parameter, 94.2% of patients with MAS had ferritin >684 ng/ml. We have found that 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= 0.78, p-value <0.0001). A cut-off of 681 U/L had a sensitivity of 72.6% and a specificity of 69.2%. CXCL9, CXCL10, neopterin and IL-18 values in T0 were significantly higher in MAS and sHLH patients compared to sJIA. IL-18 in MAS was significantly high than in 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 identified a cut off value for each biomarker in MAS (CXCL9 900 pg/ml, CXCL10 280 pg/ml, Neopterin 6.0 ng/ml, IL-18 78000 pg/ml) and sHLH (CXCL9 1900 pg/ml, CXCL10 270 pg/ml, Neopterin 8.0 ng/ml). CXCL9, CXCL10, neopterin and IL-18 levels lowered progressively at T1 with a normalization in T2. CXCL9 decreased faster compared to neopterin, similarly to the decrease of routine laboratory parameters.

Conclusion: Platelet count and ferritin have respectively high specificity and sensitivity 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. Moreover, our results confirm that the IFN-γ related biomarkers and IL-18 are significantly high in patients with MAS and sHLH and might be useful for diagnosis in addition to the traditional laboratory parameters. IL-18 could be also useful to distinguish sHLH from MAS and MAS from active sJIA.

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, C. Alizzi: None declared, G. Prencipe: None declared, F. De Benedetti Consultant for: Abbvie, SOBI, Novimmune, Novartis, Roche, Pfizer, Employee of: SOBI, C. Bracaglia Consultant for: SOBI and Novartis

Table 1 (abstract P148). Laboratory parameters in T0. Values are shown as median (IQR); p-value: Mann-Whitney U test

P149 Central nervous system involvement as a predictor of early death in children with macrophage activation syndrome and infection-associated hemophagocytic syndrome

S. Harnchoowong, S. Vilaiyuk, S. Pakakasama, B. Lerkvaleekul, S. Soponkanaporn

Pediatrics, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand

Correspondence: S. Harnchoowong

Introduction: Macrophage activation syndrome (MAS) and infection-associated hemophagocytic syndrome (IAHS) are life-threatening conditions and high mortality rate. Therefore, it is essential to identify the characteristics of patients and factors that affected outcomes.

Objectives: To evaluate outcomes and identify predictors of treatment outcomes in children with MAS and IAHS.

Methods: Fifty-nine pediatric patients diagnosed with MAS (n=21) and IAHS (n=38) were enrolled between January 2004 and December 2019 in Ramathibodi Hospital. We retrospectively reviewed medical records including, clinical and laboratory data, disease information, and parameters related to outcome. Treatment outcomes were classified as “early death” (death within 30 days after diagnosis) and “early treatment response” (resolution of clinical manifestations and some laboratory results within 4 weeks). Differences between characteristics of MAS and IAHS patients were compared. Logistic regression analysis was performed to identify predictors of the treatment outcomes.

Results: The age of patients at diagnosis of MAS was significantly older than IAHS (median [IQR]; 11.1 [6.7-11.8] vs. 4.4 [1.7-10] years, p=0.004). Clinical manifestations were not significantly different between MAS and IAHS except for splenomegaly which was less common in MAS (47.6% vs. 78.9%, p=0.014). The underlying diseases in MAS were systemic juvenile idiopathic arthritis (66.7%) and systemic lupus erythematosus (33.3%). Viral infections were the most common etiology in IAHS (44.7% Epstein-Barr virus, 23.7% Dengue, and 13.2% cytomegalovirus). The laboratory data were significantly different between MAS and IAHS as follows: the hemoglobin levels (9.8 [8.9-10.9] vs. 8.5 [7.8-9.8] g/dL, p=0.039), neutrophil counts (2,464 [1,447-6,490] vs. 1,176 [213-2,790]/mm³, p=0.011), platelet counts (89 [46.5-150] vs. 45 [23.8-87.3] x10⁶/mm³, p=0.012), total bilirubin levels (0.7 [0.3-1.8] vs. 1.8 [1.1-4.5] mg/dL, p=0.002), and direct bilirubin levels (0.4 [0.1-1.3] vs. 1.3 [0.4-3.3] mg/dL, p=0.009). The overall mortality rate was 28.8% (17/59), and 52.9% (9/17) of these were early death. There was no significant difference in early death rate and early treatment response between the two groups. For the predictors of treatment outcomes, the predictors of early death in univariate analysis were central nervous system (CNS) involvement (OR 15.9 [95%CI 2.8-89.9], p=0.002), baseline platelet counts <44x10⁶ (OR 9 [95%CI 1.7-48.7], p=0.011), partial thromboplastin time >40 seconds (OR 6.1 [95%CI 1.3-27.8], p=0.02), albumin level <23 g/L (OR 5.7 [95%CI 1.2-26.1], p=0.025), total bilirubin level >1.8 mg/dL (OR 6.8 [95%CI 1.3-36.3], p=0.025) and ferritin decline <35% from baseline during 1 week (OR 11.1 [95%CI 1.8-69.3], p=0.01). In multivariate analysis, CNS involvement was the only predictor of early death with an odds ratio of 15.8 (95%CI 1.6-156.7, p=0.018). As for predictors of early treatment response, no CNS involvement (OR 22.7 [95%CI 2.4-212.4], p=0.006) and platelet counts ≥47x10⁶/mm³ (OR 23.6 [95%CI 2.6-217.9], p=0.005) were significant factors in multivariate analysis.

Conclusion: CNS involvement was related to early death in children with MAS and IAHS. Patients without CNS involvement or patients who had initial platelet count more than 47,000/mm³ had a higher chance of early treatment response.

Patient Consent Received

No

Disclosure of Interest

None declared

P150 Peripheral blood gene expression analysis in systemic juvenile idiopathic arthritis and macrophage activation syndrome reveals dominant innate immunity but no interferon-gamma signature

C. Hinze¹, M. Saers¹, C. Kessel¹, F. De Benedetti², D. Föll¹, C. Bracaglia²

¹Department of Pediatric Rheumatology and Immunology, University Hospital Münster, Münster, Germany; ²Division of Rheumatology, Ospedale Pediatrico Bambino Gesù, Rome, Italy

Correspondence: C. Hinze

Introduction: Systemic juvenile idiopathic arthritis (SJIA) is a chronic, severe inflammatory condition that may be complicated by life-threatening macrophage activation syndrome (MAS) which is driven by activation of the interleukin (IL)-18-interferon (IFN)γ-axis. Thus, in MAS, high circulating levels of IL-18 and CXCL9 proteins are observed.

Objectives: To evaluate the pattern of peripheral blood innate immunity-driven gene expression signatures in a cohort of patients with SJIA in different disease states.

Methods: Whole-blood-derived RNA from 54 samples from 35 patients (median age at first sample 6.4 years) from a single center was analyzed using a 24 gene custom NanoString panel, including IL-1β-/NFκB-, type 1 IFN and IFNγ-driven genes (AIM2, CCL20, IL1A, IL1B, IL1RN, IL6, IL-18, NLRC4, S100A8, S100A9, S100A12, PTX3, TNFAIP3, IFI27, IFI44L, IFIT1, ISG15, RSAD2, SIGLEC1, CIITA, CXCL9, CXCL10, IDO, MRC1). Four different disease states were considered (12 clinically inactive disease [CID], 21 active disease [AD], 9 MAS [as defined by ACR/EULAR], and 12 pre-MAS, i.e. prior to the development of full-blown MAS) as well as data from 15 pediatric healthy controls (HC). Normalized NanoString counts were used for comparisons. Groups were compared using non-parametric statistics. Correlation analyses and hierarchical clustering analyses were performed. Gene expression signatures were derived by using the geometric mean of normalized NanoString counts of the respective gene sets.

Results: On an individual gene level, there were substantial differences in expression between HC and AD, pre-MAS and MAS samples for many genes, with highest expression levels in MAS samples. In contrast, for CIITA, lower expression levels were seen in these disease states, compared to healthy controls. Conspicuously absent were significant differences in CXCL9 expression between disease states. Using correlation analyses across different disease states and using hierarchical clustering analysis, distinct gene expression signatures were identified, which we termed type 1 IFN, IFNγ and innate immunity signatures. While there was a probable gradient of expression levels, with a more prominent type 1 IFN signature in MAS > pre-MAS > AD > CID > HC, and a consistently elevated innate immunity signature in AD, pre-MAS and MAS, differences were not seen for an IFNγ signature (Table).

	HC	CID	AD	Pre-MAS	MAS	p-value*
Type 1 IFN score†, median (IQR)	424 (291-792)	742 (570-1401)	1014 (223-3036)	3295 (362-8490)	4966 (1487-13300)	0.02
IFNγ score‡, median (IQR)	81 (55-111)	95 (70-136)	107 (62-168)	115 (60-233)	114 (63-327)	0.54
Innate immunity score‖, median (IQR)	332 (264-415)	565 (501-650)	1367 (718-2712)	1187 (703-2520)	1260 (625-1879)	<0.0001

1. *Kruskal-Wallis test
2. †Geometric mean of IFI27, IFI44L, IFIT1, ISG15, RSAD2, SIGLEC1 normalized NanoString counts
3. ‡Geometric mean of CIITA, CXCL9, CXCL10, IDO normalized NanoString counts
4. ‖Geometric mean of AIM2, CCL20, IL18, IL1RA, IL1A, IL1B, IL6, NLRC4, PTX3, S100A12, S100A8, S100A9, and TNFAIP3 normalized NanoString counts

Conclusion: In patients with SJIA in different disease states, a marked dysregulation of peripheral blood gene expression is seen in multiple innate immunity-related genes, including IL-1β/NFκB- and type 1 IFN-related genes, most prominently in AD, pre-MAS and MAS. In light of the suggested dominance of IFNγ-driven pathology in MAS, the absence of an IFNγ signature in the context of high CXCL9 serum levels and points to cellular IFNγ and CXCL9 sources outside of peripheral blood.

Disclosure of Interest

None declared

P151 Lysinuric protein intolerance mimicking lupus presenting as macrophage activation syndrome

B. Kasap-Demir, A. Kanık, M. Köse, M. Baran

Izmir Katip Çelebi University, Izmir, Turkey

Correspondence: B. Kasap-Demir

Introduction: Macrophage activation syndrome is a rare but potentially fatal complication seen in autoimmune rheumatic diseases, characterized by cytokine storm. In some cases, it may appear as the first sign of the disease, and in others it may be observed during follow-up. Differential diagnosis in terms of underlying disease should be made carefully.

Objectives: Here, we aimed to report a case with a metabolic disease presenting as lupus associated macrophage activation syndrome.

Methods: A 16-year-old male patient was brought to our hospital with complaints of high fever that started 6 days before admission, darkening of urine color for 3 days, and yellowish skin. His past medical history was remarkable for IVIg usage between 2 and 3 years of age for suspected infantile transient hypogammaglobulinema. Aortic root dilatation was foud at the age of 4. His had growth retardation and he was diagnosed with hypopituitarism and osteoporosis, and used somatostatin at the age of 7. He was being followed up for hepatosplenomegaly and high ferritin levels (500-750) thereafter without any specific diagnosis. On admission, he was icteric, dehydrated and had malnutrition. Body weight was 28 kg (<3p, -5.44 SDS), height was 160 cm (<3p, -1.81 SDS), heart rate was 128/min, and respiratory rate was 24/min, body temperature was 39⁰C, blood pressure was 114/77 mmHg. The liver and spleen were palpable 4 cm below the ribs. The abnormal laboratory tests were as follows: Hb: 4.1 gr/dL, WBC: 10.5/mm³, platelets: 386.000/mm³, AST: 197 IU/L, LDH: 7430 U/L, Ferritin: 6430 ng/ml, triglyceride: 246 mg/dL, D.Coombs: 4(+), reticulocyte: 8.8% and schystocytes were prominent in blood smear. All other parameters were in normal limits. Bone marrow examination revealed intense hemophagocytosis. In rheumatological examinations, anti-dsDNA: 93.85 (n<100), ANA: 1/640, anti-Ro52: ++, ant-histon antibodies: ++, C3: 38.4 mg/dL (N:79-152), C4: 8.6 (N: 16-38), antibodies against cardiolipin, and beta 2 glycoprotein 1 were negative. SLE presenting with macrophage activation syndrome was considered. Erythrocyte transfusion was performed, 30 mg/kg/day pulse methylprednisolone and IVIG therapy was initiated and cyclospoirne was added. Proteinuria was observed and in the kidney biopsy performed in the follow up revealed focal mesangial proliferation in some glomeruli and IgM(++), IgA(+/-), C3(+), which was not compatible with lupus nephritis. No other clinical findings related to SLE were detected in the follow-up, however, LDH and ferritin levels increased intermittantly that were responsive to high dose steroids. Meanwhile, the screening tests that have been sent for hepatosplenomegaly, revealed a homozygous mutation for late onset glycogen storage disease type 4. Since the clinical course of the patient could not be explained with lupus or glycogen storage disease type 4, whole exome sequencing was sent.

Results: The result was suggestive of a homozygous deletion on chromosome 14 spanning several exons of SLC7A7 compatible with lysinuric protein intolerance that may explain the MAS and intermittant hyperferritinemia in our patient. The patient's diet was regulated and he has no MAS flare in the following 18 months.

Conclusion: Lysinuric protein intolerance should be considered in a patient presenting with MAS in the presence of severe growth retardation, osteoporosis, organomegaly, and high inflammatory markers. It may mimic the laboratory findings of lupus as well, which may cause a diagnostic challenge.

Patient Consent Received

Yes

Disclosure of Interest

None declared

P152 Primary and secondary hemophagocytic lymphohistiocytosis (HLH) in pediatric intensive care: clinical characteristics, therapies and outcomes

M. Murciano¹, G. Bottari¹, D. Pires Marafon², F. De Luca³, F. Chiusolo⁴, P. Merli⁵, C. Cecchetti¹, F. De Benedetti², M. Di Nardo¹, C. Bracaglia²

¹Department of Emergency and Pediatric Intensive Care; ²Division of Rheumatology, IRCCS Ospedale Pediatrico Bambino Gesù (OPBG), Roma, Italy; ³Pediatric Clinic, Policlinico Umberto I, Sapienza University of Rome; ⁴Pediatric Intensive Care Unit; ⁵Department of Onchohematology, IRCCS Ospedale Pediatrico Bambino Gesù (OPBG), Roma, Italy, Rome, Italy

Correspondence: M. Murciano

Introduction: HLH is a severe, life threatening disease that can develop into multiple organ failure (MOF) and death in a still high percentage of cases. Some patients require intensive care assistance with advanced organ support techniques. Primary HLH (pHLH) is usually caused by mutation in genes involved in the cytolytic function while secondary HLH (sHLH) can be triggered by various agents, including rheumatological diseases. The latter form is also called macrophage activation syndrome (MAS). Nevertheless, in a high percentage of cases no trigger has found.

Objectives: To evaluate clinical characteristics, therapies and outcomes of a cohort of pediatric patients with pHLH and sHLH admitted in pediatric intensive care unit (PICU) of Ospedale Pediatrico Bambino Gesù.

Methods: Data of 48 patients with HLH who required admission in PICU from 2007 till 2019 were collected. Clinical features, laboratory parameters and supportive therapy were evaluated at two time points: at PICU admission (T1) and at the worst time during PICU admission, defined by the highest ferritin value (T2). At T1 the risk of mortality was also assessed by the Pediatric Index of Mortality (PIM2 and PIM3).

Results: Of the 48 patients, 26 males, with disease onset mean age of 6.3 years (range 0 to 17.5), 5 had pHLH, 37 sHLH and 6 MAS in the context of sJIA. Twenty-three (48%) out of 48 patients died: 4 pHLH (80%), 18 sHLH (48%) and 1 MAS (16%). Splenomegaly at onset was significantly more frequent in patients who died compared to those who survived (78.3% vs 40%; p=0.007), as well as the incidence of MOF (43.5% vs 28%; p=0.26) and acute renal failure (47.8% vs 36%; p=0.41). White blood counts and neutrophil counts were significantly lower in T1 in patients who died compared to those who survived (p=0.033 and p=0.017), while platelets count was significantly lower in patients who died only in T2 (p=0.0087). Ferritin levels were higher in patients who died both in T1 and T2 but the difference was not significant. ExtraCorporeal Membrane Oxygenation (ECMO) was used equally in the two groups of patients but for a longer period of time in those who died (Table 1). As expected, the PIM2 and PIM3 were higher in patients who died but the difference was not significant.

Conclusion: Our data confirm that patients with MAS have a lower mortality rate compared to the other forms of HLH. Splenomegaly at onset, platelets count and ferritin levels at time of PICU admission seems to identify patients with the worst prognosis. Extracorporeal support therapies, in particular ECMO, have been used in a homogeneous manner in all patients but for a longer period of time in the most severe cases and therefore with higher mortality. To our knowledge, this is the largest pediatric series of patients with pHLH and sHLH treated in the PICU setting.

Patient Consent Received

Yes

Disclosure of Interest

M. Murciano: None declared, G. Bottari: None declared, D. Pires Marafon: None declared, F. De Luca: None declared, F. Chiusolo: None declared, P. Merli: None declared, C. Cecchetti: None declared, F. De Benedetti Consultant for: Consultant for Abbvie, SOBI, Novimmune, Novartis, Roche, Pfizer., M. Di Nardo: None declared, C. Bracaglia Consultant for: Consultant for SOBI and Novartis.

Table 1 (abstract P152). Extracorporeal support therapies and outcomes of patients.

P153 Macrophages activating syndrome in pediatric visceral leishmaniasis: about a series of 14 cases

H. Nassih, R. Elqadiry, A. Bourrahouat, I. Aitsab

Pediatrics, Mohammed 6 University Hospital Center of Marrakesh, Marrakesh, Morocco

Correspondence: H. Nassih

Introduction: Macrophages activating syndrome (MAS) is one of the most common complications in pediatric visceral leishmaniasis.

Objectives: To describe the phenotype, management and prognosis of MAS complicating visceral leishmaniasis in children.

Methods: We conducted a single center retrospective descriptive study of 14 children with visceral leishmaniasis and MAS.

Results: The mean age at diagnosis was of 8 years, with extremes of 6 months and 14-year-old. Boys were predominant with 65%. Telltale symptoms were protracted fever and a bone marrow failure syndrome in all cases. Meanwhile, hemorrhage and deterioration of general condition was present in half of the cases. Physical examination found a splenomegaly in 64%, an hepatomegaly in 50%, anasarca in 21%, cholestasis in 14%, and arthritis in 7% of cases. Complete blood count found pancytopenia in 71% and bicytopenia in 29% of children. Laboratory work-up found high LDH levels in all cases, high ferritin level in 71%, high triglycerides level in half of cases, hepatic cytolysis in 64%, and liver failure and acute kidney injury in 28.6% of cases. CRP and ESR were elevated in all cases. Myelogram found hemophagocytic lymphohistiocytosis and Leishman-Donovan bodies in all cases. Management of MAS was based on methylprednisolone pulses at 1.73 g/m2/day for three consecutive days followed by prednisone at 2 mg/kg/day. Prednisone tapering schedule was decided case by case and according to the evolution of the clinical symptoms as well as the levels of acute phase reactants, the cytopenia and the liver enzymes. The mean steroid duration was of 17 days. As for leishmaniasis treatment, it was mostly based on meglumine antimoniate at 60 mg/kg/day by IM route and for 28 days. However, in four cases with liver failure, liposomale amphotericine B was prescribed at 3 mg/kg/day for 5 days. Evolution was marked by gain of apyrexia in a mean time of 5 days, normalization of acute phase reactants in a mean time of 8 days and normalization of hemogram in a mean time of 21 days. Unfortunately, we deplore two deaths during the first 24 hours of admission, the cause of death being acute respiratory distress syndrome and multiple organ dysfunction syndrome respectively.

Conclusion: Prognosis of MAS complicating visceral leishmaniasis is good when management is early. Systemic steroids are very effective in inducing remission of MAS symptoms.

Disclosure of Interest

None declared

P154 When macrophage activation syndrome presents at diagnosis

M. J. Pereira¹, Í. R. Oliveira¹, A. J. Fernandes¹, R. J. Pereira¹, F. M. Dias¹, M. C. Conde²

¹Pediatric Department, Centro Hospitalar Universitário do Algarve - Unidade de Faro, Faro; ²Pediatric Rheumatology Unit, Centro Hospitalar e Universitário Lisboa Central – Hospital Dona Estefânia, Lisbon, Portugal

Correspondence: M. J. Pereira

Introduction: Macrophage activation syndrome (MAS) is a serious, potentially life-threatening hyperinflammatory disorder that belongs to the spectrum of hemophagocytic lymphohistiocytosis (HLH) and can complicate several immunologic disorders.¹

Objectives: We aim to highlight the importance of having a high-grade suspicion of MAS when systemic juvenile idiopathic arthritis (sJIA) is suspected and to describe a case of recurrent MAS.

Methods: We present a case report.

Results: A 10-year-old male with no relevant past medical or familial history, with non-consanguineous parents, was admitted for dizziness and fatigue for 3 months, polyarthralgia for 10 days, prostration, myalgia, headache, anorexia, and high fever for 5 days (2-3 spikes/day). On the 5^th day of fever, he started a rash, more prominent during fever spikes. On physical examination, he presented a discrete micromacular rash and a cervical adenopathy. He had markedly elevated inflammatory markers [leukocytosis, elevated C-reactive protein and erythrocyte sedimentation rate (ESR)], with ferritin > 9 000 mg/dL. Abdominal ultrasound and thoracoabdominal pelvic CT scan showed splenomegaly and multiple lymphadenopathies. He received empiric antibiotics, without clinical or inflammatory markers improvement. The main suspected diagnosis was sJIA, while neoplasic and infectious etiology were being excluded.

On the 17^th day, the fever pattern changed and became persistent; hepatosplenomegaly became more evident, and he developed distributive shock. Analytically, there was a decrease in hemoglobin and leukocyte count, a slight decrease in platelet count, severe hyperferritinemia (> 54 000 ug/L), elevation of aspartate transaminase, elevated triglycerides, and a decrease in ESR. The diagnosis of MAS was made and he started methylprednisolone pulses. He completed 5 pulses of methylprednisolone, maintaining high dose corticotherapy and initiated anakinra 3 mg/kg/day with marked clinical, inflammatory and MAS markers improvement.

On the 8^th day of anakinra, the clinical and analytical condition worsened and, despite raising anakinra to 5 mg/kg/day, a second MAS was diagnosed. Due to raised liver enzymes (> 5 higher than the upper normal limit), anakinra was suspended two days later, he repeated pulses of methylprednisolone and started IV cyclosporine with clinical and laboratory improvement allowing to restart anakinra.

One year later, he is off steroids, symptom-free, maintains therapy with anakinra, and is suspending cyclosporine. HLH, primary and acquired immunodeficiency genetic panels revealed no pathogenic mutations.

Conclusion: Among pediatric rheumatic diseases, MAS is most commonly seen in patients with sJIA.^1,2 It is characterized by the acute onset of persistent high fever, pancytopenia, hyperferritinemia, hepatosplenomegaly, liver dysfunction, and coagulation abnormalities.^1,2,3,4

Regardless of the criteria used, if sJIA is suspected, sudden worsening of the clinical condition should raise a high suspicion of MAS.⁵ If left untreated, MAS can progress to multiorgan failure and be fatal.^1,3 In this case, rapid recognition and prompt therapy were critical to this child's survival and good outcome.

Heterozygous perforin-pathway mutations and mutations of other immune pathways that result in cytokine storm syndrome have been described in MAS patients.^3,4 Despite a difficult-to-treat MAS, no pathogenic mutation was found in this patient.

Patient Consent Received

Yes

Disclosure of Interest

None declared

e-Poster viewing: Imaging

P155 Ultrasound features of ankles with clinically active disease in children with new-onset juvenile idiopathic arthritis

F. Chironi¹, O. De Lucia², F. Pregnolato², G. Filocamo¹, S. Orsi³, G. Rogani¹, T. Giani⁴, S. Costi⁵, C. Agostoni^1,5, R. Cimaz^2,5, S. Lanni¹ on behalf of PRAGMA (Pediatric Rheumatology Associated Group of the Milan Area)

¹Paediatrics, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano; ²Rheumatology, ASST Centro Traumatologico Ortopedico G. Pini-CTO, Milano; ³Istituto Giannina Gaslini, Genova; ⁴Medical Biotechnology, University of Siena, Siena; ⁵Clinical Sciences and Community Health, University of Milano, Milano, Italy

Correspondence: F. Chironi

Introduction: The ankle is one of the most commonly affected sites in juvenile idiopathic arthritis (JIA). This region has a complex anatomical structure owing to the presence of multiple joint recesses and surrounding tendons. Ultrasound (US) is a useful tool to implement clinical examination, since this imaging modality allows to localize precisely the inflamed joints and tendons which are often difficult to distinguish clinically, especially in young children.

Objectives: To investigate US features of ankles with clinical disease activity in patients with JIA at disease onset.

Methods: The clinical charts of all consecutive patients with new-onset JIA between May 2018 and January 2020 at study centres (Policlinico and G. Pini Hospitals of Milan) and with clinically active ankle disease among the joints affected were reviewed retrospectively. Data on ankle US assessment were retrieved. Detailed information about joints and tendon compartments affected on US examination were then recorded.

Results: Forty-four ankles of 32 patients with new-onset JIA (12 boys and 20 girls) were included in the study. US showed inflammation in 34 (77.3%) tibiotalar (TT), 18 (40.9%) subtalar (ST), and 23 (52.3%) intertarsal (IT) joints. The TT was the only affected joint compartment in 9 (20.5%) ankles, whereas the ST and IT joints resulted inflamed without any other joint compartment affected on US in 1 (2.3%) and 5 (11.4%) ankles, respectively. Eight (18.2%) ankles displayed on US concomitant involvement of TT, ST and IT joints. Concerning tendons, US showed inflammation in 21 (47.7%) medial tendon (MT), 20 (45.5%) lateral tendon (LT), and 9 (20.5%) anterior tendon (AT) compartments. The MT compartment was the only site of tendon pathology in 6 (13.6%) ankles. The LT and the AT compartments were affected on US without concomitant involvement of other tendon compartments in 5 (11.4%) and 1 (2.3%) ankles, respectively. The MT, LT, and AT compartments were together affected on US in 4 (9.1%) ankles. Three ankles (6.8%) had isolated tenosynovitis, whereas 15 (34.1%) ankles had arthritis without concomitant tenosynovitis.

Conclusion: The TT joint and the MT compartment are the sites most commonly affected on US in ankles with clinical disease activity in patients with new-onset JIA. The majority of ankles with clinical disease activity at disease onset show on US inflammation in multiple joint and tendon compartments. Isolated arthritis is more common than tenosynovitis alone. The findings of the study highlight the utility of US in identifying precisely the location of pathology and in managing local injection therapy.

Patient Consent Received

Yes

Disclosure of Interest

None declared

P156 Self-reported acceptability of whole-body MRI in young people

V. Choida^1,2, C. Ciurtin², T. J. Bray¹, D. Sen², C. Fisher², M. Leandro², M. Hall-Craggs¹

¹Centre for Medical Imaging; ²Centre for Adolescent Rheumatology Versus Arthritis, University College London, London, United Kingdom

Correspondence: V. Choida

Introduction: Magnetic resonance imaging (MRI) can detect musculoskeletal inflammation in patients with juvenile idiopathic arthritis (JIA). Whole-body MRI (WBMRI) is a promising imaging technique as it enables us to assess multiple joints in one examination. However, less is known about young people’s experience of undergoing MRI scans and their willingness to have these tests.

Objectives: To describe the experience of young people who underwent a WBMRI scan for research purpose, designed to assess joints for inflammation, and their willingness to have this investigation again in the future.

Methods: Sixty patients, 47 JIA and 13 controls with non-inflammatory musculoskeletal pain, aged 14-24 were recruited in a tertiary hospital for a prospective study which measured the prevalence of subclinical synovitis on WBMRI. The scan was performed with gadolinium in a 3 Tesla scanner and lasted 45-60 minutes. All participants completed an anonymised questionnaire, immediately after the MRI examination. The age, gender and presence or absence of JIA diagnosis were recorded. Five-point smiley face Likert scales were used to rate anxiety and pain levels during the scan. The likelihood of agreeing to undergo a repeat WBMRI scan for clinical reasons in 6 months’ time was recorded as definitely not, not likely, likely, or definitely. The mean ± standard deviation was calculated for age, and absolute and relative frequencies (%) were calculated for ordinal data. The chi-square test was used to compare ratings and t-test for the comparison of numerical data between groups.

Results: Forty female and 20 male participants completed the survey. Two male patients with JIA did not complete the second page of the questionnaire, which included the question of having a repeat scan. The mean age of JIA patients and controls in years was 18.3 ± 2.4 and 16.5 ±1.2 (p=0.012), respectively. The pain and anxiety ratings in young people with JIA and controls are shown in the Table. A higher proportion of JIA patients rated their anxiety levels as ‘okay’ or ‘totally fine’ compared to controls (83% vs 54%, p=0.028). Male patients reported more frequently that they felt ‘totally fine’ in terms of anxiety, compared to female patients (65% vs 28%, p=0.005). There were no significant differences in the pain levels experienced during the scan between males and females, or between JIA patients and controls. Almost all patients (57/58, 98%) answered that they were ‘likely’ (24/58, 41%) or would ‘definitely’ agree (33/58, 57%) to have a repeat scan in 6 months if advised by their doctor.

Conclusion: The majority of young people, predominantly patients with JIA, who underwent a research WBMRI scan for the assessment of synovitis, reported either mild or absent symptoms of anxiety and pain during the scan. Almost all patients would likely or definitely be agreeable to undergo a repeat scan in 6 months, for clinical reasons. In conclusion, WBMRI appears to be an acceptable imaging technique amongst young people who received this test.

Disclosure of Interest

None declared

Table 1 (abstract P156). Frequency of reported pain and anxiety levels by young people undergoing a whole-body MRI, number of respondents (%)

P157 Application of computerized color telethermography in 225 children and adolescents with Raynaud's phenomenon

N. Skreb¹, M. Held¹, M. Sestan¹, N. Kifer¹, D. Turudic¹, M. Frkovic¹, J. Stipic², M. Jelusic¹

¹University Hospital Centre Zagreb, Department of Pediatrics, University of Zagreb School of Medicine; ²University Hospital Centre Zagreb, Department of Neurology, Zagreb, Croatia

Correspondence: M. Held

Introduction: Computerized color telethermography (CCTT) is an established diagnostic procedure in clinical practice that is used for assessment and follow-up of patients with microcirculatory disorders in adult population, such as Raynaud's phenomenon (RP). However, CCTT is still not validated in pediatric patients with RP.

Objectives: To analyze the CCTT findings in children and adolescents with clinically suspicious RP and its relationship with age, gender and season as well as with biochemical and immunological laboratory findings.

Methods: Retrospective study included pediatric patients with suspected RP who underwented CCTT diagnostic procedure at the University Hospital Centre Zagreb from 2010 to 2019. Laboratory findings included inflammatory parameters, complete blood count, renal function tests and immunological tests (ANA, ENA screen, ANCA, RF, antiphospholipid antibodies, serum IgG and complement levels). Differences between categorical variables were examined using Chi-Square test and among numerical using t-test, followed by logistical regression analysis.

Results: Out of 225 patients with suspected RP, 176 were females (78.2%) and 49 were males (21.7%) giving a female to male ratio bigger than 3:1. In 44 patients (19,6%) CCTT was compatible with the diagnosis of primary RP, 68 patients (30,2%) were classified as secondary RP, whereas 27 patients (12%) had CCTT results which where considered unspecific. In 86 patients (38,2%) CCTT findings were normal. Among the patients classificated as secondary RP using CCTT, the most of them, 28 (41.2%), were diagnosed with juvenile idiopathic arthritis, while 26 (38.2%) had no evident other disease. The median (range) age at the time of performing CCTT was 15.16 (13.50-16.75) years. According to their age, patients were divided into 3 groups: childhood (3-10 years), early adolescence (11-14 years) and late adolescence (15-18 years). The most of them were in late adolescence group (53,8%) and these patients were 2.4 times more likely to be diagnosed with primary RP (OR 0.41, CI 0.18-0.92, p=0.03 for early adolescence group). Seasonal influence was a statistically significant factor in CCTT confirmation of the primary RP, since the largest number of patients with primary RP were diagnosed during the winter. If CCTT was performed in the winter, there was 7.25 times higher chance to confirm the primary RP with CCTT compared to the spring time (OR 7.25, CI 2.25-23.25, p=0.03). However, such influence was not observed for secondary RP. Patients diagnosed as secondary RP on CCTT had statistically significantly lower leukocyte (p=0.03) and platelet count (p=0.04), as well as C3 levels (p=0.008), but higher creatinine levels (p=0.008) in comparison with patients with normal CCTT findings. Concerning the immunlogical findings, it was shown that females, regardless of age, with positive ENA screen had 4 times higher risk to be diagnosed with secondary RP (OR 0.25, CI 0.06-0.95, p=0.04 for females with negative ENA).

Conclusion: Patients with secondary RP in whom the underlying systemic disease had not yet manifested had the greatest benefit from CCTT. In these patients, no other diagnostic method can replace CCTT. In patients with suspected primary RP, it is best to perform CCTT in the winter months. We observed that female adolescents were referred to CCTT more often and that regardless of age females with positive ENA screen were more likely to be diagnosed as secondary RP on CCTT.

Patient Consent Received

No

Disclosure of Interest

None declared

P158 Procedures for the conduct, content and format of eular/pres pediatric musculoskeletal ultrasound courses

V. Muratore¹, E. Naredo², J. Vojinovic³, M. A. D'Agostino⁴, S. Magni Manzoni⁵

¹Dipartimento Cure Primarie, ATS Pavia, Pavia, Italy; ²Department of Rheumatology, Joint and Bone Research Unit, Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain; ³Faculty of Medicine, University of Niš, Niš, Serbia; ⁴Rheumatology Department, Gemelli Hospital; ⁵Rheumatology Department, IRCCS Children’s Hospital Bambino Gesù, Rome, Italy

Correspondence: S. Magni Manzoni

Introduction: Recently several Pediatric Musculoskeletal ultrasound (PedMSUS) courses have been held. However, content, conduct and format of PedMSUS courses have never been internationally agreed.

Objectives: To produce practical and educational recommendations for the conduct, content and format of EULAR/PReS PedMSUS courses.

Methods: The project consisted of a joined EULAR/PReS effort and was conducted in two separate phases. 1.Through a systematic literature review, including extensive search on websites and networks on educational projects/events regarding PedMSUS, a list of potential items for the content, conduct and format of basic, intermediate, advanced courses and Teach-The-Theachers (TTT) PedMSUS courses, respectively, was identified. Through two Delphi processes, a panel of experts (project Taskforce) found agreement on the items to be considered for each PedMSUS level of competency. 2. Consensus on the proposed items was reached among a broader group of physicians and health care professionals with interest in pedMSUS and/or involved in previous EULAR/PReS MSUS educational events (Consensus Group). Agreement or consensus was achieved on each topic if selected by at least 75% of the participants.

Results: Twenty-two