Proceedings of the 25th European Paediatric Rheumatology Congress (PReS 2018)

Updates in JIA management

O01 PREDICTING WHICH CHILDREN WITH JUVENILE IDIOPATHIC ARTHRITIS WILL NOT ATTAIN EARLY REMISSION WITH CONVENTIONAL TREATMENT: RESULTS FROM A CANADIAN INCEPTION COHORT

Jaime Guzman Ramirez¹, Andrew Henrey², Thomas Loughin², Roberta Berard³, Natalie J. Shiff⁴, Roman Jurencak⁵, Adam M. Huber⁶, Kiem Oen⁷, Kerstin Gerhold⁷, Brian M. Feldman⁸, Rosie Scuccimarri⁹, Kristin Houghton¹⁰, Gaelle Chedeville⁹, Kimberley Morishita¹⁰, Bianca Lang⁶, Paul Dancey¹¹, Alan M. Rosenberg¹², Julie Barsalou¹³, Alessandra Bruns¹⁴, Karen Watanabe Duffy⁵, Susanne Benseler¹⁵, Ciaran Duffy⁵, Lori B. Tucker¹⁰ and ReACCh-Out Investigators

¹Pediatrics, University of British Columbia, Vancouver; ²Statistics, Simon Fraser University, Burnaby; ³Pediatrics, Western University, London, Canada; ⁴Pediatrics, University of Florida, Gainesville, USA; ⁵Pediatrics, University of Ottawa, Ottawa; ⁶Pediatrics, Dalhousie University, Halifax; ⁷Pediatrics, University of Manitoba, Winnipeg; ⁸Pediatrics, University of Toronto, Toronto; ⁹Pediatrics, McGill University, Montreal; ¹⁰Pediatrics, UBC and BC Children's Hospital, Vancouver; ¹¹Pediatrics, Memorial University, St. John's; ¹²Pediatrics, University of Saskatchewan, Saskatoon; ¹³Pediatrics, Universite de Montreal, Montreal; ¹⁴Pediatrics, Universite de Sherbrooke, Sherbrooke; ¹⁵Pediatrics, University of Calgary, Calgary, Canada

Correspondence: Jaime Guzman Ramirez

Introduction: Accurate estimates of the likelihood of attaining early remission with conventional treatment escalation may help target aggressive treatment to children with juvenile idiopathic arthritis (JIA) who have a low chance of remission.

Objectives: To develop a clinical prediction tool to estimate the chance of early clinical remission with conventional treatment for each child at the time of JIA diagnosis.

Methods: Prediction models were developed using data from 1074 subjects in the Research in Arthritis in Canadian Children emphasizing Outcomes (ReACCh-Out) cohort diagnosed 2005-2010. Treatment was compatible with the 2011 recommendations of the American College of Rheumatology. The predicted outcome was clinical inactive disease for 6 or more months starting within one year of the diagnosis in patients who did not receive early biologic agents or triple DMARD therapy. Models were developed in 200 random splits of 75% of the cohort, and tested on the remaining 25% of subjects, calculating expected and observed frequencies of remission and c-index values.

Results: A Cox-logistic model combining 18 clinical variables at a median of 2 days after diagnosis had a c-index of 0.69 (95%CI: 0.67-0.71) and performed better than JIA category alone (0.59, 0.56-0.63). Table 1 lists the top 8 variables included in the final model. Using the model, an online calculator (https://andrew-j-henrey.shinyapps.io/JIA_Remission_Calc/) produces estimates of the chance of remission for each child with JIA at diagnosis. Children in the lowest decile of probability of remission according to the model had a 20% chance of remission and 21% of them remitted; children in the highest decile had a 69% chance of remission and 73% remitted. Compared to 5% of subjects identified by JIA category alone, the model identified 14% of the cohort as having a low chance of remission (<0.25 probability of remission), of whom 77% failed to attain remission within one year of diagnosis.

Conclusion: Although the model did not meet our a priori performance threshold (c-index>0.70), it identified three times more subjects with low chance of remission than JIA category alone, and it may serve as a benchmark for judging the value added by future biomarkers.

Disclosure of Interest

None Declared

Table 1 (abstract O01). The top 8 variables in the final prediction model (full model uses 18 variables)

New tools and some omics

O02 TREG SPECIFIC CONSTITUTIVE NRF2 ACTIVATION INDUCES AUTOIMMUNITY

Klaus Tenbrock¹, Patricia Klemm¹, Kim Ohl¹

¹Pediatrics, RWTH AACHEN UNIVERSITY, Aachen, Germany

Correspondence: Klaus Tenbrock

Introduction: Immune cells are constantly confronted with intracellular and extracellular radical oxygen species (ROS) under steady-state and even more under inflammatory and pathogenic conditions. To investigate the effects of oxidative stress and ROS molecules in regulatory T cells (T_regs), we deciphered the role of Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) in this context. T_regs were already found to be more resistant to ROS than effector T cells and activated T_reg cells show higher expression of genes, which belong to the Nrf2-mediated oxidative stress response compared to activated effector T cells.

Objectives: To analyze the specific role of Nrf2 in T_regs.

Methods: To define the role of Nrf2 in Tregs, we generated mice with a knock out of Keap in all hematopoietic cells (VAV^CRE-Keap^fl/fl) with a Treg specific knockout of Keap 1, which is the constitutive binding partner of Nrf2 (Foxp3^CRE-Keap1^fl/fl) and characterized the mice using flow cytometry, T cell suppression assays and metabolomics.

Results: While mice bearing a constitutive activation of Nrf2 activation in all immune cells (Vav^creKeap^fl/fl) accumulate high percentages of Foxp3-positive T_regs in the spleen, lymph nodes and thymus, their suppressive capacity seems to be defective. Interestingly, a T_reg specific activation of Nrf2 (Foxp3^creKeap^fl/fl) results in an auto-inflammatory phenotype with immune cell infiltrates in the lungs, enhanced effector T cell activation and high percentages of IFN-γ producing effector T cells. Moreover, the constitutive Nrf2 activation in T_regs increases their in-vitro proliferation, glucose uptake and mTOR activity, while the differentiation and Foxp3 expression in T_regs declines

Conclusion: We demonstrate for the first time that constitutive Nrf2 activation specific to T_regs affects T_reg lineage stability and metabolism and might thereby induce an auto-inflammatory phenotype.

Our results therefore may have implications for diseases associated with oxidative stress and dysregulated T_reg responses.

Disclosure of Interest

None Declared

O03 EXTENDED PHENOTYPIC IMMUNOME CHARACTERISATION (EPIC): A WEB-BASED IMMUNE REFERENCE ATLAS

Joo Guan Yeo^1,2, Pan Lu¹, Thaschawee Arkachaisri^1,2, Su Li Poh¹, Fauziah Ally¹, Jingyao Leong¹, Kee Thai Yeo^1,2, Loshinidevi D/O Thana Bathi¹, Angela Yun June Tan², Liyun Lai¹, Elene Seck Choon Lee², Salvatore Albani^1,2

¹Translational Immunology Institute, SingHealth Duke-NUS Academic Medical Centre; ²KK Women’s and Children’s Hospital, Singapore, Singapore

Correspondence: Joo Guan Yeo

Introduction: An atlas of the developing immune system is key to understanding its normal maturation and identifying disease-associated cell subsets. The availability of high dimensional mass cytometry, in comparison to traditional oligo-dimensional approach such as fluorescence-based flow cytometry, provides an opportunity for the creation of this reference. However to date, the power available from these big data has not been fully harnessed due to the absence of clinically relevant and standardised datasets. This results in issues of fragmentation by focusing on individual cell subsets and lack the ability to transverse the whole developmental gradient from neonatal to adult age. There is a critical unmet need for standardised datasets depicting at single cell level and with high dimensionality the entire human immune system. These limitations hamper translational and clinical research.

Objectives: To address this need, we aim to construct a mass cytometry based immune atlas from healthy peripheral blood mononuclear cells (PBMC) samples ranging from cord blood to adult age and make this dataset available to the research community via an interactive web portal to enable its mining and comparison with diseased dataset.

Methods: The mass cytometry data from 113 healthy individuals (cord blood, newborn to adult) using 63 immune markers encompassing the major immune lineages were obtained. Quality control was performed before dimensional reduction and clustering to identify the cell subsets using our in-house analysis and visualisation pipeline. Their frequencies across the ages were presented as 3-D frequency histograms to create the immune landscape. This database and the analytic pipeline were incorporated into a web-based portal allowing users to interact and upload their own data for comparison.

Results: Here, we described EPIC with examples of its potential by exploring the evolution of some representative immune subsets over the full gradient of ages. Three developmental trajectories made up the healthy immune landscape with the most distinct being an increase or decrease in the cell populations with age. The last trajectory constituted an increase in population size in early childhood followed by a region of levelling. There was a distinct segregation of the naive T cell subset enriched in the cord blood/newborn period with the memory T cell subset enriched in adulthood. The naive IL8+ and TNFα+ CD4+ T cells were prominent peaks in the landscape and were found in higher frequency in the cord blood/newborn period. In contrast, the memory IFNɣ+ and TNFα+ CD4+ T cells were enriched in adulthood.

For specific cell subsets, transition developmental milestones were observed in the TNFα+ CD4+ T cells where the size of its memory subset would exceed its naive subset at 8 year old. There was a significant reduction and increase with age in the frequency of the naive and memory TNFα+ CD4+ T cells with a Spearman’s correlation coefficient, rho, of -0.4662 and 0.4164 respectively (p<0.0001). A similar intersection was present for the naive and memory regulatory T cell (CD4+, CD25+, Foxp3+, CD152+) subsets at 14 year old with a rho of -0.537 and 0.5034 respectively (p<0.0001).

Conclusion: A holistic description of the developing immunome was obtained with key developmental milestones in the T cell compartment identified. This atlas has the translational potential of helping us define the stage of immune maturity and identify the pathological cell subset in both paediatric and adult immune mediated diseases by the direct comparison with this reference atlas using the web-based portal that will be made freely available.

Disclosure of Interest

None Declared

Oral presentation 1

O04 VALIDATION OF THE RECENTLY DEVELOPED EVIDENCE-BASED EUROFEVER CLASSIFICATION CRITERIA FOR HEREDITARY RECURRENT FEVERS (HRF) AND PFAPA

Silvia Federici^1,2, Federica Vanoni^3,4, Francesca Bovis⁵, Nicola Ruperto¹, Michael Hofer⁶, Marco Gattorno¹ and on behalf of the Expert Committee for the Classification Criteria in periodic fever

¹Division of Rheumatology, Istituto Giannina Gaslini, Genova; ²Division of Rheumatology, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy; ³Pediatric Rheumatology Unit CHUV, University of Lausanne, Lausanne; ⁴Departement of Pediatric of Southern Switzerland, Bellinzona, Switzerland; ⁵Biostatistic Unit, Department of Health Sciences, University of Genoa, genoa, Italy; ⁶Pediatric Rheumatology Unit, CHUV, Lausanne, Switzerland

Correspondence: Silvia Federici

Introduction: Provisional Eurofever evidence-based classification criteria for the 4 inherited recurrent fever (FMF, CAPS, TRAPS, MKD) have been published and other diagnostic criteria are available in the literature for FMF, CAPS and PFAPA. Despite a significant increase of accuracy of the recent Eurofever classification criteria in respect to the previous ones, none of them combine the clinical criteria with the results of molecular analysis. This is a major limitation considering the fact that the genetic analysis might be considered per se pathognomonic, and therefore diagnostic, at least in the presence of a confirmatory genotype. Recently new evidence-based classification criteria for hereditary recurrent fevers (HRF) and PFAPA have been identified during a Consensus Conference held in Genoa in March 2017. For each of the monogenic recurrent fever new classification criteria based on genetic and clinical variables were developed. For PFAPA novel classification criteria based on positive and negative clinical variables were also approved by experts (Gattorno et al. PRES 2017, submitted).

Objectives: To evaluate the performance of the final set of classification criteria, in discriminating patients with the different HRF and PFAPA in a separate set of real patients coming from the Eurofever Registry and to compare their accuracy with respect to existing criteria.

Methods: We selected those patients with recurrent HPF coming from the Eurofever Registry excluding patients belonging to the original dataset of 360 patients used for the development of the criteria themselves. Patients with inherited periodic fever (TRAPS, FMF, MKD and CAPS), PFAPA and undefined periodic fevers were considered and classified according to the indication of each center, without any process of validation by expert. Sensitivity, specificity, accuracy, negative and positive predictive values and AUC-ROC of the new criteria were calculated.

Results: A total of 1018 new patients coming from the Eurofever Registry were included. The performance of the criteria coming from the Consensus conference in comparison with the criteria of the literature is listed in Table 1. Overall, their performance was superior (accuracy ranging from 0.81 to 0.98) to the already published literature’s criteria (accuracy 0.56-0.94) with a very high specificity and a variable sensitivity. Most of the patients not classified with the new criteria were negative for genetic analysis or carriers of low-penetrance mutations with an inconsistent clinical phenotype.

Conclusion: The validation of the new Eurofever classification criteria in a large group of unselected patients coming from the registry confirms their high specificity and overall better performance in comparison to other criteria available in the literature. It is recommended to use them as classification rather that diagnostic criteria, for clinical trials and pathogenic studies.

Disclosure of Interest

None Declared

Table 1 (abstract O04). See text for description

O05 PERFORMANCE OF THE AUTOINFLAMMATORY DISEASE ACTIVITY INDEX (AIDAI) IN PATIENTS WITH COLCHICINE-RESISTANT FMF, HIDS/MKD AND TRAPS: RESULTS FROM A PIVOTAL, PHASE 3 TRIAL OF CANAKINUMAB

Isabelle Kone-Paut¹, Maryam Piram¹, S Benseler², J. B Kuemmerle-Deschner³, A. F Jansson⁴, I Rosner⁵, A Tomassini⁶, S Murias⁷, O Karadag⁸, J Levy⁹, S Smeets¹⁰, F De Benedetti¹¹

¹APHP, CHU de Bicêtre, Univ Paris Sud, Le Kremlin Bicêtre, France; ²Alberta Children's Hospital, Calgary, Canada; ³University Hospital Tuebingen, Tuebingen; ⁴Ludwig Maximilian University, Munich, Germany; ⁵Bnai-Zion Medical Center, Rheumatology, Haifa, Israel; ⁶Department of Internal Medicine, Università Cattolica Sacro Cuore, Rome, Italy; ⁷Hospital La Paz, Madrid, Spain; ⁸Hacettepe University Faculty of Medicine, Ankara, Turkey; ⁹BIOP, Reinach, Switzerland; ¹⁰Novartis Pharma B.V., Arnhem, Netherlands; ¹¹IRCCS Ospedale Bambino Gesú, Rome, Italy

Correspondence: Isabelle Kone-Paut

Introduction: AIDAI is a novel and unique, validated patient (pt)-reported assessment tool to evaluate disease activity in familial Mediterranean fever (FMF), hyper-IgD syndrome/mevalonate kinase deficiency (HIDS/MKD) and TNF receptor-associated periodic syndrome (TRAPS).¹

Objectives: To perform an external validation of AIDAI, we calculated scores over 40 weeks (wks) of canakinumab (CAN) treatment in pts enrolled into the CLUSTER trial and assessed correlation between AIDAI and disease/response characteristics.

Methods: CLUSTER consisted of one cohort per disease (crFMF, HIDS/MKD and TRAPS).² AIDAI was calculated as the sum of 12 items (Yes=1; No=0)¹ for 30 consecutive days. AIDAI score was calculated if the first score was recorded before ≥29 days. Missing items beyond last evaluable measurement were imputed by last observation carried forward (LOCF). Inactive disease (ID) was defined as AIDAI score <9. Correlation analysis of AIDAI with Sheehan disability score (SDS), child health questionnaire–psychological/physical (CHQ–PsCS/PCS), physician global assessment (PGA), short form 12–physical/mental component summaries (SF12–PCS/MCS), C-reactive protein (CRP) and serum amyloid A (SAA) were performed. Significance was set at p<0.05.

Results: Overall, 167 (crFMF: N=59; HIDS/MKD: N=66; TRAPS: N=42) pts were randomized to CAN 150 mg or placebo every 4 wks. Median AIDAI scores in all 3 cohorts decreased from baseline (BL) to Wk 16 (crFMF: 22.5 to 5.0; HIDS/MKD: 41.5 to 12.0; TRAPS: 89.0 to 13.0) and through Wk 40 (crFMF: 1.0; HIDS/MKD: 5.0; TRAPS: 20.5). In all 3 cohorts, the proportion of pts with ID (AIDAI score <9) was higher at Wk 40 versus BL (crFMF: 69.5% vs 5.1%; HIDS/MKD: 56.1% vs 6.1%; TRAPS: 42.9% vs 2.4%). AIDAI at Wk 40 correlated significantly with: SDS in all 3 cohorts; CHQ-PsCS in crFMF and HIDS/MKD; CHQ-PCS in crFMF; PGA in TRAPS; SF12–PCS in crFMF and TRAPS. SF12-MCS, CRP and SAA did not correlate with AIDAI (Table 1).

Conclusion: AIDAI scores decreased markedly over 40 weeks of treatment with canakinumab in crFMF, HIDS/MKD and TRAPS, with a relevant percentage of patients having inactive disease score. AIDAI improvements at Week 40 correlated with patient- and physician-driven evaluations. AIDAI is a validated patient-reported tool to assess disease activity and appears to have good sensitivity to change to be used in comparative trials. Patient’s experience on disease activity does not strictly correlate with CRP and SAA, as these reflect more closely biological inflammation than clinical symptoms.

¹Piram M, et al. Ann Rheum Dis. 2014;73:2168-73. ²De Benedetti F, et al. N Engl J Med. 2018 (in press).

Trial registration identifying number: NCT02059291

Disclosure of Interest

I. Kone-Paut Grant / Research Support from: Novartis, SOBI, Roche, Consultant for: Novartis, SOBI, Pfizer, AbbVie, Roche, M. Piram Consultant for: Novartis, Pfizer, Abbvie, Speaker Bureau of: Novartis, S. Benseler Consultant for: Novartis, SOBI, AbbVie, J. B. Kuemmerle-Deschner Grant / Research Support from: Novartis, Consultant for: Novartis, SOBI, A. F. Jansson Grant / Research Support from: Novartis, I. Rosner: None Declared, A. Tomassini: None Declared, S. Murias: None Declared, O. Karadag: None Declared, J. Levy Consultant for: Novartis, S. Smeets Employee of: Novartis, F. De Benedetti Grant/Research Support from: Novartis, Roche, Pfizer, SOBI, AbbVie, Novimmune, BMS, Sanofi

Table 1 (abstract O05). Correlation between AIDAI and disease activity variables at Week 40

O06 INTERRATOR RELIABILITY OF A STANDARDIZED SCORING TOOL TO REPORT MRI FINDINGS IN CHRONIC NONBACTERIAL OSTEOMYELITIS

Yongdong (Dan) Zhao^1,2, T. S. Sato³, Meinrad Beer⁴, Mingqian Huang⁵, Ramesh S. Iyer⁶, Michael McGuire⁷, Anh-Vu Ngo⁶, Jeffrey P. Otjen⁶, Jyoti Panwar⁸, Jennifer Stimec⁹, Mahesh Thapa⁶, Paolo Toma¹⁰, Angela Taneja¹¹, Nancy E. Gove², Polly J. Ferguson¹²

¹Seattle Children’s Hospital, Department of Pediatrics, University of Washington; ²Center for Clinical and Translational Research, Seattle Children’s Research Institute, Seattle; ³Radiology, University of Iowa Carver College of Medicine, Iowa City, USA; ⁴Department of Diagnostic and Interventional Radiology, University Hospital of Ulm, Ulm, Germany; ⁵Department of Radiology, University of Stony Brook, Stony Brook; ⁶Department of Radiology, Seattle Children’s Hospital, University of Washington, Seattle; ⁷Department of Radiology, Hackensack University Medical Center, Hackensack, USA; ⁸Joint Department of Medical Imaging, University Heath Network, University of Toronto; ⁹Hospital for Sick Children, Department of Medical Imaging, Toronto, Canada; ¹⁰Department of Imaging, Bambino Gesù Children Hospital, IRCCS, Rome, Italy; ¹¹Pediatric Rheumatology, Children’s Healthcare of Atlanta, Emory University, Atlanta; ¹²Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, USA

Correspondence: Yongdong (Dan) Zhao

Introduction: CNO is an inflammatory bone disease that can result in bone destruction, persistent bone pain and pathological fractures. For clinical and research purposes, serial MRI exams are needed to determine the objective response to treatment. A previously developed MRI scoring tool for CNO in a single center showed sensitivity to detect imaging change after aggressive treatment.

Objectives: To use a nominal group technique to develop a practical and consensus-based MRI scoring tool for clinical and research use in CNO. Furthermore, inter-rater reliability were evaluated using whole body (WB) MRI from children with CNO.

Methods: Eleven pediatric radiologists, each with at least 5 years of experience reading musculoskeletal MRI from seven different pediatric hospitals in North America and Europe, discussed definitions and grading of signal intensity, extent of signal abnormality within bone marrow and surrounding tissue, physis damage and vertebral fracture on MRI through monthly conference calls and an in-person meeting (Seattle, July 2017). Nine sets of whole body MRIs were used as a pilot reading session at the conference that demonstrated greater than 70% of agreement among the radiologist attendees. Fifty sets of pre-existing WB MRI scans between Jan 2013 and August 2016 from children with CNO at the University of Iowa Children’s Hospital were anonymized and used for an inter-rater reliability study. Inter-rater agreement of presence of abnormal signal and severity were assessed using Fleiss kappa analysis.

Results: Signal intensity was rated as absent, < fluid signal or similar to fluid signal within bone marrow. Extent of abnormal signal intensity within bone or surrounding tissues were scored according to the relative affected proportion. Long bones were divided into proximal epiphysis, proximal metaphysis, diaphysis, distal metaphysis and distal epiphysis. Complex bony regions such as the pelvis were divided into easily identifiable anatomical subareas. The agreement among 11 radiologists in readings of femur and tibia were shown in Table 1. There was moderate to substantial agreement (0.44-0.63) in all parameters except the sizes of femoral proximal epiphyseal and femoral proximal metaphyseal lesions (0.28-0.34). There were 38 tibias and 30 femurs identified as active inflammation by at least 9 of 11 radiologists. Data from other bones are being analyzed.

Conclusion: A comprehensive standardized scoring tool for MRI in children with CNO was developed. There was moderate to substantial agreements among radiologists in majority of parameters of femur and tibia. If proven reproducible, this tool can be validated in a prospective study and will become a key element of disease activity assessment in CNO.

This study was funded by CARRA-AF small grant.

Disclosure of Interest

Y. D. Zhao Grant / Research Support from: Bristol-Myers Squibbs, CARRA, Clinical Research Scholar Program from Seattle Children's Research Institute, T. Sato: None Declared, M. Beer: None Declared, M. Huang: None Declared, R. Iyer: None Declared, M. McGuire: None Declared, A.-V. Ngo: None Declared, J. Otjen: None Declared, J. Panwar: None Declared, J. Stimec: None Declared, M. Thapa: None Declared, P. Toma: None Declared, A. Taneja: None Declared, N. Gove: None Declared, P. Ferguson Grant/Research Support from: R01AR059703 from NIH/NIAMS

Table 1 (abstract O06). See text for description

O07 IMPACT OF PEDIATRIC RHEUMATIC DISEASES ON CAREGIVERS MULTIASSESSMENT QUESTIONNAIRE: CAREGIVERS QUESTIONNAIRE

Marcia D. Torres-Made¹, Nadina E. Rubio Pérez¹, Ingris Peláez Ballestas², Fernando García Rodriguez¹, Ana V. Villarreal Treviño¹, Brenda D. J. Fortuna Reyna¹, Manuel E. De la O Cavazos¹

¹Pediatría, Hospital Universitario "Dr. José Eleuterio Gónzalez", Monterrey, Nuevo León; ²Reumatología, Hospital General Dr. Eduardo Liceaga, Mexico, DF. , Mexico

Correspondence: Marcia D. Torres-Made

Introduction: Most common pediatric rheumatic disease (PRD) is juvenile idiopathic arthritis (JIA), this influence affects quality of life (QoL) of children and families. Caregiver is a cornerstone to achieve disease control however, there are no information on how this conditions affects them; neither a tool to assess this impact was reported.

Objectives: To develop and validate psycho-social impact and financial burden questionnaire in caregivers of JIA patients (CAREGIVERS Questionnaire).

Methods: We development and validate the CAREGIVERS Questionnaire in two phases. Phase 1.Design the questionnaire based in non-systematic review and qualitative study: First version (1stQ), exploratory and open questions, was constructed based on literature review by an expert group (pediatric rheumatologists and methodologist). A qualitative study of pragmatic type was conducted on 15 caregivers to identify areas affected after JIA diagnosis. Interviews were reviewed using thematic analysis with Atlas-ti software. Questionnaire was adapted based on qualitative study and second version (2ndQ) was tested on 10 participants to evaluate comprehensibility. Changes in structure were made after pediatric rheumatologists, anthropologist/methodologist, psychologist, and pedagogue analyzed the answers (3rdQ).

Phase 2. Validation of questionnaire. 3rdQ was evaluated for face, content, reliability, internal consistency, convergent, and divergent validity. Construct validity was tested for anxiety/depression (Beck), coping strategies (Reyes-Lagunes), QoL (EuroQol), and social and economic factors (Socioeconomic burden). Correlation matrix to assess the construct validity using Cohen’s kappa, and internal consistency tests using Cronbach’s alpha were performed.

Results: Qualitative study (1stQ) identified topics like socioeconomic burden, family interactions, alternative medicine, religion, information access, and prognosis. 2ndQ was conformed by 75 items. After pilot study, six items were confuse and modified, 11 were eliminated for being redundant. Items were organized in five domains to develop 3rdQ: disease impact (social, economic, family and relationship), knowledge, future, alternative medicine, and religion (13, 27, 2, 2, and 2 items, respectively). Validity analysis included 32 participants (93% women). Mean age 39 (SD 8.5) years, mean EuroQol VAS 82, minimal depression in 90%. Socioeconomic tool demonstrated family income above 14 minimum wages (65 USD) in 68% and 59% have remunerated job. Reyes-Lagunes describes “life coping” with emotional-negative strategies in 31 caregivers and straight strategies in “children´s health coping” in 100%. Finally, in 3rdQ, 22% felt sadness at diagnosis, 84% change initial feeling and currently 43% are relief. Sixty two percent mention disease has influenced in their financial situation and 72% feel anxiety about their children future. Statistical analysis show adequate inter-item reliability in all domains except for religion, consequently items were adapted to create new dimensions (Table 1). Correlation matrix shown good results in all domains, except for social and economic due to redundant items. After changes, CAREGIVERS Questionnaire was created.

Conclusion: We design CAREGIVERS Questionnaire, a specific multidimensional tool to assess burden in caregivers of patients with PRD, and validated in JIA. Further efforts will be performed to validated in other PRD.

Disclosure of Interest

None Declared

Table 1 (abstract O07). See text for description

O08 TREAT-TO-TARGET USING FIRST-LINE TREATMENT WITH RECOMBINANT IL-1 RECEPTOR ANTAGONIST IS HIGHLY EFFECTIVE FOR SYSTEMIC JIA: A 5 YEAR FOLLOW-UP STUDY

Nienke M. ter Haar^1,2, Evert H. P. van Dijkhuizen², Joost F. Swart², Wilco de Jager¹, Dirk Holzinger^3,4, Arjen P. Leek², Jorg van Loosdregt¹, Annet Van Royen-Kerkhof², Nico M. Wulffraat², Sytze de Roock^1,2, Sebastiaan J. Vastert^1,2

¹Laboratory for Translational Immunology; ²Paediatric Rheumatology and Immunology, University Medical Center Utrecht, Utrecht, Netherlands; ³Paediatric Rheumatology and Immunology, University of Muenster, Muenster; ⁴Paediatric Hematology-Oncology, University of Duisburg-Essen, Essen, Germany

Correspondence: Sebastiaan J. Vastert

Introduction: Systemic onset JIA (sJIA) is a multifactorial autoinflammatory disease. Historically, the prognosis of sJIA was very poor. The use of interleukin (IL)-1 and IL-6 blockade improved outcome, but still most studies report inactive disease in only 30-50% of patients within one year. It is hypothesized that innate immune activation is most prominent in the early phase of sJIA. To make use of this ‘window of opportunity’, we started a prospective cohort with recombinant IL-1 receptor antagonist (rIL-1RA) as first-line monotherapy in new-onset sJIA patients (Vastert et al. AR 2014).

Objectives: To analyse the long-term efficacy of this therapeutic strategy and to separately analyse a subset of sJIA patients without arthritis at disease onset.

Methods: In this single centre, prospective cohort study, new-onset sJIA patients with an unsatisfactory response to NSAIDs received rIL-1RA 2mg/kg. Inactive disease (ID) was defined according to the Wallace criteria. In patients reaching ID, rIL-1RA was tapered after 3 months and subsequently stopped. In patients with an incomplete response to rIL-1RA, our protocol directed to increase rIL-1RA dose, add prednisolone or switch to alternative therapy. Clinical data including damage (JADI) and patient reported outcomes (CHAQ and/or JAMAR) were completed in a standardized way. Cytokine profiling was performed using Luminex multiplex immunoassay.

Results: Forty-two patients were analysed, with a median follow-up of 5.8 years. At 3 months, 30/42 patients (71%) had ID with rIL-1RA monotherapy and another 6 had ID with rIL-1RA and prednisone. At one year, 32 patients (76%) had ID, of which 22 (52%) were off medication.

Twelve patients had no arthritis at onset; 4 of them developed arthritis during flares. The clinical phenotype, inflammatory parameters and cytokine profile of patients without arthritis at onset was similar to patients with arthritis. Hence, after extensive ancillary investigations to exclude other diseases, these non-arthritic patients also received rIL-1RA as first-line therapy. After 3 months, 11/12 non-arthritic patients had ID (10 on rIL-1RA monotherapy), at 1 year all 12 had ID (8/12 off medication).

Long-term outcome reflected the high efficacy of first-line rIL-1RA: 95% of all patients had ID and 72% had ID off medication at 3 and 5 years follow-up, only 5% reported articular damage and 5% extra-articular damage, no patient developed growth failure and only one developed obesity during follow-up. Moreover, around 60% of patients reported complete absence of pain and disease, no limitations in daily life and the highest possible score on well-being. One patient died due to MAS. In total, 24 patients (57%) never used other medication besides rIL-1RA and NSAIDs and only 14 patients (33%) used glucocorticoids.

Patients who achieved ID at one year were younger and had a significantly shorter disease duration, less active joints and higher neutrophil and leukocyte count before start of rIL-1RA. Multivariate analysis confirmed high neutrophil count as a significant predictor for ID at one year. Furthermore, ID at one year was highly associated with a good response at 1 month.

Conclusion: First-line, short course monotherapy with rIL-1RA is a highly efficacious strategy to induce and sustain inactive disease and to prevent disease- and glucocorticoid-related damage. Our data on sJIA patients without arthritis plea for leaving out arthritis as a prerequisite criterion in future disease classification criteria.

Disclosure of Interest

None Declared

O09 CLINICAL OUTCOMES FOLLOWING MYCOPHENOLATE MOFETIL VS. CYCLOPHOSPHAMIDE INDUCTION TREATMENT FOR PROLIFERATIVE JUVENILE-ONSET LUPUS NEPHRITIS

Eve M. Smith¹, Michael W. Beresford¹, Christian M. Hedrich²

¹Institute of Translational Medicine; ²Institue of Translational Medicine, University of Liverpool, Liverpool, UK

Correspondence: Eve M. Smith

Introduction: Treatment of proliferative class III/IV lupus nephritis (LN) in children is largely based upon adult studies. The largest study demonstrated a similar renal response rate with mycophenolate mofetil (MMF) or cyclophosphamide (CYC) induction treatment in adult patients with LN [1]. A further smaller study showed MMF to be more effective than CYC [2]. In both, MMF had a better safety profile [1,2].

Objectives: Within a predominantly Caucasian JSLE cohort, to compare efficacy of MMF vs. CYC in patients with LN, monitoring 1) response to treatment, 2) damage accrual, 3) time to achievement of inactive LN, and 4) time to subsequent LN flare, following MMF or CYC LN induction treatments.

Methods: Participants of the UK JSLE Cohort Study (2006-2018), <18 years at the time of diagnosis, with ³4 ACR criteria for SLE, were eligible for inclusion if they had ISN/RPS class III or IV LN. Median values and interquartile ranges quoted. Mann-Whitney U tests for continuous data and Fishers exact test for categorical data.

Results: 69/411 UK JSLE Cohort Study patients met the inclusion criteria; 18/61 were excluded due to insufficient follow-up. 34/51 (67%) received MMF (13/34 (38%) class III, 21/34 (62%) class IV LN), and 17/51 (33%) received CYC (8/17 (47%) class III, 9/17 (53%) class IV LN). No statistically significant differences were identified between treatment groups at 4-8, 10-14 months post renal biopsy, and last follow-up, in terms of the renal-BILAG score, urine albumin/creatinine ratio, serum creatinine, ESR, anti-dsDNA antibody, C3 levels and patient/physician global scores (all p>0.05, see Table 1). Standardised Damage Index (SLICC-SDI) scores did not differ between treatment groups at a median of 13 months, or last follow-up (all p>0.05, see Table 1). Inactive LN, following the definition of renal BILAG, was attained at 262 days [141–390] after MMF treatment, and 151 days [117-305] following CYC (p=0.17). Time to subsequent renal flare did not differ; 451 days [157–1266] for MMF, and 343 days [198–635] for CYC (p=0.47)).

Conclusion: This is the largest study to date investigating induction treatments for proliferative LN in children. In Caucasian JSLE populations, MMF and CYC may be comparably efficacious in regards to treatment response, damage accrual, and time to next flare. Remission may be reached quicker in patients treated with CYC. Future prospective comparison is warranted to inform LN treatment, given CYC’s poor safety profile.

References

1. Appel G, et al. JASN 2009, 20:1103-12.

2. Ginzler E, et al. NEJM 2005, 353:2219-28.

Disclosure of Interest

None Declared

Table 1 (abstract O09). Comparison of clinical parameters and SLICC-SDI scores following MMF vs CYC treatment

O10 WORLDWIDE COHERENCE OF ASSOCIATION OF KAWASAKI DISEASE TO MASSIVE AGRICULTURAL CROPLAND BYPRODUCTS

Xavier Rodó^1,2, Joseph Boyard-Micheau¹, Silvia Borràs¹, Dan Cayan³, Jane Burns⁴on behalf of International Kawasaki Disease Consortium, Yosikazu Nakamura⁵, Judith Sanchez Manubens⁶, Jordi Anton⁶, Josep-Anton Morguí⁷, Roger Curcoll⁷, Joan Ballester¹ and International Kawasaki Disease Consortium

¹Climate and Health Program, ISGlobal (Barcelona Institute of Global Health); ²ICREA, Barcelona, Spain; ³Climate, Atmospheric Sciences, and Physical Oceanography, Scripps Institution of Oceanography, UCSD; ⁴ Kawasaki Disease Research Center, Dept. of Pediatrics University of California San Diego, La Jolla, CA, USA; ⁵Jichi Medical Hospital, Tokyo University, Tokyo, Japan; ⁶Pediatric Rheumatology Unit, Hospital Sant Joan de Déu; ⁷Land, Atmosphere and Oceans Lab, ICTA, Universitat Autònoma de Barcelona, Barcelona, Spain

Correspondence: Xavier Rodó

Introduction: Long-standing debate continues on the factors and potential etiological agents of vasculitides and rheumatic diseases, such as Kawasaki disease (KD). Together with the genetic predisposition to suffer the condition, hitherto undefined environmental factors have been suggested to contribute to the onset of autoimmune vasculitis in susceptible individuals. A combined approach integrating research on atmospheric circulation and wind dynamics with a time-series study on Kawasaki disease epidemiology in Japan and the US led to a publication firmly pointing to the role of winds and large-scale circulation in the propagation of the potential aetiologic agent of this disease (Rodó et al., 2011).

Objectives: The hypothesis of a windborne role in the generation of KD etiology is further tested in this study for a series of other world locations where the disease is also prevalent and along the suspicion that the interaction between bioaerosols, the air chemistry and predisposed or genetically susceptible patients might similarly be associated with KD incidence there. Recovery of land source regions is attempted with the aim of exploring similarities/differences with those found for Japan. Exploration of the phenological status of vegetation in each of those region is performed to seek further mechanistic explanations on the epidemiological links to KD.

Methods: In this study, a retrospective time series analysis of historical daily hospital admissions of KD and reconstruction of air movements and source regions is presented for several locations in all continents (US and Canada, Chile, France, the United Kingdom, Catalonia, South Korea, India and Thailand). The FLEXPART v9 atmospheric particle dispersion model is used and land-surface cover and high-resolution vegetation data employed to explore relationships to stages of vegetation development.

Results: Source regions and their land-cover typology is reconstructed for all major KD world sites in terms of disease incidence. Similar strong relationships emerge to cereal croplands in all the different continents. The phenological cycle of vegetation in those areas shows a link to the stages where vegetation is decaying, indicating that a relationship between the major KD season and some kind of agricultural byproducts or remnants might play a role in the onset or exacerbation of this disease. An application of a statistical model integrating the air physics ssociated to the movement of winds from these sources further demonstrates predictive capacity to anticipate peaks in KD incidence.

Conclusion: Long-standing debate continues on the factors and potential etiological agents of vasculitides and rheumatic diseases, such as Kawasaki disease (KD) in susceptible children. Together with the genetic predisposition to suffer the condition, hitherto undefined environmental factors are now suggested to contribute to the onset of autoimmune vasculitis in susceptible individuals. The role of bioaerosols and air chemistry and physics is presented pointing to a much clearer combination of factors ultimately appearing to be crucial to the manifestation of epidemiological clusters of this pediatric vasculitis. A computational model integrating all this new environmental information in combination with epidemiological dynamics proves successful in predicting KD incidence in Japan.

Disclosure of Interest

None Declared

HPPR/PRES Joint Session JMD

O11 THE INTERACTION BETWEEN GENETIC RISK FACTORS AND AGE OF DISEASE ONSET IN JUVENILE DERMATOMYOSITIS

Claire T. Deakin^1,2,3, John Bowes⁴, Meredyth Wilkinson¹, Lucy R. Marshall¹, Cerise R. Johnson-Moore¹, Gulnara Mamyrova⁵, Rudolfo Curiel⁵, Kelly Rouster-Stevens⁶, Heinrike Schmeling⁷, Helga Sanner⁸, Adam M. Huber⁹, Brian M. Feldman¹⁰, Ann M. Reed¹¹, Lauren M. Pachman¹², Stephen Eyre⁴, Soumya Raychaudhuri^13,14, Lucy R. Wedderburn^1,2,3,15, JDCBS and MYOGEN

¹UCL Great Ormond Street Institute of Child Health; ²ARUK Centre for Adolescent Rheumatology, University College London; ³NIHR Biomedical Research Centre, Great Ormond Street Hospital, London; ⁴ARUK Centre for Genetics and Genomics, University of Manchester, Manchester, UK; ⁵George Washington University, Washington; ⁶Emory University, Atlanta, USA; ⁷Department of Pediatrics, Alberta Children's Hospital, Calgary, Canada; ⁸Oslo University Hospital, Oslo, Norway; ⁹IWK Health Centre, Halifax; ¹⁰The Hospital for Sick Children, Toronto, Canada; ¹¹Duke University, Durham; ¹²Northwestern University, Chicago; ¹³Brigham and Women's Hospital and Harvard Medical School, Boston; ¹⁴Broad Institute of MIT and Harvard, Cambridge, USA; ¹⁵Great Ormond Street Hospital for Children NHS Trust, London, UK

Correspondence: Claire T. Deakin

Introduction: Juvenile dermatomyositis (JDM) is a rare, severe autoimmune disease characterised by proximal muscle weakness and skin rash. While JDM and adult-onset dermatomyositis (DM) share similar clinical and biological features, there are differences in prevalence of these features, including cancer, calcinosis and myositis-specific autoantibodies, suggesting a possible influence of age on pathogenesis.

Objectives: To investigate genetic risk factors for JDM and age of disease onset.

Methods: Caucasian JDM cases from the UK (n=312) were genotyped (Illumina HumanCoreExome). Caucasian control data (n=2808) were obtained from the Wellcome Trust Case Control Consortium (Affymetrix 500K). Following quality control, classical human leukocyte antigen (HLA) alleles and HLA amino acids were imputed using SNP2HLA. Logistic, linear and Cox regression were performed using PLINK and R package GenABEL, with adjustment for the first two principal components. Genome-wide association was set at P<5×10^-8 and suggestive association at P<1×10^-5. We subsequently built an international consortium to create a replication cohort of Caucasian cases (n=479). Genotyping of the replication cohort is ongoing using the HumanCoreExome array.

Results: Case-control analyses confirmed involvement of HLA including multiple loci within HLA-C (p=1.35×10^‑8, OR=2.49, 95% CI = 1.82-3.42) and HLA-DRB1 (p=2.73×10^-8, OR=0.56, 95% CI=0.46-0.69). Outside the HLA region there was suggestive evidence of association at ZNF337 (p=7.49×10^-6, OR=1.81, 95% CI=1.40-2.34). Analyses of association with age of disease onset did not implicate HLA involvement, suggesting age does not influence the association between HLA and JDM/DM. Analysis of age of onset as a quantitative trait revealed suggestive associations at PDE1A (p=1.56×10^‑6, β=-1.61, 95% CI = -2.26--0.97) and AGPAT3 (p=2.26×10^-6, β=1.63, 95% CI = 0.97-2.30), genes involved in regulating intracellular cyclic nucleic acid concentrations and phospholipid biosynthesis/Golgi-to-endoplasmic reticulum retrograde transport, respectively. In addition, we now have a replication cohort via our international consortium to validate these findings. Genotyping of the replication cohort is ongoing using the HumanCoreExome array.

Conclusion: This study confirms previous findings regarding HLA involvement. Analyses of associations with age of JDM onset identified novel loci, PDE1A and AGPAT3, which if validated in an independent replication cohort could suggest novel processes involved in pathogenesis. Together with the replication cohort, this study will be the largest GWAS of JDM to date.

Disclosure of Interest

None Declared

Novel therapeutic targets: from lab bench to bed side

O12 CORRELATIONS OF TYPE I INTERFERON SCORE AND INTERFERON INDUCED CHEMOKINES (CXCL10 AND CXCL9) WITH CUTANEOUS AND MUSCULAR DISEASE ACTIVITY IN JUVENILE DERMATOMYOSITIS

Gian Marco Moneta¹, Ivan Caiello¹, Lucilla Rava’², Silvia Rosina³, Luisa Bracci-Laudiero^1,4, Angelo Ravelli³, Fabrizio De Benedetti¹, Rebecca Nicolai¹

¹Division of Rheumatology; ²Epidemiology Unit, Ospedale Pediatrico Bambino Gesù, Rome; ³Rheumatology, Giannina Gaslini Institute, Genoa; ⁴Institute of Translational Pharmacology, CNR, Rome, Italy

Correspondence: Gian Marco Moneta

Introduction: Interferons (IFNs) seem to play an important role in the pathogenesis of juvenile dermatomyositis (JDM). We previously reported that expression of both type I and type II IFN related genes is increased in muscle biopsies of JDM patients and correlates with histological and clinical features of the disease. Interferon regulated genes (IRGs) have also been reported to be upregulated in peripheral blood of JDM patients and could represent valuable biomarkers of disease activity.

Objectives: The aim of this study was to investigate expression of IRGs (measured as type I IFN score), as well as serum levels of two type I and type II IFN induced chemokines (CXCL9, CXCL10) in peripheral blood of JDM patients and to assess their correlations with clinical and laboratory findings.

Methods: We collected 125 blood samples from 28 JDM patients at different time points during follow-up. We measured expression of IRGs (IFI27, IFI44L, IFIT1, ISG15, RSAD2, SIGLEC1) by quantitative PCR (qPCR) and calculated the type I IFN score; serum levels of CXCL9 and CXCL10 were analyzed by ELISA. At each visit, the following clinical data were recorded: physician’s global assessment of disease activity VAS (Visual Analogue Scale), cutaneous VAS, Cutaneous Assessment Tool (CAT) activity score, Childhood Myositis Assessment Score (CMAS), serum levels of creatine phosphokinase (CK, IU/l), antinuclear antibody (ANA) status, presence of myositis specific or myositis associated antibodies (MSA/MAA), prednisone (or equivalent) dose (mg/kg/daily), ongoing immunosuppressive medications.

Results: Type I IFN score was significantly higher in patients with features of active disease (physician’s global VAS >0.2, CAT activity score≥1, CK>150 IU/l). CXCL10 levels were significantly higher in patients with features of active muscle disease (CMAS<46, CK>150 IU/l) whereas CXCL9 levels were significantly higher only in patients with abnormal CK levels. In a multilevel mixed effect approach, type I IFN score was significantly associated with physician’s global VAS, cutaneous VAS, CAT activity score, CMAS and CK levels; CXCL9 showed no significant association with the evaluated clinical features; CXCL10 levels were significantly associated with CK levels and CMAS. Including time from disease onset to sampling did not change the results. Immunosuppressive medications negatively modulated expression of IRGs and IFN induced chemokines.

Conclusion: Our findings indicate that expression of IRGs, measured as type I IFN score, and serum levels of CXCL10 reflect specific features of disease activity in JDM, further supporting their role as valuable disease biomarkers.

Disclosure of Interest

G. M. Moneta: None Declared, I. Caiello: None Declared, L. Rava’: None Declared, S. Rosina: None Declared, L. Bracci-Laudiero: None Declared, A. Ravelli: None Declared, F. De Benedetti Grant/Research Support from: BMS, Pfizer, Abbvie, Novartis, Novimmune, Roche, SOBI, Sanofi, UBC, Consultant for: Roche, Novartis, Novimmune, SOBI, R. Nicolai: None Declared

Oral presentation 2

O13 EARLY AGGRESSIVE TREATMENT DECREASES PAIN IN PATIENTS WITH JUVENILE IDIOPATHIC ARTHRITIS

Maarit Tarkiainen^1,2, Pirjo Tynjälä³, Paula Vähäsalo⁴, Liisa Kröger⁵, Kristiina Aalto⁶, Pekka Lahdenne⁷ and ACUTE-JIA working group

¹Department of Pediatric Rheumatology, Children’s Hospital, Helsinki University Central Hospital; ²University of Helsinki; ³Poison Information Centre, , Helsinki University Central Hospital, Helsinki; ⁴Department of Pediatrics, Oulu University Hospital, Oulu; ⁵Department of Pediatrics, Kuopio University Hospital, Kuopio; ⁶Department of Pediatric Rheumatology; ⁷Helsinki University Central Hospital, Helsinki, Finland

Correspondence: Maarit Tarkiainen

Introduction: Patients with Juvenile Idiopathic Arthritis (JIA) experience more pain than normal population. Pain has become an important outcome measure in JIA.

Objectives: To measure the level of pain during the first year of early aggressive treatment in JIA and at three years from disease onset.

Methods: This study was performed along with Acute-JIA study, in which 60 new-onset patients with polyarticular JIA were randomized to receive either infliximab plus methotrexate (IFX), combination of hydroxychloroquine, sulphasalazine, and methotrexate (Triple) or methotrexate monotherapy (MTX). Disease activity and quality of life were measured at 7 study visits during the first year from onset, and at 3 years’ follow-up visit during open-label extension. Pain VAS (0-100) was utilized. Patients continued on their originally randomized treatment until they failed the strategy or achieved inactive disease (ID) on medication for at least 6 months.

Results: All 60 patients in the original trial completed the 3-year follow-up and 56 pain surveys. 50 (83%) switched treatment strategies between 1 to 3 years. Pain-VAS decreased from 37.0 (SD 24.3) at onset to 8.5 (15.6) at 1 year (Wilk’s Lambda p<0.005). During the open-label extension, the level of pain increased to 10.1 (15.4) at 3 years (p=0.068, compared with 1 year). No differences between treatment groups were detected (p=0.21). CHAQ and JADAS at each time point associated with level of pain. Cumulative time spent in inactive disease (ID) associated with lower level of pain at 3 years (coefficient beta -0.63, p=0.004)

Conclusion: During one-year early aggressive treatment, pain decreased as disease activity diminished. Small, although not statistically different increase in pain was noted during open-label extension. The treatment strategy seemed to have no influence on pain.

Trial registration identifying number: Trial registration: ClinicalTrials.gov NCT01015547

Disclosure of Interest

None Declared

O14 PHARMACOVIGILANCE IN JUVENILE IDIOPATHIC ARTHRITIS PATIENTS TREATED WITH BIOLOGIC AGENTS AND/OR METHOTREXATE. COMBINED DATA OF MORE THAN 15,000 PATIENTS FROM PHARMACHILD AND NATIONAL REGISTRIES

Gabriella Giancane, Joost Swart, Gerd Horneff, Bo Magnusson, Michael Hofer, Ekaterina Alexeeva, Violeta Panaviene, Brigitte Bader-Meunier, Jordi Anton, Susan Nielsen, Fabrizio De Benedetti, Sylvia Kamphuis, Valda Stanevicha, Maria Trachana, Laura M. Ailioaie, Elena Tsitsami, Ariane Klein, Kirsten Minden, Ivan Foeldvari, Johannes-Peter Haas, Jens Klotsche, Alessandro Consolaro, Francesca Bovis, Francesca Bagnasco, Angela Pistorio, Alberto Martini, Nico Wulffraat, Nicolino Ruperto and for the Paediatric Rheumatology International Trials Organisation (PRINTO), BiKeR and the board of the Swedish Registry.

Clinica Pediatrica e Reumatologia - PRINTO, Istituto Giannina Gaslini, GENOA, Italy

Correspondence: Gabriella Giancane

Introduction: The availability of methotrexate (MTX) and the introduction of multiple biological agents have revolutionized the treatment of juvenile idiopathic arthritis (JIA). Several international and national drug registries have been implemented to monitor accurately the long-term safety/efficacy of these agents.

Objectives: This study aims to present the combined data coming from “Pharmacovigilance in JIA patients treated with biologic agents and/or MTX” (Pharmachild)/Pediatric Rheumatology International Organization (PRINTO) registry and the national registries from Germany (BiKeR) and Sweden.

Methods: Descriptive statistics for demographic, clinical data, drug exposure, adverse events (AE) and events of special interest (ESI) were reported. For the Swedish register, AE data were not available.

Results: A total of 15,284 patient’s data were reported, 8,274 (54%) from the Pharmachild registry, 3,990 (26%) and 3,020 (20%) from the Germany and the Swedish registries, respectively. Pharmachild children showed a younger age (median of 5.4 years versus 7.6) at JIA onset and shorter disease duration (5.3 versus 6.1-6.8) when compared to the other registries. The most frequent JIA category was the rheumatoid factor negative polyarthritis (range 24.6-29.9%). Methotrexate (61-84%) and etanercept (24%>61.8%) were the most frequently used synthetic and biologic disease-modifying anti-rheumatic drug (DMARD), respectively. There was a wide variability in glucocorticoid use (16.7-42.1%). Serious AE were present in 572 (6.9%) patients in Pharmachild versus 297 (7.4%) in BiKeR. Infection and infestations were the most frequent AE (29.4-30.1%) followed by gastrointestinal disorders (11.5-19.6 %). The most frequent ESI were infections (75.3-89%),(Table 1).

Conclusion: Sharing of data from national and international registries represents the most powerful tool for future analysis of safety and effectiveness of immunosuppressive therapies in JIA.

Trial registration identifying number: NCT01399281

Disclosure of Interest

G. Giancane: None Declared, J. Swart: None Declared, G. Horneff: None Declared, B. Magnusson: None Declared, M. Hofer: None Declared, E. Alexeeva: None Declared, V. Panaviene: None Declared, B. Bader-Meunier: None Declared, J. Anton: None Declared, S. Nielsen: None Declared, F. De Benedetti: None Declared, S. Kamphuis: None Declared, V. Stanevicha: None Declared, M. Trachana: None Declared, L. Ailioaie: None Declared, E. Tsitsami: None Declared, A. Klein: None Declared, K. Minden: None Declared, I. Foeldvari: None Declared, J.-P. Haas: None Declared, J. Klotsche: None Declared, A. Consolaro: None Declared, F. Bovis: None Declared, F. Bagnasco: None Declared, A. Pistorio: None Declared, A. Martini: None Declared, N. Wulffraat: None Declared, N. Ruperto Grant/Research Support from: The G. Gaslini Hospital, which is the public Hospital where I work as full time public employee, has received contributions from the following industries for the coordination activity of the PRINTO network: BMS, GlaxoSmithKline (GSK), Hoffman-La Roche, Novartis, Pfizer, Sanofi Aventis, Schwarz Biosciences, Abbott, Francesco Angelini S.P.A., Sobi, Merck Serono. This money has been reinvested for the research activities of the hospital in fully independent manners without any commitment with third parties., Speaker Bureau of: I received speaker’s bureaus and consulting fees from the following pharmaceutical companies: AbbVie, Amgen, Biogenidec, Alter, AstraZeneca, Baxalta Biosimilars, Biogenidec, Boehringer, BMS, Celgene, CrescendoBio, EMD Serono, Hoffman-La Roche, Italfarmaco, Janssen, MedImmune, Medac, Novartis, Novo Nordisk, Pfizer, Sanofi Aventis, Servier, Takeda, UCB Biosciences GmbH.

Table 1 (abstract O14). Most frequent events of special interest ordered by decreasing frequencies. Data are absolute numbers and frequencies (%)

O15 REMISSION STATUS AFTER 18 YEARS OF FOLLOW-UP IN THE POPULATION-BASED NORDIC JUVENILE IDIOPATHIC ARTHRITIS (JIA) COHORT.

Mia Glerup¹, Veronika Rypdal², Ellen Arnstad^3,4, Maria Ekelund^5,6, Suvi Peltoniemi^6,7, Kristiina Aalto⁸, Marite Rygg^4,9, Peter Toftedal¹⁰, Susan Nielsen¹⁰, Anders Fasth¹¹, Lillemor Berntson⁶, Ellen Nordal², Troels Herlin¹²

¹Pediatrics, Aarhus University Hospital, Aarhus N, Denmark; ²University Hospital of North Norway, Tromsø; ³Levanger Hospital, Nord-Trøndelag; ⁴Fac. of Med. and Health Sci., NTNU, Norway; ⁵Ryhov County Hospital, Jonkoping; ⁶Uppsala University, Uppsala, Sweden; ⁷University of Helsinki; ⁸Hospital for Children and Adolescents, Helsinki, Finland; ⁹St. Olavs Hospital, Trondheim, Norway; ¹⁰Rigshospitalet, Copenhagen, Denmark; ¹¹Sahlgrenska Academy, Gothenburg, Sweden; ¹²Aarhus University Hospital, Aarhus N, Denmark

Correspondence: Mia Glerup

Introduction: Innovative changes towards targeted treatment have improved the outcome dramatically for juvenile idiopathic arthritis (JIA) during the last two decades. The question remains how well these children perform during long-term follow-up.

Objectives: To study the disease activity, remission rate and damage 18 years after JIA onset.

Methods: 510 consecutive cases of JIA with disease onset in 1997 to 2000 from Denmark, Norway, Sweden and Finland were prospectively included in a longitudinal, close to population-based 18-year (mean 17.5 years; range 14.2-20.2) follow-up study. The last follow-up visit included an update on the family history, medication and clinical data such as a clinical joint examination and remission status according to the preliminary Wallace criteria.

Results: 434 (85%) out of 510 eligible JIA participants with a mean age (S.D) of 24.0 (± 4.4) years were included. 76 patients (15%) were lost to follow-up. Out of the included patients 329 (76%) attended a follow-up visit, and 105 patients (24%) were evaluated by a telephone interview.

The distribution of the JIA categories was as follows: 3% systemic, 27% persistent oligoarticular, 20% extended oligoarticular, 16% polyarticular RF negative, 1% polyarticular RF positive, 7% psoriatic, 10% enthesitis-related arthritis (ERA) and 15% undifferentiated JIA.

For all 329 patients attending a clinical visit the median active joint count was 0 (range 0-15), however during the 18 years of disease course the median cumulative joint count was 8 (range 1-59). 66 participants (15 %) received disease-modifying anti-rheumatic drugs (DMARDS) and 84 patients (19%) were treated with biologics at the last follow-up.

At the final study visit the median composite juvenile arthritis disease activity score JADAS71 was median 1.5 (range 0-31.6) with the ERA category having the highest median score of 4.5 (range 0-16.5) (p=0.003). In the follow-up cohort 48% had a JADAS71 score <1 indicating inactive disease.

Articular damage (JADI-A) was found in 20% of the patients who had a follow-up visit and 12.5% had developed extra-articular damage (JADI-E), most commonly ocular damage, found in 26/41 (63%). The highest JADI-A and JADI-E scores were found in the polyarticular RF negative and psoriatic categories.

Less than half (44%) of the participants were in remission off medication 18 years after disease onset, but 39.8% had active disease. Achievement of remission off medication was observed in the following order: persistent oligoarticular 39/72 (54%), systemic 7/13 (54%), psoriatic 9/22 (41%), undifferentiated 21/55 (38%), extended oligoarticular 19/66 (29%), RFneg poly 16/59 (27%), RFpos poly 1/5 (20%), and ERA 4/37 (11%), the latter being significantly different from the other categories (p<0.001).

Conclusion: A significant proportion of the JIA cohort do not reach remission despite new treatment options and notably more than one third receive systemic treatment even 18 years after disease onset. The worst outcome was evident in the ERA category and in general the JIA disease burden in adulthood remains extensive.

Disclosure of Interest

None Declared

O16 RESULTS AFTER 24 MONTHS OF DRUG-FREE INACTIVE DISEASE AND FLARE FREQUENCY IN JUVENILE IDIOPATHIC ARTHRITIS PATIENTS IN A TREATMENT-TO-TARGET STRATEGY STUDY

Petra Hissink Muller^1,2, Danielle M. Brinkman^1,3, Dieneke Schonenberg-Meinema⁴, Wytse B. van den Bosch¹, Yvonne Koopman-Keemink⁵, Peter Bekkering⁶, Taco Kuijpers⁴, Marion van Rossum⁷, Lisette van Suijlekom-Smit², J M. van den Berg⁸, Stefan Boehringer⁹, Cornelia F. Allaart¹⁰, Rebecca ten Cate¹

¹Pediatric Rheumatology, LUMC, Leiden; ²Pediatric Rheumatology, Erasmus MC, Sophia Children's Hospital , Rotterdam; ³Pediatrics , Alrijne, Leiderdorp; ⁴Pediatric Hematology, Immunology, Rheumatology and Infectious Diseases , Emma Children's Hospital AMC, Amsterdam; ⁵Pediatrics , Juliana Children's Hospital, The Hague; ⁶Pediatric Oncology, Princess Maxima Center of Pediatric Oncology, Utrecht; ⁷Pediatrics; ⁸Hematology, Immunology, Rheumatology and Infectious Diseases, Emma Children's Hospital AMC, Amsterdam; ⁹Medical Statistics and Bioinformatics; ¹⁰Rheumatology, LUMC, Leiden, Netherlands

Correspondence: Petra Hissink Muller

Introduction: Reaching early inactive disease is the goal in Juvenile Idiopathic Arthritis (JIA) patients. How to proceed after reaching inactive disease is subject of ongoing research. Tapering and stopping disease modyfying anti-rheumatic drug (DMARD) therapy, including observation of subsequent flares, was applied in all three arms of the BeSt for Kids study.

Objectives: The aim of the BeSt for Kids study was to investigate, which of three treatment strategies was most effective and safe, by comparing them directly. The therapeutic target, in all arms, was inactive disease. If inactive disease was reached and maintained for a specific period of time, medication was tapered and stopped.

Methods: We conducted a randomized, single-blinded, multicenter, treatment strategy study with 24 months of follow-up. DMARD-naive JIA (oligoarticular, rheumatoid factor negative polyarticular, and juvenile psoriatic arthritis patients) were randomized to 1) sequential DMARD monotherapy, 2) combination therapy: MTX and prednisolone-bridging, 3) combination therapy MTX with etanercept. For all arms, the treatment protocol described a number of subsequent treatment steps in case medication failed. After reaching inactive disease for 3 (oligoarticular) or 6 (polyarticular) months, medication was tapered and stopped according to protocol. Flare frequency was observed.

Missing data were imputed. In case of drug-free clinically inactive disease often intentionally no blood was drawn causing non-random missing ESR, and here ‘0’ was imputed for the analysis of inactive disease.

Primary outcome was time to inactive disease and time to flare after tapering and stopping DMARD therapy calculated using Kaplan Meier curve with log rank test. Secondary outcomes are adjusted ACRPedi 30/50/70/90 scores, toxicity, functional ability and quality of life. Generalised Estimated Equations were used for longitudinal data analyses.

In this abstract we share time-to-flare, flare frequencies and flare characteristics in all three arms.

Results: During 24 months 59% (19 (3 oligo)/31 (61%) of patients in arm 1, 16 (1 oligo)/32 (50%) in arm 2 and 19 (1 oligo)/29 (65%) in arm 3) had tapered and stopped all DMARDs (drug-free inactive disease) after median 15.0 (IQR 12.0-18.0) months (arm 1), 19.5 (12.0-24.0) months (arm 2) and 18.0 (12.0-21.0) months (arm 3) of therapy. However, 26% (6 (1 oligo) patients in arm 1, 3 in arm 2 and 5 in arm 3) subsequently had to restart treatment before end of study, after median time-to-flare 18.0 (15.0-21.0) months (p=0.7).

Flares were characterised by JADAS-10 of 9.7 (8.1-11.3), which improved 3 months after restart of treatment to JADAS-10 of 3.9 (1.8-6.0).

Conclusion: During 24 months of  treatment to target inactive disease, including tapering and stop-strategies, flare frequency was 26% after median 18 months. After 24 months, 71% of patients had inactive disease and 39% were in drug-free inactive disease.

It is feasible to incorporate strategies for tapering and stopping DMARD-therapy in juvenile idiopathic arthritis patients, when tight control is maintained.

Trial registration identifying number: Trial registration number: Dutch trial register 1574

Disclosure of Interest

None Declared

O17 NEW JADAS10- AND CJADAS10-BASED CUTOFFS FOR JUVENILE IDIOPATHIC ARTHRITIS DISEASE ACTIVITY STATES: VALIDATION IN A MULTINATIONAL DATASET OF 4830 PATIENTS

Chiara Trincianti¹, Giedre Janukeviciute¹, Pieter Van Dijkhuizen², Carolina Montobbio¹, Gabriella Giancane¹, Alessandra Alongi¹, Nicola Ruperto¹, Joost Swart², Angelo Ravelli^1,3, Alessandro Consolaro^1,3, on behalf of EPOCA Study Group

¹ISTITUTO GIANNINA GASLINI, Genova, Italy; ²University Medical Center, Utrecht, Netherlands; ³University of Genova, Genova, Italy

Correspondence: Chiara Trincianti

Introduction: The measurement of disease activity plays a pivotal role in the care of patients with juvenile idiopathic arthritis (JIA). To serve this purpose, the Juvenile Arthritis Disease Activity Score (JADAS) and its clinical version excluding the acute phase reactant (cJADAS) were developed.

Cutoffs for the state of remission, low disease activity (LDA), moderate disease activity (MDA) and high disease activity (HDA) are necessary to interpret the scores and are ideally suited for pursuing tight disease control in a treat-to-target strategy.

Aiming to obtain cutoffs suitable for any clinical setting, new values were recently developed for JADAS10 and cJADAS10 in oligoarthritis and polyarthritis, based on a large multinational dataset of JIA patients (Consolaro A, et al. Arthritis Rheumatol. 2017;69s10).

Objectives: To externally validate the new cutoffs for JADAS10 and cJADAS10 disease activity states.

Methods: Four not selected for cutoffs development JIA patients dataset were considered: 1) 4397 oligoarthritis and polyarthritis patients from the EPOCA study; 2) 148 oligoarthritis patients from the TRIMECA trial; 3) 172 polyarthritis patients from the Abatacept trial, 4) 113 oligoarthritis and polyarthritis patients first starting methotrexate from a monocentric retrospective cohort (Swart et al, Ann Rheum Dis. 2018;77:336-342).

Face validity was assessed in dataset 1) by plotting the proportion of patients in remission and LDA against the values of the 6 parameters in the ACR JIA core set.

Discriminative ability was assessed in datasets 2) and 3) by comparing the percentage of patients below the cutoff values in the different ACR pediatric categories of response. In dataset 1) we compared in each disease activity state, the level of pain (0-10 VAS), functional ability impairment, and number of restricted joints and the frequency of patients satisfied with disease outcome, starting a new medication for JIA, and having morning stiffness.

Predictive ability was assessed in dataset 4) by calculating the sensitivity and specificity of the cutoffs for remission and LDA after 3 months for treatment response after 12 months.

Results: Only most relevant results are described. JADAS10 and cJADAS10 cutoffs for remission allowed up to 1 active joint for polyarthritis and 0 for oligoarthritis.

In dataset 2), 42% and 63% of patients achieving an ACRp70 response met the JADAS10 cutoffs for remission and LDA, respectively. In dataset 3), these percentages were 48% and 82%, respectively. In dataset 1), the median level of pain was 0, 1.5, 3, and 5.5 for polyarthritis patients in cJADAS10 remission, LDA, MDA, and HDA, respectively (Kruskal-Wallis p<0.001). The frequency of satisfaction with disease outcome was 94%, 76%, 56%, and 24% for oligoarthritis patients in cJADAS10 remission, LDA, MDA, and HDA, respectively (Chi2 test p <0.001).

In dataset 4), 100% and 71% of patients with oligoarthritis classified as non-responders after 12 months had JADAS levels after 3 months above the cutoffs for remission and LDA, respectively. For polyarthritis, 90% and 80% of non-responders had JADAS levels after 3 months above the cutoffs for remission and LDA, respectively.

Conclusion: New JADAS cutoffs showed good face and content validity; achievement of remission and LDA defined by the cutoffs predicted the response to therapy. Cutoffs were developed and validated in a large multinational dataset and they are ready for use in clinical trials and routine practice.

Disclosure of Interest

None Declared

O18 JUVENILE INFLAMMATORY MYOPATHY WITH POSITIVE MDA5 AUTO-ANTIBODIES: A SPECIFIC SUBGROUP WITH SYSTEMIC UPREGULATION OF INTERFERON-ALPHA PATHWAY.

Isabelle Melki¹, Vincent Bondet², Cyril Gitiaux¹, Hervé Devilliers³, Marie-Louise Fremond⁴, Darragh Duffy², Yanick Crow⁴, Mathieu Rodero⁴, Brigitte Bader-Meunier¹

¹APHP; ²Pasteur Institute, Paris; ³Médecine interne 2 CHU Dijon, Dijon; ⁴Imagine Institute, Paris, France

Correspondence: Isabelle Melki

Introduction: Juvenile dermatomyositis (JDM) and overlap myositis (OM) represent heterogeneous subtypes of juvenile inflammatory myopathy (JIM). Chronic evolution may occur in 60% of cases, and morbidity/mortality is substantial (gastro-intestinal; pulmonary; organ failure).

Objectives: Clinico-biological description of JDM and OM with positive MDA5 auto-antibodies in comparison to other JIM.

Methods: Retrospective and prospective study of patients fulfilling Bohan and Peter criteria for JDM and Troyanov for OM, aged less than 16 years at diagnosis, ascertained from 3 French paediatric rheumatology reference centres between 2013 to 2018. Severe forms were defined as requiring ICU management, and/or more than 3 treatment lines and/or with fatal outcome. Muscle biopsies were reviewed. Type I interferon pathway activity was assessed by dosage of interferon alpha (IFNa) through digital elisa (Simoa) with a Pan-IFNa antibody in patient sera and myoblast lysate, mRNA expression of interferon stimulated genes (ISGs) by RTqPCR and phosphorylation of STAT by flow cytometry on whole blood.

Results: 67 patients were included, 12 (group 1) and 54 (group 2) with and without anti-MDA5 antibodies respectively. Group 1 demonstrated more arthritis (100% vs 24%), cutaneous ulcerations (42% vs 26%), interstitial lung disease (ILD) (33% vs 14%) and a milder muscular involvement (median of CK: 96 vs 149 UI/l), with better preserved muscular function (MMT and C-MAS, respectively 79/80 vs 70/80 and 50/52 vs 38/52). Total muscle biopsy scores were lower for group 1 than group 2 (respectively 5.5 vs 20). Group 1 included more severe forms (36% vs 19%). 133 IFN signatures (ISGs) and 210 IFNa Simoa measurements were assessed. Correlation between ISG expression and protein at 79 simultaneous data points was high (Pearson: r = 0,74 ****). ISGs and IFNa (signature and dosage) were higher in group 1 than 2 (median of ISGs 21 vs 7.4 and median of Simoa 3807.5 vs 49.6 fg/ml). In contrast, IFNa levels in patient myoblasts were similar to controls for group 1 (1 patient), whilst those in group 2 were higher (10 patients). A constitutive phosphorylation of STAT1 and STAT3 was observed in T and B lymphocytes and monocytes of 5 patients, including one from group 1. Treatment with steroids, tacrolimus, rituximab and immunoadsorption in one group 1 patient correlated with the disappearance of MDA5 auto-antibodies, the normalisation of IFNa levels and the induction of complete remission (normalisation of clinical, laboratory and radiological parameters).

Conclusion: This study indicates a higher frequency of cutaneous ulcerations, arthritis and ILD, and milder muscular involvement in JIM with positive MDA5 auto-antibodies compared to other JIM. These data suggest an important role of systemic IFNa in the pathology of the disease. In severe and refractory forms, IFNa may be a potential therapeutic target.

Disclosure of Interest

None Declared

O19 PREDICTING NON-RESPONSE TO BIOLOGICALS IN JUVENILE IDIOPATHIC ARTHRITIS PATIENTS; A BIOMARKER HUNT IN PERIPHERAL BLOOD SERUM

Koen Willemsen¹, Sytze de Roock¹, Wilco de Jager¹, Nienke ter Haar¹, Pieter van Dijkhuizen¹, Rae Yeung², Trang Duong², Nico Wulffraat¹, Joost Swart¹, Sebastiaan Vastert¹

¹Department of Pediatric Rheumatology and Immunology, Wilhelmina Children’s Hospital, University Medical Centre Utrecht, Utrecht, Netherlands; ²Hospital for Sick Children, Toronto, Canada

Correspondence: Koen Willemsen

Introduction: Patients with Juvenile Idiopathic Arthritis (JIA) who fail to reach a state of clinically inactive disease might start biological treatment (TNFa-blockers) [3]. Currently little is known in relation to which patients will respond or not to specific biologicals, potentially leading to a delay in achieving acceptable clinical state [4].

Objectives: To investigate the possible predictive value of serum proteins on therapeutic (non-)response prior to start of biological therapy.

Methods: This study presents a retrospective analysis of a prospectively collected and followed cohort of non-systemic JIA patients from a single pediatric rheumatology center. Non-response to biological was defined as a necessity to switch biological or when criteria for clinically relevant improvement (a change of ≤-5.5 in JADAS27 [5] while not achieving clinically inactive disease i.e. a JADAS27 ≤1 [6]) were not met and was evaluated 6 months after start of biological therapy. Serum protein concentration was analysed by Luminex® multiplex assay (44-plex including cytokines, chemokines and growth factors). We performed basic statistics, including univariate analysis (Mann-Whitney U test) to assess whether protein concentrations associate with response to therapy. Proteins associating with a p<0.1 were included for further analysis later on whereas proteins with a p<0.05 were considered significant. If proteins correlated with a Spearman’s rho >0.6 the more significant protein was included.

Results: 67 Patients were included (Table 1). 36 patients received etanercept, 30 adalimumab and 1 golimumab. Of the oligo articular JIA patients 14 (60.9%) were persistent oligo articular and 13 (56.5%) were ANA+. At t=6 months 15 patients were non-responsive (34.1% of cases with JADAS27 available). We found a significant association with non-response for TNF-ligand-1a (TL1a) and haptoglobin. With a p<0.1 interleukine-8 (IL-8) and vascular endothelial growth factor (VEGF) were of interest for further analysis.

Conclusion: This preliminary analysis yielded various proteins of which the serum concentration relates to non-response to biological therapy. These proteins might serve as biomarkers predicting therapeutic response. Further research and analyses, including a planned validation in a separate prospective cohort, is required to predict non-response.

Disclosure of Interest

None Declared

Table 1 (abstract O19). See text for description

Clinical Trials and drug development

O20 PEDIATRIC OPEN-LABEL CLINICAL STUDY OF RITUXIMAB FOR THE TREATMENT OF GRANULOMATOSIS WITH POLYANGIITIS (GPA) AND MICROSCOPIC POLYANGIITIS (MPA)

Paul Brogan¹, Gavin Cleary², Ozgur Kasapcopur³, Satyapal Rangaraj⁴, Rae Yeung⁵, Paul Brunetta⁶, Jennifer Cooper⁶, Pooneh Pordeli⁷, Patricia B. Lehane⁸

¹UCL Institute of Child Health and Great Ormond Street Hospital NHS Foundation Trust, London; ²Alder Hey Children's Hospital, Liverpool, UK; ³Cerrahpasa Medical School, Istanbul University, Istanbul, Turkey; ⁴Nottingham University Hospitals NHS Trust, Nottingham, UK; ⁵Hospital for Sick Children and University of Toronto, Toronto, Canada; ⁶Genentech, Inc., South San Francisco, USA; ⁷Hoffmann-La Roche Ltd, Mississauga, Canada; ⁸Roche Products Ltd, Welwyn Garden City, UK

Correspondence: Paul Brogan

Introduction: Rituximab in combination with glucocorticoids (GC) is approved to treat adult patients with GPA or MPA; however, limited data exist on the safety and efficacy of rituximab in pediatric patients with these potentially life- and organ-threatening diseases.

Objectives: To report the interim safety, pharmacokinetics (PK) and exploratory efficacy data from the 6-month remission induction phase of a Phase IIa international, open-label, 18-month clinical study of rituximab in pediatric patients with GPA or MPA.

Methods: Patients aged ≥2 to ≤18 years with newly diagnosed or relapsing GPA/MPA received 4 intravenous (IV) rituximab infusions of 375 mg/m² body surface area (BSA) on Days 1, 8, 15 and 22 with concomitant GC 1 mg/kg/day (max 60 mg/day) tapered to 0.2 mg/kg/day minimum (max 10 mg/day) by Month 6. All patients received 3 doses of pulse IV methylprednisolone (30 mg/kg/day, max 1g/day) prior to first rituximab infusion and mandatory prophylaxis for Pneumocystis jiroveci infection. Patients were also pre-medicated with acetaminophen and an antihistamine, 1 hour before each rituximab infusion. Adverse events (AEs) and laboratory data were measured at each study visit (1, 2, 4 and 6 months). Plasma samples for PK analysis were collected throughout the study; clearance and area under the curve (AUC) were calculated using population PK modeling from the RAVE study of rituximab in adult patients with GPA/MPA (Stone et al. NEJM. 2010;363:221-32). For exploratory efficacy assessment, the Pediatric Vasculitis Activity Score (PVAS) was measured at each study visit.

Results: Of the 25 patients enrolled, 19 (76%) had GPA and 6 (25%) had MPA (median [range] age 14 [6-17] years; 80% female). Median (range) disease duration was 0.5 (0.2-0.7) months; 2 patients had received prior cyclophosphamide therapy. All received 4/4 rituximab infusions and completed the 6-month induction phase. By Month 6, all patients had experienced ≥1 AE. The most common AEs by system organ class were infections and infestations in 16 patients (64%). Eleven serious AEs occurred in 7 patients (28%), including 3 serious infections (viral gastroenteritis, one lower and one upper respiratory tract infection). 32% of patients had ≥1 infusion related reaction (IRR). No serious IRRs or deaths were reported. The relationship between AUC and BSA was flat and comparable to adult patients. A total of 13 patients (52%) achieved remission by 6 months, defined as PVAS of 0 and GC dose 0.2 mg/kg/day (max 10 mg/day) or PVAS of 0 on 2 consecutive readings ≥4 weeks apart irrespective of GC dose.

Conclusion: In the initial 6 months of this first global clinical trial of rituximab in pediatric patients with GPA/MPA, rituximab was generally safe and well tolerated. The overall safety profile and PK parameters were comparable to rituximab-treated adults with GPA/MPA. No new safety signals were observed. However, the study size and interim nature of the analysis limit firm conclusions. The clinical trial and additional efficacy, PK and safety analyses are ongoing.

Trial registration identifying number: NCT01750697

Disclosure of Interest

P. Brogan Grant / Research Support from: Roche, SOBI, Novartis, Chemocentryx, Consultant for: Roche, SOBI, UCB, Speaker Bureau of: SOBI, Novartis, G. Cleary Speaker Bureau of: AbbVie, O. Kasapcopur: None Declared, S. Rangaraj: None Declared, R. Yeung Consultant for: Novartis, Eli Lilly, P. Brunetta Shareholder of: Roche, Employee of: Genentech, Inc., J. Cooper Employee of: Genentech, Inc., P. Pordeli Employee of: Roche, P. Lehane Employee of: Roche

Immune defensee and inflammation

O21 JUVENILE SYSTEMIC LUPUS ERYTHEMATOSUS WITH A BASELINE HIGH INTERFERON SIGNATURE ASSOCIATES WITH INCREASED IMMUNE CELL TLR7 EXPRESSION AND ENHANCED TLR7 DEPENDENT INTERFERON ALPHA PRODUCTION

Kate Webb¹, Gary Butler², Coziana Ciurtin¹, Hannah Peckham¹, Anna Radziszewska¹, Fraser Simpson³, Paola Oliveri³, Lucy Wedderburn^1,4, Yiannis Ioannou¹

¹ARUK Centre for Adolescent Rheumatology; ²Paediatric Endocrinology; ³Department of Genetics, Evolution & Environment, Nanostring Facility, UCL; ⁴NIHR Biomedical Research Centre, UCL, GOSH, London, UK

Correspondence: Kate Webb

Introduction: Juvenile onset systemic lupus erythematosus (jSLE) is characterised by a type 1 interferon (IFN) transcription signature. Up to 80% of patients with jSLE of varying severity express a predominant IFN signature which correlates with disease activity, and is abrogated by steroids. Investigating the IFN signature outside of a flare may provide insight into the true prevalence of high IFN signature disease, and underlying differences in disease pathogenesis, that may be masked by steroid or disease activity.

Objectives: To investigate the prevalence of high IFN signature in low disease activity jSLE, and to assess whether toll like receptor (TLR) 7 or 9 dependent IFNα production pathways differ between high and low IFN signature patients.

Methods: Blood was collected, with consent, from healthy volunteers (n=24:10 female; 14 male, age=12-19) and young people with jSLE (n=29:20 female; 9 male, age=14-21). Clinical data were recorded. Peripheral blood mononuclear cells (PBMC) were separated by Ficoll gradient centrifugation. Ex vivo RNA was assessed by Nanostring Plex Set. IFN score was calculated from counts of 5 IFN inducible genes (MX1+BST2+MCP1+ISG15+ IFIT1/5). Samples were classed as IFN positive (IFN+) if >2SD from the healthy mean. Separately, PBMC were stimulated with TLR7 agonist, R848, or TLR9 agonist, CPGODN2216, before assessing for secretion of IFNα and TNFα by luminex. Statistical analysis was performed using SPSS with linear regression.

Results: There was a significantly higher IFN score in jSLE than healthy controls (p=0.001). 14/29 (48.27%) jSLE patients were IFN+ vs 1/23 (0.04%) healthy controls (p=0.005). Patients with jSLE had a mean SLEDAI of 3.0 (range=0-12); 15 (52%) were on prednisone (mean= 6.9mg). In patients with jSLE, the only autoantibody that significantly predicted IFN score was towards RNP (p=0.018). There was no association between any specific organ involvement and IFN score. Four patients with jSLE were B cell depleted (<2%), with no effect of B cell depletion on IFN score. There were no significant differences in markers of disease activity (SLEDAI, CRP, ESR, C3, C4 and double stranded DNA antibodies) between IFN+ and IFN- jSLE patients. Only jSLE patients who were IFN+ produced significantly more IFNα (p=0.046) and TNFα (p=0.031) than healthy controls after TLR7 stimulation. After TLR9 stimulation, however, IFNα production was decreased in jSLE compared to healthy, regardless of IFN score. IFN+ patients with jSLE had significantly higher PBMC RNA expression of TLR7 than those who were IFN- (p=0.001), and healthy controls (p=0.04). IFN+ patients with jSLE showed a significant decrease in TLR9 expression when compared to healthy controls (p=0.023). We confirmed that TLR7 was not an IFN inducible marker, by assessing expression in healthy controls with and without IFNα pre-stimulation, which showed no significant difference.

Conclusion: We present novel data, showing that, in non-flaring patients with jSLE on low doses of steroid, half are IFN signature positive. This is lower than reported in studies that include flaring patients and may better represent prevalence of high IFN signature disease at baseline. In jSLE, IFN signature score associates with autoantibodies to RNP. PBMC from IFN+ patients produce more IFNα after TLR7 stimulation, and have a significantly higher expression of TLR7, along with a decrease in TLR9 expression compared to samples from patients with a negative IFN signature, and healthy controls.

Disclosure of Interest

None Declared

O22 STERILE INFLAMMATORY ACTIVATION OF HUMAN CORONARY ARTERY ENDOTHELIAL CELLS DEPENDS STRICTLY ON INTERLEUKIN 1Β: IMPLICATIONS FOR KAWASAKI DISEASE PATHOLOGY

Giulia Armaroli¹, Emely Verweyen¹, Carolin Pretzer¹, Katharina Kessel¹, Keiichi Hirono², Fukiko Ichida², Mako Okabe², David Cabral³, Dirk Foell¹, Kelly Brown³, Christoph Kessel¹

¹Pediatric Rheumatology & Immunology, University Children’s Hospital, Muenster, Germany; ²Department of Pediatrics, University of Toyama, Toyama, Japan; ³Department of Pediatrics, University of British Columbia, Vancouver, Canada

Correspondence: Christoph Kessel

Introduction: The granulocytic protein S100A12 is expressed at high levels in Kawasaki Disease (KD) but it is unclear whether S100A12 does actively participate in KD pathology or is a bystander of neutrophil activation.

Objectives: Kawasaki disease (KD) is an acute vasculitis of childhood, predominantly affecting coronary arteries. S100A12 is an endogenous pattern recognition receptor (PRR) ligand, which is strongly upregulated in KD and S100A12 serum levels track with KD disease activity and response to intravenous immunoglobulin (IVIG) treatment. While S100A12 was originally described as agonist of the multi-ligand receptor for glycation endproducts (RAGE), we described human monocytes to respond to S100A12-stimulation in an exclusively TLR4-dependent manner. Here, we aimed to investigate whether and how serum S100A12 might be actively involved in inflammatory processes in KD.

Methods: Serum samples (n=75) from patients with KD at different stages pre- and post-intravenous immunoglobulin (IVIG) treatment were analyzed for S100A12, cytokines, chemokines and soluble markers of endothelial activation. Primary human coronary artery endothelial cells (HCAECs) were analyzed for responsiveness following direct stimulation with S100A12 or lipopolysaccharide (LPS). Alternatively, HCAEC were cultured in conditioned medium obtained from primary human monocytes stimulated with LPS or S100A12 in the absence or presence of IVIG or cytokine antagonists.

Results: Multiple correlation analyses revealed, that in KD patients’ sera in course of IVIG-therapy soluble vascular cell adhesion molecule-1 (sVCAM-1) titers as indicator of endothelial activation exclusively associated with pre-treatment S100A12 levels. Yet, in contrast to stimulations with LPS, HCAECs were not responsive to direct treatment with S100A12, despite the presence of appropriate receptors (RAGE, TLR4). Unresponsiveness of HCAECs to S100A12 was due to lack of membrane CD14 expression. Addition of recombinant soluble CD14 or human serum benefitted LPS- but could not establish response to S100A12. Instead, HCAECs strongly responded to supernatants obtained from S100A12-stimulated primary human monocytes, as evidenced by expression of inflammatory cytokines and adhesion molecules. Inflammatory activation of HCAECs by S100A12-stimulated monocytes required monocyte-co-stimulation with ATP. Endothelial cell stimulation was completely abrogated upon IL-1β blockade but remained unaffected by treatment with IVIG or anti-TNFa and IL-6 receptor blocking antibodies.

Conclusion: We identified IL-1β-signaling in coronary artery endothelium as particularly relevant in course of sterile inflammation as induced by damage associated molecular pattern (DAMP) molecules such as S100A12. These data are in support of a potential key role for IL-1 in KD pathology but also highlight the coronary artery endothelium, which is critically involved in early KD pathology and aneurysm formation as particularly sensitive to IL-1β blockade during DAMP-induced sterile inflammation.

Disclosure of Interest

None Declared

Autoinflammatory mixture

O23 LONG-TERM EFFICACY AND SAFETY OF CANAKINUMAB-TREATED PATIENTS WITH COLCHICINE-RESISTANT FMF, TRAPS AND HIDS/MKD: RESULTS FROM THE PHASE 3 CLUSTER TRIAL

F. De Benedetti¹, J. Frenkel², A. Simon³, J. Anton⁴, H. Lachmann⁵, M. Gattorno⁶, S. Ozen⁷, I. Kone-Paut⁸, E. Ben-Chetrit⁹, M. B. Wozniak¹⁰, J. G. Wang¹¹, E. Vritzali¹¹

¹IRCCS Ospedale Bambino Gesú, Rome, Italy; ²University Medical Center Utrecht, Utrecht; ³Radboud University Medical Centre, Nijmegen, Netherlands; ⁴Hospital Sant Joan de Déu, Barcelona, Spain; ⁵UK National Amyloidosis Centre, University College London Medical School, London, UK; ⁶Pediatric Rheumatology, G. Gaslini Institute, Genoa, Italy; ⁷Hacettepe University, Ankara, Turkey; ⁸Hôpital Kremlin Bicetre, University of Paris SUD, Paris, France; ⁹Hadassah—Hebrew University Medical Center, Jerusalem, Israel; ¹⁰Novartis Ireland Ltd, Dublin, Ireland; ¹¹Novartis Pharma AG, Basel, Switzerland

Correspondence: F. De Benedetti

Introduction: Canakinumab (CAN) has demonstrated efficacy and safety in patients with colchicine-resistant familial Mediterranean fever (crFMF), TNF receptor-associated periodic syndrome (TRAPS), and hyper-IgD syndrome (HIDS)/mevalonate kinase deficiency (MKD) in epoch 2 and 3 (E2 and E3 up to week 40) of the pivotal, randomised CLUSTER study.¹

Objectives: To assess long-term maintenance of optimal control of disease activity (median of no or 1 flare, and no uptitration) and safety of CAN dosing regimens of every 4 weeks (q4w) and every 8 weeks (q8w) in patients with crFMF, TRAPS or HIDS/MKD from the epoch 4 (E4 up to week 112) of CLUSTER.

Methods: CLUSTER comprised 4 epochs (E1-E4). After lead-in E1, efficacy of CAN 150/300 mg q4w to induce complete response was assessed in E2, a 16-week randomised, double-blind, placebo (PBO)-controlled epoch. E3, a 24-week randomised withdrawal epoch, evaluated whether responders to CAN 150/300 mg q4w in E2 could maintain clinical efficacy on 150/300 mg q8w or PBO. In E4, a 72-week, open-label epoch, the long-term maintenance of efficacy and safety of CAN 150/300 mg q4w or q8w in patients with crFMF, TRAPS or HIDS/MKD was evaluated. Patients who did not maintain clinical response on q8w could be uptitrated to 150/300 mg q4w. Safety assessments included incidence of adverse events (AEs) and serious AEs.

Results: Five patients discontinued from the study in E4 (one TRAPS patient discontinued due to AE). A substantial proportion of patients maintained optimal control of disease activity following treatment with 150/300 mg q4w or q8w in all 3 cohorts at week 112 (Table 1). HIDS/MKD patients more often required uptitration to 300 mg q4w. Majority of patients had 1 or no new flare (crFMF: 96.6%, TRAPS: 94.3%, HIDS/MKD: 83.3%). In all 3 cohorts, the median SAA levels decreased rapidly from baseline and remained suppressed through E4 (crFMF: 618 to 21 mg/L, TRAPS: 243 to 12 mg/L and HIDS/MKD: 2061 to 16 mg/L). No new safety findings were reported in CAN-treated patients through week 112.

Conclusion: Long-term treatment with canakinumab 150/300 mg q4w in epoch 4 of the CLUSTER study showed that optimal control of disease activity can be maintained in patients with crFMF, TRAPS or HIDS/MKD. There were no new or unexpected safety issues reported over 112 weeks of treatment.

References

1. De Benedetti F, et al. NEJM 2018, in press.

Trial registration identifying number: NCT02059291

Disclosure of Interest

F. De Benedetti Grant / Research Support from: Novartis, Roche, Pfizer, SOBI, AbbVie, Novimmune, BMS, Sanofi, J. Frenkel Grant / Research Support from: Novartis and SOBI, A. Simon Grant / Research Support from: Novartis, Xoma/Servier, CSL Behring, Consultant for: Novartis, Takeda, SOBI, Xoma, J. Anton Grant / Research Support from: Novartis, Pfizer, Abbvie, GSK, BMS, Roche, Sanofi, Consultant for: Novartis, Sobi, Roche, Pfizer, Abbvie, H. Lachmann Consultant for: Novartis, SOBI, Takeda and GSK, Speaker Bureau of: Novartis and SOBI, M. Gattorno Grant/Research Support from: Novartis and SOBI, Consultant for: Novartis and SOBI, Speaker Bureau of: Novartis and SOBI, S. Ozen Speaker Bureau of: Novartis and SOBI, I. Kone-Paut Grant/Research Support from: Novartis, SOBI and Roche, Consultant for: Novartis, SOBI, Pfizer, AbbVie and Roche, E. Ben-Chetrit Consultant for: Novartis, M. B. Wozniak Employee of: Novartis, J. G. Wang Employee of: Novartis, E. Vritzali Employee of: Novartis

Table 1 (abstract O23). Proportion of responders who maintained optimal control of disease activity* at the end of epoch 4, following treatment with canakinumab (Week 112 analysis)

Epigenetic in inflammation and autoimmunity

O24 EXPRESSION OF THE INTERLEUKIN 1 FAMILY MEMBERS IL-1B AND IL-18 BY HUMAN MONOCYTES IS CONTROLLED BY DIFFERENT REGULATORY PATHWAYS

Emely Verweyen¹, Melissa van Dülmen¹, Dirk Holzinger², Dirk Foell¹, Christoph Kessel¹

¹Pediatric Rheumatology and Immunology, University Children's Hospital, Münster; ²Department of Child and Adolescent Medicine, University Hospital, Essen, Germany

Correspondence: Emely Verweyen

Introduction: Regulation of IL-18 gene expression by primary human monocytes is poorly understood but may provide insights into the cytokine’s still unclear role in autoinflammation.

Objectives: The interleukin (IL) 1 family cytokine IL-18 is overabundant in plasma and serum of familial mediterranean fever (FMF) and systemic juvenile idiopathic arthritis (sJIA) patients and its levels coincide with hypersecretion of the damage associated pattern (DAMP) proteins S100A8/A9 and S100A12. Comparable to IL-1b it is thought to require caspase-dependent processing to render an immature pro-form into bioactive mature IL-18. Yet, in stark contrast to IL-1b, it seems largely unknown whether and how IL-18 gene expression is regulated.

Methods: Primary human monocytes isolated from healthy donors were analyzed for kinetics of cytokine expression on gene and protein level following different stimulations and drug treatments.

Results: Initially, we performed endotoxin desensitization experiments on primary human monocytes, which suggested TNFa, IL-6 and IL-1b but not IL-18 gene expression to be subjected to LPS-tolerance. However, when studying time kinetic gene expression of cytokines, we found that IL-1b and IL-18 followed identical secretion but completely different gene expression patterns. In contrast to IL-1b, we observed human monocytes to maintain a cytoplasmic store of mature, bioactive IL-18 from which it could be readily secreted upon LPS stimulation and, following the observed attenuated IL-18 gene expression, this intracellular bioactive IL-18 store replenished. Importantly, colchicine as the mainstay of todays FMF-therapy, as well as the the microtubule polymerisation inhibitor nocodazole abrogated IL-18 expression, while IL-1b gene expression was massively enhanced.

Conclusion: We propose monocytic IL-18 transcription to be subjected to negative feedback regulation by an intracellular store of IL-18 protein. The cellular efforts to maintain such a store may suggest IL-18 to rather operate as DAMP than classical cytokine. This may explain the orchestrated hypersecretion of IL-18, S100A8/A9 and A12 in diseases such as FMF or sJIA.

Disclosure of Interest

None Declared

O25 SUPPRESSION OF T-CELL ACTIVATION VIA SIRT1 INHIBITION USING NICOTINAMIDE (VITAMIN B3)

Lotte Nijhuis¹, Isabelle Houtzager¹, Arief Lalmohamed², Bas Vastert³, Jorg Van Loosdregt¹

¹Laboratory of Translational Immunology; ²Department of Clinical pharmacy; ³Department of Pediatric Rheumatology, UMC UTRECHT, Utrecht, Netherlands

Correspondence: Lotte Nijhuis

Introduction: Juvenile Idiopathic Arthritis is hallmarked by a disturbed immunological balance between regulatory T-cells (Treg) and effector T-cells (Teff). Restoring this balance by either enhancing the suppressive function of Treg or inhibiting activation and proliferation of pro-inflammatory T-eff is therefore a promising therapeutic strategy. Previously we demonstrated that inhibition of the lysine deacetylase SIRT1 resulted in an increase in FOXP3 positive cells in vitro. Since the transcription factor FOXP3 is essential for Treg differentiation and function, this approach could positively influence immunological tolerance. Interestingly, SIRT1 can be inhibited by the well known food additive, Vitamin B3, also known as Nicotinamide (NAM). We therefore aim to translate these laboratory findings into clinical practice and envision a role for NAM as a novel therapeutic strategy in maintaining the immunological balance in patients with JIA. We demonstrated a distinctive effect of NAM on Treg, however the effect of NAM on the other side of the balance; Teff cells is still unexplored.

Objectives: To investigate the effect of SIRT1 inhibition on proliferation, activation and cytokine production of Teff cells.

Methods: T-cells were isolated from the blood of healthy controls and JIA patients as well as the synovial fluid from JIA patients. Cells were stimulated with aCD3/aCD28 and cultured in the presence of increasing concentrations of NAM (0-9mM) for 1-4 days. Proliferation and expression of activation makers were determined using flow cytometry. Cytokine production was determined by qPCR, luminex and flow cytometry. The specific SIRT1 inhibitor EX-527 was used as a control to determine the pathway involved.

Results: In vitro NAM treatment of human CD4+ T-cells significantly decreased the production of the pro-inflammatory cytokines IL-2 and IFNy measured both on mRNA and protein level. In line with this, surface activation markers were downregulated after NAM incubation. Furthermore proliferation of both CD4+ and CD8+ T-cells was inhibited with NAM treatment in a dose dependent manner in both PBMC from HC and SFMC from JIA patients. Results were verified by using another SIRT 1 inhibitor; EX-527.

Conclusion: In addition to the previously demonstrated increase of Treg numbers and function, these data demonstrate that NAM treatment in vitro inhibits proliferation and activation of Teff cells. Therefore NAM treatment could modulate the immunological balance by both increasing tolerance and suppressing immune activation. We envision that NAM treatment as an adjuvant therapy has the potential to benefit JIA patients and potentially other autoimmune diseases. To translate these findings to clinical practice and determine if NAM treatment is useful as a strategy to maintain disease remission after stopping DMARD or biologicals we are in preparation of a phase III clinical trial.

Disclosure of Interest

None Declared

Poster Walk 1: Systemic JIA and MAS

P001 NEXT GENERATION SEQUENCING ANALYSIS OF FAMILIAL HAEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS (HLH) RELATED GENES IN MACROPHAGE ACTIVATION SYNDROME (MAS) AND SECONDARY HLH (SHLH)

Chiara Passarelli¹, Manuela Pardeo², Ivan Caiello², Francesca R. Lepri¹, Antonella Insalaco², Francesca Minoia³, Andrea Taddio⁴, Francesco Licciardi⁵, Antonio Novelli¹, Fabrizio De Benedetti², Claudia Bracaglia²

¹Unit of Laboratory of Medical Genetics; ²Division of Rheumatology, IRCCS-Paediatric Hospital Bambino Gesù, Rome; ³Reumatologia Pediatrica, IRCCS Istituto Giannina Gaslini, Genoa; ⁴Institute for Maternal and Child Health - IRCCS “Burlo Garofolo”, University of Trieste, Trieste; ⁵SCDU Pediatria II, Immunoreumatologia, Ospedale Pediatrico Regina Margherita, Turin, Italy

Correspondence: Claudia Bracaglia

Introduction: Macrophage activation syndrome (MAS), a severe complication of paediatric rheumatic disease, is currently classified among the secondary forms of HLH (sHLH). Primary HLH (pHLH) are caused by mutation of genes coding for proteins involved in cytotoxic functions. Mice carrying heterozygous mutations in more than 1 pHLH gene carry a higher risk to develop HLH following viral infection, suggesting that accumulation of partial genetic defects may be relevant in HLH.

Objectives: To analyse, with next generation sequencing (NGS), genes involved in pHLH in MAS in the context of different rheumatic diseases and in sHLH.

Methods: We performed Targeted resequencing on all patients using a panel including the 7 principal HLH-related genes (PRF1, UNC13d, STX11, STXBP2, Rab27a, XIAP, SH2D1A) on MiSeq® and NextSeq550® platforms (Illumina, San Diego, CA); all variants identified were confirmed by Sanger. We took into account variants with an allelic frequency in the global population up to 5% in the dbSNP and Ensembl databases.

Results: We analysed 125 patients: 47 MAS (40 developed this complication in the context of systemic Juvenile Idiopathic Arthritis (sJIA) and 7 in the context of different rheumatic diseases), 32 sHLH, 22 sJIA (without history of MAS) and 24 with different autoinflammatory diseases (AID). sJIA and AID patients were used as control groups.

We identified at least 1 heterozygous variant in one of the pHLH-related genes in 41 patients with a detection rate of 52%, 45% of MAS and 62% of sHLH patients. More than one variant was identified in 37% patients from both groups, with 19% of both MAS and sHLH patients carrying polygenic variants. In control groups, 54% of sJIA and 33% of AID patients carry at least a variant in the analysed genes, while polygenic variants have been detected in 14% and 8% of control patients, respectively. The most involved genes in both MAS and sHLH groups were PRF1 and UNC13d, while variants in RAB27a and XIAP have been found only in sHLH patients. The most frequent variants identified in both groups were A91V in PRF1 gene and R928C in UNC13d gene. The A91V variant in PRF1 gene was identified in 19% of both MAS and sHLH patients, while this variant was present, respectively, in only 5% of sJIA and 4% of AID patients. The R928C variant in UNC13d gene was identified in 32% of MAS and 18% of sHLH patients, and in the control group in 9% of sJIA and 17% of AID patients. Considering the patients’ clinical characteristics, relapse, CNS involvement, ICU admission and death, in sHLH we observed that three of the 6 patients (50%) carrying multiple variants had recurrent episodes of HLH and that two of them (33%) presented a severe disease with exitus.

Conclusion: Monoallelic variants in pHLH-related genes are more frequent in MAS, sHLH and sJIA and less in AID patients, suggesting different molecular mechanisms involved in the diseases.

Re-occurrence and severity of disease seem to be more frequent and more severe in patients who carry mutations in two genes in sHLH group. These data may support a polygenic model of sHLH.

Disclosure of Interest

C. Passarelli: None Declared, M. Pardeo: None Declared, I. Caiello: None Declared, F. Lepri: None Declared, A. Insalaco: None Declared, F. Minoia: None Declared, A. Taddio: None Declared, F. Licciardi: None Declared, A. Novelli: None Declared, F. De Benedetti Grant/Research Support from: Novartis, Novimmune, Hoffmann- La Roche, SOBI, AbbVie, Pfizer, C. Bracaglia: None Declared

P002 RISK SCORE OF MACROPHAGE ACTIVATION SYNDROME IN PATIENTS WITH SYSTEMIC JUVENILE IDIOPATHIC ARTHRITIS

Simone Carbogno¹, Denise Pires Marafon², Giulia Marucci³, Manuela Pardeo³, Antonella Insalaco³, Virginia Messia³, Rebecca Nicolai³, Fabrizio De Benedetti³, Claudia Bracaglia³

¹Pediatric Area, University of Milan; ²Pediatric Unit, Fondazione IRCCS Ca' Grande Ospedale Maggiore Policlinico, Milan; ³Division of Rheumatology, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy

Correspondence: Simone Carbogno

Introduction: Macrophage Activation Syndrome (MAS) is a severe, life-threatening, complication of rheumatic diseases in childhood, particularly of systemic Juvenile Idiopathic Arthritis (sJIA), occurring in approximately 25% of the patients with sJIA. The mortality rate of MAS is still significantly high. A score that identify sJIA patients who are at high risk to develop MAS would be useful in clinical practice. There are no parameters available to identify from onset sJIA patients with high risk to develop MAS in their disease course.

Objectives: To evaluate whether routine laboratory parameters at disease onset may predict the development of MAS in patients with active sJIA. To define a risk score of MAS for sJIA patients using these parameters.

Methods: Laboratory parameters of disease activity and severity (WBC, N, PLT, Hb, ferritin, AST, ALT, gGT, LDH, TGL, fibrinogen, D-dimer and CRP), were retrospectively evaluated in 56 sJIA patients referred to our Division of Rheumatology from 1998 to 2016 with at least one year of follow-up. Laboratory parameters were evaluated during active sJIA, without MAS, at time of hospitalization (T1) and before treatment for sJIA was started (T2). Patients were divided in two groups: group 1 (patients without history of MAS), group 2 (patients with at least one MAS episode during disease course). To calculate a MAS risk score, laboratory parameters, collected at T2, with a statistical significant difference between the two groups of patients were selected.

Results: Fourteen patients, that fulfilled the 2016 classification criteria for MAS [1] at time of sampling, were excluded from the analysis. Therefore, we analyzed laboratory parameters of 42 patients with sJIA, 27 of whom without history of MAS (group 1) and 15 who developed at least one episode of MAS during disease course (group 2). Levels of ferritin, AST, LDH, gGT and TGL, collected at T2, were statistically significant higher in patients with a history of MAS compared to those without a history of MAS. For each of these parameters an arbitrary cut-off was defined. In order to define the final score an arbitrary rate was attributed to each parameter. Sensitivity (Se), specificity (Sp), positive predictive value (PPV) and negative predictive value (NPV) were calculated to define the best scoring system. The scoring system with the best sensitivity was chosen (Table 1). A MAS risk score >3 identified 14 out of 15 sJIA patients with a history of MAS and 3 out of 27 sJIA patients without history of MAS.

Conclusion: In conclusion we developed a MAS risk score based on routine laboratory parameters that are available worldwide, that can help clinicians to identify these patients early in the disease course. Our results need to be validated in a larger population.

Reference

1. Ravelli A et al. 2016 Classification Criteria for Macrophage Activation Syndrome Complicating Systemic Juvenile Idiopathic Arthritis: A European League Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology International Trials Organisation Collaborative Initiative. Ann Rheum Dis. 2016 Mar;75(3):481-9.

Disclosure of Interest

S. Carbogno: None Declared, D. Pires Marafon: None Declared, G. Marucci: None Declared, M. Pardeo: None Declared, A. Insalaco: None Declared, V. Messia: None Declared, R. Nicolai: None Declared, F. De Benedetti Grant/Research Support from: Novartis, Novimmune, Hoffmann-La Roche, SOBI, AbbVie, Pfizer, C. Bracaglia: None Declared

Table 1 (abstract P002). Laboratory parameters and cut-off used to create the MAS risk score in sJIA patients

P003 IDENTIFICATION OF OPTIMAL SUBCUTANEOUS DOSES OF TOCILIZUMAB IN CHILDREN WITH SYSTEMIC JUVENILE IDIOPATHIC ARTHRITIS

Fabrizio De Benedetti¹, Nicola Ruperto², Daniel Lovell³, Gerd Horneff⁴, Maria Luz Gámir Gámir⁵, Markus Hufnagel⁶, Joy C. Hsu⁷, Min Bao⁷, Wendy Douglass⁸, Navita L. Mallalieu⁷, Chris Wells⁸, Christopher M. Mela⁸, Hermine Brunner³ and PRINTO and PRCSG Investigators

¹IRCCS Ospedale Pediatrico Bambino Gesù, Rome; ²Pediatric Rheumatology International Trial Organization (PRINTO), Istituto Giannina Gaslini Pediatria II–Reumatologia, Genoa, Italy; ³Pediatric Rheumatology Collaborative Study Group (PRCSG), Cincinnati Children’s Hospital Medical Center, Cincinnati, USA; ⁴Asklepios Clinic Sankt Augustin and University Hospital of Cologne, Sankt Augustin and Cologne, Germany; ⁵Hospital Ramon y Cajal Unidad de Reumatologia Pediatrica, Madrid, Spain; ⁶Universitätsklinikum Freiburg, Freiburg, Germany; ⁷Roche Innovation Center, New York, USA; ⁸Roche Products Ltd, Welwyn Garden City, UK

Correspondence: Fabrizio De Benedetti

Introduction: The efficacy and safety of intravenous (IV) tocilizumab (TCZ) were demonstrated in patients (pts) with systemic juvenile idiopathic arthritis (sJIA) in the phase 3 TENDER study.¹

Objectives: To investigate dosing regimens of subcutaneous (SC) TCZ in pts with sJIA by bridging from TENDER data for TCZ IV to identify the optimal SC regimen through characterization of the pharmacokinetics (PK), pharmacodynamics (PD), and safety of TCZ SC in pts with sJIA; efficacy was an exploratory objective.

Methods: This was a multicenter, open-label, phase 1b study to evaluate the PK, PD, and safety of TCZ SC in pts aged 1-17 years with sJIA and inadequate response to glucocorticoids. Interim analysis was conducted after 24 pts had received TCZ SC for 14 weeks. Pts could be TCZ naive or could switch from TCZ IV to SC. TCZ SC was administered for 52 weeks according to body weight: pts <30 kg received either 162 mg every 10 days before interim analysis or 162 mg every 2 weeks (Q2W) after interim analysis; pts ≥30 kg received 162 mg every week (QW).

Results: We enrolled 51 pts, including 25 weighing <30 kg (8 before and 17 after interim analysis) and 26 weighing ≥30 kg. Twenty-six pts (51%) were TCZ naive and 25 (49%) switched from TCZ IV. Median steady state C_min was similar for pts <30 kg receiving TCZ 162 mg Q2W and pts ≥30 kg receiving TCZ 162 mg QW; the ranges largely overlapped (Table 1). More than 95% (49/51) of pts treated with TCZ SC had steady state C_min higher than the 5th percentile achieved with TCZ IV. The median and range of AUC_2weeks were similar for both body weight groups (Table 1). Changes in interleukin-6, C-reactive protein, and erythrocyte sedimentation rate were similar for both body weight groups. Almost all pts had ≥1 adverse event (AE; n = 50; 98.0%). Injection site reactions (ISRs) occurred in 21 pts (41.2%); most were mild, and none led to treatment interruption or withdrawal. The AE rate was 1200.3/100 pt-years (PY) (909.3/100 PY, excluding ISRs). The most common AEs were viral upper respiratory tract infection (13; 25.5%), neutropenia (13; 25.5%), and cough (12; 23.5%). Nine serious AEs occurred in 7 pts (13.7%; 19.3/100 PY); 5 were infections, all in the <30 kg group. Two deaths occurred, both in the <30 kg group. Median JADAS-71 improved from baseline to week 52 for TCZ-naive pts (<30 kg, –13.9; ≥30 kg, –12.4) and was maintained or improved further for pts who switched from TCZ IV (<30 kg, –0.7; ≥30 kg –0.2). At week 52, 29/43 pts (67.4%) had inactive disease (JADAS-71 <1.0).

Conclusion: A PK-based strategy was successful in bridging TCZ SC to TCZ IV in pts with sJIA. Dosing regimens of 162 mg Q2W in pts <30 kg and 162 mg QW in pts ≥30 kg provided adequate exposure to support efficacy comparable to that of TCZ IV. Except for ISRs, safety results were consistent with the known safety profile of TCZ in sJIA.

Reference

1. De Benedetti F et al. N Engl J Med. 2012;367:2385-95.

Trial registration identifying number: ClinicalTrials.gov NCT01904292

Disclosure of Interest

F. De Benedetti Grant/Research Support from: Novartis, Roche, Pfizer, SOBI, AbbVie, Novimmune, BMS, Sanofi, N. Ruperto Consultant for: AbbVie, Amgen, Biogenidec, Alter, AstraZeneca, Baxalta Biosimilars, Biogenidec, Boehringer, BMS, Celgene, CrescendoBio, EMD, Speaker Bureau of: AbbVie, Amgen, Biogenidec, Alter, AstraZeneca, Baxalta Biosimilars, Biogenidec, Boehringer, BMS, Celgene, CrescendoBio, EMD, D. Lovell Grant/Research Support from: National Institutes of Health, NIAMS, Consultant for: AstraZeneca, Bristol-Myers Squibb, AbbVie, Pfizer, Roche, Novartis, UCB, Forest Research Institute, Horizon, Johnson & Johnson, Biogen, Takeda, Genentech, GlaxoSmithKline, Boehringer Ingelheim, Celgene, Janssen, Speaker Bureau of: Genentech, G. Horneff: None Declared, M. L. Gámir Gámir: None Declared, M. Hufnagel: None Declared, J. C. Hsu Employee of: Roche, M. Bao Employee of: Roche, W. Douglass Employee of: Roche, N. L. Mallalieu Employee of: Roche, C. Wells Shareholder of: Roche, Employee of: Roche, C. M. Mela Employee of: Roche, H. Brunner: None Declared

Table 1 (abstract P003). See text for description

P004 INTERSTITIAL LUNG DISEASE IN SYSTEMIC JUVENILE IDIOPATHIC ARTHRITIS PATIENTS IN THE PHARMACHILD REGISTRY

Jelle De Groot, Bas Vastert, Gabriella Giancane, Michael Hofer, Ekaterina Alexeeva, Violeta Panaviene, Susan Nielsen, Jordi Anton, Florence Uettwiller, Valda Stanevicha, Maria Trachana, Denise P. Marafon, Constantin Ailioaie, Elena Tsitsami, Troels Herlin, Pavla Dolezalova, Gordana Susic, Berit Flato, Flavio Sztajnbok, Angela Pistorio, Francesca Bagnasco, Alberto Martini, Nico Wulffraat, Nicola Ruperto, Joost Swart

PRINTO, Genova, Italy

Correspondence: Jelle De Groot

Introduction: Lung disease might be an underreported complication in patients with systemic juvenile idiopathic arthritis (SJIA). Recently a study describing 25 patients with interstitial lung disease (ILD), pulmonary arterial hypertension (PAH) and alveolar proteinosis (AP) emerged. To what extent these complications occur in the SJIA population is still uncertain.¹

Objectives: This study will investigate how often pulmonary complications occur in children with SJIA in the Pharmachild registry. Possible associated factors and/or complications of lung disease will also be investigated.

Methods: Data of the Pharmachild registry, the world's largest pharmacovigilance database, was used. 914 Patients with SJIA were included. Focus lied primarily on pulmonary complications reported in these children. Secondarily, possible correlated events like the macrophage activation syndrome (MAS), death and adverse drug reactions will be analysed.

Results: Eighty pulmonary complications were found in 65/914 patients suffering from SJIA (7%). Complications highly suspect for ILD were found in only 9 children (1%). Patients with pulmonary complications had significantly longer follow-up (7.6 years versus 5.1), were younger at diagnosis (3.7 years versus 5.3 years), had significantly more often non-pulmonary complications and were more likely to have ever used Tocilizumab (55.4% to 40.6%) and/or Rituximab (30.8% to 5.8%) (see Table 1).

MAS occurred more often in patients with pulmonary complications (20.0% to 11.5% P=0.050) and they had significantly more adverse drug reactions, especially to Tocilizumab (9.2% to 2.7% p=0.013) and Rituximab (12.3% to 1.2% P<0.001). Fatal disease occurred more often in patients with pulmonary complications compared to those without it (4.6% to 0.6% p= 0.006).

Conclusion: Pulmonary complications were found in 7% of the SJIA population. Pulmonary complications are also associated with significant more non-pulmonary comorbidities like MAS, adverse drug reactions and even death. More adequate monitoring of pulmonary function and consistent documentation of lung disease might be helpful especially in patients at highest risk of ILD.

References

1) Kimura Y, Weiss JE, Haroldson KL, Lee T, Punaro M, Oliveira S, et al. Pulmonary hypertension and other potentially fatal pulmonary complications in systemic juvenile idiopathic arthritis. Arthritis Care Res (Hoboken). 2013 May;65(5):745-52. doi: 10.1002/acr.21889.

Trial registration identifying number: NCT01399281

Disclosure of Interest

None Declared

Table 1 (abstract P004). Patient characteristics

P005 THE INTERFERON-GAMMA PATHWAY IS ACTIVATED IN THE LIVER AND IN THE BLOOD OF PATIENTS WITH ACTIVE SECONDARY HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS

Giusi Prencipe¹, Claudia Bracaglia¹, Antonia Pascarella¹, Ivan Caiello¹, Paola Francalanci¹, Manuela Pardeo¹, Alessandra Meneghel², Giorgia Martini², Antonella Insalaco¹, Giulia Marucci¹, Francesco Zulian², Fabrizio De Benedetti¹

¹Bambino Gesù Children's Hospital, Rome; ²University of Padua, Department of Woman and Child Health, Padua, Italy

Correspondence: Giusi Prencipe

Introduction: An increasing body of evidence obtained both in patients and experimental models of secondary hemophagocytic lymphohistiocytosis (sHLH), including macrophage activation syndrome (MAS), supports the pathogenic role of Interferon-gamma (IFNγ). Nevertheless, to date, few data demonstrating the activation of the IFNγ pathway in target tissues of patients with sHLH during the active phase of the disease are available.

Objectives: In this study, in order to further clarify the involvement of IFNγ in the pathogenesis of sHLH, we investigated the activation of the IFNγ pathway in the affected liver of patients with active sHLH. In addition, we evaluated the circulating levels of IFNγ inducible chemokines CXCL9 and CXCL10 and assessed the activation of the IFNγ pathway in peripheral blood mononuclear cells (PBMCs) of patients collected during the course of the disease.

Methods: We analysed by real-time PCR the mRNA expression levels of IFNγ and IFNγ-inducible genes in the liver and in peripheral blood mononuclear cells (PBMCs) from two patients with active sHLH and one patient with active MAS, in which the disease was limited to the liver, without systemic involvement. Moreover, both in liver and PBMCs protein lysates, we evaluated by Western Blot analyses the levels of total and Tyrosine (701)-phosphorylated Signal transducer and activator of transcription 1 (STAT1), the transcription factor mainly involved in the activation of the IFNγ signaling pathways. Circulating CXCL9 and CXCL10 have been measured by ELISA.

Results: The expression levels of IFNγ and IFNγ-inducible genes were markedly up-regulated in livers from all three patients, compared to control livers. Conversely, slight differences in the expression levels of Type I IFN-inducible genes and other classical pro and anti-inflammatory cytokines were found. Further supporting the activation of the IFNγ pathway, higher protein levels of phosphorylated and total STAT1 were detected in patient livers. Accordingly, we found that mRNA levels of IFNγ-regulated genes and phosphorylated STAT1 protein levels were markedly increased in patient PBMCs collected during the active phase of the disease. Finally, circulating levels of IFNγ-inducible CXCL9 and CXCL10 were markedly increased during the active phase of the disease, paralleling the ferritin’s trend.

Conclusion: Our data provide evidence of selective and marked up-regulation of the IFNγ pathway in liver tissue as well as in PBMCs and blood of patients with active sHLH, further supporting the key role of IFNγ in the pathogenesis of the disease, and provide the rationale for the therapeutic use of an anti-IFNγ antibody in sHLH.

Disclosure of Interest

G. Prencipe: None Declared, C. Bracaglia: None Declared, A. Pascarella: None Declared, I. Caiello: None Declared, P. Francalanci: None Declared, M. Pardeo: None Declared, A. Meneghel: None Declared, G. Martini: None Declared, A. Insalaco: None Declared, G. Marucci: None Declared, F. Zulian: None Declared, F. De Benedetti Grant/Research Support from: Novartis, Novimmune, Hoffmann- La Roche, SOBI, AbbVie, Pfizer

P006 LUNG DISEASE IN SYSTEMIC JUVENILE IDIOPATHIC ARTHRITIS (SJIA)

Vivian Saper¹, Gail Deutsch², Paul Guillerman³, Ray Balise⁴, Ann N. Leung⁵, Layla Bouzoubaa⁴, Scott Canna⁶, Grant Schulert⁷, Alexei Grom⁷, Tushar Desai⁸, Elizabeth Mellins¹ and 52 Case Reporters representing 42 contributing institutions

¹Pediatrics, Stanford University, Stanford, CA; ²Pathology, Seattle Children's Hospital, Seattle, WA; ³Radiology, Texas Children's Hospital, Houston, TX; ⁴Public Health Sciences, University of Miami, Miami, FL; ⁵Radiology, Stanford University, Stanford, CA; ⁶Pediatrics, Children’s Hospital of Pittsburgh, Pittsburgh, PA; ⁷Pediatrics, Cincinnati Children’s Hospital, Cincinnati, OH; ⁸Pulmonary Medicine, Stanford University, Stanford, CA, USA

Correspondence: Vivian Saper

Introduction: Although not known to be a manifestation of sJIA, high mortality lung disease, including alveolar proteinosis (AP) and pulmonary hypertension (PH), have been increasingly noted.

Objectives: To describe clinical, radiologic and biopsy findings in children with sJIA as they develop life threatening parenchymal lung disease.

Methods: This retrospective observational case series included children diagnosed until age 18 with sJIA or sJIA-like illness and lung disease. Chest CT and/or lung biopsy was required for inclusion and underwent expert review.

Results: 61 included cases were contributed by 52 case reporters (Abulaban,K, Baszis,K, Behrens, E, Birmingham, J, Canna, S, Casey, A, Cidon,M, Cron,R, De, A, DeBenedetti,F, Deterding, R, Ferguson, I, Fishman, M, Goodman, S, Graham, B, Grom,A, Haines, K, Hazen, M, Henderson, L, Ibarra, M, Inman, CJ, Jerath,R, Kingsbury, D, Klein-Gitelman,M, Khawaja, K, Lai, K, Liptzin,DR, Lin, C, Lin, J, Lapidus,S, Milojevic, D, Mombourquette,J, Onel,K, Ozen,S, Perez, M, Phillippi,K, Prahal,S, Radhakrishna,S, Reinhardt, A, Riskalla, M, Rosenwasser,N, Roth, J, Schneider, R, Schonenberg-Meinema,D, Schulert,G, Shenoi,S, Smith,J, Sonmez,E, Stoll, M,Towe, C, Vehe,R, Young, L). 45 sJIA and 16 sJIA-like cases from the United States (54), Europe, the Middle East and Asia were studied. Median age of sJIA onset was 2 years; median time to lung disease was 2 years. Onset characteristics matched reported cohorts with the exception of younger onset age (p<.0001) and a 50x increased odds of Trisomy 21. Prior to lung disease, 46 cases were exposed to one or more inhibitors of IL-1 or IL-6. This pre-exposed group demonstrated unusual clinical and radiologic features including acute erythematous clubbing, a non-evanescent rash, and CT features not typical for the pathology observed. Respiratory symptoms, if present, were subtle. Lung pathology was primarily AP and PH and did not distinguish those pre-exposed from those who were not. Systemic inflammation typically occurred immediately prior to or with lung disease detection. Extent of evaluation for infectious causes varied and did not reveal a consistent pathogen. Of 6 cases with PCR for pneumocystis pneumonia (PCP) on BAL fluid, 4 cases were positive, and these children exhibited PCP compatible disease. Overall fatality rate was 37% and, of those surviving, only 3 report resolution of lung disease.

Conclusion: This study is the first to describe a set of unusual clinical and CT features in children with sJIA who developed lung disease during treatment with inhibitors of IL-1 or IL-6. However, this group shared (rare) lung pathologic diagnoses with subjects unexposed to these drugs. Further work is urgently needed as fatality rate is high, incidence appears to be increasing, mechanisms remain unknown and appropriate treatment is yet to be defined.

Disclosure of Interest

V. Saper Grant / Research Support from: Novartis, G. Deutsch: None Declared, P. Guillerman: None Declared, R. Balise: None Declared, A. Leung: None Declared, L. Bouzoubaa: None Declared, S. Canna: None Declared, G. Schulert: None Declared, A. Grom: None Declared, T. Desai: None Declared, E. Mellins Grant/Research Support from: Novartis

P007 PREDICTORS OF EFFECTIVENESS OF INTERLEUKIN-1 INHIBITORS IN SYSTEMIC JUVENILE IDIOPATHIC ARTHRITIS

Jessica Tibaldi¹, Benedetta Saccomanno¹, Francesca Minoia², Francesca Bagnasco³, Angela Pistorio³, Andressa Guariento³, Roberta Caorsi³, Alessandro Consolaro⁴, Marco Gattorno³, Angelo Ravelli⁴

¹Università degli Studi di Genova, Genoa; ²Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan; ³Istituto Giannina Gaslini; ⁴Università degli Studi di Genova/Istituto Giannina Gaslini, Genoa, Italy

Correspondence: Jessica Tibaldi

Introduction: Systemic juvenile idiopathic arthritis (sJIA) is the most severe and a rather distinct subtype of JIA. It is common view that sJIA is the most severe form of childhood arthritis and the most difficult to treat. Recently the use of interleukin(IL)-1 antagonists has led to a significant improvement of the disease’s long-term evolution and has confirmed this cytochin’s key-role in the pathogenesis of sJIA. A number of potential predictors of the therapeutic effectiveness of IL-1 inhibitors have been reported, which include less severe joint disease and increased white blood cell count, shorter disease duration, older age at disease onset and use of IL-1 blockade as first-line therapy. However, because the experience gained so far is still limited, there is a need of further data to better characterize the profile of sJIA patients who are more susceptible to respond to IL-1 blockade.

Objectives: To seek for predictors of therapeutic response to interleukin (IL)-1 inhibitors in children with systemic juvenile idiopathic arthritis (sJIA).

Methods: The clinical charts of all patients with sJIA who were newly treated with anakinra or canakinumab at our center between 2004 and 2017 were reviewed retrospectively. Predictors included baseline demographic, clinical and laboratory variables as well as previous or concomitant therapies. The effectiveness of IL-1 antagonists was assessed at 1 year after treatment start. Complete clinical response (CCR) was defined as absence of fever, physician’s global assessment ≤ 1, count of active joints ≤ 1, negative C-reactive protein (CRP), and ≥ 75% reduction of corticosteroid dose. According to the intention-to-treat principle, patients who had IL-1 antagonists discontinued before 1 year for any reasons other than disease remission were classified as nonresponders. Statistics included univariate and multivariable analyses.

Results:

Of the 65 patients included in the study, 25 (39%) met the criteria for CCR at 1 year, whereas 40 (61%) did not. On multivariable analysis, independent correlations with achievement of CCR were identified for shorter disease duration, lower active joint count, higher ferritin level, and greater activity of systemic manifestations (Table 1). The area under the curve (AUC) of the model was 83%.

Conclusion: Our findings help to delineate the clinical profile of sJIA patients who are more likely to benefit from IL-1 blockade. They also underscore the critical need of randomized controlled trials aimed to explore the therapeutic role of IL-1 inhibition early in the disease course.

Disclosure of Interest

None Declared

Table 1 (abstract P007). See text for description

P008 DISEASE EVOLUTION IN SYSTEMIC-ONSET JUVENILE IDIOPATHIC ARTHRITIS: PRELIMINARY DATA FROM JIRCOHORTE

Michelle Wallimann¹, Katerina Theodoropoulou¹, Elvira Cannizzaro², Daniela Kaiser³, Traudel Saurenmann⁴, Federica Vanoni⁵, Andreas Woerner⁶, Alexandre Belot⁷, Isabelle Kone-Paut⁸, Etienne Merlin⁹, Olivier Richer¹⁰, Carine Wouters¹¹, François Hofer¹², Veronique Hentgen¹³, Michaël Hofer¹

¹Department Femme Mère Enfant, Pediatric Immunology and Rheumatology Romande, Lausanne University Hospital, Lausanne; ²University Children's Hospital, Zurich; ³Children's Hospital Lucerne, Lucerne; ⁴Winterthur Cantonal Hospital, Winterthur; ⁵Bellinzona Regional Hospital, Bellinzona; ⁶University Children's Hospital, Basel, Switzerland; ⁷Hôpital Femme Mère Enfant, University Hospital, Lyon; ⁸University Hospital Kremlin-Bicêtre, Paris; ⁹Hôpital d'Estaing, University Hospital, Clermont-Ferrand; ¹⁰University Hospital Bordeaux, Bordeaux, France; ¹¹University Hospital Leuven, Leuven, Belgium; ¹²JIRcohorte, Lausanne, Switzerland; ¹³Hospital Center Versailles, Versailles, France

Correspondence: Michelle Wallimann

Introduction: Systemic onset juvenile idiopathic arthritis (SoJIA) is a potentially severe disease with both systemic and joint inflammation; different evolutive forms were described (monophasic, polyphasic or persistent), but the outcome is hardly predictable at diagnosis.

Objectives: This study aims to identify early predictors of disease evolution within the SoJIA population enrolled in the Juvenile Inflammatory Rheumatism cohort (JIRcohorte), an international prospective cohort study.

Methods: 152 SoJIA patients with a minimum of two-year follow-up were enrolled. 5 patients were excluded due to missing data on diagnostic visit. Demographics and clinical data were collected (retrospectively if diagnosis < 2015 and prospectively if diagnosis ≥ 2015) and described for 147 patients. At diagnosis, median age and disease duration was 5.3 years and 1.9 months, respectively, male to female ratio was 1:1.2. Median follow-up was 6.7 years. 123 and 98 patients were treated with biologics and DMARDs, respectively. Monophasic evolution is determined by the occurrence of active disease (systemic symptoms and/or arthritis) followed by inactive disease. No recurrence of active disease is observed, and remission is obtained. The polyphasic course is defined by the recurrence of active disease at any time after having achieved remission. A persistent evolution is characterized by the persistence of systemic symptoms and/or arthritis and/or abnormal laboratory results (for at least 24 months).

We present the preliminary results in 30 patients with complete data for disease activity and medication use.

Results: Corresponding to their evolution, patients were classified in the monophasic (n=10; MONO), polyphasic (n=14; POLY) or persistent group (n=6; PER). Females were predominant in the MONO and POLY group with 80% and 79%, respectively. No female patient was in the PER group. At diagnosis, all patients in the PER and POLY group had arthritis; only 80% did in the MONO group. Hepatomegaly and splenomegaly was present in 30% and 50% of MONO patients versus 17% and 0% of PER patients, respectively. Joint count during first 6 months was ≥ 5 joints for 83% of the PER population compared to 30% for the MONO. Four patients in the MONO group (40%) did not have any biologics, whereas all patients from the other groups had one or more (POLY: 7 patients had one, 5 patients had two and 2 patients had three different biologics). Disease Modifying Anti-Rheumatic Drugs (DMARDs) were used in 4 patients of the MONO (40%), 13 of the POLY (93%) and 5 of the PER group (83%). Median duration of corticoid-use for the MONO group and the POLY group was 0.3 years and 2.68 years, respectively.

Conclusion: Systemic presentation seems to be more prevalent in the MONO group whereas arthritis in the POLY and PER groups. Polyarticular arthritis at 6 months is suggesting persistent disease evolution. Biologics, DMARDs and corticoids are more often and longer used in the POLY and PER groups correlating with a more severe disease course. Early recognition of a monophasic evolution could help the physician to limit the use of treatments, in particular steroids.

Data are under completion for all 152 patients. Precise description of disease evolution and deep phenotypic analysis will be performed.

Disclosure of Interest

None Declared

P009 INSUFFICIENT INTERLEUKIN-10 PRODUCTION AS A MECHANISM UNDERLYING PATHOGENESIS OF SYSTEMIC JUVENILE IDIOPATHIC ARTHRITIS

Maya Imbrechts¹, Anneleen Avau¹, Jessica Vandenhaute¹, Bert Malengier-Devlies¹, Karen Put¹, Tania Mitera¹, Nele Berghmans¹, Oliver Burton², Adrian Liston², Lien de Somer³, Carine Wouters³, Patrick Matthys¹

¹Rega Institute KULeuven; ²VIB KULeuven; ³University Hospital Leuven, Leuven, Belgium

Correspondence: Carine Wouters

Introduction: Systemic juvenile idiopathic arthritis (sJIA) is a severe childhood immune-inflammatory disorder with unknown etiology.

Objectives: One of the concepts is that the disease results from an inappropriate control of immune responses to an initially harmless trigger. In the current study, we investigated whether sJIA may be caused by defects in IL-10, a key cytokine in controlling inflammation.

Methods: IL-10 production was analyzed in a sJIA mouse model, which relies on injection of Complete Freund’s Adjuvant (CFA) in IFN-γ deficient mice. Corresponding wild type (WT) mice develop a subtle and transient inflammatory reaction and were used to study the effect of IL‑10 neutralization. Cytokines and CRP were analyzed in plasma of sJIA patients (active: n=10; inactive: n=8) and healthy controls (n=15). Their PBMCs were used to study cell-specific defects in IL-10.

Results: Diseased IFN-γ deficient mice showed a defective IL-10 production in T_reg cells, B cells and NK cells, with B cells as the major source of IL-10. Neutralization of IL-10 in WT mice resulted in a chronic immune-inflammatory disorder clinically and hematologically reminiscent of sJIA. In sJIA patients, IL-10 plasma levels were strikingly low as compared to pro-inflammatory mediators. In addition, B cells from sJIA patients showed a decreased IL-10 production, both ex vivo and after stimulation.

Conclusion: Cell-specific IL-10 defects in sJIA mice and patients result in an insufficient IL‑10 production to counterbalance their pro-inflammatory cytokines. IL-10 neutralization in CFA-challenged WT mice converts a transient inflammatory reaction into a chronic disease and represents a model for sJIA in IFN-γ competent mice.

Disclosure of Interest

None Declared

Systemic JIA - MAS I

P010 EFFECTIVENESS OF MTX BEFORE BIOLOGICS IN SYSTEMIC JIA: SINGLE CENTER EXPERIENCE

Hatice Adıguzel Dundar¹, Ceyhun Acari², Serkan Turkucar², Sevket Erbil Unsal²

¹Department of Pediatrics, Pediatric Rheumatology, Dokuz Eylül Univercity Faculty of Medicine; ²Department of Pediatrics, Pediatric Rheumatology, Dokuz Eylul University Faculty of Medicine, Izmir, Turkey

Correspondence: Hatice Adıguzel Dundar

Introduction: Systemic juvenile idiopathic arthritis (SJIA) accounts for 10-20% of all JIA patients. It is characterized by findings of systemic inflammation such as fever, rash, serositis, lymphadenopathy, and hepatosplenomegaly, and arthritis. Arthritis may develop later in life with variable clinical features. Macrophage activation syndrome is the most life threatening complication. Progress in the understanding of pathogenesis has led to the development of cytokine-targeted therapies, biologics.

Objectives: This study aims to evaluate the treatment options in SJIA, particularly effect of methotrexate prior to biologics.

Methods: A retrospective review of 52 cases of systemic JIA in the last 20 years was performed.

Results: Thirty one (59.6%) of the patients were female. The mean age of diagnosis was 89.8 ± 7.88 months and the mean follow-up was 32 ± 18.5 months. Twenty seven (51.9%) had monocyclic, 9 (17.3%) had polycyclic and 16 (30.8%) had polyarticular course. All of the patients had intermittant fever at onset, followed by rash and arthritis, and the least common symptom was serous involvement.

Ten (19.2%) cases had macrophage activation syndrome (MAS). Four of them presented with MAS as the initial diagnosis. The laboratory values of MAS cases were significantly lower in ESR, platelet and fibrinogen levels and higher in ferritin and triglyceride levels when compared with other cases. Eight of the MAS cases (80%) had monocyclic, 1 (10%) had polycyclic and 1 had polyarticular course. In 8 of the MAS cases (80%) the disease was controlled by pulse steroid followed by methotrexate alone.

Fifty (96.2%) cases received pulse steroids. Methotrexate (MTX) treatment was added in 47 (88.5%) cases. Thirty two (61.5%) cases were in remission with methotrexate treatment, whereas 14 (27%) cases required an additional biological agent. Majority of patients with biologics (56.3%) had polyarticular course. Adalimumab (1), anakinra (3), tocilizumab (6), etanercept (8) and canakinumab (9) were the biologics. In 4 cases, cyclosporin was added to control the disease.

Eight patients (15.4%) were transferred to adult rheumatology clinic for persisting arthritis. Two (4.3%) of the patients died due to sepsis and MAS, respectively. Seventeen (32.7%) were in remission under medication, and 25 (48.1%) were in remission without medication.

Conclusion: Randomized controlled trials have evidence about effectiveness of biologics, particularly IL-1 and IL-6 inhibitors, in treatment of SJIA. However, this study shows that methotrexate could control the disease in about two thirds of patients, particularly in “monocyclic” SJIA. Biologics such as anakinra, canakinumab, or tocilizumab could be preferred in cases with systemic onset and polyarticular course. Multicentered studies with more patients are needed to support this “real-world data”.

Disclosure of Interest

None Declared

P011 AN UNUSUAL PRESENTATION OF PURINE NUCLEOSIDE PHOSPHORYLASE DEFICIENCY MIMICKING SYSTEMIC JUVENILE IDIOPATHIC ARTHRITIS (SJIA) COMPLICATED BY MACROPHAGE ACTIVATION SYNDROME (MAS)

Alessia Arduini¹, Emiliano Marasco², Gian Marco Moneta², Ivan Caiello², Giulia Marucci², Manuela Pardeo², Antonella Insalaco², Giusi Prencipe², Fabrizio De Benedetti², Claudia Bracaglia²

¹Pediatric Department, La Sapienza University of Rome; ²Division of Rheumatology, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy

Correspondence: Alessia Arduini

Introduction: Monogenic primary HLH (pHLH) are caused by mutations of genes coding for proteins involved in cytotoxic activity or occur in the context of immunodeficiency.

Objectives: To demonstrate that the evidence of unusual clinical and laboratory findings in a well-known condition needs further investigations to rule out a different diagnosis.

Methods: Serum CXCL9, CXCL10 and IL-18 levels measured using ELISA.T cell proliferation was assessed stimulating PBMCs with either anti-CD3 or PMA/ionomycin for five days.

Results: A 14 months old Caucasian male was admitted with a history of persistent fever, small palpable cervical lymphnodes, rash, pericardial effusion and arthralgia. He developed overt swelling of wrists and ankles. Laboratory findings showed: elevated CRP and ESR, neutropenia, lymphopenia and anaemia, with normal platelet count. Serum ferritin levels were markedly elevated and lactate dehydrogenase aspartate aminotransferase and triglyceride were also elevated. Fibrinogen was normal. Bone marrow biopsy showed haemophagocytosis. Based on the presence of arthritis in a child with fever and rash a diagnosis of sJIA was made with onset complicated by MAS. Treatment with glucocorticoid was started. Functional tests and genetic analysis of pHLH related genes were negative. After two weeks the patient presented normalization of laboratory parameters except for persistent anaemia and profound lymphopenia. Moreover, a mild muscle hypotone became apparent. These features, unusual in sJIA, triggered additional investigations. These revealed: reduced aptoglobin, high reticulocyte count and positive Coombs test, all suggestive of haemolytic anaemia. Immunological phenotyping revealed a reduced number of B cells, CD4⁺T cells, CD8⁺T cells and a defective proliferative response of T cells to phytohemagglutinin (PHA) and anti-CD3 (OKT3). A metabolic screening showed an increase in urine orotic acid, with normal citrulline serum level and low serum level of uric acid. Based on the presence of haemolytic anaemia, T lymphocyte defect and increase in urinary orotic acid, purine nucleoside phosphorylase (PNP) deficiency was suspected. The diagnosis was confirmed by marked reduction of enzymatic activity of PNP and by genetic analysis. The patient received an haplohydentical bone marrow transplantation (BMT) with a subsequent progressive clinical improvement. Serum levels of CXCL9 and CXCL10, two chemokines directly induced by IFNgamma (IFNγ) and of IL-18, were found markedly elevated at disease onset during active phase of MAS. Cytokines levels decreased progressively during disease course and completely normalized after the BMT.

Conclusion: This patient with a clinical presentation highly suggestive for sJIA onset complicated by MAS was later diagnosed with PNP deficiency with HLH. The diagnostic process was driven by some unusual features that became apparent when HLH clinical and laboratory features were controlled with glucocorticoids. Low T cells and profoundly defective response to mitogens suggested an immunodeficiency, low haptoglobin with positive Coombs test suggested an haemolytic anemia and increased urinary orotic acid suggested an alteration of the pyrimidine biosynthetic pathway. These findings were consistent with a diagnosis PNP-deficiency. CXCL9, CXCL10 and IL-18 levels suggested that patients with PNP-deficiency may have a subclinical activation of the IFNγ pathway and indeed they are predisposed to develop sHLH. Informed consent to publish had been obtained from the parents.

Disclosure of Interest

A. Arduini: None Declared, E. Marasco: None Declared, G. M. Moneta: None Declared, I. Caiello: None Declared, G. Marucci: None Declared, M. Pardeo: None Declared, A. Insalaco: None Declared, G. Prencipe: None Declared, F. De Benedetti Grant/Research Support from: Novartis, Novimmune, Hoffmann- La Roche, SOBI, AbbVie, Pfizer, C. Bracaglia: None Declared

P012 SYSTEMIC JUVENILE IDIOPATHIC ARTHRITIS: A SINGLE CENTER EXPERIENCE

Kenan Barut, Gurkan Tarcin, Gulberk Tahaoglu, Sezgin Sahin, Amra Adrovic, Ozgur Kasapcopur

Pediatric Rheumatology, Istanbul University, Cerrahpasa Medical School, Istanbul, Turkey

Correspondence: Kenan Barut

Introduction: Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in childhood, divided into several subgroups. The sJIA could be presented by monocyclic, polycyclic or persistent polyarticular clinical course. Macrophage activation syndrome (MAS) represents the most devastating complication that could appear during the disease course. Studies on follow up, treatment response and disease complications of the sJIA patients are spare and rare.

Objectives: To evaluate demographic and clinical characteristics and to explore the long-term treatment response and disease complications in a large cohort of sJIA patients from the single center.

Methods: Demographic and clinical features of the sJIA patients were reached from the patient’s recrods. The frequency of disease flares, treatment response and side effects were recorded for each patient.

Results: A total of 168 sJIA patients were included in the study: 87 (51.8) female, 81 (48.2) male. The clinical features are shown in Table 1. Fifty-three (31.5) patients had monocyclic while 23 (13.7) patients had polycyclic clinical course (mean recurrency of attacks 2.5±2 (IQR:1-4)): in 38 (42). Polyarticular course was present in 92 (54.8) patients. Initially diagnosis of patients were: infection in 86 (51.1), sJIA in 34 (20.4), acute rheumatic fever in 19 (11.3), urticaria in 10 (5.9), Kawasaki disease in 4(2.4) and juvenile systemic lupus erythematosus in 2 patients.

The most common disease complications were: MAS in 20 (11.9), growth retardation in 19 (11.3) and vertebral fracture due to osteoporosis in 3 (1.9) patients. Gastrointestinal symptoms secondary to methotrexate intolerance that led to cessation of treatment were present in 9 (7.1) patients. Among 5 (2.9) patients that developed tuberculosis, 4 (2.3) were under etanercept treatment.

All of the patients were treated with corticosteroids: a doses of 2 mg/kg/day in 118 (70.2) patients  and pulse steroids in 50 (29.8) patients with severe clinical presentation. The methotrexate was used in 126 (75), leflunomide in 5(3), cyclosporine A in 29 (17.3), intravenous immunoglobulin in 19 (11.3), anakinra in 27 (16.1), canakinumab in 27 (16.1), tocilizumab in 18 (10.7), etanercept in 50 (29.8) and adalimumab in 7(4.2) patients. The median time to remission after the initial treatment with corticosteroids was 4 (IQR:2-4) months. The remission off medications was achieved in 82 (48.8) while remission on medications was achieved in 83 (49.4) of patients.

Conclusion: Systemic JIA is a subtype of JIA characterized by significant morbidity and mortality rate with macrophage activation syndrome being the most severe disease complication. Corticosteroids represent the main treatment modality. Biological agents should be considered in the steroid-resistant patients. The clinical remission could be achieved and chronic arthritis sequelae could be prevented in a majority of patients with biological agents.

References

1. Dewoolkar M, et al. Course, Outcome and Complications in Children with Systemic Onset Juvenile Idiopathic Arthritis. Indian J Pediatr 2017;84:294-8

2. Cimaz R. Systemic-onset juvenile idiopathic arthritis. Autoimmunity reviews. 2016;15(9):931-4.

3. Barut K, Adrovic A, Sahin S, Kasapcopur O. Juvenile Idiopathic Arthritis. Balkan medical journal. 2017;34(2):90-101

Disclosure of Interest

None Declared

Table 1 (abstract P012). Demographic, clinical features of sJIA

P013 CHARACTERISTICS OF PATIENTS ENROLLED IN THE FIRST LINE OPTIONS FOR SYSTEMIC JIA TREATMENT (FROST) CONSENSUS TREATMENT PLAN STUDY

Timothy Beukelman¹, Peter A. Nigrovic², George Tomlinson³, Vincent Del Gaizo⁴, Marian Jelinek⁴, Laura E. Schanberg⁵, Anne Dennos⁵, Mary Ellen Riordan⁶, Yukiko Kimura⁶, for the CARRA Registry FROST Investigators

¹University of Alabama at Birmingham, Birmingham; ²Brigham and Women's Hospital, Harvard University, Boston, USA; ³University of Toronto, Toronto, Canada; ⁴CARRA Parent/Patient Partner; ⁵Duke University, Durham; ⁶Hackensack University Medical Center, Hackensack, USA

Correspondence: Timothy Beukelman

Introduction: The optimal initial treatment for systemic juvenile idiopathic arthritis (sJIA) is unclear. Uncontrolled reports suggest that early treatment with biologic agents likely produces superior short-term clinical outcomes, but many patients may respond well to non-biologic therapies. To further study the initial treatment of sJIA, the Childhood Arthritis and Rheumatology Research Alliance (CARRA) developed Consensus Treatment Plans (CTPs) to formalize and standardize current treatment practices. Subsequently, 4 CTPs were developed: initial systemic glucocorticoid (GC); initial methotrexate (MTX) +/- GC; initial IL-1 inhibition (IL-1i) +/- GC; and initial IL-6 inhibition (IL-6i) +/- GC.

Objectives: The FiRst Line Options for Systemic JIA Treatment (FROST) is an observational study designed to assess the effectiveness and safety of each of the 4 CTPs and to the compare the CTPs containing initial biologic therapy (IL-1i and IL-6i) to those that do not contain initial biologic therapy (GC and MTX).

Methods: Patients with recent onset sJIA who are initiating therapy are considered for enrollment in FROST. In order to be eligible for FROST, participants must have fever for ≥2 weeks, arthritis for ≥ 10 days, and at least 1 of the following: evanescent rash, generalized lymphadenopathy, hepatomegaly, splenomegaly, or serositis. Treatment assignment is at the discretion of the treating physician and family. All data are collected in the CARRA Registry. To date, 43 CARRA Registry sites have been activated to enroll FROST patients. Biosamples are collected at baseline and at 6 months. Patient reported outcomes (PRO) of presence of fever and rash and pain scores are collected at home using mobile devices every 2 days during the first 2 weeks of the study. The primary study outcome is clinical inactive disease (Wallace ACR provisional definition) and cessation of glucocorticoid therapy at 9 months.

Results: Enrollment in the FROST study began in November 2016. As of April 2018, 26 patients have been enrolled at 13 sites, and their baseline characteristics are shown in Table 1. The proportion of patients with specific SJIA disease manifestations was: rash 89%, lymphadenopathy 31%, hepatomegaly 15%, splenomegaly 23%, serositis 8%, polyarthritis 46%. Overall, 15 participants (58%) have completed every requested home PRO during the first 2 weeks of the study, and 19 (73%) have completed ≥50% of the requested home PRO. Study follow-up continues to accrue. Eight patients (31%) have completed the 9-month study visit when the primary study outcome is assessed.

Conclusion: Enrollment in the FROST study has begun. Participants enrolled thus far appear to be representative of the general population of patients with sJIA. Home PRO collection is feasible through the CARRA Registry. Additional time is needed to enroll and observe a sufficient number of patients to assess the comparative effectiveness of initial treatments for sJIA.

Disclosure of Interest

T. Beukelman Consultant for: UCB, Bristol-Myers Squibb, Sobi, Novartis, P. Nigrovic Grant/Research Support from: AbbVie, Sobi, Novartis, Consultant for: AbbVie, Sobi, Novartis, Bristol-Myers Squibb, G. Tomlinson: None Declared, V. Del Gaizo Consultant for: Sobi, M. Jelinek: None Declared, L. Schanberg: None Declared, A. Dennos: None Declared, M. E. Riordan: None Declared, Y. Kimura: None Declared

Table 1 (abstract P013). See text for description.

P014 THE FREQUENCY OF MACROPHAGE ACTIVATION SYNDROME IN SYSTEMIC JUVENILE IDIOPATHIC ARTHRITIS CASES AND LONG TERM FOLLOW-UP RESULTS

Mustafa Çakan, Şerife Gül Karadağ, Nuray Aktay Ayaz

Pediatric Rheumatology, Kanuni Sultan Süleyman Research And Training Hospital, İstanbul, Turkey

Correspondence: Mustafa Çakan

Introduction: Systemic juvenile idiopathic arthritis (sJIA) is a multisystemic disease characterized by fever, rash, arthritis and polyserositis. The most dreadful complication of sJIA is macrophage activation syndrome (MAS) that is seen in 10-25% of the cases. sJIA cases may follow monocyclic, polycyclic and chronic polyarticular course.

Objectives: The aim of this study was to demonstrate the frequency of MAS in sJIA cases and to see whether sJIA cases complicated with MAS follow a more severe course in the long term.

Methods: Files of sJIA cases that were followed in our clinic between May 2010 and September 2017 were reviewed. To be included in the study, the patient had to be coming regularly to follow-up visits and had to be completed the first six months of the disease.

Results: The cohort consisted of 53 sJIA cases. Mean duration of follow-up was 39.0 ± 24.1 months. Mean age at the time of diagnosis was 7.9 ± 4.5 years. There was a female predominance in the cohort (32 females, 21 males). The frequency of MAS was 33.9% (18 cases). MAS was observed much more common in male patients than female patients; 42% vs 28%, respectively.

Bone marrow aspiration was performed to all patients to exclude malignancy. In 27.7% of MAS cases hemophagocytosis was not observed and hemophagocytosis was observed in 8.5% of cases without MAS. Initial laboratory test at the time of diagnosis of sJIA (leukocyte, hemoglobin, platelet, ferritin, triglyceride, ESR, CRP, fibrinogen, AST, ALT, albumin, and LDH) were compared in between patients with MAS and without MAS. Only ferritin and fibrinogen levels showed significant difference in between the groups (p<0.01). Patients that developed MAS had higher ferritin (4482 mg/dl) and lower fibrinogen (371 mg/dl) values than patients without MAS (ferritin 2060 mg/dl, fibrinogen 466 mg/dl) at the time of diagnosis of sJIA. When these laboratory parameters were compared at the time of diagnosis of sJIA and at the time of diagnosis of MAS, all parameters showed significant differences except CRP.

Long term follow-up results showed that monocyclic course was observed in 45%, polycyclic course in 32% and chronic polyarticular course in 23% of the cases. We have observed that patients with MAS segregated equally into three groups.

All MAS patients were initially treated with high-dose methylprednisolone and intravenous immunoglobulin. Additional treatments in MAS were cyclosporine (12 cases), anakinra (7 cases) and plasmapheresis (4 cases).

Biologics were used in 38.8% of all cases. Biologic treatments were needed in 12.5% of monocyclic cases, in 50% of polycyclic cases and in 77% of chronic polyarticular cases. At the time of enrollment, 58% of patients were under remission without medication and 38% were under remission with medication. Only two cases were active and both cases were in the group of chronic polyarticular course.

Conclusion: All sJIA patients should be followed for the development of MAS. High ferritin and relatively lower fibrinogen levels at the time of diagnosis of sJIA may be early warning signs of impending MAS. sJIA patients that develop MAS do not seem to portend more guarded prognosis in the long term follow-up. sJIA patients that follow a chronic polyarticular course are possibly one of the hardest group of patients to treat in pediatric rheumatology.

Disclosure of Interest

None Declared

P015 THE IMPORTANT ROLE OF BONE MARROW BIOPSY TO DIAGNOSIS OF MACROPHAGE ACTIVATION SYNDROME

Kwangnam Kim¹, Jong Gyun Ahn², Young Dae Kim³

¹Pediatrics, Hallym Sacred Heart Hosptal, Hallym University Medical Center, Anyang; ²Pediatrics, Severance Children's Hospital, Yonsei University, Seoul; ³Pediatrics, Ilsan Paik Hospital, Inje University, Goyang, Korea, Republic Of

Correspondence: Kwangnam Kim

Introduction: The diagnosis of MAS is difficult. A fall in platelet count and ESR, in combination with high CRP, are early signs of impending MAS in a febrile patient with an active rheumatologic condition. Other features indicative of MAS are hyperferritinemia, cytopenia involving other cell lines (WBC and RBC), liver dysfunction, coagulopathy, decreasing serum fibrinogen and increasing triglycrides.

2016 criteria for classification of MAS in patients with systemic JIA was conducted of real patient data. These data are based on clinical and laboratory features at the time of disease onset.

Objectives: The patient with a condition that could potentially be confused with MAS and active systemic JIA without evidence of MAS. To evaluate the diagnostic convenience and efficiency of the 2016 EULA/ACR/PRINTO classification for MAS in patients with systemic JIA, it will be compared with confirmed MAS by BM biopsy.

Total 13 MAS is confirmed by BM biopsy. All of these patients are applied 2016 EULA/ACR/PRINTO classification for MAS in patients with systemic JIA.

Methods: 2016 new criteria was simplified the diagnostic process for the convenience. The MAS diagnosis tools are Ferritin, Platelet count, Aspartate aminotransferase, Triglycerides and Fibrinogen. This study was a retrospective chart review conducted in the pediatric department of a tertiary level teaching hospital from 2002 through 2016. The ILAR criteria were identified in each patient at the time of first presentation to our hospital. Seventy-four patients were diagnosed with sJIA. 12 boys and 15 girls formed this study cohort. A comparison of the baseline laboratory characteristics of patients who fulfilled the ILAR criteria and those with suspected sJIA has been shown in Table 1.

Results: Diagnosis of MAS is confirmed by presence of haemophagocytic histiocytes in bone marrow. Bone marrow biopsy confirmed activated histiocytes engulfing a band neutrophil.

Conclusion: A cytokine storm is a consistent feature in patients with MAS, and it is a potentially life-threatening complication of rheumatic diseases. The fact that highly effective treatment is needed in the early stage. So do that, early diagnosis is necessary. The conduct of the new 2016 classification critieria for MAS also underscored potential limitations. Additional validation of these criteria will be necessary. The BM biopsy will make up the weakness of limitation and early diagnosis will be more possible.

Referreces

1. Ravelli A. Minola F. Davi S. Horne A. Bovis F. Pistorio A. et al. 2016 Classification Criteria for Macrophage Activation Syndrome Complicating Systemic Juvenile Idiopathic Arthritis: A European League Against Rheumatism/American College of Rheumatology/Paediatric Rheumastology International Trials Organisation Collaboratve Initiative. Atrhritis Rheumatol. 2016;68(3):566-76.

2. Grom A. Horne A Benedetti F. et al. Macrophage activation syndrome in the era of biologic therapy. Nat Rev Rheumatol. 2016;12(5):259-268.

Disclosure of Interest

K. Kim Consultant for: pediatric clinical immunology, J. G. Ahn: None Declared, Y. D. Kim: None Declared

Table 1 (abstract P015). See text for description

P016 SYSTEMIC TYPE OF JUVENILE IDIOPATHIC ARTHRITIS IS A RISK FACTOR OF INFLUENZA INFECTION -A MULTI-INSTITUTIONAL QUESTIONNAIRE SURVEY IN JAPAN-

Tomohiro Kubota¹, Yasuo Nakagishi², Nami Okamoto³, Hiroaki Umebayashi⁴, Ken-ichi Nishimura⁵, Naomi Iwata⁶, Yuka Okura⁷, Masaki Shimizu⁸, Mao Mizuta⁸, Kosuke Shabana³, Masato Yashiro⁹, Takahiro Yasimi¹⁰, Junko Yasumura¹¹, Hiroyuki Wakiguchi¹², Noriko Kinjo¹³, Syuji Takei¹⁴, Masaaki Mori¹⁵

¹Pediatrics, KAGOSHIMA UNIVERSITY HOSPITAL, Kagoshima City; ²pediatrics, Hyogo Prefectural Kobe Children’s Hospital, Kobe; ³Pediatrics, Osaka Medical College, Takatsuki; ⁴Pediatrics, Miyagi Children’s Hospital, Sendai; ⁵Pediatrics, Yokohama City University Graduate School of Medicine, Yokohama; ⁶ Immunology and Infectious Diseases, Aichi Children’s Health and Medical Center, Obu; ⁷Pediatrics, KKR Sapporo Medical Center, Sapporo; ⁸Pediatrics, Graduate School of Medical Sciences, Kanazawa University, Kanazawa; ⁹Pediatrics, Okayama University Hospital, Okayama; ¹⁰pediatrics, Kyoto University Graduate School of Medicine, Kyoto; ¹¹Pediatrics, Hiroshima University Graduate School of Biomedical & Health Sciences, Hiroshima; ¹²Pediatrics, Yamaguchi University Graduate School of Medicine, Ube; ¹³Pediatrics, graduate school of medicine, University of the Ryukyus, Nakagami; ¹⁴Pediatrics, KAGOSHIMA UNIVERSITY HOSPITAL, Kagoshima; ¹⁵Lifetime Clinical Immunology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan

Correspondence: Tomohiro Kubota

Introduction: The influenza (Flu) is one of the most prevalent infections in the world and the vaccination is recommended for the patients treated with immunosuppressive therapy and there is some immunological research on the Flu vaccination in the patients with juvenile idiopathic arthritis (JIA). However, the morbidity of Flu in the patient with JIA in the real-world is unknown.

Objectives: We aimed to evaluate Flu morbidity and side effect of vaccination in patients with JIA in comparison with the general population in Japan. And clarify the risk factor of Flu infection for the patient with JIA.

Methods: From October 2016 to May 2017, a total of 13 participating medical institutions collected questionnaires from patients with JIA. The questionnaires focused on the incidence of Flu infection and Flu vaccination, and the efficacy and side effects of Flu vaccination. The frequency of each item was compared to that in the general population. Multivariable logistic regression analysis was performed to determine the risk factor on the Flu infection.

Results: A total of 473 patients with JIA (159 males [34%]; 314 females [66%]) were enrolled (mean age, 13.3 years; range, 2.4-37.3 years). Two hundred sixty-eight (57%) patients got the Flu vaccine; side effects were observed in 58 patients (22%), with no severe cases. Patients were treated with methotrexate (n=235 [50%]; mean dose, 7.35 mg/m^2/week), prednisolone (n=110 [23%]; mean dose, 0.14 mg/kg/day), and biological disease-modifying anti-rheumatic drugs (n=327 [69%]). Seventy-four patients (15.6%) had a Flu infection and the influenza morbidity was significantly smaller in patients with JIA compared to that in the general population in Japan (21%)(p=0.005). JIA disease activity flared in one patient after Flu infection, but no one flared after Flu vaccination. In logistic regression analysis, the patients with systemic JIA were high risk for Flu infection (odds ratio:2.666, 95% confidence interval: 1.321-5.475, p=0.007).

JIA: juvenile idiopathic arthritis, MTX: methotrexate, PSL: prednisolone, bDMARDs: biological disease-modifying anti-rheumatic drugs, OR: odds ratio; CI: confidence interval

Conclusion: Influenza vaccination is safe and effective for patients with JIA treated with glucocorticoids and disease-modifying antirheumatic drugs. The risk of Flu infection is significantly high in the patient with systemic JIA.

Disclosure of Interest

None Declared

Table 1 (abstract P016). Multivariable logistic regression analysis to determine the risk factor on the influenza morbidity

P017 Withdrawn

P018 LIPID BIOMARKERS IN PATIENTS WITH JUVENILE IDIOPATHIC ARTHRITIS: IS THERE A DIFFERENCE BETWEEN THE POLYARTICULAR AND SYSTEMIC SUBTYPES?

Wellington D. Rodrigues, Roseli S. Sarni, Fernando A. Fonseca, Patricia P. Aires, Claudio A. Len, Maria T. Terreri

Pediatric Rheumatology, Universidade Federal de São Paulo, São Paulo, Brazil

Correspondence: Claudio A. Len

Introduction: Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in the pediatric population. These patients coexist with the chronic disease, and present to a greater extent negative outcomes such as osteoporosis and cardiovascular diseases.

Objectives: To describe the biomarkers of lipid metabolism related to the cardiovascular risk of children and adolescents with JIA and to relate them to variables of the disease, lipid and glucose profile, nutritional status and food consumption.

Methods: Cross-sectional study with 62 JIA patients. The following were evaluated: disease activity and medications used, body mass index, height for age (z score), food intake (24 hour recall), lipid profile (total cholesterol - CT, low density lipoprotein - LDL, high density lipoprotein – HDL, triglycerides - TG and non - HDL), lipid markers such as apolipoproteins A-I and B (Apo A-I and Apo B). The association analyses were stratified as follows: HDL-c and Apo A-I into adequate and borderline/low; LDL-c, CT, TG, NHDL-c and Apo B into adequate and borderline/high; levels of C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). For statistical analysis: Exact Fischer, Chi-square, Mann-Whitney and Spearman Correlation tests; p <0.05.

Results: The mean age and time since diagnosis were 7.7 years (± 4.3) and 5.0 years (± 3.4), respectively. Active disease was observed in 33.9% of the patients and the prevalence of dyslipidemia was 62.9% overall when we considered lipid profile alone (CT, LDL-c, HDL-c, non-HDL-c and TG) and 82.3% when we included altered apolipoproteins (Apo A-I and Apo B). HDL-c and Apo A-I were the most frequently altered lipid markers. When comparing the subtypes, the systemic subtype had a higher value and higher frequency of altered LDL-c and NHDL-c and increased Apo B/Apo A ratio, when compared to the polyarticular subtype (p = 0.017, 0.042 and 0.03, respectively). When we cross-referenced the adequate or borderline/low HDL-c variable against other variables, patients with borderline/low HDL-c presented lower values ​​and higher frequency of altered Apo A-I (p<0.001 and 0.001, respectively). There was no significant correlation between us-CRP and variables related to lipid metabolism. However, ESR showed a negative correlation with Apo A-I levels (r = -0.25, p = 0.047).

Conclusion: We conclude that dyslipidemia and alteration of lipid biomarkers are common in patients with JIA. The systemic subtype and elevated ESR were associated with lower concentrations of Apo A-I, indicating the participation of the inflammatory process in this alteration. Furthermore, the systemic subtype presented higher value and frequency of atherogenic particles, suggesting that patients with this subtype are at increased risk for the development of cardiovascular disease.

Disclosure of Interest

None Declared

P019 HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS (HLH) MIMICKERS: CXCL9 AS A POTENTIAL BIOMARKER DISTINGUISHING HLH FROM OTHER HYPERFERRITINEMIC SYNDROMES

Giulia Marucci, Ivan Caiello, Manuela Pardeo, Virginia Messia, Giusi Prencipe, Antonia Pascarella, Fabrizio De Benedetti, Claudia Bracaglia

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

Correspondence: Giulia Marucci

Introduction: Increased ferritin is considered biomarker highly suggestive of primary and secondary HLH and it is one of the HLH-2004 diagnostic and MAS guidelines (1, 2), nevertheless it could also be elevated in other inflammatory conditions. Interferon-gamma (IFNγ) and IFNγ induced chemokines, particularly CXCL9, have been demonstrated to be markedly elevated in patients with primary and secondary HLH.

Objectives: To describe eight patients with hyperferritinemia who fully or partially met the HLH-2004 diagnostic guideline, but in which the subsequent clinical course and further investigations led to different diagnosis that required different therapies and to investigate the CXCL9 levels in identify diseases that may mimic HLH. To be noted that soluble CD25 was not measured in these patients.

Methods: Serum CXCL9 levels were analyzed by DuoSet ELISA KIT DY392 (R&D Systems, Minneapolis, Minn). Normal values of CXCL9 are lower than 700 pg/ml.

Results: We identified 8 patients with laboratory features suggestive of HLH, included high ferritin levels (>500 ng/ml). Three of these patients met five of the HLH-2004 criteria, two of them met four criteria and the others two met three criteria. One patient presented only high serum ferritin level and cytopenia. CXCL9 levels were <300 pg/ml in seven of them and approximately 600 pg/ml in one patient. The clinical disease course and the other investigations ruled out the diagnosis of HLH and every patient received a different diagnosis. None of them received treatment for HLH (Table 1).

Conclusion: Since HLH is a life-threatening condition, early recognition and promptly therapy are essential to modify the disease course. One of the most typical feature of primary and secondary HLH is high ferritin levels. Due to the severity of the disease, sometimes patients need to be treated before all criteria are fulfilled. The eight patients reported had features highly suggestive of HLH and met the HLH-2004 criteria, or part of them. However they all received a different final diagnosis. Despite all presented with high ferritin levels, CXCL9 was low in all. CXCL9 is a chemokine specifically induced by IFNγ, and has been demonstrated to be markedly elevated in patients with primary and secondary HLH due to the activation of the IFNγ pathway. In these cases CXCL9 was able to differentiate diseases with high ferritin that mimics HLH. High CXCL9 levels appear to be a potential specific biomarker for HLH diagnosis. Early dosage of CXCL9 levels in patients with hyperferritinemia and with clinical suspicion of HLH may be helpful for a timely differential diagnosis.

Reference

1. Henter JI et al. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2007 Feb; 48(2):124-31.

2. Ravelli A et al. 2016 Classification Criteria for Macrophage Activation Syndrome Complicating Systemic Juvenile Idiopathic Arthritis: A European League Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology International Trials Organisation Collaborative Initiative. Ann Rheum Dis. 2016 Mar;75(3):481-9.

Disclosure of Interest

G. Marucci: None Declared, I. Caiello: None Declared, M. Pardeo: None Declared, V. Messia: None Declared, G. Prencipe: None Declared, A. Pascarella: None Declared, F. De Benedetti Grant/Research Support from: Novartis, Novimmune, Hoffmann-La Roche, SOBI, AbbVie, Pfizer, C. Bracaglia: None Declared

Table 1 (abstract P019). Patients’ features

P020 THROMBOTIC MICROANGIOPATHY: AN UNDER-RECOGNIZED, DREADFUL COMPLICATION OF MACROPHAGE ACTIVATION SYNDROME

Francesca Minoia^1,2, Jessica Tibaldi^2,3, Valentina Muratore⁴, Romina Gallizzi⁵, Concetta Micalizzi², Angelo Ravelli^2,3

¹Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan; ²Istituto G. Gaslini; ³Università degli Studi di Genova, Genoa; ⁴IRCCS Policlinico San Matteo, Pavia; ⁵Università degli Studi di Messina, Messina, Italy

Correspondence: Francesca Minoia

Introduction: Macrophage activation syndrome (MAS) is part of the spectrum of hemophagocytic disorders and is a serious complication of rheumatologic conditions, mainly systemic juvenile idiopathic arthritis (sJIA). Thrombotic microangiopathy (TMA) is a heterogeneous group of life-threating diseases characterized by microangiopathic hemolytic anemia, thrombocytopenia and organ injury. The association between TMA and hemophagocytic syndromes has been described only in single reports in adult renal transplant recipients and in two pediatric cases of virus-induced hemophagocytic lymphohistiocytosis. TMA complicating MAS has never been reported so far

Objectives: To describe clinical and laboratory features, treatment and outcome of a cohort of patients with MAS complicated by TMA

Methods: The clinical charts of patients with MAS and TMA seen at 3 Italian tertiary-care pediatric rheumatologic centers were reviewed retrospectively. Demographic, clinical and laboratory data at the time of TMA diagnosis were collected. Therapeutic intervention and outcome were also recorded

Results: Five patients who met the criteria for MAS and developed TMA during the course of MAS were identified; one patient was excluded due to insufficient data. The underlying disease was sJIA or a sJIA-like disease in all patients. The median age at MAS onset was 8.6 years (4.2–12.8 yr), and the median interval between onset of MAS and occurrence of TMA was 13.5 days. TMA was characterized in all patients by renal failure with hematuria, and presence of schistocytes in blood smear. Three of the 4 patients experienced severe CNS involvement, with lethargy, seizures, or coma. The main laboratory features at TMA onset are shown in Table 1. For the management of MAS, all patients received high-dose corticosteroids and cyclosporine; in 3 cases anakinra was added. All TMA episodes were treated with plasma-exchange; two patients were also given biologics (rituximab or eculizumab) with good results. During the course of TMA, aggressive and prolonged management in the Intensive Care Unit was required in all cases. All patients survived

Conclusion: TMA is a dreadful complication of MAS, which is likely under-recognized. If not diagnosed timely and treated appropriately, TMA may precipitate the course of MAS and lead to a fatal outcome. Clues to suspect TMA in a patient with MAS are the increase in lactic dehydrogenase and decrease in platelet count out of proportion of the other laboratory abnormalities, the drop in haptoglobin level, the finding of schistocytes in blood smear, and the new onset of hematuria. Biologic medications, particularly rituximab and eculizumab may offer an adjunctive therapeutic option for refractory cases

Disclosure of Interest

None Declared

Table 1 (abstract P020). See text for description

Poster Walk 2: JDM and vsculitides

P021 AN INTERNATIONAL CONSENSUS SURVEY OF DEVELOPING CLASSIFICATION CRITERIA FOR JUVENILE DERMATOMYOSITIS-SCLERODERMA OVERLAP

Parichat Khaosut^1,2, Clarissa Pilkington², Lucy R. Wedderburn^2,3,4, Sandrine C. Lacassagne², on behalf of JDCBS and JDCBS

¹Paediatrics, Faculty of medicine, Chulalongkorn University, Bangkok, Thailand; ²Paediatric Rheumatology, Great Ormond Street Hospital; ³ARUK Centre for Adolescent Rheumatology, University College London; ⁴NIHR Biomedical Research Centre, Great Ormond Street Hospital, London, UK

Correspondence: Parichat Khaosut

Introduction: There is no internationally agreed definition of ‘JDM-Scleroderma overlap’ in children and little data on the clinical characteristics, laboratory features and outcome in this specific group of JDM have been published. The goal of this survey is to achieve consensus on a meaningful definition of JDM-Scleroderma overlap in paediatric population and to determine whether overlap features affect outcome and management.

Objectives: To develop criteria for the diagnosis of JDM-Scleroderma overlap using an international consensus process.

Methods: A survey was circulated to all investigators in the Juvenile Dermatomyositis Cohort and Biomarker Study and Repository (JDCBS) and extended to other members of the Network for JDM in Paediatric Rheumatology European Society (PReS JDM working party) through a Delphi survey. Each individual was asked to identify those clinical manifestations that were felt to be most characteristic to enable them to make the diagnosis of JDM-Scleroderma overlap. The opinions on the importance of identification this subtype of JDM ware collected and the role of myositis autoantibodies has been mentioned in the questionnaire.

Results: The survey had a response rate of 26.9% (41 individuals) from both JDCBS and PReS JDM working party. The most common clinical features identified by survey responders as found in JDM patients with scleroderma overlap were sclerodactyly, sclerodermatous skin change proximal to MCP joints, Raynaud phenomenon and ulceration at the tip of fingers, respectively. 95.1% of responders though the scleroderma overlap presentations influence the outcome of JDM, while 86.4% agreed that these features influence the choice of treatment. Interestingly, all of responders (100%) thought that negative myositis autoantibodies could not exclude the diagnosis JDM-Scleroderma overlap, but almost 11% used positive myositis autoantibodies to diagnose this subgroup of JDM. Myositis associated autoantibodies occurring in systemic sclerosis overlap (anti PM-Scl, anti U1-RNP and anti Ku) were thought to be the most commonly associated autoantibodies with JDM-Scleroderma overlap (78%), followed by systemic sclerosis specific autoantibodies (anti Scl70, anti RNA polymerase III) (44%). Although 83% felt that autoantibody profile influences the outcome, only 49% thought that autoantibody profile would influence the choice of medication. 89% of participants in this survey have seen patients with JDM-Scleroderma overlap.

Conclusion: This process identified clinical features that clinicians felt to be helpful or important in the diagnosis of JDM-Scleroderma overlap. A further process of secondary survey is necessary to agree an internationally acceptable, clinically usable set of classification criteria.

Disclosure of Interest

None Declared

P022 DEFINING THE RISK OF INTRAVENOUS IMMUNOGLOBULIN RESISTANCE IN NON-ASIAN PATIENTS WITH KAWASAKI DISEASE

Maryam Piram^1,2, Martha Darce³, Stéphanie Tellier⁴, Sylvie Di-Filippo⁵, Franck Boralevi⁶, Fouad Madhi⁷, Ulrich Meinzer⁸, Rolando Cimaz⁹, Celine Piedvache¹⁰, Isabelle Kone-Paut^1,2, Kawanet study group

¹Pediatric Rheumatology, CEREMAIA, CHU de Bicêtre; ²Univ Paris Sud; ³Pediatric Rheumatology, CHU de Bicêtre, Le Kremlin Bicêtre; ⁴Pediatric Rheumatology, Nephrology and Internal medecine, CHU de Toulouse, Toulouse; ⁵Cardiology, Hospices civils de Lyon, Lyon; ⁶Dermatology, CHU de Bordeaux, Bordeaux; ⁷Paediatrics, CHIC, Créteil; ⁸Paediatrics, CHU Robert Debré, Paris, France; ⁹Pediatric Rheumatology, Meyer Hospital, Firenze, Italy; ¹⁰Clinical Research Unit, CHU de Bicêtre, Le Kremlin Bicêtre, France

Correspondence: Isabelle Kone-Paut

Introduction: About 10-20% of patients with Kawasaki disease (KD) are resistant to intravenous immunoglobulin (IVIg) and are at increased risk of coronary artery abnormalities (CAAs). Early identification is critical to initiate aggressive therapies, but available scoring systems lack sensitivity in non-Japanese populations.

Objectives: We investigated the accuracy of 2 Japanese scoring systems and studied factors associated with IVIg resistance in a large multiethnic French population of children with KD to build a new scoring system.

Methods: Children admitted for KD between 2011-2014 in 65 centers were enrolled. For patients fulfilling American Heart Association (AHA) criteria, we identified factors predicting resistance to IVIg by multivariate regression analysis. The performance of our score and the Kobayashi and Egami scores were compared in our population and in ethnic subgroups.

Results: Overall, 465 children were reported by 84 physicians; 355 (76%) fulfilled AHA criteria (55% European Caucasian, 12% North African/Middle Eastern, 10% African/Afro-Caribbean, 3% Asian and 11% mixed). Eighty patients (23%) needed second-line treatment. Japanese scores had poor performance in our whole population (sensitivity 52-44.5%). Predictors of IVIg resistance were ALT≥30 IU/L, hemoglobin level <10 g/dl, lymphocyte count <1500/mm³, modification of extremities, CAAs at initial echocardiography, and time to treatment <5 days. The best sensitivity (80%) and specificity (65%) of this model was with weighted variables and cut-off ≥ 17.5/50 points. The sensitivity remained good in our 3 main ethnic subgroups (78-83%).

Conclusion: We identified predictors of IVIg resistance and built a new score with good sensitivity and specificity in a non-Asian population.

Disclosure of Interest

None Declared

P023 THE USE OF INTERLEUKIN 1 RECEPTOR ANTAGONIST (ANAKINRA) IN KAWASAKI DISEASE: A RETROSPECTIVE CASES SERIES

Isabelle Koné-Paut¹, Rolando Cimaz², Jethro Herberg³, Oliver Bates³, Aurelia Carbasse⁴, Jean Pierre Saulnier⁵, Maria Cristina Maggio⁶, Jordi Anton⁷, Maryam Piram⁸

¹Pediatric rheumatology, APHP, hôpital de Bicêtre, CEREMAIA, university of Paris Sud, Le Kremlin Bicêtre, France; ²Pediatric rheumatology, Meyer hospital, Firenze, Italy; ³Pediatrics, Imperial college of London, London, UK; ⁴Pediatric rheumatology, Hôpital arnaud de villeneuve, Montpellier; ⁵Intensive Care Unit, Poitiers university hospital, Poitiers, France; ⁶Pediatrics, University Department Pro.Sa.M.I.G d’Alessandro, Palermo, Italy; ⁷Pediatric rheumatology, Hospital San Joan de Deu, Espluges de Llobregat, Spain; ⁸pediatric rheumatology and dermatology, APHP, hôpital de Bicêtre, CEREMAIA, university of Paris Sud, Le Kremlin Bicêtre, France

Correspondence: Isabelle Koné-Paut

Introduction: Persistent fever and inflammation after infusion of 2g/kg of IVIG, the standard treatment of KD represents a high-risk situation for coronary aneurysms in Kawasaki disease. Identifying patients at risk for IVIG resistance is difficult outside the Asian population, and there remains a critical unmet need to identify an anti-inflammatory treatment that is efficacious in all KD patients. Recent evidence from studies in animals and humans suggest a critical role for interleukin-1 (IL-1) α and β in the pathogenesis of KD.

Objectives: To identify the clinical characteristics, reasons for use and response to treatment with anakinra in a retrospective series of patients with Kawasaki Disease (KD).

Methods: A retrospective chart review of patients treated with anakinra for KD diagnosed according to the AHA criteria. We compared clinical, biological and echocardiographic characteristics of KD before and after anakinra use. We analysed reasons for use of anakinra, and compared treatment regimens used in 7 European KD referral centres.

Results: Eight boys and 3 girls with treatment-refractory KD, aged 4 months to 9 years old, received at least 2 different KD treatments prior to anakinra, which was given on mean at 25 days after disease onset (8 to 87 days). The main reasons for use of anakinra were clinical and biological inflammation, progression of coronary dilatations, and severe myocarditis with cardiac failure. Doses of anakinra ranged from 2 to 8 mg/kg and duration varied from 6 to 81 days. On anakinra treatment, fever disappeared within hours (<24 h) in 3 patients, and within 2 and 6 days in two patients respectively. Six others patients were not febrile at onset of anakinra. In addition, CRP levels fell two to three fold within 48 hours in 7/9 evaluable patients. In terms of its effect on coronary artery dilatation, Z scores decreased in 10/11 patients and increased in one who died suddenly of pericardial hemorrhage.

Conclusion: Anakinra used late in the disease course led to a rapid and sustained improvement in clinical and biological inflammation. However, our retrospective analysis did show neither a striking nor a rapid decrease of coronary dilatations and we cannot determine if anakinra itself had an effect on coronary artery dimensions. More robust data will be available soon from the two Phase II ongoing trials, KAWAKINRA using anakinra treatment early after one failure of IVIG treatment (European Clinical Trials no. 2014-002715-41) and ANAKID (ClinicalTrials.gov identifier: NCT02179853), focused on patients with coronary giant aneurysms.

Disclosure of Interest

None Declared

P024 OUTCOME OF 24 PATIENTS WITH CHILDHOOD-ONSET TAKAYASU ARTERITIS: A RETROSPECTIVE STUDY IN TWO TERTIARY CENTRES IN JAPAN

Kenichi Nishimura¹, Seira Hattori¹, Ayako Murase¹, Ai Ohnishi¹, Ryoki Hara¹, Masao Ogura², Kenji Ishikura², Shuichi Ito¹

¹Department of Pediatrics, Yokohama City University Graduate School of Medicine, Yokohama; ²Division of Nephrology and Rheumatology, National Center for Child Health and Development, Tokyo, Japan

Correspondence: Kenichi Nishimura

Introduction: Takayasu arteritis (TA) is a chronic large-vessel vasculitis affecting the aorta and its major branches. Glucocorticoids (GCs) can achieve remission in most patients with TA. As most patients suffer relapse after reducing GCs, additional therapy such as methotrexate, azathioprine and intravenous cyclophosphamide (IVCY) has been applied. Recently, the efficacy of TNF-α inhibitors or tocilizumab (TCZ) has been reported. However, there remain insufficient data on clinical characteristics and outcomes of patients with childhood-onset TA, including recent therapeutic advances.

Objectives: We aimed to retrospectively analyse the characteristics and outcomes of patients with childhood-onset TA in two tertiary centres in Japan.

Methods: Subjects were 24 patients with TA diagnosed when younger than 18 years. Follow-up duration was more than 2 years. Diagnosis of TA was based on the EULAR/PRINTO/PRES criteria. We divided the subjects into two groups: those who did and did not experience relapse. Relapse was defined as NIH criteria for active disease in TA.

We analysed the patients’ background, treatment and complications. We additionally compared two groups according to prednisolone (PSL) reduction rate and whether or not they carried HLA-B52.

Binary data were analysed by Fisher’s exact test, and quantitative data by Mann-Whitney U test. The cumulative relapse rates after the diagnosis were estimated using the Kaplan-Meier method; differences between two groups were assessed by the log-rank test.

Results: Median age at onset was 13.0 (range; 0.5-18.0) years old (male:female, 11:13). Thirteen patients (54%) had HLA-B52. Period from onset to diagnosis was 1 (0-66) months. Angiographic classifications were I, IIa, IIb, III, IV and V (n=3, 2, 4, 1, 2 and12), respectively. Four patients and one patient had pulmonary artery involvement and coronary involvement, respectively.

Three patients achieved drug-free remission. Median dose of prednisolone (PSL) was 0.8 (0.4-2.4) mg/kg/day at initiation of treatment and 0 (0-0.3) mg/kg/day at the last visit. Immunosuppressants were used in 13 (54%) from the onset and in 21 (88%) at the last visit. IVCY was used in 10 patients (42%) from the onset, and 4 after the relapse. Some biologics were used in 4 (17%) from the onset, and in 12 (50%) at the last visit.

Twelve patients (50%) experienced relapse, and median number of relapses was 3 (1-6) times. The ratio of relapse was not significantly different between the HLA-B52 positive and negative patients (69% vs 27%, P=0.099). However, median duration from diagnosis to the first relapse was significantly shorter in HLA-B52 positive patients than negative patients (6 vs 51months, P=0.016). The reduction pace of PSL was significantly greater in relapsed patients than non-relapsed patients (0.058 vs 0.025 mg/kg/month, P=0.017). The cumulative relapse rates after the started IVCY or TCZ were not significantly difference between the patient who introduced IVCY (n=14) and TCZ (n=12) (P=0.10).

Nine patients (38%) had cardiovascular complications (aortic valve regurgitation (AR) (n=4), annuloaortic ectasia (AAE) (n=1) and AR+AAE (n=4)). Two patients underwent cardiac surgery. Ten patients had osteoporosis, 2 had surgery for glaucoma and 5 had some mental disorders in their clinical coarse.

Conclusion: Approximately half of the patients with childhood-onset TA experienced relapse despite using immunosuppressants and/or biologics. HLA-B52 positivity and rapid reduction rate of PSL significantly increased risk of early relapse. Furthermore, cardiovascular involvement and GCs-related complications were common. Our study suggests the outcome of childhood-onset TA remains unfavourable.

Disclosure of Interest

None Declared

P025 MYOSITIS DAMAGE INDEX IN A COHORT OF INDIAN CHILDREN WITH JUVENILE DERMATOMYOSITIS

Santan Godad, Pallavi Pimpale Chavan, Raju P. Khubchandani

Pediatric Rheumatology Clinic, Department of Pediatrics, Jaslok Hospital and Research Centre, Mumbai, India

Correspondence: Pallavi Pimpale Chavan

Introduction: International Myositis Assessment and Clinical Studies Group (IMACS) developed the Myositis Damage Index (MDI) structured separately for pediatrics and adults, to provide consistency in myositis outcomes. The MDI documents persistent changes in 11 organ systems thought to be related to damage. There is a dearth of studies on damage caused by Juvenile Dermatomyositis (JDM) especially from less resourced countries and hence our study.

Objectives: Primarily to assess the myositis damage index in a cohort of children with JDM from a single centre in Mumbai, India and secondarily to study associations of factors leading to long term damage in these children.

Methods: After ethics approval and consents, a total of 23 patients with JDM under regular treatment and at least a 2 year follow up, at first study visit were identified. Specifically excluded were children with overlap syndromes eg scleromyositis. The MDI was assessed as severity of damage and extent of damage at the first study visit and reassessed at a second visit at least six months later and only damage present at both visits were scored to give a final severity and extent of damage score. There were no drop outs.

Results: 23 children with age range at disease onset 1y - 17.9 y (mean 6.9 y, median 6.8 y, IQR 3.5-8.8) were diagnosed as JDM after a duration of symptoms ranging 1m-30 m (mean 6.8 m, median 5 m, IQR 3-8.5). Their age at the study visit ranged from 5.5 y - 24.8 y (mean 13.4 y, median 12.9 y, IQR 10.4-15.3) after a follow up duration ranging from 2 y - 20.1 y (mean 5.9 y, median 4.2 y, IQR 2.6-8.5, Total 136.5 patient years). The disease course was monocyclic in 14, continuous in 6 and polycyclic in 3. The total MDI extent of damage score ranged from 0- 8 / 35 (children) or 37 (adolescents) (mean 2.04, median 2.0, IQR 0.5-2.5) and severity of damage score ranged from 0-24.7 /110 (mean 4.7, median 3.5, IQR 1.3-6.4). 17/23 children had damage in one or more organ systems, with 9 showing damage in one organ system, 4 in two organ systems, 3 in three organ systems and 1 child showed damage in six systems. Cutaneous (16/23), endocrine ie growth retardation (6/23) and muscle (5/23) were the most commonly damaged organ systems with 2 children showing skeletal damage while ocular, gastrointestinal and cardiac domains were involved in one each. Importantly, over this duration of follow up there were no children with infection, pulmonary, peripheral vascular disease or malignancy. Correlation between age at onset, gender, time to diagnosis, course of disease and duration of follow up did not yield statistically conclusive results.

Conclusion: This is amongst the earliest studies to report damage due to JDM from less resourced countries. Over the median follow up period of 4.2 years about 75% of the children suffer damage in one or more domains, cutaneous damage being the commonest. Uniquely despite high infection rates in the community, this domain was unaffected in our population. Continued enrolment with longer duration of follow up are needed to shed light on factors influencing damage.

Disclosure of Interest

None Declared

P026 PRELIMINARY PROSPECTIVE VALIDATION OF THE JUVENILE DERMATOMYOSITIS ACTIVITY INDEX (JDMAI)

Silvia Rosina^1,2, Giulia Camilla Varnier^1,2,3, Alessandro Consolaro^1,2, Pieter van Dijkhuizen¹, Kiran Nistala³, Nicolino Ruperto¹, Angela Pistorio¹, Clarissa Pilkington³, Angelo Ravelli^1,2

¹Istituto Giannina Gaslini; ²Università degli Studi di Genova, Genova, Italy; ³Great Ormond Street Hospital, London, UK

Correspondence: Silvia Rosina

Introduction: The first composite disease activity score for juvenile dermatomyositis (JDM), named JDMAI, has recently been developed and validated in retrospective patient datasets. It is composed of 4 domains and takes into account the parents’ perception of disease status. The 6 preliminary versions of the tool performed similarly in previous validation analyses.

Objectives: To test prospectively the validity of the JDMAI in a sample of JDM patients seen in daily practice.

Methods: A total of 53 JDM patients seen consecutively at 2 tertiary-care paediatric rheumatology centers, either at disease onset or at a follow-up visit, a median of 2.3 years after disease onset, were enrolled. Each patient received a retrospective assessment and a cross-sectional evaluation at study entry. Twenty-two patients also underwent a second (prospective) assessment after a median of 3.5 months from study entry. Physician-centered evaluations included assessment of muscle, skin and overall disease activity on a visual analogue scale (VAS) or through the Disease Activity Score (DAS), rating of disease state and course and measurement of disease damage with the Myositis Damage Index (MDI). Laboratory data comprised muscle enzymes and ESR. Parent-reported outcomes were collected through the administration of the Juvenile Dermatomyositis Multidimensional Assessment Report (JDMAR). Validation analyses included assessment of construct validity, internal consistency (with Cronbach’s α), discriminant ability, and responsiveness to change in disease state over time (with standardized response mean, SRM).

Results: All JDMAI versions showed strong (r>0.7) correlations with muscle disease activity VAS (0.85-0.87), muscle section of DAS (0.81-0.83), total DAS (0.89-0.92), pain VAS (0.72-0.75), and fatigue VAS (0.92-0.93). The correlations of the different JDMAI versions with the skin index not contained in the specific version (skin disease activity VAS or skin section of DAS) were strong (0.74-0.79). As expected, JDMAI correlations were moderate (r=0.4-0.7) or low (r<0.4) with laboratory parameters (CK, LDH, AST, ALT, and ESR) and with the MDI (0.1-0.11). The SRM was greater in patients judged as improved by the physician or the parent (1.26-1.56) than in those judged as not improved (0.88-1.11). Cronbach’s α was very high (0.89-0.91) for all JDMAI versions. All JDMAI versions discriminated strongly between patients classified in different disease activity states by the physician (p<0.0001) or by the parent (p=0.002-0.005), and between patients whose parents were satisfied or not satisfied with their children’s disease status (Mann-Whitney U test, p=0.0005-0.0008).

Conclusion: Validation analyses in this prospective patient sample confirmed that the JDMAI possesses good measurement properties and is a suitable and reliable tool for the assessment of disease activity in children with JDM both in clinical practice and research. Importantly, the new tool revealed a strong capacity to capture the improvement of disease activity over time.

Disclosure of Interest

None Declared

P027 QUALITATIVE NAILFOLD VIDEOCAPILLAROSCOPY ASSESSMENT OF MICROVASCULAR INVOLVEMENT IN JUVENILE DERMATOMYOSITIS

Ana V. Villarreal Treviño¹, Fernando García-Rodríguez¹, Vicente Baca², Samara Mendieta-Zerón³, Manuel de la O-Cavazos⁴, Dionicio Á. Galarza-Delgado⁵, Nadina E. Rubio-Pérez¹

¹Pediatric Rheumatology, Hospital Universitario "José Eleuterio González", Monterrey; ²Pediatric Rheumatology, Centro Médico Nacional Siglo XXI, Ciudad de México; ³Pediatric Rheumatology, ISSEMYM Hospital Materno Infantil, Toluca; ⁴Pediatric; ⁵Rheumatology, Hospital Universitario "José Eleuterio González", Monterrey, Mexico

Correspondence: Ana V. Villarreal Treviño

Introduction: Juvenile dermatomyositis (JDM) is the most common of the pediatric inflammatory myopathies characterized   by inflammatory microvasculopathy.

Nailfold videocapillaroscopy (VCP)  is an in vivo, rapid, and inexpensive imaging technique that allows quantitative assessment of microcirculation. VCP has demonstrated a key role in diagnosis and disease monitoring. The most severe videocapillaroscopy  semi-quantitative changes  previously reported  as loss of capillaries, enlarged loops  and brushy capillaries  are associated with longer  disease duration¹. There is a lack of  specific quantitative measures of the capillaries  during disease curse.

Objectives: To describe  qualitative and  semi-quantitative VCP assessment in Mexican patients with JDM

.

Methods: The present study was a cross-sectional observational study that analyzed 192 images from 24 patients with JDM during different  of the disease course, form 3 diferent centers in Mexico. VCP was performed by the same examiner (AVT),  images were obtained  from   all fingers except thumbs of both hands using a videocapillaroscope with a 200x optical probe.  The images were collected, coded, and stored using OptiPix  software (version 1.7.16).Semi-quantitative assessment for architecture were scoredfollowing the international definitions for the capillary abnormalities.2 Quantitative assessment consist in the measurement of the number of capillaries per millimeter, capillary loop length, capillary width,  intercapillary distance  in  micron (μm)³.

Results: Twenty four patients with JDM were included, 62.5% female. The qualitative assessment  reveal only 4  images  with normal capillaroscopy pattern,   nonspecific alterations  were found in  31.2%.

Conclusion: VCP is a noninvasive image method that’s provides a window to microcirculation and allows quantitative assessment of nailfold capillaries with a grave reliability and gave reproducible results. This study found more quantitative alterations than previously reported. A combination of qualitative and quantitative measures can be used for JDM diagnosis, monitoring and response to treatment.

To our knowledge this study is the first in measuring quantitative, semi-quantitative and qualitative parameters of the microvasculature in juvenile dermatomyositis.

Disclosure of Interest

None Declared

Table 1 (abstract P027). See text for description

P028 EMERGING UNIQUE IMMUNE SIGNATURES FOR THE IDIOPATHIC INFLAMMATORY MYOPATHIES: SIMILARITIES AND DIFFERENCES COMPARING ADULT AND JUVENILE DISEASE

Meredyth Wilkinson^1,2, Anna Radziszewska², Elizabeth Jury³, Jessica Manson⁴, David Isenberg³, Centre for adolescent rheumatology biobank

¹IIR, Great Ormond Street Institute of Child Health; ²Centre for adolescent rheumatology, Division of Medicine; ³Rheumatolgy, Division of Medicine, UCL; ⁴Rheumatology, UCLH, London, UK

Correspondence: Meredyth Wilkinson

Introduction: The inflammatory idiopathic myopathies (IIM) are a rare group of myopathic autoimmune diseases diagnosed in both adults and children. Patients’ present with proximal muscle weakness with associated skin changes in dermatomyositis. Immunohistochemical analysis of muscle tissue from these patients has identified immune cell infiltrate and the expression of pro-inflammatory cytokines however, little is known about the peripheral immunological profile in juvenile and adult patient groups.

Objectives: To identify specific immune cell signatures and cytokine profiles for disease subtypes and correlate this data with measurements of disease activity.

Methods: 44 adult myositis (AM) patients, 15 Adolescent-onset juvenile dermatomyositis (JDM) patients, 25 age-matched adult healthy controls (AHC), and 15 age-matched teenage healthy controls (THC) were recruited with appropriate ethical approval after obtaining written informed consent. Peripheral blood mononuclear cells (PBMC) were isolated from patient and control samples. PBMC from all groups were analysed by flow cytometry to quantify 32 lymphocyte populations including; T-cell, B-cell and monocyte subsets. The AM patients were grouped according to myositis subtype; 19 dermatomyositis (DM), 9 polymyositis (PM), 7 DM + overlap, 4 DM + cancer and 5 PM + overlap). Disease activity was determined by MITAX score and clinicians’ decision on treatment; remission off treatment, remission/mildly active/active on treatment. Cell populations were analysed by group for differences in fold change/adjusted p value (1-way ANOVA with Tukey’s multiple comparison).

Results: There was an idenified T cell signature in ADM (increased Th17, Tregs and CD4+ naïve), a B cell signature in APM (CD27+/- B cell ratio) and a T cell signature in JDM (CD4/CD8+ T cell ratio). A decrease in CD8+ central memory T-cells was observed in both AM and JDM patients compared to healthy controls, this reduction was most significant in active disease. AM patients also had reduced CD27+ memory B-cells compared to both JDM patients and healthy controls. AM patients in remission off treatment had increased non-classical monocyte subset frequencies, whereas JDM patients off treatment had elevated CD8+ EMRA T-cells. Th17 cells were significantly increased in ADM compared to JDM samples (mean = 3.68 vs. 0.64, adjusted p value = 0.0032). More specifically increased Th17 cells were found in ADM but not APM (mean = 3.67 vs. 0.68, adjusted p value = 0.0019). However, the Th17 population was highest in AM patients that were in remission on treatment (remission on treatment vs AHC, mean = 2.68 vs. 0.84, adjusted p value = 0.038).

Conclusion: This group of diseases are notably heterogeneous both clinically and immunologically as shown by the complex immunophenotyping patterns identified within myositis subgroups. This study identified signatures unique to adult compared to juvenile disease, and between AM patients on treatment and during remission. The Th17 signature concurs with studies pinpointing these cells within the muscle tissue. This data supports the need for further investigation for the use of IL-17A inhibitors in the treatment of the IIM.

Disclosure of Interest

None Declared

P029 VALIDATION OF THE EULAR/ACR CLASSIFICATION CRITERIA FOR JUVENILE IDIOPATHIC INFLAMMATORY MYOSITIS IN JAPAN

Kazuko Yamazaki¹, Akiko Ohta², Shinji Akioka³, Tomo Nozawa⁴, Asami Ohara⁴, Haruna Nakaseko⁵, Yuichi Yamasaki⁶, Norimoto Kobayashi⁷, Yutaka Nishida⁸, Satoshi Sato⁹, Shunichiro Takezaki¹⁰, Naomi Iwata⁵, Ichiro Kobayashi¹⁰, Masaaki Mori¹¹

¹Pediatrics, Saitama Medical Center, Saitama Medical University, Kawagoe; ²Division of Public Health, Department of Social Medicine, Saitama Medical University Faculty of Medicine, Moroyama; ³Pediatrics, Kyoto Prefectural University of Medicine, Kyoto; ⁴Pediatrics, Yokohama City University School of Medicine, Yokohama; ⁵Infection and Immunology, Aichi Children’s Health and Medical Center, Ohfu; ⁶Pediatrics, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima; ⁷Pediatrics, Shinshu University School of Medicine, Matsumoto; ⁸Pediatrics, Gunma University Graduate School of medicine, Maebashi; ⁹ Infectious Diseases and Immunology, Saitama Children's Medical Center, Saitama; ¹⁰Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo; ¹¹Lifetime Clinical Immunology, Tokyo Medical and Dental University, Tokyo, Japan

Correspondence: Kazuko Yamazaki

Introduction: There are various diagnostic and classification criteria for myositis, but they are not always suitable for juvenile idiopathic inflammatory myositis (JIIM). To establish standard diagnostic criteria, the International Myositis Classification Criteria Project (IMCCP) published the EULAR/ACR classification criteria for idiopathic inflammatory myositis (IIM) in 2017.

Objectives: To evaluate the validity of the EULAR/ACR classification criteria with JIIM cases in Japan.

Methods: We used clinical and laboratory data from a group of JIIM patients and a comparator group comprised of non-JIIM patients with mimicking conditions collected at seven major pediatric rheumatology centers in Japan between 2008 and 2015. A diagnostic confirmation made at least 6 months prior to the study by a pediatric rheumatologist was used as the inclusion criterion for this study.

Results: The total of 117 patients (68 JIIM patients and 49 non-JIIM patients) were included to the study. For the validation analysis, we applied 55% probability cutoff, which corresponds to “probable IIM”, based on the IMCCP study. The IMCCP’s diagnostic standard gave us an almost equivalent sensitivity (86.7% without muscle biopsies; 92.1% with muscle biopsies) and a higher specificity (100% without/with muscle biopsies) compared to the data reported in the IMCCP study. We also confirmed an improved sensitivity with the EULAR/ACR classification criteria, compared to other traditional diagnostic criteria (e.g. 86.7 % with the EULAR/ACR criteria vs 80.9% with the Bohan and Peter criteria). In terms of the diagnostic accuracy, the agreement proportions between the classification subgroups of the EULAR/ACR criteria and the physician-diagnosed subgroups in our dataset were 100% for Juvenile amyopathic dermatomyositis (DM) and Juvenile hypomyopathic DM. The proportions were 93.2% for JDM and 43.2% for Juvenile polymyositis (JPM), for seven cases (3 JDM patients and 4 JPM patients) were not properly classified as JIIM.

Conclusion: Our validation study with Japanese JIIM cases indicates that the EULAR/ACR classification criteria for IIM generally perform better than existing diagnostic criteria for myositis in diagnosing JIIM.

Disclosure of Interest

None Declared

Juvenile dermatomyositis

P030 A CHILD WITH SEVERE NXP2-POSITIVE JUVENILE DERMATOMYOSITIS SUCCESSFULLY TREATED WITH RUXOLITINIB

Florence A. Aeschlimann¹, Marie-Louise Fremond^1,2, Darragh Duffy³, Gillian I. Rice⁴, Jean-Luc Charuel⁵, Vincent Bondet³, Benedicte Neven¹, Christine Bodemer⁶, Laurent Balu⁷, Anne Hulin⁸, Cyril Gitiaux⁹, Yanick J. Crow², Brigitte Bader-Meunier^1,10

¹Pediatric Immunology, Hematology and Rheumatology, Necker - APHP; ²Laboratory of Neurogenetics and Neuroinflammation, INSERM UMR 1163; ³Immunobiology of Dendritic Cells, Institut Pasteur, Paris, France; ⁴Division of Evolution and Genomic Sciences, Manchester Academic Health Science Centre, Manchester, UK; ⁵Laboratory of Immunology, La Pitié-Salpêtrière; ⁶Dermatology and Pediatric Dermatology, Necker - APHP, Paris; ⁷Pediatrics, CHU de La Réunion, Saint Denis; ⁸Pharmacology and toxicology laboratory, Mondor, Créteil; ⁹Pediatric Neurolophysiology and referral center for neuromuscular diseases, Necker - APHP; ¹⁰Laboratoty of Immunogenetics of paediatric autoimmune diseases, INSERM UMR 1163, Paris, France

Correspondence: Florence A. Aeschlimann

Introduction: Juvenile dermatomyositis (JDM) is a rare and heterogeneous inflammatory myopathy. Clinical features may be severe and disease course refractory to standard treatment with corticosteroids and methotrexate (MTX). Evidence for a critical role of the type I interferon (IFN) pathway in the pathophysiology of dermatomyositis exists in both childhood and adult forms of the disease.

Objectives: To report the first case of severe vasculopathic JDM successfully treated with the JAK 1/2 selective inhibitor ruxolitinib.

Methods: Retrospective chart review from initial presentation to last follow-up. We assessed type I IFN status by IFNα digital-ELISA quantification in serum, STAT1 phosphorylation and RNA expression of IFN-stimulated genes in whole blood.

Results: A previously healthy 13-year-old girl presented with cutaneous lesions and a severe proximal muscle weakness (Childhood Muscular Assessment Score, CMAS 2/52, and Manual Muscle Testing, MMT 38/80) characteristic of JDM. CK level was elevated and anti-NXP2 antibodies positive. Muscle biopsy revealed severe vasculopathic lesions. Despite treatment with prednisone (1.2mg/kg/day) and MTX, she developed tetraplegia, dysphonia, dysphagia, intestinal involvement, and new skin lesions. Treatment escalation with IVIG, plasma exchange (5/week), rituximab, and increased prednisone resulted in clinical improvement. Thus, plasma exchanges were subsequently spaced out and discontinued 6 months after diagnosis. However, three weeks later, recurrent muscle weakness necessitated the restart of plasma exchanges, increase of prednisone, a 4^th dose of rituximab, and initiation of mycophenolate mofetil (MMF). While prednisone and the frequency of plasma exchanges were slowly tapered, she developed two further muscular, cutaneous and intestinal relapses, as well as a diffuse fascia calcinosis, at 12 and 18 months after diagnosis. High levels of IFNα protein in the serum (238, 75, and 46 fg/mL, normal < 10 fg/mL) and an increased expression of ISGs were documented. A constitutive phosphorylation of STAT1 and STAT3 was recorded in T lymphocytes and monocytes from the patient compared with controls. Considering these results, ruxolitinib was started (10mg x 2/day). Rituximab and MMF were discontinued. Within 2 months, CMAS and MMT scores increased from 47 to 52 and from 57 to 79, respectively. Plasma exchanges were discontinued and prednisone decreased. Eight months post initiation of ruxolitinib, JDM was clinically inactive according to the PRINTO criteria and prednisone was tapered (0.15mg/kg/day). Ruxolitinib was well tolerated. Serum levels of IFNα stabilized and STAT1 phosphorylation in monocytes was comparable to a control 4 hours after drug intake. Informed parental consent was obtained for the use of ruxolitinib on a compassionate basis and for conducting the experiments.

Conclusion: Efficacy of JAK1/2 inhibitors has previously been reported for severe dermatomyositis in adults and for certain monogenic interferonopathies in children. Our findings suggest that JAK inhibition may also represent an efficacious and well-tolerated therapeutic option in a subset of patients with recalcitrant JDM. Informed consent for publication had been obtained from the parents.

Disclosure of Interest

None Declared

P031 UNDERSTANDING THE LIVED EXPERIENCE OF JUVENILE DERMATOMYOSITIS

Polly Livermore^1,2, Suzy Gray³, Kathleen Mulligan⁴, Jennifer Stinson⁵, Lucy R. Wedderburn⁶, Faith Gibson^7,8

¹Institute of Child Health, University College London Great Ormond Street Institute of Child Health; ²Orchid, Nursing Research, Great Ormond Street Hospital for Children; ³Psychology/Rheumatology, Evelina Hospital; ⁴School of Health Sciences, City, University of London, London, UK; ⁵Chronic Pain, Hospital for Sick Children, Toronto, Canada; ⁶Rheumatology/NIHR GOSH Biomedical Research Centre, University College London Great Ormond Street Institute of Child Health, London; ⁷Nursing Research, University of Surrey, Surrey; ⁸Orchid, Nursing Research, Great Ormond Street Hospital for Children, London, London, UK

Correspondence: Polly Livermore

Introduction: Juvenile Dermatomyositis (JDM) is a rare, potentially life threatening condition. Beginning with mild fatigue and weakness, the condition can occur at any age, and currently there is no known cure. Some children and young people can experience fluctuations between remission and relapse throughout their childhood, into adolescence and beyond. There is very little evidence about the psychological impact this condition has on children and young people, and none that has asked them directly, however, through experience from clinical practice and conversations with those affected, we know the effects can be profound.

Objectives: The aim of this study was to identify the lived experience of children and young people between the ages of 8 and 19 years of age diagnosed with JDM. This study constitutes the first part of a larger mixed-methods study.

Methods: Ethical approval was gained to interview children and young people who were enrolled in a wider cohort study. Young people were interviewed either using creative arts based methods, such as drawing in a comic book and parallel discussion, or with a standard verbal interview. Young people were all asked: ‘what it is like to have JDM?’ Further questions were used to probe or to add clarity. Interviews took place when attending a specialist Rheumatology clinic or the inpatient Rheumatology Ward of a tertiary specialist Rheumatology Centre or during a specially arranged home visit.

Results: Fifteen young people offered to share their story, their demographics are shown in Table 1. The interviews lasted between 18 to 130 minutes and all, with permission, were audio recorded. They were transcribed verbatim and analysed using Interpretive Phenomenology.

The overarching metaphor of a ‘Rollercoaster’ was developed from the interview transcripts, to depict the ups and downs of having JDM. From initial difficulties with diagnosis by local health professionals of a rare disease to feeling comfort at getting a diagnosis, to the low of not being able to walk, to the relief when medications start to work and some improvement is felt. The ‘Rollercoaster’ metaphor is visual, easy to explain and understand, and will allow young people to feel some support from seeing the journey ahead.

Within this overarching construct, there are five themes which emerged from the data. These are: being-confused in the beginning; being-different; sick-steroidal-and-scared of the medicines; being-uncertain; and having-acceptance, as the JDM journey continues for many years.

Conclusion: This study is the first to ask children and young people what it is like to have JDM, and to recount the ‘ups and downs’ of their lives and describe the ways that JDM affects them. The results from this study will lead to a wider study asking young people all over the United Kingdom to share their story through surveys examining aspects which have been highlighted so far, this will lead into dissemination workshops to share the results found not only with children, young people and their families, but also with health professionals.

Disclosure of Interest

P. Livermore Grant / Research Support from: Doctoral Nursing Fellowship funded by NIHR HEE/CDRF, S. Gray: None Declared, K. Mulligan: None Declared, J. Stinson: None Declared, L. Wedderburn Grant/Research Support from: NIHR GOSH BRC & Arthritis Research UK, F. Gibson: None Declared

Table 1 (abstract P031). Demographics of the 15 young people interviewed

P032 DISTINCT CLINICAL FEATURES BETWEEN ADULT AND JUVENILE DERMATOMYOSITIS PATIENTS

A. T. Melo^1,2, S. Sousa³, A. Cordeiro³, I. Cordeiro^1,2, P. Costa-Reis⁴, F. Oliveira-Ramos^1,2, J. E. Fonseca^1,2, R. Campanilho-Marques^1,2

¹Unidade de Reumatologia Pediátrica, Serviço de Reumatologia e Doenças Ósseas Metabólicas, Hospital de Santa Maria, CHLN, Centro Académico de Medicina de Lisboa; ²Unidade de Investigação em Reumatologia, Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Centro Académico de Medicina de Lisboa, Lisboa; ³Serviço de Reumatologia, Hospital Garcia de Orta, Almada; ⁴Serviço de Pediatria, Hospital de Santa Maria, CHLN, Lisboa, Portugal

Correspondence: A. T. Melo

Introduction: Adult and juvenile patients share several hallmark features of dermatomyositis (DM) but important clinical differences may reflect different disease triggers between children and adults.

Objectives: We aimed to compare the disease characteristics between children with juvenile dermatomyositis (JDM) and adults with DM and to explore the presence of nailfold capillaroscopy (NFC) changes abnormalities between the two populations.

Methods: Data were analyzed from children and adults who met Bohan-Peter criteria for DM. Childhood Myositis Assessment Scale (CMAS), Manual Muscle Testing (MMT8), muscle enzymes and physicians global assessment (PGA) were recorded at the time of last clinical appointment. Skin disease was assessed using modified skin disease activity score (DAS). By NFC was assessed nailfold capillary density, capillaries shape, presence of hemorrhage and neovascular pattern. Fisher's test was used to test differences between categorical variables and Mann-Whitney U test for continuous not-normally distributed variables.

Results: In total 23 patients were analyzed and compared (13 JDM and 10 adult DM). The female:male ratio was 9:4 in JDM and 9:1 in DM. The median age at disease onset was 5.6 years [2.7-10.1] for JDM and 50.6 years [43.3-60.4] for adult DM, the median disease duration was 8.4 years [4.4-15.38] for JDM and 2.3 years [1.2-12.5] for adult DM (p=0.1) and the median time of disease follow-up was 6.7 years [4.3-9.3] for JDM and 2.3 years [1.3-11.3] for adult DM. Table 1 reports the clinical characteristics for both groups. Adult DM had a significantly higher proportion of lung involvement and ANA positivity compared with JDM (p=0.002 and p=0.02, respectively). Dilated capillaries, giant capillaries, hemorrhage and neovascular pattern were found in 86%, 0%, 29% and 14% of JDM patients, respectively, and in 71%, 26%, 43% and 29% of adult patients, respectively, but with no statistically significant difference between children and adults. Clinically inactive disease was found in 38% and 10% of JDM and adult DM patients, respectively. All of those children have stopped medication. There was one case of malignancy in an adult DM patient.

Conclusion: Nailfold microvascular abnormalities were found in most of the NFC parameters, in JDM patients assessed for after a median of 8 years of disease, which might reflect the long-term microangiopathy associated with this disease. Regarding the studied clinical features, in our cohort, the adult DM patients have higher lung involvement when compared to JDM.

Disclosure of Interest

None Declared

Table 1 (abstract P032). Clinical characteristics of children with JDM and adults with DM

P033 JUVENILE DERMATOMYOSITIS: DESCRIPTION OF A COLOMBIAN COHORT

Angela C. Mosquera¹, Clara Malagon¹, Maria del Pilar Gomez², Tatiana Gonzalez³, Ricardo Yepez², Camilo Vargas⁴, on behalf of GRIP and Grupo de Reumatología e Inmunología Pediátrica (GRIP) Colombia

¹Pediatric Rheumatology, UNIVERSIDAD EL BOSQUE, Bogota; ²Pediatric Rheumatology, Postgraduate of pediatrics, Libre University, Cali; ³Pediatric Rheumatology, Postgraduate of pediatrics, Cartagena University, Cartagena; ⁴Pediatric Rheumatology, Postgraduate of pediatrics, Del Valle University, Cali, Colombia

Correspondence: Angela C. Mosquera

Introduction: Idiopathic myopathies are heterogeneous disorders characterized by muscle weakness and inflammation. Dermatomyositis is the most frecuent subgroup in pediatrics. Juvenile Dermatomyositis (JDM) in addition to muscle involvement is characterized by typical skin rashes (Gottron´s sign and heliotrope rash). Recently, a new proposal of diagnostic criteria was presented but patients at debut may had a great variety of manifestations due to the multisystemic nature of this condition. Close to the diagnosis and in the long term, a great variety of complications can occur and affect the survival and the quality of life of patients

Objectives: To descrive debut and course of a group of Colombian patients with Juvenile dermatomyositis

Methods: Multi-center, retrospective, descriptive, case series study. The review of medical records with a unique format was carried out in Bogotá, Cali, Cartagena and Barranquilla. The data analysis was performed with SPSS 20

Results: N = 94 patients. 67% female with an average age at diagnosis of 7,78 years (range of 1-18 years) and follow-up time of 46 months (SD 39 months). The average time between the onset of symptoms and the definitive diagnosis was 7,6 weeks (1-60). In 37% of patients, skin manifestations preceded muscle involvement and was moderate-severe in 67%. Clinical manifestationts at debut: 88% heliotrope rash, 90% Gottron´s sing, malar erythema 78%, periungueal erythema 67%, skin ulcers 25%, 37% arthritis (31% polyarticular), pulmonary compromise 4%, vasculitis 14% fever 19% and 25% calcinosis (22% mild-moderate). Seventy five percent of patients had CPK < 5000 at debut and 49% had positive antinuclear antibodies. Monocyclic course in 53% of patients. During the follow-up 33% presented calcinosis, 44% muscular atrophy, 52% persistent muscular weakness, 14% osteoporosis and 14% short stature. 99% of patients received steroid at debut (44% intravenous) and 86% during follow-up. 97% received methotrexate and 13% required a biological medication (92% Rituximab). 70% of the patients were classified by the treating rheumatologist as adherent to the treatment and 14% of patients had associated other autoimmune diseases. Patients with mild skin involvement at debut had a higher frequency of monocyclic course (p 0,009)

Conclusion: The skin involvement can be the initial manifestation in an important percentage of patients with JDM. The severity of skin involvement can be variable and related to the type of course. JDM requires an intensive, dynamic and monitored management that allows a rapid control of the disease, monitor the appearance of short and long term complications and the association with other autoimmune diseases

Disclosure of Interest

None Declared

P034 POST-STREPTOCOCCAL POLYMYALGIA (3 CASES): PROPOSED COIMBRA CRITERIA

João Nascimento¹, Paula Estanqueiro¹, Teresa S. Simão², Manuel Salgado¹

¹Pediatric Rheumatology Unit, Hospital Pediátrico Coimbra - CHUC, Coimbra; ²Pediatrics, Hospital da Senhora da Oliveira, Guimarães, Portugal

Correspondence: João Nascimento

Introduction: Post-streptococcal syndrome consists of a wide spectrum of non-suppurative disorders: erythema nodosum, uveitis and/or scleritis, post-streptococcal glomerulonephritis, periostitis, vasculitis, rheumatic fever and post-streptococcal reactive arthritis. It can also include an entity with myalgia as the solitary presenting symptom called post-streptococcal polymyalgia (PSPM).

Objectives: To alert to clinical features of PSPM and present Coimbra classification criteria.

Methods: Retrospective study. Selection of the patients with post-streptococcal reactive polymyalgia followed in Coimbra’s pediatric rheumatology department in the last 30 years.

Patients were included based on the following criteria (all):

1) Diffuse myalgia – acute onset, incapacitating and severe pain;

2) Palpation induced muscle pain;

3) Normal serum creatine kinase (CK);

4) Supporting evidence of a recent preceding streptococcal infection (elevated streptococcal antibodies, or (+) cultures or rapid antigen tests for streptococcus groups;

5) No Exclusion criteria: a) > 1. major manifestations of the revised Jones criteria for rheumatic fever (2015); b) periostitis.

Results: The unit followed 119 children with poststreptococcal reactive musculoskeletal symptoms: 61 rheumatic fever, 55 poststreptococcal reactive arthritis and 3 had only diffuse myalgia - acute onset, incapacitating and severe pain (one girl and two boys).

The mean age at diagnosis was 5,7 years. Tonsillitis was the previous streptococcal infection in all patients (one scarlet fever). The time span between the infection and myalgia presentation had a variation between 25 and 30 days. The longest myalgia duration was nine weeks and the shortest was one week and four days. Lower limbs were involved in all patients and upper limbs in two. Arthralgia without arthritis was present in two patients. At diagnosis visual analog score (VAS) of muscle pain was ≥ 80 mm and all patients had elevation of inflammatory markers (erythrocyte sedimentation rate between 86 and 102mm/h and C-reative protein between 4,9 and 6 mg/dl) and normal creatine kinase (CK) values. The antistreptolysin O titre (ASLO) performed in all patients were strongly positive (≥ 800 U/l and ≤ 1820 U/I) and echocardiography was normal. Two patients had full recovery with NSAIDs but one refractory patient also needed prednisolone (1mg/kg) during four weeks.

Conclusion: Severe diffuse pain and tenderness of skeletal muscles without accompanying arthritis is an under-recognized feature of post-streptococcal disease. High ASLO titre with normal CPK in a child with myalgia should alert PSPM diagnosis. We propose the Coimbra diagnostic criteria for PSPM.

References

1. Jansen TL, Janssen M, Macfarlane JD, de Jong AJ. Poststreptococcal reactive myalgia: a novel syndrome secondary to infection with group A or G streptococci. Br J Rheumatol. 1998;37:1343–8

2. Subramanian S, Carty JE, Gaywood I. A rare case of recurrent poststreptococcal myalgia. Rheumatology. 2002;41:827–8

3. Arun Babu T, Venkatesh C. Post Streptococcal Myalgia: An Under-recognized Clinical Syndrome. Indian J Pediatr. 2012; 79(3):383–385

Disclosure of Interest

None Declared

P035 EFFECTIVENESS OF ULTRASONOGRAPHY FOR MYOSITIS SCREENING IN CLINICALLY AMYOPATHIC JUVENILE DERMATOMYOSITIS: A CASE SERIES

Kazutaka Ouchi^1,2, Shinji Akioka¹, Hiroshi Kubo¹, Norio Nakagawa¹, Hajime Hosoi¹

¹Pediatrics, Kyoto Prefectural University of Medicine, Kyoto; ²Pediatrics, Ayabe city hospital, Ayabe, Japan

Correspondence: Kazutaka Ouchi

Introduction: Juvenile dermatomyositis (JDM) is a systemic autoimmune capillary vasculopathy that predominantly affects the muscles and cutaneous tissues. In JDM cases, myosonography can reportedly be used to evaluate disease activity and perform follow-up monitoring. However, the effectiveness of myosonography in clinically amyopathic JDM (CA-JDM) is undetermined.

Objectives: To investigate the myosonographic findings in patients with CA-JDM.

Methods: Myosonography was performed in three patients with CA-JDM. Case 1 was a 2-year-old male with full range of motion in manual muscle testing (MMT), positive anti-TIF-1γ antibody results, and superficial perivascular dermatitis; case 2 was a 4-year-old male with full range of motion in MMT, negative myositis-specific autoantibody results, and superficial perivascular dermatitis; case 3 was a 14-year-old female with full range of motion in MMT, positive anti-MDA5 antibody results, interstitial pneumonia, and superficial perivascular dermatitis. Case 3 had minimal evidence of myositis on MRI and in a biopsied specimen. Laboratory testing revealed normal creatinine kinase concentration in all three cases. The ultrasonographic assessment was performed in the bilateral biceps brachii and quadriceps femores.

Results: In case 1, the right biceps and quadriceps had increased echo intensity compared with the left side, and the power Doppler signal was positive on the perimysium in the left biceps and quadriceps. In case 2, the echo intensity was increased in the bilateral biceps and quadriceps, and there was a positive power Doppler signal on the perimysium in all muscles. In case 3, there was a high echo intensity and positive power Doppler signal on the perimysium in the left quadriceps, and there was a suspected positive power Doppler signal on the epimysium in the left quadriceps.

Conclusion: Myosonography detected muscle abnormalities in CA-JDM. Myosonography may be effective for JDM screening in patients with no clinical muscular abnormalities who are suspected of having JDM due to skin characteristics. Informed consent to publish had been obtained from the parents.

Disclosure of Interest

None Declared

Vasculitides I

P036 EARLY FEATURES OF KAWASAKI DISEASE WITH PYURIA IN FEBRILE INFANTS YOUNGER THAN 6 MONTHS

Jong Gyun Ahn¹, Young Dae Kim², Kwang Nam Kim³

¹Department of Pediatrics, Severance Children's Hospital, Yonsei University College of Medicine, Seoul; ²Department of Pediatrics, Ilsan Paik Hospital, Inje University College of Medicine, Goyang; ³Department of Pediatrics, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Korea, Republic Of

Correspondence: Jong Gyun Ahn

Introduction: Children with Kawasaki disease (KD) and pyuria have been misdiagnosed with urinary tract infection (UTI).

Objectives: We compared clinical and laboratory features at admission between two groups of infants under 6 months of age, who showed initial pyuria, to find useful clinical clues to the initial suspicion of KD.

Methods: We reviewed the medical records of febrile infants under 6 months of age with pyuria over a 10-year period (2007-2017). We included infants with sterile pyuria who were finally diagnosed with KD and those with UTI.

Results: During the 10-year study period, a total of 121 patients under aged 6 months were diagnosed as KD. 41 (33.9%) of the 121 KD children had pyuria. Of the 41 pyuria patients, 12 had sterile pyuria, 7 had concomitant UTI, and 16 had combined bacterial growth which had to be excluded. The other 6 patients were unidentified because they did not perform the urine culture tests. Two patients satisfied the diagnostic criteria of complete Kawasaki disease, whereas the others were diagnosed with incomplete Kawasaki disease.

During the same period, 378 infants under 6 months of age were diagnosed with UTI. We compared the clinical and laboratory features between the 12 KD infants with sterile pyuria and the 378 UTI infants. The median age of the KD group (5.2 months; range,2.5-5.9 months) was higher than that of the UTI group (3.6 months; range 0.9-6 months) (P =.002). The male/female ratios in the KD and UTI infants were 1.4 (7/5), and 2.8 (277/101), respectively.

The days of fever before admission and total duration of fever were longer in the KD group than in the UTI group (P < 0.01). Compared with the UTI group, the KD group demonstrated a significantly higher platelet count (P = .04), level of C-reactive protein (CRP) (P < 0.01) and erythrocyte sedimentation rate (ESR) (P < 0.01). UTI group showed higher presence of positive urine nitrite test (P < 0.01). No significant differences were evident in blood leukocyte count, absolute neutrophil count, haemoglobin, alanine transaminase, aspartate aminotransferase, albumin, sodium, total bilirubin and urine β2-microglobulin (β2-MG)

Conclusion: Our study can provide early clues to suspect KD in febrile infants with pyuria.

Disclosure of Interest

None Declared

P037 ACUTE PANCREATITIS ASSOCIATED WITH TWO COMMON CHILDHOOD VASCULITIS: KAWASAKI DISEASE AND HENOCH-SCHÖNLEIN PURPURA

Nuray Aktay Ayaz, Gul Karadag, Ayse Zopcuk

Pediatric Rheumatology, Saglik Bilimleri University KSSEAH, Istanbul, Turkey

Correspondence: Nuray Aktay Ayaz

Introduction: Henoch Schönlein purpura (HSP) and Kawasaki disease (KD) are the most common childhood vasculitis. Rare conditions like pancreatitis, aseptic menengitis, pneumonia do not belong to the classical criteria of KD and defined as atypical KD. Similarly gastrointestinal involvement are excepted features of HSP. Few cases of HSP and KD related pancreatitis have been reported. Herein, we report two acute pancreatitis cases associated with KD and HSP.

Objectives: A 10-year-old boy consulted with a 6-days history of fever, abdominal pain, vomiting and a scarlatiniform rash. Initial blood tests showed Hb 9.7 g/dl, WBC 14.2 × 10 ⁹/L, platalet count 442 ×10 ⁹/L, C-reactive protein 68.8 mg/L, erythrocyte sedimentation rate 65 mm/hr, albumine: 2.8 g/dL, increased amylase of 639 U/L and lipase 2056 U/L. In echocardiographic examination myocarditis was seen and pro-BNP level was 11418 pg/ml. Intravenous immünoglobulin (IVIG) at a dose of 2 g/kg and aspirin 40 mg/kg/day was given with a preliminary diagnosis of atypical Kawasaki disease. The patient became afebrile 24 hours later. In the second week of the disease thrombocytosis (platelet count, 780 ×10 ⁹/L) and periungual desquamation of his fingers and toes were observed. Coronary arteries were normal and cardiac contractions were good in echocardiography. His pancreatitis had resolved with a normal amylase of 97 U/L and lipase of 29 U/L within two weeeks.

Methods: A 6-year-old girl was referred with a 4-days history of vomiting and abdominal pain. Her physicial examination was normal except abdominal tenderness. Initial investigations showed Hb 14.4 g/dl, WBC 41.8 × 10 ⁹/L, platalet count 443 ×10 ⁹/L, C-reactive protein 50.6 mg/L, erythrocyte sedimentation rate 1mm/hr, albumin: 1.9 g/dL. In abdominal ultrasonograpy hydrops of gallbaldder was detected. Few days later purpuric rash on her legs was observed. She was diagnosed as HSP and prednisolone at a dose of 2 mg/kg/day was given to her. Despite steroid treatment, back and chest pain added to abdominal pain. Increased amylase of 344 U/L and lipase 294 U/L levels were detected at the seventh day of disease, but ultrasonographic pancreatitis was not observed. In addition to fat free diet intravenous fluids and pulse steroid treatment (30 mg/kg, for 3 days) was given. In the second week of the disease proteinüria was detected in 24 hour urine testing, and mesengioproliferative glomerulonephritis was diagnosed in renal biopsy. Pulse cyclophosphamide treatment was started her for HSP nephritis. Her pancreatitis resolved within a month

Results: HSP and KD are most common types of vasculitis in children. But, HSP and KD associated pancreatitis is uncommon. There are autopsy studies about KD associated pancreatitis. The association between pancreatitis and HSP is rare.

Conclusion: In conclusion HSP and KD related pancreatitis is rare. HSP-related pancreatitis should be considered when abdominal pain is prolonged and present with changing character of pain. KD should be considered in the presence of acute pancreatitis and prolonged fever even the patient does not meet all the criteria. Informed consent to publish had been obtained.

Disclosure of Interest

None Declared

P038 CAN WE PREDICT THE COURSE OF KAWASAKI DISEASE: A SINGLE CENTER SERIES FROM THE EASTERN MEDITERRANEAN

Elif Arslanoglu Aydin¹, Erdal Sag², Selcan Demir², Hafize E. Sönmez², Ezgi D. Batu², Yelda Bilginer², Seza Ozen²

¹Department of Pediatrics; ²Division of Pediatric Rheumatology, Department of Pediatrics, Hacettepe University, Ankara, Turkey

Correspondence: Elif Arslanoglu Aydin

Introduction: Kawasaki disease (KD) is one of the most common vasculitis of childhood. Coronary artery involvement is the most important complication of the disease and the major cause of the mortality. IVIG resistance is defined as persisting or recurring fever at least 36 hours after the end of intravenous infusion of immunoglobulin (IVIG). Although there are some scoring systems trying to predict, it is not always possible to forsee the IVIG resistance and coronary artery involvement.

Objectives: The aim of this study is to assess the success of the Kobayashi scores and other parameters in predicting IVIG resistance and coronary artery involvement in Turkish population.

Methods: Patients who were diagnosed in the acute phase of Kawasaki disease at Hacettepe University Faculty of Medicine (Ankara,Turkey) between June 2007- January 2016 were retrospectively and January 2016- February 2018 were prospectively reviewed and included in this study. Clinical findings, laboratory parameters, echocardiographic findings, response to IVIG treatment, Kobayashi, Egami, Formosa, Harada scores were evaluated. The diagnosis of Kawasaki disease was made using the criteria of the American Heart Association.

Results: A total of 100 patients with Kawasaki disease were included in this study. Of the patients with KD, 61 (61 %) were male and 39 (39%) were female. The mean age at diagnosis of Kawasaki disease was 48.9 ± 34.9 months, with an age range of 4–164 months. All of the patients had fever while, 77 (77%) of them had conjunctival congestion, 74 (74%) of them had mucosal, 72 (72%) of them had rash, 69 (69%) of them had lymphadenopathy and 68 (68%) of them had extremity changes. Fifty two (52%) patients had complete KD and 48 (48%) patients had incomplete KD.

Patients younger than 1 year (p<0,001) were found to be associated with a significantly higher risk for coronary artery involvement. No significant differences were found between the IVIG-resistant and IVIG-responsive groups in terms of age (p:0.215).

Significant differences were found between the coronary artery lesions (CAL) and non-CAL groups in terms of age, white blood cell and erythrocyte sedimentation rate.

Compared with the IVIG-responsive group, the IVIG-resistant group had higher C-reactive protein (CRP) and gamma glutamyl transferase (GGT) levels.

Of the 100 patients who were administered IVIG, 85 (85%) responded to IVIG treatment, whereas 15 (15%) were IVIG resistant. Coronary artery involvement was detected in echocardiography at diagnosis in 38 patients. Twenty patients had Kobayashi high-risk scores, 9 patients had Egami high risk scores. The Formosa score assigned 45 patients as high-risk. The Harada score assigned 54 patients as high-risk. Only the Egami score predicted IVIG resistance in the Turkish population, none predicted coronary artery involvement.

Conclusion: Studies from different countries revealed that the risk scores were incapable of defining the IVIG resistance in KD. This may be atributed to ethnic differences. The Kobayashi score, Harada score, Formosa score in Turkish population did not predict the IVIG resistance and coronary artery involvement, but high white blood cell count, high erythrocyte sedimentation rate and age ≤1 were associated with coronary artery involvement; high CRP, high GGT, and Egami score are associated with IVIG Resistance in Turkish population.

Disclosure of Interest

None Declared

P039 EOSINOPHILIC GRANULOMATOSIS WITH POLYANGIITIS-A CLINICAL CASE

Ana Barbosa Rodrigues¹, Filipa Oliveira Ramos^2,3, Patrícia Costa Reis^1,3

¹Pediatrics Department, Hospital de Santa Maria, Centro Académico de Medicina de Lisboa; ²Pediatric Rheumatology Unit, Rheumatology Department, Centro Académico de Medicina de Lisboa Hospital de Santa Maria; ³Unidade de Investigação em Reumatologia, Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Centro Académico de Medicina de Lisboa, Lisbon, Portugal

Correspondence: Ana Barbosa Rodrigues

Introduction: Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare small and medium-sized-vessel vasculitis characterized by the presence of vasculitis manifestations and eosinophilia in a previously asthmatic patient.

Objectives: Increase awareness for the diagnosis of EGPA and discuss possible treatment strategies.

Methods: Description of a patient with EGPA.

Results: 13-year-old male with allergic rhinitis, asthma and history of dust mite allergy, under therapy with montelukast and inhaled and nasal corticosteroid, with multiple episodes of wheezing and shortness of breath in the last year. The patient presented to the emergency department after seven days of arthralgias, myalgias and asthenia and two days of fever. On physical exam a diffuse petechial rash with hemorrhagic suffusions was detected. Blood tests revealed hemoglobin 15.9g/dL, leukocytes 34990/μL, neutrophils 27.4%, eosinophils 63.2%(23160/μL), platelets 202000/μL, C-reactive protein (CRP) 10.56mg/dL, ALT 129UI/L, AST 92UI/L, LDH 529UI/L and CK 515UI/L. Ceftriaxone and doxycycline were started and the patient was admitted to the hospital. Blood cultures were negative, as well as the aspergillus galactomannanantigen and serologies for Rickettsia conori, erlichia, brucella, leptospira, cytomegalovirus, Ebstein Barr virus, parvovirus, adenovirus, cocsakie and echovírus.  Within 72 hours a deterioration of the clinical status was observed. The patient had dyspnea, chest pain, signs of respiratory distress, hypoxemia, tachycardia, hipotension and olyguria. It was detected leukocytosis 48390/μL, eosinophilia 30000/μL and elevated CRP 16.5mg/dL, CK 962 mg/dL, troponin 1686ng/L and NT-proNBP 14800pg/mL. Tryptase was normal (3.9mcg/L). Bilateral pulmonary insterstitial infiltrates with bilateral pleural effusion were identifed on chest x-ray and ECG and echocardiogram were suggestive of myopericarditis. The patient was admitted to the pediatric intensive care unit. Antibiotherapy was switched to vancomicin plus meropenem and anti-inflammatory drugs, furosemide, espironolactone and immunoglobulin were started. Due to hemodinamic instability, mechanic ventilation and  aminergic support were needed. Further exams were performed: bronchoalveolar lavage was negative for bacteria and fungi; myelogram showed hypercellular medulla with increased non-clonal eosinophils (41%); skin biopsy revelead leukocytoclastic vasculitis with eosinophils and direct immunofluorescence compatible with vasculitis. Anti-myeloperoxidase (MPO) antineutrophil cytoplasm antibodies (ANCA) were negative. The genetic analysis for hypereosinophilia syndrome mutations was negative. The pediatric rheumatology team was called to observe the patient and, according to the clinical presentation and laboratory results, the diagnosis of EGPA was made. The patient was started on methylprednisolone i.v. 1 g per day for three days. A fast clinical, laboratory and radiological improvement occurred, including complete regression of eosinophilia. Currently, more than six months after this episode, the patient is followed at the pediatric rheumatology outpatient clinic and there are no signs of disease activity under therapy with azathioprine (2mg/kg) and prednisolone in progressively lower doses.

Conclusion: We present a patient with EGPA, fulfilling 5 of 6 criteria (asthma, eosinophilia exceeding 10% of the total white blood cell count, history of allergy, pulmonary infiltrates, extravascular eosinophils), associated with musculoskeletal and cardiac abnormalities and negative anti-MPO ANCA. In conclusion, EGPA is a potentially life-threatening condition, clinical suspicion and early treatment of these patients are thereby crucial.

For this case submission written informed consent was obtained from the patient and family.

Disclosure of Interest

None Declared

P040 HENOCH-SCHÖNLEIN PURPURA NEPHRITIS IN CROATIAN CHILDREN: A RETROSPECTIVE STUDY IN FIVE TERTIARY CARE CENTERS

Mateja Batnozic Varga¹, Nastasia Cekada², Mario Sestan², Sasa Srsen³, Lucija Ruzman⁴, Maja Zaninovic⁴, Aleksandar Ovuka⁴, Ivana Ozdanovac¹, Marija Pecnjak⁵, Domagoj Kifer⁶, Marijan Frkovic², Alenka Gagro⁷, Marija Jelusic²

¹Department of Paediatrics, University Hospital Centre Osijek, Osijek; ²Department of Paediatrics, University Hospital Centre Zagreb, University of Zagreb, School of Medicine, Zagreb; ³Department of Paediatrics, University Hospital Centre Split, Split; ⁴Department of Paediatrics, University Hospital Centre Rijeka, Rijeka; ⁵Department of Paediatrics, University Hospital Centre Zagreb; ⁶Faculty of Pharmacy and Biochemistry, University of Zagreb; ⁷Children's Hospital Zagreb, Zagreb, Croatia

Correspondence: Mateja Batnozic Varga

Introduction: Henoch-Schönlein purpura nephritis (HSPN) is the most severe complication of Henoch-Schönlein purpura (HSP) that can occur at any time of the disease process and includes isolated microscopic or macroscopic hematuria, mild or heavy proteinuria with or without nephrotic syndrome, renal failure and hypertension.

Objectives: To determine a possible prognostic factor for earlier HSPN onset, to explore indications for kidney biopsy according to urine analysis and the correlation between 24-h urinary protein levels and biopsy findings, as well as biopsy findings and patient outcome.

Methods: The cross-sectional study included all children with HSPN diagnosed by EULAR/PRES/PRINTO criteria from 2009 to 2017 at 5 tertiary care centres in Croatia.

Results: Out of 540 patients diagnosed with HSP, 91 children who developed HSPN (16.85%) were included. The patient population with HSPN included 52 boys (57.14%) and 39 girls (42.86%). Median (range) age of HSP diagnosis was 8 years (1.5-17.5) and from the HSP diagnosis to HSPN onset was 1.5 (0-60) months. Median (range) follow-up time was 44 (4-167) months. Nephritis was present in 18.68% of cases at the HSP onset. No statistically significant difference or correlation was found between the time of HSP diagnosis to HSPN onset and gender, age, purpura distribution, joint and gastrointestinal involvement. Kidney biopsy was done in 26 patients (28.57%). Among them, 3 patients had isolated persistent hematuria, 3 had isolated proteinuria and 20 patients had both hematuria and proteinuria. Median (range) 24-h urinary protein levels in patients who underwent biopsy was 1.28 (0-7.46) g/dU. The leading indication for biopsy was simultaneous hematuria and proteinuria (p<0.001), while isolated proteinuria was not a determining factor (p=0.592). Isolated hematuria was a statistically significant factor in detecting patients who were not likely to have a biopsy (p<0.001). Biopsy findings were graded with different classifications: 7 with Oxford classification, 6 with Haas, 1 with ISKDC, while 4 were classified simultaneously with Oxford and ISKDC. Only descriptive findings were available for 8 biopsy specimens. No statistically significant difference was found in 24-h urinary protein levels between different biopsy findings. 68% of HSPN patients were treated with corticosteroids out of which 17.6% patients took immunosuppressive or/and antihypertensive drugs in addition to corticosteroids. Most patients had good outcome, with normal physical exam findings and no signs of renal disease in laboratory tests (78%), or with microhematuria and proteinuria <1g/dU (17.6%), while only 4 patients (4.4%) had a more severe outcome with proteinuria >1g/dU. No significant difference was found in patient outcome for different biopsy findings (p=0.214).

Conclusion: Simultaneous hematuria and proteinuria was a statistically significant factor for kidney biopsy. However, while isolated proteinuria was not the sole determining factor, excessive levels of 24-h urinary proteins should be taken in consideration. Due to the small number of patients and no uniform classification generally used in grading biopsy findings, a statistically significant difference in regard to outcome could not be confirmed, indicating the need for both in future research.

Disclosure of Interest

None Declared

P041 POLYARTERITIS NODOSA: OVER 20 YEARS’ EXPERIENCE.

Hafize E. Sönmez¹, Ezgi D. Batu¹, Gizem Ayan², Kenan Kenan Barut³, Berkan Armağan⁴, Abdulsamet Erden⁴, Serdal Uğurlu⁵, Yelda Bilginer¹, Özgür Kasapçopu⁶, Ömer Karadağ⁴, Sule A. Bilgen⁴, Huri Özdoğan⁵, Seza Özen⁴

¹Department of Peditarics, Division of Rheumatology, Hacettepe University Faculty of Medicine, Ankara; ²Department of Internal Medicine, Cerrahpasa Medical School, Istanbul University, İstanbul; ³Department of Peditarics, Division of Rheumatology, Cerrahpasa Medical School, Istanbul University; ⁴Hacettepe University Vasculitis Centre, Ankara; ⁵Division of Rheumatology, Department of Internal Medicine; ⁶Department of Peditarics, Division of Rheumatology, Cerrahpasa Medical School, Istanbul University, İstanbul, Turkey

Correspondence: Ezgi D. Batu

Introduction: Polyarteritis nodosa (PAN) is a necrotizing vasculitis of predominantly medium size vessels.

Objectives: The present study aimed to summarize the characteristics of PAN patients, and also analyse the trend of decreasing PAN frequency in the last 25 years, in Turkey.

Methods: Paediatric and adult PAN patients followed up in Hacettepe University and Istanbul University Cerrahpasa Faculty of Medicine between 1990 and 2015, were included. The demographics, clinical findings and outcomes were evaluated retrospectively.

Results: One hundred thirty-three patients, including 66 children, were enrolled in the study. The median (minimum-maximum) age at symptom onset and diagnosis were 16 (2-75) years and 17 (3-75) years, respectively. The mean follow-up duration was 13 (2-27) years. Among 133 patients, 86 (64.7%) had fever, 108 (81.2%) had skin involvement, 54 (40.6%) had renal involvement, 43 (32.3%) had neurological involvement, 32 (24.1%) had gastrointestinal involvement, 10 (7.5%) had cardiac involvement, 6 (4.5%) had pulmonary involvement. The median (minimum-maximum) leukocyte count, erythrocyte sedimentation rate and C-reactive protein levels at the time of diagnosis were 10400 (6100-32000)/mm³, 58 (2-132) mm/h and 5.22 (0-46) mg/dL, respectively. All patients were ANCA negative. Hepatitis serology was analyzed in 121 patients and found positive in 13 of them. MEFV mutations were screened among 65 patients, 24 of them had mutations in at least one allele. Biopsy was performed in 109 patients and computerized tomography (CT) angiography was performed in 92 patients. Myalgia and skin involvement were significantly more frequent in children whereas neurologic involvement was much more common among adults (Table 1). The number of PAN patients declined significantly after 2010. 9 patients were re-categorized as DADA2 after 2014 and no patient were diagnosed with FMF+PAN after 2008.

Conclusion: Our results suggest a decrease in PAN in our country which may be due to improved healthcare and dissecting mimicking diseases. Further prospective studies with prolonged follow-up could help us to better understand the disease characteristics.

Trial registration identifying number:

Disclosure of Interest

None Declared

Table 1 (abstract P041). Characteristics of paediatric and adult PAN patients

P042 GENERATION OF ADA2 GENETIC KNOCKOUT IN A MYELOID CELL LINE USING CRISPR/CAS9 GENOME EDITING: AN IN VITRO CELL LINE MODEL TO STUDY GENE THERAPY FOR DADA2.

Marina S. Casimir, Ying Hong, Paul Brogan, Despina Eleftheriou

Infection, Inflammation and Rheumatology, UCL Great Ormond Street Institute of Child Health, London, UK

Correspondence: Marina S. Casimir

Introduction: Deficiency of adenosine deaminase type 2 (DADA2) is an autosomal recessive genetic disease causing systemic inflammation and vasculitis resembling polyarteritis nodosa, caused by loss of function mutations in the ADA2 gene. Treatment of DADA2 with biologic agents targeting TNF-alpha is particularly effective, but has side effects, is expensive and is required to be given by injection for life. We are curently exploring an alternative treatment strategy for DADA2 using gene therapy. Since there is no rodent orthologue of ADA2 an important first objective for this programme of work was to develop a cell line model to explore if it is possible to correct in vitro the defects associated with DADA2 using gene transfer strategies.

Objectives: To develop an ADA2 knockout (KO) monocyte cell line (THP-1) derived using Clustered Regularly-Interspersed Small Palindromic Repeats (CRISPR)/CAS9 and to confirm that this KO has comparable immunophenotype to macrophages from DADA2 patients as indicated by reduced ADA2 expression and M1/M2 skewing and pro-inflammatory cytokine production.

Methods: A plasmid delivered CRISPR/CAS9 system was used to generate the ADA2 KO THP-1 cell line. ADA2 enzyme activity was assessed using a modified commercially available assay and ADA2 protein expression using immunoblotting. THP-1 cells were treated with PMA to induce differentiation into macrophages before polarisation into M1 through LPS/INF-γ stimulation; and M2 polarisation through IL-4, IL-10 and Il-13 stimulation. Immunophenotyping was assessed using qPCR.

Results: We first confirmed effective knockout of ADA2 at both genetic sequencing and protein expression level. We further established reduction of ADA2 enzyme activity by almost 50% in culture supernatants when compared to scramble control THP-1 cells (p<0.01). There was significant upregulated gene expression for several proinflammatory molecules: TNF-α (p<0.001), CXCL-10 (p<0.001), STAT-1 (p<0.01), CCL2 (p=0.05) and IL-1β (p<0.001) in M1 polarised ADA2 KO THP-1 cells when compared to control THP-1 cells. M2 polarisation of ADA2 KO THP-1 cells did not affect expression of CD200R and CD206 compared to control cells.

Conclusion: We have successfully generated an ADA2 genetic KO myeloid cell line using the CRISPR/Cas9 system. We confirmed that ADA2 KO THP-1 cells have a comparable immunophenotype to macrophages from DADA2 patients and exhibit reduced ADA2 enzyme activity. This in vitro cell line model can now be used to examine the possibility of reversing the defects associated with DADA2 using gene editing strategies.

Disclosure of Interest

None Declared

P043 KAWASAKI DISEASE IN INTENSIVE CARE UNIT: ARE COMPLETE AND INCOMPLETE FORMS DIFFERENT?

Helene Yager¹, Fleur Le Bourgeois², Blandine Vanel³, Isabelle Kone-Paut¹, Maryam Piram¹, Bilade Cherqaoui¹

¹Pediatric Rheumatology, CHU Bicetre - APHP, CEREMAIA, LE KREMLIN BICETRE; ²Pediatric Intensive care unit, CHU Robert Debré - APHP, Paris; ³Pediatric Intensive care unit, HFME - HCL, Lyon, France

Correspondence: Bilade Cherqaoui

Introduction: Kawasaki disease (KD) is an acute vasculitis occurring mainly in children under 5 years of age. The central issue is the prevention of cardiac damage that may occur early and be life-threatening, requiring admission in intensive care unit (ICU). At admission in ICU, clinical features of KD may be incomplete or atypical; especially difficult to distinguish from a severe sepsis. In this context, the criteria defined by the American Heart Association (AHA) are not always conclusive to guide the management in acute phase, including initiation of appropriate treatment, such as intravenous immunoglobulin (IVIG).

Objectives: The aim was to compare phenotype and evolution of KD hospitalized in ICU (KD-ICU) with complete AHA criteria (cKD-ICU) or incomplete criteria (iKD-ICU).

Methods: Complete criteria of KD were defined as: ≥5 days of fever and ≥4 main clinical items. Incomplete criteria were defined as: ≥5 days of fever and ≥2 main clinical items (or ≥7 days of unexplained fever) and inflammatory syndrome with either ≥3 evocative biological abnormalities or coronary dilatation. All patients had to be hospitalized in ICU. We collected retrospectively KD-ICU cases between 2001 and 2018, from a national appeal of French medical societies (SOFREMIP, GRFUP). Data regarding clinical, biological, ultrasound and therapeutic features were recorded. Statistics were performed with Fischer test (PRISM 5.0); averages were compared with significance defined as p <0.05 (MedCalc).

Results: 25 patients met the criteria of cKD-ICU, 23 patients met the criteria of iKD-ICU. Patients were hospitalized in ICU for: shock (37.5%), unstable hemodynamics (16.7%), acute neurological disorder (10.4%), myocarditis (8.3%), large coronary artery aneurysm (6.2%); ICU hospitalization duration was 7.8 ± 6.2 days, intubation rate of 45.8%, amines / cardiotropes of 45.8%, vascular filling 33.3% (all similar in both groups). 2 patients died of myocardial infarction. Differential diagnoses initially suggested were: unexplained fever / poorly tolerated bacteremia (45.8%), peritonitis / severe colitis (25%), toxin shock (12.5%); the diagnostic delay was 4.4 ± 1 days (similar in both groups). No significant differences were found concerning age at baseline (3.6 ± 0.6 vs. 2.1 ± 0.5 years old), sex ratio (0.9 vs 0.5 M / F, p> 0.05) respectively in cKD-ICU and iKD-ICU patients; total duration of fever, initial biology or extreme values ​​(hemoglobin, platelets, leucocytes, CRP, ASAT, ALAT, natremia) were also similar in both groups. iKD-ICU patients were more frequently hospitalized in ICU before onset of fever (43.4 vs 8%, p = 0.01). The delays between onset of signs or hospitalization in ICU and the first course of IGIV were similar in both groups. Intravenous corticosteroid therapy was used in 36% of cKD-ICU vs 20% of iKD-ICU patients (p = 0.2); a second course of IGIV was used in 52% of cKD-ICU vs 47% of iKD-ICU patients (p = 0.7). All patients received a broad-spectrum antibiotic. Other therapeutics and evolution features were not significantly different between 2 groups.

Conclusion: KD-ICU patients had no initial or evolutive differences whether they met complete or incomplete AHA criteria. The strong suspicion of KD is therefore enough to initiate specific therapeutics even in severe complicated forms. An upcoming study will precise the phenotype of patients with KD-ICU to target them earlier, comparing them to KD patients who did not need ICU stay, via the KAWANET French database.

Disclosure of Interest

None Declared

P044 PULMONARY RENAL SYNDROME IN HENOCH SCHONLEIN PURPURA: A RARE BUT SERIOUS COMPLICATION.

Katherine Clarke¹, Elena Kurteva², Neil Sebire³, Muthana Al Obaidi¹

¹Great Ormond Street Hospital, Department of Paediatric Rheumatology; ²Great Ormond Street Hospital, Department of Paediatric Gastroenterology; ³Great Ormond Street Hospital, Department of Paediatric Histopathology, London, UK

Correspondence: Katherine Clarke

Introduction: We present the case of a five year old male presenting with fever, abdominal pain and rectal bleeding. He had a history of rash and arthralgia, diagnosed as Henoch Schonlein Purpura (HSP).

Objectives: To illustrate the life threatening complications that can infrequently occus with HSP

Methods: He had a widespread purpuric rash with necrotic lesions and swollen extremities (figure 1). He was anaemic. Urine dipstick detected proteinuria and erythrocytes. Renal biopsy showed proliferative glomerulonephritis with strong deposition of IgA (figure 2). Anti-neutrophil antibodies, Anti- nuclear antibodies and double stranded DNA were negative with normal complement. IV methyl-prednisolone was commenced. He continued to deteriorate with worsening renal function and respiratory deterioration. Chest X Ray showed bilateral focal abnormalities (figure 3). During intubation, he bled secondary to pulmonary haemorrhage. He required high frequency oscillation ventilation.

Results: He received cyclophosphamide and plasmapheresis followed by prednisolone and enalapril. He made slow improvement. He continued to have heavy proteinuria and haematuria but his renal function gradually improved. He made good recovery. Within two weeks he was mobile, off oxygen, with no cutaneous scars and no gastrointestinal symptoms.

Conclusion: Henoch-Schönlein purpura (HSP) is the most common type of IgA vasculitis in childhood. It usually runs a benign and self-limiting course [1]. Pulmonary-Renal involvement is a rare but life-threatening complication requiring early recognition and aggressive treatment [2]. In the deteriorating child with HSP, one must be aware of this serious complication.

(1) Petty R, Laxer RM, Lindsley CB, Wedderburn LR (eds): Textbook of Pediatric Rheumatology, ed 7. Philadelphia, Elsevier, 2016.

(2) Aeschlimann FA, Yeung RSM, Laxer RM, et al. A toddler presenting with pulmonary renal syndrome. Case Rep Nephrol 2017; 7:73-80

Disclosure of Interest

None Declared

P045 ANAKINRA AND ABCIXIMAB. SUCCESSFUL MANAGEMENT OF AN INFANT WITH REFRACTARY KAWASAKI DISEASE

María Isabel García Ruiz-Santa Quiteria¹, Marisol Camacho Lovillo¹, María José Lirola Cruz², Esther Perez Borrego¹, Israel Valverde Pérez¹, Ana Mendez Santos¹, Peter Olbrich¹, Laura Fernández Silveira¹

¹Hospital Universitario Virgen del Rocío; ²Instituto Hispalense de Pediatría, Sevilla, Spain

Correspondence: María Isabel García Ruiz-Santa Quiteria

Introduction: Kawasaki Disease (KD) is an acute and self-limited vasculitis, potentially leading to severe complications such as coronary artery aneurysms (CA). Patients with giant aneurysms (z score> 10 or > 8 mm) are at high risk of complications such as thrombosis and stenosis. Young infants and those with refractory KD have a high risk of developing CA. These patients would likely benefit from an early and aggressive treatment, although the most appropriate treatment strategy remains unknown. To date 3 cases of pediatric patients with giant aneurysms have been published showing a good response to anti IL-1 (anakinra). In addition, 3 clinical trials with antiIL-1 are currently ongoing. Abciximab (monoclonal antibody against the GPIIb / IIIa glycoprotein receptor located on the surface of platelets) has been used in cases with giant aneurysms and preliminary data suggests a positive effect on the vascular remodeling.

Objectives: We highlight the favorable medium term outcome and suggest the potential benefit of anti-Il-1 therapy and abciximab in this clinical setting.

Methods: We report the case of KD with a severe clinical course and the development of multiple, large CA despite an early and aggressive treatment.

Results: A 6 months-old male Asian infant was admitted with high fever for 4 days, submandibular adenopathy, conjunctival injection, red lips and macular rash. He was initially treated as a bacterial infection but lack of clinical improvement despite empirical intravenous antibiotic therapy and the development of clinical symptoms suggestive of KD lead to the performance of a trans-thoracic echocardiogram revealing a dilatation of the left coronary artery and an aneurysm of the anterior descending coronary artery. Treatment with intravenous immunoglobulins (IVIG) 2 mg/kg and ASA 50 mg/kg/d was initiated (day 6). Due to the persistence of fever and raised acute phase reactants a second IVIG dose was administered at day 8. Given the severity of symptoms, laboratory tests (49160/mcl leukocytes, PCR 295 mg/l, proBNP 1261pg/ml), the patients’ age and the echocardiographic findings, corticosteroids (30mg/kg/dose) were prescribed (day 8, 9 and 10) without clinical improvement and the patient was therefore transferred to our center.

Because of the refractory clinical picture and the remarkable coronary findings(multiple CA, the highest in right coronary artery:14mm, z-score: 39.89) anakinra(4mg/kg/day) was started on day 11. The dose was increased to 8mg/kg/day, and abciximab(initial dose of 2 mg/kg/day followed by a 12 hour intravenous infusion of 1.6 mg with ICU monitoring) was added to the treatment plan on day 14 with resolution of the clinical symptoms and normalization of the laboratory parameters (except trombocytosis 1295000/mm3). He was discharged 1 month after the onset of symptoms and managed as an outpatient with anakinra (8mg/kg/day), ASA, heparin and tapered corticosteroids. At discharged the ecocardiogram showed a significant dilation of the coronary aneurysms, with 2 giant aneurysms of 9.7 mm, z-score 26.17 and 12 mm, z-score 33.59 in the right coronary artery. Anakinra was stopped one month after discharge. Subsequent echocardiographic controls (seven months later), showed a significant improvement (largest aneurysm 2.5 mm, z-score: 2.93). Current treatment is limited to AAS and heparin.

Conclusion: Despite adequate initial KD management, there remains a group of patients which develop serious cardiac complications. The identification of these high risk patients and the establishmentof guidelines forrisk-adjusted therapy are needed in order to optimize the management and subsequently the outcome of these patients. Informed consent had been obtained from the parent.

Disclosure of Interest

None Declared

P046 ARTHRITIS IN THE SUBACUTE PHASE OF KAWASAKI DISEASE

Seira Hattori, Ayako Murase, Ai Ohnishi, Kenichi Nishimura, Ryoki Hara, Shuichi Ito

Pediatrics, Yokohama City University graduate school of medicine, Yokohama, Japan

Correspondence: Seira Hattori

Introduction: Kawasaki disease (KD) is a systemic vasculitis of medium-sized arteries in young children. KD has various complications, including arthritis, which is a common complication. Arthritis in the febrile acute phase of KD is likely to resolve following improvement of systemic symptoms. However, some patients have persistent or new-onset arthritis in the subacute phase of KD. There have been few studies of arthritis in the subacute phase of KD.

Objectives: This study aimed to evaluate the clinical characteristics, laboratory findings, imaging findings, treatment, and prognosis of arthritis in the subacute phase of KD.

Methods: We assessed patients with arthritis in the subacute phase of KD in our institute, a tertiary medical facility in Yokohama city, from April 2008 to January 2018. We retrospectively examined the treatment for KD, coronary artery lesions (CALs), affected joints, C-reactive protein (CRP) levels, matrix metalloproteinase-3 (MMP-3) levels, imaging findings, treatment for arthritis, and outcome of arthritis using the patients’ electronic medical records.

Results: Fifteen patients were enrolled. The median age of patients was 46 months (range, 10–116 months) and most were boys (60%). Five (33%) patients had arthritis in the acute phase of KD, and the arthritis resolved once with acute treatment of KD, except for one patient. Four (27%) patients were treated with single administration of intravenous immunoglobulin (IVIG) and 11 (73%) required additional IVIG. Infliximab (IFX) was administrated to seven (47%) patients and plasma exchange was performed in one because of IVIG resistance. One patient developed CALs. Arthritis was detected most in the knees (67%), followed by the ankles (47%) and hip joints (40%). Six (40%) patients had a consistent fever. At diagnosis of arthritis, CRP levels increased again in 14 (97%) patients and MMP-3 levels were elevated in 14 (97%) patients. Ultrasound showed joint fluid in all patients, but none showed synovial proliferation accompanied by a positive power Doppler signal. Nonsteroidal anti-inflammatory drugs, steroids, and methotrexate were administered for arthritis in 13 (87%), 11 (73%), and one (6.7%) patient, respectively. Among these treatments, steroids promptly improved arthritis without developing CALs. The median administration period of steroids was 46 days (range, 12–249 days). The arthritis resolved without sequelae in all of the patients, and they successfully discontinued treatment.

Conclusion: Arthritis in the subacute phase of KD is relatively common, and the arthritis does not cause destruction of joints and cartilage. However, some patients suffer from persistent arthritis for several weeks. For persistent arthritis, short-term steroid therapy can help to ensure rapid improvement without a new complication of CALs. The pathogenesis of arthritis in the subacute phase of KD remains unclear, but arthritis occurs, despite administration of IFX. Therefore, this condition appears to be unrelated to tumor necrosis factor-α.

Disclosure of Interest

None Declared

P047 THE FIRST REPORT OF POST PENTAVALENT VACCINATION ACUTE HEMORRHAGIC EDEMA OF INFANCY

Shabnam Hajiani, Mohsen Jari, Reza Shiari

Pediatrics rheumatology, Shahid Beheshti university of medical sciences, Tehran, Iran, Islamic Republic Of

Correspondence: Mohsen Jari

Introduction: Background:Acute hemorrhagic edema of infancy (AHEI) is an immune complex-mediated leukocytoclastic vasculitis and rare disease that age of onset for it usually is 4-24 months. Clinical findings such as low grade fever,edema of face, upper and lower limbs and generalized petechiae,purpura or ecchymosis develop rapidly over 24-48 hours. Upper respiratory tract infection, gastroenteritis, or vaccination have been reported to cause of this disease. AHEI was reported after heptavalent vaccination ( Hemophilus influenza type B, diphtheria, tetanus, acellular pertussis, hepatitis B, polio, and conjugate pneumococcal vaccines).To our knowledge there is^’nt any report of post pentavalent vaccination ( Hemophilus influenza type B, diphtheria, tetanus, acellular pertussis and hepatitis B)AHEI. asystemic involvement such as arthritis/arthralgia,abdominal pain,intussusception and scrotal pain and testicular torsion are rare.Diagnosis of AHEI is clinical and routine laboratory tests are nondiagnostic, although leukocytosis and thrombocytosis ,elevation of erythrocyte sedimentation rates((ESR), c-reactive protein(CRP) and liver function test may be occured. No effective therapy need for AHEI. The use ofantihistamines and steroids has been controversial . systemic corticosteroids may be used to sever conditions or systemic involvement such as abdominal pain,intussusception ,nephritis ,scrotal pain and testicular torsion. Monitor patients for rare systemic involvement such as renal involvementhas been controversial.

Objectives: Case report:Our patient was a 6-month boy injected by pentavalent vaccine 5days ago.since 3 days ago he had low grade fever,edema of face, upper and lower limbs and generalized petechiae,purpura and ecchymosis. His condition was good.Mild scrotal swelling was seen. Other review of system and physical examinations were normal. Labratoary findings showed only high ESR,CRP.Abdominal-pelvic and testicular ultrasonographies were normal. We treated this patient with supportive treatment and after ruled out of infectious diseases single dose 10mg/kg methlprednisolon infusion. There were no complications in follow up. Informed consent for publication had been obtained.

Methods: case report

Results: case report

Conclusion: Conclusion: Pentavalent vaccination can induced AHEI.

Disclosure of Interest

None Declared

P048 TAKAYASU ARTERITIS INITIALLY DIAGNOSED WITH FEVER OF UNKNOWN ORIGIN

Özlem Üzüm¹, Ali Kanık², Kader Vardı¹, Yeliz Pekçevik³, Kayı Eliaçık¹, Belde Kasap Demir⁴

¹Departments of Pediatrics, Tepecik Training and Research Hospital; ²Departments of Pediatrics, İzmir Katip Çelebi University; ³Department of Radiology, Tepecik Training and Research Hospital; ⁴Pediatric Nephrology and Rheumatology, İzmir Katip Çelebi University, İzmir, Turkey

Correspondence: Belde Kasap Demir

Introduction: Fever of unknown origin (FUO) in children is defined as fever >38.3°C (101°F) at least once per day for ≥8 days with no apparent diagnosis after initial outpatient or hospital evaluation that includes a detailed history, thorough physical examination, and initial laboratory assessment. The most common causes are infectious diseases, rheumatologic diseases and malignant diseases. This case is presented to emphasize that Takayasu Arteritis should be considered in patients examined for FUO.

Objectives: An 11-year-old girl presented with a fever increasing up to 38.3°C 1-2 times a day for one month, and up to 39°C for the last five days, despite continued antibiotic therapy. It has been learnt that she had a pain in the upper abdominal region for a week and she had lost 10 kilograms in the last two months after using a teeth retainer. On physical examination, body weight was under 3th percentile, while height was at 25-50 percentile. Vitals were normal except a fever reaching up to 38.5°C. There was no finding in systemic examination except general sensitivity in the abdomen. Hemoglobin was 8.1 g/dL. Biochemical values, immunoglobulin levels, and complements were normal. C-reactive protein (14.9 mg/dL) and erythrocyte sedimentation rate (140 mm/h) were high. Rheumatoid factor and viral serology were negative. No microorganism was yielded in the blood, throat or urine cultures. There was no sign of active tuberculosis on chest X-ray and PPD evaluation. Anti-nuclear antibody, anti-dsDNA, and p/c-anti-cytoplasmic antibodies were negative. Ophthalmologic evaluation, echocardiography and abdominal USG were normal. No additional features were found in peripheral smear and bone marrow examination.

Methods: Abdominal Doppler USG was performed upon ongoing fever, abdominal pain and high levels of acute phase reactants. The patient was diagnosed with Takayasu Arteritis due to the wall thickening in the first 4-5 cm proximal segment of the anterior mesenteric artery and severe thickening in the left carotid artery wall.

Results: She was treated with steroids and azatioprin. Abdominal pain regressed and acute phase reactants decreased to normal limits at the end of the second week.

Conclusion: Although Takayasu arteritis is included in the etiology of FUO, diagnosing a patient may take time in the absence of common findings including pulselessness or claudication. Takayasu Arteritis should be kept in mind in patients with FUO and further investigation should be considered. Written consent for publication was obtained from the parents.

Disclosure of Interest

None Declared

P049 GENDER DIFFERENCES IN RISK FACTORS (OF IVIG-RESISTANT) IN PATIENTS WITH KAWASAKI DISEASE

Young Dae Kim¹, Jong Gyun Ahn², Kwang Nam Kim³

¹Department of Pediatrics, Inje University Ilsan Paik Hospital, Goyang; ²Department of Pediatrics, Severance Children’s Hospital, Yonsei University College of Medicine, Seoul; ³Department of Pediatrics, Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Korea, Republic Of

Correspondence: Young Dae Kim

Introduction: Kawasaki disease (KD) is one of the most common vasculitis that may cause coronary artery complications. KD is more common in boys than in girls with a male-to-female ratio of 1.36:1 to 1.62:1. Thus, it has been suggested that the susceptibility is closely associated with sex differences.

Objectives: This study investigated the gender differences in clinical and laboratory findings in patients with KD.

Methods: We reviewed the medical records of 148 patients (78 boys and 70 girls) with KD who had been treated at our hospital between September 2012 and March 2017.

Results: The incidence of coronary artery aneurysm and intravenous immunoglobulin (IVIG) -resistant KD was significantly higher in the boys as compared with the girls (P=0.02). But there were no significant differences in WBC, Hb, CRP, ESR and urine abnormalities, such as proteinuria, pyuria and microscopic hematuria, between the two groups (P>0.05). There were significant differences in % neutrophil counts (>80), CRP (>8mg/dL), AST (>100IU/L), ALT (>80IU/L), hyponatremia (<134mmol/L), total bilirubin (<0.9mg/dL) and illness at initial treatment (≤4 days) between IVIG-responsive and IVIG-resistant groups (P<0.05).

Conclusion: Coronary artery aneurysm and intravenous immunoglobulin (IVIG) -resistant KD was more common in boys and there were several risk factors, such as % neutrophil counts, CRP, illness at initial treatment to progress IVIG resistant KD.

Disclosure of Interest

None Declared

P050 EVALUATION OF THE ROLE OF SIGNAL PEPTIDE-CUB-EGF DOMAIN-CONTAINING PROTEIN (SCUBE)1 AND SCUBE2 IN IMMÜNOGLOBULIN A VASCULITIS

Gülbahar Kurt¹, Ferhat Demir², Suleyman C. Karahan³, Mukaddes Kalyoncu²

¹Department of Pediatrics; ²Department of Pediatric Rheumatology; ³Department of Biochemistry, Karadeniz Technical University, Faculty of Medicine, Trabzon, Turkey

Correspondence: Gülbahar Kurt

Introduction: Immünglobulin A vasculitis (IgAV) is a systemic, inflammatory, leucocytoclastic vasculitis which is caused by IgA deposit to small blood vessels. It is a self-limiting disease and etiopathogenesis of IgAV is still unclear and cytokines such as TNF-α, IL-6 have been implicated in the active phase of the disease. Signal peptide-CUB (complement C1r/C1s, Uegf, and Bmp1)-EGF (epidermal growth factor)-like domain-containing protein (SCUBE)1 is a new described, can be secreted cell surface protein. It has been proven that SCUBE1 and SCUBE 2 has a role in various pathophysiologic processes like vascular endothelial cells, inflammation, cancer metastasis and vascular diseases.

Objectives: We aimed to research whether there is a relationship between SCUBE1 and SCUBE2 proteins and IgAV.

Methods: Between January 2016 and May 2017, the patient admitting to outpatient clinics in pediatric department of Farabi Hospital in Karadeniz Technical University and diagnosed with IgAV according to Ankara 2008 diagnostic criteria were included. Patients who used steroid or non-steroidal inflammatuary drug in last three months were excluded. Blood samples collected from patients who were in active and recovery phases of their diseases and healhty control group. IL-1, IL-6, TNF-α, SCUBE1 and SCUBE2 levels studied by ELISA method.

Results: A total of 26 patients, 13 (50%) male and 13 (50%) female, aged between 3 and 17 years, who were diagnosed with IgAV, were included in the study. The average age in healthy control group was 7.15±3.34 years. There was skin involvement in all of the patients who were diagnosed with IgAV. Twenty three (88.4%) patients had joint involvement, seven (26.9%) patients GI involvement, five (19.2%) patients kidney involment and three (11.5%) patients testicular involvement. IL-1 levels are significantly higher in active phase of disease than in healthy control group and recovery phase of disease (p=0.03). IL1, IL-6 levels were statistically significant higher then in healthy control group (p=0.006 and p=0.01, respectively). SCUBE1 and SCUBE2 levels were not different in active and VIII recovery phases of the disease. SCUBE2 levels have found significantly higher in recovery phases of the disease when compared to healthy control group (p=0,008).

Conclusion: Increase of SCUBE2 levels in the recovery phase of disease suggests that SCUBE proteins has a different role from inflammation in tissues and various cell types. We believe that this situation can be elucidated by studies on more patients in this regard.

Disclosure of Interest

None Declared

P051 TOCILIZUMAB AS TREATMENT OPTION FOR ACHIEVING SUSTAINED REMISSION IN A CHILD WITH TAKAYASU ARTERITIS

Dragana S. Lazarevic¹, Jelena Vojinovic^1,2

¹Pediatric Rheumatology, Clinic of Pediatrics, Clinical Center Nis; ²Pediatrics, Faculty of medicine, University of Nis, Nis, Serbia

Correspondence: Dragana S. Lazarevic

Introduction: Takayasu arteritis represents idiopathic large vessels vasculitis of aorta and its main branches, rarely affecting children.

Objectives: Diagnostic and treatment delay can lead to potentially life treating complications if neurological and cardiovascular injuries occur. Reducing inflammation and achieving sustained remission is important therapeutically goal, but not yet standardized.

Methods: We report a case of sixteen year old girl with refractory Takayasu arteritis to standard treatment who entered remission and could stopped steroids after inducing tocilizumab

Results: Sixteen year old girl was treated with antibiotics as having pneumonia due to fever and cough. After two weeks she was admitted to the pulmology department of our hospital due to prolonged fever, dizziness and weakness, but without reporting other symptoms. After excluding respiratory tract infection and tuberculosis she was transferred to the department of pediatric rheumatology and immunology. Possible infection causes were ruled out as procalcitonin, all cultures, virusology and atypical infections testing were negative. Bone marrow biopsy, detailed immunological and endocrinological laboratory testing were not proved hematological, immunodeficiency or autoimmune disease background. Due to persistently elevated inflammatory markers we suspected on autoinflammatory disease, but feritin was mildly elevated. Slit lamp examination and angiotenzin converting enzym have excluded possibile diagnosis of sarcoidosis. Abdominal ultrasound and echocardiography were normal. After the treatment with non-steroid anti-inflammatory drugs (NSAIDs) fever has gone, but elevated inflammatory markers persisted with profound feeling of fatigue, weakness, and dizziness. Physical examination has revealed less palpabile right radial pulse and higher blood pressure on the same side. F-fluorodeoxyglucose positron emission tomography (PET-CT) have confirmed diagnosis of Takayasu arteritis of thoracic and abdominal aorta. Magnetic resonance angiography (MRA) of the brain was normal. Methyl-prednisolon pulses were induced with gradually steroid tappering and metotrexate treatment, but unfortunately this could not stopped inflammation. Six months later she was steroid dependent with chronic fatigue and persistently elevated inflammatory parameters. MRA of the heart and large blood vessels have revealed evidence of still active inflammation in the thoracic aorta. Decision was made and tocilizumab was added on regular basis treatment. Four months after inducing tocilizumab she was without any symptoms with normalized inflammatory markers and steroids could be tapered and stopped.

Conclusion: In the cases of the fever of unknown origin we should consider Takayasu arteritis, even though it is rarely seen in childhood. Early diagnosis and treatment could prevent serious systemic complications. Although we lack treatment algorithm recommendations in children, this is the evidence that early and aggressive inducing of tocilizumab could lead to sustained remission in Takayasu artertitis in children. Informed consent to publish had been obtained.

Disclosure of Interest

None Declared

P052 AUDITORY EVOKED POTENTIALS AND VISUAL EVOKED POTENTIALS: A HELPFUL TEST IN THE DIAGNOSIS AND FOLLOW UP OF KAWASAKI DISEASE

Maria Cristina Maggio¹, Giuseppe Salvo¹, Rolando Cimaz², Domenico Puma³, Crocifissa Maria Ministeri⁴, Giovanni Corsello¹

¹University Department Pro.Sa.M.I. “G. D’Alessandro”, University of Palermo, Palermo; ²NEUROFARBA Department University of Florence, and AOU Meyer, University of Florence, Florence; ³Paediatric Neuropsychiatry Operative Unit, Children Hospital “G. Di Cristina”; ⁴O.U.of Neurophysiopathology, ARNAS, Palermo, Palermo, Italy

Correspondence: Maria Cristina Maggio

Introduction: Kawasaki disease is a systemic vasculitis affecting mainly children; the most serious complications are coronary artery lesions (CAL). Nonetheless, the spectrum of complications involves all the vascular districts, such as the eyes, skin, kidneys, gallbladder, liver, central nervous system. Sensorineural hearing loss is a low diagnosed complication of KD, however, it may be permanent.

Objectives: Auditory evoked potentials (ABR) and visual evoked potentials (VEPs) are useful in evaluating children without auditory and/or visual symptoms but with diseases that could sub clinically involve these functions.

Methods: We enrolled 52 children (31 M, 21 F; age: 3 months-10 years) with KD and evaluated ABR and VEPs in the acute phase of the disease and during the follow up. We correlated the neurophysiological study with clinical, biochemical parameters, the type of KD (typical, atypical, incomplete) with cardiac involvement and time of IVIG and/or other non-conventional treatment in the acute phase of KD.

Results: VEPs were pathological in 6 children (4 M; 2 F) (1 patient with CAL had monoliteral alterations; 2 patients had ABR pathological as well). ABR were pathological in 36/52 patients (69%) (2 patients without CAL had monoliteral alterations). Furthermore, in those patients (31M; 21 F) there were no significant differences in age, time of the diagnosis, time of the first dose of IVIG, biochemical parameters (leukocytes, neutrophils percentage, AST, ALT, gamma-GT, albumin, Na, fibrinogen, D-Dimer) vs KD patients without alterations of ABR and VEPs.

One patient showed a persistent sensorineural auditory loss.

During the follow up, ABR and/or VEPs alterations persisted in the 80% of the patients.

Most of the patients showed alterations of the wave V and the I-V, expression of mesencephalic involvement.

Conclusion: We suggest evaluating ABR and VEPs in patients with KD, both in patients with precocious diagnosis and treatment either in children treated later than 10 days with IVIG.

We suggest studying also patients without CAL, in whom neurophysiological study may contribute to the complete follow up of these patients.

Disclosure of Interest

None Declared

Poster Walk 3: JIA basic

P053 ASSOCIATION OF INCREASED SUN EXPOSURE OVER THE LIFE-COURSE WITH A REDUCED RISK OF JUVENILE IDIOPATHIC ARTHRITIS

Justine A. Ellis¹, Rachel Chiaroni-Clarke¹, Jane Munro^2,3, Angela Pezic⁴, Joanna Cobb¹, Jonathan Akikusa^2,3, Roger Allen^2,3, Terence Dwyer^4,5, Anne-Louise Ponsonby⁴

¹Genes, Environment & Complex Disease, Murdoch Children's Research Institute; ²Paediatric Rheumatology, Royal Children's Hospital; ³Arthritis & Rheumatology; ⁴Environmental & Genetic Epidemiology Research, Murdoch Children's Research Institute, Parkville, Australia; ⁵George Institute for Global Health, University of Oxford, Oxford, UK

Correspondence: Justine A. Ellis

Introduction: Cutaneous sun exposure is an important determinant of circulating vitamin D. Both sun exposure and vitamin D have been inversely associated with risk of autoimmune disease, including multiple sclerosis and rheumatoid arthritis. In children with juvenile idiopathic arthritis (JIA), low circulating vitamin D is reportedly common, but disease-related behavioural changes may have influenced sun exposure behaviours (reverse causation).

Objectives: We aimed to determine whether sun exposure across the life-course prior to diagnosis is associated with JIA.

Methods: Using validated questionnaires, we retrospectively measured sun exposure for 202 Caucasian JIA case-control pairs born and living in Victoria Australia and recruited to the CLARITY JIA Biobank. Cases and controls were matched for year of birth and time of recruitment. All subtypes of JIA were included in the analysis. Measures included maternal sun exposure at 12 weeks of pregnancy, and child sun exposure across the life-course pre-diagnosis. We converted sun exposure to UVR dose using location-specific (Melbourne Australia, latitude 37.5°S) UVR data. We looked for case-control sun/UVR exposure differences at various ages pre-diagnosis, and cumulatively across the pre-diagnosis life-course, using logistic regression, adjusting for potential confounders.

Results: Higher cumulative child pre-diagnosis UVR exposure was associated with reduced risk of JIA (e.g. total UVR dose quartile 1 vs 4, adjusted odds ratio (AOR) 0.19, 95% CI 0.04 – 0.85, p = 0.030), with a clear dose response relationship (test for trend p=0.025). UVR exposure at 12 weeks of pregnancy was similarly inversely associated with JIA (e.g. UVR quartile 1 vs 4, AOR 0.32, 95% CI 0.13 – 0.80, p = 0.014) with evidence of a dose response (test for trend p=0.031). Associations were robust to sensitivity analyses for disease duration, and for pre-diagnosis behavioural changes and knowledge of the hypothesis as collected by parent questionnaire.

Conclusion: Increased UVR exposure across the pre-diagnosis life-course is associated with reduced risk of JIA in our setting. This suggests lower circulating vitamin D in JIA may be causative, but prospective studies that directly measure pre-disease vitamin D in JIA are required. If confirmed, the associations point to an environmental factor amenable to intervention that may reduce risk of JIA in the population.

Disclosure of Interest

None Declared

P054 AN ACTIVE PRONGF/P75NTR AXIS IN ARTHRITIS PATIENTS INFLUENCES CYTOKINE PRODUCTION IN SYNOVIAL FIBROBLASTS

Gaetana Minnone¹, Luciapia Farina¹, Marzia Soligo², Luigi Manni², Antonio Manzo³, Pierre Miossec⁴, Fabrizio De Benedetti¹, Luisa Bracci-Laudiero¹

¹Division of Rheumatology, Bambino Gesu’ Children Hospital; ²Institute of Translational Pharmacology, CNR, Rome; ³Division of Rheumatology and Translational Immunology Research Laboratories, IRCCS Policlinico S Matteo Foundation/University of Pavia, Pavia, Italy; ⁴Immunogenomics and Inflammation Research Unit, Edouard Herriot Hospital, Hospices Civils de Lyon and University Claude Bernard Lyon 1, Lyon, France

Correspondence: Luciapia Farina

Introduction: In addition to its well-known neurotrophic activity, the nerve growth factor (NGF) is involved in the immune regulation. Our previous studies showed that the immature NGF, proNGF, is the prevalent form in synovial fluids of patients with juvenile idiopathic arthritis (JIA) and rheumatoid arthritis (RA). The distinct roles of NGF, pro-NGF and their different receptors (TrkA and p75NTR) in the regulation of the inflammatory response are still unclear.

Objectives: To investigate if p75NTR and its specific ligand proNGF modulate the activity of synovial fibroblasts and mononuclear cells playing a role in the inflammatory response in the synovia of arthritis patients.

Methods: Mononuclear cells (MNC) were purified from blood and synovial fluids of JIA patients. Fibroblasts-like synoviocytes (FLS), obtained from synovial tissue of RA patients (RA FLS), were used to evaluate pro-inflammatory activity of proNGF. Skin fibroblasts (SF) from healthy donors (HD) were used as controls. TrkA, p75NTR, Sortilin, NGF, and cytokines expression were evaluated by quantitative PCR (qPCR). Specific ELISA were used to analyze NGF, proNGF and cytokine concentrations. p75NTR was inhibited using a synthetic inhibitors (LM11A-31) or by small interference RNA in order to evaluate how its inhibition can modify pro-inflammatory pathways.

Results: Our data showed that p75NTR expression was significantly up-regulated in MNC purified from blood and synovial fluid of JIA patients and in FLS of RA patients. TrkA expression was highest in HD cells and down-regulated in patient cells. Patient FLS but not MNC expressed high levels of NGF mRNA and high amounts of proNGF. On the contrary, low levels of mature NGF were detected in their conditioned media. Inflammatory stimuli, such as IL-1β, IL-6, LPS, TNFα, further up-regulated both p75NTR expression and proNGF production in synovial FLS. The inhibition of the binding of proNGF to its specific receptor p75NTR using synthetic inhibitor LM11A-31 in synovial FLS resulted in a marked reduction of IL-6 release induced by either IL-1β or other inflammatory stimuli.

Conclusion: The abnormal p75NTR expression levels and the modified p75NTR/TrkA ratio observed in JIA and RA patients might have a crucial role in the chronicity of the inflammatory response. In addition to inducing p75NTR up-regulation, inflammatory stimuli increased the release of proNGF in synovial FLS. ProNGF further enhances pro-inflammatory cytokine production, creating a vicious circle that amplify the inflammatory response. Blocking the binding of endogenous proNGF to its receptor p75NTR, using a specific p75NTR inhibitor, strongly reduces the production of inflammatory mediators and suggests the use of p75NTR inhibitors as a new therapeutic approach to chronic arthritis.

Disclosure of Interest

G. Minnone: None Declared, L. Farina: None Declared, M. Soligo: None Declared, L. Manni: None Declared, A. Manzo: None Declared, P. Miossec: None Declared, F. De Benedetti Grant/Research Support from: BMS, Pfizer, Abbvie, Novartis, Novimmune, Roche, SOBI, Sanofi, UBC, Consultant for: Roche, Novartis, Novimmune, SOBI, L. Bracci-Laudiero: None Declared

P055 COMPARISON OF B CELL AND T CELL SUBSETS, CYTOKINE EXPRESSION AND SYNOVIAL PATHOLOGY IN DA AND JIA

Charlene Foley¹, Achilleas Floudas², Mary Canavan², Monika Biniecka², Emma J. MacDermott^1I, Ronan Mullan³, Orla G. Killeen¹, Ursula Fearon²

¹NCPR, OLCHC; ²TBSI; ³Rheumatology, Tallaght, Dublin, Ireland

Correspondence: Charlene Foley

Introduction: Down syndrome (DS) is a common chromosomal disorder associated with the development of a range of medical and immune abnormalities such as haematologic malignancies, increased susceptibility to infections, and a high incidence of autoimmune diseases, including Down’s Arthritis (DA). Previous work by our group suggests that the prevalence of DA is 18-21 fold greater than JIA, much higher than the previously reported DA prevalence of 8.7/1000. Children with DA most often follow a polyarticular course of disease, with erosive joint damage observed more frequently in this cohort when compared to a cohort of children with JIA. Small joint involvement is frequently observed, again in a significantly greater proportion (p<0.01) of children with DA than expected in a typical JIA cohort. These characteristics suggest that DA may be distinct from JIA, however little is known about the differences in synovial pathology or immunological regulation. Indeed no studies to date have examined synovial pathology in DA

Objectives:

- To examine B-cell and T-cell subsets, and cytokine profiles in children with DA and JIA

- To characterise & compare the synovial membrane immunohistochemistry in DA & JIA.

Methods: Multicolour flow cytometry was used to analyse the phenotype of B and T cells in peripheral blood mononuclear cells (PBMCs) from 40 children (n=10 per group; Healthy Control (HC), JIA, DS, DA). Cells were stained with the following panels; Panel 1 B cells (CD38, CD24, CD20, CD80, CD27, IgM, CD138, CD45, CD19, MHCclassII, BCMA, CD40, CD86, IgD); Panel 2 T cell cytokines analysed after 5hours PMA/Ionomycin stimulation (CD3, CD8, CD161, IFN-γ, TNF-α, IL-17a, GM-CSF). Flow cytometry data was assessed by Flowjo software analysis.

Synovial tissue obtained through ultrasound guided biopsy and analysed by immunohistochemistry for CD3, CD20, CD68, Factor VIII (DA n=3; JIA n=6). Synovial Inflammation and lining layer thickness were also scored. Analysis was performed using semiquantification scoring method.

Flow cytometry was performed on PBMC samples from 4 distinct gps; HC (50%F, age 9.2y (2.5-15.6)), JIA (91%F, age 13.2y (8.2-16.1)), DS (45%F, age 6.5y (1-11.9)) & DA (60%F, age 11.4y (3.8-17.8)). All of the children in the DA & JIA cohorts had a polyarticular RF negative pattern of disease. Synovial tissue was obtained from 3 children with DA & 6 JIA cases.

Results: Flow cytometry analysis revealed that children with DA have a significantly lower number of circulating CD19⁺CD20⁺ B cells when compared to children with JIA (p<0.05) & HC (p<0.001). However, children with DA have a greater proportion of memory B cells (CD27⁺) when compared to children with DS & no arthritis (p<0.05).

Analysis of cytokine production by CD8⁺/CD8^- T cells showed that IFN-γ & TNF-α production was greater in DA compared to both JIA (CD8+IFNγ+ p<0.001; CD8+TNFα+ p<0.01; CD8-IFNγ+ p<0.05; CD8-TNFα p<0.05) and HC (CD8+IFNγ+ p<0.05; CD8+TNFα+ p<0.05; CD8-IFNγ+ p<0.05; CD8-TNFα p<0.01).

Examination of synovial tissue demonstrated higher levels of CD3+ cells (p<0.05), Macrophages (p<0.05), CD20+ cells & FVIII in the joints of children with DA.

Conclusion: There are significant differences in B cell populations, cytokine production and immunohistochemical features of synovial tissue in children with DA & JIA. More work is required to verify these results. Preliminary findings may begin to help explain the differences observed in the clinical picture of children with DA & JIA.

Disclosure of Interest

None Declared

P056 MICROENVIRONMENT DRIVEN RE-SHAPING OF PATHOGENIC T EFFECTOR AND REGULATORY SUBSET IN ACTIVE JUVENILE IDIOPATHIC ARTHRITIC PATIENTS

Jing Yao Leong¹, Pavanish Kumar¹, Phyllis Chen¹, Joo Guan Yeo^1,2, Camillus Chua¹, Sharifah Nur Hazirah¹, Suzan Saidin¹, Thaschawee Arkachaisri^1,2, Alessandro Consolaro³, Marco Gattorno³, Alberto Martini³, Salvatore Albani¹

¹Translational Jing Yao Leong Institute/Duke-NUS Academic Medical Centre; ²KK Women’s and Children’s Hospital, SINGAPORE HEALTH SERVICES PTE LTD, SINGHEALTH, Singapore, Singapore; ³Second Paediatric Division, University of Genoa and G Gaslini Institute, Genova, Italy

Correspondence: Jing Yao Leong

Introduction: We have previously published and identified two dichotomous dysregulated populations within the Teff (CPLs) and Treg (iaTreg) compartments that are inflammatory, antigen experienced, correlating with disease activity and exhibiting similar TCR oligoclonality with synovial T cells. Their commonality in phenotype despite being in two functionally distinct compartments, signal the possibility of a common pathogenic origin during active disease manifestation.

Objectives: To determine the common transcriptomic drivers influencing dysregulation in both Teff and Treg compartments during active disease in JIA patients.

Methods: Next generation RNA sequencing was performed on sorted CPLs (CD3⁺ CD4⁺ CD14^- HLADR⁺ CD25/CD127 Teff gate) and iaTregs (CD3⁺ CD4⁺ CD14^- HLADR⁺ CD25^hi CD127^lo Treg gate) from 16 active disease JIA PBMCs, 8 age-matched healthy PBMCs, and 8 paired SFMCS. The corresponding total pool of Teff (Non-CPLs) or Treg (Non-iaTreg) was also sorted as a comparative control. Sorted cells were lysed and extracted for RNA, and cDNA conversion/amplification were then carried out using SMART-seq v4. Libraries are prepared and multiplexed using Nextera XT DNA library preparation kit, and ran on the Illumina HiSeq High output platform. RNA-Seq raw reads were mapped to human genome using STAR aligner with default options and reads were counted/summarised at gene level by feature Count programme. Differential expression analysis were performed using edgeR package, and pathway enrichments were done under R statistical environment and Reactome.

Results: Comparative differential gene expression (DEG) reveal strong transcriptomic convergence between CPLs and iaTregs as compared with the common pool of Teff and Treg. Phylogenetic analysis indicate the convergence has uncoupled the CPLs or the iaTregs away from their respective original compartments (Teff or Treg) into a common branch point. Restriction in TCR sequence oligoclonality in CPLs/iaTregs versus that of the common Teff/Treg pool reinforce the possibility of a common selection pressure. Pathway enrichment analysis reveal similar dysregulated pathways (IFN-g, PD1, CD28 costimulation) within T cell signalling for both CPLs and iaTregs. Furthermore, Weighted gene correlation network analysis (WGCNA) identified strongly coordinated HLA-DR gene network module and suggests its potential role as the driver of pathogenic T cell subsets away from conventional subsets. Gene set enrichment analysis (GESA) suggest that HLA-DR module genes are involved in TNFA signalling, inflammatory response, complement, and apoptosis. Global transcription factors gene regulatory network (TF-GRN) analysis identified several key regulatory molecules (FOXP3, CEBP, SPI and E2F1) driving the convergence of pathogenic CPLs and iaTreg populations. Taken together , we have shown that reveal several layers of mechanism operate to drive the convergence of CPLs and iaTregs, suggesting the possibility of common disease drivers in active JIA patients.

Conclusion: Overall the transcriptomic data indicate strong similarity in both pathogenic populations and underscore a potential mechanistic role of the inflammatory microenvironment in shaping two functionally dichotomic populations.

Disclosure of Interest

None Declared

P057 ASSOCIATION BETWEEN THE IL2-IL21 RS6822844 LOCUS POLYMORPHIC VARIANTS AND AGE AT JUVENILE IDIOPATHIC ARTHRITIS ONSET

Liliia S. Nazarova¹, Kseniia V. Danilko¹, Tatiana V. Viktorova^1,2, Viktor A. Malievsky¹

¹Bashkir State Medical University; ²Institute of Biochemistry and Genetics, Ufa, Russian Federation

Correspondence: Viktor A. Malievsky

Introduction: Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in pediatrics and is characterized by marked clinical heterogeneity, including the age-related features of the disease onset [1, 2].

Objectives: The aim of the study was to analyze the relationship between the IL2-IL21 rs6822844 locus polymorphic variants and age at JIA onset.

Methods: The study included 328 patients with JIA from the Republic of Bashkortostan, Russia. Genotyping was performed by real-time PCR method and statistical processing of the results – with the Mann-Whitney U test.

Results: The study of the IL2-IL21 rs6822844 single-nucleotide polymorphism showed, that in the carriers of the GG genotype (n=271), JIA developed statistically significantly earlier than in the carriers of the T allele (4.16 (2.14;8.09) vs 6.00 (3.03;8.78) years respectively, p=0.045). In contrast, patients with the GT genotype (n=54) tended to have a later onset of the disease than the other patients had (6.00 (3.01;8.78) vs 4.19 (2.19;8.09) years respectively, p=0.072). In a sex-stratified analysis, similar patterns for the GG and GT genotypes were found only for girls with JIA, being even more pronounced and in both cases reaching a statistical significance level (GG (n=174) vs GT+TT (n=42): 3.19 (1.90;6.79) vs 4.97 (3.01;9.65) years, p=0.008 and GT (n=41) vs GG+TT: 4.64 (3.01;8.25) vs 3.21 (1.90;6.99) years, p=0.013 respectively). It should be noted, however, that there was only one girl with the TT genotype in the studied JIA patients’ sample, and age at the disease onset of this girl was 9.65 years.

Conclusion: In this study, the association between the IL2-IL21 rs6822844 locus polymorphic variants and age at JIA onset in girls was established.

References

1. Ravelli A, Martini A. Juvenile idiopathic arthritis. Lancet. 2007 Mar 3; 369 (9563): 767-78.

2. Donn R, De Leonibus C, Meyer S, Stevens A. Network analysis and juvenile idiopathic arthritis (JIA): a new horizon for the understanding of disease pathogenesis and therapeutic target identification. Pediatr Rheumatol Online J. 2016 Jul 2;14(1):40.

Disclosure of Interest

None Declared

P058 MOLECULAR AND CELLULAR BIOMARKERS THAT DISCRIMINATE JUVENILE IDIOPATHIC ARTHRITIS FROM SEPTIC ARTHRITIS

Nadege Nziza^1,2,3, Mailys Cren^1,3, Aurelia Carbasse⁴, Perrine Mahe⁴, Marion Delpont⁵, Djamel Louahem⁵, Hugues Chevassus⁶, Mirna Khalil⁶, Thibault Mura⁷, Christian Jorgensen^1,3,8, Isabelle Duroux-Richard^1,3, Eric Jeziorski⁴, Florence Apparailly^1,3,8, Pascale Louis-Plence^1,3

¹National Institute of Health and Medical Research, Montpellier; ²Arthritis R&D, Neuilly sur Seine; ³University of Montpellier; ⁴Paediatric Department; ⁵Pediatric Orthopedic Surgery Unit; ⁶Centre d'Investigation Clinique, University Hospital of Montpellier; ⁷Department of Medical Information, La Colombière Hospital; ⁸Clinical department of Osteoarticular diseases and Biotherapy, University Hospital Lapeyronie, Montpellier, France

Correspondence: Nadege Nziza

Introduction: Juvenile idiopathic arthritis (JIA) and septic arthritis (SA) are the most frequent cause of arthritis among children under the age of 16 years. JIA is an auto-immune disorder involving articular inflammation that persists for more than 6 weeks, while SA is caused by bacterial infection in children joints. Although these diseases have different physiopathological basis and involve different treatments and prognoses, they share clinical similarities.

Objectives: To date, there are no markers sufficiently reliable to discriminate between these two forms of arthritis at the onset of the disease. Our goal is to respond to this clinical need by identifying diagnostic biomarkers capable of discriminating between JIA and SA. To that end, we focused on microRNAs (miRNAs) and myeloid cell subsets, both playing a major role in inflammation and autoimmune disorders.

Methods: We analyzed serum and synovial fluid (SF) samples from patients with inflammatory or septic arthritis using a miRNAs Whole Transcriptome Assay associated with a next-generation sequencing detection technology to measure the expression level of 2083 miRNAs in a pilot study (oligoarticular JIA (oJIA): n=5; SA: n=3) and validated using RT-qPCR in a replicative study (oJIA: n=9; SA: n=9). In parallel, we performed a phenotypic characterization of peripheral blood (PB) and SF myeloid subpopulations using a flow cytometer in order to identify cellular biomarkers (oJIA: n=9; SA: n=8).

Results: Principal component analysis and hierarchical clustering characterizations did not show significant differences between serum miRNAs of oJIA and SA patients. However, we observed a distinct miRNA profile signature in SF between the two diseases with 16 upregulated miRNAs and 5 down-regulated that perfectly discriminates oJIA and SA (p<0.01). In addition, phenotypic characterization revealed the existence of 5 myeloid cell subsets with distinct accumulation profile between the SF of oJIA and SA (p<0.05). A study of their activation profile indicated differences in the expression of cellular markers between the two groups.

Conclusion: In this study, we propose for the first time a synovial fluid-based miRNA signature as well as 5 myeloid cell subsets that discriminate between oJIA and SA and might be used as potential diagnosis markers in juvenile arthritis.

Disclosure of Interest

None Declared

Translational science

P059 EVALUATION OF PLASMA MICRORNA EXPRESSIONS IN PATIENTS WITH JUVENILE IDIOPATHIC ARTHRITIS

Ferhat Demir¹, Alper H. Çebi², Mukaddes Kalyoncu¹

¹Department of Pediatric Rheumatology; ²Department of Medical Genetics, Karadeniz Technical University Faculty of Medicine, Trabzon, Turkey

Correspondence: Ferhat Demir

Introduction: Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease of childhood and its etiology is unknown. Microribonucleic acids (miRNAs) are small (16–24 nucleotides), non-coding RNA molecules that have roles on the regulation of gene expression at the post-transcriptional stage. It is also known that microribonucleic acid (miRNA)s play a role in immunoregulation.

Objectives: We aimed to evaluate plasma expression of some candidate miRNAs that associated with pathogenesis of autoimmunity.

Methods: Thirty-one patients diagnosed with JIA and age-sex matched 31 healthy children were enrolled for the study. Plasma levels of four candidate miRNAs (miRNA-16, miRNA-155, miRNA-204 and miRNA-451), which is known to be associated with autoimmunity were examined in all subjects. Plasma levels of miRNAs were measured with Real Time PCR in patients in active and inactive period and in healthy controls. Groups were compared with each other.

Results:

Plasma miRNA-155 levels were found to be increased in JIA patients compared to the healthy controls and it was statistically more significant in inactive period. We found that JİA patients had higher levels of miRNA-16 and lower levels of miRNA-204/miRNA-451 expressions compare with the control group, but there was no statistically significant difference. A statistically significant decrease in plasma levels of miRNA-204 was found in patients that were in inactive disease with only methotrexate therapy. Plasma miRNA expressions were compared in JIA subtypes and it was observed that miRNA-204 levels were higher in polyarticular JIA and miRNA-451 levels were higher in entesitis related arthritis without statistical significance.

Conclusion: Significant alterations in the plasma expression of miRNA-155 and miRNA-204 suggest to us that these molecules may be related to pathogenesis of JIA. More comprehensive and functional researches about the role of this molecules are needed in this regard.

Disclosure of Interest

None Declared

Table 1 (abstract P059). The mean plasma miRNA 2^-ΔCT level of patients in aJIA, iJIA and HC groups and comparison of it (include JIA patients that treated with only methotrexate)

P060 RENAL AUTOIMMUNITY IN IPEX SYNDROME

Cécile Frachette¹, Alain Lachaux², Marc Nicolino³, Irene Loras-Duclaux², Frederique Dijoud⁴, Nicole Fabien⁵, David Goncalves⁵, Christophe Malcus⁶, Maud Rabeyrin⁷, Olivia Gillion-Boyer⁸, Gwenaëlle Kesler-Roussey⁹, Alexandre Fabre¹⁰, Bertrand Roquelaure¹⁰, Michel Tsimaratos¹¹, Joelle Terzic¹², Anne-Laure Mathieu¹³, Sebastien Viel¹³, Justine Bacchetta¹, Thierry Walzer¹³, Pierre Ray¹⁴, Alexandre Belot¹

¹Pediatric nephrology and rheumatology; ²Pediatric Gastroenterology department; ³Pediatric endocrinology; ⁴Pathologist departement, Hôpital Femme Mère Enfant, Bron (Lyon); ⁵Immunology, CHU de Lyon, Groupe hospitalier Sud, Pierre-Bénite (Lyon); ⁶Immunology; ⁷Pathologist department, Hôpital Edouard Herriot, Lyon; ⁸Pediatric nephrology, Hôpital Necker-enfants-malades, Paris; ⁹Pediatric nephrology, CHU de Nantes, Nantes; ¹⁰Pediatric Gastroenterology; ¹¹Pediatric nephrology, Hôpital de La Timone Enfants, Marseille; ¹²Pediatric nephrology, Hôpital de Hautepierre, Strasbourg; ¹³Innate Immunity and Autoimmune diseases, Centre international de Recherche en Infectiologie, Lyon; ¹⁴Genetic department, CHU Grenoble-Alpes, Grenoble, France

Correspondence: Cécile Frachette

Introduction: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare monogenic primary immunodeficiency affecting T regulatory lymphocytes caused by FOXP3 mutation and is associated with multiple autoimmune disorders including enteropathy, diabetes and atopic dermatitis. Kidney involvement is uncommon but has been already reported. Little is known regarding the impact of Tregs deficiency on renal tolerance.

Objectives: This study is intended to describe the renal phenotype of IPEX patients and to determine the self reactivity of patient’s sera using a protoarray assay enabling the detection of the autoimmune repertoire across 8000 peptides.

Methods: We retrospectively collected clinical, histopathological and immunological data from IPEX patients seen in French pediatric immunology, rheumatology or nephrology centres. We retrieved patients sera and analyse the autoimmune repertoire targeting the kidney with a combined strategy of immunofluorescence crossreactivity on rats cell lines and direct crossreactivity on 8000 peptides (Protoarray, Thermofisher).

Results: In the index case, immunofluorescence staining showed linear deposits along the tubular basal membrane suggesting a B-cell mediated immunopathogeny. The patient serum was tested on regular renal cells from rats and indirect immunofluorescence showed crossreaction over species suggesting the presence of autoantibodies targeting the basal membrane in the serum of the patient.

Four other pediatric patients were included in this study in order to better characterize nephropathy in IPEX syndrome. A total of three patients had tubulonephritis, and this feature was the first manifestation of the disease for two of them. One of the patients had membranous nephritis and the other one presented microangiopathy secondary to calcineurin inhibitors toxicity. All patients were treated with immunosuppressive drugs, two underwent hematopoetic stem cell transplantation and one had kidney transplantation. The results of the protoarray in the first patient elicited more than 100 antibodies with high titers. Among them, about 15 were kidney specific. Additional samples may help to detect a common tubulointerstitial autoantibody.

Conclusion: This study highlights genetic and clinical heterogeneity of renal lesions in IPEX patients. Autoimmune nephropathy is rare but does exist in IPEX syndrome and may appear as glomerulopathy or tubulopathy. It is noteworthy to define specific autoantibodies that may help clinician to screen IPEX patients for renal lesions.

Disclosure of Interest

None Declared

P061 COMPARISON BETWEEN BIOMARKERS IN SYNOVIAL FLUID AND PLASMA IN JUVENILE IDIOPATHIC ARTHRITIS: PRELIMINARY DATA.

Mikhail Kostik¹, Daria Kozlova^2,3, Alexandr Popov^2,4, Dmitry Vasiliev^2,3, Vera Masalova¹, Eugenia Isupova¹

¹SAINT-PETERSBURG STATE PEDIATRIC MEDICAL UNIVERSITY; ²Ltd. "Scientific and Production Firm" ABRIS +; ³Sechenov Institute of Evolutionary Physiology and Biochemistry Russian Academy of Sciences; ⁴St. Petersburg State Technological Institute (technical university), Saint-Petersburg, Russian Federation

Correspondence: Mikhail Kostik

Introduction: Juvenile idiopathic arthritis (JIA) – is a chronic immune-mediated inflammatory joint disease in children under the 16 years. The peculiarities of JIA pathogenesis depend on JIA category and related to autoimmune or autoinflammatory mechanisms. Currently there are no unique approaches to evaluate JIA activity. The classical clinical and laboratory test, such as ESR and CRP no always correlate with local inflammation, joint erosions and so on. The finding of new biomarkers is actual, because can help more precise evaluate JIA activity, choose the appropriate treatment and better prognosis of outcomes.

Objectives: The aim of our study was to demonstrate possibility using of calprotectin, 14-3-3η and butirylcholinesterase (BUCHE) as a potential JIA biomarkers.

Methods: in pilot study were included 13 patients with JIA (4 boys and 9 girls) with enthesitis-related (n=3) and oligoarticular (n=9) JIA categories in whom calprotectin and 14-3-3η levels and activity of BUCHE in blood plasma - BP (n=12) and synovial fluid -SF (n=7) were measured. The onset age of patients was 3.9 (3.1; 8.9) years, disease duration – 3.7 (1.3; 6.6) years. Plasma and synovial fluid supernatant were used to determine the content of interleukin-6, calprotektin, protein 14-3-3η by the ELISA. Statistical analysis of data was carried out with the program Statistica 10.0. We utilized descriptive statistics (Me; IQR), Mann-Whitny and Wilcoxon tests, Pirson’s and Spearmen’s correlation analysis.

Results: Obtained data showed that the content of calprotectin in JIA in SF - 57.3 (47.3; 102.8) ng/ml was higher than in blood plasma – 5.8 (3.6; 15.0) ng/ml (р=0.02). It was shown that the content of 14-3-3η protein in JIA SF – 66.7 (56.4; 98.6) ng/ml is also higher than in BP- 46.4 (37.1; 53.1) ng\ml (р=0.02) that is also coincides with literature data obtained for blood plasma 14-3-3η levels in adult persons with rheumatoid arthritis (Walter P. et al., 2014). Activity of typical fraction of BUCHE was higher in BP -47.3 (39.8; 60.6) U/l than in SF - 30.2 (22.8; 39.1) U/l (р=0.027). Activity of atypical fraction of BUCHE was 14.2 (11.6; 16.7) U/l and 6.2 (5.0; 9.1) U/l in BP and SF, relatively (р=0.046), and activitiy of minor fraction of BUCHE was 0.46 (0.1; 1.1) U/l and 14.7 (12.2; 15.5) U/l in BP and SF, relatively (р=0.027). There weren’t found correlation between studied biomarkers and JIA measures, such as onset age, JIA duration, active joints count, ESR, CRP, JIA category, beside positive correlation between minor fraction of BUCHE in BP and active joints count (r=0,998; r<0,05) and negative correlation between CRP and 14-3-3η (r=-0.999; p<0.05) in SF. It was found that levels of calprotectin, 14-3-3η and minor fraction of BUCHE more effective reflect local inflammation than routine markers. We have found positive correlation between BP and SF for calprotectin (r=0.997; r<0.05) and 14-3-3η (r=0.958; r<0.05), but not for minor fraction of BUCHE.

Conclusion: We suppose that calprotectin and 14-3-3η in BP can be used as possible non-invasive biomarkers of JIA activity. Further investigations required.

Disclosure of Interest

None Declared

P062 MOLECULAR MECHANISMS OF PATHOGENIC T CELL RESILIENCE IN HUMAN ARTHRITIS

Pavanish Kumar¹, Leong Jing Yao¹, Bhairav Paleja¹, Joo Guan Yeo², Jorg van Loosdregt¹, Suzan Saidin¹, Camillus Chua¹, Thaschawee Arkachaisri³, Alessandro Consolaro⁴, Marco Gattorno⁴, Alberto Martini⁴, Gary W. Williams⁵, Ken D Pischel⁵, Martin Lotz⁶, Salvatore Albani¹

¹Translational Immunology Institute, SingHealth, DukeNUS; ²Translational Immunology Institute,SingHealth DukeNUS; ³Duke-NUS Graduate Medical School and Rheumatology and Immunology Service, KK Women's and Children's Hospital, Singapore, Singapore; ⁴Second Pediatrics Division, University of Genoa and G Gaslini Institute, Genova, Italy; ⁵Scripps Clinic, La Jolla, California; ⁶Department of Molecular Medicine, The Scripps Research Institute, La Jolla, Callifornia, USA

Correspondence: Pavanish Kumar

Introduction: One of the key elements of immune pathogenesis of human autoimmune arthritis is the resilience of pathogenic T cells. We have previously described that CD4+ T cells in patients with arthritis have an increased level of autophagy than their healthy equivalents. Here, we sought to explore at epigenetic and transcriptional levels the concept of persisting increased autophagy as the consequence of “autophagic memory”, as one of the mechanisms conferring resilience to pathogenic T cells, in particular to a subset of CD4+ T cells (CPL: Circulating Pathogenic-like Lymphocytes), which are significantly more represented in patients with active arthritis and resistant to therapy with biologics

Objectives: T-cell resilience is critical to the immune pathogenesis of human autoimmune arthritis Autophagy is essential for memory T cell generation and associated with pathogenesis in rheumatoid arthritis (RA). Our aim was to delineate the role and molecular mechanism of autophagy in resilience and persistence of pathogenic T cells from autoimmune arthritis

Methods: Autophagy was assessed in CD4+ T cell subsets from autoimmune arthritis pateints and healthy subjects using flow cytometry. RNA sequencing and methylation array analysis was performed to understand the molecular mechanism of autophagic memory. Transcription-factor gene regulatory network analysis was build to identify key regulators. qPCR was used to confirm the gene expression level of key regulator

Results: We demonstrate “Autophagic memory” as elevated autophagy levels in CD4+ memory T cells compared to CD4+ naive T cells and in Jurkat Human T cell line trained with starvation stress. We then showed increased levels of autophagy in pathogenic CD4+ T cells subsets from autoimmune arthritis patients. Using RNA-sequencing, transcription factor gene regulatory network and methylation analyses we identified MYC as a key regulator of autophagic memory. We validated MYC levels using qPCR and further demonstrated that inhibiting MYC increased

Conclusion: The present study proposes the novel concept of autophagic memory and suggests that autophagic memory confers metabolic advantage to pathogenic T cells from arthritis and supports its resilience and long term survival. Particularly, suppression of MYC imparted the heightened autophagy levels in pathogenic T cells. These studies have a direct translational valency as they identify autophagy and its metabolic controllers as a novel therapeutic target.

Disclosure of Interest

None Declared

P063 EXTENDED OLIGOARTICULAR AND POLYARTICULAR JUVENILE IDIOPATHIC ARTHRITIS PATIENTS HAVE A SIMILAR B CELL PHENOTYPE WHEN COMPARED TO ESTABLISHED RHEUMATOID ARTHRITIS

Rita A. Moura¹, Alexandre Brito¹, Susana Oliveira¹, Rui L. Teixeira^1,2, Vasco C. Romão^1,2, Vítor Teixeira^1,2, Raquel Campanilho-Marques^1,2, Filipa Oliveira-Ramos^1,2, João E. Fonseca^1,2

¹Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal; ²Rheumatology Department, Centro Hospitalar de Lisboa Norte, EPE, Hospital de Santa Maria, Lisbon Academic Medical Centre, Lisbon, Portugal

Correspondence: Rita A. Moura

Introduction: Our group has recently described that the majority of polyarticular juvenile idiopathic arthritis (pJIA) and a large fraction of extended oligoarticular JIA (oJIA) patients fulfil classification criteria for rheumatoid arthritis (RA) in adulthood. B cells play several important roles in RA pathogenesis, but it is still unclear if the pattern of B cell involvement in pJIA and extended oJIA follows what has been described for adults with RA.

Objectives: The main goal of this study was to characterize peripheral blood B cell phenotype and cellular activation in pJIA and extended oJIA patients when compared to established RA.

Methods: Blood samples were collected from JIA patients (N=10; mean age 10 ± 4 years), established RA patients treated with synthetic DMARDs (N=10; mean age 72 ± 7 years) and two corresponding groups of age- and sex-matched healthy donors. B cell phenotype was characterized by flow cytometry and B cell apoptosis was assessed after 48H of in vitro cell culture.

Results: JIA patients recruited in this study were either classified as extended oJIA (N=6) or pJIA (N=4). Seven JIA patients (4 extended oJIA and 3 pJIA) were treated with methotrexate and three patients (2 extended oJIA and 1 pJIA) were untreated. We found that JIA patients had similar CD19+ B cell levels in circulation when compared to controls, but significantly higher CD19+ B cell frequencies in comparison to established RA. In addition, increased frequencies of transitional (IgD+CD38++) and naïve (IgD+CD27+) B cell subpopulations were observed in JIA patients when compared to RA. However, established RA patients had significantly higher levels of CD21^lowCD38^low, post-switch (IgD-CD27+) and IgD-CD27- memory B cell subsets when compared not only to controls, but also to JIA patients. No significant differences were detected in pre-switch (IgD+CD27+) memory and plasmablasts (IgD-CD38++) levels in JIA patients when compared to both controls and RA. Furthermore, the frequency of CD5+ B cells, CD5 median fluorescence intensity (MFI), CD40 MFI and CXCR5 MFI B cell expression levels were significantly increased in JIA patients when compared to established RA, but not to controls. No significant differences were observed between JIA and established RA patients in BAFF-R, FcgRIIB, CD21, CD23, CD38, CD86, CD95, HLA-DR, TLR9 and RANKL expression on B cells. After 48H of in vitro cell culture a significantly higher B cell death was found in JIA in comparison to RA patients.

Conclusion: The increased frequencies of transitional, naïve and CD5+ B cells in circulation and reduced levels of memory B cell subpopulations in JIA patients when compared to established RA are probably related to an immature immune system present in children when compared to adults. Nevertheless, the similarity in B cell phenotype found between extended oJIA, pJIA and established RA patients suggests an early B cell involvement in the pathogenesis of these two categories of JIA.

Disclosure of Interest

None Declared

P064 THE AUSTRALIAN ARTHRITIS AND AUTOIMMUNE BIOBANK COLLABORATIVE [A3BC] PROTOCOL

Jane E. Munro¹, Lyn March², Craig Willers³, Chris Jackson³, Meilang Xue³, Catherine Hill⁴, Mihir Wechalekar⁵, Susan Lester⁶, Helen Benham⁷, Tony Kenna⁷, Helen Keen⁸, Chandima Perera⁹, Davinder Singh-Grewal¹⁰, Kevin Murray¹¹, Pavla Walsh¹², Peter Gowdie¹³, Christina Boros¹⁴, Navid Adib¹⁵, Joanna Cobb¹, Rachelle Buchbinder¹⁶, Marissa Lassere¹⁷, Jeff Chaitow¹⁸, Mike Inouye¹⁹, Claire Barrett²⁰, Graeme Carroll²¹, Justine Ellis¹

¹Murdoch Children's Research Institute, Melbourne; ²Institute for Bone and Joint Research (IBJR): University of Sydney & Royal North Shore Hospital, NSW; ³Institute of Bone & Joint Research - Sydney University & Kolling Institute, Sydney; ⁴Royal Adelaide Hospital6; ⁵Flinders Hospital; ⁶Queen Elizabeth Hospital, Adelaide; ⁷University of Queensland Diamantina Institute, Brisbane; ⁸Fiona Stanley Hospital, Perth; ⁹Canberra Hospital, Canberra; ¹⁰Westmead Children's, Sydney; ¹¹Princess Margaret Hospital21; ¹²Princess Margaret Hospital, Perth; ¹³Monash Children's, Melbourne; ¹⁴Women's and Children's, Adelaide; ¹⁵Wesley Hospital, Brisbane; ¹⁶Monash Univeristy, Melbourne; ¹⁷Uni NSW; ¹⁸Westmead Childrens, Sydney; ¹⁹Baker Institute, Melbourne; ²⁰Royal Brisbane and Women’s Hospital25, Brisbane; ²¹Private practice, Perth, Australia

Correspondence: Jane E. Munro

Introduction: The australian arthritis and autoimmune biobank collaborative = a3bc a national paediatric and adult rheumatology clinical research network

Objectives: The A3BC seeks safer, more effective and evidence-based prevention, diagnosis, treatment and prognosis strategy in arthritis and autoimmune disease. Key A3BC aims are to

Develop a higher level of capability by collaborating across multiple disciplines and sector

Progress precision medicine by growing capacity in open-access, data-linked biobanking

Innovate preventive medicine by forming unique partnerships with population health research

Demonstrate a new era of data linkage and use to inform policy and practice decision-making

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Methods: The A3BC protocol was developed in consultation with leading researchers, clinicians, industry and best practices. A3BC processes will initially run parallel to the Australian Rheumatology Association Database (ARAD), but will merge in the future. The initial A3BC disease focus is Rheumatoid Arthritis, Juvenile Arthritis, Psoriatic Arthritis and Ankylosing Spondylitis.

Recruited through over 40 sites nationally, participants donate blood (20-53mls) and synovial tissue/fluid, stored across 10 biobank nodes as plasma, serum, PBMCs, DNA and RNA. On a project basis, newborn screening cards, urine and/or faeces are accessed.

These samples are accompanied by standardised pre-analytical variables and clinical data, and linked datasets including the ARAD, electronic medical records, Commonwealth health (e.g. Pharmaceutical Benefits Scheme, Medicare)), registries (e.g. cancer, death), longitudinal/lifecourse data (e.g. Juvenile Arthritis national CLARITY project), and consumer entry (My Health Record).

Using cutting-edge capture, real-time analytics and dashboarding processes and systems, all data is integrated and mined for patterns and associations, then effectively communicated to practitioners and policy-makers.

Results: The A3BC protocol will result in new dataset integration systems, new multidisciplinary collaborations, and identification of new risk factors, biomarkers and cross-dataset associations. It will improve research by enabling innovative research questions and faster translation. And facilitate health policy/practice decision-making in precision and preventive medicine.

Conclusion: The A3BC protocol provides best-practice, quality assured and validated methods to realise its aims. Current experience from recruiting and processing participants demonstrates that the protocol’s methods and technologies are fit-for-purpose.

Disclosure of Interest

None Declared

P065 ROLE OF THE ORAL MICROBIOME IN PEDIATRIC AUTOIMMUNE AND AUTOINFLAMMATORY DISEASE

Prasad T. Oommen, Benjamin Reinbeck, Arndt Borkhardt, Ute Fischer

¹Clinic for Paediatric Oncology, -Hematology and Clinical Immunology, Heinrich-Heine-University, Medical Faculty, Duesseldorf, Germany

Correspondence: Prasad T. Oommen

Introduction: Neither genetic, epigenetic nor environmental factors alone have been able to unravel the pathogenesis of autoimmune and autoinflammatory diseases in children and adolescents. The specific aspects which determine the individual susceptibility to the development of a rheumatic disease are still to be elucidated. As of now, these conditions are seen as multifactorial in respect of pathogenesis. The microbiome has been under discussion as a contributing factor. Microbial communities who play an important role in the physiological development of the immune system may turn into "false friends" leading to the state of dysbiosis.

Objectives: We aimed to gain new data in this context via examing the oral microbiome in patients with different rheumatic diseases in children and adolescents.

Methods: We examined the oral microbiome by obtaining oral swabs of 11 patients with juvenile idiopathic arthritis and 20 patients with chronic non-bacterial osteomyelitis (CNO).

The hypervariable region V6–V7 of the 16S rRNA gene was amplified and subsequently sequenced. The following bioinformatic analysis was performed with QUIIME (Quantitative Insights Into Microbial Ecology).

Results: In accordance to previous studies we were able to identify Actinobacteria and Fusobacteria on the phylum level as microbiota only present in our JIA cohort. In the CNO cohort so far no distinct microbiotic players could be detected. For this entity the only data so far describe an advantage in mice who were fed with a high-fat diet resulting in a shift in the microbial environment leading to a better course of the disease. These mice data could - as of now - not be shown in our patients.

Conclusion: The microbiome may open a new door to a better understanding of multifactorial autoimmune and autoinflammatory disease. In accordance to previous studies we were able to identify specific microbiota present only in JIA patients. However, the clinical consequence and the exact immunological effects of dysbiosis are still to be unravelled. As of now, studies of the microbiome may enhance the pathophysiologic understanding of these diseases.

Disclosure of Interest

None Declared

P066 EVALUATION OF THE ROLE OF SIGNAL PEPTIDE-CUB-EGF DOMAIN-CONTAINING PROTEIN (SCUBE)1 AND SCUBE2 IN JUVENILE IDIOPATHIC ARTHRITIS

Duygu Selimoğlu¹, Ferhat Demir², Süleyman C. Karahan³, Mukaddes Kalyoncu²

¹Department of Pediatrics; ²Department of Pediatric Rheumatology; ³Department of Biochemistry, Karadeniz Technical University Faculty of Medicine, Trabzon, Turkey

Correspondence: Duygu Selimoğlu

Introduction: Juvenile idiopathic arthritis (JIA) is a disease that begins in patients under sixteen years of age, continues longer than six weeks, and diagnosed with arthritis in at least one joint. Other causes of arthritis should be excluded for diagnosis of JIA. The etiopathogenesis is still unclear and it is thought that it is the result of the immunological response due to environmental and genetic factors.  Signal peptide-CUB (complement C1r/C1s, Uegf, and Bmp1)-EGF (epidermal growth factor)-like domain-containing protein (SCUBE) is a newly defined, secreted cell surface protein. SCUBE1 and SCUBE2 have been shown to play a role in various pathophysiological processes such as vascular endothelial cells, inflammation, cancer metastasis, and vascular diseases.

Objectives: We aimed to research whether there is a relationship between SCUBE1 and SCUBE2 proteins, and JIA.

Methods: Between January 2016 and May 2017, the patients admitting to outpatient clinics in Pediatric Department of Farabi Hospital in Karadeniz Technical University and diagnosed with JIA according to ILAR criteria were included. Patients who used steroid or non-steroidal anti-inflammatory drugs in last three months were excluded. Blood samples collected from patients who were in active and recovery phases of their diseases and healhty control group. IL (interleukin)-1, IL-6, TNF (tumor necrosis factor)-α, SCUBE1 and SCUBE2 levels were studied by ELISA method. Patients with oligoarticular JIA were classified as Group 1, patients without oligoarticular JIA as Group 2 and these two groups were compared according to the blood results of cytokines and SCUBE’s mentioned above.

Results: A total of 24 patients, 11 (45.8%) were male and 13 (54.2%) female, aged between 2 and 17 years old, who were diagnosed with JİA, were included in the study. Fifteen (62.5%) patients were diagnosed as oligoarticular JIA, eight (33.3%) patients polyarticular JIA and one (4.2%) patient systemic JIA. İn the active phase of disease, IL-1 and IL-6 levels found significantly higher in Group 2 than in Group 1 (p=0.01 and p=0.004, respectively). TNF-α and SCUBE1 levels were higher in healing phase of the disease than in active phase (p=0.03 and p=0.01, respectively). TNF-α levels were higher in the active period of the disease than in the control group (p=0.02). SCUBE1 levels in the healthy control group were found to be significantly higher than the active period of the disease (p=0.009). TNF-α levels were higher in the recovery period of the disease than in the control group (p=0.004). SCUBE1 and TNF-α levels were found to be higher in the healing period of disease than in the active period (p=0.02 and p=0.03, respectively). SCUBE2 levels were found to be higher in patients with thrombocytosis in acute period (p= 0.01).

Conclusion: These results concluded that SCUBE can not be used as early biomarker in JIA, but SCUBE may has a role of JIA pathogenesis. We believe that this situation can be elucidated by studies on more patients in this regard.

Disclosure of Interest

None Declared

P067 FEATURES OF IMMUNOLOGICAL PARAMETERS IN CHILDREN WITH VARIOUS ARTICULAR PATHOLOGIES.

Anna Y. Spivakovskaya¹, Yuri Spivakovskiy¹, Yuri Chernenkov¹

¹Depertment of Hospitality Pediatrics, Saratov State Medical University, Saratov, Russian Federation

Correspondence: Anna Y. Spivakovskaya

Introduction: Timely diagnosis of various diseases of their nature, manifested by inflammatory changes in the joint apparatus of the child, is one of the priority tasks of modern children's rheumatology. Juvenile idiopathic arthritis (JIA) remains one of the most serious and potentially disabling diseases. At the same time, one of the most complicated tasks is the timely differential diagnosis of various variants of the articular form of juvenile arthritis and reactive arthropathy (ReA).

Objectives: To determine the concentration of individual Th1- (IL-1β, IL-6, INF-γ), Th2- (IL-4) and Th17-associated interleukins (IL-17) in serum in children with JIA and ReA.

Methods: The study involved 78 children, aged 1.1 years to 16.11 years. A group of children with a verified diagnosis of JIA consisted of 56 patients - 30 patients with an oligoarticular variant of the course of the disease and 26 with a polyatricular variant, an average age of 10.2 ± 3.8 years, a group of ReA - 22 children an average age of 7.49 ± 3.95 years. To compare the revealed relationships, a similar analysis was carried out in the group (n = 20) of relatively healthy children, the average age was 9.2 ± 3.99 years.

The concentration of interleukins in the blood serum was determined by ELISA using ready-made commercial kits for the detection of IL-1β IL-4 IL-6 INF-γ from Vector-Best Europe (Novosibirsk, Russia) and IL-17 firm "eBioscience" (Vienna, Austria).The work was carried on the automated enzyme immunoassay analyzer "Lazurite" (Dynex Technologies Inc., USA).

Results: In children with JIA, a higher concentration of Th1-associated cytokines was observed with respect to similar parameters in children with ReA and from the comparison group, so the concentration of IL-1β was 1.5-2 times higher than in patients with ReA and in relatively healthy children , INF-ɣ was 1.9 times higher than in patients with ReA and 3.5 times higher than the values ​​in the comparison group. At the same time, the concentration of Th2-associated cytokine (IL-4) in the blood serum of children with JIA was practically the same as for the comparison group and children with ReA.

In patients with ReA, in the absence of significant differences in the concentration of IL-1β, IL-6, IL-4 in the blood serum from similar parameters in relatively healthy children, 1.8-fold increase in the INF-отмеча level and a 1.5-fold decrease concentration of IL-17.

In children with articular form of JIA and ReA, there was a mixture of immune responses toward the activation of Th1-associated cytokines relative to the parameters of the comparison group, but with JIA this imbalance was greater than in patients with ReA. A key role in mixing immune responses towards the activation of Th1 cells in patients with ReA was played by a change in the ratio INF-ɣ / IL-4. A change in the balance in the Th1 / Th17 cell system was due to a change in the INF-ɣ / IL-17 ratio.

When performing the correlation analysis in patients with different variants of articular pathology, the following significant correlation pairs were obtained: for the oligoarticular version of JIA-INF-ɣ and IL-4; polyarticular JIA-IL-1β and IL-4, IL-1β and IL-17, IL-6 and IL-17; ReA-INF-ɣ and IL-17, 1β and IL-17.

Conclusion: The course of JIA and ReA is characterized by a definite unidirectional disorder in the Th1- and Th2-associated cytokines, which fits into the overall picture of the deployment of the cascade of immuno-inflammatory reactions, which is relatively universal, but both by the severity of the established imbalance and by the nature of the revealed relationships immunological parameters has its own characteristics. The most informative at the stage of the differential diagnostic process of the joint form of JIA and ReA can be considered an interrelated analysis of the immunological activity of the inflammatory reaction.

Disclosure of Interest

None Declared

P068 ANTI-CYTOSOLIC 5′-NUCLEOTIDASE 1A AUTOANTIBODIES ARE COMMON IN PATIENTS WITH JUVENILE IDIOPATHIC ARTHRITIS AND ARE NEGATIVELY ASSOCIATED WITH UVEITIS IN PATIENTS WITH OLIGOARTICULAR DISEASE

Sarah L. Tansley¹, Zoe E. Betteridge², Diana Bosneaga², Eleanor Pring², Daniel M. Slade², Angela Midgley³, Michael Beresford³, Andrew Dick⁴, Wendy Thomson⁵, Lucy R. Wedderburn⁶, Athimalaipet Ramanan⁴, Neil J. McHugh² and Childhood Arthritis Prospective Cohort Study

¹Rheumatology, Royal National Hospital for Rheumatic Diseases; ²Pharmacy and Pharmacology, University of Bath, Bath; ³University of Liverpool, Liverpool; ⁴University of Bristol, Bristol; ⁵University of Manchester, Manchester; ⁶Institute of Child Health, UCL, London, UK

Correspondence: Sarah L. Tansley

Introduction: Autoantibodies targeting cytosolic 5′-nucleotidase 1A (cN1a) were first identified in adults with inclusion body myositis but have subsequently been reported in a variety of other autoimmune diseases. They have recently been described in patients with Juvenile Idiopathic Arthritis (JIA) but to date clinical associations are unknown [1].

Objectives: We aimed to determine the prevalence and clinical associations of anti-cN1a in a UK cohort of patients with JIA.

Methods: We screened sera from 227 patients with JIA enrolled in the Childhood Arthritis Prospective cohort study for anti-cN1a by ELISA (16 systemic, 98  oligoarthritis, 52 rheumatoid factor negative polyarthritis, 12 rheumatoid factor positive polyarthritis, 9 enthesitis related arthritis, 16 psoriatic, 12 undifferentiated). In addition, sera from 45 healthy juvenile controls, 52 patients with Juvenile-onset myositis (JDM) and 20 patients with Juvenile onset Systemic Lupus Erythematosus (JSLE) were also screened. The negative cut-off was defined as more than 5 standard deviations above the mean of 34 normal healthy (adult) serum controls.

Results: Anti-cN1a were not identified in any healthy controls nor children with JDM but were present in 3 (15%) of patients with JSLE.

Anti-cN1a were present in 19 (8%) of children with JIA. They were present in all ILAR defined subgroups with the exception of systemic-onset JIA and were most common in those with enthesitis related JIA (22% anti-cN1a positive).

JIA patients with anti-cN1a were typically older at disease onset, although the age range was wide, median 8.8 years (IQR 2.7-12.1) versus 5.5 (IQR (2.0-11.0). The proportion of females was similar in both groups (74%  anti-cN1a positive and 66% anti-cN1a negative). Patients with anti-cN1a were more likely to be ANA positive 84% versus 53% (p=0.02) a dense fine speckle or homogenous immunofluorescence pattern was most common but different immunofluorescence patterns and ANA negative individuals were found in both groups.

Data on uveitis was limited to 139 JIA patients (10 patients with anti-cN1a). Three patients with anti-cN1a had a history of uveitis (one each of rheumatoid factor negative polyarthritis, enthesitis related arthritis and psoriatic arthritis) compared to 56 of 129 patients with available data who were anti-cN1a negative.  Of the 68 patients with oligoarthritis with uveitis data, 10 were anti-cN1a positive  and this group were less likely to develop uveitis than oligoarthritis patients who were anti-cN1a negative (p=0.03).

Conclusion: cN1a is a common target of circulating autoantibodies in UK children with JIA and are seen in all subtypes except systemic JIA. In patients with oligoartiuclar JIA, who are at a higher risk of uveitis, the presence of anti-cN1a was negatively associated with a history of uveitis. Further work is needed but patients with oligoarticular JIA and anti-cN1a may be at a lower risk of uveitis and may therefore not require as frequent ophthalmological screening.

References

1. Yeker, R.M., et al., Anti-NT5C1A autoantibodies are associated with more severe disease in patients with juvenile myositis. Ann Rheum Dis, 2018. 77(5): p. 714-719.

Disclosure of Interest

None Declared

Poster Walk 4: JIA clinical 1

P069 ‘A FIRST-DEGREE RELATIVE WITH PSORIASIS’ AS A CRITERION FOR THE ILAR CLASSIFICATION SYSTEM FOR JUVENILE IDIOPATHIC ARTHRITIS

Roselie Achten¹, Joost Swart¹, Gabriella Giancane¹, Tom Wolfs¹, Michael Hofer¹, Ekaterina Alexeeva¹, Violeta Panaviene¹, Susan Nielsen¹, Jordi Anton¹, Florence Uettwiller¹, Valda Stanevica¹, Maria Trachana¹, Denise Pires Marafon¹, Constantin Ailioaie¹, Elena Tsitsami¹, Sylvia Kamphuis¹, Troels Herlin¹, Pavla Dolezalova¹, Gordana Susic¹, Berit Flato¹, Flavio Sztajnbok¹, Angela Pistorio¹, Alberto Martini¹, Nicolino Ruperto¹, Nico Wulffraat¹

¹PRINTO, Istituto Gaslini, Genova, Italy

Correspondence: Roselie Achten

Introduction: Literature showed the importance of classifying patients into the right Juvenile Idiopathic Arthritis (JIA) category to provide them with optimal treatment¹. However, a substantial amount of patients were classified as ‘undifferentiated JIA’ (UJIA) due to the strict exclusion criteria, harbouring the risk of losing the indication of the preferred treatment.

Objectives: The aim of this study was therefore to investigate the influence of ‘a first-degree relative with psoriasis’, which is an inclusion criterion for psoriatic arthritis and an exclusion criterion for the ‘remaining five JIA categories’. This results in more insight in the accuracy of the classification system for JIA from the International League of Associations for Rheumatology (ILAR).

Methods: Analyses were made in a retrospective and prospective cohort of 8,309 patients with JIA. 606 patients were classified as UJIA, 303 patients as ‘psoriatic arthritis’ (PSA) and 7,400 patients as one of the ‘remaining five categories’.

Results: 225 (37.1%) patients with UJIA had ‘a first-degree relative with psoriasis’. No significant difference was found between the PSA and UJIA category in the number of patients with ‘a first-degree relative with psoriasis’. None of the abovementioned 225 patients developed psoriasis during the observation period. Only 60 (20.8%) patients were classified as PSA because of the inclusion criterion of having ‘a first-degree relative with psoriasis’ in the PSA category.

Conclusion: The exclusion criterion ‘a first-degree relative with psoriasis’ increases the number of patients classified as UJIA. No significant difference was found between the PSA and UJIA category in the number of patients with ‘a first-degree relative with psoriasis’, suggesting this criterion is not of added value for the ILAR classification system for JIA. We conclude that ‘a first-degree relative with psoriasis’ is not a necessary inclusion criterion for psoriatic arthritis. For these reasons, we suggest removing the inclusion and exclusion criterion ‘a first-degree relative with psoriasis’ for all the JIA categories.

References

1. Beukelman T, Patkar NM, Saag KG, 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. 2011;63(4):465–82.

Disclosure of Interest

None Declared

P070 THE FREQUENCY OF JUVENILE SPONDYLOARTHROPATHIES IN CHILDREN WITH FAMILLIAL MEDITERRANEAN FEVER

Emre Ozer¹, Demet Seker¹, Emir Taner¹, Amra Adrovic¹, Sezgin Sahin¹, Kenan Barut¹, Oya Koker¹, Ozgur Kasapcopur¹

¹Department of Pediatric Rheumatology, Istanbul University, Cerrahpasa Medical School, Istanbul, Turkey

Correspondence: Amra Adrovic

Introduction: Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease characterized with fever, recurrent episodes of self-limiting polyserositis and arthritis. FMF arthritis is generally acute monoarthritis especially in the larger joints of the lower extremities, healing without a sequelae. However some of the patients develop different type of chronic arthritis, predominantly oligoarticular juvenile idiopathic arthritis (JIA) and juvenile spondyloarthropathies (JSpA). Studies on JSpA among childhood FMF patients are scarce.

Objectives: To evaluate the frequency of JSpA in a large childhood FMF cohort. Furthermore, we aimed to define main characteristics of JSpA among childhood FMF patients.

Methods: A total of 320 juvenile FMF patients were blindly questioned according to recently proposed criteria for JSpA by 3 researchers (EO, DS, ET). A standardized case report form including demographic data, clinical features, MEFV mutation and treatment was prepared and completed for each patient. Patients fulfilled the JSpA criteria were previously classified as probable JSpA. Afterwards, an expert in pediatric rheumatology (OK) reevaluated the classified patients and some of them were confirmed to be a definite while some of them were accepted as potential JSpA patients.

Results: 37 patients (11.5%) were initially classified as potential JSpA: 32 (10%) were accepted as definite and 5 (1.5%) as probable JSpA. Demographic, clinical and treatment data of definitive JSPA patients are shown in Table 1.

Conclusion: Articular involvement compatible with JSpA could be seen in childhood FMF patients. Spondyloarthropathies were detected in 10% of childhood FMF cases. The M694V mutation is the most common MEFV mutation among JSpA patients with FMF. JSpA should be considered in childhood FMF patients, especially in those chronic arthritis, axial involvement and enthesopathy.

Disclosure of Interest

None Declared

Table 1 (abstract P070). See text for description

P071 DIFFERENCES IN THE PERCEPTION OF DISEASE IMPACT BETWEEN US AND ITALIAN CHILDREN WITH JUVENILE IDIOPATHIC ARTHRITIS: A NETWORK ANALYSIS OF VIRTUAL FOCUS GROUPS

Alessandra Alongi¹, Serena Calandra¹, Susan Thornhill², Jennifer Stinson³, Stephanie Luca³, Jennifer Horonjeff⁴, Angelo Ravelli⁵, Jane E. Munro⁶, Esi M. Morgan⁷, Alessandro Consolaro⁵, OMERACT JIA Core Set Working group

¹UNIVERSITÀ DEGLI STUDI DI GENOVA, Genoa, Italy; ²Thornhill Associates, Hermosa Beach, USA; ³The Hospital for Sick Children, Toronto, Canada; ⁴Columbia University Medical Center, New York; ⁵Istituto Giannina Gaslini, Genoa, Italy; ⁶Murdoch Children’s Research Institute, Melbourne, Australia; ⁷Cincinnati Children’s Hospital Medical Center, Cincinnati, USA

Correspondence: Alessandra Alongi

Introduction: The OMERACT JIA Core Set Working Group formed in 2015 as an international initiative to revise the existing Core Set with relevant patient/caregiver input. In efforts to develop an updated, patient-centered Core Outcome, virtual focus groups (VFGs) to identify main patient/caregivers-valued themes regarding the physical, mental, and social impact of JIA disease activity states were conducted.

Objectives: To identify and prioritize key features defining patient-perceived inactive disease state and to examine possible cross-cultural differences in the main domains

Methods: Two sets of paired VFGs were conducted with JIA patients (adolescents and young adults) and parents (split by ages of their children) in two clinics, in the US and in Italy respectively. Eligibility included prior or current experience of JIA disease inactivity (>3 months). A 3-day facilitated online board was held per group, focusing on the impact of JIA on physical, mental and social health, and the perceived differences between active and inactive JIA. Participants were asked to identify and rank their five top priority features defining inactive disease. Content analysis of transcripts was conducted independently in the two centers and compared. Coded transcripts were further analyzed using network analysis, an approach that allows to study the structure of the connections between domains and the impact of specific items, measured by centrality indexes.

Results: 86 subjects were included. Caregiver were split by ages of their children (under and over 15 years old in the US sample; under and over 10 years old in the Italian sample). Patients were split in adolescents (15-17 years old in the US sample, 15-18 years old in the Italian sample) and young adults (18-24 years old in the US sample, 19-25 years old in the Italian sample). Qualitative analysis revealed psychosocial impact and limitations in daily activities emerged as main domains in both samples; fear of relapses and burden of medications were indicated as concerns mostly by Italian patients and caregivers, while the impact on children’s activities and family life appeared relevant in US groups. Network models of ranked “top five” remission-defining items identified absence of pain as the single item with the highest degree, closeness and between centrality, indicating high relevance; others central themes in both samples were absence of functional limitations, improved engagement and autonomy. When comparing network models by the two populations, reduction of anxiety and absence of uveitis showed the greatest differences in centrality across the samples, respectively showing higher centrality in the Italian and in the US groups.

Conclusion: Data analysis revealed several domains that need to be evaluated for the development of patient/parent-centered outcomes assessment instruments. Network models revealed the central role of pain, functional limitation and restricted participation in patient-perceived remission in both populations. Main differences in the two populations include the role of relapses, treatments and secondary demands in the impact of disease. Further analysis and cross-cultural validation of the results is planned to inform the development of patient/parent-centered outcomes measures.

Disclosure of Interest

None Declared

P072 POLYARTICULAR JUVENILE IDIOPATHIC ARTHRITIS WITH RHEUMATOID FACTOR: A RETROSPECTIVE MONOCENTRIC STUDY OF 46 PATIENTS

Charlotte Boussard¹, Ambre Hittinger¹, Pierre Quartier-Dit-Maire^1,2, Wouters Carine¹, Brigitte Bader-Meunier^1,2

¹IMAGINE Institute and Pediatric Immunology, Hematology and Rheumatology Unit, Necker-Enfants Malades Hospital, Assistance Publique Hôpitaux de Paris; ²Paris-Descartes University, Paris, France

Correspondence: Charlotte Boussard

Introduction: Rheumatoid factor (RF) positive polyarticular juvenile idiopathic arthritis (JIA) with is a rare subtype of JIA (2-5%) of patients. No series have been published on this topic.

Objectives: Our objective was to describe the demographics characteristics and the course of RF positive polyarticular JIA.

Methods: We performed a monocentric retrospective study of patients with RF positive polyarticular JIA included between 2008 and February 2018 in the database CEMARA of the French reference center for juvenile arthritis and rare pediatric systemic autoimmune diseases (RAISE). This data base has been approved by the French Commission Nationale Informatique et Libertés. We recorded patients age at onset, gender, familiy history, comorbities, growth-height charts, acute phase reactants, positivity of antinuclear antibodies (ANA) and anti-citrullinated protein antibodies (ACPA), treatments, side effects and course. Clinical remission was defined according to Wallace criteria¹.

Results: Fourty-six patients (40 girls, 6 boys) were included. The median age at onset was 13 years (5-23) and the median follow-up 3 years (1-15). Sixteen patients (35%) had a familial history of auto-immunity or juvenile inflammatory rheumatism. Two patients were siblings from the same non-consanguineous parents. Fourteen patients (30%, 4/6 boys, 10/40 girls) had associated conditions: 4 patients had auto-immune diseases (thyroiditis, vitiligo, Raynaud syndrome, insulin dependent diabetes), 3 (6,5%) had bronchiectasis, 5 (10,8%) a growth retardation. Finally two patients had a Mendelian diseases: Marfan syndrome and hereditary multiple osteochondromas resulting from heterozygote mutation of EXT1. ACPA and ANA were positive in 27/33 (82%) and 19/24 (79%) patients respectively. Twenty-one patients (45,6%) had an elevation of acute phase reactants at disease onset. Eight patients (17%) had erosive arthritis within the first year of evolution. The first line treatment was METHOTREXATE for 34 patients (74%) alone in 11 patients (32%)) or in association with anti-TNF in 23 patients (67%)). Twenty-four/27 patients (88%) were treated by anti-TNF: ETANERCEPT (74%), ADALIMUMAB (11%), and INFLIXIMAB (3.7%). Other biologic agents were RITUXIMAB (n=2), TOCILIZUMAB (n=4). ABATACEPT (n=6). Sixteen patients (35%) received short or sustained treatment with corticosteroids. Primary or secondary resistance for the first biological agent occurred in 3 (6.5%) and 4 patients (8.6%) respectively. Seventeen out of 35 patients (48%) were on remission on treatment or off treatment  (mean follow-up without relapse: 7 and 8 years respectively). Four patients (15%) who were treated by at least one biological agent presented side effects, which required to stop the treatment.

Conclusion: Our study confirms the severity of RF positive polyarticular JIA and emphasizes its demographic and immunological heterogeneity. This first report of bronchiectasis in this population emphasizes the need for a careful pulmonary evaluation. The frequency of family auto-immunity history and the occurrence in two siblings suggest that some FR positive polyarticular JIA might be monogenic diseases.

References

1. Wallace CA, Giannini EH, Huang B, Itert L, Ruperto N, Null N, et al. American College of Rheumatology provisional criteria for defining clinical inactive disease in select categories of juvenile idiopathic arthritis. Arthritis Care & Research. 1 juill 2011;63(7):929‑36.

Disclosure of Interest

None Declared

P073 FREQUENCY OF THORACOLUMBAR SPINE INVOLVEMENT IN PATIENTS WITH JUVENILE IDIOPATHIC ARTHRITIS

Selcan Demir, Fatma B. Ergen², Hafize E. Sönmez¹, Erdal Sag¹, Yelda Bilginer¹, Ustun Aydıngöz², Seza Ozen¹

¹Department of Pediatric Rheumatology; ²Department of Radiology, HACETTEPE MEDICAL FACULTY, Ankara, Turkey

Correspondence: Selcan Demir

Introduction: Juvenile idiopathic arthritis (JIA), is the most common chronic rheumatic disease among the world and the diagnosis is based on the exclusion of other causes in the presence of arthritis, lasting at least 6 weeks in children under 16 years of age.

Objectives: We aim to assess the frequency of thoracolumbar spine (TLS) involvement and Magnetic Resonance Imaging (MRI) findings in the patients with JIA.

Methods: Patients who underwent for thoracolumbar MRI, known or suspected JIA between January 2015–2017, were retrospectively re-examined by a musculoskeletal radiologist for the presence of inflammatory (central/corner lesion, costovertebral inflammation, supraspinous or interspinous enthesitis) and erosive (wedging, central erosion) lesions. At the time of spinal MRI we also investigated the presence of sacroiliac joint (SIJ) involvement, peripheral joint (PJ) involvement and symptoms for spine involvement.

Results: Totally 108 patients were re-examined. Finally, 52 patients (mean age: 14.5±3.4) with a definitive diagnosis of JIA were enrolled in the study. Among them 41 had enthesitis related arthritis (ERA), 4 had oligoarticular (OA), 5 had polyarticular (PA) JIA, one had psoriatic arthritis (PsA) and one had systemic JIA (sJIA). Among ERA patients there were at least one inflammatory lesion in 23 (56%), one erosive lesion in 3 (%7), and both inflammatory and erosive lesions in 3 (7%) patients. In ERA patients with positive findings at TLS MRI, 19 (82%) had sacroiliitis and 14 (60%) had peripheral arthritis concurrently. 15 (65 %) were clinically asymptomatic in terms of TLS involvement (none of them had inflammatory back pain or morning stiffness, the Schober’s test [>6 cm] and chest expansion [>10 cm] were normal). Among the patients with other subtypes of JIA, there were at least one inflammatory lesion in 5 (45%) and at least 1 erosive lesion in 1 (9%). In non-ERA patients with positive findings at TLS MRI, 6 (83%) were clinically asymptomatic for TLS involvement. Of note, one patient had sacroiliitis and 5 patients had peripheral arthritis in addition to TLS involvement.

Conclusion: Although current literature indicates that spinal MRI shows insufficient evidence for detecting early JIA; with this study we demonstrated that, Inflammatory and/or erosive lesions of thoracolumbar spine can be seen in asymptomatic patients of ERA and even in non-ERA JIA patients and the majority of spinal lesions detected in asymptomatic ERA and non-ERA JIA patients were inflammatory.

Disclosure of Interest

None Declared

P074 DAILY PHYSICAL ACTIVITY AND SLEEP IN CHILDREN WITH JUVENILE IDIOPATHIC ARTHRITIS AND HEALTHY CHILDREN IN RELATION TO PAIN

Simon Esbersen¹, Troels Herlin¹, Birgitte T. Mahler¹

¹Pediatrics and Adolescents Medicine, Pediatric Rheumatology, Aarhus University Hospital, Skejby, Denmark

Correspondence: Simon Esbersen

Introduction: Around 30% of children with juvenile idiopathic arthritis (JIA) suffer from daily pain regardless of medication. Pain in JIA causes disturbances in the circadian rhythm compared to healthy children.

Objectives: To study if pain is related to disturbed sleep, physical activity, and higher JIA disease activity compared to healthy age-matched controls.

Methods: A prospective observational study was conducted between 2016 and 2018. We wanted to include 100 JIA patients and 200 healthy age-matched controls between 6-16 years old. JIA patients were consecutively asked during their routinely visits to our outpatient clinic. Controls were invited by notice on the parents IT-based communication platform in schools. They were asked to complete a sleeping schedule and a pain app daily for one week. One time they answered retrospective surveys about pain, sleep, and activity.

Results: 93 with JIA and 188 controls were included. 76% of JIA patients and 43% of controls reported pain in retrospective questionnaires. In one week's observation, 84% with JIA and 70% of controls had pain minimum once. 32% with JIA and 6 % of controls reported daily pain. Pain intensity (VAS score 0-10) reported as median [min;max] was: 1.00 [0;8.25] for JIA patients and 0.29 [0;6.29] for controls. Pain prevalence and pain intensity were significantly higher in JIA patients compared to controls (p<0.05). 55% with JIA and 90% of controls always participated in physical education, thus JIA patients were significantly less active than controls. Pain did not reduce physical activity in JIA, but pain significantly lowered the level of activity in controls (p<0.001). No significantly relation between neither sleep disturbances and study groups nor sleep disturbances and pain was found. Disease activity (JADAS-27) in JIA was significantly positively correlated to pain intensity, and significantly related to reduced physical activity (p<0.05).

Conclusion: Pain is common in JIA patients and controls. JIA patients are significantly less active compared to controls. Low physical activity in JIA is not related to pain, but to increased disease activity. Higher pain intensity is related to higher disease activity in JIA. In controls, pain is related to reduced activity.

Disclosure of Interest

None Declared

P075 MUSCULOSKELETAL CONDITIONS AMONG PERINATALLY HIV-INFECTED ADOLESCENTS IN THE CAPE TOWN ADOLESCENT ANTIRETROVIRAL COHORT

Sana Mahtab^1,2, Chris Scott¹, Takwanisa Machemedze^1,2, Susan Joubert^1,2, Nana Akua Asafu-Agyei^1,2, Landon Myer³, Heather J. Zar^1,2

¹Department of Pediatrics & Child Health, Red Cross War Memorial Children's Hospital, University of Cape Town; ²SA MRC Unit on Child & Adolescent Health; ³Epidemiology & Biostatistics, School of Public Health & Family Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa

Correspondence: Sana Mahtab

Introduction: Perinatally HIV-infected adolescents (PHIVA) have been shown to have a higher risk of developing musculoskeletal diseases. Increasing access to antiretroviral therapy (ART) has dramatically improved life expectancy but little is known about musculoskeletal disease in PHIVA who are on ART in Africa.

Objectives: To study the prevalence and spectrum of musculoskeletal abnormalities in PHIVA on ART using the pediatric Gait, Arms, Legs, Spine (pGALS) screening tool.

Methods: HIV-infected and matched HIV-uninfected adolescents (HIV-) enrolled in the Cape Town adolescent antiretroviral cohort (CTAAC) had pGALS examination and screening musculoskeletal questionnaires completed by trained study clinicians. Childhood Health Assessment Questionnaires (CHAQ) were used to assess participants’ musculoskeletal health status; participants with abnormal pGALS examinations were referred to rheumatology.

Results: pGALS was performed on 473 PHIVA (median age: 13.1 years; 49% female; median age at ART initiation: 4.3 years) and 101 HIV negative adolescents (median age: 12.8 years; 54% female). Median duration on ART was 8.8 years (IQR 5.8-10.5) with 38% initiating ART at ≤2 years of age. Twenty-three percent of PHIVA were WHO HIV stage 4 at time of HIV diagnosis. At the time of pGALS screening, 60% were on two nucleoside reverse transcriptase inhibitors and a non-nucleoside reverse transcriptase inhibitor and 36% were on two nucleoside reverse transcriptase inhibitors and a protease inhibitor. Eighty percent of the PHIVA had viral load ≤100 copies/ml and the median CD4 count was 711cells/uL.

Of the 23 (4%) participants with abnormal pGALS screening, 21 (4.4%) were PHIVA and 2 (2%) were HIV negative adolescents, p=0.25. 45% of those with abnormal pGALS had abnormal CHAQ, or a positive musculoskeletal screening question. Ten (44%) of participants with abnormal pGALS screening reported physical symptoms (4 had joint pain, 3 had difficulty in getting dressed and 2 had difficulty in both getting dressed and taking stairs, 1 had joint pain along with difficulty in getting dressed and taking stairs).

Fifty percent of the PHIVA with abnormal pGALS were WHO HIV stage 4 while 22% of those with a normal pGALS were WHO stage 4, p=0.02. An abnormal pGALS was associated with longer duration of ART (median duration: 9.9 years vs 8.7 years with normal pGALS, p=0.01).

Amongst the 23 participants with abnormal pGALS, 2 PHIVA were diagnosed with Osgood-Schlatter Disease, 6 (4 PHIVA and 2 controls) with orthopedic conditions including scoliosis or osteochondroma, 9 PHIVA had underlying neurological conditions including cerebral palsy or a prior stroke and 6 PHIVA had mechanical joint conditions.

Conclusion: There was a low prevalence of musculoskeletal abnormalities in this group of PHIVA established on ART. Advanced HIV stage and longer exposure to ART were associated with musculoskeletal abnormalities. Screening for musculoskeletal abnormalities may target these subgroups of PHIVA.

Disclosure of Interest

None Declared

P076 LONG-TERM PRESERVATION OF MEASLES AND RUBELLA SPECIFIC-IGG ANTIBODIES IN CHILDREN WITH JUVENILE SPONDYLARTHRITIS ON ANTI-TNF TREATMENT- A PROSPECTIVE CONTROLLED STUDY

Despoina Maritsi¹, Stavroula Papailiou¹, John Kopsidas¹, Olga Vougiouka¹, Maria Tsolia¹

¹Second Department of Paediatrics, Medical School, National and Kapodistrian University of Athens, Athens, Greece

Correspondence: Despoina Maritsi

Introduction: Patients with autoimmune diseases are susceptible to infections due to their defective immune system and the receiving immunosuppressive treatment. Juvenile spondylarthritis (jSpA) often requires life-long treatment with biologics, which manage to fully control the disease. However, data regarding response and long-term immunological memory to specific vaccines are lacking.

Objectives: We aimed at a comprehensive assessment of how anti-TNfα therapy interferes with vaccine-specific-IgG titers in children with jSpA.

Methods: Prospective controlled study including 41 patients with jSpA and 149 matched-healthy controls. All patients had received two doses of MMR vaccine in early childhood. Demographic, clinical and laboratory data were collected. Type and duration of treatment was recorded. Samples were collected at diagnosis and at one and two years’ follow-up. Seroprotection rates as well as measles and rubella-IgG titers were measured and expressed as GMC's. The Hospital’s Research and Ethics’ Committee approved the study; written informed consent was obtained. Statistical significance was set at p<0.05 and analyses were conducted using STATA (version 13.0).

Results: The two groups had similar demographic characteristics, vaccination history and immunization status. No significant differences were detected in terms of vaccine type, time interval between the two vaccines as well as mean elapsed time from last vaccination to blood sampling. All patients in the ERA group were HLA-B27 positive. Seroprotection rates were adequate for both groups at all times. Both rubella and measles GMC’s were significantly lower in the jSpA compared to the control group (p<0.01) at one and three years’ follow up but not at diagnosis. During the follow-up period, the jSpA group had greater decrease in antibody levels as indicated from the significant interaction effect of analysis. Subgroup analysis showed that longer disease duration was directly correlated to lower antibody concentrations (p<0.01). Subgroup analysis on other parameters tested such as uveitis, sacroileitis, enthesitis, JADAS scores and type of anti-TNFa treatment did not specifically correlate with antibody loss. The same was true for comcommitant use of synthetic DMARD's.

Conclusion: Ant-TNFα treatment seems to reduce measles and rubella GMC’s. Further studies are required to assess long-term immunity conveyed by immunizations given at an early stage in children with rheumatic diseases, especially the ones receiving biologics. However, evaluation of immunization status against all vaccine preventable diseases in such patients may be beneficiary.

Disclosure of Interest

None Declared

P077 DISCORDANCES BETWEEN THE PARENT GLOBAL ASSESSMENT OF DISEASE ACTIVITY AND GLOBAL ASSESSMENT OF GENERAL WELL-BEING IN A MULTINATIONAL COHORT OF 9137 CHILDREN WITH JUVENILE IDIOPATHIC ARTHRITIS

Ellen Nordal^1,2, Alessandro Consolaro³, Marite Rygg³, Ingrida Rumba-Rozenfelde³, Nahid Shafaie³, Tadej Avcin³, Pierre Quartier³, Violeta Panaviene³, Nico Wulffraat³, Daniel Lovell³, Chris Pruunsild³, Gordana Susic³, Gaëlle Chédeville³, Soamarat Vilaiyuk³, Yosef Uziel³, Maria Trachana³, Pavla Doležalová³, Pekka Lahdenne³, Alberto Martini³, Nicolino Ruperto³, Angelo Ravelli³, For the EPOCA study group

¹Department of Pediatrics, University Hospital of North Norway; ²UiT The Arctic University of Norway, Tromsø, Norway; ³Pediatria II Reumatologia, PRINTO, Istituto Giannina Gaslini, Genova, Italy

Correspondence: Ellen Nordal

Introduction: The parent global assessment of disease activity (PDA) has been suggested to replace the parent global assessment of overall well-being (PWB) as the main patient-reported outcome incorporated in the Juvenile Arthritis Disease Activity Score (JADAS). JADAS is an important tool in a treat-to target-strategy in children with juvenile idiopathic arthritis (JIA).

Objectives: To investigate any discordance between PDA and PWB among children with JIA.

Methods: The EPidemiology, treatment and Outcome of Childhood Arthritis (EPOCA) study collected information on the health status of children with JIA currently followed worldwide. More than 9137 children with JIA from 118 pediatric rheumatology centers in 49 countries were included, and we analyzed the PDA and PWB reported by the parents. The differences between the visual analogue 10-cm scale (VAS) (range 0-10) of PDA and PWB were assessed. Discordance was defined moderate for a VAS difference >1 and ≤3, high for a VAS difference >3, and agreement if VAS difference was ≤1.

Results: PDA and PWB were available in 8615/9137 (94.3%) of the EPOCA participants. Mean (SD) PDA was 2.1 (2.7), while mean (SD) PWD was 2.0 (2.6). Among the one-fourth of patients with a VAS difference >1, the number of active joints, percentage of children with morning stiffness, and pain scores were significantly higher in the group assessing PDA higher than PWB. In contrast, there was a higher score indicating impaired quality of life when PWB was higher than PDA (Table 1). Also, in parents assessing PWB higher than PDA, the number of girls and the age at visit were significantly higher.

Conclusion: Overall,there is a high rate of agreement between PDA and PWB. In parents rating PDA higher than PWB, patients have higher number of active joints and pain scores, and more morning stiffness, while parents rating PWB highest had lower quality of life scores.

Disclosure of Interest

None Declared

Table 1 (abstract P077). Clinical characteristics of the cohort according to level of discrepancy between the parent assessment of overall disease activity (PDA) and the parent assessment of overall well-being (PWB).

P078 BENIGN COURSE UVEITIS ASSOCIATED WITH JUVENILE IDIOPATHIC ARTHRITIS

Alessandro Poletto¹, Maria Elisabetta Zannin¹, Giorgia Martini¹, Alessandra Meneghel¹, Fabio Vittadello², Francesco Zulian¹

¹Department of Woman and Child Health, University of Padua; ²Centro explora, Padua, Italy

Correspondence: Alessandro Poletto

Introduction: Up to now, few studies have been addressed to the natural history of uveitis associated to Juvenile Idiopathic-Arthritis (JIA-U) in order to properly select the treatment approach since the early disease manifestations.

Objectives: Aim of the present study was to identify the clinical characteristics of patients with benign course JIA-U in order to early select the appropriate treatment and predict the final outcome.

Methods: Patients with JIA-U with at least 3 year follow, classified according with the SUN criteria for uveitis and followed at our Pediatric Rheumatology/Ophthalmology unit entered the study. Information gathered for each patient included: sex, age at onset of arthritis and uveitis, interval time between arthritis and uveitis onset; uveitis laterality, intraocular inflammation grading, number and yearly distribution of flares, structural complications. Uveitis flare was defined as an increase of cells in the anterior chamber of 2+ or more as compared to the baseline. JIA-U patients in which DMARDs or biological agents have been started at first for arthritis have been excluded. Collected data were analyzed using descriptive statistics

Results: A cohort of 75 patients with JIA-U, with a median follow-up of 12.2 years (range 3-23.6), entered the study. In 21 (28%) uveitis has treated with just topical drugs (Group A), the remaining 54 (72%) with systemic treatments (DMARDs or biological agents etc.) (Group B). No relevant differences were found between the two groups as far as sex distribution, JIA subtype, ANA frequency or uveitis laterality. Age at uveitis onset was significantly higher in Group A (5.4 years) than in Group B (4.3 years). The interval time between arthritis and uveitis onset was also greater in Group A (1.56 years) as compared to Group B (0.85 years). No patient in Group A reported ocular complications while in Group B they were 0.61/patient. The mean number of uveitis flares during the observation period was significantly less frequent in Group A than in Group B (1.57 versus 6.96, p < 0.001). The same was observed considering the mean number of relapses/year. Interestingly, patients in Group A had no relapses during the second year of follow-up and achieved a complete uveitis remission, on just topical treatment, after mean 2.6 years from onset, significantly earlier than in severe forms (Group B) (7.37 years, p < 0.001).

Conclusion: Benign course JIA-U can be identified as self-limiting condition, with low number of relapses and lack of structural complications. Patients with uveitis onset after five years of age, interval time between arthritis and uveitis onset greater than one year and no relapses during the second year of follow-up are likely to have a mild uveitis course.

Disclosure of Interest

None Declared

JIA (oligo, poly, psoriatic)

P079 IMPROVEMENT OF PATIENTS WITH JUVENILE IDIOPATIC ARTHRITIS IN TREATMENT WITH BIOLOGICAL THERAPY

Cespedes C. Adriana¹, Villezcas C. Janeth², Torres J. Alfonso²

¹Pediatric rheumatology, High Specialty Medical Unit National Medical Center Hospital general "La Raza", Mexico; ²Pediatric rheumatology, High Specialty Medical Unit National Medical Center Hospital generates "La Raza", Coyoacan, Mexico

Correspondence: Cespedes C. Adriana

Introduction: Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in childhood. In the last two decades, advances in the knowledge of pathogenesis has allowed the development of specific biological therapies for the treatment of JIA with an improvement ACR 50 of 70% on average with anti TNF and Tocilizumab a year of treatment.

Objectives: To evaluate the improvement and adverse events in patients with juvenile idiopathic arthritis treated with biological therapy (Etanercept, Adalimumab and Tocilizumab.).

Methods: Were included patients with JIA, <16 years who received biological therapy (Adalimumab, Tocilizumab, Etanercept), for a minimum of 6 months, from 2012-2017, all had signed informed consent. Demographic variables were obtained at diagnosis, clinical characteristics, laboratory and improvement variables at the beginning of the biological, 6 months, a year and when entering the study (current).

Descriptive statistics were used, averages, frequencies and percentages for, Wilcoxon and McNemar test to measure differences between two related samples.

Statistical significance was considered p <0.05.

Results: Forty-three patients were included, 20 male and 23 female. Average age 12 years, average age at diagnosis 8 years, average evolution time before the biological 24 months. Subtypes: Polyarticular FR+ 16 (37%), Polyarticular FR– 14 (32%), enthesitis related arthritis 6 (14%), systemic 5 (12%), oligoarticular 2 (5%). Extra-articular symptoms: fever 6 (14%) uveitis 5 (12%). Average improvement ACR at 6 months, a year and current with adalimumab 66%, 76%, 74%; Tocilizumab 81%, 80%, 80% and Etarnecept 88%, 67%, 67%, respectively.

The adverse events reported were pain in the puncture site 40%, transaminasemia 9% and seroconversion of PPD 12%.

Conclusion: The ACR pedi improvement was greater than 70% with the 3 biological therapies used in this study during the first 6 months of treatment, which is maintained during 28 months of follow-up (ACR average of 66%). There is an adequate safety profile with the biological treatment, without having a tuberculosis case so far.

Disclosure of Interest

None Declared

P080 A DECISION ALGORITHM TO PREDICT SYNOVITIS AND GUIDE CLINICAL MANAGEMENT IN JIA PATIENTS WITH CLINICALLY SUSPECTED TMJ INVOLVEMENT

Alessandra Alongi¹, Gabriella Giancane¹, Alessandro Consolaro¹, Giacomo Chiappe¹, Nicola Laffi¹, Gian Michele Magnano¹, Angelo Ravelli¹

¹Istituto Giannina Gaslini, Genoa, Italy

Correspondence: Alessandra Alongi

Introduction: Temporomandibular (TMJ) synovitis is a common but rarely symptomatic involvement that can lead to severe functional disabilities in children with Juvenile Idiopathic Arthritis (JIA). Individual clinical signs lack sensitivity and specificity to distinguish acute synovitis from chronic damage or functional alterations, while the current gold standard test to detect acute and chronic changes in TMJ - contrast-enhanced MRI- is demanding and not available everywhere.

Objectives: To identify potential patterns of clinical predictors of MRI findings useful to stratify risk of synovitis in patients with suspected TMJ involvement and select which patients mostly require MRI testing and which can be treated directly.

Methods: Reports from 166 JIA patients (332 TMJ) followed in our clinic who underwent contrast-enhanced MRI for suspected TMJ involvement between 2007 and 2017 were retrospectively collected and analyzed. Data included TMJ symptoms and their timing, clinical signs of rheumatological and orthodontic examinations preceding MR execution and MRI abnormalities. Using MR findings (synovial fluid, bone marrow edema, synovial enhancement, condylar head erosions, disc displacement) we estimated a latent class model that identified subgroups of patients with different synovitis probability. The ability of clinical findings to predict class membership was then assessed through a Tree Augmented Naive (TAN) Bayes model. Finally, decision analysis network and tree were estimated to identify the most advantage clinical strategy for different combinations of signs and symptoms.

Results: Latent class analysis of MR findings classified patients into low (class 1, n = 176) and high (class 2, n = 156) likelihood of TMJ synovitis. Condition probabilities of items in the two groups are showed in the table. The classes showed association with specific profiles of TMJ signs and symptoms. A TAN Bayes model predicted low (class 1), high (class 2), and intermediate (class 3) synovitis probability based on signs and symptoms with an AUC of 0,87 for class 2, 0,89 for class 1 and 0,97 for class 3. 9 variables (limitation since less than 3 months, previous TMJ synovitis, retrognathia, TMJ palpation pain, temporalis palpation pain, laterodeviation at visit, limitation for 3-6 months, reduced condylar translation, laterodeviation since < 3 months) showed direct association with class membership. Based on these variables a Bayesian decision analysis (DAN) was conducted, assigning higher rewards respectively to immediate treatment for patients in class 2, non-treatment for class 1 and testing with MR in subjects with intermediate probability (class 3). The DAN resulted in a decision tree that revealed 4 clinical scenarios where immediate treatment was most favorable, 3 where non-treatment was suggested, and 7 where testing with MR was indicated.

Conclusion: Our analysis has the potential to inform clinical practice as it can be used to stratify patients according to TMJ synovitis risk. Particularly in limited-resource settings, the model could provide a diffusible and potentially extendable tool to guide the clinical work-up selecting patients who are most likely to benefit from MR testing.

Disclosure of Interest

None Declared

Table 1 (abstract P080). See text for description.

P081 RISK FACTORS OF DEVELOPING AUTOIMMUNE THYROID DISEASE IN PATIENTS WITH JUVENILE IDIOPATHIC ARTHRITIS

Laurie Baas¹, Joost Swart¹, Gabriella Giancane², Gerd Horneff³, Michael Hofer⁴, Ekaterina Alexeeva⁵, Violeta Panaviene⁶, Brigitte Bader-Meunier⁷, Jordi Anton⁸, Susan Nielsen⁹, Fabrizio De Benedetti¹⁰, Sylvia Kamphuis¹¹, Valda Stanevica¹², Maria Trachana¹³, Laura Marinela Ailioaie¹⁴, Elena Tsitsami¹⁵, Ariane Klein¹⁶, Kirsten Minden¹⁷, Ivan Foeldvari¹⁸, Johannes-Peter Haas¹⁹, Jens Klotsche¹⁷, Alessandro Consolaro², Francesca Bovis², Francesca Bagnasco², Angela Pistorio², Alberto Martini², Nico Wulffraat¹, Nicolino Ruperto²

¹Wilhelmina Children’s Hospital, Utrecht, Netherlands; ²Istituto Giannina Gaslini, Genova, Italy; ³Asklepios Klinic Sankt Augustin, Sankt Augustin, Germany; ⁴Lausanne University Hospital, Lausanne, Switzerland; ⁵Federal State Autonomous Institution, Saint-Petersburg, Russian Federation; ⁶Vilnius University, Vilnius, Lithuania; ⁷Université Paris-Descartes, Paris, France; ⁸Hospital Sant Joan de Deu, Barcelona, Spain; ⁹Juliane Marie Centret, Copenhagen, Denmark; ¹⁰IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy; ¹¹Sophia Children’s Hospital, Rotterdam, Netherlands; ¹²Bernu Kliniska Universitates Slimnica, Riga, Latvia; ¹³Hippokration General Hospital, Athens, Greece; ¹⁴“Alexandru I. Cuza” University, Iasi, Romania; ¹⁵Aghia Sophia Childrens Hospital, Athens, Greece; ¹⁶Asklepios Klinik Sankt Augustin, Sankt Augustin; ¹⁷German Rheumatism Research Centre Berlin, Berlin; ¹⁸Hamburger Zentrum für Kinder- und, Hamburg; ¹⁹German Center for Pediatric and Adolescent, Garmisch-Partenkirchen, Germany

Correspondence: Laurie Baas

Introduction: Juvenile idiopathic arthritis (JIA) is a chronic inflammatory disease of unknown origin which can be considered as an autoimmune disease.

Objectives: The aim of this study was to evaluate the frequency of symptomatic autoimmune thyroid disease (AITD) in children with JIA and to investigate if there are any factors contributing to a higher risk of developing AITD.

Methods: 8,309 patients, with a total observation time of 51,324 patient-years, were studied. PharmaChild, the largest JIA-registry was used for this, containing clinical and laboratory data. Patients who were members of the Paediatric Rheumatology INternational Trials Organisation (PRINTO) were enrolled for the registry. Numerous patient characteristics and the family history were calculated separately for the JIA patients with AITD and the patients without AITD.

Results: 96 of the 8,309 patients had AITD, which provided a prevalence of 1,2%. The median age of onset was significantly higher in the children with AITD (9,1 versus 7,1). Furthermore, significantly more females (84,4% versus 67,3%), ANA positivity (51,7% versus 40,8%), rheumatoid factor (RF) positive JIA (9,4% versus 3,8%) and psoriatic JIA (7,3% versus 3,4%) were seen in the AITD group. Additionally,  the AITD group had significantly more first degree relative with any autoimmune disease (26,4% versus 13,4%), or more specific with Hashimoto’s thyroiditis (13,2% versus 2,6%). Systemic JIA was significantly less prevalent in the AITD group (3,1% versus 11,1%).

Conclusion: This study showed that there is a higher prevalence of AITD among children with JIA than in the general population. Older at diagnosis of JIA, not having systemic JIA, ANA positivity, RF positive JIA and psoriatic JIA seemed to be risk factors, as well as as having a family history of autoimmune diseases, especially first degree relatives or more specific having a family history of Hashimoto’s thyroiditis.

Disclosure of Interest

None Declared

P082 PREDICTING RESPONSE TO METHOTREXATE IN CHILDREN WITH JUVENILE IDIOPATHIC ARTHRITIS: ROLE OF BIOMARKERS

Narendra K. Bagri¹, Subhradip Karmakar², Partha Haldar³, Rakesh Lodha¹, Sushil K. Kabra¹

¹Pediatrics; ²Biochemistry; ³Centre for Community Medicine, ALL INDIA INSTITUTE OF MEDICAL SCIENCES,NEW DELHI, INDIA, New Delhi, India

Correspondence: Narendra K. Bagri

Introduction: Introduction

Approximately 40% of the subjects fail to respond to 1st line therapy including methotrexate and DMARDs, thereby requiring additional therapy. This additional therapy is offered only after a failed trial of methotrexate owing to non-availability of a reliable predictive biomarker. This approach exposes children to ineffective drugs in addition to accrual of ongoing inflammation and joint deformities. Pretreatment estimation of inflammatory biomarkers like myeloid related protein (MRP) 8/14 may predict the response to methotrexate. We are presenting interim analysis of our ongoing study on role of biomarkers in predicting the response to methotrexate in children with JIA.

Objectives: To correlate baseline serum biomarkers; IL2, IL6, IL12, TNF a and  MRP 8/14 levels  in children with JIA before starting methotrexate with response to methotrexate as assessed by American college of Rheumatology (ACR) criteria at 3 months follow-up.

Methods: Baseline clinical characteristics of consecutive children with JIA were recorded and blood samples for estimation of biomarkers were collected prior to starting methotrexate. Clinical response at 3 months follow up was assessed as per ACR. Patients achieving ACR ≥50 were classified as responders, whereas those with ACR ≤ 30 were classified as Non-responders to methotrexate. The predictive ability of baseline levels of biomarkers for the response to methotrexate was studied using binary logistic regression models.

Results: 44 children (21 girls) with JIA who completed 3 months follow up after starting methotrexate were included for this interim analysis. 20 children were classified as responders while 14 were Non-responders. 10 subjects having an ACR between 30 and 50; have been excluded for this analysis. The median baseline values of MRP 8/14 and IL-6 were significantly higher in responders as compared to non-responders (Table 1). Children with higher baseline values of MRP8/14 and IL-6 were more likely to achieve ACR 50 or more; unadjusted OR (95%CI) 1.02 (1,1.04), p=0.047 and 1.28 (0.99,1.63), p=0.05 for MRP 8/14 and IL-6 respectively.

References

1. Moncrieffe H, Ursu S, Holzinger D, Patrick F, Kassoumeri L, Wade A, et al. A subgroup of juvenile idiopathic arthritis patients who respond well to methotrexate are identified by the serum biomarker MRP8/14 protein. Rheumatology. 2013 Aug;52(8):1467–76.

2. Singh G, Athreya BH, Fries JF, Goldsmith DP. Measurement of health status in children with juvenile rheumatoid arthritis. Arthritis Rheum. 1994 Dec;37(12):1761–9.

Conclusion:

The interim analyses showed that higher levels of baseline serum MRP8/14 and IL-6 have prognostic value in predicting response to methotrexate. Estimating these biomarkers at baseline may help in predicting the therapeutic response and guiding initial therapy.

Disclosure of Interest

None Declared

Table 1 (abstract P082). Baseline clinical and biomarker levels

P083 LEVELS OF IGG ANTIBODIES AGAINST COW’S MILK PROTEINS ARE RELATED TO DISEASE ACTIVITY IN JUVENILE IDIOPATHIC ARTHRITIS (JIA)

Anders Öman¹, Miika Arvonen², Martin Carlsson³, Panagiota Christoforaki¹, Maryam Poorafshar⁴, Lillemor Berntson¹

¹Institution of Women´s and Children´s health, Uppsala University, Uppsala, Sweden; ²Department of Pediatrics, Kuopio University Hospital, Department of Pediatrics, Oulu University Hospital and University of Oulu, Oulo, Finland; ³Department of Pediatrics, Hudiksvall Hospital, Institution of Women´s and Children´s health, Uppsala University; ⁴Thermofisher Scientific, Uppsala, Sweden, Uppsala, Sweden

Correspondence: Lillemor Berntson

Introduction: The role of the gastrointestinal tract in pathogenesis of JIA has raised attention since some of the risk factors for JIA relate to an altered gastrointestinal immunological situation. Early introduction of cow’s milk is one such risk factor. Cow’s milk includes more than 25 different proteins. In bovine milk β-lactoglobulin is the main whey protein, but antibodies against α-lactalbumin are more common in cow´s milk allergy in children. IgG antibodies against cow’s milk antigens are produced in plasma cells in the intestinal canal. The role of these antibodies is unclear, they have been elevated in cow´s milk allergy but not in cow´s milk intolerance. IgG4 antibodies against a specific food antigen mainly relates to the degree of exposition. Antibodies against nutritional antigens in children with JIA are only scarcely studied.

Objectives: We wanted to investigate levels of antibodies against cow’s milk antigens in children with JIA, at high compared with low disease activity, and compare the results with antibody levels in healthy controls. We also wanted to evaluate whether a history of milk intolerance affected the results.

Methods: We investigated levels of IgG and IgG4 antibodies against β-lactoglobulin, α-lactalbumin and casein in serum of 65 children with different categories of JIA, at high and low disease activity, and in 30 healthy controls. The analyses were performed with an automated FEIA method, ImmunoCAP ThermoFisher. At low disease activity the majority of children were treated with metotrexat and/or biological agents. Disease activity was assessed by analysis of calprotectin by ImmunoCAP in plasma and E-SR. In the group of children reporting milk intolerance, IgE antibodies against milk antigens were analysed with ImmunoCAP.

Results: Analyses revealed a significantly higher concentration of IgG antibodies against all three milk antigens in high compared with low disease activity, Md 4.7 mgA/L compared to 3.4 (p=0.001) for IgG β-lactoglobulin, Md 2.2 mgA/L compared to 0.0 (p=0.032) for IgG α-lactalbumin, and Md 7.3 mgA/L compared to 6.9 (p=0.003) for IgG casein. There was no difference between high and low disease activity in concentration of IgG4 β-lactoglobulin. When comparing children in high disease activity with children in the control group, there was no difference regarding levels of β-lactoglobulin (p=0.29), α-lactalbumin (p=0.14) or casein (p=1.0). The levels of β-lactoglobulin in serum correlated with the levels of calprotectin in plasma in all samples at high and low disease activity, r_s= 0.26 (p=0,004), as well as with E-SR, r_s= 0.24 (p=0,007). There was a high correlation between E-SR and calprotectin, r_s= 0.82 (p<0.001). None of the eight children with current or earlier milk intolerance had positive IgE antibodies against milk antigens and the milk intolerance did not influence levels of IgG antibodies against milk antigens.

Conclusion: In this study children with high disease activity in JIA had the same degree of antibody-production against milk antigens in serum as healthy children, but the levels were significantly decreased in lower disease activity. The stable concentration of IgG4 β-lactoglobulin was considered a sign of unchanged exposition of cow´s milk at high compared with low disease activity. Our results support influence on the gastrointestinal immune system by disease activity and treatment in JIA.

Disclosure of Interest

None Declared

P084 APPLICABILITY OF THE CASPAR CRITERIA OF PSORIASIC ARTHRITIS IN A COHORT OF CHILDREN PATIENTS FOLLOWING IN A PEDIATRIC RHEUMATOLOGY UNIT OF A TERTIARY HOSPITAL

Alina L. Boteanu, Adela Alia Jimenez, Maria Angeles Blazquez Cañamero

Rheumatology, University Hospital RAMÓN Y CAJAL, MADRID, Spain

Correspondence: Alina L. Boteanu

Introduction: The ILAR consensus establishes classification criteria, dividing the JIA into 7 subcategories, with juvenile psoriatic arthritis (APsJ) being one of them. In the adult population, the CASPAR classification criteria are usually used to classify a patient with psoriatic arthritis. However, the two classifications have some differences that sometimes produce confusion

Objectives: To assess the applicability of the CASPAR classification criteria in a series of patients previously diagnosed in pediatric age of JPAs or undifferentiated arthritis by exclusion criteria to be male> 6 years old and HLA B27 positive, comparing these with the ILAR classification criteria, through the study of clinical features

Methods: Retrospective cross-sectional observational study. Clinical, epidemiological, sociodemographic and analytical variables were collected from 30 patients previously diagnosed with JPAs (6 years in HLA B27-carrying male. It was assessed whether the patients met the ILAR classification criteria as well as the CASPAR classification criteria, which, unlike the previous ones, did not exclude HLA B27 positive patients, considered the family history of the 2nd degree and added a test radiographic

Results: The mean age at diagnosis was 11.23 ± 4.6 years; 15 of them being women and 15 men. 15 (15/30) patients presented cutaneous psoriasis at some point during the follow-up, in 5/15 patients psoriasis began before arthritis while 7/15 patients were previously diagnosed with arthritis than cutaneous psoriasis; in 3/15 patients the diagnosis was simultaneous during the medical visit. 9 (9/30) patients presented a family history of 1st degree cutaneous psoriasis and 7/30 of them had a family history of 2nd grade psoriasis. Of the total number of patients, 10 of them would not meet the ILAR classification criteria, 8 because they presented as exclusion criteria being male, HLA-B27 positive and> 6 years of age, among which, 7/8 would fulfill CASPAR criteria, and 2 other patients who were not classified according to ILAR criteria, did meet the CASPAR classification criteria, given the presence in these criteria of negative RF, family history of the 2nd degree and typical radiological alterations, which are not present in the ILAR criteria. 1 (1/30) patient did not meet CASPAR criteria, and belonged to the group of patients excluded from the ILAR criteria for being male> 6 years HLA-B27 +. If we did not take into account the negative FR of the CASPAR criteria, 14 patients would not meet these criteria and if we eliminated the 2nd grade AF, 5 patients would not be classified (among them 2 who meet CASPAR and do not ILAR)

Conclusion: In our series of patients despite the fact that the presence of current skin psoriasis contributes 2 points in the CASPAR criteria, only 1 patient would not meet the CASPAR criteria, since the majority of patients present other clinical or analytical manifestations, such as the presence of negative rheumatoid factor or 2nd degree family history. Patients who do not meet criteria for PsA by exclusion criteria, practically all of them would be diagnosed with psoriasic arthritis by CASPAR criteria.

Disclosure of Interest

None Declared

P085 METHOTREXATE RESPONSE IN JUVENIL IDIOPATHIC ARTHRITIS

Nilgun Cakar¹, Ayten Guliyeva¹, Elif Çelikel¹, Fatma Aydın¹, Beyza Doganay², Z. Birsin Ozcakar¹, Fatos Yalcinkaya¹

¹Department of Pediatric Rheumatology; ²Biostatistics, Ankara University School of Medicine, Ankara, Turkey

Correspondence: Nilgun Cakar

Introduction: Methotrexate (MTX) is a second line drug in the treatment of juvenile idiopathic arthritis (JIA), either alone or in combination with biologic agents. However, there is variation in the clinical response to MTX.

Objectives: The aim of this study was to investigate the role of factors such as age, gender, ANA status, number of active joints, and JADAS-10 in predicting MTX response.

Methods: Clinical and laboratory data of oligoarticular and polyarticular JIA patients diagnosed according to the International League of Association for Rheumatology (ILAR) criteria, who had received MTX treatment between January 2012 and March 2017, and continued MTX treatment for at least 12 months were evaluated retrospectively. The age at diagnosis, gender and ANA status were recorded. The number of active and tender joint and levels of acute phase reactants were assessed at baseline, and 3, 6, and 12 months. Disease activity score (JADAS-10) was calculated at onset of MTX and at months 3, 6 and 12. Patients' responses to MTX treatment were assessed according to the American College of Rheumatology Paediatric (PedACR) improvement criteria. At each time the patients were divided into responders and non-responders according to PedACR 30 and 70

Results: This study included 55 JIA patients (40 female). Thirt-four were oligoarticular (2 extended oligoarticular) and 21 were polyarticular (5 rheumatoid factor positive) JIA. The mean age at onset of the disease was 7.71± 4.83 years.(mean age was 6.75 ± x4.99 years in patients with oligoarthritis, 9.27 ± 4.21 years in polyarticular patients). The median JADAS 10 at beginning for all 55 children was 19 (10–40), and 16 (10-27)  for oligoarticular, and 28 (19-40) for polyarticular JIA. At month 3, 45% of all patients, %41 of oligoarticular, and 52% of polyarticular JIA patients had a minimum PedACR 30 response. 13 patients (2 at 4^th and, 11 at 7^th months) received biologic agents along with MTX. These patients were not included in the evaluation of treatment responses at 12^th month. The remaining 42 patients had PedACR 30 response at month 12. Moreover 81% of these patients (% oligoarticular, % polyarticular JIA) reached pedACR 70 response at month 12. Patients who had PedACR 30 response at 3 months had a higher rate of reaching the Ped ACR 70 response at 12 months (p=0.009). In patients with oligoarticular JIA, the 12^th month Ped ACR response was negatively correlated with the number of involved joints (OR). The initial JADAS 10 did not effect the PedACR response at 3 months (OR), but it was found that the 6^th month of JADAS 10, had a significant effect on PedACR 70 response at 12^th month (p<0.05). Age, gender and ANA status had no effect on PedACR responses.

Conclusion: PedACR 30 response at the 3^rd month, JADAS-10 at 6^th month and number of active joints in oligoarticular JIA were found to be predictors of the ACR response at 12^th month.

Disclosure of Interest

None Declared

P086 CHARACTERIZATION OF PATIENTS WITH POLYARTICULAR IDIOPATHIC JUVENILE ARTHRITIS AND INFILTRATIVE LUNG DISEASE

Bilade Cherqaoui¹, Brigitte Bader-Meunier², Christophe Delacourt³, Isabelle Kone-Paut¹, Alice Hadchouel-Duverge³

¹Pediatric Rheumatology, CHU Bicetre, APHP - CEREMAIA, LE KREMLIN BICETRE; ²Pediatric Immunology & Rheumatology, Necker Hospital, APHP - RAISE; ³Pediatric Pneumology, Necker Hospital, APHP - RESPIRARE, Paris, France

Correspondence: Bilade Cherqaoui

Introduction: There is an association between juvenile idiopathic arthritis (JIA) and chronic lung disease. These pulmonary disorders are multiple - interstitial (ILD) or non-inflammatory - depending on the type of underlying JIA - mainly polyarticular or systemic. In children, because of absence of accurate and multi-center data, the management of these chronic lung diseases remain difficult.

Objectives: This work aimed to constitute a national cohort of JIA patients presenting chronic lung disease.

Methods: A retrospective multicenter study was conducted. The cases between 2007 and 2018 were obtained from appeal of French Medical societies (SOFREMIP, RespiRare, SFR, CRI, database of pediatric pulmonary arterial hypertension). JIA was defined according to ILAR criteria; all had to have chronic pulmonary disease. Exclusion criteria were: age at onset> 18 years old, systemic JIA, other documented auto-immune or auto-inflammatory disease, asthma, cystic fibrosis, bronchopulmonary dysplasia, chronic lung infection, pulmonary primitive malformation. Data regarding clinical, paraclinical, therapeutic and evolution items were collected.

Results: 8 files were selected; 4 met the study criteria. All patients had positive rheumatoid factor polyarticular JIA, with female predominance (3/4), mean age at rheumatism onset of 11.5 years (7.5-16). They all had disabling polyarthritis, involving small/big articulations, mostly symmetrical, involving neck in 3/4 and hips in 1/4 patients, X-ray erosions in 2/4 patients. All had markedly erythrocyte sedimentation rate (32-107 mm, mean=65), hypergammaglobulinemia (14.8-30.8 g/l, mean=22.5), high titers of CCP antibodies, elevated antinuclear antibodies (>1/320) - with specificities in patient 4 (SSA/SSB/RNP without criteria for any connective tissue disease); patient 2 had positive TRAK antibodies without functional consequences. Each patients had different subtypes of ILD (Table 1). Pulmonary symptoms at diagnosis were: cough (2/4), exercise dyspnea (2/4), dyspnea at rest (1/4), hemoptysis (1/4 – patient 4), digital clubbing (1/4 – patient 2), auscultation abnormalities (2/4). In patient 2, ILD/fibrosis was related to SFTPC mutation. She had familial history of dominant inheritance of lung fibrosis and 2 ascendants with inflammatory rheumatic disease (rheumatoid arthritis, unclassified). Treatment was based on oral steroids, that could be associated with variable immunomodulation. In contrast to methotrexate - used in all patients, Etanercept was associated in patient 2 with ILD worsening, that improved at treatment discontinuation. Among all patients at last visit, patient 2 was the only who needed nutritive and respiratory support, and died at age of 15 years old, 13 years after lung disease beginning, on a graft waiting list.

Conclusion: The chronic pulmonary diseases related to JIA are extremely scarce. In this cohort only ILD form was observed in positive rheumatoid factor polyarticular JIA patients. Treatment strategies of both combined diseases were heterogeneous: oral corticosteroid was used in all, methotrexate did not seem to aggravate ILD, conversely to etanercept. The long-term interest will be to propose consensual recommendations for management of these patients. Informed consent had been obtained from the parents.

Disclosure of Interest

None Declared

Table 1 (abstract P086). See text for description

P087 “ONCE A DAY, ‘CAUSE YOU’RE GETTING LOTS OF INFORMATION”: HOW CHILDREN AND YOUNG PEOPLE WITH JUVENILE IDIOPATHIC ARTHRITIS WANT TO REPORT PAIN

Rebecca R. Lee¹, Amir Rashid¹, Wendy Thomson², Lis Cordingley³

¹NIHR Manchester Musculoskeletal Biomedical Research Centre, Arthritis Research UK Centre for Epidemiology, Division of Musculoskeletal and Dermatological Sciences; ²NIHR Manchester Musculoskeletal Biomedical Research Centre, Arthritis Research UK Centre for Genetics and Genomics, Division of Musculoskeletal and Dermatological Sciences; ³Centre for Musculoskeletal Research, Division of Musculoskeletal and Dermatological Sciences, University of Manchester, Manchester, UK

Correspondence: Lis Cordingley

Introduction: Digital, remote, mobile health (mHealth) pain assessments are increasingly used in the research and care of children and young people (CYP) with long-term conditions, such as Juvenile Idiopathic Arthritis (JIA). However, little is currently known about the influence, impact or patient preference for particular ecological momentary assessment (EMA) techniques in pain reporting.

Objectives: To explore patient preferences of different pain assessment timing and frequencies in CYP with JIA remotely monitoring pain at home.

Methods: The study was a randomised n-of-1 crossover trial. Participants aged between 5 and 16 years of age were recruited from The Childhood Arthritis Prospective Study, UK. Participants were loaned an iPad for the duration of the study. The iPads were uploaded with My Pain Tracker (MPT), a valid and acceptable multi-dimensional pain assessment application for CYP with JIA. MPT collects information about pain intensity, severity, location, qualities and interference and can be used by CYP to track their pain independently. Participants were randomised into one of four groups. Each group followed different administrative patterns of pain assessment reporting. Four different timing schedules (once-a-week, once-a-day, twice-a-day and as-and-when pain occurred) were randomised within the groups to occur twice within an eight-week data collection period. Semi-structured interviews were conducted over the telephone at the end of the study to explore which timing schedules participants and their parents preferred and why. Questions about subjective measurement reactivity (whether participants or parents noticed a change in pain or emotion in response to particular pain reporting schedules) were also included.

Results: Fourteen CYP took part in the study (M=11.93, SD=2.65). An equal number of CYP reported that they preferred once-a-day and as-and-when reporting schedules (42.9%). As-and-when reporting facilitated flexibility in pain tracking. Some participants considered this an advantage and others, a burden. Flexibility was problematic because participants did not know what level of pain was sufficient to report or how to report when they were in school. Furthermore, CYP were not able to record and review ‘good’ or pain free days with this schedule, which CYP found valuable for evaluating the contrast with ‘bad’ pain days. Creating habits or routines was one of the most important factors for successfully remembering to report pain. A priority for CYP was capturing comprehensive information about recent pain which they could still remember. The once-a-day schedule accommodated these advantages. Higher frequency of pain reporting (more than once-a-day) was perceived to affect mood and fatigue by some participants and their parents. One parent reported a perceived physical change in their child’s pain as a response to more intense pain reporting schedules. The majority of participants and their parents did not report any subjective measurement reactivity, with some suggesting frequent assessment served as a distraction from pain.

Conclusion: To our knowledge, this is the first study to investigate the impact of different EMA schedules with CYP with JIA and persistent pain. Findings suggest that daily reporting of pain using multi-dimensional mHealth assessment tools is feasible, sustainable and a reporting preference for CYP with JIA. Findings are important for the development of administrative guidelines for new mHealth pain assessment tools.

Disclosure of Interest

None Declared

P088 ANTIBODIES AGAINST CITRULLINATED PEPTIDE PROTEINS (CCP, MCV AND CYCLIC MCV) IN JUVENILE IDIOPATHIC ARTHRITIS

Talia Diaz-Prieto¹, Ana Villarreal-Treviño¹, Rocío Maldonado-Velázquez¹, Enrique Faugier-Fuentes¹, Andrés Rodríguez-García¹, Carlos Núñez-Álvarez²

¹Pediatric Rheumatology, Hospital Infantil De México Federico Gómez; ²Laboratory of Immunology and Rheumatology, Instituto Nacional De Ciencias Médicas Y Nutrición Salvador Zubirán, Mexico City, Mexico

Correspondence: Talia Diaz-Prieto

Introduction: Juvenile Idiopathic Arthritis (JIA), is the most frequent rheumatic disease in Pediatrics. Within the JIA, there are different subtypes, better prognosis in oligoarticular JIA, but not in JIA polyarticular rheumatoid factor (FR) positive, recent treatments allow patients to be diagnosed and treated as soon as possible to prevent joint damage. It would be useful to have biomarkers for both diagnosis and prognosis. Citrulline vimentin was recognized as a target within the family of citrullinated proteins. The presence of mutated citrullinated vimentin antibodies in JIA has been little studied.

Objectives: To determine levels of anti-citrullinated cyclic peptide, citrullinated anti-vimentin and mutated citrullinated vimentin in patients with JIA. Describe clinical and epidemiological characteristics.

Methods: Cross-sectional study, patients with JIA from Pediatric Rheumatology of the HIMFG, June 2017. Informed consent, 1ml of blood serum. ELISA technique in INCMNSZ.

Results: Total of 62 patients (n = 62), female n = 46. Anti-CCP cut-off value of 9.1U / ml, sensitivity of 71% and specificity of 97.8%. Anti-VMCc value cut 18 U / ml, sensitivity 62.9% and specificity of 88.4%, Anti-VMC value cut 18.7 U / ml, sensitivity 56.5% and specificity of 86.96%, U of Mann-Whitney anti-CMVc patients vs healthy controls p0.5976, anti-CCP patients vs healthy controls p0.5220, anti-VCM patients vs healthy controls p0.003. 12 patients were reported with anti-CCP negative and positive for anti-VMC.

Conclusion: A significant difference was observed in anti-MCV levels compared to healthy controls. The anti-VMC could be supportive in the diagnosis of Juvenile Idiopathic Arthritis.

Disclosure of Interest

None Declared

P089 ROLE OF ANTI-CCP, HSCRP AND MUSCULOSKELETAL ULTRASOUND IN DETECTION OF DISEASE ACTIVITY AND SEVERITY OF JUVENILE IDIOPATHIC ARTHRITIS

Mervat Eissa¹, Mona M. Elmetwally², Aldosoki A. Fouda², Mohammed T. M. Abdelhak³, Samia A.-H. Abdel-Mageed²

¹Department of rheumatology and rehabilitation, Cairo University; ²Department of rheumatology and rehabilitation; ³Department of Radiology, Al Azhar University, Cairo, Egypt

Correspondece: Mervat Eissa

Introduction: Juvenile idiopathic arthritis is a common systemic autoimmune inflammatory disease. Anti-CCP is important biomarker to differentiate those patients with aggressive JIA. hs CRP could identify patients in clinical remission and their risk of disease relapse. Ultrasound on the joints is more sensitive in the detection of disease activity than clinical examination alone. The aim: evaluate the role of anti-CCP 2and hs CRP, MSUS in early detection of activity of JIA.

Objectives: Evaluate the role of anti-CCP 2 and hs CRP, MSUS, and Doppler study in early detection of activity of JIA children

Methods: Assessment of the disease activity of JIA was done using the Juvenile Arthritis Disease Activity Score (JADAS27). Conventional radiography, musculoskeletal US examination in a minimum of two planes (longitudinal and transverse) and Global ultrasound score were done for all 60 patients. Blood tests included (IgM RF was assayed using quantitative immunonephelometry test, hs CRP and Anti-CCP 2 (IgG) was measured by commercially available second-generation ELISA kits DiastatTM Axis, Shield Diagnostics, Dundee, Scotland) were done for all patients and 20 healthy control.

Results: 60 JIA patients; (41.66%) males and (58.33%) females. Their mean age was 7.9. Their mean disease duration 3.5. They were divided according to disease activity into 2 groups: group 1: 30 patients with JADAS27 score <3.8, group 2: 30 JIA patients of high disease activity according to JADAS27 score ≥3.8 There was a highly significant positive correlation between ESR, CRP, hs CRP and JADAS27. On the other hand, there was a non-significant positive correlation between anti-CCP levels and JADAS27. Global ultrasound score had a highly significant positive correlation with JADAS27 P < 0.001. Global ultrasound score had a significant positive correlation with hs CRP. Diagnostic performance of different parameters in discrimination of disease activity of group I and group II ROC curve, hs CRP was more sensitive in early detection of disease activity followed by ultrasound score while anti-CCP and routine CRP showed lower global sensitivity

Conclusion: hs CRP, MSUS Doppler are important tools in detection of activity of JIA children.

Disclosure of Interest

None Declared

P090 JUVENILE IDIOPATHIC ARTHRITIS AND THE TEMPOROMANDIBULAR JOINT:PREVALENCE, CLINICAL FACTORS AND DIAGNOSTIC TOOLS

Lina von Schuckmann¹, Ivan Foeldvari¹, Anna Suling², Jens Klotsche³, Bärbel Kahl-Nieke⁴

¹Hamburg Center for Pediatric and Adolescent Rheumatology, Am Schoen Klinik Eilbek; ²Department of Medical Biometry and Epidemiology, University Medical Centre Hamburg-Eppendorf, Hamburg; ³German Rheumatism Research Centre, Berlin; ⁴Department of Orthodontics, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany

Correspondence: Ivan Foeldvari

Introduction: Temporomandibular joint (TMJ) involvement occurs around 30 to 80 % in children with Juvenile idiopathic Arthritis (JIA). The correlation with certain subtypes with hypothesized. There are several studies looeked at predictors of TMJ involvement. We reviewed in a monocentric study a large patient population to asses the prevalence in the different subtypes and prognostic markers for the TMJ involvement.

Objectives: To study the prevalence of TMJ involvement, as well as associated clinical signs, symptoms and factors in children with JIA.

Methods: We performed a retrospective chart review on 3,999 consecutive patients who were followed in the Hamburg Centre for Paediatric and Adolescent Rheumatology Eilbek between January 2010 and July 2012. Demographic, clinical, laboratory and radiographic data were collected. TMJ involvement was diagnosed clinically by the attending rheumatologist, or radiologically by MRI.

Results: 35 % of 2,413 included patients had TMJ involvement. In a multivariable analysis we found female sex (p = 0.021), increasing number of joints with active arthritis (p < 0.001) and antinuclear antibody (ANA) positivity (p = 0.023) were significantly associated with TMJ involvement. In the oligoarticular group (persistent and extended) was a positive association of TMJ involvement and age (OR = 1.07, p < 0.001), while this association was negative in the enthesitis related arthritis group (OR = 0.94, p = 0.015). A significant correlation revealed between pathological MRI results and laterotrusion of the chin (p = 0.012) and pain on palpation (p = 0.020).

Conclusion: Based upon our data we cannot recommend one unique clinical parameter to diagnose TMJ involvement, and MRI is still the gold standard to assure the diagnosis. Female sex, ANA positivity and disease activity were correlated significantly with an increased OR for TMJ involvement, and a significant interaction between age and JIA categories (oligoarticular and enthesistis related arthritis) was found. Further prospective controlled studies are still needed.

Disclosure of Interest

None Declared

P091 VALIDATING AND DEVELOPING A SELECTED QUESTIONNAIRE TO PREDICT EARLY DIAGNOSIS OF JUVENILE IDIOPATHIC ARTHRITIS IN GERMAN POPULATION

Tristan Scheer¹, Jens Klotsche², Claudio Len³, Ivan Foeldvari⁴

¹Asklepius campus Semmelweiss University Budapest, Hamburg; ²German Rheumatism Research Center, Berlin, Germany; ³Pediatric Rheumatology Unit, São Paulo Federal University, São Paulo, Brazil; ⁴Hamburg Center for Pediatric and Adolescent Rheumatology, Hamburg, Germany

Correspondence: Ivan Foeldvari

Introduction: Juvenile idiopathic arthritis (JIA) is the most common chronic inflammatory rheumatologic disease in children and adolescents with a prevalence of 1 in 1000 children in Germany. An early referral of children suspected to have JIA to a pediatric rheumatologist is essential for an early diagnosis and starting treatment in the therapeutic window to reach a better outcome. An easy-to-use and time efficient questionnaire originally developed by a Brazilian study group led by Claudio Len may detect children and adolescent under risk for JIA.

Objectives: To determine, whether the German version of the screening tool is reliable for the early diagnose of JIA and secondly, whether a weighting scheme of individual questions improves its diagnostic performance.

Methods: The original questionnaire was translated into German by Dr. med Ivan Foeldvari. The questionnaires were distributed among patients at the first clinical visit at the Hamburger Centre für Kinder- und Jugendrheumatologie. The questionnaire includes 12 disease-orientated questions each with three possible responses, either: “Yes”, “No” or “I don’t know”. A retrospective evaluation of patients diagnosed with JIA or with a non-inflammatory joint pain (NJP) was performed later on. The sample consisted of patients seen between August 2015 and July 2017. All patients were at least older than 2 years and younger than 17 years at the time of evaluation. Only questionnaires, which were fully answered, were evaluated. Subsequently, a weighting scheme (based on the factor loadings from a confirmatory factor analysis) of individual questions was applied in order to increase the sensitivity of the tool. Standard statistical techniques were used to find associations between the sum scores and clinical characteristics and to compare the weighted and non-weighted sum scores.

Results: In total 165 of 800 questionnaires could be evaluated for the study. 133 (81%) were diagnosed with JIA and 32 (19%) with NJP. The group of JIA patients consisted of 79 (59%) girls, whereas the control group consisted of 21 (66%) girls. The analysis of the individual questions was performed by comparing the rate of a positive response to the questions (“Yes”) between the two groups. Four questions showed a highly significant difference by comparing answers of the control group with a subgroup of JIA patients having at least one active inflammatory joint. In particular, questions regarding physical constraints (p= 0.20; AUC= 0.62), joint pain (p= 0.040; AUC = 0.61), swelling in the joints (p= 0.040; AUC =0.60) and stamina (p= 0.047; AUC = 0.60) seem to be relevant in the diagnostic approach. A weight of 3 was assigned to the first and seventh, 2.5 to the fourth and sixth, and 1.5 to the third and fifth item. The diagnostic accuracy of the respective weighted sum score increased from 64% to 68% to discriminate between patients with JIA with at least one active joint and the control group in comparison to the ordinary sum score. An optimal cutoff of 6.0 for referral to a pediatric specialist was calculated.

Conclusion: The validation of the questionnaire showed a discriminative difference in patients with clinical diagnosed JIA and a control group diagnosed with NJP. Furthermore, the weighted sum score performed better to differentiate between JIA and NJP patients. The modified questionnaire can be useful to screen for JIA and speed up the referral to a pediatric rheumatologist.

Disclosure of Interest

None Declared

Table 1 (abstract P091). ROC-Analysis of the questionnaire in different groups

P092 METHYLENETETRAHYDROFOLATE REDUCTASE 677 NUCLEOTIDE MUTATION IS A PREDICTIVE TOOL IN METHOTREXATE NON-RESPONSIVE JIA PATIENTS

Vladimir Iacomi, Ninel Revenco

Rheumatology, Mother and Child Institute I.M.S.P., Chisinau, Moldova, Republic of

Correspondence: Vladimir Iacomi

Introduction: One of the aim of the international child arthritis associations is to provide proper treatment regimens in children with juvenile idiopathic arthritis (JIA) with proving effectiveness and safety. Methylenetetrahydrofolate reductase (MTHFR) mutations, according to Genome-Wide Association Studies (GWAS) are being involved in most toxicities. The effective response to methotrexate (MTX) treatment in JIA is remaining contradictory.

Objectives: To assess the MTHFR gene mutations in children with JIA, treated with MTX for more than 6 months, and correlate them with the Juvenile Arthritis Disease Activity Score (JADAS71) and Pediatric ACR 20,50,70,90 Index.

Methods: There has been initiated a PhD observational case-control study, involving at least 24 patients using MTX for JIA treatment. All data is processed through IBM SPSS Statistics 22 programe.

Results: There has been examined 18 children yet, including 7 (38,9%) cases of no mutation, 2 (11,1%) cases of T/T homozygotes and 9 (50%) cases of C/T heterozygotes in the 677 nucleotide of the MTHFR gene. The JADAS71 score was higher in the heterozygote cases with the mean value 18,1(p=0,0013), compared to the non-mutation sample - 2,4 (p=0,0022). The Pediatric ACR index in heterozygote sample had a mean value of 22% (p=0,0011) improvement compared to the control group - 37% (p=0,001).

Conclusion: There has been determined a significant correlation between the MTHFR gene heterozygote mutation status and the MTX non-responsiveness. The MTHFR mutation screening is an available tool in assessing immunosuppressive therapy failure.

Disclosure of Interest

None Declared

P093 ‘REAL-LIFE’ USE OF MRP8/14 SERUM LEVEL MEASUREMENT IN CLINICAL PRACTICE AS A PREDICTOR OF OUTCOME AFTER STOPPING METHOTREXATE IN PATIENTS WITH JUVENILE IDIOPATHIC ARTHRITIS

Beverley Almeida^1,2, Emma J. Jordan², Jason Palman², Peter Bale¹, Elizabeth Ralph¹, Clare Heard², Emily Robinson², Simona Ursu², Kimberly Gilmour¹, Lucy R. Wedderburn^1,2,3,4

¹Great Ormond Street Hospital for Children NHS Trust, London; ²University College London Great Ormond Street Institute Of Child Health; ³ARUK Centre for Adolescent Rheumatology; ⁴NIHR BRC at Great Ormond Street Hospital, London, UK

Correspondence: Emma J. Jordan

Introduction: Many patients with JIA who reach clinical remission on treatment harbour residual inflammation that is not detectable by standard measures. MTX remains the first line DMARD for JIA, but is frequently poorly tolerated due to gastrointestinal side effects. After stopping MTX there is a significant risk of disease flare. Myeloid related protein (MRP) 8/14 has been shown as a marker of subclinical disease activity and a predictor of patients with risk of disease flare after stopping MTX.

Objectives: This study reviewed the impact of measuring serum MRP8/14 concentration in clinical practice, to identify patients who have reduced risk of disease flare if they stop MTX therapy.

Methods: MRP8/14 tests performed at a single paediatric centre using a commercially available assay (Bühlmann) were analysed. Patients included all subtypes of JIA, treated by MTX monotherapy at time of test and had not previously been on a biologic or other disease-modifying drug. All were considering stopping MTX. Clinically inactive disease (CID) was defined by Wallace criteria. JIA subtype, gender, age at diagnosis, disease duration, age at sample and disease activity variables were recorded at time of test and over time. Disease flare in those off MTX was defined as a patient that no longer met Wallace criteria and required new intervention. Patients who met the inclusion criteria were divided into those who did or did not meet Wallace criteria, and whether they stopped, weaned or did not stop MTX. Statistical analyses were performed using Prism Graphpad, Version 7.

Results: A total of 72 serum MRP8/14 concentrations from 72 patients were analysed. In patients who met Wallace criteria, comparison of serum MRP8/14 concentration values in those who stopped versus those who didn’t stop MTX, demonstrated statistically significant difference (Mann-Whitney test). In the group who stopped MTX (n=18), sensitivity (high MRP8/14 indicating flare) was 86%, specificity (low MRP8/14 indicating no flare) was 18% and the positive predictive value (percentage of patients with a high MRP8/14 result who went on to flare) was 40%. Flares in patients who met Wallace criteria and stopped MTX treatment were plotted over time, split by the MRP8/14 result; low (<4000ng/ml), n=6 and high (>4000ng/ml), n=1. Statistical analysis showed no significant difference between groups, likely due to small numbers in the analysis, however the trend matched previous data.

Conclusion: Measurement of serum MRP8/14 can be used in clinical practice to assist therapy decisions and as a predictor of flare post stopping MTX therapy in JIA patients who have achieved CID. However, biomarkers providing greater predictive power are needed to enable more accurate tailoring of treatment.

Disclosure of Interest

None Declared

P094 WHICH ONE IS MORE EFFECTIVE ON FUNCTION AND PSYCHOSOCIAL STATUS IN JIA?: NUMBER OF JOINTS INVOLVED OR PRESENCE OF PAIN

Nur Banu Karaca¹, Hafize Emine Sönmez², Gamze Arın¹, Erdal Sağ², Aykut Özçadırcı¹, Selcan Demir², Fatma Birgül Oflaz¹, Yelda Bilginer², Edibe Ünal¹, Seza Özen²

¹Department of Physiotherapy and Rehabilitation, Hacettepe University Faculty of Health Sciences; ²Department of Pediatric Rheumatology, Hacettepe University Faculty of Medicine, Ankara, Turkey

Correspondence: Nur Banu Karaca

Introduction: Juvenile idiopathic arthritis is a chronic inflammatory childhood disease with symptoms such as joint inflammation, pain, loss of quality of life. The number of joints and presence of pain cause the child to be affected psychosocially as well as affecting functional activity.

Objectives: The aim of this study is to examine the results of functional and psychosocial status according to the type of joint involvement and the presence of pain symptoms in children with JIA.

Methods: The study included 71 children diagnosed with JIA who applied to Hacettepe University İhsan Doğramacı Children's Hospital Rheumatology Department. After demographic information of children was collected, functional and psychosocial status was assessed with the scale which was developed in Hacettepe University for children with rheumatism and functional status assessed with Child Health Assessment Questionnaire (CHAQ). Children were divided into groups according to joint involvement as oligoarthritis or polyarthritis and presence or absence of pain. Mann-Whitney U test was used to compare the data.

Results: Mean age and numbers of children were shown in Table 1. There were no difference between groups, according to disease type (p>0,05). On the other hand, comparing the scores according to pain presence, CHAQ total, CHAQ general VAS assessment, functional and psychosocial status were significantly different (p<0,05).

Conclusion: It is concluded that pain is an important determinative on functional, psychosocial and overall disease assessment comparing to number of joints involved. It can be implicated that affected joint number may be compansatible by muscle activation but pain may require a central organisation to be alleviated. Thus, it must be taken into consideration that he child’s ability to cope with pain should be improved.

Disclosure of Interest

None Declared

Table 1 (abstract P094). See text for description

P095 EXPERIENCES OF PARTICIPATION IN ACTIVITIES AMONG CHILDREN WITH JUVENILE IDIOPATHIC ARTHRITIS

Johanna T. Kembe

¹Function Area Occupational Therapy & Physiotherapy, Karolinska University Hospital, Occupational Therapy, Stockholm, Sweden

Introduction: Children with JIA are affected in participation and according to Unicef every child is entitled to daily life participation. Through participating in activities children develop abilities that form upbringing and adult life. Children with JIA have effects on participation that is caused by the disease.

Objectives: The aim of the study was to describe experiences of participation in activities among children with JIA.

Methods: A qualitative design with an interview method where eight girls in ages 12-15 have been interviewed with semi-structured interviews. Data handling has been executed according to a content analysis.

Results: Based on collected data the theme Participation influences through interaction between the individual and the surroundings with corresponding categories symptoms’ immediate effect, physical environment, strategies, personal treatment, relations and the individual’s inner life were formed. Outcome shows that children with JIA experience participation in every day life is influenced by the disease symptoms, physical environment, social environment and the individual herself. Experiences of increased participation were affected by the individual’s choice of strategies, and social environment.

Conclusion: Children with JIA experienced that participation in activities was influenced by disease symptoms, which resulted in absence, and excluding participation. The social environment could increase participation through good treatment and understanding, but the social environment could also decrease participation through misunderstanding and misinterpretation about the disease. The individual’s attitude using strategies and adjustments during activities led to increased participation, and those that chose not to, experienced a decreased participation.

Disclosure of Interest

None Declared

P096 PREDICTOR FACTORS OF Q ANGLE IN PATIENTS WITH JUVENILE IDIOPATHIC ARTHRITIS AND HEALTHY CHILDREN

Eylul P. Kisa¹, Serap Inal², Ela Tarakcı³, Nilay Arman⁴, Ozgur Kasapcopur⁵

¹Department of Physiotherapy and Rehabilitation, Faculty of Health Science, Istanbul Aydin University; ²Department of Physiotherapy and Rehabilitation, Faculty of Health Science, Istanbul Bahcesehir University; ³Department of Neurological Physiotherapy and Rehabilitation; ⁴Department of Physiotherapy and Rehabilitation, Faculty of Health Science, Istanbul University; ⁵Department of Pediatric Rheumatology, Medical Faculty of Cerrahpasa, Istanbul University, Istanbul, Turkey

Correspondence: Eylul P. Kisa

Introduction: Juvenile idiopathic arthritis (JIA) is the childhood disability from a musculoskeletal disorder. It generally affects large joints such as the knee and the ankle. Muscle weakness, poor flexibility, atrophy, pain, and decreased proprioception of the affected joints, abnormal biomechanics, articular cartilage damage are the most common problems in patients with JIA. A greater Q angle has been suggested as a risk factor for musculoskeletal problems in various disease.

Objectives: We aimed to investigate the factors affecting Q angle in patients with JIA having pes planovalgus and healthy children.

Methods: Thirty-six participants as age range 4-16 years (25 female, 11 male) were enrolled this study. Children divided 2 groups (Group I: patients with JIA have pesplanovalgus, Group II; Healthy children). Hand held dynamometry was used to assess the strength of the lower extremity muscles. Also, Range of Motion (ROM) of lower extremity was evaluated with a universal goniometer. While static balance evaluated with Flamingo Balance Test (FBT), dynamic balance evaluated with Prokin balance system. Prokin balance system assesses perimeter length, Medium equilibrium center (A-P, M-L). Q angle was calculated by universal desktop ruler. Universal Desktop Ruler allows you to measure not only a straight-line distance but any curved distance on the screen. For statistical analysis SPSS Version 19.0 program was used.

Results: The means of age were 11.33±4.51 (Group I) and 11.28±1.87 (Group II) years. When the groups were compared with each other, Q angle was significantly higher in Group I (p=0.001). Correlations were found between strength of knee extension (r=-0.560, p=0.016) and ROM of knee flexion (r=0.528, p=0.024 with Q angle for group I. Also, Correlations were found between strength of hip abduction (r=-0.504, p=0.033), strength of hip adduction (r=-0.564, p=0.015), strength of knee extension (r=-0.470, p=0.049) and strength of ankle dorsiflexion (r=-0.713, p=0.001) with Q angle for group I. But, there was no correlation between Q angle and any parameters in Group II (p>0.05). According to linear regression analysis, Q angle was affected by only strength of knee extension for Group I (β=-0.13, p=0.000).  However, it was not found relationships between FBT, A-P and M-L with Q angle for both of the groups (p>0.05).

Conclusion: Q angle as excessive dynamic knee valgus is an abnormality of neuromuscular control over the lower limb. This study shows that Q angle was significantly increased and affected by strength of knee extension negatively in patients with JIA having pes planovalgus. So, this clear result suggests that the lower extremity should be evaluated holistically and strengthening of the knee extension should be considered in the treatment of patients with JIA even if the problem is only on the ankle. Besides, in future studies should assess educational status and quality of life.

Disclosure of Interest

None Declared

P097 RECESSIVE MULTIPLE EPIPHYSEAL DYSPLASIA IN DIFFERENTIAL DIAGNOSIS OF JUVENILE ARTHRITIS

Aleksey Kozhevnikov^1,2, Nina Pozdeeva¹, Evgeniy Melchenko¹, Michael Konev¹, Vladimir Kenis¹, Konstantin Afonichev¹, Gennadiy Novik²

¹Federal state budget institution “The Turner Scientific Research Institute for Children's Orthopedics” under the Ministry of Health of the Russian Federation; ²Federal state budget institution of higher professional education “Saint-Petersburg State Pediatric Medical University” of the Ministry of Health of the Russian Federation, Saint-Petersburg, Russian Federation

Correspondence: Aleksey Kozhevnikov

Introduction: Juvenile arthritis (JA, JIA) is an umbrella-term describing a heterogeneous group of musculoskeletal diseases characterized by chronic synovitis of unknown etiology. Typical classic forms of JIA (oligo, poly, psoria, entheso) are well known. Genetic disorders with musculoskeletal involvement that mimic chronic arthritis should be considered in the differential diagnostics of JIA. The topically of the problem in children is determined by frequent cases of treatment of skeletal dysplasia by the DMARDs.

Objectives: The goal of this study was to improve the diagnosis of skeletal dysplasia manifested as JIA.

Methods: We carried out a retrospective review of more than fifty children with past-onset chronic undifferentiated arthropathy (low laboratory activity; progressive idiopathic contracture with entheso/synovitis) which were hospitalized at Children Orthopedics Institute, Saint-Petersburg between 2006 and 2016. The data of clinical of joint involvement, laboratory, x-ray, ultrasound, MRI were analyzed.

Results: All children were divided into two groups based on their disease. The first group (large) consisted of children with recessive multiple epiphyseal dysplasia (rMED/MED4, gene SLC26A2 Mut, OMIM 226900) characterized by abnormal development of the bone and cartilage of the epiphyses. A second group (small) was children with JIA. Children with congenital or early-onset forms of skeletal dysplasia and other monogenic arthritis-like diseases were excluded from study.

1. Less of morning stiffness, bilateral painless joint contractures and axial deformation of the lower limbs were the main finding of children with pseudo-rheumatoid pathology. Most children with rMED in the early childhood were characterized by a lack of signs of physiological hypermobility, reduced daily motor activity and treated of bilaterally delayed ossification of femoral heads. Morning stiffness and painful joint contractures were actually for children with JIA.

2. Radiology of JIA was characterized by inflammatory dynamic picture: overgrowth of metaepiphysis and joint osteoporosis at onset of disease, development dystrophic and erosive changes of osteochondral tissue at progressive durated and arthros-arthritis deformation like outcome. Symmetric flattening of epiphyses of hands, hips, knees and feet, double-layered patella were x-ray hallmarks of rMED. Avascular necrosis may be superimposed on rMED. Dystrophic spondylolisthesis at the L5-S1 vertebrae to 10-12 years of life was a frequent sign of epiphyseal dysplasia.

3. Instrumental sign of synovitis (ultrasound, MRI) was detected in most children. Synovitis in cases of skeletal dysplasia was secondary nature due to chronic damage and degeneration of the genetic defective articular hyaline cartilage (erosive-like chondrolysis).

4. Sensitivity to anti-inflammatory therapy was not always verified of the genesis of arthropathy and in most cases was dictated by the presence of synovitis.

Conclusion: This comparative study was revealed some clinical and instrumental characteristics of the skeletal dysplasia which mimic JIA. Early orthopedic-related "hip problems" at anamnesis, symmetric deformity of epiphyses, double-layered of patella indicate a possible of pseudo-rheumatoid genesis of arthropathy. Sequence of SLC26A2 gene should be recommended for use in cases with the not typical clinical and x-ray findings for JIA.

Disclosure of Interest

None Declared

P098 SERUM CALPROTECTIN LEVELS AS A MARKER OF DISEASE ACTIVITY IN CHILDREN WITH JUVENILE IDIOPATHIC ARTHRITIS

Sathish Kumar, Anish S. George

Pediatrics, Christian Medical College, Vellore, India

Correspondence: Sathish Kumar

Introduction: Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disorder of childhood and encompasses a complex group of disorders comprising several clinical entities with the common feature of arthritis. Calprotectin is a calcium- and zinc-binding protein that belongs to the S100 protein family and is released during the interaction of leucocytes with inflammatory activated endothelium at the sites of inflammation as occurs in JIA. We undertook this study to assess the usefulness of Calprotectin as a marker of disease activity in Indian children with JIA.

Objectives: To assess the effetiveness of serum Calprotectin levels as a marker of disease activity in children with JIA.

Methods: Children who fulfilled the International League of Associations For Rheumatology (ILAR) criteria for JIA were recruited into the study. Baseline demographic details were collected and Blood counts, ESR, CRP and Calprotectin levels were analyzed in all children after obtaining consent. Children were then divided into 2 groups based on disease activity as per Wallace criteria. Calprotectin levels were also analysed in 10 normal healthy children. Calprotectin levels were measured by using a “Human Calprotectin Kit” which works on the basis of sandwich-enzyme linked immune sorbent assay technology (ELISA).

Results: 121 children with JIA were recruited into the study, 63 had active disease and 58 had inactive disease. Systemic onset JIA constituted 42% of the study population and was the predominant disease subtype. Calprotectin levels were elevated in children with active disease compared to those with inactive disease. Mean Calprotectin value in active disease (3954ng/ml) was 2 fold higher than those with inactive disease (1899ng/ml) (p value ˂0.001) and 16 times higher than children who were normal healthy controls (mean of 233ng/ml). Area under curve for Calprotectin was 0.744. For a cut off value of 1760 ng/ml, Calprotectin had a sensitivity of 77% and specificity of 61% for assessment of disease activity in JIA.

Conclusion: Serum Calprotectin levels was found to be a good marker of disease activity in children with JIA. However, further studies which involve serial monitoring of Calprotectin levels in a study population will provide additional information about accuracy of these markers.

Disclosure of Interest

None Declared

P099 CROSS-SECTIONAL STUDY OF SERUM CALPROTECTIN LEVELS IN NON-SYSTEMIC JUVENILE IDIOPATHIC ARTHRITIS PATIENTS AND CHILDREN WITH ACUTE INFLAMMATORY DISEASE

Lovro Lamot^1,2, Lea Oletić¹, Mandica Vidović¹, Mirta Lamot¹, Marijana Miler¹, Nora Nikolac Gabaj¹, Miroslav Harjaček^1,2

¹Sestre Milosrdnice University Hospital Center; ²University of Zagreb School of Medicine, Zagreb, Croatia

Correspondence: Lovro Lamot

Introduction: in the past few years, various indicators of disease activity in juvenile idiopathic arthritis (JIA) patients have been investigated, allowing for the interpretation of different aspects of underlying inflammatory process (e.g. clinical, immunological, radiological etc.). Nevertheless, there is still evident lack of satisfactory support in diagnostic and prognostic evaluations in everyday clinical practice, focusing research activities on discovery of adequate biomarker that would support initial diagnosis and allow feasible disease monitoring. While growing number of evidence indicates phagocytic S100 proteins, like MRP8/14 complex (i.e. calprotectin), can be used to detect subclinical inflammatory activity in systemic JIA, their performance in other forms of JIA is still debatable, while in acute infectious diseases it is almost unknown.

Objectives: compare serum calprotectin (sCAL), CRP and PCT levels in patients with various forms of non-systemic JIA and previously healthy children with acute febrile illness lasting <3 days, as well as with juvenile arthritis disease activity score (JADAS).

Methods: out of 37 patients included in study, 17 were diagnosed with polyarticular form of JIA (pJIA), 8 with oligoarticular form (oJIA), 2 with juvenile spondyloarthritis (jSpA) and 10 with acute febrile respiratory illness of possible viral etiology (AFI). sCAL, PCT and CRP were measured in all of the patients, while JADAS70CRP was measured in all of the JIA patients. Inactive disease was defined as JADAS ≤1. The average duration of JIA was 64,2 (7-132) month, and all of the JIA patients were treated with standard therapy, including biological (n=16) and conventional (n=20) DMARDs. sCAL was measured by a commercial ELISA assay (Buhlmann MRP8/14, Switzerland).

Results: among JIA patients, 8 pJIA, 4 oJIA and 1 jSPA had inactive disease, while 9 pJIA, 4 oJIA and 1 jSpA had active disease. Average concentration of sCAL among patients with inactive disease was 1,86 (0,5-4,2) μg/mL, while in patients with active disease it was 2,37 (0,93-5,2) μg/mL (p=0,37). Statistically significant correlation was observed between sCAL and JADAS (Spearman r=0,523; p=0,005) in JIA patients and between sCAL and CRP (Spearman r=0,745; p=0,017) in children with AFI. Average concentration of sCAL in children with AFI was 4,67 (1,67-8,32) μg/mL, significantly higher than in patients with inactive (p=0,0024) or active JIA (p=0,0084) or in all JIA patients (p=0,0012).

Disease		N	sCAL μg/mL (range)	CRP mg/L (range)	PCT ng/mL (range)	JADAS (range)
Inactive	pJIA	8	1,67 (0,65-2,66)	3,475 (0,4-17,5)	0,03 (0,01-0,10)	0,5 (0-1)
	oJIA	4	2,575 (0,8-4,2)	1,225 (0,5-2,2)	0,02 (0,01-0,03)	0,75 (0-1)
	Total	13	1,86 (0,5-4,2)	2,53 (0,02-17,5)	0,02 (0,01-0,10)	0,5 (0-1)
Active	pJIA	9	2,55 (0,93-4,1)	6,59 (0,2-40,4)	0,01 (0,01-0,02)	9,9 (2-22)
	oJIA	4	2,26 (1,3-4,2)	10,3 (0,7-37,7)	0,01 (0,01-0,02)	7,4 (3-17,7)
	Total	14	2,37 (0,93-5,2)	7,31 (0,2-40,4)	0,01 (0,01-0,02)	8,7 (2-22)
All JIA patients		27	2,11 (0,65-5,2)	4,92 (0,2-40,4)	0,02 (0,01-0,10)	4,6 (0-22)
All AFI patients		10	4,67 (1,67-8,32)	5,93 (0,4-26,7)	0,19 (0,09-0,16)	/

Conclusion: preliminary results of our cross-sectional study showed sCAL correlates with JADAS in non-systemic JIA patients, although there was no significant difference between those with active and inactive disease. Interestingly, sCAL concentrations in long lasting JIA patients were significantly lower than in children with short lasting viral illness. This is a novel observation that emphasizes the need for vigilance in interpreting sCAL levels in patients with concomitant acute communicable disease and gives a possible explanation for some of the high(er) values noted in patients with clinically inactive non-systemic JIA.

Disclosure of Interest

None Declared

P100 STREPTOCOCCAL SEROLOGY IN A TWO-YEAR COHORT OF JIA PATIENTS - PRACTICAL GUIDANCE

Tanya Li¹, Kathy Gallagher², Peter Bale², Kate Armon²

¹University of Cambridge; ²Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK

Correspondence: Tanya Li

Introduction: For a child presenting to the paediatric rheumatology clinic with a swollen, painful joint it can be difficult to differentiate between a post-infective reactive arthritis and JIA. Antistreptolysin O titre (ASOT) and anti-DNase B can be used, but the literature suggests taking two samples 10-14 days apart for interpretation. (1) This can be difficult in the clinical setting.

Objectives: · To analyse the use and interpretation of streptococcal serology in new onset JIA patients at a tertiary hospital in the UK

· To compare this to evidence in the literature to recommend practical clinical guidance

Methods: The cohort consisted of patients with a new diagnosis of JIA made in 2016-2017. Data was collected from patient records on the following: recent illness, serology results and action taken. P values were calculated using Fisher’s exact test.

Results: 36 of the 54 patients identified had streptococcal serology (ASOT and anti-DNase B) at presentation. 16 (84%) of the 19 patients who reported a recent illness received streptococcal serology, compared to 20 (57%) of the 35 patients without recent illness. This difference was not statistically significant (p = 0.06).

There was no difference between the proportion of patients with abnormal titres in those who reported recent illness (7 of 16, 44%) compared to those without (8 of 20, 40%; p = 1). Furthermore, reporting recent illness was not associated with antibiotic use (6 of 16 (38%) compared with 4 of 20 (20%) without; p = 0.29).

In total 10 patients received antibiotics after initial serology results. 10-14 days of penicillin was always given when both ASOT and anti-DNase B titres were raised, but the decision to treat when only one titre was raised was variable. 6 of 11 (54%) patients with one abnormal titre were given antibiotics. Antibiotics were not given to patients with normal serology, or borderline ASOT alone.

No patients had repeat serology within 10-14 days. 5 patients had serology repeated, varying from 5 weeks to 14 months later.

Conclusion: This cohort consisted of patients with JIA and did not include those diagnosed with reactive arthritis, which would be valuable. ASOT typically rises 1 week after a streptococcal infection, falling between 2-8 months to baseline. Anti-DNase rises 2 weeks after infection and returns to baseline from 3-12 months. (2) A fourfold rise in titres taken 10-14 days apart provides evidence of recent streptococcal infection. However, taking repeat blood tests in young children can be both traumatic and practically difficult, with limited access to age-appropriate phlebotomy. A history of recent illness is not predictive of a raised titre in the context of JIA. A pragmatic approach, therefore, is to treat a single abnormal titre.

References

1. Sen ES, Ramanan AV. How to use antistreptolysin O titre. Arch Dis Child - Educ Pract. 2014 Dec 1;99(6):231–7.

2. Ayoub EM, Wannamaker LW. Evaluation of the Streptococcal Desoxyribo-Nuclease B and Diphosphopyridine Nucleotidase Antibody Tests in Acute Rheumatic Fever and Acute Glomerulonephritis. Pediatrics. 1962 Apr 1;29(4):527–38.

Disclosure of Interest

None Declared

Table 1 (abstract P100). Number of patients with abnormal serology results at initial presentation (% treated with antibiotics). Reference ranges from local laboratory. Titres given in international units (IU)

P101 A UK STUDY: VOCATIONAL EXPERIENCES OF YOUNG ADULTS WITH JUVENILE IDIOPATHIC ARTHRITIS

Laura E. Lunt^1,2, Matthew Bezzant³, Ailsa Bosworth³, Janet E. McDonagh^1,2, Kimme Hyrich^1,2, Wendy Thomson^2,4, Suzanne Verstappen^1,2,5

¹Arthritis Research UK Centre for Epidemiology, Centre for Musculoskeletal Research, Manchester Academic Health Science Centre, The University of Manchester; ²NIHR Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester; ³National Rheumatoid Arthritis Society (NRAS), Maidenhead; ⁴Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, The University of Manchester, Manchester; ⁵Arthritis Research UK/MRC Centre for Musculoskeletal Health and Work, University of Southampton, Southampton, UK

Correspondence: Laura E. Lunt

Introduction: Little is known about the experiences of young adults living with Juvenile Idiopathic Arthritis (JIA) preparing for employment and career development.

Objectives: The purpose of this study was to understand the impact JIA has on career planning and early employment experiences of young adults (16-30 years).

Methods: Using existing literature (including grey literature), an online survey (consisted of 152 questions, 29 items related to young adults two of which were free text questions) was developed and sent to National Rheumatoid Arthritis Society (NRAS) members and distributed to non-members via social media tools including Facebook, Twitter and HealthUnlocked. Data collected included views and experiences in career planning and employment. The data pertaining to young adults are presented here.

Results: Of 1241 respondents 19 were young adults with JIA (range 16-30 years), 89% were female and 84% had university or equivalent qualifications. Due to incomplete responses there is missing data on all 19 young adults. 4/13 young adults were studying at university, 9/13 were in paid employment. 9/17 respondents reported their school did not offer additional work-related activities to students with disabilities and/or additional needs. 10/14 young adults felt their school did not provide advice about coping with possible limitations on placements/traineeships due to their arthritis. 11/14 respondents thought about their condition when thinking about future career plans e.g. “I wanted to work as a ranger or similar for the National Trust but it’s a fairly physically demanding job and I knew my joints would suffer so I changed track slightly”. However, 8/14 felt their career advisors did not take their arthritis into account e.g. “I had to cease my physiotherapy master’s degree as my arthritis got too bad to continue and change career choice. I wish there would have been more discussion about it not being a reasonable choice for me at the time as we just didn't have the information then”. 8/14 young adults changed their career plans because of their arthritis. Managing JIA symptoms and a physically demanding role, as well as wanting to stay healthy, were the main reason for changing career. Important aspects of employment included: good relationships with your line manager, work you like doing and a job you can use your initiative.

Conclusion: Despite small numbers these results highlight potential current unmet vocational needs of young adults with JIA in the UK and the need for further research with this age group. There appears to be a lack of structured support within schools and universities offered to students with disabilities and/or additional needs, about work-related activities and careers. Young adults with JIA actively consider their condition whilst thinking about career opportunities and value a productive and challenging job with a good working environment, including relationships with colleagues and supervisors.

Disclosure of Interest

None Declared

P102 BODY MASS INDEX AND JUVENILE IDIOPATHIC ARTHRITIS: IS THERE A CORRELATION WITH SEVERITY, PROGNOSIS AND TREATMENT RESPONSE?

Ilaria Maccora, Francesca Tirelli, Edoardo Marrani, Teresa Giani, Gabriele Simonini, Rolando Cimaz

Rheumatology Unit, University of Florence, A. Meyer Children's Hospital, NEUROFARBA Department, Florence, Italy

Correspondence: Ilaria Maccora

Introduction: There is evidence that obesity could be a risk of factor for the development of RA due both to the mechanical effect of overweight and to the potential pro-inflammatory effects of cytokines produced by adipose tissue.

Objectives: To evaluate the role of overweight and obesity in a cohort of JIA patients, in terms of incidence, disease activity, outcome and response to treatments.

Methods: This single-center retrospective cohort study evaluated 125 children affected by JIA under treatment with anti-rheumatic agents (NSAIDs/IAS, DMARDs, biologic agents). Change from baseline in ERS, CRP, number of active joints (with distinction between upper and lower limb joints), and BMI was analysed under each treatment until last visit. BMI categories of 5-84th (normal weight), 85-94th (overweight), and ≥ 95th (obese) percentile were used. Patients with systemic JIA or chronic comorbidity under potentially confounding systemic treatments were excluded. Informed consent was obtained by the patients and their family.

Results: One hundred twenty-five JIA patients (36% oligoarticular JIA, 42,4% RF-negative polyarticular JIA, 0,8% RF-positive polyarticular JIA, 8% enthesitis related arthritis, l’11,2% psoriatic JIA, and 1,6% undifferentiated unclassified arthritis) were enrolled in the study, 76,8% girls, 23,3 boys. The mean age was 5,9 years (± 3,8). Baseline BMI was ≤ 84th percentile in 73,22% of patients, 85-94th in 19,64%, and ≥ 95th in 7,14%.

We did not observe a significative association between BMI and ERS (p=0,29), CRP (p=0,24), or number of active joints (p=0,45) at baseline, while the involvement of the joints of lower limb was significantly greater (p=0,025) in overweight/obese patients.

We also demonstrated a substantial equality in remission and relapse rates in subjects with different BMI.

Conclusion: This study focuses on the complex relationship between overweight/obesity and JIA. A significant correlation between obesity and a greater involvement of the joints of the lower limbs was observed at baseline. Furthermore, we observed that obesity does not influence the course of the disease nor treatment response. These data seem to suggest a prevalent mechanical effect of ponderal excess on JIA, rather than a biochemical influence due to pro-inflammatory cytokines released by adipocytes.

Disclosure of Interest

None Declared

P103 JUVENILE IDIOPATHIC ARTHRITIS AND FITNESS: A TEAMWORK

Maria Cristina Maggio¹, Antonio Palma², Giuseppe Messina², Jessica Brusa², Angelo Iovane², Livia Cimino¹, Giovanni Corsello¹

¹University Department Pro.Sa.M.I. “G. D’Alessandro”; ²Department of Psychology and Educational Science, University of Palermo, Palermo, Italy

Correspondence: Maria Cristina Maggio

Introduction: Patients with Juvenile Idiopathic Arthritis (JIA) have limited fitness and reduced aerobic and anaerobic exercise capacity vs. healthy peers. Furthermore, low intensity exercise programs are safe in children with JIA and may improve fitness, joint excursion and quality of life, reduce pain, fatigue and the employ to anti-inflammatory drugs.

Objectives: The purpose of the study was to evaluate postural and balance deficits and fitness with specific test battery in children and adolescents affected by JIA.

Methods: We enrolled 30 patients with JIA (13 M; 17 F; age: 8-18 years); among those, 7 were evaluated longitudinally in the period 2016-2018, comparing the tests in different periods of the illness. The posturography test was administered with the FreeMed posturography system (the FreeMed baropodometric platform and FreeStep v.1.0.3 software). A specific fitness test battery was used to evaluate the physical fitness level of the patients (Abalakov test, backsaver sit and reach, the toe touch test, sit-up test and hand grip test).

Results: 2 M and 5 F was in an acute phase of the disease (1 sJIA; 5 polyarticular JIA; 1 psoriatic JIA).

At the posturography test, the distribution of the weight between left and right was pathological in 15 (4 sJIA; 9 polyarticular JIA; 2 oligoarticular JIA).

The load distribution between forefoot and hindfoot was pathological in all the patients, with a more severe overload in polyarticular JIA patients.

Hand-grip test in 8 patients was <3°Centile; in 11 was < 20°Centile. The patients who performed a regular physical activity program showed fitness test in the normal range, and these parameters were not correlated with the type of JIA and/or the treatment for the arthritis.

Among the patients evaluated in follow up, 2 (1 with sJIA and 1 with polyarticular JIA) maintained an asymmetry in the weight distribution between left and right and a reduced fitness. 5 patients (2 M with sJIA and 3 F with polyarticular JIA) normalized their parameters.

Conclusion: The persistent asymmetry of the load distribution between left and right foot and the persistent pathological distribution between forefoot and hindfoot was more frequent in patients with polyarticular JIA.

A regular physical activity program is the best strategy to maintain an adequate fitness and the best control of the disease.

Disclosure of Interest

None Declared

P104 TITLE: “SERUM CALPROTECTIN AND JOINT ULTRASOUND IN PATIENTS WITH JUVENILE IDIOPATHIC ARTHRITIS”

Manuela Marsili¹, Marina Primavera¹, Giovanni Cannataro², Caterina Di Battista¹, Giuseppe Lapergola¹, Roberto Troiani¹, Debora d'Angelo¹, Raffaella Faricelli³, Francesco Chiarelli¹, M. Loredana Marcovecchio⁴, Luciana Breda¹

¹Department of Pediatrics, University of Chieti; ²Department of Neuroscience, Imaging and Clinical Sciences; ³Unit of Clinical Pathology, SS Annunziata Hospital, Chieti, Italy; ⁴Department of Pediatrics, University of Cambridge, Cambridge, UK

Correspondence: Manuela Marsili

Introduction: The identification of new biomarkers, the development of more effective outcome measures and the refinement of imaging techniques may foster the implementation of targeted and personalized therapeutic interventions in patients with juvenile idiopathic arthritis (JIA). Among new biomarkers, serum calprotectin (MRP8/MRP14), a complex of calcium- and zinc-binding proteins, seems to be promising. Besides, musculoskeletal ultrasonography (MSUS) is a useful imaging tool for evaluating JIA patient disease activity. Many studies have demonstrated that MSUS can improve the sensitivity and the accuracy in the detection of the exact sites of inflammation in the joint compared to the clinical examination only.

Objectives: To evaluate MRP8/MRP14 and MSUS in a group of JIA patients and to verify which of these tools best identifies disease activity.

Methods: 70 children with JIA referred to the Rheumatology Unit of the Department of Pediatrics of Chieti, were enrolled. Serum MRP8/MRP14 of each patient was detected by PhiCal Calprotectin ELISA. MRP8/MRP14 was defined normal for values < 3 μg/ml. JADAS-27 was used to define disease activity. At study enrollment, all patients underwent an ultrasound assessment of all joints clinically affected. A total of 452 joints were scanned for the presence of synovial effusion (SE), synovial hyperplasia (SH) and power Doppler (PD) signal. The ultrasound examinations technique as well as definitions and scoring features were based on guidelines provided by the OMERACT study group. In each joint, SE, SH and PD signal were graded on a 0–3 scale. The threshold used for synovial abnormalities was 1.

Results: MRP8/MRP14 serum levels were increased in active vs inactive disease patients (p-value <0.001). Significant differences between active and inactive patients were found in CRP, ESR, JADAS score and the prevalence of synovitis (Table 1). According to the score evaluating SE or SH and PD, 20 out of 28 (71.4%) JIA patients with active disease had a score equal to 2 vs 2 out 40 (4.7%) patients achieving remission (p-value 0.001). ESR, CRP, MRP8/MRP14 and synovitis with its specifics components were all positively related to JADAS-27. MRP8/MRP14 was positively correlated with presence of synovitis and its specific characteristics.

Conclusion: To our knowledge, this is the first study comparing MRP8/MRP14 and MSUS in a group of JIA patients. We found a significant association between MRP8/MRP14 levels, clinical and laboratory markers of disease activity. Moreover, we demonstrated an association between MRP8/MRP14 serum levels and ultrasonography-determined synovitis. Our study confirmed that both MSUS and MRP8/MRP14 may be considered valid and reliable tools in the assessment of synovial inflammation in JIA. Larger longitudinal studies are needed to establish the role of MRP8/MRP14 and MSUS in the diagnosis and follow-up of childhood arthritis.

Disclosure of Interest

None Declared

Table 1 (abstract P104). Clinical, laboratory and ultrasound data at baseline between active and inactive patients. Data represent means ± SD or median (interquartile range)

P105 CREATION OF AN ONLINE LEARNING RESOURCE FOR JIA IN ADULTS

Joanne May^1,2, Nicola Smith², Helen Foster²

¹Paediatric Rheumatology, Oxford University Hospitals, Oxford; ²Institute of Cellular Medicine, Newcastle University, Newcastle, UK

Correspondence: Joanne May

Introduction: We present the development of an evidence based online learning resource for rheumatologists who manage adolescents and adults with JIA as part of their routine practice, including translation of a learning needs analysis into learning activity design and the creation of three interactive learning modules.

Objectives: Many children and young people with JIA will continue to have active disease as adults and will need treatment delivered by adult rheumatology services. A learning needs analysis of the UK adult rheumatology community identified key areas where further training in the management of JIA is required:

- Knowledge about JIA, including understanding JIA subtypes, how JIA manifests in adults, and how JIA differs from adult onset arthritis.

- Knowledge, skills and guidance for the management of adolescents and young adults with JIA.

- Approaches to management in adults with JIA.

The JIA in Adults e-learning series was developed with the British Society for Rheumatology (BSR) to target these educational needs.

Methods: The content and format were informed through our research to gather opinion from adult and paediatric rheumatologists in the UK (Smith et al, 2017).  A PACT analysis (People, Activities, Context, Technology) informed the design process. Learning activities were based on constructivist learning theory with cognitive considerations for online learning activity design: activation of prior knowledge, construction of new knowledge and knowledge transfer.

Results: The ‘People’ element of the PACT analysis was an essential consideration – experienced clinicians with a varied prior exposure to adolescent and young adult (AYA) rheumatology, both through formal training and clinical practice. Therefore, learning activities designed to activate prior knowledge and therefore optimise the foundation for further leaning were key.

Social considerations and the wider, National and Global view were used to define purpose, motivate and prepare for learning. New knowledge was presented around clinical cases so that key concepts could be explored in depth and related back to prior experience. A series of interactive cases with questioning focusing on evidence, explanation, hypothetical reasoning, cause and effect and synthesis of understanding were used to develop clinical reasoning skills and to facilitate knowledge transfer to new clinical scenarios. The inclusion of the ‘more knowledgeable other’ in the form of feedback from an expert in the field of AYA rheumatology further enhanced the development of advanced clinical reasoning.

The learning needs analysis demonstrated that many find managing the complex psychosocial needs of AYA to be particularly challenging, therefore the cases explored these particular elements in more depth.

Further cognitive considerations in the module design included enhancing learning through the use of video media, data interpretation, interviews, pictures and quizzes, and through the reduction and segmentation of text.

Conclusion: An e-learning series for adult rheumatologists who manage JIA in adults as part of their routine clinical practice was successfully created through the application of an evidence-based learning needs analysis to inform learning activity design, appropriate to the prior experience of the learners through interactive case-based learning.

Reference

Biological treatments for adults with Juvenile Idiopathic Arthritis: a clear need for improved access to targeted education and training.  Nicola Smith, Tim Rapley Flora McErlane Lianne Kearsley-Fleet, Kimme L Hyrich Helen E Foster. Rheumatology, Volume 56, Issue suppl_7, 1 December 2017, kex390.049, https://doi.org/10.1093/rheumatology/kex390.049

Disclosure of Interest

None Declared

JIA-Spondyloarthritis

P106 THE IMPACT OF ADALIMUMAB ON GROWTH IN PATIENTS WITH PEDIATRIC ENTHESITIS-RELATED ARTHRITIS

Ruben Burgos-Vargas¹, Shirley M. Tse², Kirsten Minden³, Pierre Quartier⁴, Jaclyn K. Anderson⁵, Kristina Unnebrink⁶, Ivan Lagunes⁵, Gerd Horneff⁷

¹Hospital General de Mexico, Universidad Nacional Autonoma de Mexico, Mexico City, Mexico; ²2The Hospital for Sick Children, Toronto, Canada; ³Charite University Medicine, Berlin, Germany; ⁴Hopital Necker-Enfants Malades, Paris, France; ⁵AbbVie, N Chicago, USA; ⁶AbbVie, Ludwigshafen; ⁷Asklepios Klinik, Sankt Augustin, Germany

Correspondence: Ruben Burgos-Vargas

Introduction: Children with one or more subtypes of juvenile idiopathic arthritis, such as enthesitis-related arthritis (ERA), often exhibit growth impairments.

Objectives: To explore the impact of adalimumab (ADA) on growth in pediatric patients (pts) with ERA.

Methods: Pts aged 6-<18 with ERA were enrolled in a phase 3, multicenter, randomized, double-blind, study. Following 12 weeks of treatment with ADA (24 mg/m² BSA up to 40 mg every other week [eow]) or placebo, pts were eligible to enroll in an open-label extension and receive ADA eow for up to an additional 192 weeks. For this analysis, all pts who received ≥1 dose of ADA were included, and pts were grouped by baseline height percentiles into 2 categories: ≤25^th and >25^th percentiles based on the World Health Organization (WHO) growth charts. Mean WHO percentile changes in height, weight, and body mass index (BMI) percentiles were calculated through 204 weeks. Per protocol, bone age and familial height were not collected. Growth and efficacy data were analyzed as observed.

Results: Among the 46 pts who received ≥1 dose of ADA in this study, 67% were male with a mean age of 12.9 years; no pts had associated IBD. Eleven pts (24%) were in the ≤25^th height percentile, and these pts had a numerically lower baseline height (147.7 cm) and weight (42.5 kg) compared with those pts who were in the >25^th height percentile (156.0 cm and 51.5 kg, respectively). Additionally, numerically higher proportions of pts in the ≤25^th percentile received concomitant corticosteroids than did the >25^th percentile group (54.5% vs 28.6%). Pts in the ≤25^th percentile group experienced a larger change in mean height percentile through 204 weeks of ADA treatment (70.3 vs 20.5 for the >25^th percentile), a finding that was evident within the first 6 months of treatment. Juvenile males in the ≤25^th baseline height percentile demonstrated the numerically highest rates of growth, although similar levels of growth improvement were observed for the lowest quartile of females as well. None of the 11 pts in the ≤25^th baseline height percentile remained in this category at their final study visit (Table 1). Similar percentile increases were observed for BMI percentiles between groups. ACR Pedi90 response rates improved over time in both ≤25^th and >25^th percentile groups, reaching approximately 80% at the end of 3 years treatment with ADA.

Conclusion: Long-term ADA treatment was associated with growth improvement and maintenance in children with ERA. These improvements among children in the lowest WHO quartiles at baseline may improve their quality of life and psychosocial environment. ADA treatment improved ERA signs and symptoms, regardless of baseline growth status.

Reference

1. Burgos-Vargas R, et al. Arthritis Rheumatol 2016;68(Suppl 10).

Disclosure of Interest

R. Burgos-Vargas Grant / Research Support from: AbbVie, Consultant for: AbbVie, BMS, Janssen, Pfizer, and Roche. , S. Tse Grant / Research Support from: AbbVie, Consultant for: AbbVie and Pfizer, K. Minden Grant / Research Support from: AbbVie and Pfizer, Consultant for: AbbVie, Pfizer, Pharm-Allergan, and Roche/Chugai, P. Quartier Grant / Research Support from: AbbVie, Novartis, Pfizer, and Roche/Chugai, Consultant for: AbbVie, BMS, MedImmune, Novartis, Pfizer, Roche/Chugai, Servier, and Sobi, J. Anderson Employee of: AbbVie, K. Unnebrink Employee of: AbbVie, I. Lagunes Employee of: AbbVie, G. Horneff Grant / Research Support from: AbbVie, Pfizer, and Roche, Consultant for: AbbVie, Novartis, Pfizer, and Roche

Table 1 (abstract P106). Distribution of Height and BMI by WHO Percentile at Baseline and Final Visit

P107 CLINICAL AND THERAPEUTICAL FACTORS LINKED TO THE JOINT INVOLVEMENT IN PEDIATRIC INFLAMMATORY BOWEL DISEASE

Emanuela Del Giudice¹, Ilaria Battagliere¹, Anna Dilillo¹, Franca Viola¹, Giuseppe La Torre², Salvatore Cucchiara¹, Fabrizio De Benedetti³, Marzia Duse¹

¹Department of Pediatrics; ²Department of Public Health and Infectious Diseases, Sapienza University of Rome; ³Division of Rheumatology, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy

Correspondence: Emanuela Del Giudice

Introduction: The association between inflammatory bowel disease (IBD) and joint involvement are well known, but the clinical and therapeutical features linked to them has been poorly investigated mostly in pediatrics.

Objectives: To identify factors associated with the joint involvement in pediatric IBD

Methods: A retrospective cohort of 83 pediatric IBD with joint complain(56 Crohn’ s disease [CD]/27 Ulcerative colitis[UC] were enrolled in two medical centers in Rome, evaluated at the time of the first rheumatologic manifestation and after 6,12 and 24 months.

The diagnosis of IBD was based on agreed endoscopic and histological criteria, CD and UC disease activity was measured respectively by PCDAI and PUCAI.

Demographic data and disease related IBD variables at first joint complain were recorded for each patient.

Laboratory tests and clinical examination including the type of active, limited joints were assessed. Moreover the gastrointestinal tract affected, the step up or top down therapy approach, the disease joint remission were collected.

Joint complaints were categorized on the basis of clinical documentation as sacroileitis, peripheral arthritis, and arthralgia.

Results: Regarding the different types of rheumatic manifestations compared to the IBD diagnosis, arthritis begins earlier than arthralgia(p=0.031). Of the 83 patients,44(53%) had arthralgia and 39(47%) arthritis, and in this last subgroup 23 had peripheral arthritis and 16 sacroileitis. The prevalence of arthritis or arthralgia was not significantly different in both groups: CD(48% 44%) and UC(52%>56%)(p=0.930).16/83 patients enrolled had a sacroileitis,11(69%) had a CD and 5(31%) UC. In IBD group the frequency of small, coxo-femoral and sacroiliac joints complain was higher in the arthritis than arthralgia patients(p=0.006;p=0.001;p=0.001,respectively).

CD patients in both arthritis and arthralgia groups, showed a higher prevalence of the Ileum-colon involvement (L3)(63%vs52%) than ileum (L1)(15%vs27.7%) and colon disease (L2)(22%vs20.7%). Also in the subgroup of sacroileitis in CD the L3 involvement was higher(73%) than L1(18%) and L2(9%).

The joint remission was higher in arthritis patients on top down treatment than those on step up and the difference was already statistically significant at follow up at times 6 and 12 months(p=0.043,p=0.036,respectively).The peripheral arthritis group showed a higher frequency of remission at the follow up at 6,12 and 24 months compared with the sacroileitis.

Conclusion: Arthritis is an earlier extraintestinal manifestation in pediatric IBD compared to arthralgia, and sacroileitis is more frequent in CD. Otherwise UC and CD have the same frequency to develop arthritis or arthralgia.

The L3 localization in CD may be related itself to the development of joint involvement.

The top down therapy in case of joint manifestation showed a higher frequency of remission.

Disclosure of Interest

None Declared

P108 SPONDYLOARTHRITIS RESEARCH CONSORTIUM OF CANADA SACROILIAC JOINT INFLAMMATION SCORE IN CHILDREN WITH ENTHESITIS-RELATED ARTHRITIS

María Katsicas¹, Monica Galeano², Martin Pradier¹, Clara Anoni², Ricardo Russo¹

¹Immnulogy & Rheumatology; ²Department of Imaging, HOSPITAL DE PEDIATRÍA GARRAHAN, Buenos Aires, Argentina

Correspondence: María Katsicas

Introduction: Enthesitis-related arthritis (ERA) is a category of juvenile idiopathic arthritis considered to be a form of Juvenile Spondyloarthropathy (SpA). Spondyloarthritis Research Consortium of Canada sacroiliac joint score (SPARCC SIS) measures inflammation in sacroiliac joints. It has been used in adults but limited experience exists in children.

Objectives: To assess SPARCC SIS in children with ERA. To investigate the association between SPARCC SIS score and clinical–biochemical features

Methods: Patients with ERA (according to ILAR criteria) who had sacroiliac (SI) joints MRI were included in a cross sectional study. Demographic features and time of follow up were recorded. ASAS classification criteria were applied to patients. SI joints were examined using T1-weighted images, T2 fast –suppressed and short-tau inversion recovery. The SPARCC was scored independently by 2 radiologists. Readers were blinded to clinical features. SPARCC SIS assessed the presence, depth and intensity of bone marrow edema on consecutive six slices as an increased signal in the iliac and sacrum bones. Scoring is composed by 3 components: bone marrow (BM) edema (0-48), BM intensity (0-12), BM depth (0-12). Maximum:72. Clinical variables were collected in random visits: active joint (AJ), sacroiliac pain (SIP) , lumbar pain (LP),lumbar limitation (LL) by Schöber´s test, wellbeing according to the patient using a visual analogue scale (VASp), disease activity according to the physician (VASphy), VAS pain ,JADAS-10(juvenile arthritis disease activity score), JSpADA(juvenile spondyloarthritis disease activity index), ESR and functional capacity by CHAQ. Treatment with TNF inhibitors (TNFi) were recorded. Descriptive, summary statistics, Intraclass Correlation Coefficient (ICC) for concordance between readers, Kruskal wallis one way AOV -test and post-hoc comparisons were done. Chi² for categoric variables were used.

Results:

Thirty patients (83% M) fulfilled inclusion criteria. Median age was 12 (5-17) years and disease duration 5.6 (1-8) years. HLA-B27 positive in 12 (40%). TNFi in 17 (57%). Twenty-five patients (83%) had abnormal SI MRI. SPARCC SIS score was (medians±SD) 24±14.71. ICC for concordance between readers =0.73(p=0.02) IC 95% 0.43-0.88. MRIs were divided into 3 groups according to score. Clinical and demographic variables were compared among groups (Table 1).

There were no significant differences in activity measures (VASp, VASphy, VAS pain, JADAS-10, JSpADA) neither ESR, nor CHAQ among groups. MRI showed inflammation in 7 patients with normal X-rays(p=0.005). All patients fulfilled ASAS criteria for SpA. All patients who fulfilled ASAS-axial (14 patients) showed MRI abnormalities (SPARCC SIS 24 ±13.6). 10/16 patients who were classified as peripheral according to ASAS showed sacroiliitis (24 ±15.09). Eight patients met criteria for Ankylosing Spondylitis (AS) according modified New York Criteria:their SPARCC score was 24±12.0.

Conclusion: SPARCC SIS score was associated with age and disease duration. Patients classified as peripheral according to ASAS had similar SPARCC scores to those of patients classified as axial, which probably indicates this classification is not relevant for ERA patients.

Disclosure of Interest

None Declared

Table 1 (abstract P108). See text for description

P109 DIFFERENCES OF CYTOKINE LEVELS BETWEEN ABORIGINAL AND NON-ABORIGINAL CHILDREN WITH JUVENILE IDIOPATHIC ARTHRITIS IN SAKHA REPUBLIC (YAKUTIA).

Fekla Vinokurova¹, Tatiana Burtseva¹, Vyacheslav Nikolaev¹, Vera Argunova², Vyacheslav Chasnyk³, Mikhail Kostik³

¹Yakut Scienсе Center of Complex Medical Problems; ²National Medical Center, Yakutsk; ³SAINT-PETERSBURG STATE PEDIATRIC MEDICAL UNIVERSITY, Saint-Petersburg, Russian Federation

Correspondence: Mikhail Kostik

Introduction: juvenile idiopathic arthritis (JIA) is not uncommon disease among aboriginals in Sakha Republic (Yakutia) - SR(Y), which can be related to high spreading of HLA B27 antigen. Aboriginals in SR(Y) have higher prevalence of enthesitis-related category of JIA and juvenile ankylosing spondylitis, increased family history of rheumatic diseases, especially arthritis and have higher requirement in biologic medicine (anti-cytokine antibodies) for arthritis control compare to Caucasians.

Objectives: The aim of our study was to evaluate cytokine profile in aboriginals in SR(Y) and compare to Caucasians have been living in the same area.

Methods: In continuous study were included 108 JIA patients before age 18 consisted of 96 SR(Y) aboriginals and 12 Caucasians with JIA whom have been living in SR(Y). All patients have an active disease course. In children HLA B 27 and interleukin-1β, interleukin-6, interleukin-10, interleukin-4, tumor necrosis factor-α, γ-interferon levels were detected.

Results: The prevalence of HLA B27 antigen was 50% in RS(Y) aboriginals. We have found differences in cytokines levels between aboriginals and Caucasians: inerleukin-10: 3.75±1.7 and 3.24±0.9 pg/ml (р=0.038), inerleukin-1β: 2.9±8.4 and 2.0±0.9 pg/ml (р=0.0000001), tumor necrosis factor-α: 6.3±9.1 and 4.9±2.2 pg/ml (р=0.00001), γ-interferon: 22.7±11.4 and 20.1±3.5 pg/ml (р=0.007). No differences were observed in inerleukin-4 and inerleukin-6 levels between groups. Inerleukin-6 positively correlated with ESR (r=0.72, p<0.05). There was not found correlation between cytokines level and presence of HLA B27 antigen.

Conclusion: the prevalence of pro-inflammatory cytokines were observed in aboriginals in SR(Y) compare to Caucasians. Further investigations required to validate these data in clinical practice.

Disclosure of Interest

None Declared

Uveitis

P110 THE COURSE OF UVEITIS IN PATIENTS WITH JUVENILE IDIOPATHIC ARTHRITIS TREATED WITH ADALIMUMAB

Ekaterina Alexeeva^1,2, Tatyana Dvoryakovskaya^1,2, Rina Denisova¹, Tatyana Sleptsova¹, Kseniya Isaeva¹, Alexandra Chomahidze¹, Anna Fetisova¹, Anna Mamutova¹, Victor Gladkikh³, Alina Alshevskaya³, Andrey Moskalev³

¹Federal State Autonomous Institution “National Medical Research Center of Children's Health” of the Ministry of Health of the Russian Federation; ²Federal State Autonomous Educational Institution of Higher Education I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation, Moscow; ³Biostatistics and Clinical Trials Center, Novosibirsk, Russian Federation

Correspondence: Ekaterina Alexeeva

Introduction: Although predictors for the development of uveitis in patients with juvenile idiopathic arthritis (JIA) are well known, uveitis regarded as a separate, parallel disease has its own models of disease course, and accordingly, its own trends for remission. Adalimumab (ADA) is a highly effective anti-TNF drug having a strong therapeutic effect on both JIA and uveitis.

Objectives: This study aimed to assess the parameters associated with achieving remission of uveitis as a comorbid disease in JIA during ADA therapy.

Methods: The study involved 112 patients with uveitis who had initiated ADA therapy at the National Medical Research Center of Children's Health (Moscow). The median duration of JIA was 4 years (IQR 2:8.1); the median duration of uveitis was 1 year (IQR 0:5). Twenty-nine patients (25.9%) had only one eye affected. At ADA treatment initiation, 10 (8.9%) of patients had remission of uveitis. Almost half (49.1%) of the patients had a history of uveitis complication and 17.9% of patients had already undergone eye surgery. Treatment efficacy was evaluated according to the dynamics of clinical and laboratory signs, as well as according to achieving stable remission of uveitis.

Results: ADA therapy showed high efficacy in children with uveitis. After the first year of therapy, 89 patients (79.5%) achieved stable remission of uveitis; none of them had uveitis flares during the subsequent follow-up (the maximum follow-up period was 5 years). At the last visit, 92 patients (82.1%) achieved remission of uveitis. Among the remaining 20 patients (Flare group, 17.9%), only one patient demonstrated no positive dynamics of the uveitis course; the other 19 patients developed uveitis flare after 2-17 months of remission. Having compared the Flare group with the Remission group, we found the factors potentially associated with treatment response. The factors associated with recurrent uveitis included the greater number of uveitis flares in the past; complications affecting the vitreous body or the cornea; two eyes affected; and longer JIA duration before uveitis presentation.

Conclusion: ADA proved to be highly efficacious when used to treat children with uveitis. However, the severe uveitis affecting eyes with a large number of flares in the past and complications affecting the vitreous body and the cornea reduced the likelihood of achieving stable remission in children with JIA.

Disclosure of Interest

None Declared

P111 THE ETIOLOGIC SPECTRUM OF PEDIATRIC NON-INFECTIOUS UVEITIS

Mustafa Çakan¹, Şerife Gül Karadağ¹, Dilbade Yıldız Ekinci², Nuray Aktay Ayaz¹

¹Pediatric Rheumatology; ²Ophthalmology, Kanuni Sultan Süleyman Research And Training Hospital, İstanbul, Turkey

Correspondence: Mustafa Çakan

Introduction: The most common causes of non-infectious uveitis in pediatric age group are rheumatologic diseases [juvenile idiopathic arthritis (JIA), Behçet disease (BD), sarcoidosis, and vasculitides], tubulointerstitial nephritis and uveitis (TINU) and idiopathic uveitis.

Objectives: The aim of this study was to demonstrate the etiologic spectrum and long term follow-up results of pediatric non-infectious uveitis cases.

Methods: The files of patients with the diagnosis of non-infectious uveitis were reviewed between May 2010 and September 2017.

Results: The cohort consisted of 54 juvenile uveitis cases. Mean duration of follow-up for uveitis was 18.6 months (6-60 months). Twenty seven (50%) patients had JIA, 17 (31%) patients had idiopathic uveitis, 6 patients (11%) had BD, and 4 patients (7%) had TINU. The frequency of uveitis in all JIA patients was 6.6% (27/405), and in BD it was 22.2% (6/27).

Juvenile idiopathic arthritis cases consisted of 18 (67%) persistent oligoJIA, 3 extended oligoJIA, 2 enthesitis-related arthritis (ERA), 2 RF-negative polyarticular JIA, 1 psoriatic arthritis, and 1 systemic JIA. Five JIA cases had uveitis at the time of diagnosis of arthritis (4 persistent oligoJIA, 1 RF-negative polyarticular JIA). Only one case had initial diagnosis of uveitis and later diagnosed as ERA. Mean duration between diagnosis of JIA and uveitis was 21.2 months (0-77 months).

Male and female ratio was close to each other in the whole cohort (26 males, 28 females) and in JIA cases (12 males, 15 females). While idiopathic uveitis cases (6 males, 11 females) had female predominance, BD (5 males, 1 female) and TINU (3 males, 1 female) cases had male predominance.

Mean age at the time of diagnosis of uveitis was 9.1 years (1-17.5 years) in the whole cases and this number was 5.0 years in persistent oligoJIA cases, 11.8 years in idiopathic uveitis, and 13.7 years in BD.

Bilateral anterior uveitis was observed in 20 (74%) of JIA cases. Six JIA patients had unilateral anterior uveitis and one case had intermediate uveitis. Anti-nuclear antibody was positive in 90.4% of oligoarticular JIA-uveitis cases and 95.2% of oligoJIA associated uveitis cases were asymptomatic.

Idiopathic uveitis cases had unilateral anterior uveitis (6 cases), bilateral anterior uveitis (5 cases), bilateral intermediate uveitis (5 cases), and bilateral panuveitis (1 case). All of the idiopathic uveitis cases were symptomatic as red eyes being the most common symptom. Three BD patients had bilateral panuveitis, 2 cases had unilateral anterior and 1 case had bilateral anterior uveitis. Only one BD case was asymptomatic. TINU cases had bilateral anterior uveitis (3 cases) and unilateral anterior uveitis (1 case) and all of them had red eyes.

At the time of enrollment 45 uveitis cases (83.3%) were under remission while 9 cases (5 idiopathic uveitis, 2 JIA, 1 BD, and 1 TINU) had active uveitis. Biologics were used in 14 cases of methotrexate-resistant JIA-related uveitis (adalimumab in 11 and tocilizumab in 3 cases). Half of BD uveitis patients were treated with biologics (2 cases with interferon-alpha, 1 case with adalimumab).

Complications of uveitis were observed in 10 cases (18.5%) such as intraocular hypertension (5 cases), adhesions (2 cases), band keratopathy (2 cases) and decreased visual acuity (1 case).

Conclusion: Patients with JIA and BD should be regularly checked for uveitis. It is hard to find an etiology in uveitis cases that were sent from ophthalmologist if initial examination and questioning do not reveal an overt rheumatologic disease but simple urine test may help in diagnosis of TINU.

Disclosure of Interest

None Declared

P112 JUVENILE IDIOPATHIC ARTHRITIS, UVEITIS AND ANTI-DFS70 ANTIBODIES – AN UNDEFINED RELATIONSHIP

Federica Martinis¹, Sara Pieropan¹, Gloria Dallagiacoma¹, Eugenia Bertoldo¹, Federico Caldonazzi², Domenico Biasi¹, Maurizio Rossini¹, Caterina Mansoldo³

¹Rheumatology Unit, AOUI Verona, Verona; ²Paediatric Unit, Ospedale di Rovereto, Rovereto; ³Ophthalmology Unit, AUOI Verona, Verona, Italy

Correspondence: Gloria Dallagiacoma

Introduction: Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease of childhood and uveitis is one of the major extra-articular manifestations. Uveitis occurs more frequently in children with antinuclear antibodies (ANA) positive disease and is often asymptomatic and may lead to permanent visual impairment, if not treated properly. ANA is the only biomarker that currently guides uveitis screening in JIA but it remains not conclusive. Among various ANA patterns, anti-DFS70 antibodies has been proposed as a novel biomarker for uveitis screening, being positive in children likely to develop uveitis. By contrast, in adults these antibodies seem to identify healthy individuals among asymptomatic ANA positive subjects.

Objectives: Aim of this observational study was to evaluate the correlation between uveitis and anti-DFS70 antibodies in children affected by JIA.

Methods: A total of 34 children (22 females, 12 males; median age 13.3 years) admitted to Rheumatology Unit of Verona and affected by JIA were enrolled. Following data were recorded retrospectively: JIA subtype, ANA positivity, anti-DFS70 positivity, presence of uveitis, diagnosed by a well-trained ophthalmologist.

Results: In our series oligoarticular ANA+ JIA was the predominant subtype (23 cases, 67.6 % of total), followed by oligoarticular ANA- subtype (6 cases, 17.6 % fo total), polyarticular ANA- JIA (3 cases, 8.8% of total), and lastly polyarticular ANA+ JIA (2 cases, 5.9% of total).

23 (67.8% of total) patients presented a DFS/homogeneous ANA pattern. 6 out of 34 patients (17.6%) developed mono- or bialteral uveitis and all of them were ANA positive, confirming that DFS/homogeneous ANA pattern is the most common pattern associated to uveitis. None of patients presented antibodies anti-DFS70, regardless of clinical history of uveitis.

Conclusion: DFS/homogeneous ANA pattern remains the most common pattern seen in JIA patients and seems to be an hallmark of uveitis. In our series, we found that neither JIA nor uveitis risk in JIA patients correlate with anti-DFS70 positivity. The role of these antibodies in children remains thus unclear. Further studies are needed to identify a reliable biomarker to guide ophthalmologic screening in JIA patients and to identify children likely to develop uveitis.

Disclosure of Interest

None Declared

P113 CHOIСE AND SWITCH BETWEEN BIOLOGICAL AGENTS IN JUVENILE IDIOPATHIC ARTHRITIS WITH UVEITIS

Anna Ignatova¹, Nina Seylanova², Elena Zholobova³

¹5th year student; ²3'd year student; ³Pediatric Rheumatology, Federal State Autonomous Educational Institution of Higher Education I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation, Moscow, Russian Federation

Correspondence: Anna Ignatova

Introduction: Chronic anterior uveitis (CAU) is the most common extra-articular sign of juvenile idiopathic arthritis (JIA) that can result in a serious impairment and/or loss of vision in children. Standard antirheumatic drugs in combination with local therapy are effective in 60%. When these drugs are ineffective, biological agents are used in JIA with CAU. The issue of optimal and personalized biologic therapies prescription and problem of switching between drugs are relevant questions of modern pediatric rheumatology.

Objectives: The aim of this retrospective observation was to describe trends in the biologic DMARDs prescription in first and subsequent lines of biologic therapies for the treatment of JIA associated with CAU.

Methods: We recruited 53 patients with JIA and eye involvement, who received medical treatment at the Department of Pediatric Rheumatology of Sechenov University since January 2015 to December 2017. Study group included 39 girls and 14 boys (2,8/1). Mean age was 11,19 ± 3,87 years, age of disease onset was 4,80 ± 3,06 years; mean disease duration was 6,39 ± 3,45 years. Among included patients 28 children (53%) had oligoarticular JIA, 25 children (47%) – polyarticular RF- JIA. ANF was positive in 36 patients (68%). Disease onset with initial joint damage was observed in 35 children (66%), with eye involvement – in 7 children (13%), with both joint damage and eye involvement – in 11 children (21%). Thirty-eight (72%) patients had bilateral ocular involvement, 15 patients (28%) – unilateral.

At baseline, 51 patients (96%) received concomitant therapy with non-biological immunosuppressive drugs: 49 children (96%) received Methotrexate, 2 children (4%) Cyclosporine A. Two children (4%) received biologic DMARD as monotherapy. All patients received local therapy due to the ophthalmologist recommendations.

Results: As a first biologic abatacept was used in 10 patients, etanercept in 8 patients, infliximab in 1 patient. Adalimumab was used in 34 patients (64,15%±8,23), which was significantly more frequently than abatacept, etanercept and infliximab as a whole – 19 (35,85%±11,01) (t=2,06; P>95,5%).

Later 13 children (24,53%) were switched from a first to a second biologic agent. 11 patients were switched from the other biologics to adalimumab. The main reasons for switching was the appearance of CAU in 4 patients (36%), who were initially treated with etanercept, and aggravation of CAU in 3 patients (27%), 2 of them received etanercept as a first biologic and 1abatacept. The second reason for switching was lack of therapeutic response or inefficacy (in 4 – 36%): 3 patients were initially treated with abatacept and 1 with infliximab. Adalimumab was discontinued due to inefficiency only by 1 patient. One patient discontinued adalimumab due to remission. At the end of our observation alimumab was chosen as treatment for 43 (81,13%) patients with JIA and CAU.

Conclusion: Thus, adalimumab was preferred as a first- and second-line biologic agent in treatment of JIA with CAU.

Disclosure of Interest

A. Ignatova: None Declared, N. Seylanova: None Declared, E. Zholobova Consultant for: AbbVie, Roche, BMS, Pfizer, Novartis, MSD

P114 UVEITIS IS RISK FACTOR OF SIGNIFICANT FLARE IN NON-SYSTEMIC JUVENILE IDIOPATHIC ARTHRITIS ON THE FIRST BIOLOGICS.

Mikhail Kostik, Ekaterina Gaidar, Lyubov Sorokina, Ilia Avrusin, Elizaveta Orlova, Yuri Korin, Margarita Dubko, Vera Masalova, Tatyana Likhacheva, Ludmila Snegireva, Eugenia Isupova, Olga Kalashnikova, Vyacheslav Chasnyk

SAINT-PETERSBURG STATE PEDIATRIC MEDICAL UNIVERSITY, Saint-Petersburg, Russian Federation

Correspondence: Mikhail Kostik

Introduction: Treatment of moderate-severe form of juvenile idiopathic arthritis (JIA) required using biologics in the cases of methotrexate inefficacy or intolerance. The presence of extra-articular features, especially uveitis usually required more intensive treatment approaches. The finding of predictors of biologics efficacy is still actual problem.

Objectives: to evaluate the role of uveitis as a risk factor of flare and survival of first biologic medication in non-systemic JIA.

Methods: Inclusion criteria: patient whom first biologic was administrated with or without MTX or MTX was discontinued after start of biologics due to different reasons (remission, intolerance, adverse events). Exclusion criteria: treatment with current systemic corticosteroids, infliximab, rituximab. After selection 175 patients were eligible to analysis. We evaluate clinically significant flare with joint involvement (required change of biologic or non-biologic DMARD), time to flare. We compare two groups: i) patients with uveitis (n=32) and ii) patients without uveitis. For statistical analysis we Cox’s regression models, Log-Rank test, x2 test and Mann-Whitny test.

Results: the data of comparison between groups depending on the uveitis in the Table 1. There was no difference in the gender distribution, and achievement of remission. The main biologic in non-uveitis group was etanercept (64.3%), in uveitis group – adalimumab (71.9%). Presence of uveitis increases the risk of JIA flare: OR= 3.8 (95%CI: 1.7; 8.7), and cumulative probability of flare: RR=4.5 (95%CI: 1.7; 12.1), р=0.003; Log Rank test, p=0,001; after adjustment on methotrexate RR=3.1 (1.6; 6.0), p=0.0008. In subgroup of patients treated with adalimumab absence of methotrexate increases the cumulative probability of flare RR=6.5 (95%CI: 1.4; 31.1), р=0.02.

Conclusion: presence of uveitis was assumed as risk factor of JIA flare, methotrexate can decrease the cumulative flare probability. Further trials are required.

Disclosure of Interest

None Declared

Table 1 (abstract P114). See text for description

P115 LONG-TERM OUTCOME AND COMPLICATIONS IN UVEITIS, 18 YEARS AFTER DISEASE ONSET IN A POPULATION-BASED NORDIC JUVENILE IDIOPATHIC ARTHRITIS COHORT

Veronika Rypdal¹, Mia Glerup², Terje Christoffersen³, Geir Bertelsen³, Ellen Dalen Arnstad^4,5, Kristiina Aalto⁶, Suvi Peltoniemi⁶, Lillemor Berntson⁷, Maria Ekelund^7,8, Anders Fasth⁹, Troels Herlin², Susan Nielsen¹⁰, Peter Toftedal¹⁰, Rasmus Nielsen¹¹, Sanna Leinonen¹², Regitze Bangsgaard¹³, Susanne Lindqvist¹⁴, Marite Rygg^5,15, Ellen Nordal¹, the Nordic Study Group of Pediatric Rheumatology (NoSPeR)

¹Department of Pediatrics, University Hospital of North Norway, Tromsø, Norway; ²Department of Pediatrics, Aarhus University Hospital, Aarhus, Denmark; ³Department of Ophthalmology, University Hospital of North Norway, Tromsø; ⁴Department of Pediatrics, Levanger Hospital, Levanger; ⁵Department of Clinical and Molecular Medicine, NTNU, Trondheim, Norway; ⁶Department of Pediatrics, University of Helsinki, Helsinki, Finland; ⁷Department of Women’s and Children’s Health, Uppsala University, Uppsala; ⁸Department of Pediatrics, Ryhov County Hospital, Jonkoping; ⁹Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; ¹⁰Department of Pediatrics, Rigshospitalet Copenhagen University Hospital, Copenhagen; ¹¹Department of Ophthalmology, Aarhus University Hospital, Aarhus, Denmark; ¹²Department of Ophthalmology, University of Helsinki, Helsinki University Hospital, Helsinki, Finland; ¹³Department of Ophthalmology, Rigshospitalet Copenhagen University Hospital, Copenhagen, Denmark; ¹⁴Department of Ophthalmology; ¹⁵Department of Pediatrics, St. Olavs Hospital, Trondheim, Norway

Correspondence: Veronika Rypdal

Introduction: Uveitis is the most common extra-articular manifestation in children with juvenile idiopathic arthritis (JIA). Early identification and treatment is important in order to prevent sight-threatening complications and ongoing disease activity in to adulthood. Long-term population-based data on uveitis course, outcome and complications are sought for.

Objectives: The aim was to assess long-term course, outcome and complications of uveitis in the Nordic JIA cohort 18 years after disease onset.

Methods: A multicenter longitudinal prospective Nordic JIA cohort study in which 510 patients from defined geographical areas of Denmark, Finland, Sweden and Norway with disease onset in 1997-2000 were included. The study aimed to be as population-based as possible. At the 18-year follow-up 434 patients were included. Uveitis information was available for 431 participants, and 272 were examined by an ophthalmologist at the study visit. Otherwise information about uveitis and medication was collected by the pediatric rheumatologist.

Results: Uveitis developed in 94/431 (22%) patients during the observation period of 18 years. Non-symptomatic uveitis was found in 73% of the patients, and 84% had an insidious onset of their uveitis. Anterior uveitis was described in 70%. Among the uveitis patients 83% had received treatment with methotrexate and 58 % treatment with biologics at some point during the disease course. At the final study visit 36% had ongoing local treatment with eye drops, while 32% used systemic medication due to, or partly due to, uveitis. 7/94 (8%) had a best corrected visual acuity ≤0.5 in at least one eye. Cataract developed as a complication in 25/94 (27%) and glaucoma in 22/94 (23%). Surgery was performed for cataract in 20/25 (80%) and for glaucoma in 18/22 (82%) of the patients.

Conclusion: We found a high incidence of uveitis among nordic young adults with JIA. Cataract and glaucoma were the most common structural complications. For the majority of the young adults with these complications surgery was needed within 18 years after onset of JIA, pointing to severe implications of uveitis in a life-long perspective.

Disclosure of Interest

None Declared

P116 THE SPECTRUM OF NON-INFECTIOUS UVEITIS IN CHILDREN MANAGED AT A TERTIARY PAEDIATRIC RHEUMATOLOGY SERVICE IN CAPE TOWN

Waheba Slamang, Christopher Tinley, Christiaan Scott

Red Cross War Memorial Children's Hospital and University of Cape Town, Cape Town, South Africa

Correspondence: Waheba Slamang

Introduction: Non-infectious uveitis is a leading cause of blindness in the developed world. Juvenile idiopathic arthritis associated uveitis (JIA-U) is one of the most commonly reported immune mediated cause of uveitis in children. However, as in other developing countries, infectious uveitis is more common in Africa and there is a paucity of data on the epidemiology of non-infectious uveitis in children in this setting. To our knowledge, this is the first description of non-infectious uveitis managed at a tertiary paediatric rheumatology service from sub-Saharan Africa.

Objectives: To describe the disease characteristics and treatment of children with non-infectious uveitis at a tertiary paediatric rheumatology service in Cape Town

Methods: A retrospective analysis of children managed by the paediatric rheumatology and ophthalmology service for uveitis from 1 January 2010 to 31 December 2017, was conducted. Ethics approval was obtained, and relevant data extracted from patient medical rheumatology and ophthalmology case files. Descriptive statistics were employed and comparisons between JIA-U and idiopathic uveitis groups were made, with p-values < 0.05 considered significant.

Results: Thirty-four children (60 eyes) were reviewed - 18 boys and 16 girls with a median age at first visit of 76 months (age range 25 to 156 months).

Chronic anterior uveitis predominated in 23 (68%), acute anterior uveitis occurred in 3 (9%), panuveitis in 4 (14%), followed by 3 (9%) posterior, and 1 (3%) intermediate uveitis.

Fourteen (41.1%) were associated with juvenile idiopathic arthritis (JIA), 12 (35.3%) were considered idiopathic, while 2 (5.8%) were due to sarcoidosis, 1 (3%) to Behcet’s, 2 (5.8%) to human immune deficiency virus (HIV), 2 (5.8%) post streptococcal and 1 (2.9%) to toxocara.

The JIA-U group were characterised by a female preponderance, median age of onset of 56 months and chronic anterior uveitis. Further review according to the International League of Association for Rheumatology (ILAR) classification showed 10 (71,4%) to be oligo-persistent antinuclear antibody (ANA) positive while 3 (21,4%) were poly-articular rheumatoid factor negative and 1 (7,1%) had psoriatic-JIA.

9 (64.2%) of the JIA-U group and 8 (73%) of the idiopathic group presented with complications, predominantly cataracts, followed by band keratopathy and posterior synechiae. There was no significant difference in age and complications at presentation, between the two groups, p-values 0.4 and 0.62 respectively, though a male preponderance was evident in the idiopathic group.

All children were treated with standard initial therapy which included steroids (topical, oral and/ or intravenous) and methotrexate, of which 21 (61.7%) achieved remission. Thirteen children required the addition of a tumour necrosis factor (TNF) inhibitor, due to failure of Mycophenolate Mofetil in 2 and Azathioprine in 7. Eight (61.5%) achieved remission (Table 1).

Conclusion: Here, JIA-U appears to have similar disease characteristics as previously described. However, the high rate of complications at presentation, requires further review of overall visual outcomes and the effectiveness of current screening and treatment strategies. Optimum management of non-infectious uveitis therefore necessitates a close relationship between paediatric rheumatologists and ophthalmologists.

Disclosure of Interest

W. Slamang Grant / Research Support from: Abbvie, Pfizer, C. Tinley: None Declared, C. Scott Grant / Research Support from: Abvvie, Pfizer. Roche

Table 1 (abstract P116). TNF inhibitor treatment

P117 EFFICIENCY AND SAFETY EVALUATION OF BIOSIMILAR INFLIXIMAB FOR TREATMENT OF PEDIATRIC NON-INFECTIOUS UVEITIS IN SINGLE CENTER

Betul Sozeri¹, Esra Kardes², Gizem Leyla Bolac¹, Betul Ilkay Sezgin Akcay²

¹Pediatric Rheumatology; ²Ophtalmalogy, University of Health Sciences, Istanbul, Umraniye Training and Research Hospital, Istanbul, Turkey

Correspondence: Betul Sozeri

Introduction: Biosimilar infliximab (Remsima®) has been introduced in our country, together with other European countries in 2014. Information regarding the use in child age group is limited but it is reported that its therapeutic efficiency and safety is similar to the reference molecule regarding the pediatric Chron disease

Objectives: In this study, our aim was to reporte the efficiency and safety of BI used for children with non-infectious uveitis.

Methods: In this study, there were 13 subjects (9 boys, and 4 girls) diagnosed with non-infectious uveitis.

BI (Remsima9 treatment had been given in 5 mg/kg in 0.,2.,4 th week and then every 8^th week. Ophthalmic assessment of disease activity and ocular complications were measured throughout the trial with the use of slit-lamp biomicroscopy for uveitis activity, according to the SUN criteria. The Drug exposure has been evaluated by calculated of patient year (HY), adverse event (AE) was assessed using the CTCAE criteria. The median values due to the small number of patients are considered.

Results: The patients who were include the study, 5 had diagnosed extended oligo JIA, 2 with enthesitis-related arthritis (ERA) ,2 with persistent oligo JIA, 2 with pars planitis and one of them Behcet’s disease. At the time of evaluation, the median age was 10 years (3-13), age at diagnosis of their disease 8 years (1-13), respectively. The median age of uveitis diagnosis was 8 years. The median disease duration before BI was 10 months. All of the patients had methotrexate therapy with BI and BI before.

Only one patient used a different biological agent prior to BI, and revealed they were determined that considered unresponsive.

Other patients (n=12) had biosimilar infliximab as first biologic drug due to the activation of disease after using the drug methotrexate.

After therapy of BI, in all of the patients, joint and eye symptoms were improvement.

The systemic steroid therapy was cut down in the first month in all patients, 2 of them continue prophylactic topical steroids.

The median duration of BI therapy was 10 months. There was one case of anaphylaxis in all the patients, whereas five of them frequent upper respiratory tract infection have been observed as side effect.

Conclusion: In this preliminary report, This biosimilar infliximab treatment appears to be safe and effective in pediatric age group on the pediatric patients with non-infectious uveitis. These results must be supported by multicenter studies and registries.

Disclosure of Interest

None Declared

P118 FIRST MULTI-CENTER SURVEY FOR THE TREATMENT IN JUVENILE IDIOPATHIC ARTHRITIS-ASSOCIATED UVEITIS (JIA-U) AT CLINICAL SETTINGS IN JAPAN; THE REPORT FROM PEDIATRIC ASSOCIATION OF JAPAN (PRAJ)

Masato Yashiro¹, Junko Yasumura², Nami Okamoto³, Kosuke Shabana³, Yuka Okura⁴, Hiroaki Umebayashi⁵, Minako Tomiita⁶, Kenichi Nishimura⁷, Naomi Iwata⁸, Masaki Shimizu⁹, Mao Mizuta⁹, Tomohiro Kubota¹⁰, Syuji Takei¹¹, Masaaki Mori¹²

¹Pediatrics, OKAYAMA UNIVERSITY HOSPITAL, Okayama; ²Pediatrics, Hiroshima University Graduate School of Biomedical & Health Sciences, Hiroshima; ³Pediatrics, Graduate School of Medicine, Osaka Medical College, Takatsuki; ⁴Pediatrics, KKR Sapporo Medical Center, Sapporo; ⁵Rheumatics, Miyagi Children’s Hospital, Sendai; ⁶Allergy and Rheumatology, Chiba Children's Hospital, Chiba; ⁷Pediatrics, Yokohama City University Graduate School of Medicine, Yokohama; ⁸Infection and Immunology, Aichi Children’s Health and Medical Center, Obu; ⁹Pediatrics, Graduate School of Medical Sciences, Kanazawa University, Kanazawa; ¹⁰Pediatrics, Graduate School of Medical and Dental Sciences, Kagoshima University; ¹¹Pediatrics, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima; ¹²Lifetime Clinical Immunology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan

Correspondence: Masato Yashiro

Introduction: There are no established treatment guidelines for patients with juvenile idiopathic arthritis-associated uveitis (JIA-U).

Objectives: Therefore, multi-center survey was conducted to examine the present treatment status for JIA-U in Japan to establish treatment guideline in the future.

Methods: Questionnaires were sent to medical centers with pediatric rheumatologists at April in 2016 to investigate the patients’ profile and how JIA-U was treated in each center.

Results: Of 726 patients involved in this study, 44(6.1%) had JIA-U and 36/44 (81.8%) was oligoarticular onset. Of 40 JIA-U patients recruited by the 2^nd detailed survey, 23 (57.5%) had been treated with NSAIDs in 13 (32.5%), MTX in 16 (40.0%), glucocorticoids (GCs) in 1(2.5%), and etanercept (ETN) in 1 (2.5%) by the time when JIA-U was diagnosed. After JIA-U was diagnosed, topical GC was started in all cases in combination with MTX in 3(7.5%) and/or systemic GC in 2(5.0%). Some biologic agents (infliximab (IFX) and adalimumab (ADA)) were used more frequently in JIA-U patients than non-uveitis patients (P <0.0001, P = 0.0029). Of 40 JIA-U patients, 22 patients (55.0%) were treated with biologic agents such as IFX in 9(22.5%), and ADA in 11 (27.5%). Surgical treatments for JIA-U such as intraocular lens implantation underwent in 15 cases (37.5%). Symptoms and findings related to uveitis improved with treatment in all 40 JIA-U patients, and no blindness was observed in this survey.

Conclusion: Treatment for JIA-U in real clinical settings in Japan was similar to that of previous reports from other countries. Higher incidence of JIA-U onset in MTX treated patients in Japan may be explained by the differences in administration dose or method. Further investigation with larger scale is essential to establish the evidence-based treatment recommendation for JIA-U.

Disclosure of Interest

None Declared

Poster Walk 5: HPPR - e-health and digital health applications

P119 SMARTPHONE APPLICATION “MY PATHWAY” GUIDING THE YOUNG PATIENT WITH JIA THROUGH TRANSITION TO ADULT MEDICINE.

Anette Pieler, Heidi K. Ipsen, Anne E. Christensen, Peter Toftedal

H.C. Andersen Childrens Hospital, Odense University Hospital, Odense, Denmark

Correspondence: Heidi K. Ipsen

Introduction: In 2014 the Region of Southern Denmark created the application (app), “Mit forløb” (“My Pathway”) giving the different departments at the hospitals, the option to create their own specific section of the app. The app is available for everybody but using the communication and registration tools requires access granted by the relevant department.

“My Pathway” is patient empowerment put into practice because the patients can be more involved in their own treatment and gain knowledge about different aspects of their disease and management thereof.

Objectives: To provide the young patients with JIA an easy and accessible way to find information on their disease, treatment and rights before and during transition to adult medicine a smart phone app was created.

Methods: The information in the app was written in collaboration between health professionals from the pediatric department and the department of Rheumatology, securing a uniform structure and language. It covers JIA, pain management, treatments and their side effects. Also included is general information on the department, its structure and staff.

A chat function was developed which enables communication with the hospital in a flexible way; the patient can write whenever the question occurs and the hospital staff can answer when they have the time and have looked into the patient journal.

“My Pathway” meets the young patient where they are; online anytime and anywhere via the smartphone in their pocket. Regarding transitioning focus was put on patients’ rights and the app was created to it could be accessed both as a patient at the pediatric department and the department of Rheumatology.

Results: The app is still a very new initiative and has not yet been widely spread to the young patients. Around 30 young patients have been granted access to the app, and the feedback has been positive.

Feedback from the patients has been a wish for more personalized information, regarding treatment and consultations, and to be able to see future appointments.

As of yet the chat feature has not been in much use probably due to reduced awareness among families and staff.

Conclusion: The pediatric team succeeded in creating an app geared towards informing the young patients about JIA, medication, pain-management, transfer to the department of Rheumatology etc.

As the app is a new implementation there must be expected a period of time for adjusting, both for patients and health professionals.

There is need for further development for the app to achieve full potential. Adapting the feedback from the young patients and the health professionals working with the app is an ongoing process.

The app is planned to include all rheumatic diagnoses and also access for younger children and their parents in the future.

Disclosure of Interest

None Declared

P120 REUMA2GO, A PLATFORM TO EMPOWER PATIENTS, PARENTS AND CAREGIVERS BY IMPROVING, DIALOGUE, PARTICIPATION AND MONITORING DISEASE BURDEN

Mark Klein¹, Joost Swart¹, Astrid Willemsen¹, Gerrie Joode², Annemarijn van Rheenen³, Vicky Seyfert⁴, Nico Wulffraat¹

¹Pediatric Rheumatology, Wilhelmina Children’s Hospital, University Medical Center Utrecht; ²Pediatrics; ³IT, University Medical Center Utrecht, Utrecht, Netherlands; ⁴MyOwnMed, Bethesda, USA

Correspondence: Mark Klein

Introduction: Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease of childhood requiring long-term treatment. JIA has an fluctuating and unpredictable course. The fluctuation of disease activity, asks for continuous monitoring by a pediatric rheumatologist to achieve good health outcomes. Children with JIA live with chronic or recurrent pain and disability, which can severely limit their ability to complete daily physical tasks and participate in school and social activities.

An app was developed with input of patients, parents and caregivers to help close the gap between hospital care and the normal daily life activities of children with JIA in between hospital visits.

Objectives: To create an ehealth platform (Reuma2GO) that aims to significantly improve the care for children with JIA and the dialogue between children with JIA, their parents and team of caregivers and hence, to advance true patient participation both in care and research.

Methods: We performed a two-day workshop which was attended by patients, parents, app developers and caregivers about the added value of eHealth for the JIA patient and their parents. The participants were asked what they wanted from an app in their therapy that they are not currently finding. The workshop participants then worked together to come up with design and concept features that their ideal app should have and identify the critical success factors giving app developers a clear, clinically-approved model to work to.

The Reuma2GO app tracks joint pain, fatigue, morning stiffness, daily activities and manages appointments and medication. Patients can communicate with health professionals in the app for advice or questions. Weekly feedback is sent on the self-reports by the care team to support patients and parents. The patient-generated data in the app will be integrated into the EMR in the near future.

Results: The Reuma2GO app is developed and tested among patients and care professionals according to the agile scrum method. 180 JIA patients and 7 rheumatologists/immunologists are using the Reuma2GO app. The app was evaluated as helpful in self-management and recommended by patients. The app generates a dynamic reflection of the daily life of a JIA patient. This allows patients to efficiently monitor the impact and actual status of their disease.

Conclusion: Reuma2GO is an eHealth platform that enables JIA patients to better understand and monitor the burden of the disease and thereby providing patients a way to become more actively involved in their disease management. By sharing their data in between hospital visits both patients and care professionals should benefit by offering more personalized care and using monitored data for research. Planning is to scale up the app to other hospitals in Europe that participate in the PRES network in the coming period.

Disclosure of Interest

None Declared

P121 REUMA2GO-APP CREATES A CONTINUUM OF CARE

Mark Klein¹, Joost Swart¹, Sytze Roock¹, Astrid Willemsen¹, Nathan Buijsse¹, Gerrie Smink¹, Annemarijn van Rheenen², Vicky Seyfert³, Nico Wulffraat¹

¹Pediatric Rheumatology, Wilhelmina Children’s Hospital, University Medical Center Utrecht; ²IT, University Medical Center Utrecht, Utrecht, Netherlands; ³MyOwnMed, Bethesda, USA

Correspondence: Mark Klein

Introduction: From the patients perspective, the big promise of health apps (mHealth) is to increase self-awareness and self-care. For chronic conditions such as juvenile idiopathic arthritis (JIA), mHealth may provide a way for patients to become more actively involved in their disease management. With input of patients, parents and caregivers the Reuma2GO app was developed in 2017. It was intended to close the gap between hospital care and the normal daily life activities of children with JIA. The Reuma2GO app creates insights for patient, parents and caregivers into all aspects of JIA that influence the burden of disease (e.g. joint pain, fatigue, morning stiffness, daily activities, medication use, side effects). By offering the possibility of instant reporting about health issues one does not have to rely on their memory for conditions that were present weeks before the routine visit. Moreover the app allows for built-in thresholds with automatic alerts to physicians. A closed communication system allows the patient to open discussions with their physician.

We feel that some routine visits of JIA patients, when in a stable inactive episode (either on or off medication), can be skipped as long as the patients agree that they are still doing fine.

Objectives: To evaluate if patients/parents are capable of self-monitoring with the Reuma2GO app when they feel the disease is quiet in order to skip future hospital visits.

Methods: Data from the Reuma2GO-app, the JAMAR at the hospital visit (question 6: “Considering all the symptoms…. evaluate the level of activity of your child’s illness at the moment”) and the physician’s global assessment of disease activity (PGA) were compared.

The data used from the Reuma2Go app were the following (total score 0-40)

• 1: How much pain did you have in the past week (0-10)?

• 2: Do you have pain and/or swelling in your joints today (max 10 joints)?

• 3: Did you suffer from morning stiffness in the last week (5 step-scale; 2 points per step)?

• 4: How active is your illness at this moment (0-10)?

We only included those patients that had completed the abovementioned questions in the Reuma2Go-app 0-3 weeks before the routine visit and scored a maximum of 1 point in total and only allowed for question 1 and 4 (=Wallace’s criteria for inactive disease according to parent/patient).

Results: 186 (128 Female) patients aged 12.07±4.27 years use the Reuma2GO app.

The distribution of JIA categories was: 19.4% polyarticular RF-negative, 6.9% enthesitis-related arthritis, 3.5% polyarticular RF positive, 11.8% extended oligoarticular, 40.3% persistent oligoarticular, 5.6% systemic JIA, 4.9% artritis psoriatica and 7.6% had undifferentiated arthritis.

Preliminary data show that 17 patients completed the questions and considered the JIA to be inactive. In 16 (94%) of the cases the physician confirmed that the JIA was inactive and the JAMAR question on disease activity reflected the same. Only one patient score a 1/10 at the JAMAR during the visit, while the app scored a 0 before. This patient was suspected to have still a bit of unilateral TMJ arthritis and received a PGA of 1/10 as well, although no change in medication was performed

Conclusion: The Reuma2Go-app creates a continuum of care by which the physician does not need to make treatment plans depending on one-point in time conditions at prescheduled visits. Moreover 94% of the patients that felt their disease was quiet were right about it. The only one that changed his/her mind at the visit was backed up by the physician, although no treatment change was needed. Future studies will look into the safety of giving autonomy to patients when they feel a visit can be skipped.

Disclosure of Interest

None Declared

P122 THE TRIALS AND TRIBULATIONS OF DEVELOPING AN ACTIVITY DIARY APP FOR CHILDREN AND YOUNG PEOPLE WITH PERSISTENT PAIN

Claire L. Pidgeon

Rheumatology Service, Birmingham Women's and Children's Hospital, Birmingham, UK

Introduction: Identifcation of a need to replace a paper based activity diary used as part of pain management intervention with a more accessible and user friendly smart technology resource. Researchers within the field of E-technology have demonstrated the use of smart phones for self-monitoring pain and symptoms preferable to paper based forms noting that the information recorded was more accurate and time efficient. Pain diary apps exist however they tend to focus on reporting and recording pain rather than activity levels. At the time of development there were no activity diary apps specifically aimed at children and young people.

Objectives: To develop an interactive user-friendly e-diary app that is accessible on android and iOS smart mobile phone.

Methods: At concept a business plan was submitted to secure financial funding and obtained authorisation clinical design group within NHS trust. Consultation with multi-disciplinary team and user groups on the style, content, usability. This led to consultations with the nominated app developer to bring the concept to wireframe draft format. Educational content was then researched and drafted. Further consultation with user-groups to sign off the final draft of the app.

Results: The development process was initially estimated to be completed within 12 months. In fact the entire process was 3 years in duration, underestimating the volumes of work and time that would be involved. A particularly steep learning process for the therapist who was a novice to app development. Despite this editing drafts and trailing the app was required to ensure that all glitches were identifeid and rectified the app is now a the point of final sign off.  The app is at point of release on app store(s). The next phase is to research the efficacy of the app in the following 12 months.

Conclusion: Many challenges emerged during the app development process, with important lessons learnt. Technology is ever-evolving at a fast pace. Ensuring the app was relevant was a key driver in the development process, the additional time taken to complete this project increased the risk that the app would be out of date or other activtiy diary apps may become available before the completion date was reached.

Having to use an external organisation to develop the app had limitations in being able to communicate quickly and easily to ensure alterations to the drafts were completed in a timely manner. Future updates that may be required to the app will be limited as this will have to go through the app developer and will have a cost implication.

Improvements emerged during the development phase that were beyond the scope of the app and were not included in the original costings therefore could not be included. It is hoped once the efficacy of the app is researched that further funding can be secured to include the additional functions to the app to build of the scope.

Engagement with user groups was a vital part of the development process providing opinions on the look, and userability of the app interface. The focus group contributed significant modifications to the final app and included setting reminders and a notification facility as well as assisting with naming the app.

The next phase is to research the efficacy of the app in the following 12 months. An essential part of the process is making links with other researchers in this field to continue to the build on the access to evidence-based e-technology tailored specifically for young people.

Disclosure of Interest

None Declared

P123 GENIA- A PATIENT SUPPORT MOBILE HEALTH APP FOR JIA

Sara Rostlund,Johanna Kembe

Function Area Occupational therapy & Physiotherapy, Allied Health Professionals Function, KAROLINSKA UNIVERSITY HOSPITAL, ASTRID LINDGREN CHILDREN HOSPITALSTOCKHOLM, Stockholm, Sweden

Correspondence: Sara Rostlund

Introduction: Genia is an app created as a patient support system for improved communication and collaboration with patients, families and the health care team. Its designed for IOS so far and is available in app store in both Swedish and English.

Objectives: Through the app, patients can take notes and track self-assessed observations in daily living, which could include Visual Analog Scale trackers on various symptoms, activities and other areas reflecting quality of life. Automatic data collection, such as Steps from Apple eHealth, is also included. In addition users can send Pre-Visit report to health care to help both patients/families and care team to prepare for meetings as well as to help understand patients needs and preferences.

Methods: A pilot project using the app has been driven by a physiotherapist, occupational therapist and the head physician of the Childrens rheumatology department in Karolinska University Hospital in Stockholm. Currently 56 patients at the clinic have Genia.

Results: The feedback on experience from both patient/families and the clinic include that the app:

1. helps patients/families remember, reflect and prepare

2. support clinic visits

3. support patient activation and communication

Conclusion: As health professionals we see great potential in the app to get the patient more active, understanding their disease and aware that their behavior and selfcare can make a different in how they feel.

Genia is co-designed with JIA patients, families and members of the care team and continues to be iterated with feedback and ideas provided by stakeholders. There are further opportunities to co-develop the app to be helpful to patients and clinics, for example the creation of different types of reports, new or improved trackers that could support patients or/and assist care teams to support patients in self-care, etc.

Disclosure of Interest

None Declared

P124 ΤHE IMPACT OF A PHYSIOTHERAPY TELE-REHABILITATION PROGRAM ON CHILDREN WITH JUVENILE IDIOPATHIC ARTHRITIS

Maria Stavrakidou^1,2,3, Maria Trachana², Artemis Koutsonikoli², Kyriaki Spanidou¹, Alexandra Hristara-Papadopoulou³, Ioannis Xinias⁴

¹Pediatric Physiotherapy, Asklepeio Physiotherapy Clinic; ²First Dept of Pediatrics, Pediatric Immunology and Rheumatology Referral Center, Hippokration Hospital; ³Postgraduate Program in Pediatric Physiotherapy, Alexandrian Technological Educational Institute; ⁴Third Dept of Pediatrics, Hippokration Hospital, Thessaloniki, Greece

Correspondence: Maria Stavrakidou

Introduction: The Juvenile Idiopathic Arthritis (JIA) chronicity, combined with the psychosocial effects of the entire therapeutic process on children and parents, often leads to non-compliance and a significant financial burden. These parameters, in the era of the economic crisis, are an incentive to seek new approaches to physiotherapy.

Objectives: To investigate the applicability of a physiotherapy tele-rehabilitation program on children with JIA and to explore the program’s impact on children and their families.

Methods: Thirty JIA patients, with Medical Doctor’s global assessment (MDVAS) <2, who applied a home-exercise program, were selected and randomly divided in the tele-rehabilitation (TRG, n=15) and the control group (CG, n=15). Each child from the TRG participated, additionally at home-exercise program, in a 30-minute tele-session (using personal computers, at home) with a qualified pediatric physiotherapist, twice a week, for 12 weeks, performing their exercises under the supervision and guidance of the specialist. Before and after the tele-rehabilitation program (T1 and T2, respectively), TRG and CG patients and a parent/guardian completed the Juvenile Arthritis Multi-demensional Assessment Report questionnaire (JAMAR) and a relevant one for the implementation and compliance on the home-exercise program. Residual disease was estimated at T1 and T2 from a physiotherapist, different from the one performing the tele-rehabilitation program. At T2, TRG patients and their parents completed a questionnaire, evaluating the tele-rehabilitation program. One month after T2, a reassessment of compliance with the home-exercise program was performed.

Results: The children’s median (range) age was 12.8 (8-16) years. Nineteen children (63%) had JIA with poly-articular course and 11 (37%) with oligo-articular. All TRG children completed the tele-rehabilitation program. At T2, the TRG children performed the home-exercise program more frequently (p=0.023), for a longer time (p=0.034) and with less promoting (p=0.004), compared to T1. Moreover, there was increased compliance with the home-exercise program (p=0.001), functionality (p=0.008) and quality of life (p=0.007) and less pain due to JIA (p=0.017). In the CG children, there was no statistical significant change in the abovementioned parameters. The residual disease was improved in both groups (TRG: p=0.002, CG: p=0.018), but the improvement in TRG children was greater (p=0.043). The applicability of the tele-rehabilitation program was rated in a 0-10 VAS scale with a median (range) of 10 (7-10) by children and 10 (9-10) by their parents. The tele-rehabilitation program’s total benefit was rated with a median of 10 (8-10) by TRG children and 10 (9-10) by their parents. Finally, one month after T2, the compliance with the home-exercise program was still greater, compared to T1 (p=0.001).

Conclusion: The implementation of an interactive physiotherapy tele-rehabilitation program, is applicable and effective in children with JIA, providing an additional tool in their rehabilitation.

Disclosure of Interest

None Declared

Systemic lupus erythematosus and antiphospholipid syndrome

P125 ESTIMATED GLOMERULAR FILTRATION RATE IN A SINGLE CENTRE CHILDHOOD LUPUS NEPHRITIS COHORT

Manjari Agarwal, Sujata Sawhney

Division of Pediatric and Adolescent Rheumatology, Sir Ganga Ram Hospital, New Delhi, India

Correspondence: Manjari Agarwal

Introduction: Ongoing proteinuria causes long term damage to the kidney. This is reflected by a change in estimated glomerular filtration rate(eGFR) over a period of time. A fall in eGFR is a poor marker and heralds damage. There is paucity of data about eGFR in children with lupus nephritis. We undertook this study to add to the existing data

Objectives: To estimate the eGFR by using the bedside Schwartz formula at the onset of nephritis,at one year after treatment and at last follow up

Methods: Charts were reviewed retrospectively of 82 children with lupus nephritis. Height records at disease onset were available for 69 and these were included for analysis. eGFR was calculated using the bedside Schwartz formula: 0.413*(Height/Creatinine).

Results: 69 children with lupus nephritis were included for the analysis of eGFR. Two children did not complete one year of treatment and were thus not included for analysis of eGFR at one year and at last follow up.

Median age at onset of nephritis was 12 years. Median duration of follow up of the cohort was 55 months(9-164months).

Median eGFR at onset of nephritis prior to treatment was 82ml/min./1.73m²(IQR 63-115). Median eGFR at one year after treatment was 127ml/min/1.73m²(IQR 89-150).eGFR at last follow up was 128ml/min/m²(IQR 101-145)

The change in eGFR from baseline to one year was statistically significant (p =<0.001) and the change at last follow up visit from baseline was also better and was statistically significant (p=<0.001). However there was no statistically significant change in eGFR from one year to last follow up value (p=0.72).

39 children had eGFR less than 90ml/min/m2 at onset of nephritis and of these 14 had eGFR <60ml/min/m2.After one year of therapy one child had eGFR< 60ml/min./m2 and 18 had eGFR <90ml/min/m2.

39 children had eGFR less than 90ml/min/m2 at onset of nephritis and of these 14 had eGFR <60ml/min/m2.After one year of therapy one child had eGFR< 60ml/min./m2 and 18 had eGFR <90ml/min/m2.

This could imply that aggressive treatment early on led to a significant improvement and there was not much deterioration subsequently.

Conclusion: Stringent follow up is practiced at our unit and a tight treat to a target approach is employed. Early aggressive therapy is the norm. This is probably a reason for better outcomes.

Another possibility is that many children have not spent a long time in the disease course and a longer follow up is needed to actually determine the renal damage.

Disclosure of Interest

None Declared

P126 MORBIDITIES AND COMORBIDITIES IN PATIENTS WITH JUVENILE SYSTEMIC LUPUS ERYTHEMATOSUS AND ITS RELATION WITH THE PED-SDI ORGAN DAMAGE INDEX IN 2 PEDIATRIC RHEUMATOLOGY CLINICS IN BOGOTA, COLOMBIA.

Christine Arango¹, Clara Malagon², Catalina Mosquera²

¹Medicine program, Universidad Tecnologica de Pereira, Pereira; ²Pediatric rheumatology program, Universidad El Bosque, Bogotá, Colombia

Correspondence: Christine Arango

Introduction: Juvenile systemic lupus erythematosus (jSLE) is a multisystemic disease that has its onset in childhood. It is accompanied by an important morbidity related to the disease and its therapy. Ped-SDI index is used to measure the organ damage in these patients. Morbidities and comorbidities can impact this index in a positive or negative way.

Objectives: To evaluate the relationship between morbidities and comorbidities with the ped-SDI damage index in patients with juvenile systemic lupus erythematosus being followed up in 2 paediatric rheumatology clinics in Bogotá, Colombia.

Methods: A descriptive, cross-sectional study of a retrospective cohort of patients evaluated between 1997 and 2016. Morbidities, comorbidities and treatment were identified and the ped-SDI damage index was measured in the last visit. The statistical analysis was done using Stata V12.

Results: 112 participants with juvenile systemic lupus erythematosus were included, the female: male ratio was 5,2:1. Sixty-two percent were 12 years or older at the diagnosis. The mean time of follow up was 49,3 months (6-161). Seven patients (6,25%) died during follow up with variable causes of death. The most frequently involved organs were musculoskeletal, mucocutaneous and hematologic. Patients who have taken 3 o more different immunosuppressive drugs (excluding antimalarial and steroids) during their disease, had a statistically higher damage index at last visit. Medication non-adherence was found in 40% of patients, being this related with a higher damage index at last visit. The morbidities associated with a higher organ damage index were acute kidney injury (p=0,0277), chronic kidney disease (p=0,0275), dialysis requirement (p=0,0072), neuropsychiatric (p=0,0020), cardiovascular (p=0,0000), pulmonary (p=0,0000), gastrointestinal (p=0,0082) and ocular involvement (p=0,0001). The presence of polyautoimmunity was also associated with a higher index (p=0,003). In contrast, the presence autoimmune thrombocytopenia was associated with a lower damage index (p=0,0378).

Conclusion: These findings showed that morbidities and comorbidities can impact the prognosis of juvenile lupus patients in a positive or negative way. These findings help to understand some different factors that can contribute to organ damage in these pediatric patients. Searching for these conditions and starting an early and directed therapy would impact the prognosis in a positive way.

Disclosure of Interest

None Declared

P127 HEPATITIS AS THE MAIN INITIAL MANIFESTATION OF JUVENILE SYSTEMIC LUPUS ERYTHEMATOSUS (J SLE)– 2 CASE REPORTS

Erato Atsali¹, Ekaterini Siomou², Sapfo A. Alfantaki³, Pelagia Katsibri⁴, Sorina Boiu¹, Lampros Fotis¹, Ioana Muresan¹, Vana Papaevangelou¹, Dimitrios T. Boumpas⁴

¹3rd Pediatric University Clinic, “ATTIKON” UNIVERSITY HOSPITAL, CHAIDARI; ²Faculty of Medicine,School of Health Sciences, UNIVERSITY OF IOANNINA; ³UNIVERSITY HOSPITAL OF IOANNINA, Ioannina; ⁴4TH Department of Medicine, “ATTIKON” UNIVERSITY HOSPITAL, CHAIDARI, Greece

Correspondence: ERATO ATSALI

Introduction: Although hepatic disease is not a significant cause of morbidity/mortality in jSLE,it is now considered to have greater clinical significance.

Objectives: To report two cases of SLE who presented with abnormal liver function tests several months before the onset of the rest clinical manifestations.

Methods: The first case is a 12,5 years old girl who presented with a one month history of malar rash and joint pain (ankles and knees). One and a half year before, elevated transaminases (2fold above the upper normal limit) were noticed during a routine exam. An extensive laboratory work up for viral hepatitis A,B and C,Wilson disease, celiac disease, hepatotropic viruses (EBV),a1 antithrypsin level and autoimmune hepatitis (ASMA,AMA.anti LC-1) had failed to reveal any kind of hepatic disease. Antinuclear antibodies were positive (1/320). Liver elastography was normal.

The second case is a 15,5 years old girl who came to our department with the diagnosis of autoimmune hepatitis (AIH).8 months earlier, laboratory exams done due to a persistent maculopapular rash of hands and feets had revealed a significant increase of transaminase levels (4fold above the upper normal limit). Based on positive serological markers (positive antinuclear, smooth muscles and anti liver cytosol type 1 antibodies) the diagnosis of AIH had been considered as most probable although liver biopsy was normal.

Results: On physical examination the first girl had malar rash and arthritis of both knees and ankles. Blood examinations showed leucopenia (3370/μL),low C3 (32,3mg/dl),ANA positive (1/640),anti DNA positive (254units) and mild proteinuria (120mg/24h).The diagnosis of jSLE was set and treatment with hydroxychloroquine and steroids was started. Transaminases level returned to normal quickly after the initiation of treatment.

The second girl had on physical examination reticular peliosis, arthritis of metatarsophalangeal joints and a papular rash of hands and feet. Supplemental laboratory exams revealed low C3 and positive anti Ro antibodies and Coombs test. JSLE was diagnosed while the diagnosis of autoimmune hepatitis was considered as less probable based on normal liver histology. She started hydroxychloquine and prednisone leading to a complete resolution of hepatitis. Nine months later, while receiving a low dose of steroids, she developed a typical malar rash and nephritis with significant proteinuria and hypoalbuminemia. A renal biopsy showed early membranous nephritis. Treatment with pulses of methylprednisolone followed by per os steroids and azathioprine leaded to a complete resolution of symptoms.

Conclusion: A wide spectrum of liver disorders is associated with SLE classified as liver parenchymal injury associated with SLE (“lupus hepatitis”),overlap syndromes with autoimmune liver disease and non-autoimmune hepatopathy (drug induced, viral hepatitis, fatty liver, thrombosis). Although abnormalities of liver function are not included in the diagnostic criteria, hepatitis is frequently noticed at disease onset. The diagnosis of SLE should be kept on mind in every child who presents with asymptomatic biochemical liver abnormalities (even if it doesnot fulfill the diagnostic criteria) and proper clinical and laboratory examination should be done towards this direction.

Informed consent to publish these case reports has been obtained from the patients and their parents.

Disclosure of Interest

None Declared

P128 CAROTID INTIMA-MEDIA THICKNESS AS EARLY MARKER OF SUBCLINICAL ATHEROSCLEROSIS: A PRELIMINARY SINGLE-CENTER STUDY IN CHILDHOOD ONSET SYSTEMIC LUPUS ERYTHEMATOUS

Francesco Baldo, Federico Annoni, Micaela Carini, Antonio Mastrangelo, Valentina De Cosmi, Carlo Virginio Agostoni, Francesca Minoia, Giovanni Filocamo

IRCCS OSPEDALE POLICLINICO CÀ GRANDA, Milan, Italy

Correspondence: Francesco Baldo

Introduction: The association between systemic lupus erythematous (SLE) and early onset atherosclerosis has been widely accepted. In 2006, childhood-onset SLE (cSLE) was included by the American Heart Association and the American Academy of Pediatrics in the list of pediatric diseases with an increased risk of cardiovascular diseases (CVD). Carotid intima-media thickness (IMT) is frequently used as a precocious marker to detect early subclinical atherosclerosis and to identify higher risk patients.

Objectives: To assess early subclinical atherosclerosis in patients affected by cSLE, and to investigate its possible correlation with disease related parameters and traditional cardiovascular risk factors

Methods: Patients with diagnosis of cSLE by ACR classification criteria, followed at our center were included in the study. Demographic, clinical and laboratory features and therapeutic interventions were retrospectively collected from clinical charts. In all patients IMT of the distal 10mm of the far wall of common carotid artery was determined by ultrasonography with an highly automated method (qIMT). Concurrently with carotid IMT measurement, atherosclerosis-related biomarkers, such as plasma lipid levels and blood pressure were measured, and an accurate evaluation of traditional clinical CVD risk factors (smoke, exercise, familiar history of CVD, renal disease and hypertension) was performed. The SLEDAI was used to measure the disease activity. Correlation between carotid IMT and disease related parameters and traditional CVD risk factors was calculated by means of Spearman's test or Mann-Whitney U test as appropriate.

Results: We present the preliminary data on 15 cSLE patients (12 females, 3 males) enrolled so far. The median age at time of IMT evaluation was 15 years. The median SLEDAI was 7 at cSLE onset and 4 at time of IMT evaluation. Median lipid and apolipoprotein plasma levels, uric acid, and renal functional index were in range with age related references. Measured carotid IMT values observed in our 12 patients were in range with age and sex matched published values. In three patients an IMT >75° centile was detected: all of them had a higher SLEDAI at onset and a short disease course (< 3 years). IMT values according to ENA profile and treatment are shown in Table 1.

No traditional blood marker of dyslipidemia nor other disease related features nor therapeutic intervention were associated with IMT in our cohort.

Conclusion: Carotid IMT is a non-invasive marker for subclinical atherosclerosis that should be considered in the follow up of cSLE patients. Our data suggest that patients with short disease duration could be at higher risk of having higher IMT values. The correlation with short disease duration may be due to the burden of the induction steroidal therapy or to the effect of new onset uncontrolled disease. Our results are preliminary from a small cohort and needed a further confirmation in a larger prospective sample with a control group.

Disclosure of Interest

None Declared

Table 1 (abstract P128). Differences of IMT values according to ENA profile or treatment

P129 LAMOTRIGINE-INDUCED SYSTEMIC LUPUS ERYTHEMATOSUS

Ana Barbosa Rodrigues¹, Filipa Oliveira Ramos^2,3, Patrícia Costa-Reis^1,2

¹Pediatrics Department, Centro Académico de Medicina de Lisboa, Hospital de Santa Maria; ²Pediatric Rheumatology Unit, Rheumatology Department, Centro Académico de Medicina de Lisboa, Hospital de Santa Maria; ³Unidade de Investigação em Reumatologia, Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Centro Académico de Medicina de Lisboa, Lisbon, Portugal

Correspondence: Ana Barbosa Rodrigues

Introduction: Drug induced-lupus erythematosus (DILE) is an autoimmune disorder characterized by typical lupus-like symptoms in the setting of drug exposure. Genetic factors, including differences in drug metabolism and immunologic features, affect the risk of developing the disease. Recently, it was found that DILE might also be associated with epigenetics, since some drugs known to induce a lupus-like phenotype inhibit DNA methylation.

Lamotrigine is used as an anticonvulsant and mood stabilizer drug. Between 5 to 10% of the patients develop a skin reaction to the drug, which, infrequently, can be life threatening, namely Stevens-Johnson syndrome, DRESS syndrome and toxic epidermal necrolysis. DILE associated with lamotrigine has been, very rarely, described.

Objectives: Describe a patient with lamotrigine-induced systemic lupus erythematosus in order to improve our knowledge of the drugs and phenotypes associated with DILE.

Methods: Clinical description of a patient with more than two years of follow up.

Results: CASE DESCRIPTION: 17-year-old female, with panic and generalized anxiety disorders, treated with quetiapine, propranolol and lamotrigine. The latter was started four days before the beginning of the symptoms. The patient presented to the emergency room with a three week history of daily fever, fatigue, odynofagia, arthralgias and myalgias. On physical exam it was identified a  non-pruritic diffuse erythematous maculopapular rash, vasculitic lesions on the fingers and lips and vulvar edema. There were no manifestations of serositis or neurological involvement. Alopecia, oral and nasal ulcers, organomegalies and arthritis were not detected. It was identified leukopenia (3920/μL), lymphopenia (880/μL) and a slightly elevated C-reactive protein (2.9mg/dL), with normal hemoglobine and platelets count; serologies were negative for cytomegalovirus, epstein barr, parvovirus, coxsakie, echovirus, herpes virus, Mycoplasma pneumoniaeand Chlamydia. The patient was admitted to the hospital and treatment with lamotrigine was immediately stopped. There was a significant clinical improvement including apirexia and regression of the maculopapular rash in less than 24 hours after withdrawal of the drug. Positive antinuclear antibodies (1/80), positive anti-double stranded DNA (anti-dsDNA) antibodies (50.5 UI/mL), positive anti-Ro (SSA) antibodies (163.2 UQ) and low serum C3 (59 mg/dL) and C4 complement level (9 mg/dL) were found; antibodies anti-histones were negative (<1.1 U/mL).

The patient remained asymptomatic for two years under therapy with hydroxychloroquine (6.5mg/kg/day). C3 and C4 remained below normal ranges and anti-dsDNA antibodies persisted elevated. Recently, the patient developed photosensitivity and had a new vasculitic rash on the fingers, which improved with a short course of steroids.

Conclusion: We describe a rare case of lamotrigine DILE, who presented with a diffuse erythematous rash, leukopenia, lymphopenia, low serum C3 and C4 and antinuclear and anti-dsDNA antibodies, thereby fulfilling the SLICC criteria. The withdrawal of the drug was essential for clinical improvement. In conclusion, DILE should always be included in the differential diagnosis of a patient with systemic lupus erythematosus and the medical community should be aware of the drugs that might cause it. Drug withdrawal is a fundamental step for a favourable outcome.

For this case submission written informed consent was obtained from the patient and family.

Disclosure of Interest

None Declared

P130 JUVENILE SYSTEMIC LUPUS ERYTHEMATOSUS AND THROMBOTIC THROMBOCYTOPENIA PURPURA, CASE REPORT SIMULTANEOUS DIAGNSOSIS IN A 5 YEARS OLD GIRL

Edith A. Benitez Vazquez¹, Sofia B. Osorio Sagrero², Luis A A. Aparicio Vera¹, Maria T. Braña Ruiz², Merari Elizabeth G. Cortez², Velka A. Cortez Lopez¹, Enrique Faugier¹, Maria D. R. Maldonado Velazquez¹

¹Reumatología; ²Hospital Infantil de México Federico Gómez, Ciudad de México, Mexico

Correspondence: Edith A. Benitez Vazquez

Introduction: The association of thrombotic thrombocytopenic purpura (TTP) and systemic lupus erythematosus (SLE) is a rare entity and usually occurs in advanced stages of SLE, here we present a case of a female patient 5 years old with simultaneous diagnosis of systemic lupus erythematosus and thrombotic thrombocytopenic purpura.

Objectives: Present the clinical case with diagnosis and treatment of systemic lupus erythematosus and thrombotic thrombocytopenic purpura in a pediatric patient.

Methods: Description of diagnosis and management of a case of newly diagnosed SLE and PPT in pediátric patient.

Results: Women's 5 years previously healthy age with symptoms of fever and arthritis 5 months of evolution, admitted to the institute by the presence of generalized edema and decrese output urine, elevated serum creatinine, proteinuria, metabolic acidosis and hypertension, presenting a rapidly progressive glomerulonephritis requiring renal replacement therapy with hemodialysis, renal biopsy was performed finding diffuse proliferative glomerulonephritis endocapillary, class IV lupus nephritis and thrombotic microangiopathy and hypertensive; The antibody profile denote ANA, antiDNA, anti B2-IgM glycoprotein and anticoagulante lupic positiv. For a history of seizures (7 days prior to admission) craneal MRI showed consistent data are with periventricular ischemia, ultrasound doppler renal absence of arterial and venous flow in both kidneys was performed and required anticoagulation heparin infusion for 21 days.

She was presented persistent thrombocytopenia, elevated DHL, 1% schistocytes peripheral smear and Ac IgG Anti ADAMS 13 positive (activity normal limit) in addition to histological finding of renal biopsy thrombotic microangiopathy integrated diagnostic thrombotic thrombocytopenic purpura, was administered treatment with methylprednisolone, gamma globulin, monthly cyclophosphamide, and plasmapheresis every 48 hours (first sessions entirely with albumin later albumin and plasma 1: 1), requiring 17 sessions, after which presented remission, with platelet count in 150,000, improvement of renal function and neurological status.

Conclusion: The incidence of SLE and PTT is unclear, lower incidence of 0.5% reported being more common in adult patients with prolonged evolution of SLE, it is difficult to establish the diagnosis because the two entities have laboratory findings in common, being key finding schistocytes in peripheral blood smears, and antibodies ADAMS 13.

There are no clear for the number of sessions of plasmapheresis patients requiring these guidelines, however The British Committee for Standards in Hematology (BCHS) guidelines recommend continuing the sessions at least two days after having a platelet count above 150.000, normal neurological status, hemoglobin levels and lactic dehydrogenase normal.

The diagnosis of thrombotic thrombocytopenic purpura in patients with SLE is underdiagnosed, it´s essential to consider no matter the time of diagnosis of SLE if there is presence of persistent thrombocytopenia, neurological and kidney disease or histological findings compatible with thrombotic microangiopathy. Informed consent for publication has been obtained from the parent.

Disclosure of Interest

None Declared

P131 INTERRELATION OF BLOOD LIPID PROFILE AND IMMUNO-INFLAMMATORY ACTIVITY IN CHILDREN WITH COMORBID CONDITIONS IN SYSTEMIC LUPUS ERYTHEMATOSUS

Ljudmila F. Bogmat^1,2, Irina N. Bessonova^1,2, Nataly S. Shevchenko^1,3

¹department of cardiorheumatology, Institute for the Health Care of Children and Adolescents of the National Academy of Medical Sciences of Ukraine; ²Department of pediatrics; ³Department of pediatrics № 2, V.N. KARAZIN NATIONAL UNIVERSITY, Kharkiv, Ukraine

Correspondence: Ljudmila F. Bogmat

Introduction: In the mechanisms of atherosclerotic arterial damage and the formation of comorbid conditions in rheumatic diseases, including systemic lupus erythematosus (SLE), many factors are involved, both traditional and those that are induced by inflammation and damage to the vessels by thrombosis and various kinds of antibodies.

Objectives: The aim was to study the relationship between the activity indices of the process (C-reactive protein (CRP), complement titer, circulating immune complexes (CIC)) with lipid profile (total cholesterol, triglycerides (TG), high-density lipoprotein cholesterol), the clotting system (prothrombin index, fibrinogen) and the functional state of the kidneys and liver (serum creatinine, glomerular filtration rate).

Methods: 35 children with SLE at the age of 7-18 years were examined, of which 4 (11.4%) were boys and 31 (88.6%) were girls. The majority (in 74.29%) patients was diagnosed with comorbid pathology. In the structure of comorbid conditions, violations of the functional state of the liver (in 40%) and kidneys (in 80%), pulmonary lesions (in 20%) and hip joint prevailed (in 20.0%), as well as cardiovascular disorders (in 11 %). Changes in the lipid spectrum of atherogenic orientation and signs of osteoporosis were recorded in half of patients (in 51.43% and in 50.0%, respectively), and changes in the coagulogram with signs of hypercoagulability occurred in 35.7% of the examined patients.

Results: In patients with SLE and comorbid conditions, an inverse correlation was established between the values of CRP and the level of complement (r = -0.477, p <0.05), the complement level was inversely correlated with the level of triglycerides (r = -0.744, p <0.05), and triglyceride levels correlated closely with the level of circulating immune complexes (r = 0.896, p <0.01), which confirms the interdependence of atherogenesis and immunocomplex inflammation.

The level of triglycerides of blood also had an inverse correlation with the parameters of the glomerular filtration rate (r = -0.892, p <0.05) and the straight line with serum creatinine (r = 0.834, p <0.05, and transaminases, in particular with ALT (r = 0.848, p <0.05).

With the help of multiple regression analysis it was found that an increase in the activity of the disease with an increase in the level of circulating immune complexes in children suffering from SLE and comorbid conditions is accompanied by an increase in the level of total cholesterol and triglycerides, a decrease in the complement titer, which is represented by the equation:

$$ {\displaystyle \begin{array}{l}\mathrm{CEC}=1.44278+0.188976\cdotp \mathrm{OKS}\hbox{-} 1.51503\cdotp \mathrm{complement}+0.35388\cdotp \mathrm{TG}\\ {}\left(\mathrm{R}=94.25\%,{\mathrm{R}}^2=90.02\%,\mathrm{p}<0.01\right).\end{array}} $$

Conclusion: Thus, changes in the lipid spectrum of atherogenic orientation in patients with SLE of childhood not only take place against the background of the disease, but also contribute to the development of comorbid pathology

Disclosure of Interest

None Declared

P132 DAMAGE INDEX IN CHILDREN WITH SYSTEMIC LUPUS ERYTHEMATOSUS

Ljudmila F. Bogmat^1,2, Irina N. Bessonova^1,2, Nataly S. Shevchenko^1,3

¹department of cardiorheumatology, Institute for the Health Care of Children and Adolescents of the National Academy of Medical Sciences of Ukraine; ²Department of pediatrics; ³Department of pediatrics № 2, V.N. KARAZIN NATIONAL UNIVERSITY, Kharkiv, Ukraine

Correspondence: Ljudmila F. Bogmat

Introduction: One of the important aspects in estimating the prognosis of patients with systemic lupus erythematosus and creating optimal differentiated therapies for them is to identify potentially irreversible lesions of various organs and systems.

Objectives: The purpose of the study was to determine the damage index in children with systemic lupus erythematosus.

Methods: A total of 39 children with systemic lupus erythematosus (SCL) aged 7-18 years were examined. The average duration of the disease at the time of the survey was 45.8 ± 2.9 months. The diagnosis of SLE was based on the SLICC classification criteria (2012), an adult rating scale (SLICC / ASR Damage Index) was used to assess the damage index.

Results: In 46.2% of patients (18 people), PI was zero. The duration of the disease at the time of examination of patients in this subgroup was 45 ± 3.3 months. The remaining 21 patients (53.8%) had an IE of 1 to 4 points, i.e. there were signs of irreversible damage to certain organs and systems, namely, the nervous, cardiovascular systems, the lungs, the kidneys, the bone and muscle system, and the eyes. The duration of the disease in these patients varied from 3 to 113 months, on average 47 ± 6.9 months.

In 15 cases the IP was equal to 1 point. These patients had an irreversible damage to the nervous (9 persons) and cardiovascular systems (1 person), as well as the kidneys (1 person) and lungs (4 people). In 5 patients, PI was 2 points due to irreversible damage to the organ of vision (4 persons) and musculoskeletal system (1 child). In one patient, the injury index was 4 points due to persistent damage to the organ of vision as a cataract of both eyes and the nervous system in the form of convulsive seizures requiring prolonged use of anticonvulsants.

The most commonly damaged CKD was the damage to the nervous system, which was observed in 25.6% of patients and in all cases was represented by cognitive impairment, and only one patient had convulsive seizures. In the second place, the frequency of occurrence was damage to the organ of vision (in 12.8% of patients). This kind of damage was due to the presence of cataracts of both eyes. Somewhat less frequently, lung damage was detected (10.3% of the subjects) in the form of pleural fibrosis according to the X-ray examination. Irreversible damage to the kidneys, cardiovascular and musculoskeletal systems was noted at the same frequency (2.6%). Damage to the kidneys was represented by the development of massive proteinuria, cardiovascular system - cardiomyopathy, and damage to the musculoskeletal system is due to avascular necrosis of the femoral head.

Conclusion: Thus, the obtained results testify to the expediency of the use of PI in systemic lupus erythematosus in childhood in order to clarify the nature and degree of damage to organs and systems, which will allow timely correction of treatment.

Disclosure of Interest

None Declared

P133 ANTIPHOSPHOLIPID SYNDROME IN MEXICAN CHILDREN: EVOLUTION, LABORATORY AND CLINICAL CHARACTERISTICS: A 10-YEAR EXPERIENCE

Maria T. Brana¹, Luis Aparicio², Sofia Osorio², Velka Cortez², Adriana Benitez², Merari Gomez², Andres Rodriguez², Enrique Faugier², Rocio Maldonado²

¹Pediatric Rheumatology, Hospital Infantil de Mexico Federico Gomez; ²Hospital Infantil de Mexico, Federico Gomez, Hospital Infantil de México, Mexico, Mexico

Correspondence: Maria T. Brana

Introduction: The antiphospholipid syndrome (APS) is a multisystem and autoimmune disease, which is mainly characterized by the presence of thrombotic events, gestational morbidity, in the presence of high titers of antiphospholipid antibodies. It can present as a primary entity, or secondary to another autoimmune disease. The understanding of this pathology is still evolving and even more in its presentation in the pediatric patients. The presence of antiphospholipid antibodies has been widely reported in pediatric patients with thrombosis. APS is considered the most common acquired cause of a prothrombotic state. At the moment, there are no reliable data of its presentarion in pediatrics. The long-term morbidity and mortality associated with thrombosis events in pediatric population may be minored by determining prognosis and select patients for prophylactic treatment and more rigorous follow-up.

Objectives: To describe the clinical presentation and evolution, in addition to laboratory findings, in Mexican pediatric population with diagnosis of APS. Identified patients with arterial or venous thrombosis and its relation with laboratory findings. Describe epidemiology of Mexican pediatric population with APS.

Methods: Retrospective cohort study of the Children’s Hospital of Mexico Federico Gomez, last 10 years. We reviewed the data form the clinical archives of the patients with diagnosis of APS according to the Miyakis criteria, from 2007 to 2017. The variables analyzed include age at diagnosis, sex, subtype of APS, clinical finding of thrombosis, laboratory finding of antiphospholipid antibodies and outcome.

Results: A total of 29 patients fulfil the diagnosis criteria of APS. The mean age of patients at diagnostic was 9.8 years, with a minor age at diagnosis of 2.2 years and a maximum of 16.4 years of age. Of the total population 52% were females and 48% males. Primary APS was diagnosed in 48%, of which 71% were males. Secondary APS was present in 52% of the population, all diagnosed with Systemic Lupus Erythematosus. Of the patients with secondary APS, 85% were female. Arterial thrombosis was present in 48% of the cases, primarily in the group of secondary APS. Of the total cases 20% presents with a second thrombosis event despite anticoagulant therapy, of this 66% were diagnosed with secondary APS. Lupus anticoagulant (LA) was present in high titers in 93% of the patients, while anti-B2 glycoprotein-1 antibody IgG was present in 27% and IgM in 31%. Anticardiolipin antibody IgG was positive in 17% of the population, while isotype IgM in 24%. All patients receive long term anticoagulant therapy. One male patients, with secondary APS developed catastrophic APS. One patient required of amputation for deep venous thrombosis, and another patient died as a complication of gastrointestinal thrombosis, both males with primary APS.

Conclusion: During a 10 year follow up, we diagnosed 29 patients with APS. As reported in literature, a greater percentage of patients are female and present with a secondary APS. Most patients with primary APS are males. In our population, in contrast with what literature report, secondary APS presents with a greater percentage of arterial thrombosis. The mayor site of venous thrombosis was low extremities and of arterial thrombosis was cerebrovascular events. The presence of positive LA implicates a higher risk of thrombosis. Our pediatric population diagnosed with APS requires of a close follow up in order to monitor anticoagulant therapy and to prevent the patients from developing a second thrombotic event that may lead to death.

Disclosure of Interest

None Declared

P134 SEVERE PULMONARY ARTERIAL HYPERTENSION AS THE INITIAL MANIFESTATION OF SYSTEMIC LUPUS ERYTHEMATOSUS IN A 7-YEAR-OLD MALE PATIENT: A CASE REPORT.

Maria T. Brana¹, Luis A. Aparicio², Sofía Osorio³, Enrique Faugier⁴, Andres Rodriguez⁴, Rocio Maldonado⁴

¹Pediatric Rheumatology; ²Hospital Infantil de Mexico, Federico Gomez, Hospital Infantil de Mexico Federico Gomez; ³Hospital Infantil de Mexico, Federico Gomez, Hospital Infantil de Mexico, Federico Gomez; ⁴Hospital Infantil de Mexico, Federico Gomez, Hospital Infantil de México, Mexico, Mexico

Correspondence: Maria T. Brana

Introduction: Pleural pulmonary manifestations in patients with systemic lupus erythematosus are reported in approximately 5% of cases. Presenting as pleural effusion, alveolar hemorrhage, diffuse interstitial lung disease, pulmonary infections and pulmonary arterial hypertension, among others, they are a manifestation difficult to diagnosis. Pulmonary arterial hypertension is defined as a pressure greater than or equal to 25mmHg. The world health organization has classified pulmonary arterial hypertension into five categories, the first group being associated with connective tissue disease such as systemic lupus erythematosus. Pulmonary arterial hypertension is a rare condition, usually occurring 3 to 5 years after the diagnosis of systemic lupus erythematosus and conditioning a high risk of morbidity and mortality. Initially, the majority of patients with SLE and PAH are asymptomatic and as the disease progresses, they present with progressive dyspnea, fatigue, intolerance, exercise, chest pain and non-productive cough.

Objectives: We report the case of a 7-year-old male patient who presented with pulmonary arterial hypertension as the initial manifestation of systemic lupus erythematosus.

Methods: Case report.

Results: Clinical case

A 7-year-old male patient who was admitted to the Pneumology Department at Children's Hospital of Mexico Federico Gómez due to respiratory distress. In emergency assessment, pulmonary arterial hypertension of 66mmHg was identified, of unknown cause. The patient did not have significant medical background, having enjoyed of good health up to 6 months prior to his admission. He presented with a history of non-quantified fever, as well as episodes of fatigue and dyspnea. Two months before admission, chest pain was added, exacerbated with inspiration. On admission, transthoracic echocardiography revealed severe dilatation of right cavities, moderate tricuspid insufficiency, with left ventricular ejection fraction of 56% and arterial pulmonary pressure of 66mmHg. The diagnostic approach is initiated. Due to a history of pulmonary tuberculosis in the patient grandmother, the patient was studied with BAAR and cervical lymph node biopsy, ruling out the diagnosis. Infectious process causing the manifestations was also ruled out. The patient was discharged with medical treatment, requiring readmission in for 7 days, with facial edema and in lower extremities, generalized pallor, asthenia, adynamia and 4 days before a decrease in urinary volumes and frequency. On admission, right heart failure, secondary to increase of pulmonary hypertension for discontinuation of diuretic administration. A renal biopsy was performed, which was reported as class IV lupus nephropathy, with an index of activity and chronicity of 0. The diagnosis of systemic lupus erythematosus is integrated based on the ACR criteria. Induction of remission of lupus nephropathy based on the CARRA protocol. As treatment was administered the patient showed important clinical improvement.

Conclusion: Pulmonary arterial hypertension is a rare condition, usually occurring 3 to 5 years after the diagnosis of systemic lupus erythematosus. In pediatric population, it is reported as a lupus complication in 5 to 14% of patients, and less than 1% as an initial manifestation. It is a clinical complication that gives the patient a high risk of morbidity and mortality. It is important to acknowledge that pulmonary arterial hypertension can be the initial manifestation of lupus in pediatric population. A prompt identification assures a prompt treatment and a better prognosis. Informed consent to publish had been obtained from the parents.

Disclosure of Interest

None Declared

P135 PREDICTING ORGAN DAMAGE IN PATIENTS WITH CHILDHOOD-ONSET SYSTEMIC LUPUS ERYTHEMATOSUS: A RETROSPECTIVE STUDY OVER THE LAST 25 YEARS

Nastasia Cekada¹, Mario Sestan¹, Emilija Hosticka¹, Maja Novoselec¹, Mateja Batnozic Varga², Ivan Padjen³, Marijan Frkovic¹, Domagoj Kifer⁴, Branimir Anic³, Drago Batinic⁵, Kristina Potocki⁶, Ivan Malcic¹, Marija Jelusic¹

¹Department of Paediatrics, University Hospital Centre Zagreb, University of Zagreb School of Medicine, Zagreb; ²Department of Paediatrics, University Hospital Centre Osijek, Osijek; ³Department of Internal Medicine, University Hospital Centre Zagreb, University of Zagreb School of Medicine; ⁴Department of Biophysics, Faculty of Pharmacy and Biochemistry, University of Zagreb; ⁵Clinical Department of Laboratory Diagnosis; ⁶Diagnostic and Interventional Radiology Department, University Hospital Centre Zagreb, University of Zagreb School of Medicine, Zagreb, Croatia

Correspondence: Nastasia Cekada

Introduction: Childhood-onset systemic lupus erythematosus (cSLE) is a multisystemic, chronic autoimmune disease occurring in children and adolescents under 18, presenting heterogeneously, with the course of the disease often more severe than in adults, and the activity of the disease widely being evaluated by Systemic Lupus Erythematosus Disease Activity Index (SLEDAI 2K) and damage by the SLICC/ACR damage index (SDI).

Objectives: To compare and explore the correlation between the SLEDAI-2K disease activity index at the time of diagnosis and the SLICC/ACR damage index (SDI) of patients at their last follow up, to examine the quantity of organ damage in regard to patients’ characteristics and disease duration and to predict the risk of organ damage occurrence in time.

Methods: The retrospective study included children treated for cSLE in the period from January 1991 to September 2017 at Department of Pediatrics, University Hospital Center Zagreb. The follow up data of patients after the age of majority at 18 and who were under care of the Department of Internal Medicine, University Hospital Center Zagreb was also included. All children were diagnosed according to the ACR 1997 and SLICC 2012 criteria. Data analysis was done using R environment for statistical computing.

Results: The disease development of 93 children (74 females and 19 males) with cSLE was examined in this study. The median (range) follow up time was 7 (0.5-24) years and the median (range) age at diagnosis was 13 (5-19) years. Two patients have died during the examined period. Mean (SD) SLEDAI-2K was 18.3 (9.0) at the disease onset. 35 children (38 %) had organ damage at the last follow up with the median (range) SDI 0 (0-7). The first organ systems damaged in affected patients were renal (28%), musculoskeletal (22%), ocular (19%), neuropsychiatric (17%), cardiovascular (11%) and peripheral vascular (2.8%), but with no significant statistical difference regarding the type of organ damage. Kendall rank correlation coefficient was used to evaluate the relationship between SLEDAI-2K at the disease onset and SDI, determining a positive correlation which was statistically significant (τb = 0.252, p = 0.003). However, no significant correlation was determined between the duration of the disease and SDI (τb = 0.042, p = 0.628) or follow up period and SDI (τb = 0.111, p = 0.191) nor was there significant difference of SDI in regard to gender (Asymptotic Wilcoxon-Mann-Whitney Test, p= 0.574). Using Kaplan-Meier method we estimated the decrease in ratio of patients without organ damage since diagnosis or the occurrence of the first symptoms. Since the estimated ratio of patients with organ damage at the endpoint was less than 50%, we could not estimate the time required for damage development in 50% of patients. However, we are 95% sure that the damage is not happening in the first 9 or 10 years after diagnosis or the occurrence of the first symptoms, respectively.

Conclusion: The high correlation detected between SLEDAI-2K and SDI indicated that the presentation of the cSLE at onset can be prognostic of the course and long-term prognosis of lupus. Our findings suggest that it is unlikely that organ damage will occur in 50% of patients in the first nine years of the disease course.

Disclosure of Interest

None Declared

P136 RUXOLITINIB TREATMENT IN A PATIENT WITH ANTI-DNASE 2 DEFICIENCY: BENEFITS AND BURDENS

Luisa Cortellazzo Wiel¹, Anna M. C. Galimberti¹, Giulia Gortani², Serena Pastore², Alessandra Tesser³, Andrea Taddio^1,2, Alberto Tommasini³

¹Paediatrics, University of Trieste; ²Paediatrics; ³Clinical Immunology, IRCCS Burlo Garofolo, Trieste, Trieste, Italy

Correspondence: Luisa Cortellazzo Wiel

Introduction: A seventeen-year-old boy was admitted to our Hospital after an episode of lipothimia, followed by dyspnea and tachycardia with prolabial cyanosis.

The patient was in a follow-up program for an anti-DNAse2 deficiency syndrome (Rodero et al., Nat Commun, 2017): a newly described, auto-inflammatory genetic disorder with significant overlap with systemic lupus erythematous.

His past medical history was characterized by the presence of neonatal hepatopathy, cytopenia, recurrent fever, polyarticular arthritis, chronic glomerulonephritis, lipodystrophy, lupus pernio and growth retardation. The diagnosis of anti-DNAse2 deficiency was made at the age of 14 by whole exome sequencing and was suggested by the high value of the interferon signature that highlighted the pivotal pathogenetic role of type 1 interferon.

This clinical picture progressively worsened despite several therapeutic trials with glucocorticoids, immunosuppressant and biological agents. Therefore, a trial treatment with two antimalarials (hydrossichloroquine and mepacrine) and ruxolitinib was started, together with abatacept: this treatment had led in the previous months to an overall improvement of his symptoms and a reduction of the glucocorticoids dosage.

Objectives: At admission, clinical and instrumental evaluation showed a severe pulmonary hypertension (PAH) with a mean pulmonary pressure of 77 mmHg and a severe dysfunction of his right cardiac chambers. A drug adverse effect was considered and all the treatments were discontinued. Considering the possibility that PAH was an interferonopathy manifestation, similarly to what can occur in SLE, steroid boluses were administered. Moreover, a vasodilatant therapy with iloprost, ambrisentan, sildenafil and diuretics was started. During the hospital course he developed a severe pancytopenia (Hb 10 g/dl, WBC 1020/mmc, PLT 20.000/mmc). Hemophagocytic Limphohistiocytosis (HLH) and malignancy were ruled after performing a bone marrow aspiration, showing an hypocellular bone marrow. A viral infection was also excluded.

Methods: Given the poor response to corticosteroids, ruxolitinib was then reintroduced at higher doses than previously administered (10 mg twice daily), based on the previous benefits and on the anecdotal evidence of efficacy in PAH.

Results: A dramatic improvement of his pulmonary pressures was noted, more successful than expected with only vasodilatant therapy, with an estimated pulmonary pressure at discharge of 35 mmHg.

His cardiologic follow-up showed a slow but progressive improvement of PAH so far; the symptoms related to his basal condition also improved. Ruxolitinib was maintained at the dose of 7.5mg BID. No other adverse event was noticed a part from a moderate title elevation of BK virus in the urine and a transient herpes zoster infection that rapidly healed with acyclovir therapy.

Conclusion: We therefore concluded that specific therapies for genetically determined conditions are double-edged with the need of carefully balancing efficacy with potential adverse events. Great caution should be taken in particular with JAK inhibitors as an abrupt stop of treatment may associate with severe inflammatory rebound. Informed consent to publish had been obtained.

Trial registration identifying number: This work was funded by IRCCS Burlo Garofolo grant RC24/17 anf Telethon Foundation grant GGP15241.

Disclosure of Interest

None Declared

P137 EVALUATION OF CHOROIDAL THICKNESS AND PERIPAPILLARY RETINAL NERVE FIBER LAYER IN PATIENTS WITH JUVENILE SYSTEMIC LUPUS ERYTHEMATOSUS

Selcan Demir¹, Abdullah Ağın², Ata Baytaroğlu², Hafize E. Sönmez¹, Erdal Sağ¹, Yelda Bilginer¹, Sibel Kadayıfçılar², Bora Eldem², Seza Özen¹

¹Department of Peditarics, Division of Rheumatology; ²Opthalmology Departmant, Hacettepe University Faculty of Medicine, Ankara, Turkey

Correspondence: Selcan Demir

Introduction: Systemic lupus erythematosus (SLE) is an autoimmune disease that involves multiple organs, including ocular involvement.

Objectives: This study aims to evaluate choroidal thickness and peripapillary retinal nerve fiber layer in patients with juvenile SLE (jSLE).

Methods: We have included all jSLE patients (n=21) diagnosed according to Systemic Lupus International Collaborating Clinics classification criteria between January 2017 and April 2017 and age sex-matched control group (n=21). The SLE disease activity index (SLEDAI) was used to assess disease activity. After routine eye examinations, choroidal thickness (ChT) in five points (750 and 1500 microns from the center of the fovea both in the temporal, nasal quadrant and under the fovea), presence of subretinal and/or intraretinal fluid, retinal nerve fiber layer thickness of optic disc (RNFL) were evaluated.

Results: In ophthalmologic evaluation, only one patient was active [SLEDAI 2 (1-4)]. One patient had episcleritis, one patient had corticosteroid-induced cataract and glaucoma. Median age was 3,5 years (1-8,5 years), despite the use of hydroxychloroquine retinal pigmentation or visual field defects were absent in patients. There was a significant increase in ChT at 5 points, but RNFL thicknesses were similar compared to healthy controls in jSLE patients. When the relationship between OCT findings and other variables were evaluated, a significant negative correlation was found between the initial creatinine values and the ChT. Intraretinal or subretinal fluid were not present in any of the patients.

Conclusion: The results of our study suggest that increased ChT is related to mononuclear cell infiltration, immune complex accumulation, autoantibodies against retinal pigmentation or some vascular mechanism in jSLE patients.

Disclosure of Interest

None Declared

P138 Withdrawn

P139 SOCIAL AND PROFESSIONAL OUTCOME OF CHILDHOOD ONSET SYSTEMIC LUPUS ERYTHEMATOSUS: A COHORT OF 65 PATIENTS ISSUED FROM PEDOLUP

Anita Duncan¹, Camille Braun², Marine Desjonqueres¹, Bruno Ranchin¹, Michael Hofer³, Isabelle Durieu⁴, Jean-Christophe Lega⁴, Eric Hachulla⁵, Alexandre Belot¹

¹service de rhumatologie et néphrologie pédiatrique, Hôpital Femme Mère Enfant; ²Université Claude Bernard, Lyon 1, Lyon, France; ³service d’immuno-allergologie et rhumatologie, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; ⁴service de médecine interne, Centre Hospitalier Lyon Sud, Lyon; ⁵service de médecine interne, Hôpital Claude Huriez, Lille, France

Correspondence: Anita Duncan

Introduction: Systemic Lupus Erythematosus (SLE) is a rare, chronic, systemic disease with juvenile onset occurring in 10 to 20% of cases. Its variety of clinical presentations with an unpredictable relapsing-remitting course can make it a challenging illness to diagnose and deal with throughout childhood.

Objectives: The aim of this study was to evaluate educational, professional and family outcome along with quality of life appreciation in a cohort of pediatric SLE (SLEp) patients, fields for which data is still scarce.

Methods: This multi-center study included all 65 SLEp patients from the PedOLup unit (JIR cohort) of two french centers, Lyon (Hôpital Femme Mère Enfant, Centre Hospitalier Lyon Sud) and Lille (Hôpital Claude Huriez). Data regarding clinical presentation, education, employment, personal family outcome and quality of life were obtained from the PedOLup database and completed with medical records and oral interview.

Results: 75,4% of our patients had visceral involvement with a mean disease duration of 13,6 years. Disease activity and damage scores (SLEDAI and SDI) were low at the time of the study (median of 0). The proportion of graduates in those over 25 years of age was similar to national references and 87,3% of patients were presently either employed of following a study course. Half of those over 20 lived as a couple and 34% of them had children with a mean number of person per household comparable to French references. There seemed to be little difference when comparing quality of life in our patients to a healthy French reference population.

Conclusion: Despite the severity of juvenile forms of SLE on diagnosis, long term social and professional outcome of patients followed in this cohort seems satisfying. However, this study points out elements of precarity in the field of employment opening the way for thinking about work support and accommodation.

Disclosure of Interest

None Declared

P140 SICKLE CELL DISEASE AND LUPUS NEPHRITIS WITH NEGATIVE SEROLOGIC MARKERS

André Garrido¹, Marta Ezequiel², Andreia Martins¹, Marta Moniz², Rita Manso³, Vanda Anacleto⁴, Teresa Ferreira⁵, Marta Cabral⁶, Helena C. Loureiro¹, Helena I. Almeida²

¹Paediatric Department; ²Paediatric Intensive Care Unit; ³Pathology Department; ⁴Paediatric Nephrology; ⁵Paediatric Haematology; ⁶Paediatric Rheumatology, Hospital Prof. Doutor Fernando Fonseca, E.P.E., Amadora, Portugal

Correspondence: André Garrido

Introduction: The presence of immunologic markers (autoantibodies, hypocomplementemia or a positive direct Coombs test) are key features in the Systemic Lupus International Collaborating Clinics (SLICC) criteria for the classification of Juvenile Systemic Lupus Erythematosus (jSLE).

Objectives: The authors present a case of a female adolescent with sickle cell disease and lupus nephritis with a severe presentation and without any serologic markers to corroborate the diagnosis.

Methods: A 14-year-old female with Sickle Cell Disease (SCD), born and living in Angola until 3 days before admission, was hospitalized in the past 3 months due to a nephrotic syndrome, complicated with pneumonia with empyema, arterial hypertension, seizures and exacerbations of the SCD requiring frequent red blood cell transfusions and long term corticosteroids.

Results: The patient arrived to Portugal for further investigation and was admitted in the Paediatric Intensive Care Unit with respiratory deterioration due to a pyopneumothorax, requiring thoracentesis and intravenous antibiotics. At D13 of hospitalization she presented seizures and neurological deterioration. The magnetic resonance imaging performed was suggestive of a posterior reversible encephalopathy syndrome. The renal biopsy revealed a proliferative glomerulonephritis with mesangial and capillary deposition of several types of immune complexes, mainly IgG, also known as “full-house” immunofluorescence pattern, highly suggestive of a class III lupus nephritis. The laboratory results were inconsistent with the diagnosis of jSLE – negative autoantibodies, mild elevation of complement and a negative direct Coombs test. Treatment with mycophenolate mofetil and prednisolone was started in order to induce remission of lupus nephritis, having attained a clinical remission (without proteinuria, normal renal function and normal blood pressure) in one week.

Conclusion: In jSLE, renal involvement compromises the prognosis with significant morbidity and mortality. Few cases of lupus nephritis without serologic markers have been described to date. The literature reports two main presentations of seronegative lupus nephritis: one with a lifelong seronegativity, either with renal-limited or extra-renal manifestations; other with a serologic conversion, latter in the course of the disease. The authors hypothesized if the diagnosis of sickle cell disease and previous corticotherapy are related with this atypical presentation. Regardless of the clinical picture, a prompt and accurate treatment should not be delayed. This is an example of how an association of two complex diseases can present an hard treatment challenge. Informed consent to publish had been obtained from the parent.

Disclosure of Interest

None Declared

P141 PAEDIATRIC SYSTEMIC LUPUS ERYTHEMATOSUS PATIENTS IN SOUTH AFRICA HAVE HIGH PREVALENCE AND SEVERITY OF CARDIOVASCULAR MANIFESTATIONS

Michael Harrison¹, Laura Lewandowski^2,3, Liesl Zuhlke^4,5, Christiaan Scott^1,3

¹University of Cape Town, Cape Town, South Africa; ²National Institute of Arthritis, Musculoskeletal, and Skin Diseases, NIH, Boston, USA; ³Paediatric Rheumatology; ⁴Division of Paediatric Cardiology, Red Cross War Memorial Children’s Hospital; ⁵Division of Cardiology, Department of Medicine, Groote Schuur Hospital, Cape Town, South Africa

Correspondence: Michael Harrison

Introduction: Paediatric onset of systemic lupus erythematosus (SLE) is associated with a high rate of major organ involvement, and patients of African ancestry tend to develop more aggressive SLE than those of Caucasian descent. A particularly severe disease phenotype has been described in this multi-ethnic South African cohort of children with SLE. Although cardiovascular involvement appears to be common in paediatric SLE, there are few published reports on the subject and none have been conducted in an African paediatric SLE population.

Objectives: This study aims to describe the frequency and characteristics of cardiovascular manifestations of paediatric SLE in a multi-ethnic South African cohort.

Methods: Demographic, clinical, and echocardiographic data were collected from paediatric SLE patients at 2 centres in Cape Town, South Africa. At the time of investigation, this cohort consisted of 93 participants diagnosed with SLE according to the Systemic Lupus International Collaborating Clinics (SLICC) or 1997 American College of Rheumatology (ACR) SLE criteria, prior to the age of 19 years. Individuals with cardiovascular involvement were identified by retrospective chart review. Cardiovascular involvement was defined as presence of: pericardial effusion, myocarditis, cardiomyopathy, cardiac failure, Libman-Sacks endocarditis, myocardial infarction, deep vein thrombosis, pulmonary embolism, sinus thrombosis, stroke, arrhythmia, central nervous system vasculitis, or other vasculitis. Echocardiographic data were included in the analysis, when available. Statistical analysis was performed with R software package version 3.4.1.

Results: Cardiovascular involvement was present in a total of 44 participants, or 47% of the PULSE cohort (Table 1.) This is much higher than previously published reports of 3-32%. Those with cardiovascular involvement did not differ significantly in gender, age at diagnosis, or race/ethnicity from the overall cohort. Echocardiographic data were available for 23 of these participants. The most common cardiovascular manifestation observed in this cohort was pericardial effusion (n=24), followed by cardiac failure (n=8) and stroke (n=7). Cardiovascular manifestations were frequently severe, with one third of cases of pericardial effusion requiring intervention, and 3 patients presenting with cardiac tamponade. Mortality was high in patients with cardiovascular involvement, at a rate of 20.5%.

Conclusion: Cardiovascular involvement was found to be common in this multi-ethnic cohort of South African children with SLE, with pericardial effusion being the commonest cardiovascular manifestation. The mortality rate was high, and severe cardiovascular manifestations including stroke and cardiac tamponade were frequent. Prospective research is required to identify risk factors for cardiovascular involvement, in order to inform practice and improve outcomes for this high-risk population.

Disclosure of Interest

None Declared

Table 1 (abstract P141). Demographic information and cardiovascular manifestations in a paediatric SLE cohort from South Africa

P142 TREATMENT OF NON-RENAL, NON-NEUROPSYCHIATRIC SYSTEMIC LUPUS ERYTHEMATOSUS IN GERMANY – AN ONLINE SURVEY

Claas Hinze¹, Gerd Ganser², Fabian Speth³, Christian Hedrich⁴, Kirsten Moenkemoeller⁵, Catharina Schuetz⁶, Klaus Tenbrock⁷, Johannes-Peter Haas⁸ and PRO-KIND working group SLE of the GKJR

¹Pediatric Rheumatology and Immunology, University Hospital Münster, Münster; ²Pediatric Rheumatology, St. Josef Stift, Sendenhorst; ³Pediatric Rheumatology, University Medicine Rostock, Rostock, Germany; ⁴Pediatric Rheumatology, University of Liverpool, Liverpool, UK; ⁵Pediatric Rheumatology, Kinderkrankenhaus Amsterdamer Strasse, Cologne; ⁶University Hospital Ulm, Ulm; ⁷University Hospital Aachen, Aachen; ⁸German Center for Pediatric and Adolescent Rheumatology, Garmisch-Partenkirchen, Germany

Correspondence: Claas Hinze

Introduction: Treatment patterns of non-renal and non-neuropsychiatric systemic lupus erythematosus (non-renal, non-NP SLE) in Germany are not well understood and formal treatment recommendations do not exist, unlike for patients with severe lupus nephritis or neuropsychiatric SLE.

Objectives: To assess treatment preferences for patients with non-renal, non-NP SLE among German pediatric rheumatologists.

Methods: We designed an online survey including a generic case scenario of a patient with moderate juvenile non-renal, non-NP SLE and one main disease manifestation based on the premise that treatment of SLE is typically dictated by the most severe organ involvement. One question targeted general management of patients with non-renal, non-NP SLE. Then, overall, 21 manifestations of SLE were queried, ranging from constitutional symptoms to various organ-related, and laboratory manifestations and from mild to severe. Responses were given via multiple choice, including various pharmacologic treatment options: non-steroidal anti-inflammatory drugs, various disease-modifying antirheumatic drugs, biologics, i.v. immune globulins and anticoagulants. Descriptive statistics are used to report the findings.

Results: Forty-seven pediatric rheumatologists experienced in the management of SLE responded. There is consensus that all patients with non-renal, non-NP SLE should receive hydroxychloroquin (97% or respondents), should be counseled about important preventive measures, including sun protection, contraception, avoiding smoking (100%), that vaccinations should be kept up-to-date (91%) and that vitamin D should be considered (25% in all patients, 25% only in case of glucocorticoid therapy and 47% according to blood levels). Regarding pharmacologic management of the different manifestations, there was overall marked variability. For some life-threatening manifestations (myo-/pericarditis with tamponade, pulmonary hemorrhage and mesenteric vasculitis), the majority of respondents opted for high-dose glucocorticoid therapy and intensive immunosuppression with mycophenolate mofetil or cyclophosphamide, similar to what is often used in severe lupus nephritis. The preferences for different glucocorticoid regimens were especially variable, for example, ranging from none to high-dose for constitutional symptoms or fatigue. Methotrexate was preferred for various musculoskeletal manifestations whereas azathioprin was preferred for cutaneous and hematologic manifestations.

Conclusion: Treatment preferences for non-renal, non-NP SLE in Germany among pediatric rheumatologists are markedly variable. There is consensus that all patients with non-renal, non-NP SLE should receive hydroxychloroquin, be counseled regarding preventive measures, that vaccinations should be up-to-date and vitamin D substitution be considered. Data obtained with this survey may be helpful in developing consensus-based strategies for the management of non-renal, non-NP SLE.

Disclosure of Interest

None Declared

P143 TREATMENT OUTCOME IN CHILDHOOD LUPUS NEPHRITIS PATIENTS TREATED WITH MYCOPHENOLATE MOFETIL: REAL-WORLD DATA IN COMPARISON WITH ADULT LUPUS NEPHRITIS

Seung Min Jung¹, Hye Won Kim², Hyun-Sook Kim³, Yong-Beom Park¹

¹Yonsei University College of Medicine, Seoul; ²Seoul National University Bundang Hospital, Seongnam; ³Soonchunhyang University Seoul Hospital, Seoul, Korea, Republic Of

Correspondence: Seung Min Jung

Introduction: Childhood-onset systemic lupus erythematosus is a rare and severe autoimmune disease with a high prevalence of lupus nephritis (LN). Although there is a growing interest on treatment with mycophenolate mofetil (MMF) in LN, data on treatment outcome in childhood LN is limited.

Objectives: This study aimed to evaluate the therapeutic outcome of MMF in childhood LN from a real-world clinical practice, and compare the clinical characteristics with adult LN.

Methods: Korean pediatric and adult patients with pathologically proven LN class III, IV, and V were recruited from rheumatology clinic in Severance Hospital, Yonsei University College of Medicine between Nov 2011 and Aug 2017. Patients who treated with MMF for at least 3 months were included in the analysis. The probability of remission after MMF therapy, and the difference between pediatric patients and adult patients were analyzed using the survival analysis and the descriptive statistics.

Results: Of 153 patients with pathologically proven LN class III, IV, and V, 16 pediatric patients and 100 adult patients were included in this study. Pediatric patients showed a more preserved renal function, and adult patients had a higher prevalence of LN class IV. Mean protein/creatinine ratio in spot urine was 3.7 and 4.8 in childhood LN and adult LN, respectively. However, the baseline characteristics showed no statistically significant difference between childhood and adult. During median follow-up period of 5 years (childhood 7.5 years vs. adult 4.7 years), 75 % of pediatric patients and 77% adult patients achieved clinical remission of LN after MMF treatment. Median time to remission after initiation of MMF was shorter in pediatric patients (4.3 months vs 7 months), although statistically insignificant. Risk factors for failure of remission in pediatric patients were nephrotic-range proteinuria and seronegativity of anti-dsDNA antibodies, whereas impaired renal function was also important for predicting remission failure in adult LN.

Conclusion: This study shows the real-world data on MMF treatment in childhood LN and adult LN. In childhood LN, MMF has a good therapeutic effect, similar to adult LN.

Disclosure of Interest

None Declared

Autoinflammatory diseases I

P144 FAVORABLE EFFECT OF TOCILIZUMAB IN BLAU SYNDROME

Reem Abdwani

Child Health, SULTAN QABOOS UNIVERSITY HOSPITAL, Muscat, Oman

Introduction: Blau syndrome (BS) is a rare auto inflammatory granulomatous disorder, characterized by a clinical triad of recurrent uveitis, arthritis and dermatitis. It is a dominantly inherited condition due to mutation in the pattern recognition receptor of NOD gene. No therapeutic trials have been conducted in Blau syndrome and only limited case reports regarding treatment are available

Objectives: The aim of this study is to report the first Arab patient with BS who was refractory was conventional therapy but had rapid quiescence after using Tocilizumab. We also conducted a systematic literature review about biologic treatments in BS.

Methods: A 3.5 year old boy was referred at the age of 8 month for evaluation of intermittent fever, rash and polyarthritis that started at the age of 2 months. He also had a granulomatous panuveitis with posterior synchia and lens cataract. Skin biopsy revealed non-caseating epitheloid granuloma. DNA analysis identified a heterogenous missense mutation in exon 4 of the NOD2 gene. Over the course of years, patient had a difficulty stormy course with severe polyarthritis that was refractory to conventional treatment including pulses of methlyprednislone, oral prednisolone, methotrexate, adalimumab and infliximab. Tocilizumab 12mg/kg every 2 week was introduced 8 months ago with rapid improvement of arthritis with ability to taper oral prednisolone to 2mg/day. Serum Amyloid levels dropped from 246 mg/L to >6.4 within 3 months. Further attempts to decrease the dose or interval of Tocilizumab infusions were unsuccessful.

Results: On literature review, we identified 32 cases of Blau syndrome that were treated with biologic agents; Etanercept (13), Infliximab (14), Adalimumab (10), Anakinra (3), Canakiumab (2), Tocilizumab (3), Abatacept (1). The clinical characteristics and treatment outcome are shown in Table 1 (table could not be inserted due to limitations in number of rows)

Conclusion: There is wide diversity in the clinical phenotype of Blau syndrome in terms of age of onset, clinical presentation, disease severity and response to treatment which may be related to functional difference in NOD 2 mutation. Informed consent to publish had been obtained.

Trial registration identifying number: not applicable

Disclosure of Interest

None Declared

P145 CHRONIC RECURRENT MULTIFOCAL OSTEOMYELITIS: SINGLE CENTER EXPERIENCE

Ceyhun Acari¹, Hatice Adiguzel Dundar¹, Serkan Türkuçar¹, Balahan Makay², Erbil Ünsal¹

¹Department of Pediatrics, Pediatric Rheumatology Unit, Dokuz Eylul University, Faculty of Medicine; ²Pediatric Rheumatology Unit, Dr. Behcet Uz Children's Hospital, Izmir, Turkey

Correspondence: Ceyhun Acari

Introduction: Chronic recurrent multifocal osteomyelitis (CRMO) is an autoinflammatory bone disease that is characterized by sterile bone lesions. 500 CRMO cases are reported as individual cases or case series in the literature.

Objectives: In this study, we aim to share our clinical experience of 10 pediatric patients with CRMO.

Methods: The files of patients were retrospectively reviewed by pediatric rheumatologist. The cases were analyzed to define symptoms at onset, clinical findings, laboratory parameters and imaging results. Patients were re-evaluated according to CRMO diagnostic criteria.

Results: The mean age of cases was 8.7 years (min:3, max: 13) at diagnosis and 7 patients were male and the others were female. The mean lack time for diagnosis was 8.8 months (min:2, max:24). The mean follow-up of cases was 45.1 months. Magnetic resonance imaging (MRI) in all patients and bone scintigraphy in 9 patients were performed. The diagnosis of 9 cases were confirmed by histopathological examination. Two of the cases were brothers. Other diagnoses were Familial Mediterranean fever in two cases, nephrolithiasis in one case and keratite-bound corneal ulcer in one case. At the time of admission, all patients were suffering from pain of bone and/or joint and showed multifocal involvement such as femur (7 cases), pelvic bones (5), tibia (4), clavicle (2), vertebra (2), ankle (2) and mandible (1). In laboratory results, C-reactive protein level was found as elevated (18.7 mg/L [1.8-78]; mean erythrocyte sedimentation rate was found as elevated (51 mm/h [15-119]. Sulfasalazine and nonsteroid antiinflammatory drugs were used in all cases and methotrexate was added in 6 cases. Three cases required steroid treatment. Resistant cases needed anti-TNF (etanercept or adalimumab) in two patients and IV pamidronate in one patient. The mean time of remission was 19.25 months (min: 6, max:48). Currently, three patients are in remission without medication, and five patients are in remission with medication.

Conclusion: Chronic recurrent multifocal osteomyelitis (CRMO) is a rare idiopathic inflammatory disease that affects usually children and young adults. Clinical signs and symptoms are nonspecific and usually the diagnosis is delayed. Diagnosis is based on excluding infections especially osteomyelitis and malignant diseases. Mostly, metaphyseal-diaphyseal region of long bones such as the femur and tibia are involved, Laboratory tests show a mild to moderate acute phase elevation. Nonsteroids are used as the first step in the treatment, but usually sulfasalazine or methotrexate is added, particularly with vertebral involvement. Anti-TNF agents may be effective in patients those unresponsive to conventional treatments and frequent relapses. In recent years, bisphosphonate (pamidronate) is used as an effective and safe agent for the treatment of bone lesions, as well as pain control.

Disclosure of Interest

None Declared

P146 COLCHICINE RESISTANCE IN FMF: POSSIBLE RISK FACTORS AND USE OF ANTI-IL-1

Hatice Adıguzel Dundar¹, Ceyhun Acari¹, Serkan Turkucar¹, Ozge Altug gucenmez², Balahan Makay³, Sevket Erbil Unsal¹

¹Department of pediatrics, child rheumatology, Dokuz Eylul University faculty of medicine; ²Department of pediatrics, child rheumatology, Dr. Behcet Uz Childrens' Hospital; ³Department of pediatrics, child rheumatology, Dr. Behcet Uz Childrens' Hospital, izmir, Turkey

Correspondence: Hatice Adıguzel Dundar

Introduction: Familial Mediterranean fever (FMF) is the most common autoinflammatory disease with autosomal recessive inheritance. There is MEFV gene mutation encoding the pyrine protein in the short arm of chromosome 16 that leads to overexpression of IL-1. The basic treatment in FMF has been colchicine since 1972. Colchicine is effective both in the prevention and treatment of attacks, and in reducing the frequency of amyloidosis. However, there is resistance to colchicine in 5-10% of FMF cases, and anti interleukin-1 (anti IL-1) is effective in these cases.

Objectives: In this study, we aimed to find out possible risk factors for colchicine resistance in FMF by comparing the clinical and demographic data of patients with and without colchicine resistance, and to examine anti IL-1 effectiveness in patients with colchicine resistance

Methods: Data charts of children with FMF from Dokuz Eylul University childrens’ hospital and Dr.B.Uz childrens’ hospital (n=950) were reviewed. Despite the use of adequate doses of colchicine, the patients with over 3 attacks in last 6 months were considered to be colchicine resistant. Then, colchicine resistant patients were compared with colchicine responsive group.

Results: Thirty four (3.6%) of 951 patients had colchicine resistance and all of them used anti IL-1 (canakinumab). 67.7% of these patients were male and 47.1% had positive family history. Median age of symptoms onset was 40 (24-75) months, median age of diagnosis and colchicine onset were 72 (43-115) months. Median diagnosis delay time was 12 (9-47) months and median time of follow-up was 52 (33-99) months. There was not statistically difference between the 2 groups. Most common symptoms were fever, abdominal pain and musculoskeletal symptoms in both groups, while fever (85.3%), arthralgia (53%), arthritis (41.2%) were significantly higher in group with colchicine resistance when compared with other group (p:0.032, p:0.048 and p:0.001 respectively) Other frequent symptoms were myalgia, chest pain and erysipelas like rash in both of groups. The number of attacks in last 6 months after colchicine treatment was statistically higher in group of colchicine resistance than in other group (median numbers of attack: 6(3-10) (p:0,000). Colchicine resistant group response to canakinumab was good; the median number of attacks was 1(0-2) in the last year

When the groups were compared in terms of FMF gene mutation, exon 10 mutation was 88.2% positive in-group of colchicine resistance, while 67.7% in other group. M694V mutation was also significantly higher when compared with other group (85.3% and 50.2% respectively) (p:0.000).

All patients with colchicine resistance responded the canakinumab treatment except one who had enthesitis related arthritis. There was pneumonia in one patient, urinary tract infection in 2 patients, recurrent upper respiratory tract infection in 2 patients after canakinumab treatment. No serious side effects were reported in the patients that use canakinumab.

Conclusion: Colchicine is still best treatment in FMF. 96.4% of our cases responded to colchicine. In cases with colchicine resistance, IL-1 inhibition was successful. Resistant cases had specific features. Male dominance, exon 10 with M694V mutation and arthritis constituted the major properties of this group.

Disclosure of Interest

None Declared

P147 FAMILIAL COLD AUTOINFLAMMATORY SYNDROME-2 (FCAS-2), PRESENTING ONLY WITH RECURRENT ARTHRITIS

Hatice Adıguzel Dundar¹, Serkan Turkucar², Ceyhun Acari¹, Sevket Erbil Unsal¹

¹Department of pediatrics, child rheumatology; ²Department of pediatrics, child rheumatology, Dokuz Eylul University faculty of medicine, izmir, Turkey

Correspondence: Hatice Adıguzel Dundar

Introduction: Familial cold auto-inflammatory syndrome-2 (FCAS-2) is an autosomal dominant disorder due to the NLRP12 mutation which plays a role in the regulation of proinflammatory cytokines. It is characterized by fever, headache, joint symptoms, urticarial rash that is triggered by cold; usually starting in early infancy. Episodes are generally last for 5-10 days. It can also be accompanied by conjunctivitis, hearing loss and myalgia.

Objectives: Presenting a familial cold auto-inflammatory syndrome case with atypical presentation.

Methods: Case presentation.

Results: A 17-year-old girl presented to outpatient clinic with recurrent arthritis, urticarial rash for 6 years. She had no accompanying fever in any of the episodes. The frequency of attacks increased in last 2 years, often lasting for 10 days, which were unresponsive to NSAIDs. Attacks were triggered irrelevant from cold exposure. She also had clinical diagnosis of mature onset diabetes in young (MODY), and autoimmune thyroiditis. On physical examination, she had arthritis and urticarial rash on left ankle. Acute phase reactants were increased. FMF was the initial diagnosis, however no mutation was found in MEFV gene sequencing. Auto-inflammatory next generation sequencing (NGS) panel demonstrated NLRP-12 gene mutation (p.Arg352Cys) compatible with FCAS-2. Colchicine treatment (1.5 mg/day) was able to provide disease control.

Conclusion: Familial cold auto-inflammatory syndrome (FCAS) is characterized by recurrent attacks of cold-triggered fever, arthritis and urticarial rash mostly starting in infancy. This case differs from the classical pattern by old age, and it seems fever is not always one of the presenting symptoms. Informed consent to publish had been obtained from the parent.

Trial registration identifying number: Note: Followings case report contains a method which in our thought is not appropriate in a case report abstract. Hence, the method was depicted as “case presentation”. If committee have any suggestion in following days it could be changed accordingly.

Disclosure of Interest

None Declared

P148 MUSCLE ASEPTIC ABSCESSES IN PEDIATRIC PATIENTS DIAGNOSED WITH SYSTEMIC ONSET JUVENILE IDIOPATHIC ARTHRITIS OR POLYARTHRITIS: IS IT A NEW AUTO-INFLAMMATORY DISEASE?

Kokou Placide Agbo-Kpati¹, Pierre Quartier², Sylvain Breton³, Brigitte Bader-Meunier⁴

¹Pediatrie, GHEF-Site de Marne La Vallée Jossigny, JOSSIGNY; ²Pediatrie, Paris-Descartes University, Paris, France, 4Imagine Institut and RAISE Reference Center, Pediatric Immunology-Hematology and Rheumatology Unit, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France; ³Radiology, Pediatric Radiology Department, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris France; ⁴Pediatrie, Paris-Descartes University, Paris, France, 4Imagine Institut and RAISE Reference Center, Pediatric Immunology-Hematology and Rheumatology Unit, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France., Paris, France

Correspondence: Kokou Placide Agbo-Kpati

Introduction: Abscesses Aseptic (AA) syndrome is an autoinflammatory disorder mostly reported in adult, of unknown etiology characterized by occurrence of fever, AA and elevated acute phase reactants. It responds to steroid treatment. It is either associated with inflammatory diseases, such as Crohn's disease or relapsing polychondritis, or as « idiopathic ». Pediatric-onset AA has been reported in only 8 patients and never in association with JIA.

Objectives: To report the association of JIA and muscle AA.

Methods: we retrospectively analyzed the medical notes from patients followed in two pediatric departments from the French FAI2R network for rare autoimmune and autoinflammatory diseases who presented both Juvenile Idiopathic Arthritis and multiple aseptic muscle abscesses. Patients had been included in the CEMARA platform for rare diseases, which benefits from an agreement from the French Commission Nationale Informatique et Liberté. According to the French legislation, no ethics committee agreement was requested for such a retrospective, observational survey.

Results: We identified 3 male patients diagnosed with JIA between the age of 4 and 5 years. Patient 1 had systemic-onset with spiking fever, polyarthritis, myalgia, pericarditis; patient 2 had a seronegative polyarticular JIA; patient 3 had Rhumatoid Factor and ANA positive polyarticular JIA. There was no familial anamnesis of interest and the 3 patients were born from unrelated parents. Biological inflammation was present at in all cases with CRP > 70mg/L at diagnosis. Muscle abscesses developed 4, 30 and 48 months respectively after the diagnosis of JIA. At this time, patient 1 was on oral steroids, patient 2 on remission off treatment and patient 3 on oral steroids and subcutaneous etarnercept. Abscesses were revealed by painful tumefactions, associated with fever, flare of polyarthritis and an elevation of CRP. Ultrasound and MRI revealed a collection consistent with abscess in the biceps (patients 1 and 2) or the mesogluteus muscles (Patient 3). Corticosteroids and biologics were stopped and surgical drainage was performed in patient 1 and 2, showing an exudate of polymorphonuclear neutrophils. An extensive microbiological screen for bacteria, fungi and mycobacteria was negative in both cases. We also ruled out in the 3 patients chronic granulomatous disease as well as XIAP and PSTPIP1 mutations. In the 3 patients after 7 to 10 days on large spectrum of antibiotic treatment with no effect on lesions nor on the CRP level, steroid 1 to 2mg/kg/day were re-introduced or initiated, which was associated with quick improvement and a complete resolution of symptoms within 5 to 10 days. After tapering the dose of steroid, patient 1 developed a relapsing-remitting course, with recurrent biceps muscle abscesses that responded each time to increase of the steroid dosage. After 4 to 5 years from the onset of abscesses and the failure of several treatments including, in 2 cases the interleukin (IL)-1 receptor antagonist anakinra, all 3 patients were put on the anti-IL-6 receptor antibody tocilizumab and achieved remission that persisted, off steroid at the latest follow-up, 10 to 12 years later. However, severe bilateral erosive hips arthritis had developed in two patients before the onset of tocilizumab.

Conclusion: The diagnosis of muscle AA should be considered in a patient with abscesses associated with polyarthritis, particularly in the absence of documented infection or response to antibiotics. The association of early-onset polyarthritis, systemic inflammation and aseptic muscle abscess is likely a peculiar autoinflammatory disorder that may respond to anti IL-6 blockade.

Disclosure of Interest

None Declared

P149 COMPARISON OF THE DEMOGRAPHIC, CLINICAL AND GENETIC DATA OF CHILDREN WITH FMF WHOSE SYMPTOMS BEGIN BEFORE AGE OF 5 WITH THE CHILDREN HAVING ONSET OF SYMPTOMS AFTER AGE OF 5.

Gökçen Erfidan, Gül Karadağ, Ayşe Zopçuk, Mustafa Çakan, Nuray Aktay Ayaz

Pediatric Rheumatology, Sağlık Bilimleri University KSSEAH, Istanbul, Turkey

Correspondence: Nuray Aktay Ayaz

Introduction: Familial Mediterranean fever (FMF) is an inherited autoinflammatory disease characterized by recurrent episodes of fever and acute inflammation of the membranes lining the abdomen, joints. FMF usually begins during childhood. Most affected individuals experience their initial episode before the age of 20.

Objectives: We aimed to compare the demographic, clinical and genetic data of the patients whose symptoms started before the age five and after the age five to see the effect of age to the severity and outcome of disease, to evaluate the presence of mutations according the the age of symproms onset.

Methods: Children who are diagnosed as FMF at Sağlık Bilimleri University KSSEAH Pediatric Rheumatology outpatient-clinic according to Tel-Hashomer Criteria were involved to the study. Patients were grouped based to the age of onset of the symptoms related to FMF. In the first group consisted 100 children with the clinical features that began before age of 5 and the second group consisted 100 children with the clinical features starting after age of 5. All the patients were carrying either heterozygous or homozygous MEFV mutations. Retrospective analysis of the files of the patients were done. Demographic data, genetic analysis, consanguinity, family history, age that first symptom ensue, duration passed until the diagnosis was made, frequency of attacks, duration of attacks and the involved sites during attacks, reports of MEFV analysis, laboratory data including CRP, ESR, SAA, blood counts, urinary protein levels were recorded. Severity of the disease were evaluated according to the Pras score.

S

Results: Mean age of the patients was 11.7±4.04. Mean age of the children whose symptoms began before age of 5 (Group 1) was 9.65±3.83 years, mean age of the children whose symptoms began after age of 5 (Group 2) was 13.7±3.09 years. Group 1 consisted 57 girls, group 2 consisted 46 girls. Consanguinity was 35% for group 1and 21% for group 2 (p<0.05). Clinical features started at the mean age of 2.37±1.19 years in group 1 and 8±2.39 years in group 2. The duration that passed till diagnosis was 2.19±1.99 years and was not different between groups. Although group 1 had more frequent attacks than group 2, the duration af attacks were similar in both groups. Colchicine dose was more than the dose needed for age in group 1, 14% of children needed increased doses, while in group 2 only 2% needed higher doses appropriate for their age (p<0.05). Fever and abdominal pain was present in 64% of all patients as the first symptom. Fever only was the presenting symptom in 19 children under age 5, while non of the patienst in group 2 had just fever as the presenting symptom (p<0.05). Artrhitis and chest pain were the presenting symptoms in group 2, but not the first symptom in group 1 (p<0.05). Mean Pras score of patients in group 1 was significantly higher (7.35±1.24) than the mean score of group 2 (6.14±1.55). Homozygous M694V mutations were statistically more frequent in group 1 (p<0.05). Leukocyte counts and CRP levels were higher, hemoglobin concentrations were lower during attacks in group 1 than group 2 (p<0.05).

Conclusion: Age of onset of FMF is an important factor while eavluating clinical features and severity of the disease. Increased doses of colchicine may be needed in children with early onset of disease. Severe disease causing mutations are also frequently seen when the disease starts early. Presence of recurrent fevers even without accompanying symptoms must warn the physician about the presence of FMF that will prevent the delay in diagnosis. So, both the complications like amyloidosis and the severe burden of disease will be avoided

Disclosure of Interest

None Declared

P150 TARGETED PERSONALIZED BIOLOGIC THERAPY IN CHILDREN WITH AUTOINFLAMMATORY SYNDROMES

Ekaterina Alexeeva^1,2, Tatyana Dvoryakovskaya^1,2, Rina Denisova¹, Tatyana Sleptsova¹, Kseniya Isaeva¹, Alexandra Chomahidze¹, Anna Fetisova¹, Anna Mamutova¹, Victor Gladkikh³, Alina Alshevskaya³, Andrey Moskalev³

¹Federal State Autonomous Institution “National Medical Research Center of Children's Health” of the Ministry of Health of the Russian Federation; ²Federal State Autonomous Educational Institution of Higher Education I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation, Moscow; ³Biostatistics and Clinical Trials Center, Novosibirsk, Russian Federation

Correspondence: Ekaterina Alexeeva

Introduction: Misdiagnosis in patients with such autoinflammatory syndromes as juvenile idiopathic arthritis (JIA) occurs rather frequently in routine practice. Because of the heterogeneity of JIA and the lack of widespread genetic testing, children with autoinflammatory syndromes can be treated for many years using the standard protocols before they turn out to be ineffective.

Objectives: The objective of this study was to estimate the incidence of autoinflammatory syndromes among biologic-naïve patients with JIA and those with a long-term disease, as well as the ineffectiveness of therapy with one or more biologics.

Methods: The prospective study conducted at the National Medical Research Center of Children's Health (Moscow) involved 300 patients having a diagnosis of systemic JIA at enrollment. All the patients underwent automated direct sequencing on an ABI 3500 XL automated DNA sequencer (Applied Biosystems) using a BigDye Terminator Cycle Sequencing Ready Reaction kit (Applied Biosystems, Foster City, CA, USA). If no mutations were detected in the hot spots of the MEFV, MVK, NLRP3, and TNFRSF1A genes, all the coding and the adjacent intronic regions of the MVK, MEFV, TNFRSF1A, NLRP3, NLRP12, CECR1, IL1RN, TMEM173, NLRC4, LACC1, NOD2, PSTPIP, LPIN2, PSMB8, and TRNT1 genes in patients with suspected autoinflammatory syndromes were examined by next-generation sequencing, which allows one to simultaneously analyze extensive areas of the human genome. After genetic verification of the diagnosis, the patients were assigned to the groups receiving either TNFα inhibitors, or anti-IL6 receptor monoclonal antibodies, anti-IL1 monoclonal antibodies. At the final visit (within 1 year), the efficacy and safety of targeted personalized biologic therapy was evaluated.

Results: Among the 300 patients enrolled, 180 were biologic-naïve (60%, the naïve group). Among the remaining cohort (40%, the switched group), 27% of patients were previously treated with 2 or more biologics. Prior to molecular genetic examination, only 16% of patients had inactive disease. An ACR70 response (compared with the disease onset) was achieved in 16.3% of patients (27 (15%) naïve and 22 (18.3%) switched patients). Only 8% of patients (13 (7.2%) naïve and 11 (3.6%) switched patients) reached the inactive disease phase/remission.

The conducted molecular genetic study showed that biologic therapy was personalized in 53/180 (29%) naïve patients and 46/120 (38%) switched patients according to the revealed pathogenic variants of the genome. Personalized treatment reduced the JADAS71 index down to < 3 in 71% of patients and allowed 70% of children achieve the inactive disease phase and remission after one-year follow-up

Conclusion: The frequency of pathogenic variants of the genome and autoinflammatory syndromes in patients with juvenile idiopathic arthritis is high. The revealed genomic abnormalities make it possible to personalize biologic therapy, which allows achieving the remission rate of > 70%.

Disclosure of Interest

None Declared

P151 THE CHARACTERISTICS OF PEDIATRIC FAMILIAL MEDITERRANEAN FEVER WHO ARE USING CANAKINUMAB

Ozge Altug Gucenmez¹, Balahan Makay¹, Neslisah Uslu²

¹Izmir Dr. Behcet Uz Children’s Hospital, Izmir; ²Koc University, Istanbul, Turkey

Correspondence: Ozge Altug Gucenmez

Introduction: Familial Mediterranean Fever (FMF) is an inflammatory disease related to MEFV gene mutations which is characterized recurrent fever and abdominal pain. Colchicine is used for preventing attacks as the routine treatment. However, the effect of anti-interleukin-1 (IL-1) was shown in colchicine resistant patients.

Objectives: It is aimed to present the characteristics of pediatric FMF patients who followed with an anti-IL-1 agent, canakinumab.

Methods: The medical files of 29 pediatric FMF patients who are followed in Izmir Dr. Behcet Uz Children’s Hospital were investigated retrospectively.

Results: Seventeen male and 12 female cases with colchicine resistant FMF were included in the study. The cases with three or more attacks in the last six months and high AFR while using adequate dose colchicine were defined as the colchicine resistant. The median age was 16 years (min-max: 4.5-19 years), median symptom onset age was 4 years (min-max: 1-15 years), median diagnosis age was 6 years (min-max: 2-15 years), and median follow-up time was 7 years (min-max: 2-14 years). Twenty-two cases were (75.9%) M694V homozygote. Recurrent fever (100%), abdominal pain (86.2%), and arthritis (48.3%) were the most common symptoms. The cases used colchicine for median 7 months (min-max: 2-14 months) prior to canakinumab. Four of the cases (13.8%) have tried anakinra treatment prior to canakinumab. Canakinumab was started with 3-5 mg/kg (max: 150 mg). The cases in the present study were used canakinumab for 11 months (min-max: 2-76 months). Two cases had a urinary tract infection (6.9%), and pneumonia was developed in one case (3.4%) following the canakinumab. Total remission was achieved in 26 cases (89.7%) following canakinumab treatment.

Conclusion: Although the colchicine is still the first line therapy in the FMF, anti-IL-1 agents provide effective treatment in colchicine resistant cases. Canakinumab is a promising agent which controls FMF attacks effectively. According to our experience, the colchicine resistant FMF patients might achieve high rates of total remission without severe adverse effects following canakinumab treatment.

Disclosure of Interest

None Declared

P152 CHRONIC RECURRENT MULTIFOCAL OSTEOMYELITIS: FOUR TERTIARY SPANISH HOSPITALS EXPERIENCE. A MULTICENTRIC STUDY.

Antía García Fernández¹, Jaime Arroyo Palomo¹, Daniel Clemente Garrulo², Belén Serrano Benavente³, Javier Nóvoa Medina⁴, Juan Carlos Nieto González³, Sergio Machín García⁴, Anahy María Brandy García⁵, Juan Carlos López Robledillo², Indalecio Monteagudo Sáez³, Alina Lucica Boteanu¹

¹Paediatric Rheumatology, Ramón y Cajal University Hospital; ²Paediatric Rheumatology, Niño Jesús University Child Hospital; ³Paediatric Rheumatology, Gregorio Marañón General University Hospital, Madrid; ⁴Paediatric Rheumatology, Insular Maternity Child University Hospital of Gran Canaria, Las Palmas de Gran Canaria; ⁵Rheumatology, Central University Clinic Hospital of Asturias, Oviedo, Spain

Correspondence: Jaime Arroyo Palomo

Introduction: Chronic recurrent multifocal osteomyelitis (CRMO) is a rare autoinflammatory polygenic bone disease characterized by aseptic bone inflammation that affects more frequently pediatric population. Its management, clinical, radiological findings and treatment have not yet been standardized.

Objectives: The clinical, radiological characteristics were analyzed as well as response to treatment options.

Methods: We performed a retrospective, descriptive multicentric study of patients diagnosed of CRMO in four tertiary level hospitals’ pediatric rheumatology section. There were 16 patients included.

Results: The median age at diagnosis was 10,5 years, female:male ratio 62,5:37,5%. The delay in the diagnosis had a median of 4.5 months, being less than one year in 11 patients,taking up to 24 months in a patient with unifocal pelvic involvement. Bone pain was the first symptom in 100% of the patients accompanied by fever in 25% of them. A single patient presented perilesional arthritis. A slight-moderate increase on acute fase reactants was observed at the debut of the disease: median ESR 47.5mm/h.

The median number of locations at disease onset was 2.5 (range 1-14), with multifocal involvement in 75%. The most frequent location was tibia (56%), followed by pelvis (44%) and vertebrae (31,25%). Other locations less frequent were: carpus (12.5%), femur (12.5%) mandible (6%) and sternum (6%).

Biopsy was performed in 14/16 patients and bone scintigraphy with Tc99 in 12/16 patients, with pathological uptake observed in 91.6% of cases. MRI was the radiological test of suspected diagnosis in 15/16 patients.

NSAIDs were the initial treatment being Ibuprofen and Naproxen the most frequently used. 5 patients received different antibiotic therapy regimens, without clinical or radiological improvement. 56.25% of patients required other treatments. Systemic corticosteroids were used in 12.5% of patients and bisphosphonates in 43.75%(100% of patients with axial involvement). After 6 months of treatment with biphosphonates, 57.14% had complete remission, 28.57% partial remission and 14.28% worsening. 12.5% of the patients had a torpid evolution, receiving sequential therapies with multiple synthetic or biological DMARDs (Anakinra, Canakinumab, Etanercept), and another 12.5% required surgery.

Conclusion: The diagnosis of CRMO represents a big challenge in the absence of pathognomonic features which frequently leads to delay in diagnosis and the initiation of treatment. In our centers the biphosphonates were the treatment strategy used in patients with spinal involvement with 85.67% response at 6 months.

Disclosure of Interest

None Declared

P153 A MALE WITH BLAU SYNDROME AND INFLAMMATORY CNS MANIFESTATION

Stefan Berg¹, Anders Fasth¹, Gunilla Drake¹, Yonas Berhane²

¹Dept of Pediatrics, Institute of Clinical Sciences, Gothenburg; ²Dept of Pediatrics, Sunderby Hospital, Luleå, Sweden

Correspondence: Stefan Berg

Introduction: Blau syndrome is an autoinflammatory syndrome caused by a mutation in NOD2. The syndrome is often a challenge to treat. A variety of anti-inflammatory agents have been used but none has so far being universally effective.

We describe an 18 year-old boy previously treated with several non-biologic DMARDS in combination with TNF-blockade, Il-1 blockade and IL-6 blockade. He has never been free of inflammation and always needed oral corticosteroids (0.15-0.20 mg/kg). His main clinical problems have been arthritis and uveitis. During the last 5 years he had intermittent headache that seems to correlate with flares of the disease. In December 2017 his headache became worse.

Objectives: Investigate CNS symptoms in a child with Blau syndrome

Methods: Repeated lumbar punctures and serial measurements of CSF biomarkers were performed. Extensive infectious work-up was done.

Results: Repeated MRI of the brain between 2011 and 2017 did not show any progress but only a discrete periventricular signaling of unclear significance around both anterior horns. Brain MRI 2018 was unchanged compared to earlier MRIs. The infectious work-up was normal.

	CSF findings
	181228	180131	180321	180503
opening	27	27	47	33
pressure cm H2O
WBC count (/μl)	188	45	6	7
Lymphocytes (/μl)	180	44	6	6
Neutrophils (/μl )	8	1	0	1
Protein (g/L)	0,71	normal	normal
NFL(<380ng/L)	4350	4740	50700	pending
GFA(<175ng/L)	390	670	330	pending
Tau (<250 ng/L)	759	526	500	pending
Glucose(mmol/L)	3.0	3.1
Lactate (mmol/L)	2.3	1.8
Serum findings
181228; CRP 4 mg/L, WBC 17.1 x 109/L, ANC 13.2 x 109/L, ALC 2.4 x 109/L

His symptoms and CSF leukocytes have decreased after increasing the corticosteroids and after changing from prednisolone to dexamethasone with better penetrance of the blood-brain barrier.

Conclusion: CNS inflammation in Blau syndrome was not described earlier. The results of the investigations clearly points to CNS inflammation in this teenager and that this is possibly a part of Blau syndrome. The late increase of NFL is reflecting the dynamics of this biomarker and not an evidence of worsening of the CNS involvement. Our conclusion is that CNF involvement should be part of the work-up of children with Blau syndrome.

Disclosure of Interest

None Declared

P154 CHARACTERIZATION OF A HOMOZYGOUS KNOCK-IN MOUSE MODEL FOR NLRP3 GENE THAT DEVELOP CINCA DISEASE

Arinna Bertoni¹, Sonia Carta², Chiara Baldovini³, Federica Penco¹, Enrica Balza², Silvia Borghini⁴, Michele Fiore⁴, Paolo Nozza³, Emanuela Ognio⁵, Francesca Schena¹, Marco Di Duca⁴, Roberta Caorsi¹, Isabella Ceccherini⁴, Alberto Martini¹, Marco Gattorno¹, Anna Rubartelli², Sabrina Chiesa¹

¹Centro Malattie Autoinfiammatorie ed Immunodeficienze, ISTITUTO GIANNINA GASLINI; ²Unità di Biologia Cellulare, San Martino-IST; ³UOC Anatomia Patologica; ⁴Genetica Medica, ISTITUTO GIANNINA GASLINI; ⁵UOS Animal Facility, San Martino-IST, Genova, Italy

Correspondence: Arinna Bertoni

Introduction: Cryopirin associated periodic syndromes (CAPS) are autoinflammatory diseases associated to NLRP3 gene mutations, leading to inflammasome hyperactivity and IL-1βhypersecretion. Three phenotypes (FCAS, MWS and CINCA) represent a continuum of the same disease characterized by different severity degrees. Chronic infantile neurologic, cutaneous, articular (CINCA) patients, affected by the most severe form, presented recurrent fever, systemic inflammation and central nervous system disabilities.

Objectives:

• increase the knowledge on pathologic consequences of NLRP3 mutations;

• understand central nervous system involvement;

• identify new drugs and molecular targets for the treatment of CAPS diseases.

Methods: Cytokines secretion from bone marrow derived dendritic cells (BMDCs) was evaluated by ELISA.

Hystological analysis was evaluated with hematoxylin and eosin staining.

Results: We engineered N475K mutation (corresponding to mutation N477K in human) in mouse NLRP3 gene and generated a novel knock-in (KI) model that presents two different phenotypes: heterozygous and homozygous form. Although both KI mimic CAPS human disease, homozygous (homo)-KI mice presented a much more severe phenotype and exhibited typical clinical manifestation of CINCA patients. Homo-KI mice showed severe skin rush and growth delay respect to Wild Type (WT) controls. Survival and body weight were severely decreased. Interestingly, IL-1β, IL-18 and IL-1α secretion was strongly increased respect to WT and heterozygous mice of the same littermate mice, while IL-1RA antagonist secretion was extremely reduced when compared to the same littermate mice.

Hystological analysis showed a generalized inflammatory phenotype characterized by alteration of spleen, lungs, liver and kidneys. More interestingly, homo-KI mice presented serious cerebral complication that prevent walking. Hematoxylin and eosin staining reveal a delay in cerebellum development and an alteration of the lamination of cerebral cortex.

Conclusion: Homo-KI mice recapitulate clinical and immunological features of CINCA patients. In the future this mouse model could be used to gain insights into the mechanisms associated to neurological defects and their consequent treatment.

Disclosure of Interest

None Declared

P155 CHRONIC NON INFECTIOUS OSTEITIS- A MULTICENTRE STUDY

Chandrika Bhat¹, Catriona Anderson², Aoibhan Harbinson³, Liza McCann³, Marion Roderick¹, Adam Finn⁴, Joyce Davidson², Athimalaipet Ramanan⁵

¹BRISTOL ROYAL HOSPITAL FOR CHILDREN, Bristol; ²Scottish Paediatric and Adolescent Rheumatology Network, Glasgow; ³Alder Hey Children’s NHS Foundation Trust, Liverpool; ⁴University of Bristol; ⁵Bristol Medical School, Bristol, UK

Correspondence: Chandrika Bhat

Introduction: Chronic non-infectious osteitis (CNO) or Chronic recurrent multifocal osteomyelitis (CRMO) is a rare auto inflammatory disorder characterised by the presence of sterile bone lesions. The disease affects the metaphyses of long bones, pelvis, vertebra and clavicle.

Objectives: To understand the demographics, clinical features and treatment outcomes of Chronic Non-Infectious Osteitis (CNO) from three tertiary paediatric rheumatology services in the United Kingdom.

Methods: Children less than 18 years of age diagnosed with CNO between 2001 to 2016 from one tertiary service and between 2001 to 2017 from two tertiary services were included. Clinical notes were reviewed and all pertinent data were collected on a pre-defined proforma. One hundred and thirty one patients were included in the study. The Bristol diagnostic criteria was applied retrospectively.

Results: Retrospective analysis of the data showed that the disease was more common in girls than boys (2.5:1), the mean ± SD age at diagnosis was 10.64 ± 2.93 years and the mean ± SD time to diagnosis was 16.48 ± SD 16.18 months. Bone pain was the predominant symptom in 118/129 (91.4%) followed by swelling in 50/102 (49.01%). Associated auto inflammatory conditions included IBD (n=1) and psoriasis (n=5). Raised inflammatory markers were present in 39.68% of the patients. Whole body Magnetic Resonance Imaging (MRI) was a useful diagnostic tool. Metaphyses of long bones were most often involved and the distal tibial metaphyses 65/131 (49.6%) was the most common site. With the use of Bristol Diagnostic Criteria 31.50% of the bone biopsies could have been avoided. Non-steroidal anti-inflammatory drugs were used as first line (81.67%) followed by bisphosphonates (61.79%). The disease was in remission in 80.91% of the patients during the last follow up and 17.55% had recurrent disease.

CHARACTERISTICS	NUMBER(%)
Age at diagnosis (mean±SD years)	10.64± 2.93
Gender F/M;ratio	94/37;2.54
Fever (n=79)	6(7.59%)
Raised inflammatory markers(n=126)	50(39.68%)
HLA B27 positive(n=15)	1(6.66%)
Number of clinical sites	1.29 (range 0-3)
Number of radiological sites	3.27 (range 1-13)

Conclusion: Our multicentre study describes features and outcomes of CNO in a large number of patients in the United Kingdom. It also highlights the ability to avoid biopsies in some children and the need to develop standardised pathways for management of CNO.

Disclosure of Interest

None Declared

P156 VACCINATION IN CHILDREN WITH PFAPA (PERIODIC FEVER WITH APHTHOUS STOMATITIS, PHARYNGITIS, AND ADENITIS) SYNDROME AND OTHER AUTOINFLAMMATORY DISEASES

Maša Bizjak¹, Tadej Avčin^1,2, Nataša Toplak^1,2

¹Department of Allergology, Rheumatology and Clinical Immunology, University Children's Hospital; ²Medical faculty, University of Ljubljana, Ljubljana, Slovenia

Correspondence: Maša Bizjak

Introduction: Immunologic processes are altered in patients with autoinflammatory diseases. Little is known about efficacy and safety of vaccinations in these patients, which might affect decision to vaccinate.

Objectives: The aim of this study was to determine vaccination coverage in children with PFAPA syndrome and other autoinflammatory diseases, to find out the reasons for potential vaccination dropout and to assess the frequency and nature of potential side effects after vaccination in these patients.

Methods: All children with PFAPA syndrome and other autoinflammatory diseases who visited rheumatology outpatient clinic at the University Children's Hospital (UCH) Ljubljana since 2008 were invited to participate in the study. They were asked to provide a written vaccination record and they were sent a questionnaire about the reasons for potential vaccination dropout and potential side effects after vaccination. The study was approved by the national ethics committee. Hereby we report the preliminary results of the study.

Results: Since 2008, 191 children with autoinflammatory diseases (including 147 children with PFAPA syndrome) were seen in rheumatology outpatient clinic at UCH Ljubljana. By the end of April 2018 we sent the questionnaires to 78 patients, 26 (33 %) returned the data. Among them, 23 had PFAPA, 2 FMF and 1 CAPS. 17 (65 %) were boys. Median age was 7 (3.5 – 19.2) years, median age at diagnosis, disease onset and end of fever episodes in children with PFAPA was 3.5 (1.6 – 7) years, 1.9 (0.08 – 3.8) years and 6 (3 – 10) years, respectively. Six of the patients with PFAPA still have fever episodes at this point. Five of the patients with PFAPA received methylprednisolone at least once and 9 had a tonsillectomy. Twenty-two (84.6 %) patients had a complete vaccination status according to the Slovenian immunization programme. Reasons for vaccination dropout included recommendation of the primary physician, fear of side effects of vaccination and recurring febrile illness. 6 patients had fever 0-7 days after vaccination that lasted 2-14 days, one of them also had a rash and another one had diarrhoea and vomiting. None experienced serious side effects or disease flares.

Conclusion: Vaccination coverage in children with autoinflammatory diseases seems to be lower than in general population in Slovenia. Vaccination didn’t cause serious side effects or worsening of the autoinflammatory disease in our cohort.

Disclosure of Interest

None Declared

P157 CORNELIA DE LANGE SYNDROME WITH A NOVEL MUTATION IN SMC1A GENE IN PATIENT WITH AICARDI-GOUTIÈRES SYNDROME

Sorina Boiu¹, Andrianos Nezos², Isabelle Melki³, Argyrios Dinopoulos⁴, Manolis Gialitakis⁵, Erato Atsali¹, Kleio Mavragani², Periklis Makrythanasis⁶, Vassiliki Papaevangelou⁴, Dimitrios Boumpas^5,7, Aggelos Banos⁵

¹Pediatric Rheumatology Unit, Third Department of Pediatrics, “Attikon” University Hospital, National and Kapodistrian University of Athens; ²Department of Physiology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece; ³Laboratory of Neurogenetics and Neuroinflammation, INSERM, Paris, France; ⁴Third Department of Pediatrics, “Attikon” University Hospital, National and Kapodistrian University of Athens; ⁵Lab of Autoimmunity and Inflammation; ⁶Systems Biology, Biomedical Research Institute of the Academy of Athens; ⁷Fourth Department of Medicine, “Attikon” University Hospital, National and Kapodistrian University of Athens, Athens, Greece

Correspondence: Sorina Boiu

Introduction: Type I interferonopathies are a clinically heterogeneous group of Mendelian disorders characterized by constitutive upregulation of type I interferon activity. Aicardi-Goutières syndrome (AGS) manifests as an early-onset encephalopathy and mimics a congenital viral infection. Cohesinopathies such as Cornelia De Lange syndrome, are characterized by both physical and mental abnormalities. Mutations in cohesin complex genes (NIPBL, SMC1, SMC3, RAD21, HDAC8) result in increased sensitivity to DNA damage and exhibit global gene expression deregulation. However, the true extent of the phenotype associated with pathogenic variants in CdL-related genes is not yet known.

Objectives: To report on a patient with combined Cornelia de Lange syndrome and AGS.

Methods: A twenty years old male presented since early infancy with violaceous, scaling lesions of the fingers and toes, resorption of distal phalanges, dystrophic nail changes and, violaceous lesions on the nose that worsened during the cold season. He was diagnosed at the age of 7 years with Cornelia de Lange syndrome (CdLS) based on the phenotype associating severe somatic and psychomotor retardation, microcephaly, hypertrichosis, synophrys, arched palate, strabismus, hearing loss, cryptorchidism and unilateral vesicoureteral reflux with kidney scarring. Laboratory investigations showed mild thrombocytopenia and positive anti-thyroid antibodies. A cerebral MRI showed an important intracerebral large vessel involvement with cerebral vascular accidents. The patient was found to be homozygous for a novel NM_015474.3:c.66del:p.(Ser23Glnfs*43) variant in SAMHD1 gene. Whole Exome Sequencing (WES) of the patient was performed. PBMCs were isolated from peripheral blood and cell subsets were monitored for aberrations compared to healthy donors. DNA damage was assayed in cell subsets through phospho-γ-H2AX staining. Finally, RNA-seq (in progress) for CD14⁺ monocytes and total PBMCs of patient will provide a list of differentially expressed genes as well as explain immune abnormalities correlating to the patient phenotype.

Results: Using WES, we confirmed the presence of the homozygous mutation in SAMHD1 gene. Moreover, a novel mutation of SMC1A gene associated with Cornelia de Lange syndrome was identified (SMC1A, NM_006306.3:c.3306C>A :p.(Asn1102Lys)). The population of classical monocytes (CD14⁺CD16^-) in the patient was enhanced compared to healthy individuals, while intermediate and non-classical monocytes were not significantly altered. Total T cell abundance was different (reduced at 50%) and much lower for dendritic cells. Levels of DNA damage in PBMCs of patient seem rather similar to healhty ones. RNA-seq analysis is in progress for CD14⁺ monocytes and total PBMCs of patient.

Conclusion: We describe a novel mutation in SMC1A gene, diagnosing genetically Cornelia de Lange syndrome in a patient diagnosed already with AGS. Immune cell abundance abnormalities are expected to reflect gene expression alterations. Informed consent to publish has been obtained from the parents.

Disclosure of Interest

None Declared

P158 APPLICABILITY OF THE PROVISIONAL CRITERIA FOR CHILDREN BEHCET DISEASE IN A SERIES OF PATIENTS FOLLOWING IN A PEDIATRIC RHEUMATOLOGY UNIT

Alina L. Boteanu, Adela Alía Jiménez, Sixto Zegarra Mondragón, Maria Angeles Blazquez Cañamero

Rheumatology, University Hospital RAMÓN Y CAJAL, MADRID, Spain

Correspondence: Alina L. Boteanu

Introduction: Behçet's disease (BD) usually appears in young adults between 25 and 40 years of age, although in a smaller percentage of patients the disease can begin in the pediatric age. Classically, the criteria published by the International Study Group of EB (ISGBD-1990) have been used for the diagnosis, but recently new criteria have been proposed of the Study Group on Childhood EB (PEDBD2016) in order to impove the sensitive and specific

Objectives: Assess the applicability of the new criteria for the childhood BD in a cohort of patients previously  diagnosed with BD, comparing these with the classification criteria previously used (ISGB1990 and ITR-ICBD 2014) and compare with an adult cohort.

Methods: This is a retrospective cross-sectional observational study. Clinical and analytical variables were collected from 9 juvenile patients previously diagnosed with childhood BD, according to criteria of ISGB 1990 and / or of ITR-ICBD 2014, followed in a Pediatric Rheumatoloy Unit in at a tertiary hospital and also from 43 adult patients. It was assessed whether the juvenile patients met the new criteria for provisional classification of childhood EB 2016, analyzing and comparing the spectrum of clinical manifestation of the 2. The mean age at diagnosis was 11.4 ± 5.1 years; 8 of them being women and 1 male. Five patients (5/8) fulfilled the criteria of the ISGB-1990 and eight (8/8) had a score greater than or equal to 4 points that defined the BD according to the criteria of the ITRICBD - 2014. Only 3 of our patients (3/8) fulfilled the new criteria for pediatric BD of the PEDBD-2016. In the group of patients who fullfiell the new criteria: 100% had oral aphthae and genital ulcers as well as joint involvement and skin lesions (3/8). Ocular involvement was detected in two patients and neurological manifestations was seen in two patients; being 2 of them HLA-B51 (+). The 5 patients (5/8) who did not meet these criteria were those who presented mild clinical manifestations as oral ulcers, genitals and/or positive paternity test, with only one of them ocular involvement. One of the patients had incomplete Behcet follow-up

Conclusion: In our series, patients classified as pediatric BD by the 2016 criteria presented cutaneous, ocular and neurological manifestations. A greater number of patients met the previous classification criteria, since it was enough to have mucocutaneous manifestations. Additional studies are required to improve the diagnostic performance and characterization of patients with childhood BD

Disclosure of Interest

None Declared

P159 EMAPALUMAB, AN ANTI-INTERFERON GAMMA MONOCLONAL ANTIBODY IN TWO PATIENTS WITH NLRC4-RELATED DISEASE AND SEVERE HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS (HLH)

Claudia Bracaglia¹, Giusi Prencipe¹, Antonella Insalaco¹, Ivan Caiello¹, Giulia Marucci¹, Raffaele Pecoraro², Manuela Pardeo¹, Pavla Dolezalova³, Sarka Fingerhutova³, Maria Ballabio⁴, Cristina de Min⁴, Fabrizio De Benedetti¹

¹Division of Rheumatology, IRCCS Ospedale Pediatrico Bambino Gesù; ²Pediatric Department, La Sapienza University of Rome, Rome, Italy; ³Paediatric Rheumatology and Autoinflammatory Diseases Unit, General University Hospital, Prague, Czech Republic; ⁴Novimmune, S.A., Geneva, Switzerland

Correspondence: Claudia Bracaglia

Introduction: Interferon gamma (IFNγ) plays a pathogenic role in primary and secondary HLH. An ongoing phase 2/3 trial with emapalumab in primary HLH provides encouraging preliminary data and a pilot trial in MAS in the context of sJIA has just been initiated. Gain-of-function mutations in NLRC4 are associated with a distinct autoinflammatory syndrome, with recurrent HLH.

Objectives: To report safety and efficacy of emapalumab treatment in two patients carrying de novo missense mutations in NLRC4, with severe early onset HLH.

Methods: Cytokine levels were measured by multiplex assay and by specific ELISAs and expression of IFNγ in freshly isolated PBMCs by cytometry.

Results: Pt 1. Caucasian male, presented, at age 20 days, fever and rash and progressively developed clinical and laboratory features of HLH leading to multi-organ failure. A de novo missense mutation in NLRC4 (T337N) was found. High-dose glucocorticoids and cyclosporine-A (CyA) led only to partial improvement. A sepsis triggered HLH reactivation. Emapalumab was started (compassionate use) on background of dexamethasone (13.6 mg/m2) and CyA. After 3 months, the child was discharged in excellent conditions (prednisone 0.3 mg/kg). Infections resolved during treatment with emapalumab. After 7 months of emapalumab treatment, all therapies, including emapalumab, were discontinued, without clinical or laboratory signs of HLH reactivation.

Pt 2. This is 16 months old Caucasian boy with recurrent HLH and vasculitic skin lesions, since 1 month of life, secondary to a de novo missense mutation in NLRC4 (I343N). His disease was not controlled despite treatment with repeated methylprednisolone pulses and chronic daily  glucocorticoid therapy, CyA (5 mg/kg) and anakinra (ranging from 5 to 25 mg/kg/day). When anakinra was withdrawn prior to start emapalumab he immediately developed high-grade fever, skin rash with vasculitic lesions and diarrhoea with laboratory features of HLH. Emapalumab was started (compassionate use) on background of methylprednisolone and CyA with rapid resolution of fever and improvement in biochemical parameters. During emapalumab treatment the patient resolved his initial HLH flare and presented two HLH episodes of mild intensity controlled with moderate intensification of glucocorticoid therapy. These episodes were triggered by systemic infections caused by pathogens translocated from the gut. His diarrhoea persisted with low grade inflammation; emapalumab was eventually withdrawn after 3 months. His subsequent course was characterized by additional mild episodes of MAS. In both patients increased production of IFNγ was demonstrated by high levels of CXCL9 (pt.1: 5670 pg/ml, pt.2: 3310 pg/ml), a chemokine induced specifically by IFNγ, by increased IFNγ expression in NK cells and CD8T cells, and by presence of high levels of total IFNγ bound to circulating emapalumab.

Conclusion: In both patients with HLH secondary to NLRC4-related disease, treatment with emapalumab was well tolerated, no safety concerned emerged, normalization of all HLH clinical and laboratory abnormalities was achieved. Pt. 1 showed no disease reactivation even in the absence of treatments In pt. 2 IFNγ neutralization has provided control of HLH, while his underlying disease and, in particular, gut inflammation and gut colonization by MDR pathogens remained unchanged. Informed consent to publish had been obtained from the parents.

Disclosure of Interest

C. Bracaglia: None Declared, G. Prencipe: None Declared, A. Insalaco: None Declared, I. Caiello: None Declared, G. Marucci: None Declared, R. Pecoraro: None Declared, M. Pardeo: None Declared, P. Dolezalova: None Declared, S. Fingerhutova: None Declared, M. Ballabio: None Declared, C. de Min Employee of: Novimmune, F. De Benedetti Grant / Research Support from: Novartis, Novimmune, Hoffmann- La Roche, SOBI, AbbVie, Pfizer

P160 A CASE REPORT OF NLRP1-ASSOCIATED AUTOINFLAMMATION WITH ARTHRITIS AND DYSKERATOSIS (NAIAD SYNDROME) IN AN 8-YEAR-OLD RUSSIAN GIRL.

Vasily I. Burlakov¹, Anna Kozlova¹, Ekaterina Viktorova¹, Julia Rodina¹, Elena Deripapa¹, Dmitry Abramov², Anna Shcherbina¹

¹Immunology; ²Pathomorphology, FEDERAL RESEARCH AND CLINICAL CENTER OF PEDIATRIC HEMATOLOGY, ONCOLOGY AND IMMUNOLOGY, MOSCOW, RUSSIA, Moscow, Russian Federation

Correspondence: Vasily I. Burlakov

Introduction: NLRP1-associated autoinflammation with arthritis and dyskeratosis (NAIAD syndrome) is a monogenic autoinflammatory syndrome caused by mutations in NLRP1 gene. It was first reported in 2016 and described as a complex syndrome of inflammasome hyperactivation with release of pro-inflammatory cytokines, dyskeratotic and papilloma-like skin lesions, arthritis and features of antibody-mediated autoimmunity with impairment of B-lymphocyte maturation.

Objectives: To report a case history of an 8-year-old Russian girl with some clinical features of NAIAD syndrome who was referred to our Center.

Methods: genetic defect was confirmed via exome next generation sequencing; lymphocyte immunophenotyping was done according to the standard flow cytometry protocols.

Results: We identified a heterozygous mutation in NLRP1 c.160 G>A, p.Ala54Thr in the patient, presenting with severe anemia (hemolytic and chronic inflammation anemia), thrombocytopenia, hyperkeratotic skin rash, dyskeratotic nail changes, additional auricular appendages, alopecia, arthritis and short episodes of alveolitis. The clinical feature that had not been previously described in NAIAD patients was corneal opacity with severe vision impairment. Until 8 years of age the patient suffered mostly from skin and eye sympthoms and cytopenia, that was treated by regular blood transfusions but otherwise had stable clinical condition. While in the process of clinical evaluation in our Center the patient deteriorated rapidly and developed a life-threatening condition with respiratory and acute kidney failure and secondary HLH, requiring artificial lung ventilation. Features of respiratory distress was found on CT-scans. The blood tests showed highly elevated inflammatory serum markers (CRP up to 220 mg/l), hypergammaglobulinemia. Peripheral blood B-cells predominantly consisted of transitory forms with decrease of the post-switch B-cells. Urine tests showed proteinuria and hematuria. After the evaluation of potential clinical significance of the discovered mutation, the patient was started on IL-1R inhibitor (anakinra) and rituximab (N=4) with dramatic improvement in a matter of days. We further enhanced her therapy with ruxolitinib addition, hoping to curb IL-18 hyperproduction. Currently the patient is at home and well, on ruxolitinib and anakinra therapy.

Conclusion: Since its first description in 2016 by S. Grandemange et al. there are only 3 patients reported worldwide so far. We conducted a literature search and found that NLRP1 c.160 G>A, p.Ala54Thr mutation was reported in a patient diagnosed with another NLRP1-associated entity – Multiple Self-Healing Palmoplantar Cracinoma (MSPC). Except for skin and corneal lesions the disorder is characterized by the elevated serum IL-1a, IL-1b and IL-18 levels (C.-H. Yu et al, 2017). One more disease associated with mutations in NLRP1 is Corneal Intraepithelial Dyskeratosis (CID) (V.Soler et al, 2013). Informed consent to publish had been obtained from the parent.

Disclosure of Interest

None Declared

P161 ADA2 DEFICIENCY WITHOUT ADA2 MUTATIONS EXPLAINED BY A STRUCTURAL HOMOZYGOUS VARIATION IN 22Q11.1

Roberta Caorsi¹, Alice Grossi², Roberto Cusano³, Marta Rusmini², Federica Penco¹, Francesca Schena¹, Rosa Anna Podda⁴, Paolo Uva³, Marco Gattorno¹, Isabella Ceccherini²

¹Clinica pediatrica e reumatologia; ²UOC Genetica Medica and UOSD Genetica e Genomica delle Malattie Rare, GASLINI INSTITUTE, GENOA, ITALY, Genova; ³Centre for Advanced Studies, Research and Development in Sardinia (CRS4), Science and Technology Park Polaris, Pula; ⁴Clinica Pediatrica, Talassemie e Malattie Rare, Ospedale Brotzu e Università degli studi di Cagliari, Cagliari, Italy

Correspondence: Roberta Caorsi

Introduction: ADA2 gene (previously named CECR1 gene), located on chromosome 22q11.1, encodes for adenosine deaminase 2, an enzymatic protein also involved in the homeostasis of endothelial and hematopoietic cells. Loss of function mutations in ADA2 gene are responsible of a rare autosomal recessive condition, named DADA2, characterized by a broad clinical spectrum ranging from a systemic inflammatory disease with vascular and multiorgan involvement, resembling Panarteritis Nodosa, to clinical conditions associated to a variable range of immunodeficiency and immune-deregulation. A certain percentage of patients, despite a consistent phenotype and lack of the ADA2 enzymatic activity, have an incomplete or negative genotype.

Objectives: to define the genetics underlying a patient with a clinical phenotype consistent with DADA2 and a deficient enzymatic activity but without any mutation in the coding region of the CECR1 gene.

Methods: Whole exome sequencing (WES) was performed in a 9 year old patient with a clinical phenotype consistent with DADA2 (fever, livedo reticularis, hypertension, hypogammaglobulinemia and two episodes of ischemic stroke) and a complete lack of ADA2 activity in circulating monocytes. In particular, we analyzed the proband and the asymptomatic parents by using Illumina’s Nextera Rapid Capture Expanded Exome libraries and Illumina Hiseq2000 Instrument with 75bp paired-end reads. Since no coding mutation was identified as potentially candidate to account for the clinical phenotype, whole Genome Sequencing (WGS) was performed in the proband by TruSeq Nano DNA Library Prep kit and HiSeq 3000 Instrument with 150bp paired-end reads. Structural variants were identified with Manta.

Results: a homozygous tandem duplication of the genomic region encompassing exons 3 and 4 (involving 12895 bases), generated by two breakpoints in intron 2 and intron 4 respectively, was assessed by the WGS data. This has led to a gene transcript postulated to contain 1967 instead of 1536 nucleotides, due to an in tandem duplication of the sequences corresponding to exons 3 and 4, thus leading to a frameshift starting from codon V252 followed by a premature stop codon after 11 aminoacid residues (p.V252Gfs11*).

Conclusion: The structural variation identified in the patient represents the first evidence of a genetic defect, different from the presence of bi-allelic loss-of-function point mutations, involving the ADA2 gene. A timely identification of ADA2 enzymatic impairment in the presence of a phenotype clearly consistent with DADA2 should lead to a careful and extensive molecular approach in all patients presenting a monoallelic variant or even in the absence of any mutation at standard DNA sequencing.

Disclosure of Interest

None Declared

P162 WHEN A RECURRENT FEVER DOES NOT ONLY DEPEND ON A RHEUMATIC CARDITIS

Martina Capponi¹, Emanuela Del Giudice¹, Annalisa Di Coste¹, Metello Iacobini¹, Flavia Ventriglia¹, Chiara Passarelli², Fabrizio De Benedetti³, Marzia Duse¹

¹Department of Pediatrics, Sapienza University of Rome; ²Laboratory of Medical Genetics; ³Division of Rheumatology, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy

Correspondence: Martina Capponi

Introduction: Autoinflammatory diseases are a group of immunological disorders characterized by ‘seemingly unprovoked’ episodes of fever and inflammation without evidence of autoantibodies or antigen-specific T cells, implying the importance of dysregulation in the innate immune system.

Objectives: To report a case of severe rheumatic carditis that, in a significant host predisposition, could trigger an underlying autoinflammatory syndrome (associated with a mutation in MVK gene)

Methods: M, a caucasian previously healthy 11-years old boy, diagnosed with a rheumatic fever with carditis at the age of 10 (years old) based on the following criteria: fever, polyarthralgia, erythrocyte sedimentation rate > 60 mm/h, C-reactive protein (RCP) > 3.0 mg/dl, increased anti-streptolysin O titer (1700), prolonged PR interval on ECG and echocardiography/Doppler evidence of mitral and aortic valve regurgitation. He was treated with steroid therapy and secondary prophylaxis with Benzathine penicillin (every 21 days). After two months of the steroid withdrawal, he presented recurrent fever attacks (every 2-3 weeks). Each attack was heralded by chills, followed by a sharp rise in body temperature and lasted 4-5 days with gradual defervescence. Abdominal pain with vomiting or diarrhea and increased acute phase markers almost always accompanied the fever attack. Laboratory exams such as immunologic tests for autoimmunity as well as serology for CMV, parvovirus B19, EBV, adenovirus, coxsackie virus, and antistreptolysin O titer resulted negative or within normal limits. Common causes of infections were ruled out. Intravenous antibiotics were administered at any episode of fever and induced a partial remission of the disease activity and inflammatory markers, but his heart disease dramatically worsened such he needed to undergo to cardiac surgery (mitral valve repair and aortic valve replacement using mechanical prosthesis). Three days after the surgery, because of hyperpyrexia despite antibiotic therapy, he started corticosteroid therapy again achieving a partial remission in the following three months. When off steroid therapy, he developed four fever attacks lasting 4-7 days in 3-5 weekly intervals accompanied by abdominal pain and recurrent serositis (e.g., pleuritis, pericarditis) with acute phase markers increased and infectious disease tests, immunological and autoimmune exams always negative. SAA (serum amyloid A) levels were reported to be high in the inter-episode periods while acute phase markers were negative.

Results: Because of the recurrence of pericarditis and steroid dependence, we decided to start the treatment with daily subcutaneous injections of IL-1 receptor antagonist IL-1Ra (Anakinra) at a dosage of 1 mg/kg.

He performed the extended genetic analysis for autoinflammatory syndromes that detected the presence of the genomic variant C.1129G > A in heterozygosity in the MVK gene (mevalonate kinase) due to maternal segregation. After a follow-up of 2 months, we noticed a decreased duration and severity of flare on therapy with Anakinra.

Conclusion: Although the identified variant has been described as associated with MVK deficiency (MKD) if present in homozygosity or compound heterozygosity, some patients with classical disease and only a single identified mutation have reported too (Ref. Barron KS Arthritis Rheum. 2013). In our case, because of maternal segregation, we must suppose whether a hypomorfic expression of gene in the mother or the additional influence of other unknown genes as modifiers of the residual mevalonate kinaseactivity. Otherwise the SBEGA infection might have unmasked the underlied MKV. Informed consent to publish had been obtained.

Disclosure of Interest

None Declared

P163 NEONATAL-ONSET MULTISYSTEM INFLAMMATORY DISEASE (NOMID) DUE TO A NEW SEQUENCE VARIANT C.1568T>A OF NLRP3 GENE IN AN INFANT OF ASIAN ANCESTRY

Grace Chiang¹, Catherine T. Chung², Miriam Weinstein³, Ronald M. Laxer^1,4

¹Division of Rheumatology; ²Division of Pathology; ³Division of Dermatology, The Hospital for Sick Children; ⁴Department of Paediatrics and Medicine, University of Toronto, Toronto, Canada

Correspondence: Grace Chiang

Introduction: Neonatal onset multisystem inflammatory disease (NOMID) is a rare autoinflammatory disease with onset in infancy. Together with familial cold autoinflammatory syndrome (FCAS) and Muckle-Wells syndrome (MWS), they form the spectrum of cryopyrin-associated periodic syndrome (CAPS) with NOMID at the most severe end of the spectrum. CAPS is caused by single heterozygous germline or somatic gain of function mutations in the NLRP3 gene encoding the protein cryopyrin. To date, 209 different sequence variants of the NLRP3 gene and more than 90 heterozygous mutations are identified in patients with CAPS, and the list is expanding [1]. The case report here demonstrates a new sequence variant of NLRP3 gene in a patient with NOMID phenotype of Asian ancestry.

Objectives: To report the finding of a new sequence variant c.1568T>A of NLRP3 gene in an Asian infant with NOMID

Methods: Case report

Results: A 10-month old girl developed a generalized skin rash within hours of birth. The rash was described as “migratory” and “waxes and wanes” every day. A skin biopsy at 7 months of age showed periadnexal and perivascular neutrophilic infiltrates. At 8 months of age she developed a prolonged fever of 2 weeks. Physical examination showed frontal bossing, a mild delay of gross motion function and mild central hypontonia. A generalised macular rash was found and some of them were of urticarial morphology.  There was persistent elevation of inflammatory markers with highest C-reactive protein (CRP) of 180mg/L (0.1-1.0mg/L), erythrocyte sedimentation rate (ESR) 77mm/h (2-34mm/h), and serum amyloid A greater than 16,000 ng/ml (1000-5000ng/ml). MRI brain showed macrocephaly with prominent supratentorial ventricular and extra-axial cerebral spinal fluid (CSF) spaces with bilateral papilloedema. Lumbar puncture (LP) showed elevation of white cell count (WCC) 38x10^6/L and protein 0.41g/L (0.15-0.4g/L) in CSF. There was no skeletal deformity found on radiographic bone survey. Next generation sequence genetic testing revealed a rare sequence variant of the NLRP3 gene (c.1568 T>A). Genetic testing of the parents were negative for this variant. Thus, it appears to have arisen de novo and is likely pathogenic. Anakinra (4mg/kg/day) was started and the fever and rash resolved within a day.  A repeated LP after one year of treatment showed normalization of WCC and protein in CSF. The follow up MRI brain also showed interval improvement of supratentorial extra-axial CSF spaces and resolution of bilateral papilledema. Her development is appropriate to age.

Conclusion: NOMID is a severe disease with onset within hours of life. Different systems can be affected and permanent organ damage can occur if treatment is delayed. However, not every feature presents in early infancy and they may appear later in the disease course. The skin biopsy finding of neutrophil infiltrates in our case provides a crucial clue of an autoinflammatory condition. CNS involvement is a unique feature of NOMID in the CAPS spectrum. Treatment with IL-1 blocking agents results in significant clinical and laboratory improvements in NOMID and has become the standard of care [2,3]. The IL-1 receptor antagonist anakinra can penetrate into the CNS and treatment improves CNS inflammation. The list of sequence variants of NOMID or other diseases in the CAPS spectrum is expanding, with emerging new variants among Asian populations. This case report documents a pathogenic sequence variant recently discovered in a newly diagnosed NOMID patient of Asian background. Written onsent for publication was obtained from the parent.

Disclosure of Interest

None Declared

P164 EFFECTIVENESS AND SAFETY OF TREATMENT WITH INTRAVENOUS PAMIDRONATE IN PEDIATRIC PATIENTS WITH BONE DISEASES

Mireia L. Corbeto, Consuelo Modesto, Estefanía Moreno

Pediatric Rheumatology, Hospital Vall d'Hebron, Barcelona, Spain

Correspondence: Mireia L. Corbeto

Introduction: The use of bisphosphonates has increased in recent decades in patients of pediatric with osteoporosis (OP) and bone pain. The effectiveness and safety data of Pamidronate (PA) in OP secondary schools are limited.

Objectives: To describe the effectiveness and safety of PA in pediatric patients with bone diseases.

Methods: A retrospective study of patients below 18 years of age who had received PA in a third level hospital between 2012 and 2017 was performed. The demographic, analytical variables and densitometry data have been collected by DXA (L1-L4) prior to PA infusion and 2 years after its onset, the existence of pathological fractures and the adverse events of the treatment. Descriptive and analytical statistics have been used through the IMB SPSS Statistics20 program.

Results: Twenty-eight patients (46.4% males) with an average age of 12.6 years received an average total dose of 32 mg (0.8 mg/kg/infusion) of PA. The indication was in 53.6% of the cases OP secondary to corticosteroids, in 39.3% due to bone pain and in 7.1% OP secondary to immobility. In 39.3% of the patients a previous fracture was detected, decreasing to a 32% at 2 years after the treatment has begun. 78.6% of the patients reported an improvement on the pain. Only 2 mild adverse events were reported. A statistically significant increase in BMD was observed in gr/cm² after two years of treatment (0.631 to 0.729, p = 0.001).

Conclusion: Treatment with PA increases bone mass 2 years after its onset and provides an improvement on bone pain. Adverse effects were very infrequent.

Disclosure of Interest

None Declared

P165 INTERFERON SIGNATURE IN CHRONIC NON-BACTERIAL OSTEOMYELITIS: PRELIMINARY DATA FROM PROSEPCTIVE SERIES

Luisa Cortellazzo Wiel¹, Anna M. C. Galimberti¹, Francesco Baldo¹, Giulia Gortani², Serena Pastore², Alessandra Tesser³, Andrea Taddio^1,2, Alberto Tommasini³

¹Paediatrics, University of Trieste; ²Paediatrics; ³Clinical Immunology, IRCCS Burlo Garofolo, Trieste, Trieste, Italy

Correspondence: Luisa Cortellazzo Wiel

Introduction: Chronic non-bacterial osteomyelitis (CNO) is an inflammatory disorder of uncertain pathogenesis. On one hand, the occurrence of inflammatory osteomyelitis with similar characteristics in Majeed syndrome and DIRA syndrome supports the classification of CNO among autoinflammatory diseases. On the other hand, the existence of subgroups of CNO with associated autoimmune disorders, such as arthritis and psoriasis, suggest that more complex pathogenic mechanisms may be implied in the disease.

Objectives: Since autoinflammatory and autoimmune manifestations are common in interferonopathies, we hypothesized that interferon mediated inflammation could be involved as well in CNO.

Methods: To determine the role of interferon in the pathogenesis of the disease we started to quantify the interferon signature (IS) in our CNO patients.

All patients with CNO currently followed at our clinics were enrolled in the study. Blood specimens were withdrawn after obtaining a signed informed consent and collected in RNA preserving tubes. Interferon signature was assessed by analyzing the six genes (IFI27, IFI44L, IFIT1, ISG15, RSAD2, SIGLEC1) and the interferon score was calculated as described by Crow et al (J Clin Immunol, 2017). We considered as positive values above 10 (as almost all SLE display IS>10), and negative score below 5 (as almost all JIA in our experience have IS<5). Values between 5 and 10 were considered border-line.

Results: Five patients were enrolled (3 females, 2 males, mean age 16.6 years, range 13.6-20.6). Positive/border-line interferon score was recorded in four out of five patients (Table 1). There was no apparent correlation with disease activity and ESR.

Conclusion: Apart from a single patient with concomitant hematologic cytopenia, we detected only mild or border-line elevation of IS scores. It is uncertain whether these low scores can reflect or not an involvement of type 1 interferon in the inflammatory pathogenesis of CNO. However, it is worth noting that these results could be influenced by low disease activity in most of the investigated patients.

Further investigations are needed to evaluate the real role of interferon 1 in the pathogenesis of CNO and the potential utility of this assay in stratification of patients for therapeutic choices.

Trial registration identifying number: This work was funded by IRCCS Burlo Garofolo grant RC24/17 and Telethon foundation grant GGP15241

Disclosure of Interest

None Declared

Table 1 (abstract P165). See text for description.

P166 AUTOINFLAMMATORY DISEASES: IDENTIFIED TWO VARIANTS OF THE NLRC4 GENE

Emanuela Del Giudice¹, Annalisa Di Coste¹, Martina Capponi¹, Eleonora Romeo¹, Ilaria Battagliere¹, Chiara Passarelli², Fabrizio De Benedetti³, Marzia Duse¹

¹Department of Pediatrics, Sapienza University of Rome; ²Laboratory of Medical Genetics, IRCCS Ospedale Pediatrico Bambino Gesù; ³Division of Rheumatology, IRCCS Ospedale Pediatrico Bambino Gesù Rome, Rome, Italy

Correspondence: Emanuela Del Giudice

Introduction: Autoinflammatory diseases (AIDs) are a group of heterogeneous disorders characterized by recurrent fever and systemic inflammation (aseptic and non-autoimmune) , and the NLRC4- associated autoinflammatory diseases have been only recently described.

Objectives: To describe two pediatric cases with two variants of NLRC4 gene with a different spectrum of clinical manifestations

Methods: We describe two pediatric patients presented with recurrent fever and nonspecific symptoms.

Patient 1 F., caucasian, 8 years old boy presented with recurrent fever (maximum of 39°C), lasting 3-10 days with intervals of 3 days in apyrexia, not always responsive to oral corticosteroids, associated with rhinitis, cough, not-itchy rash on trunk and face, sometimes periorbital edema and conjunctivitis. In the last two years he developed arthralgia involving the small joints of the hands and bilateral knee pain, in some cases associated with joint swelling. He reported headache, vomiting and recurrent abdominal pain, often diarrhea without blood or mucus. Laboratory tests revealed a persistent increase of inflammatory markers and serum amyloid A (SAA) . The abdominal ultrasound showed a thickening of ileum wall tract of about 30 mm with an intestinal distension and fluid-corpusculated material upstream, without hepatosplenomegaly and the fecal calprotectin was negative. Screening for infectious diseases and malignancies was negative.

Patient 2 A., caucasian, 17 years old girl. At 11 years she was hospitalized due to persistent fever associated with pharyngodynia, rash located on the upper eyelids, edema of the face and disabling joint pain and she was diagnosed a macrophage activation syndrome (MAS). At the age of 15 years she had the second episode of MAS, likely to be triggered by an EBV infection. At 16, the appearance of polyarthritis evolved in MAS in the absence of febrile episodes / previous infectious and a diagnosis of juvenile idiopathic arthritis in a patient with recurrent MAS was made.

Results: In the patient 1 the genetic molecular analysis revealed the presence of a heterozygosis mutation of the genomic variant c.2785G> T of NLRC4 gene. This child is currently on therapy with colchicine with clinical and laboratory remission. Otherwise the patient 2 is currently on therapy with methotrexate and anti-TNF Etanercept with good clinical response. The extended analysis for autoinflammatory syndromes has detected the presence of the genomic variant c.2357G> T in heterozygosis of the NLRC4 gene. The related family genetic studies are going in both cases.

Conclusion: Mutations in heterozygosis of the NLRC4 gene, although defined as not-causative, appear to be associated with various clinical pictures in the context of auto-inflammatory syndromes, as well as a high susceptibility to developing MAS. In first our cases it could be associated to the autoinflammatory syndrome with enterocolitis (SCAN4), also called as autoinflammation with infantile enterocolitis (AIFEC), while in the second one, according to the reported literature, corresponds to a variant with uncertain meaning. In these cases, genetics can help us in the management of infective episodes, which must be treated promptly and appropriately to prevent the occurrence of complications and focus attention at follow up on onset of gastrointestinal symptoms. Informed consent to publish had been obtained.

Disclosure of Interest

None Declared

P167 EVALUATION OF PLASMA MICRORNA EXPRESSIONS IN PATIENTS WITH FAMILIAL MEDITERRANEAN FEVER

Ferhat Demir¹, Alper H. Çebi², Mukaddes Kalyoncu¹

¹Department of Pediatric Rheumatology; ²Department of Medical Genetics, Karadeniz Technical University Faculty of Medicine, Trabzon, Turkey

Correspondence: Ferhat Demir

Introduction: Familial Mediterranean fever (FMF) is one of the most common cause of autosomal recessive inherited autoinflammatory disease in childhood. The MEFV mutations cause the impaired function of a protein called pyrine by incorrect coding and that process results with uncontrolled inflammation. Microribonucleic acids (miRNAs) are small (16–24 nucleotides), non-coding RNA molecules that have roles on the regulation of gene expression at the post-transcriptional stage. The plasma expressions of miRNAs are altered in various autoimmune and autoinflammatory diseases. Therefore, miRNAs may have a role in the pathogenesis of autoinflammation and may be used in diagnosis and follow-up of these diseases.

Objectives: We aimed to evaluate plasma expression of some candidate miRNAs that associated with pathogenesis of autoimmunity and autoinflammation in patients with FMF.

Methods: Thirty patients diagnosed with FMF and age-sex matched 30 healthy children were enrolled for the study. Plasma levels of four candidate miRNA (miRNA-16, miRNA-155, miRNA-204 and miRNA-451), which is known to be related to autoimmunity and inflammation, were examined in all subjects. Plasma levels of miRNAs were measured with Real Time PCR in attack and remission period of patients and healthy controls. Groups were compared with each other.

Results: Plasma miRNA-204 levels were decreased 6.5-fold in remission period of FMF patients, compared to the healthy controls (p <0.001). This decrease was more prominent in M694V mutation carriers. It was also found that plasma miRNA-155 levels were lower in remission period of FMF patients (p <0.03).

Conclusion: Our data suggest that, miRNA-155 and miRNA-204 may play a role in the pathogenesis of FMF. Further investigations about the role of miRNAs in FMF may help to elucidate the pathogenesis of the disease.

Disclosure of Interest

None Declared

Table 1 (abstract P167). The mean plasma miRNA 2-^ΔCT level of patients in aFMF, rFMF and HC groups and comparison of it

P168 NEW CLASSIFICATION CRITERIA FOR RECURRENT AUTOINFLAMMATORY DISEASES APPLIED TO AN INDEPENDENT COHORT: EXPERIENCE FROM THE JIR COHORT DATABASE.

Glory Dingulu¹, Isabelle Kone-Paut², Sophie Georgin-Lavialle³, Pascal Pillet⁴, Anne Pagnier⁵, Etienne Merlin⁶, Daniela Kaiser⁷, Alexandre Belot⁸, Michael Hofer⁹, Veronique Hentgen¹⁰

¹Pediatrics, CENTRE HOSPITALIER VERSAILLES, Le Chesnay; ²Pediatric Rheumatology, CHU Bicêtre, Kremlin-Bicêtre; ³Internal Medicine, CHU Tenon, Paris; ⁴Pediatrics, CHU Bordeaux, Bordeaux; ⁵Pediatrics, CHU Grenoble, Grenoble; ⁶Pediatrics, CHU Clermont Ferrand, Clermont Ferrand, France; ⁷Pediatrics, CHU Luzern, Luzern, Switzerland; ⁸Pediatric Rheumatology, CHU Lyon, Lyon; ⁹Pediatric Rheumatology, CHU Vaudois, Lausanne; ¹⁰Pediatrics, Centre Hospitalier de Versailles, Le Chesnay, France

Correspondence: Glory Dingulu

Introduction: New classification criteria for the inherited periodic fever syndromes (TRAPS, FMF, MKD and CAPS) have recently been developed during a Consensus Conference held in Genoa in March 2017.

Objectives: The aim of our study was to compare these new classification criteria for monogenic recurrent fever syndromes with the diagnoses of clinicians in a real-life setting. For this purpose we used the JIRcohort database, an international platform gathering data of patients with pediatric inflammatory disease.

Methods: All the patients included to the JIRcohorte database with a recurrent fever syndrome were enrolled to the study. Criteria were applied to all the patients and then compared to the clinical diagnosis of the treating physician. An analytical study, describing concordance between clinician diagnosis and Genoa criteria classification was performed.

Results: Cryopyrin Associated Periodic Syndrom: 14 patients of the JIRcohorte matched Genoa criteria for CAPS. 8 had also been diagnosed CAPS by clinicians. The remaining 6 patients fulfilling the classification criteria for CAPS had various diagnoses made by the clinicians: SURF in 2 cases, PFAPA in 3 cases, FMF in 1 case. Clinicians considered CAPS in 19 further patients but none of them fulfilled the Genoa classification criteria for CAPS. None of these patients displayed a confirmatory genotype for CAPS.

Familial Mediterranean Fever: 153 patients matched Genoa criteria for FMF of whom 77 patients had also been diagnosed as FMF by the treating physician. The remaining 76 patients had various clinical diagnoses made by the treating physician: 14 SURF patients, 12 PFAPA patients, 12 TRAPS patients, 2 MKD patients and 2 CAPS patients. Interestingly 3 out of these 76 patients displayed genetic variants in another gene than MEFV while the others matched clinical Genoa criteria for FMF. The new classification criteria for FMF needs to be restricted to patients with genetic variants in MEFV. Clinicians diagnosed FMF in 23 further patients not classified as FMF according to the Genoa criteria for FMF: 6 with a heterozygous pathogenic MEFV mutation, 1 with a heterozygous VOUS, 3 with homozygous undetermined mutations, 12 without any genetic mutation.

Tumour Necrosis Factor Receptor Associated Periodic Syndrom: 18 patients matched Genoa criteria for TRAPS of whom all had been diagnosed TRAPS by the treating physician. All these patients had pathogenic or likely pathogenic mutations. Clinicians diagnosed TRAPS in 4 further patients, but none of them had a confirmatory genotype.

Mevalonate Kinase Deficiency: 217 patients matched Genoa criteria for MKD, of whom only 5 were diagnosed as having MKD by their treating physician. The remaining 212 patients fulfilling the Genoa criteria for MKD had various diagnoses: 119 PFAPA, 3 CAPS, 31 SURF, 5 TRAPS and 41 FMF with half matching Genoa criteria for FMF. 5 patients had been diagnosed MKD without matching Genoa criteria for MKD: 2 did not have genetical screening, 3 had heterozygous mutation with incomplete data.

Conclusion: This study is the first evaluation of the Genoa criteria in a real-life setting. The classification concordance with physician diagnosis is high for patients with confirmatory genotype and helps classifying patients with non confirmatory genotype. The classification concordance with physician diagnosis is low when patients did not display at least one gene mutation.

Disclosure of Interest

None Declared

P169 AUTO INFLAMMATORY DISEASE WITH LIPOID PNEUMONIA, A NEW ENTITY? REPORT OF TWO CASES

Anita Duncan¹, Camille Ohlmann², Philippe Reix², Sophie Collardeau-frachon³, Brigitte Bader-meunier⁴, Alexandre Belot¹

¹Rheumatology and Nephrology unit; ²Pneumology unit, Hopital Femme Mère Enfant; ³Histopathology unit, East Hospital Group, Lyon; ⁴Immunology-Hematology and Rheumatology unit, Hôpital Necker Enfants Malades, Paris, France

Correspondence: Anita Duncan

Introduction: Lipoid pneumonia (LP) is a rare entity with two clinical forms. Endogenous LP, putting aside cases associated with an obstructive cause, has been reported to be associated with metabolic, infectious or systemic inflammatory diseases. Diagnosis may be challenging as clinical presentation is insidious and non-specific. Radiological findings are well described with an unusually low density on chest CT scan suggesting the presence of fat. Histopathology, when available, describes lipid laden alveolar macrophages.

Objectives: Lipoid pneumonia is scarcely described in pediatric rheumatology and treatment strategy remains unclear.

Methods: We report the cases of two patients sharing a similar presentation of auto-inflammatory disease of early onset with the association of arthritis, urticarial eruption and hyper eosinophilia. For both, progression was marked by lung involvement (lipoid pneumonia) with major clubbing in the absence of hypoxia.

Results: The auto inflammatory presentation resembles systemic Juvenile Idiopathic Arthritis (JIA) with a form particularly resistant to biotherapies and hypersensitivity reactions to drugs. Biologically, we did not detect any marker of auto immunity and genetic analysis with whole exome sequencing did not enable us to identify mutations in the genes associated with auto inflammatory diseases nor new variants in a common gene to the two patients. However, it is interesting to point out that under high doses of anti interleukine 1(IL1) therapy (10mg/kg), these patients maintain positive circulating levels of IL1 suggesting a central role of the inflammasome in the presentation of these patients. The early onset of clubbing associated with lipoid pneumonia and in the absence of hypoxia seems characteristic and syndromic of this entity.

Conclusion: The combination of systemic autoinflammation with lipoid pneumonia (AILP) illustrates a new clinical entity with IL1 hypersecretion.

Disclosure of Interest

None Declared

P170 LESSON FROM THE EUROFEVER REGISTRY AFTER 10 YEARS OF ENROLLMENT

Martina Finetti, Silvia Federici, Joost Frenkel, Seza Ozen, Helen Lachmann, Luca Cantarini, Pavla Dolezalova, Fabrizio De Benedetti, Annette Jansson, Isabelle Koné-Paut, Paul Brogan, Gayane Amaryan, Jordi Anton Lopez, Joost Swart, Michael Hofer, Troels Herlin, Efimia Papadopoulou-Alataki, Romina Gallizzi, Marco Cattalini, Consuelo Modesto, Yonatan Butbul Aviel, Yosef Uziel, Alberto Martini, Nicola Ruperto, Marco Gattorno

Clinica Pediatrica e Reumatologia, Istituto Giannina Gaslini on behalf of Centers affiliated to Eurofever project and for the Paediatric Rheumatology International Trials Organisation (PRINTO), GENOA, Italy

Correspondence: Martina Finetti

Introduction: In 2008 the Paediatric Rheumatology European Society (PReS) promoted an International Project for the study of Autoinflammatory Diseases (AIDs) named Eurofever, whose main purpose is to create a web-based registry for the collection of information in AIDs patients.

Objectives: To implement the Registry with the new recently described AIDs and to increase the collection of longitudinal data.

Methods: The data analyzed in the study were extracted from the Eurofever registry, which is hosted in the PRINTO website (http://www. printo.it). From February 2015 we started the longitudinal collection of follow-up data with particular focus on treatment, modification of the clinical picture, onset of complication/adverse events.

Results: Up to date 4046 patients have been enrolled in the Registry from 62 different countries (3773 of them with complete baseline demographic information, represented in Table 1). Most of patients (2618; 69%) reside in western Europe, 489 (13%) in central-eastern Europe, 452 (12%) in southern-eastern Mediterranean countries (Turkey, Israel, North Africa), 127 in Asia, 76 in South America and 11 in Australia. Compared to the first Eurofever report (Toplak et al, 2012) we have observed an increase of enrollment in central-eastern Europe (from 6 to 13% of the total). 3444 (91%) patients have a pediatric onset of disease (< 16 years); 400 (12%) of them received diagnosis in adult age. 329 (9%) patients had an adult onset (81 FMF patients, 52 TRAPS patients, 40 CNO patients, 12 Schnitzler syndrome). The median onset age is 4 years (range 1 month – 75 years), the median diagnosis age is 8 years (range 1 month - 78 years). The median diagnosis delay is 2 years (range 0-76 years); the diseases with the longer diagnostic delay were NLRP-12 mediated FCAS2 (mean 25 years, range 5-71), CAPS (mean 14 years, range 0-65), PAPA (mean 13 years, range 0-50) and TRAPS (mean 12 years, range 0-76). In 3292 pts (81%) complete clinical information from disease onset to diagnosis are also available. At the moment of enrollment 3062 patients were in the pediatric age, 230 were adults. Longitudinal data on treatment are available for 448 pts (11%).

Conclusion: The enrolment in Eurofever Registry is still ongoing. The analysis of data will improve our knowledge both on the natural history of the single disease and on the efficacy/safety of treatment commonly used in the clinical practice.

Disclosure of Interest

M. Finetti: None Declared, S. Federici: None Declared, J. Frenkel: None Declared, S. Ozen: None Declared, H. Lachmann: None Declared, L. Cantarini: None Declared, P. Dolezalova: None Declared, F. De Benedetti: None Declared, A. Jansson: None Declared, I. Koné-Paut: None Declared, P. Brogan: None Declared, G. Amaryan: None Declared, J. Anton Lopez: None Declared, J. Swart: None Declared, M. Hofer: None Declared, T. Herlin: None Declared, E. Papadopoulou-Alataki: None Declared, R. Gallizzi: None Declared, M. Cattalini: None Declared, C. Modesto: None Declared, Y. Butbul Aviel: None Declared, Y. Uziel: None Declared, A. Martini: None Declared, N. Ruperto Grant / Research Support from: The G. Gaslini Hospital, which is the public Hospital where NR works as full time public employee, has received contributions from the following industries for the coordination activity of the PRINTO network: BMS, GlaxoSmithKline (GSK), Hoffman-La Roche, Novartis, Pfizer, Sanofi Aventis, Schwarz Biosciences, Abbott, Francesco Angelini S.P.A., Sobi, Merck Serono. This money has been reinvested for the research activities of the hospital in fully independent manners without any commitment with third parties., Speaker Bureau of: NR has received speaker’s bureaus and consulting fees from the following pharmaceutical companies: AbbVie, Amgen, Biogenidec, Alter, AstraZeneca, Baxalta Biosimilars, Biogenidec, Boehringer, BMS, Celgene, CrescendoBio, EMD Serono, Hoffman-La Roche, Italfarmaco, Janssen, MedImmune, Medac, Novartis, Novo Nordisk, Pfizer, Sanofi Aventis, Servier, Takeda, UCB Biosciences GmbH., M. Gattorno Grant / Research Support from: MG has received unrestricted grants from Sobi and Novartis., Speaker Bureau of: MG has received speaker bureaus from Sobi and Novartis.

Table 1 (abstract P170). Demographic features of enrolled patients

P171 MUTATIONS IN TRNT1 GENE ASSOCIATED WITH ENHANCED TYPE I IFN SIGNALLING

Marie-Louise Frémond^1,2, Isabelle Melki^1,2,3, Sven Kracker⁴, Vincent Bondet⁵, Darragh Duffy⁵, Gillian I. Rice⁶, Yanick J. Crow^1,7, Brigitte Bader-Meunier^2,8

¹Laboratory of Neurogenetics and Neuroinflammation, INSERM UMR 1163; ²Paediatric Haematology-Immunology and Rheumatology, Necker AP-HP; ³General Paediatrics, Robert Debré AP-HP; ⁴Laboratory of Human Lymphohematopoiesis, INSERM UMR 1163; ⁵Immunobiology of Dendritic Cells, Institut Pasteur, Paris, France; ⁶Division of Evolution and Genomic Sciences, Manchester Academic Health Science Centre, Manchester; ⁷Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, , Edinburgh, UK; ⁸Laboratory of Immunogenetics of Paediatric Autoimmunity, INSERM UMR 1163, Paris, France

Correspondence: Marie-Louise Frémond

Introduction: Efficacy of TNF inhibitors in sideroblastic anaemia with immunodeficiency, fevers, and developmental delay (SIFD) has been recently reported¹. The authors also demonstrated high levels of IL-6, IL-12p40, IL-18, and interferon (IFN)-γ in two patients.

Objectives: To describe activation of the type I IFN pathway in two patients with SIFD.

Methods: We assessed type I IFN status by IFN-α digital-ELISA quantification in serum, STAT1 phosphorylation and RNA expression of IFN-stimulated genes (ISGs) in whole blood.

Results: Patient 1 (P1) was a 12-month-old girl referred because of recurrent attacks of fever with high levels of CRP from the age of two months, with or without documented infections, chronic microcytic anaemia and failure to thrive. Aseptic febrile manifestations included vulvitis, parotiditis, adenitis, and neutrophilic panniculitis. She developed progressive lymphopenia, with undetectable levels of B cells by age 15 months, so that IVIG was initiated at this time. At last follow-up, aged six years, her height and development were normal and she was no longer subject to recurrent infections. However, she continued to experience three to four febrile attacks each month, associated with elevated CRP levels. Whole exome sequencing identified compound heterozygous mutations in the TRNT1 gene (c.1213G>A, p.G405R / c.1057-7C>G). Patient 2 (P2), a girl born at term to first-cousin parents presented with intrauterine growth retardation (IUGR) and severe neonatal anaemia necessitating blood transfusion on the first day of life. During infancy she required regular blood transfusions because of sideroblastic anaemia, which resolved spontaneously at the age of four years. She also demonstrated developmental delay and severe auto-inflammatory flares associated with fever and high levels of CRP, diarrhoea and dehydration. Mild T and NK lymphopenia together with a profound B cell defect were evident at four years of age. Sanger sequencing of TRNT1 identified a homozygous mutation in exon 7 (c.977T>C, p.I326T). Using an ultra-sensitive digital ELISA combined with a high specificity pan-IFN-α antibody pair, we observed an increased concentration of IFN-α protein in the serum from P1 (246.44 fg/mL, healthy controls <10 fg/mL) and P2 (108.18 and 38.05 fg/mL, healthy controls < 10 fg/mL), comparable to the levels measured in the context of certain monogenic type I interferonopathies. We also recorded an increased expression of ISGs in the whole blood of P1 and P2 on 3 occasions. In an ex vivo flow cytometry assay, STAT1 and STAT3 were constitutively phosphorylated in T lymphocytes and monocytes from P2. Both patients also displayed a negative IFN score on one occasion, suggesting a fluctuating biological process.

Conclusion: These data indicate a constitutive activation of the type I IFN pathway in patients with biallelic mutations in TRNT1, and thus suggest a possible role for type I IFN in the pathogenesis of SIFD. An increase in serum IFN-α protein and an enhanced expression of ISGs have been previously reported in one patient². How aberrant tRNA processing secondary to TRNT1 dysfunction might mediate enhanced type I IFN production and signalling remains to be determined. Informed consent to publish had been obtained from the parents of the two patients.

References

1. Giannelou A et al. Ann Rheum Dis 2018;77(4):612-619

2. Frans G et al. J Allergy Clin Immunol 2017 ;139(1):360-363

Disclosure of Interest

None Declared

P172 NEW MUTATION OF TREX1 - A STEP TOWARD THE DEFINITIVE UNDERSTANDING OF AICARDI-GOUTIÈRES SYNDROME

Marijan Frkovic¹, Sanda Huljev Frkovic¹, Daniel Franjic², Marija Jelusic¹

¹Department of Pediatrics, University Hospital Centre Zagreb, Zagreb, Croatia; ²Department of Neurobiology, Kavli Institute for Neuroscience, New Haven, USA

Correspondence: Marijan Frkovic

Introduction: So far several mutations of three prime repair exonuclease 1 (TREX1) were identified as cause of Aicardi-Goutières syndrome (AGS). This rare autoimflammatory disease has been recently in focus of research due to its pathogenetic and phenotypic similarities with systemic lupus erythematosus (SLE).

Objectives: Autors present case of a child with AGS caused by newly discovered mutation of TREX1 gene.

Methods: Retrospective analysis of AGS patient medical data including results of whole exome sequencing.

Results: A seven days old female newborn was referred to our department of Pediatrics due to diffuse petechiae, hypotonia with intermittent tremor and high-pitched crying. The child was born from the third, normal pregnancy, at term, BW 3520 g, BL 50 cm, Apgar scores 10/10. Family history is unremarkable.

Diagnostic evaluation revealed mild trombocytopenia combined with cerebrospinal fluid lymphocytosis. Results of serological tests and PCR for intrauterine and perintal infections were negative. MR brain scans showed simplified gray matter gyration, cerebelar hypoplasia and multiple periventricular and basal ganglia calcifications.

Due to suspicion of AGS, whole exome sequencing was performed and two heterozygous mutations in TREX 1 gene have been identified. The mother and dauther are carryers of c.506G>A mutation previously linked to AGS. The father and dauther have novel, to our best knowledge, undescribed mutation c.197T>G.

Beside experimental attempts, there is no specific therapy for this condition so far. Two-year follow-up of our patient was marked by classical signs of AGS: severe developmental delay, occasional occurrence of chilblain like nail folds dyscolorations and mild progression of periventricular calcifications verified by repeated MR brain scans.

Conclusion: Our discovery of new TREX1 mutation represent a small step toward the definitive understanding of AGS. Reveling the mysteries of this rare interferonopathy will eventually improve our comprehension of SLE.

Written consent for participation in this presentation was obtained from both parents of the child.

Disclosure of Interest

None Declared

P173 RESPONSE TO TOFACITINIB IN A CASE WITH FAMILIAL CANDLE-LIKE DISEASE.

Anna M. C. Galimberti¹, Luisa Cortellazzo Wiel¹, Giulia Gortani², Serena Pastore², Flavio Faletra³, Alessandra Tesser⁴, Andrea Taddio^1,2, Alberto Tommasini⁴

¹Pediatrics, University of Trieste; ²Pediatrics; ³Human Genetics; ⁴Clinical Immunology, IRCCS Burlo Garofolo, Trieste, Italy

Correspondence: Anna M. C. Galimberti

Introduction: We report the case of an 18-year-old girl with clinical symptoms supportive of CANDLE syndrome. Her medical history included: lupus pernio, ulcerative lesions distributed to extremities and face, alopecia areata, periorbital edema, diffuse arthralgias, poliarticular arthritis and growth hormone deficiency. Another remarkable clinical feature was multiple painful pannicular nodules, which resulted in a severe diffuse lipodystrophy, particularly on the face, with subsequent need to undergo a course of lipofilling. She displayed a highly positive interferon signature, but her genetic evaluation, including whole exome sequencing, performed taking into account the family history of connective tissue disease, was inconclusive.

Objectives: Her disease had always showed a moderate response to corticosteroids, while several therapeutic attempts with immunosuppressant drugs (cyclosporine, azathioprine, ciclophosfamide, hydroxychloroquine), intravenous immunoglobulins and biological agents (anakinra, infliximab and abatacept), together with hyperbaric therapy did not lead to significant improvement of her symptoms.

Methods: Given the severity of the cutaneous involvement with its related emotional burden and acknowledging the role of interferon in the pathogenesis of the disease, a therapy with 10 mg BID tofacitinib (JAk1-JAK3 inhibitor) was started.

Results: She displayed a prompt improvement of her lipodystrophy and chilblains along with a slow but progressive hair re-growth. An almost complete healing of the panniculitic lesions was observed, along with the halving of her interferon signature score.

Conclusion: However, during therapy she developed raised levels of CK and LDL cholesterol. While the latter is an adverse event frequently reported in subjects treated with tofacitinib and easily manageable, increased CK are rarely observed and more difficult to be interpreted. For this reason, the dosage of the drug was reduced to 7,5mg BID. No other adverse event was noticed. Informed consent to publish had been obtained from the patient.

Trial registration identifying number: This work was funded by IRCCS Burlo Garofolo grant RC24/17 and Telethon Foundation grant GGP15241.

Disclosure of Interest

None Declared

P174 TYPE I INTERFERON AND CXCL9 GENE EXPRESSION SIGNATURES IN HEALTHY CONTROLS, MONOGENETIC INTERFERONOPATHIES AND VARIOUS PEDIATRIC RHEUMATIC DISEASES

Claas Hinze, Melanie Saers, Georg Varga, Toni Weinhage, Helmut Wittkowski, Dirk Foell

Pediatric Rheumatology and Immunology, University Hospital Münster, Münster, Germany

Correspondence: Claas Hinze

Introduction: Type I interferon (IFN) gene expression signatures have been found to be strongly up-regulated in patients with various monogenetic diseases, i.e. in type I interferonopathies. These extremely rare diseases share manifestations with autoimmune connective tissue diseases. Others have used so-called IFN scores to assess the degree of type I IFN expression in peripheral blood.

Objectives: To report patterns of IFN gene expression in patients with monogenetic interferonopathies, pediatric rheumatic diseases and healthy controls.

Methods: PAXgene blood samples were obtained from children with rheumatic diseases and healthy controls (children with non-inflammatory conditions). We measured the expression of several IFN-stimulated genes (ISGs), namely ISG15, RSAD2, IFIT1, IFI44L, IFI27, SIGLEC1 (preferentially activated by type I interferons) and CXCL9 (preferentially activated by IFN-gamma) compared to the housekeeping genes GAPDH and RPL by SYBR Green PCR. Expression values were normalized to the same batch of healthy control RNA. The median normalized expression value of ISG15, RSAD2, IFIT1, IFI44L, IFI27 and SIGLEC1 (the IFN score) was assessed. Descriptive statistics were performed to analyze the findings.

Results: Among 24 children with non-inflammatory disease in PAXgene-derived RNA, there was strong correlation among the individual probe sets within the IFN score (Pearson’s r ranging from 0.57-1,00) but no relevant correlation of those probe sets with CXCL9; the correlation was even stronger among patients with varying degrees of type IFN activation. The 5^th and 95^th centile for the IFN score among healthy children were 1 and 4.8 and for CXCL9 2.4 and 13.7, respectively. We could demonstrate a robust and persistent up-regulation of the IFN-score in patients with known monogenetic type I interferonopathies, including C1q deficiency, SAVI or Aicardi-Goutières syndrome. The highest IFN-score was demonstrated in a patient with new-onset anti-NXP2 antibody-positive juvenile dermatomyositis, and this was responsive to change, normalizing with therapy and clinical remission. In contrast, some patients with Still’s disease demonstrated a marked up-regulation of CXCL9 with normal IFN-score.

Conclusion: We have established normal values for a type I IFN gene and CXCL9 gene expression signature. Assessment of the expression of ISGs may be useful in clinical practice, e.g. in order to screen for potential monogenetic type I interferonopathies, autoimmune connective tissue diseases and to assess changes in disease activity upon treatment. The use of an extended gene expression panel to also include CXCL9 which is up-regulated by IFN-gamma may assist in the understanding of the disease process in individual patients.

Disclosure of Interest

None Declared

P175 DIVERSITY IN PRESENTATION AND EVOLUTION OF AUTOINFLAMMATORY DISEASES IN A FRENCH PEDIATRIC COHORT OF REFERRAL CENTER OF RHEUMATOLOGY.

Ambre Hittinger, Sorina Boiu, Brigitte Bader-Meunier, Wouters Carine, Pierre Quartier-Dit-Maire

IMAGINE Institute and Pediatric Immunology, Hematology, Rheumatology Unit, Necker-Enfants Malades Hospital, Assistance Publique Hôpitaux de Paris, Paris, France

Correspondence: Ambre Hittinger

Introduction: The autoinflammatory diseases (AID) include monogenic and polygenic disorders characterized by primary dysfunction of the innate immune system¹.

Objectives: Our objective was to analyze the clinical spectrum, genetic background, therapeutic strategy and outcome in a cohort of AID patients followed in a reference Pediatric Rheumatology center.

Methods: We performed a retrospective analysis of the medical records of monogenic AID patients followed in the French reference center for juvenile arthritis and rare pediatric systemic autoimmune diseases (RAISE) between May 2007 and February 2018. Patients had been included in the French data base system for rare diseases (CEMARA) with an agreement of the Commission Nationale Informatique et Liberte. According to the French legislation, no ethics committee approval was requested for such a retrospective survey.

Results: One hundred sixty-six patients were included: 21 Cryopyrin-Associated Periodic Syndromes (CAPS), 5 TNF-Receptor-Associated Periodic Fever Syndrome (TRAPS), 16 Mevalonate Kinase Deficiency (MKD), 38 Familial Mediterranean Fever (FMF), 20 Behçet’s Disease (BD), 61 Chronic Recurrent Multifocal Osteomyelitis (CRMO) and 5 Synovitis, Acne, Pustulosis, Hyperostosis, Osteitis Syndrome (SAPHO). Demographics features (Table 1), show a median follow-up of 8 years (0-26), a sex-ratio of 62/104 and a median age of 8 years at disease onset. Eighty-two patients (49%) have relevant familial history. Clinical manifestations included musculoskeletal (83%), fever (50%), gastrointestinal (47%), mucocutaneous (35%), neurological (21%), ocular (16%), cardiorespiratory (10%) and genitourinary (0,6%) findings, lymphadenopathy with/or hepatosplenomegaly (12%) and growth impairment (12%). Complications/sequelae appeared in 40% of cases. One mutant allele was found in 18/21 CAPS, 4/5 TRAPS and 11/38 FMF. Two mutant alleles were present in 14/16 MKD and 20/38 FMF. The most used treatment were NSAID (62%), biological DMARDs (37%), colchicine (35%) and corticosteroids (31%). Sixty-six patients received one or more biological DMARDs: Anakinra (56%), Canakinumab (50%), Etanercept (30%), Adalimumab (4.5%), Infliximab (4.5%) and Tocilizumab (3%). Anti-interleukin-1 therapy and colchicine proved efficacy in CAPS and FMF, respectively. In addition, favorable responses have been demonstrated anti-interleukin-1 therapy in MKD, TRAPS, and colchicine-resistant FMF patients, as well as Etanercept in TRAPS, MKD and CRMO patients non-responsive to NSAIDs. Fifty-seven% and 41% of patients were in complete and partial remission, respectively, at last visit.

Conclusion: AID in children are associated with a broad spectrum of manifestations. Early diagnosis and referral are essential, as efficient therapy can be proposed in most cases and early complications avoided.

Reference

1. Russo RAG, Brogan PA. Monogenic autoinflammatory diseases. Rheumatology (Oxford). 2014 Nov 1;53(11):1927–39.

Disclosure of Interest

None Declared

Table 1 (abstract 175). Demographical data and evolution of different disease groups

P176 Withdrawn

P177 CLINICAL CHARACTERISTICS AND PREDICTIVE FACTORS OF RECURRENT HISTIOCYTIC NECROTIZING LYMPHADENITIS

Hyun Joo Jung

Pediatrics, Ajou University Hospital, Suwon, Korea, Republic Of

Introduction: Although histiocytic necrotizing lymphadenitis (HNL) or Kikuchi-Fujimoto disease, which is characterized by self-limiting regional lymphadenopathy with prolonged fever, has a low recurrence rate, this rate appears to be higher and the disease progresses to severe forms associated with autoimmune diseases such as systemic lupus erythematosus (SLE) in some previous reports.

Objectives: We analyzed the clinical characteristics of patients with HNL focusing on cases with recurrence to define the predictive factors of recurrent HNL.

Methods: This was a retrospective study of patients diagnosed with Kikuchi-Fujimoto disease from April 1995 to May 2017 in South Korea. Electronic medical records were searched for clinical and laboratory manifestations. Patients with pathologically confirmed HNL through biopsy of an enlarged lymph node were enrolled and recurrence was defined as having additional episodes of febrile lymphadenopathy before or after the pathological diagnosis.

Results: A total of 151 pediatric patients under 18 years of age (31.5%) and 480 patients of all ages was analyzed. In the case of children under 18 years of age, the proportion of boys (43%; n = 65) and girls (57%; n = 86) was similar, but in adults, the ratio of women increased with 95 men (28.9%) and 234 women (71.1%). At the pathologic diagnosis, 455 (94.8%) had lymphadenopathy and were mainly involved in the cervical lymph nodes. Fever was present in 381 of the patients (79.4%). Cutaneous lesions (skin rash or maculopapular erythema) (5%) were the most common extranodal symptoms, and complained of myalgia, fatigue, cough, or rhinorrhea. Laboratory wise included leucopenia (22.5%; n = 108), neutropenia (9.8%; n = 47), and lymphopenia (33.3%; n = 160). Antinuclear antibodies (ANAs) were present in 14.4% of the patients (n = 69), of whom 32 (46.4%) were children under 18 years of age. Fifty-four patients (11.3 %) experienced recurrent HNL, and 1 patient recurred up to 4 times. In comparison between patients with recurrent HNL and non-recurrent HNL groups, more extranodal symptoms including cutaneous lesions, myalgia, or fatigue (p=0.013) and a prolonged duration of lymphopenia were significantly associated with recurrent HNL. The number of patients with lymphopenia was higher in the recurrent HNL groups.

Conclusion: Our results suggest that recurrent HNL is more frequent than reported, and recurrent HNL should be considered in patients with extranodal symptoms or prolonged lymphopenia.

Disclosure of Interest

None Declared

P178 EVALUATION OF CASES DIAGNOSED WITH CRMO; SINGLE CENTER EXPERIENCE

Sara Sebnem Kilic, Sukru Cekic, Yasin Karali

Pediatric Rheumatology, ULUDAG UNIVERSITY MEDICAL FACULTY, Bursa, Turkey

Correspondence: Sara Sebnem Kilic

Introduction: Chronic recurrent multifocal osteomyelitis (CRMO); is a rare autoinflammatory bone disease characterized by recurrent, sterile inflammatory lesions occurring primarily in children and adolescents. Symptoms of presentation may range from mild unspecific bone pain, local swelling and warmth to severe pain, malaise, fevers and even fractures.

Objectives: In this study, we aimed to evaluate our patients who had a diagnosis of CRMO , retrospectively.

Methods: Six patients who were diagnosed with CRMO between 2010-2017 years were included in the study. The CRMO diagnosis was based on characteristic clinical features and magnetic resonance imaging findings. The clinical data were obtained from the records of electronic files.

Results: The female to male ratio of the cases was 4/2 and the median age was 11.15 years (6-12). The age of diagnosis was 10.35 years (4-12.5), the median period for diagnosis delay was 3 years (0.75-8). The most common complaint was localized pain (n = 6, 100%). Accompanying diseases were detected in 3 patients; 1 case had inflammatory myositis, 1 case had PFAPA syndrome and 1 case had selective IgA deficiency. Multifocal bone involvement was present in 4 (66%) cases and unifocal bone involvement in 2

(33%) cases. The most common site of disease was femur. Acute phase reactants were high most of the cases; elevated erythrocyte sedimentation rate (ESR) in 5 cases (83.3, n=6), elevated c-reactive protein level in 4 cases (66.6%, n = 6), elevated serum amyloid a level in 3 cases (60%, n=5), and elevated fibrinogen in 2 cases (50%, n=4) were present. ANA was found positive at low titer in only 1 case, whereas rheumatoid factor was negative in all cases. Non-steroidal anti-inflammatory drugs were prescribed in all cases and anti TNF drugs in 3 (Etanercept in 2 cases and adalimumab in 1 case).

The diagnosis of CRMO is difficult and no consensus exist on diagnosis and treatment. Multifocal bone lesions with characteristic radiological findings are very suggestive of CNO. The first line treatment is usually NSAIDs, however, anti TNF treatment are needed in some patients to achieve for remission. Our case is the second one who had inflammatory myositis and CRMO according the literature.

Conclusion: The diagnosis of CRMO is difficult and no consensus exist on diagnosis and treatment. Multifocal bone lesions with characteristic radiological findings are very suggestive of CNO. The first line treatment is usually NSAIDs, however, anti TNF treatment are needed in some patients to achieve for remission. Our case is the second one who had inflammatory myositis and CRMO according the literature.

Disclosure of Interest

None Declared

P179 A CASE OF BEHÇET’S DISEASE IN A CHILD : A YOUNG GIRL WITH MULTIPLE ULCERATION AND STENOSIS OF THE HYPOPHARYNX AND LARYNGOPHARYNGEAL INVOLVEMENTS

Noriko Kinjo, Kazuya HAMADA, Koichi NAKANISHI

Pediatrics, University of the Ryukyus, Nishihara-cho, Japan

Correspondence: Noriko Kinjo

Introduction: Behςet’s disease (BD) is a chronic, relapsing, multisystem inflammatory disorder classified as vasculitis and characterized by recurrent oral and genital ulcerations, uveitis, and protean clinical signs of skin, central nervous system, musculoskeletal, and gastrointestinal involvements. Oral ulceration is more common in younger patients. However, there are few reports about chronic hypopharyngeal ulceration, are rare involvements in child in early phase. We report the case of a 4-year-old Japanese girl with refractory laryngeal edema who was successfully treated with multidrug therapy including infliximab (IFN).

Objectives: This report aimed to scrutinize of BD-related laryngeal and hypopharyngeal manifestations in a Japanese young girl. We show that rare clinical phenotype in early phase of pediatric-onset BD.

Methods: A young girl with multiple ulceration and stenosis of the hypopharynx and laryngopharyngeal involvement at onset.Clinical features, especially laryngeal findings by laryngoscopy in our patient were described in detail about the findings symptoms at onset and during the course. By using the paediatric Behςet’s disease (PEDBD) classification criteria, the case was diagnosed.

Results: In a 4-year-old Japanese girl with a 2-year history of recurrent fever, recurrent ulcerative gingivostomatitis, snoring or respiratory disorder during sleeping, was referred to our hospital with the suspicion of rheumatic diseases after tracheotomy was enforced due to the breathing disorder and dysphagia. Before tracheotomy, physical examination revealed that her voice was hoarse and dysphasia. Soft tissue lateral neck film revealed straightening of the cervical spine with edema of the epiglottis and upper airway. Laryngeal endoscopy findings showed that laryngeal and hypopharyngeal involvements were edematous severely. After tracheotomy, the patient received oxygen supplementation, methylprednisolone. Involvement in ulcerative colitis was estimated by using colon fiverscopy. By using the PEDBD classification criteria, the case was diagnosed.Her symptoms except for intestinal involvement did not change with these maneuvers. On admission, the patient showed body temperature of 37 °C, heart rate of 107/min, respiratory rate of 28/min, and blood pressure of 108/66 mmHg. Genital ulcers were absent, and repeat ophthalmologic examinations showed no symptoms. Laboratory examinations revealed the presence of nonspecific inflammation: white blood count, 11,100/μL; C-reactive protein (CRP) level, 2.0 mg/dL; electron spin resonance (ESR) level, 20 mm/h. Hypocomplementemia was absent. The results of immunological examinations were negative for specific autoantibodies, including antinuclear antibody, anti-dsDNA antibodies, and anti- neutrophil cytoplasmic antibodies. The test for HLA- B51 was positive. Bone marrow examination showed no evidence of malignancy. Then, colchicine and 1mg/kg/day of prednisolone (PSL) therapy was started. When the dose of PSL was decreased, her snoring and respiratory disorder relapsed. Therefore, infliximab (IFX) therapy was started and the dose of PSL was gradually decreased. For approximately 1 years, she showed a good general condition with laryngeal swelling improved.

Conclusion: There is a case of BD in a child, who has multiple ulceration and stenosis of the laryngeal and hypopharyngeal involvementsThe Upper airway manifestations could be critical to identify potentially life-threatening laryngeal involvement at onset by direct laryngoscopy. In our case might deal with the successful treatment of a laryngopharyngeal involvements with IFX as anti-TNF-alpha agents. Informed consent to publish had been obtained from the parent.

Disclosure of Interest

None Declared

P180 ADENOSINE DEAMINASE TYPE 2 (ADA2) ENZYME ACTIVITY IN PAEDIATRIC RHEUMATIC DISEASES

Kateřina Kobrová^1,2, Šárka Fingerhutová², Pavla Doležalová²

¹Department of Paediatrics, Masaryk Hospital, Ústí nad Labem; ²DEPARTMENT OF PAEDIATRICS AND ADOLESCENT MEDICINE, GENERAL UNIVERSITY HOSPITAL IN PRAGUE, Praque, Czech Republic

Correspondence: Kateřina Kobrová

Introduction: Adenosin deaminase type 2 (ADA2), encoded by CECR1 gene, is an important enzyme in purine metobolism and a growth factor for endothelial and myeloid cells. Loss-of-function mutation in CECR1 gene causes deficiency of ADA2 (DADA2) leading to an autoinflammatory disease with vasculitic features. While DADA2 patients have decreased ADA2 enzyme activity, its increase has been shown in other inflammatory diseases like systemic lupus erythematosus (SLE). Less is known about ADA2 in other conditions.

Objectives: To assess ADA2 activity in a spectrum of inflammatory diseases and in controls in order to optimize its use as a screening test for DADA2 in the Czech Republic.

Methods: Serum ADA2 enzyme activity was measured using Adenosin Deaminase Assay Kit (Diazyme Laboratories) with using specific ADA1 inhibitor in patients recruited from our clinics and from controls after appropriate consent. Enzyme activity was expressed in U/L and values were compared among disease groups and controls using Mann-Whitney test.

Results: Total of 109 individuals were examined: 88 children (mean age 10.2, SD 5.4yrs) and 21 healthy adult volunteers. Disease groups were as follows: children with stroke of unknown aetiology (Stroke), hyper-IgD syndrome (HIDS), systemic vasculitis (VAS), systemic lupus erythematosus (SLE), juvenile dermatomyositis (JDM), PFAPA syndrome (Periodic Fever, Aphtae, Pharyngitis, Adenitis), children with non-inflammatory conditions. ADA2 activity in Stroke, HIDS and JDM patients was comparable to controls while patients with vasculitis had lower and patients with SLE and PFAPA higher ADA2 activity than controls (p=0.012;0.001;0.025 respectively. (Table 1). The lowest absolute ADA2 activity was detected in a 18 years old patient with HIDS (3 U/L) while 17 years old SLE patient had the highest activity (23 U/L).

Conclusion: We have demonstrated wide range of ADA2 enzyme activity in a spectrum of rheumatic diseases in children. As age influences ADA2 activity inversely highest levels in the youngest PFAPA subgroup is not surprising. Mechanisms that lead to increased ADA2 in SLE noticed also by others are not fully understood. Nevertheless, in respect to DADA2 low enzyme activity is of importance, though its exact cut-off value has not yet been established. All our patients had ADA2 activity above levels reported in DADA2. It appears that ADA2 activity assessment is a feasible method that may serve as a useful screening test in patients with clinical picture suggestive of DADA2.

Disclosure of Interest

None Declared

Table 1 (abstract P180). See text for description.

P181 CHARACTERIZATION OF A GROUP OF 15 PATIENTS WITH MEVALONATE KINASE DEFICIENCY: SYMPTOMS AND TREATMENT WITH IL-1 INHIBITORS

Anna Kozlova¹, Vasiliy Burlakov¹, Tatiana Varlamova ¹, Elena Raikina¹, Olga Barabanova², Sergey Zimin², Anna Shcherbina¹

¹Immunology, Federal State Budgetary Institution "National Medical Research Center of Pediatric Hematology, Oncology and Immunology named after Dmitry Rogachev" of the Ministry of Healthcare of the Russian Federation; ²Immunology, Children's Clinical Hospital N9, Moscow, Russian Federation

Correspondence: Anna Kozlova

Introduction: Mevalonate kinase deficiency (MKD) is a rare autosomal recessive autoinflammatory disease caused by mutations in MVK gene.

Objectives: MKD patients typically have an early onset of symptoms including recurrent episodes of high fever, abdominal pain, diarrhea and vomiting, arthralgia and lymphadenopathy (AIDAI criteria for HIDS). However not all patients have typical symptoms at the time of onset. MKD treatment remains an unsolved problem, since none of the modalities previously used for MKD treatment are fully effective in the disease control.

Methods: We conducted a retrospective analysis of clinical features of fifteen patients (7 females, 8 males) with genetically confirmed MKD. Ten patients received therapy with inhibitors of IL-1 (Anakinra and\or Canakinumab). One of the  patients died from amyloidosis and macrophage activation syndrome (MAS) prior to treatment initiation, her diagnosis was verified post mortem.

Results: Thirteen patients had manifested within  the first 6 months of life, one – at the age of 1.5 years, one – at three years of age. During the course of the disease all patients had periodic fever and peripheral lymphadenopathy ( mainly cervical group), as well as abdominal pain, nausea\vomiting. Six patients had diarrhea, sometimes with blood, one patient suffered from  severe constipation. Rash was seen in eight patients, myalgia, artralgia were observed only in nine. Oral ulcers were noted in eight children. Three patients had neurological involvement, one patient had it as the main symptom. One patient had periorbital edema and hyperemia during attacks, which to our knowledge, have not been reported previously in MKD. Thrombocytopenia, neutropenia were only one. One patient developed amyloidosis and MAS before IL1 inhibitor treatment initiation, which led to her death. In patients receiving anti-IL-1 therapy AIDAI index decreased from 58.3±11,2 before to 1,5±1,4 after 6 month of therapy (p =0.003).

Conclusion: MKD symptoms can be variable and sometimes atypical, which requires physician’s awareness. In our cohort of MKD patients anti IL-1 therapy was highly effective.

Disclosure of Interest

None Declared

Treatment I

P182 COMPARATIVE EFFICACY OF ETANERCEPT AND ADALIMUMAB IN CHILDREN YOUNGER THAN 4 YEARS

Ekaterina Alexeeva^1,2, Tatyana Dvoryakovskaya^1,2, Rina Denisova¹, Tatyana Sleptsova¹, Kseniya Isaeva¹, Alexandra Chomahidze¹, Anna Fetisova¹, Anna Mamutova¹, Victor Gladkikh³, Alina Alshevskaya³, Andrey Moskalev³

¹Federal State Autonomous Institution “National Medical Research Center of Children's Health” of the Ministry of Health of the Russian Federation; ²Federal State Autonomous Educational Institution of Higher Education I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation, Moscow; ³Biostatistics and Clinical Trials Center, Novosibirsk, Russian Federation

Correspondence: Ekaterina Alexeeva

Introduction: In 2011, Etanercept (ETA) was approved for clinical application in patients with juvenile idiopathic arthritis (JIA) older than 2 years of age; adalimumab (ADA) was approved in 2013. However, the available data for these patients are not sufficient even in large-scale registers. Uveitis in older children is a factor taken into consideration when choosing anti-TNF therapy, so we believe that its onset at early age may affect efficacy of treatment with different anti-TNF drugs.

Objectives: This study aimed at evaluating comparative efficacy of ADA and ETA in children of young age depending on their uveitis status.

Methods: Comparative analysis involved patients who had initiated ETA (n=49) or ADA (n=25) therapy at the National Medical Research Center of Children's Health (Moscow) at an age of ≤4 years. None of ETA patients had previous history of uveitis. ADA patients were allocated into 2 subgroups depending on their uveitis status. Patients in group 1 had active uveitis (n=13), while group 2 patients had no active uveitis (n=12). Treatment efficacy was evaluated according to the dynamics of clinical and laboratory signs using the ACRPedi criteria. The Wallace criteria were used to evaluate whether or not remission had been achieved.

Results: Therapy with ETA and ADA in children under 4 years of age was found very efficacious as soon as after the first month. The CHAQ and JADAS disease activity scores, CRP and ESR laboratory values, morning stiffness duration, and the VAS score (assessed by both patient and physician) significantly decreased after 4-week therapy in all three groups (p<0.01). After 3 months of therapy, the number of affected joints (swollen or painful joints, joints with the limited range of motion and with active arthritis) reduced substantially in all three groups (p<0.01).

The percentage of ETA patients who achieved ACR50/70/90 by the end of follow-up period, with allowance for patients who discontinued treatment because of AEs or poor efficacy, was 85.7/83.7/77.6%, respectively. The percentage of ADA patients who achieved ACR50/70/90 by the end of follow-up period was 76.9/76.9/69.2% (ADA patients with uveitis) and 75/58.3/41.7 (ADA patients without uveitis). The groups were characterized by different dynamics of achieving ACR (Figs. 1-2). Treatment efficacy was comparable in ADA patients with uveitis and ETA patients without uveitis, while significantly fewer ADA patients without uveitis reached ACR70/90.

Comparable percentages of ETA patients and ADA patients with uveitis achieved remission (53.1% and 53.8%, respectively), while only 3 (25%) of ADA patients without uveitis achieved long-term clinical remission (p-values are insignificant)

Conclusion: In patients younger than 4 years of age, efficacy of ADA and ETA treatment differs in different patient groups according to baseline clinical parameters. ADA shows higher efficacy in achieving ACR70/90 and inactive stage of the disease according to the Wallace criteria in patients with uveitis as compared to patients with the negative uveitis status. Children without uveitis show better response to ETA, although there is a 6-10% risk of de novo uveitis. Therefore, ADA is the drug of choice for children with uveitis under 4 years of age, while ETA is preferable in children without uveitis.

Disclosure of Interest

None Declared

P183 ETANERCEPT CONCENTRATION AND IMMUNOGENICITY DO NOT INFLUENCE THE RESPONSE TO ETANERCEPT IN PATIENTS WITH JUVENILE IDIOPATHIC ARTHRITIS

Brigitte Bader-Meunier¹, Roman Krysiek², Irene Lemelle³, Christine Pajot⁴, Aurelia Carbasse⁵, Isabelle Melki⁶, Pierre Quartier¹, Jean-Marc Treluyer¹, Alexandre Belot⁷, Salima Hacein-Bey-Abina², Saik Urien¹

¹Hôpital Necker, PAris; ²Hôpital Kremlin Bicêtre, Assistance Publique-Hôpitaux de Paris , Le Kremlin Bicêtre; ³CHRU Nancy, Vandoeuvre les Nancy; ⁴Hôpital Purpan, Toulouse; ⁵Hôpital A de Villeneuve, Montpellier; ⁶Hôpital R.Debré, Paris; ⁷Hospices Civils de Lyon, Bron, France

Correspondence: Brigitte Bader-Meunier

Introduction: Approximately 10–22% of biologic naive juvenile idiopathic arthritis (JIA) patients discontinue etanercept (ETN) within 12 months because of primary inefficacy or loss of response. In adult patients with rheumatoid arthritis (RA) and ankylosing spondylitis (AS), the results of studies that investigated the relationship between serum ETN levels and clinical response are conflicting. In children, no study has investigated the possible relationship between ETN circulating level or immunogenicity and disease activity in a population of JIA patients

Objectives: To investigate the relationship between etanercept (ETN) levels, the presence of anti-drug antibodies to ETN (ADAb) and clinical response to ETN in patients with Juvenile Idiopathic Arthritis (JIA).

Methods: Prospective study of JIA patients under 18. Clinical and pharmacological data were collected at two visits. Clinical remission and JIA activity on ETN were assessed according to the Wallace criteria and the Juvenile Arthritis Disease Activity Score (JADAS) respectively. ETN and ADAb serum levels assessments were determined using ELISA-based assays. The relationship between ETN concentration and the remission status or disease activity was assessed by an univariate logistic analysis and a multiple regression analyses adjusted on age, size descriptors, co-treatments and JIA classification.

Results: One hundred and twenty-six patients were enrolled. The median duration of ETN treatment at inclusion was 569 days (range 63-2,330). ADAb were undetectable (< 10 ng/ml) in 171/224 (76%) samples, and were > 25 ng/mL in 2. No significant relationship between ETN concentration and the remission status or disease activity was found using either univariate or multiple logistic regression analyses. No correlation was found between the remission status and the detection of ADAb.

Conclusion: This study did not demonstrate any correlation between circulating ETN levels and JIA activity in a large population of patients with JIA previously treated with ETN for at least 2 months. As described for adults, it confirms that ETN is marginally immunogenic in pediatric patients. These results do not support monitoring ETN concentrations or ADAb for the management of such JIA patients.

Trial registration identifying number: The study is registered at Clinical Trials.gov under number NCT02030613. All patients (or their parents) gave written informed consent

Disclosure of Interest

None Declared

P184 EFFICACY OF JOINT INJECTIONS WITH APPLICATION OF CORTICOSTEROID IN PATIENTS WITH JUVENILE IDIOPATHIC ARTHRITIS

Marek Bohm, Valentina Leone, Tania Amin, Mark Wood

Paediatric Rheumatology, Leeds General Infirmary, Leeds, UK

Correspondence: Marek Bohm

Introduction: Although nowadays intraarticular corticosteroid injections may be considered a somewhat obsolete method of treatment of juvenile idiopathic arthritis, they still might serve as an alternative to stronger but more expensive DMARDs/biologic drugs.

Objectives: To assess the outcome of joint injections (JI) with application of corticosteroid in children with juvenile idiopathic arthritis (JIA) and factors affecting the time to flare of arthritis.

Methods: Clinical documentation of patients with JIA under the care of the Paediatric Rheumatology Department in Leeds General Infirmary, UK, who received joint injections with triamcinolone hexacetonide (or in some cases methylprednisolone acetate if small joints were injected) between January 2015 and December 2016 was analysed. The time to flare of arthritis was recorded based on follow-up visits. We evaluated predictors such as gender, age of disease onset, oligo- or polyarticular course of disease, disease duration, general anaesthesia, concurrent medication, CRP and ESR at the time of JI application.

Results: 117 patients (41 boys and 76 girls in age 1-17 years) with JIA received in total 460 intraarticular injections (75 patients in general anaesthesia). 75 children had history of arthritis in 5 or more joints. Flare of arthritis was observed in 64.1% of children after a median of 115 days. The cumulative probability of survival without flare of synovitis was 63.2% after 6 months and 49.6% after 12 months. In our cohort of patients, the outcome of joint injections was not influenced by any of named predictors.

Conclusion: Even in the age of DMARDs and biologic drugs, joint injections with application of corticosteroid can be considered an effective therapy in the treatment of JIA.

Disclosure of Interest

None Declared

P185 BIOLOGICS IN PEDIATRIC RHEUMATOLOGY

Mustafa Çakan, Şerife Gül Karadağ, Nuray Aktay Ayaz

Pediatric Rheumatology, Kanuni Sultan Süleyman Research And Training Hospital, İstanbul, Turkey

Correspondence: Mustafa Çakan

Introduction: Biologics are medications that target specific molecules expressed on cells or secreted into the extracellular space. Use of biologics has increased in pediatric rheumatology since 2000s and patients with sequels have decreased sequentially.

Objectives: The aim of this study was to demonstrate indications of biologic usage in pediatric rheumatology.

Methods: Between May 2010 and September 2017, the files of all patients that biologics were used were reviewed. The patient had to be using a biologic agent for at least three months and had to be coming regularly to follow-up visits.

Results: In this study, 236 biologic agents were used in 172 patients. Mean duration of biologic use was 18.7 ± 14.0 months. In 69% of patients only one biologic was used while 31% of the patients needed 2 or more biologics. Six patients needed 3^rd biologic, one patient 4^th and one patient needed 5^th biologic agent.

Indications for biologic use were; JIA (123 cases), FMF (29 cases), CAPS (5 cases), HIDS (4 cases), Behçet disease (3 cases), CRMO (2 cases) and one case for each of the following diseases; Takayasu disease, SLE, DADA2, idiopathic recurrent pericarditis, idiopathic uveitis and pyoderma gangrenosum.

Juvenile idiopathic arthritis was the most common indication for biologics. Biologics were needed in 30.3% of all JIA cases (123/405). The most common subtypes that biologics were used in JIA were extended oligoarticular JIA (64.7%) and rheumatoid factor positive polyarticular JIA (57.1%). With biologic treatment, remission was achieved in 79% of cases while 21% of cases were active despite use of biological treatment. In 14 JIA cases biologics were used for refractory uveitis.

Familial Mediterranean fever was the second most common indication for biologic use with 29 cases. Total number of FMF patients that were followed during the same period was 1097, so the frequency of colchicine-resistant FMF was 2.6%. M694V homozygous mutation was present in 76% of colchicine-resistant FMF patients. With biologics complete remission was achieved in all FMF patients.

In 236 biologic agents, etanercept (34%) was the most commonly used agent followed by anakinra (19%), adalimumab (17%), and canakinumab (14%).

In 29% of patients isoniazid prophylaxis were used due to tuberculin skin test positivity. None of the patients develop tuberculosis infection during follow-up.

Conclusion: Biologics are being used more frequently in pediatric rheumatology. With the report of good outcomes biologics are used at the earlier stages of the diseases to prevent sequel formation. Our cohort also supports this opinion that biologics seem to be effective and safe in children with rheumatic diseases.

Disclosure of Interest

None Declared

P186 EFFICACY AND SAFETY OF INTRA-ARTICULAR STEROID THERAPY IN CHILDREN WITH JUVENILE IDIOPATHIC ARTHRITIS

Nilgun Cakar¹, Elif Çelikel¹, Ayten Guliyeva¹, Fatma Aydın¹, Beyza Doganay², Zeynep B. Özçakar¹, Fatoş Yalçınkaya¹

¹Department of Pediatric Rheumatology; ²Biostatistics, Ankara University School of Medicine, Ankara, Turkey

Correspondence: Nilgun Cakar

Introduction: The usefulness of intra-articular steroids (IAC) are well described, including rapid resolution of synovitis, relief of pain, support for normal functioning, and reduction of arthritis complications. IACs may have side effects, but they may be relatively mild compared to those associated with disease modifying antirheumatic drugs (DMARDs) or biologics.

Objectives: To investigate the efficacy and safety of IAC treatment in single and multiple joints in children with juvenile idiopathic arthritis (JIA) and to investigate the factors staying in remission of synovitis.

Methods: The clinical records of 41 patients who received IAC injection between January 2012 and December 2017 were reviewed. A total of 65 procedures were evaluated for efficacy, length of time between repeat injections, safety, and post-procedural complications. The corticosteroid used was triamcinolon hexacetonide for large joints and methylprednisolone for small or difficult to access joints. The effect of JIA subgroups, disease duration until performing IAC, ANA status, acute phase reactants and concurrent methotrexate (MTX) and biological drug treatment on the duration of remission in joints treated with IAC was investigated.

Results: A total of 65 IACs were performed in 41(27 female) patients. Among 41 patients, 32 had persistent oligoarthritis, 4 extended oligoarthritis, 3 polyarthritis and 2 enthesitis related arthritis. The median age at diagnosis was 7 (1.5-16) years, median follow-up time was 38 (5-69) months and the median time of the first IAC injection was 2 (0-49) months after diagnosis. Anti-nuclear antibodies were positive in 28(68%) patients. The median ESR was 33( 1-120) mm/h, and CRP was 9( 4-110) mg/L at the time of injection.

First IAC injection was done in 47 knees, 4 ankles, and 1 each wrist, elbow and proximal interphalangeal joint. In 13 patients two joints were injected at the same time. Repeat injection was done in 11 joints, all were knee.

Twenty-one of 41 patients received IAC, 17 received concurrent or ongoing MTX with IAC, 4 received MTX and anti-TNF therapy. The duration of remission without exacerbation of synovitis in joints treated with injection was found to be median 11,5 (range 1-66 ) months. The median interval between repeat injections was 27.5 (6-57) months. Three joints did not respond to IAC injection.

Subgroups of the disease and disease duration had no effect on the duration of remission. The duration of remission was longer in boys (11.5 vs 8 months), in ANA positives (13,5 vs 10 months), and in patients with concurrent MTX treatments (12 vs 9 months) . However, the differences were not statistically significant. The level of acute phase reactants had not been shown to correlate with the duration of remission.

No early or late adverse events were observed after the IAC procedure.

Conclusion: In single or multiple joints, IAC treatment induced remission in a significant proportion of patients without major side effects.

Disclosure of Interest

None Declared

P187 TOSILIZUMAB TREATMENT IN JUVENILE IDIOPATHIC ARTHRITIS: SINGLE CENTER EXPERIENCE

Selcan Demir, Hafize E. Sönmez, Elif A. Aydın, Yelda Bilginer, Seza Özen

Deparment of Pediatric Rheumatology, HACETTEPE MEDICAL FACULTY, Ankara, Turkey

Correspondence: Selcan Demir

Introduction: Tocilizumab is a monoclonal antibody against interleukin-6 that has recently emerged as an alternative treatment modality for juvenile idiopathic arthritis (JIA).

Objectives: We aimed to discuss the clinical and laboratory findings and treatment response of JIA cases to tocilizumab therapy.

Methods: The study group consists of JIA patients who were treated with tocilizumab and followed up between the years of 2014-2016 in the Department of Pediatric Rheumatology of Hacettepe University Faculty of Medicine. Clinical characteristics, laboratory findings, treatment responses and disease activity were reviewed from medical charts and electronic files of the patients, retrospectively.

Results: There were 20 JIA patients aged between 0-18 years, were followed up from 2014 to 2016 and received tocilizumab treatment in our clinic. Treatment response could be not evaluated in two patients since they developed anaphylactic reactions due to tocilizumab. Of the remaining 18 patients, seven of them (38.9%) had polyarticular JIA, and eleven (61.1%) had systemic JIA. Platelet counts, erythrocyte sedimentation rate(ESR) and C-Reactive Protein(CRP) levels, active joint counts, and JADAS71 were significantly decreased at the third month in both polyarticular and systemic JIA, while there were not any significant differences between the third and sixth months. All of the patients with polyarticular JIA had low disease activity at six months. Eight patients with systemic JIA had an inactive disease at six months, whereas the remaining three patients had high levels of CRP without presence of any clinical symptoms. Steroid treatment was terminated at the sixth month in all patients except for three patients who continued to receive 0.05-0.25 mg/kg steroid treatment. Two patients developed thrombocytopenia, one patient developed macrophage activation syndrome, and one patient had elevated transaminases due to tocilizumab treatment.

Conclusion: Previous studies have shown that tocilizumab treatment is well-tolerated, effective, and safe for use in JIA patients. In the present study, we also demonstrated the efficacy of tocilizumab treatment in JIA patients from our clinic.

Disclosure of Interest

None Declared

P188 AN ALTERNATIVE TREATMENT IN BIOLOGICAL DRUG ALLERGY: DESENSITIZATION

Selcan Demir, Hafize E. Sönmez, Erdal Sag, Yelda Bilginer, Özge Soyer, Seza Ozen

Department of Pediatric Rheumatology, HACETTEPE MEDICAL FACULTY, Ankara, Turkey

Correspondence: Selcan Demir

Introduction: The introduction of biologic drugs (BD) (such as monoclonal antibodies, cytokines, and fusion proteins) has represented a major breakthrough for the treatment of rheumatic diseases during the last two decades. However due to their high molecular weight, long half-life and parenteral use, hypersensitivity reactions may be seen frequently and may limit their use.

Objectives: In cases where the use of the drug is absolutely necessary, the drug may be given by desensitization if there is no contraindication.

Methods: In this report, we presented four cases with rheumatic diseases who were successfully treated by desensitization following anaphylaxis due to that biological drug.

Results: Four patients (1 systemic lupus erythematosus, 1 granulomatous polyangiitis, 1 polyarteritis nodosa, and 1 systemic juvenile idiopathic arthritis) participated [duration of follow-up: 5.5 (0.5-9) years]. Two patients had anaphylaxis during rituximab infusion and two patients had anaphylaxis during tocilizumab infusion [number of infusion dosage: 3 (2-5)]. All patients had active disease at time of reaction. Two patients had received another biologic drug previously. All patients were administered premedication before desensitization [methylprednisolone 2 mg / kg (maximum 60 mg) before 4 hours and 1 mg / kg hydroxyzine (25 mg maximum), ranitidine 2 mg / kg, paracetamol before 1 hour]. In the presence of respiratory distress, montelukast was also added. Desensitization protocol consisted of 12 step, drug dosage was increased by every 15 minutes. After the desensitization protocol, all patients received a median of 12 (8-15) drug infusions without any reaction.

Conclusion: In some cases, biologic drugs may be the only treatment alternative, however allergic reactions restrict the usage of them. In referral centers, desensitization protocols may help to control disease activity in these resistant patients.

Disclosure of Interest

None Declared

P189 LONG-TERM SAFETY AND EFFICACY OF ETANERCEPT IN GREEK JIA ADULTS AT THE TRANSITION PERIOD

Despoina Dimopoulou¹, Maria Trachana², Dimitrios Deligeorgakis¹, Artemis Koutsonikoli², Polyxeni Pratsidou-Gertsi², Alexandros Garyfallos¹

¹Rheumatology Unit, 4th Department of Internal Medicine; ²Pediatric Immunology and Rheumatology Referral Center, 1st Department of Pediatrics, Aristotle University, Hippokration Hospital, Thessaloniki, Greece

Correspondence: Despoina Dimopoulou

Introduction: Our published follow-up assessment on adults with Juvenile Idiopathic Arthritis (JIA) until 2011, revealed that half of the patients had flares in adulthood, despite previous administration of several anti-TNFs.

Objectives: a) To describe the long-term outcome of JIA adults after transition, who had received Etanercept (ETN) (from 8/2001 to 12/2017), as the only or the last anti-TNF. B) To evaluate our model of transition in a subgroup of refractory to conventional DMARDs JIA patients, who had attended the 1^st Greek Rheumatology Transition Clinic for Pediatric Rheumatic Diseases, following its establishment in 2013.

Methods: Retrospective cohort analysis of Greek adults with established diagnosis of JIA. The disease activity state was assessed by 2 contemporary quantitative tools: the Juvenile Arthritis Disease Activity Score-10 (JADAS 10) (Clinical Remission, CR, Low, Moderate and High Disease Activity, LDA, MDA, HDA, respectively) and Wallace criteria (CR on/off ETN). Baseline was defined as the 1^st ETN dose.

Results: 35 patients (female 25), aged (mean±SD) 23.5±4.6 years, were followed for a median (IQR) of 9 (3.6, 12.7) years. The median (IQR) patients’ age at the 1^st ETN dose was 16.4 (12.1, 17.8) years and the lag time from JIA onset to baseline was 6.5 (2.8, 12.5) years. The majority of the patients had a polyarticular course (27/35, 77.1%), regardless of the JIA subtype. ANA positivity was recorded in 16/35 (45.7%) and previous uveitis in 4/35 (11.4%). Nine patients (25.7%) had previously received other anti-TNFs (Adalimumab n=6, Infliximab n=3). The baseline median (IQR) patients’ JADAS-10 was 14/40 (9.5, 20.5) and the ETN yr-administration was 3.5 (2, 5.5). 33/35 (94.3%) patients were compliant to ETN and the study drug was well-tolerated. Regarding safety, only 3 patients (8.6%) experienced 6 adverse events (0.04/patient-years), namely injection site reaction (n=1), uterine hemorrhage (n=1), transient ANA positivity (n=1) and uveitis (n=3, 2/3 as flares). Uveitis under ETN led to the drug discontinuation in 2 patients (1 with new, 1 with pre-existing). Four patients discontinued ETN due to efficacy loss and one due to latent TB infection. 7/35 (20%) achieved CR and discontinued ETN after 3.3 (2, 4.5) years (median, IQR). The remaining 21 patients were still on ETN at the last evaluation. The median (IQR) percent duration of CR remission on ETN, according to the Wallace criteria, was 86%. CR off ETN lasted 1.17 (0.8, 4.3) years (median, IQR). In respect to the disease activity state at the last assessment: A) among the ETN ongoing receivers, 66.7% were in a CR state, 19% in LDA, 14.3% in MDA (median JADAS: 1). B) CR achievers still remaining off ETN, sustained this state in 85.7% (median JADAS: 0).

Conclusion: ETN in the critical transition period proved to be safe as adverse events were rare. ETN had a long-term and sustained efficacy, allowing CR off anti-TNF in 20% of the patients. Our transition policy supported the patients’ meticulous follow-up and compliance to ETN in adulthood.

Disclosure of Interest

None Declared

P190 INFECTIOUS ADVERSE EVENTS IN CHILDREN WITH JUVENILE IDIOPATHIC ARTHRITIS: DATA FROM THE JIRCOHORTE

Cécile Dumaine¹, Véronique Hentgen²

¹Pediatrics, Hôpital Robert Debré, Paris; ²Pediatrics, Hôpital Mignot, Le Chesnay, France

Correspondence: Cécile Dumaine

Introduction: Over the last fifteen years, the development of biological agents improved dramatically the outcome of children suffering from Juvenile Idiopathic Arthritis (JIA). Adult studies indicate that treatment with biological agents lead to an increased risk of serious infections, but very little is known about this risk in children.

Objectives: The main objective of our study is to assess the infectious adverse events (IAEs) occurring in JIA children treated with biological agents.

Methods: Patients were selected from the retrospective module of the JIRcohorte, a multicenter registry for children with inflammatory and rheumatological diseases. Data concerned the period between January, 10th 2001 and August 2015. Besides demography, diagnosis and treatment options of the patients, infectious adverse event (IAE) were retrieved. For every infectious side effect, the date, the severity, the need for an hospitalization, the accountability of the treatment on the occurrence, and the consequence of the event on the biologic course were noted. The type of microorgansim and the affected organ were also analyzed. Incidence rates were expressed in number of events per 100 person-years (100p-y), and OR were calculated; for their comparison, we used the Fischer test with a significance threshold at 0.05.

Results: Six hundred eighty-six patients with JIA from thirteen French-speaking rheumatologic reference centers were included in the study. A total of 1095 treatments with biological agent, for 3075.4 person-years of exposure were analyzed. One hundred eighty-four IAE occurring under a treatment with biologics were described, that is to say an incidence rate of 6.0 events/100 p-y, 15.5/100 p-y with Tocilizumab, 9.6/100 p-y with Canakinumab, 7.4/100 p-y with Abatacept, 6.9/100 p-y with Golimumab, 6.7/100 p-y with Aankinra, 6.3/100 p-y with Infliximab, 4.8/100 p-y with Etanercept, and 3.7/100 p-y with Adalimumab. Risk of developing an infection was significantly higher with IL6 antagonists than with TNF-inhibitor (TNFi) (OR 3.67 IC95% [2.41 ; 5.49] p<0.001), or with IL1 antagonists (OR 2.34 IC95% [1.7 ; 4.4] p=0.004). Forty point eight percent of the IAE affected the upper respiratory tract or the ENT sytstem. A total of 12 IAE were described as severe or very severe, which represented an incidence rate of 0.4/100p-y, 43% occurring with TNFi. The risk of developing a severe or very severe infection was higher with IL6 antagonist or IL1 antagonist than with TNFi. Twenty-two herpes zoster infections, including twenty under biologics were reported (0.7/100 p-y), and there were more virus due to immunosuppression with IL6 antagonist than with TNFi. No case of tuberculosis, opportunistic infection, or death was reported.

Conclusion: Infectious complications with biologics occurring in children treated for JIA are rare, and in most of the cases have a mild or moderate severity, affecting mainly the upper respiratory tract or the ENT.

Disclosure of Interest

None Declared

P191 ASSESSING THE CLINICAL RELEVANCE AND RISK MINIMIZATION OF ANTIBODIES TO BIOLOGICS IN JUVENILE IDIOPATHIC ARTHRITIS (JIA) (ABIRISK) - PRELIMINARY RESULTS

Martina Finetti, Gabriella Giancane, Francesca Bagnasco, Pavla Dolezalova, Elena Tsitsami, Maria Trachana, Isabelle Koné-Paut, Despoina Maritsi, Erkan Demirkaya, Giovanni Filocamo, Pierre Quartier, Olga Vougiouka, Rolando Cimaz, Rebecca Nicolai, Helga Sanner, Alina L. Boteanu, Alma N. Olivieri, Elzbieta Smolewska, Elisabeth Solau Gervais, Maria C. Maggio, Valda Stanevicha, Seza Ozen, Michael Hofer, Mihaela Spirchez, Maria G. Magnolia, Veronika Vargova, Denis Mulleman, Florian Deisenhammer, Marc Pallardy, Xavier Mariette, Laura Carenini, Mariangela Rinaldi, Alberto Martini, Nicolino Ruperto and for the Paediatric Rheumatology International Trials Organisation (PRINTO)

Clinica Pediatrica e Reumatologia - PRINTO, Istituto Giannina Gaslini, GENOA, Italy

Correspondence: Martina Finetti

Introduction: ABIRISK is a project funded by Innovative Medicine Initiative, with the aim to investigate anti-drug antibody (ADA) formation in the treatment of JIA with biologics (BPs). A major limitation to the use of biologics is the development of ADA that may decrease the efficacy of BPs.

Objectives: The aim of this project is to improve the capability to predict biologic immunogenicity in JIA patients.

Methods: JIA Patients (by ILAR criteria) followed by 24 PRINTO centres in 12 countries were prospectively enrolled and treated with Etanercept, Adalimumab or Tocilizumab. Patient’s data were obtained from Pharmachild, a pharmacovigilance data registry of JIA patients. For each patient detailed demographic and clinical information were reported; biologic samples were collected for PK and ADA detection before therapy start as well as at periodic visits up to month 18 of follow-up. Disease activity was assessed with Juvenile Arthritis Disease Activity Score-10 (JADAS10) and JIA American College of Rheumatology (JIA ACR) criteria.

Results: 148 patients were included in the analysis. Five patients were considered twice because treated with 2 different sequential biologics. Demographic and clinical data by therapy are represented in the table. 54% of the patients were treated with Adalimumab. Disease duration was higher in the group receiving Tocilizumab. Disease activity showed a pattern of improvement over time both globally and for each treatment