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The treatment of juvenile idiopathic arthritis (JIA) has made substantial progress within the last 25 years. Modern medicinal treatment enables inflammatory activity of the disease to be controlled in most of the cases. Mutilating courses of disease, which were formerly the rule have now become the exception. Today remission of disease is the aim of pediatric rheumatological treatment. Apart from effective control of inflammation this includes complete restoration of functional abilities of affected joints and the surrounding structures also affected. To achieve this goal a holistic and foresighted view of each patient's course is required. Therefore, even in an apparently uncomplicated course of disease in some cases of JIA it is advisable to plan an early interdisciplinary consultation including the pediatric rheumatologist and the orthopedic surgeon, in order to discuss an early surgical intervention, which can then be carried out in a timely manner, if necessary. This article provides an overview of the orthopedic rheumatological indications and options.Die Behandlung der juvenilen idiopathischen Arthritis (JIA) hat in den vergangenen 25 Jahren dramatische Fortschritte gemacht. Durch moderne medikamentöse Therapie lässt sich die Entzündungsaktivität in den meisten Fällen erfolgreich kontrollieren. Mutilierende Verläufe, wie sie früher regelhaft zu sehen waren, sind die Ausnahme geworden. Ziel einer kinderrheumatologischen Therapie ist heute die Remission. Dazu gehört neben einer erfolgreichen Kontrolle der entzündlichen Aktivität auch die vollständige funktionelle Wiederherstellung der betroffenen Gelenke und der gelenknahen, mitbetroffenen Strukturen. Dies erfordert eine ganzheitliche, vorausschauende Betrachtung des Erkrankungsverlaufes. Daher ist es auch bei scheinbar unkompliziertem Verlauf in einigen Fällen einer JIA ratsam, frühzeitig ein interdisziplinäres Konsil zwischen Kinderrheumatologen und orthopädischem Rheumatologen zu planen, um frühzeitig chirurgische Interventionen zu erörtern, die dann erforderlichenfalls rechtzeitig angegangen werden können. Die vorliegende Arbeit gibt eine Übersicht über die orthopädisch-rheumatologischen Indikationen und Möglichkeiten.

BackgroundThe ProKind Commission of the Society for Paediatric and Adolescent Rheumatology (GKJR) has developed evidence- and consensus-based protocols for the diagnosis and therapy of children and adolescents with defined rheumatic diseases (e.g., [1]). In the ProKind-Rheuma project, it is now investigated whether the protocols are followed in everyday clinical practice and what the treatment-associated outcomes are.ObjectivesTo investigate the mode of treatment and treatment response in patients with polyarticular juvenile idiopathic arthritis (pJIA).MethodsProKind-Rheuma is a multicenter prospective non-interventional observational study. Patients with pJIA enrolled until 17/1/2022 were included into this analysis. Treatments and outcomes up to the 3-month follow-up visit (3FU) were analyzed. Disease states were categorized based on the 2021 cJADAS10 cutoffs [2].ResultsTo date, 18 pediatric rheumatology facilities have participated in ProKind-Rheuma. Data from 203 patients with JIA are available. Of those, 44% have oligoarthritis, 36% polyarthritis, 9% systemic JIA, 6% enthesitis-related arthritis and 3% psoriatic arthritis.In total, 76 patients were diagnosed with pJIA, 38 with already completed 3FU:For 23 patients with pJIA and completed 3FU, we were able to analyze the protocol-defined [1] treatment goal of at least “minimal improvement”. In total, 18 (78%) achieved minimal improvement, 5 (22%) missed it. For 4 of those 5 patients, the underlying MTX therapy was escalated to a bDMARD (3 changed to MTX+bDMARD-combi, 1 to bDMARD-mono). In 3 other patients, therapy was also escalated to an MTX+bDMARD-combi.Between baseline and 3FU, 72% achieved cJADAS10-disease state improvement (Table 1) by at least one category (range 1 - 2), 0% decreased.Table 1.*based on non-missing valuesAt Baseline allAt Baseline with 3FUAt 3FUTotal7638Female, n (%)58 (76)30 (79)Age (years), Mdn (IQR)9 (3-12)7 (2-12)7.5 (3-12)Time since diagnosis (months), Mdn (IQR)0 (0-1)0 (0-1)4 (3-4)RF-positivity, n (%)8 (11)3 (8)Number of active joints (arthritis), Mdn (IQR)7 (4-12)7 (5-12)2 (0-4)JADAS10 (0-40), Mean (SD) (NBL+3FU= 23)18.6 (7.4)19.6 (7.6)7.2 (4.2)cJADAS10 (0-30), Mean (SD) (NBL+3FU= 29)16.3 (5.9)16.7 (6.1)7.1 (4.1)State of inactive disease (cJADAS10≤2.5), n (%*)0 (0)0 (0)4 (13)State of minimal disease activity (2.51 (2)1 (3)9 (28)State of moderate disease activity (533 (54)17 (50)18 (56)State of high disease activity (cJADAS10>16), n (%*)27 (44)16 (47)1 (3)CHAQ (0-3), Mean (SD)0.8 (0.8)0.9 (0.8)0.3 (0.5)Pain (NRS 0 - 10), Mean (SD)4.3 (3)4.7 (3)2.2 (2.7)PedsQL 4.0 total score, Mean (SD)66.3 (22.2)65.4 (21.8)78.4 (17.6)Intraarticular glucocorticoids > 4 joints (ever), n (%)12 (16)5 (13)7 (18)Glucocorticoid pulses (ever), n (%)22 (29)12 (32)13 (34)Methotrexate, n (%)56 (74)31 (82)34 (90)bDMARDs, n (%)7 (9)2 (5)9 (24)Within the first 3 months after diagnosis, the treatment pathways proposed by the ProKind Commission [1] were followed in about three-quarters of patients: i) 5 (13%) received MTX and intra-articular glucocorticoid injections in more than 4 joints (IAGC), but no high-dose intravenous glucocorticoid pulse (HDGC) or bDMARD; ii) 8 (21%) received MTX and HDGC (no bDMARD, no IAGC); iii) 16 (42%) patients received MTX, of whom 4 received a bDMARD up to or at the 3FU (no HDGC, no IAGC). Nine (24%) patients were not treated with MTX or did not fit any of these categories, mostly due to starting bDMARD therapy in conjunction with HDGC or IAGC.ConclusionIn the routine care of JIA patients with polyarthritis, the proposed treatment protocol and treat-to-target strategy are followed in most patients. At 3FU, improvements of JADAS10 and other outcomes were evident, with 41% having achieved inactive or minimal active disease.ProKind is funded by the Innovation Fund “Gemeinsamer Bundesausschuss”, FKZ: 01VSF18031References[1]Horneff et al. Pediatric Rheumatology 2017; 15:78[2]Trincianti et al. Arthritis Rheumatol. 2021 Nov; 73(11):1966-1975AcknowledgementsWe are grateful to all physicians, medical professionals and everyone else who has so far contributed and supported the ProKind-Rheuma project.Moreover, we want to express special gratitude to all patients and their parents for their participation.Disclosure of InterestsSascha Eulert: None declared, Kristina Vollbach: None declared, Klaus Tenbrock: None declared, Jens Klotsche: None declared, Dirk Foell Speakers bureau: Speaker fees/honoraria from Boehringer, Novartis, Werfen and Sobi, Grant/research support from: Novartis and Sobi, Johannes-Peter Haas: None declared, Frank Weller-Heinemann: None declared, Sonja Mrusek: None declared, Prasad Oommen: None declared, Daniel Windschall Speakers bureau: Research support and speakers fee: Pfizer, Novartis, Abbvie, Medac, Sobi, Canon, Grant/research support from: Research support and speakers fee: Pfizer, Novartis, Abbvie, Medac, Sobi, Canon, Kirsten Moenkemoeller: None declared, Tilmann Kallinich: None declared, Markus Hufnagel: None declared, Ivan Foeldvari Consultant of: Addvisory board: Hexal, Novartis, Pfizer, Toni Hospach Consultant of: Advisory board: Sobi, Novartis, Moritz Klaas: None declared, Michael Rühlmann: None declared, Ralf Trauzeddel: None declared, Normi Brueck: None declared, Catharina Schütz: None declared, J. B. Kuemmerle-Deschner: None declared, Ariane Klein: None declared, Kirsten Minden Speakers bureau: Speaker: Pfizer, Novartis, Gerd Horneff: None declared

BackgroundAlthough regular physical activity (PA) is known to have many health-related benefits for children and adolescents with chronic conditions, JIA has been associated with reduced physical activity (PA) and increased time spent sedentary [1]. Sedentary behaviour is an important consideration alongside PA when examining the contribution of both behaviours to the health of young patients. Because young people show more complex but less structured movement behaviour than adults, capturing their many spontaneous and impulsive movements is a great challenge for PA assessment.ObjectivesSince accurate, objective measures of PA related to potential factors promoting PA have been scarce, this study aimed i) to objectively assess moderate to vigorous PA (MVPA) as well as sedentary behaviour and ii) to identify facilitators for PA in patients with JIA.MethodsWithin the framework of the ActiMON study as part of the TARISMA research network, data were collected at several German paediatric rheumatology centres. Objectively assessed PA of adolescent patients with JIA was recorded exclusively during school months in the period June - December 2021 using the accelerometer ActiGraph wGT3X-BT laterally on the right hip. In accordance with the International Children’s Accelerometry Database criteria [2], ActiGraphs were worn on seven consecutive days during all waking hours, including at least 4 valid weekdays and 1 weekend day (wear time >8 hours) in the evaluation. Self-reported PA-related data were measured using a physical activity questionnaire (PAQ), while clinical parameters were used from the National Paediatric Rheumatologic Database (NPRD). Achievement of the WHO recommendation of at least 60 minutes MVPA per day and compliance with the national recommendation of no more than 120 minutes of daily screen time were determined among 12- to 18-year-olds.ResultsData of 41 patients (mean age 14.6 ± 1.9 years, female 73%, patients’ disease duration 7.9 ± 4.6 years, polyarthritis 40%, cJADAS-10 2.3 ± 2.4) were available for evaluation. Almost 71% of participating patients met the WHO-recommended minimum level of MVPA, while the average daily step count achieved was 7804. Almost 80% of the patients rated their motor and coordination skills as being good. The most frequently mentioned reasons for doing sports (multiple answers possible) included feeling good (78%), giving energy (70%), pleasure (65%) and enjoyment (60%). Patients whose parents are active in sports and support their child in finding a suitable offer were more likely to fulfil the WHO recommendation than patients without family support. The average daily time spent sedentary was 10.5 ± 1.9 hours. About half of the patients reported spending more than 4 hours a day with screen-based media, especially video games.ConclusionThese preliminary results suggest that while a large proportion of patients achieve the WHO recommended minimum level of PA, they exhibit very pronounced sedentary behaviour with increased screen use. In addition to controlled disease activity as a well-known prerequisite for achieving PA recommendations, these results also point to the importance of family support and emotional well-being. With ongoing recruitment, further potential facilitators and barriers to PA should be identified in more in-depth analyses.References[1]Gualano B et al. Physical activity for paediatric rheumatic diseases: standing up against old paradigms. Nat Rev Rheumatol 2017;13:368-379.[2]Sherar LB et al. International children’s accelerometry database (ICAD): design and methods. BMC Public Health 2011;11:485.AcknowledgementsActiMON is funded by the Federal Ministry of Education and Research (01EC1902F).Disclosure of InterestsFlorian Milatz: None declared, Ralf Trauzeddel: None declared, Tilmann Kallinich: None declared, Moritz Klaas: None declared, Hermann Girschick: None declared, Sandra Hansmann: None declared, Gerd Horneff: None declared, Daniel Windschall Speakers bureau: Pfizer, Novartis, Abbvie, Medac, Sobi, Canon, Johannes-Peter Haas: None declared, Nadja Baumeister: None declared, Martina Niewerth: None declared, Kirsten Minden Speakers bureau: Pfizer; Novartis

BackgroundIn recent years, transition clinics have been set up at an increasing number of paediatric rheumatology sites in Germany to reduce identified deficits in the care of young people with rheumatic diseases1. In addition, the German Rheumatic Diseases League (Deutsche Rheuma-Liga, DRL), the largest self-help organisation in Germany, has been offering support services for young people in transition since 2016, including the interactive website www.mein-rheuma-wird-erwachsen.de.ObjectivesTo assess the transition competence of young people with juvenile idiopathic arthritis (JIA) and their knowledge of self-help services.MethodsCross-sectional data of the National Paediatric Rheumatology Database (NPRD) from 2016 to 2020 were used to evaluate the health-related transition competence of young people with JIA aged ≥16 years. Health-related knowledge and health-care competence were assessed using a modified self-report instrument2 on a 4-point Likert scale as part of routine documentation in the NPRD. Young people were also asked about their information behaviour and knowledge of new support services. Linear mixed models were used to determine whether health-related transition competence changed between 2016 and 2020, adjusted for disease duration.ResultsDuring the years 2016 to 2020, between 1.908 to 2.536 patients with JIA aged ≥16 years were annually recorded in the NPRD from 56 to 61 paediatric rheumatology sites. The annual patient collectives comprised 34-39% oligoarthritis, 23-26% RF-negative or RF-positive polyarthritis and 22-27% enthesitis-related arthritis cases. In the years from 2016 to 2020, about one-third of patients had inactive disease (cJADAS-10≤1) and about 60% had no functional limitations (CHAQ=0).Over the years, the proportions of patients who rated their disease knowledge and health care competence as “very well” increased significantly in most areas. Although over time, no increase in numbers of patients seeking information about their disease outside of rheumatology consultations were recorded (2016: 22.8%; 2020: 20.9%), awareness of the DRL’s new website for young people with rheumatic diseases increased from 7.7% in 2016 to 26.9% in 2020. Compared to those who were unaware of the new website, those who knew about the website were more likely to have received care in rheumatology settings that offer transition clinics and were more likely to be girls (75% vs 65%), to attend high school (51% vs 46%) and to be slightly older (17.6 vs 17.1 years).ConclusionThe transition competence of young people with JIA seems to have improved over the last five years. During this time, more transition services were made available for young people with rheumatic diseases. However, most young people are not yet aware of these services. Moreover, the effectiveness of the different measures/interventions has yet to be evaluated.References[1]Luque Ramos A et al. Semin Arthritis Rheum 2017;47:269-75.[2]Herrmann-Garitz C et al. Gesundheitswesen 2017;79:491–6.Table 1.Health-related transition competence in JIA patients ≥16 years who participated in the NPRD201620182020p (difference over time)PatientsN=2536N=2068N=1908Disease duration, years6.7±4.97.2±5.07.6±5.1DMARDs at documentation, %576263Disease-related knowledge (best answer “very well”), %N=1992N=1598N=1265name of illness3542420.001names of medicines5459560.717what medicines are for5054520.357who to contact in case of health problems5965650.015influence of smoking, drugs, and alcohol on disease4955540.002how to make a doctor’s appointment6868650.087which doctors are responsible after leaving paediatric care4246490.031Health-care competence (best answer “most of the time”), %N=1784N=1443N=1143inform my doctor of any unusual changes in my health6672690.038keep information about my illness8184840.281ask my own questions5156550.016answer the questions I am asked6973740.014take care of my health concerns and needs6671690.041attend the consultation alone5961610.599speak up for myself and say what I need6468680.537AcknowledgementsThe NPRD has been funded by the Federal Ministry of Health and the companies Abbvie, Chugai, ask, Novartis, PfizerDisclosure of InterestsKirsten Minden Speakers bureau: Pfizer, Novartis, Consultant of: Pfizer, Novartis, Martina Niewerth: None declared, Susanne Schalm: None declared, Ivan Foeldvari: None declared, Johannes-Peter Haas: None declared, Gerd Horneff: None declared, Daniel Windschall Speakers bureau: Pfizer, Novartis, Abbvie, Medac, Sobi, Canon, Grant/research support from: Pfizer, Novartis, Abbvie, Medac, Sobi, Canon, Tilmann Kallinich: None declared, Frank Dressler: None declared, Frank Weller-Heinemann: None declared, Rainer Berendes: None declared, Toni Hospach Consultant of: SOBI, Novartis, Markus Hufnagel: None declared, Maria Haller: None declared, Sandra Hansmann: None declared, Jens Klotsche: None declared

BackgroundUveitis is an extra-articular manifestation of Juvenile idiopathic arthritis (JIA) with a prevalence of up to 20% developing most frequently in young girls and patients positive for antinuclear antibodies (ANA). Untreated and uncontrolled uveitis may lead to vision-threatening complications and even blindness.ObjectivesThe main objectives of the analyses were to determine the visual prognosis, uveitis complications and necessity of ocular surgery during the first five years of ocular disease. The likelihood of achieving an inflammation-free phase or even a remission without medication were investigated.MethodsThe Inception Cohort of Newly diagnosed patients with JIA (ICON) was initiated in 2010 in order to prospectively follow JIA patients up to 10 years after JIA disease onset. 953 Patients were assessed at enrollment, three-monthly during the first year, and six-monthly afterwards by a standardized physician’s and patient’s case report form including clinical parameters, treatment data and several laboratory parameters such as ESR, CRP or S100A12. Patients who developed uveitis underwent a regular ophthalmological assessment. The treating ophthalmologist three-monthly completed an additional questionnaire, documenting the anterior chamber (AC) cell grade, current uveitis activity (UA) and UA during the previous three months, best corrected visual acuity (BCVA), uveitis-related complications, previous ocular surgery, current topical treatment and clinical course of uveitis and additional parameters. Inactive uveitis was defined by AC cell grade of 0, quiescence of uveitis by inactive uveitis for at least 6 months, and remission by inactive uveitis for at least 6 months without topical steroids or systemic anti-inflammatory medication (steroids or DMARDs).ResultsA total of 133 children developed uveitis in the JIA disease course, of which 97 patients were documented via the ophthalmological questionnaire for at least two years resulting in a mean follow-up of 5.8 years (SD 1.8). 76% were female, 86% ANA positive, 70% oligoarthritis, and 22% rheumatoid factor negative polyarthritis and mean age at JIA onset was 3.1 (SD 2.1) and uveitis onset at 4.4 (SD 2.2) years. The mean duration between JIA onset and uveitis onset was 15.7 (SD 15.6) months. At least one ocular complication was reported for 24% of patients at first uveitis documentation and 47% of patients had at least one ocular complication until the five year follow-up. Among those, posterior synechiae (31%) and cataract (27%) were the most frequent, followed by an increased IOP (12%) with or without glaucomatous changes. Ocular surgery was rarely necessary, and visual acuity remained quite good in the majority of patients: After five years, >90% had BCVA of ConclusionThe rate of ocular complications is already remarkable at uveitis diagnosis, and increases during uveitis disease course despite anti-inflammatory treatment. However, the visual acuity frequently remains unaffected, and the majority of patients achieve uveitis quiescence and even 40% uveitis remission within 5 years of follow-up.AcknowledgementsThe ICON study is funded by a research grant of the Federal ministry of education and research (BMBF, FKZ 01ER0812, FKZ 01ER1504A-C)Disclosure of InterestsJens Klotsche: None declared, Claudia Sengler: None declared, Frank Dressler: None declared, Dirk Foell: None declared, Ivan Foeldvari: None declared, Johannes-Peter Haas: None declared, Gerd Horneff Speakers bureau: Pfizer, Novartis, Janssen, Chugai, Abbvie, Grant/research support from: Pfizer, Novartis, MSD, Chugai, Roche, Abbvie, Toni Hospach Consultant of: SOBI, Novartis, Tilmann Kallinich: None declared, Ina Liedmann: None declared, Kirsten Moenkemoeller: None declared, Martina Niewerth: None declared, Frank Weller-Heinemann: None declared, Daniel Windschall: None declared, Arnd Heiligenhaus: None declared, Kirsten Minden: None declared, Karoline Baquet-Walscheid: None declared

Adalimumab (ADA) has become a valuable treatment option for juvenile idiopathic arthritis (JIA). The importance of combination with methotrexate (MTX) is unclear.Data from the German Biologics in Paediatric Rheumatology (BIKER) registry are reported. Response to treatment was analysed using JIA American College of Rheumatology (ACR) scores, 10-joint Juvenile Arthritis Disease Activity Score (JADAS10), and improvement of functional status and ACR inactive disease criteria. Compa-risons between rates of adverse events (AEs) and serious adverse events (SAEs) provided data for the safety assessment.Overall, 584 patients with non-systemic JIA started ADA therapy, 61% of whom received concomitant MTX treatment at baseline. The latter patients were younger (p 0.001), with shorter disease duration (p = 0.001), more frequently had antinuclear antibodies (p = 0.04), and had higher baseline JADAS10 scores (p = 0.03). In patients with ADA monotherapy, enthesitis-related arthritis (p = 0.004) and presence of human leucocyte antigen-B27 (p = 0.008) were documented more often. Mean treatment duration in both cohorts was 15 months. Comparable last follow-up rates for JIA ACR 30/50/70/90% response, JADAS minimal disease activity, JADAS remission, and ACR inactive disease were, respectively, 75/72/64/49%, 66%, 46%, and 58% for ADA monotherapy, and 77/72/61/45%, 64%, 48%, and 55%, for ADA + MTX. During 1082 patient-years (PY) of ADA exposure, 725 AEs (67/100 PY), including 57 SAEs (5.3/100 PY), were reported. Serious infections were reported in 10 patients (0.9/100 PY) and 11 (1.0/100 PY) had varicella infections/zoster reactivation. Rates of AEs, SAEs, infectious events, and serious infections did not differ between the cohorts. Elevated transaminases (p = 0.005) and gastrointestinal events (p 0.0001) were reported more often in the combination cohort. Two pregnancies and no deaths were reported.ADA demonstrated an acceptable risk profile and high percentages of patients in both cohorts showed sufficient treatment response. No differences in treatment response or adherence to treatment were found.

Background:Juvenile idiopathic arthritis (JIA) associated uveitis is an extra-articular manifestation of the JIA disease that may cause vision-threatening complications and an uncontrolled uveitis may even lead to blindness. Uveitis occurs in up to 20% of patients with JIA, depending on the JIA category. The majority of patients develop uveitis within the first two years after JIA symptom onset, but uveitis can continue into adulthood.Objectives:The main objective of this study was to analyze the risk for uveitis events after discontinuing disease-modifying antirheumatic drugs (DMARD) in patients with extended oligoarthritis and rheumatoid factor (RF)-negative polyarthritis.Methods:Data of the two ongoing multicenter biologic registers: German Biologics in Pediatric Rheumatology (BiKeR) and the Juvenile arthritis Methotrexate/Biologics long-term Observation (JuMBO) were used to analyze the adverse-event (AE) and events of special interest (ESI) reports about uveitis events during treatment and after discontinuation of DMARDs. Biker started recruitment of children and adolescent patients with JIA exposed to biological (b) or conventional (cs) DMARD’s in 2001. The patients were further followed in JuMBO after reaching the age of 18 or transitioning to an adult rheumatologist. Disease characteristics, treatment data, AE’s and ESI’s were reported by the pediatric or adults rheumatologist, respectively.Results:A total of 2,041 patients with RF-negative polyarthritis (n=1,280) or extended oligoarthritis (n=761) were included into the analyses. The mean follow-up of this study was 7.6 years (SD 5.3). About half of the patients were enrolled in BiKeR with start of etanercept (1,137, 55.7%), followed by 635 (31.1%) patients with start of methotrexate (MTX) monotherapy or adalimumab (ADA, n=198, 9.7%). A history of uveitis was reported for 238 (11.7%) patients at enrolment in BiKeR. More patients with a history of uveitis treated with ADA were included in BiKeR initiating ADA (n=98 of 238, 41.2%). Patients with uveitis had a lower age at JIA onset in comparison to patients without uveitis (mean 3.6 (SD 3.0) versus 7.0 (SD 4.5) years). A total of 142 recurrent (84% of 169) uveitis events were reported in 93 patients and for 27 patients (1.3% of 2,041) was an incident uveitis reported during follow-up. More than one uveitis event was reported for 32 patients with a maximum number of 4 uveitis flares in 3 patients. Nineteen uveitis flares (11.2% of 169) were reported for patients after the age of 18. The longer the time since DMARD discontinuation the fewer uveitis events occurred. Uveitis events were significantly more often reported in the first 24 months after MTX discontinuation (2 at last MTX intake had a higher likelihood for uveitis events (OR=1.40, 95%CI: 1.02 to 1.92).Conclusion:This is the first study that analyzed the risk of uveitis after DMARD withdrawal. Uveitis relapses are common. Patients who discontinued DMARD therapy were at high risk for uveitis within the first 3 to 24 months after discontinuation. Rheumatologists and ophthalmologists should be aware about this risk which should lead to a regular uveitis screening after DMARD withdrawal.Disclosure of Interests:Jens Klotsche: None declared, Ariane Klein: None declared, Martina Niewerth: None declared, Tilmann Kallinich: None declared, Daniel Windschall: None declared, Johannes-Peter Haas: None declared, Frank Weller-Heinemann Speakers bureau: Pfizer, Abbvie, SOBI, Roche, Novartis, Toni Hospach: None declared, Frank Dressler: None declared, Kirsten Minden: None declared, Gerd Horneff: None declared

Background:Various treatment strategies are used for children with newly diagnosed polyarticular JIA. MTX is usually prescribed, sometimes in combination with high-dose intravenous glucocorticoid pulses (HDGC) or multiple intra-articular GC injections (IAGC). These different approaches were considered in the German consensus-based treatment protocols for polyarticular JIA1, they were also the leading therapies in patients with rheumatoid factor-negative polyarthritis (RF- PA) included in the JIA inception cohort ICON.Objectives:To compare the effectiveness of three different treatment strategies in nearly DMARD-naïve patients with RF- PA.Methods:Patients with RF- PA who were included in the ICON cohort and received one of the following treatments within the first three months were considered for the analysis: Group 1: MTX + IAGC in >4 joints, Group 2: MTX + HDGC, Group 3: MTX, no IAGC in >4 joints, no HDGC. Propensity score-adjusted group differences in outcomes after one and two years were analysed by linear and logistic regression analyses.Results:The analysis included data from 150 patients (79% female, mean age 6.7±4.8 years) enrolled in ICON 1.6±1.9 months after the diagnosis of RF- PA, of whom 52 were in Group 1, 54 in Group 2 and 44 in Group 3. Disease activity did not differ significantly between the groups at treatment start (cJADAS-10 16.7±4.7, 15.8±5.7, 15.9±6.5, respectively).Of the total group, at 1- and 2-year follow-up (FU), 60.9%/60.1% and 52.3%/58.8% of patients had inactive disease (cJADAS ≤1/Wallace criteria2), 21.3% and 35.6% were in remission off drug2, and mean cJADAS-10 scores were 2.6±3.9 and 3.0±3.5, respectively. 60.5% and 67.0% had no functional limitations (CHAQ=0).Patients in Group 1 more often had an inactive disease (according to Wallace2) at the 1-year FU and tended to have inactive disease more often at 2-year FU than patients in Group 3 (78.1% vs. 45.2%, p=0.025; 73.3 vs. 49.1%, p=0.075, respectively). Group 2 patients (inactive disease in 56.1% and 53.4% at 1- and 2-year FU) did not differ significantly from either Group 1 or Group 3. In addition, Group 1 patients had a significantly better quality of life than patients of Group 2 at the 2-year FU (mean PedsQL 4.0 total score 90.4±9.3 vs. 83.8±11.2, p=0.031). At that time, Group 3 patients had a mean PedsQL 4.0 total score of 85.0±14.6, which was not significantly different from either Group 1 or 2.On the other hand, Group 1 patients tended to develop new uveitis more frequently within the first two years of treatment than patients in Groups 2 and 3 (13% vs. 2.2% and 3.6%, p=0.101 and 0.131, respectively). At the 2-year FU, patients in Group 1 also had a significantly lower mean height SDS than patients of Group 3 (-0.3±1.1 vs. 0.2±1.1, p=0.038). Mean height SDS was lowest (-0.5±0.8) in patients in Group 2 and significantly lower than in Group 3 (0.019). Mean body mass index SDS also differed significantly between the groups at 2-year follow-up. The mean BMI SDS was highest in Group 1 patients (0.2±0.8), differing significantly from Group 2 (-0.3±0.7, p=0.014) and Group 3 (-0.4±1.1, p=0.023).There were no significant differences in inactive disease (according to cJADAS) and functional status (CHAQ) between the three groups at 1- and 2-year FU. Over time, treatments were very different in the three groups. In Group 3, biologics were used significantly more often over time than in group 1 (54.0% vs. 18.3%, p=0.014), and Group 2 patients received bDMARDs in 36.1%.Conclusion:While patients with numerous early joint injections seem to achieve inactive disease more frequently and earlier, they have a slightly smaller body height and tend to develop uveitis slightly more often than patients with more intensive DMARD therapy. However, the differences are small between the groups. Further comparative effectiveness studies with higher patient numbers are needed to identify particularly effective and safe treatment strategies.References:[1]Horneff et al. Pediatric Rheumatology 2017;15:78.[2]Wallace et al. Arthritis Care Res (Hoboken) 2011;63:929-36.Acknowledgements:The ICON study is funded by a research grant of the Federal ministry of education and research (BMBF, FKZ 01ER0812, FKZ 01ER1504A-C).Disclosure of Interests:Kirsten Minden Speakers bureau: Pfizer, Abbvie, Consultant of: Novartis, Tobias Schwarz: None declared, Frank Dressler: None declared, Ivan Foeldvari Consultant of: Gilead, Novartis, Pfizer, Hexal, BMS, Sanofi, MEDAC, Johannes-Peter Haas: None declared, Gerd Horneff Speakers bureau: Pfizer, Consultant of: Novartis, Toni Hospach Consultant of: Novartis, Jasmin Kümmerle-Deschner: None declared, Kirsten Moenkemoeller: None declared, Frank Weller-Heinemann Speakers bureau: Pfizer, AbbVie, SOBI, Roche, Novartis, Klaus Tenbrock: None declared, Martina Niewerth: None declared, Claudia Sengler: None declared, Dirk Foell: None declared, Jens Klotsche: None declared

Background:Although children and adolescents are less likely to develop COVID-19 and generally show milder disease courses, it is unclear what impact the SARS-CoV2 infection has on children and adolescents with rheumatic and musculoskeletal disease (RMD). Due to their underlying disease as well as therapeutic immunosuppression these patients may be at higher risk of being more severely affected by SARS-CoV2. Furthermore, SARS-CoV2 infection might trigger a flare of the underlying disease.Objectives:To evaluate clinical characteristics and disease course of COVID-19 in children and adolescents with RMD and to analyze possible effects of SARS-CoV2 infection on the underlying disease under different therapeutic regimens.Methods:Data from juvenile patients with RMD recorded via the SARS-CoV2 questionnaire within the National Pediatric Rheumatology Database and the registry for hospitalized children and adolescents with COVID-19 of the German Society for Pediatric Infectious Diseases were analyzed. In addition to age, sex and diagnosis, information was collected about the date and method of a positive SARS-CoV2 testing, reason for testing, on clinical manifestations, disease course, treatment and outcome of COVID-19, on drug therapy at the time of virus detection, on disease activity (NRS 0 – 10, 0 = best) of the underlying disease at the last visit before and after the SARS-CoV2 infection.Results:From April 17th 2020 until January 25th 2021, data of 67 patients with RMD and confirmed SARS-CoV2 infection were collected. Mean age was 13.5 ± 3.9 years with equal sex distribution. The majority of patients were diagnosed with juvenile idiopathic arthritis (JIA, 64%), 12 (18%) patients had an autoinflammatory disease (FMF, CAPS, PFAPA, TRAPS) and 5 (7%) a connective tissue disease. Fifty-two patients (78%) were treated with a disease modifying antirheumatic drug (DMARD), 39% with a biological DMARD and 9% systemic glucocorticoids at the time of SARS-CoV-2 infection. Nineteen patients (28%) were tested for SARS-CoV-2 because of typical symptoms, the majority (67%) because of contact to an infected person. PCR was used most often (in 60 %).52 patients (78%) developed symptoms of COVID-19, 15 patients remained asymptomatic. The most common symptom of COVID-19 was rhinitis (42%) and fever (38%), followed by fatigue (34%), taste/smell disorder (33%), sore throat (27%) and cough (23%).Disease severity was graded as mild in 44 of 52 (85%) symptomatic patients, only two patients were hospitalized, one of whom required intensive care and died of cardiorespiratory failure 3 days after symptom onset. In 22 of 26 (85%) SARS-CoV2-positive patients, no relevant increase in disease activity (difference in NRS ≤ 1 before/after infection) of the underlying disease was observed 31 days after symptom onset (median, IQR 17-52 days). One patient, who had paused tocilizumab for 2 doses, experienced a flare of his seronegative polyarthritis 2 months after asymptomatic SARS-CoV-2 infection.Conclusion:In our cohort, the clinical picture of COVID-19 in children and adolescents with RMD was similar to that of healthy peers. The majority of patients showed mild disease course with good outcome under various medications, however, one patient with a severe course of COVID-19 died. In addition, SARS-CoV2 infection does not appear to have a relevant impact on the underlying disease activity, whereas discontinuation of therapy might pose a risk of flare.Disclosure of Interests:None declared.

Background:In patients with JIA, growth impairment and variance in body composition are well-known long-term complications that may be associated with prolonged drug therapy (e.g. glucocorticoids) as well as impaired physical and psychosocial well-being. An increased accumulation of body fat represents a significant risk factor for metabolic abnormalities and a modifiable variable for a number of comorbidities. Recently, evidence has emerged in favour of the potential negative influence of overweight on the course of the disease and treatment response [1].Objectives:The study aimed a) to estimate the prevalence of underweight, overweight and obesity in children and adolescents with JIA compared to the general population, and b) to investigate correlates of patients’ weight status.Methods:A cross-sectional analysis of physicians’ recorded body weights and heights of patients with JIA enrolled in the NPRD in the year 2019 was performed. Underweight (BMI 90th) and obesity (BMI >97th) were defined according to age- and sex-specific percentiles used in the German reference system. For comparison with data from the general population [2], sex- and age-matched pairs of 3-17-year-old patients and controls were generated. A multinomial logistic regression analysis was performed to examine the association between weight status and patients’ clinical and self-reported outcomes.Results:In total, data from 6.515 children and adolescents with JIA (age 11.2 ± 4.1 years, disease duration 4.9 ± 3.8 years, 67% girls, 40% persistent oligoarthritis) were included. Of these, 3.334 (age 5.9 ± 2.1 years, 52.5% girls) could be considered for matched-pair analysis. Compared with the general population, patients underweight, overweight and obesity rates were 10.6% (vs. 8.1%), 8.8% (vs. 8.5%) and 6.1% (vs. 5.7%), respectively. No significant sex differences were found in either group. Largest difference in prevalence was registered for underweight, specifically in the age group 3-6 years (12.9% patients vs. 5.9% controls). Similar to the general population, higher rates of overweight were observed in adolescent patients than in affected children (19.1% age group 11-13 vs. 8.4% age group 3-6). While the highest underweight prevalence was registered in patients with RF+ polyarthritis (16%), patients with Enthesitis-related arthritis (22%), psoriatic arthritis (21%) and systemic JIA (20%) showed the highest overweight rates (including obesity). Younger age (OR = 0.51, 95% CI = 0.31-0.83), more frequent physical activity (OR = 0.92, 95% CI = 0.85-0.99) and high parental vocational education (OR = 0.39, 95% CI = 0.18-0.80) were independently associated with a lower likelihood of being overweight/obese.Conclusion:The overall prevalence of underweight, overweight and obesity in children and adolescents with JIA is comparable to that found in the general population. Behavioural health promotion, including regular physical activity, as part of the treatment strategy in JIA should preventively already begin at preschool age and necessarily be made accessible to patients of all educational levels.References:[1]Giani T et al. The influence of overweight and obesity on treatment response in juvenile idiopathic arthritis. Front Pharmacol 2019;10:637.[2]Schienkiewitz A et al. BMI among children and adolescents: prevalences and distribution considering underweight and extreme obesity. Bundesgesundheitsbl 2019;62:1225–1234.Acknowledgements:The National Paediatric Rheumatological Database has been funded by AbbVie, Chugai, Novartis and GSK.Disclosure of Interests:Florian Milatz: None declared, Jens Klotsche: None declared, Martina Niewerth: None declared, Jana Hörstermann: None declared, Daniel Windschall: None declared, Frank Weller-Heinemann Speakers bureau: Pfizer, AbbVie, SOBI, Roche and Novartis., Frank Dressler: None declared, Rainer Berendes: None declared, Johannes-Peter Haas: None declared, Gerd Horneff: None declared, Kirsten Minden Speakers bureau: Pfizer, AbbVie, Consultant of: Novartis

Hintergrund: Bei verschiedenen chromosomalen Storungen wird ein erhohtes Risiko fur eine Juvenile Idiopathische Arthritis (JIA) vermutet. Vor allem bei Patienten mit einem Morbus Down (Trisomie 21) und einer JIA besteht daruber hinaus eine Unsicherheit bezuglich der geeigneten Therapie mit DMARDs, weil auch das Risiko bezuglich einer AML erhoht ist. Methode: In einer retrospektiven Fall-Kohorte eigener Patienten wurde das typische Verteilungsmuster und die Entzundungsaktivitat bei Patienten mit Trisomie 21 und JIA (T21-JIA) sowie deren Ansprechen und Nebenwirkungen von MTX im Vergleich zu JIA-Patienten mit seronegativer polyartikularer JIA (SNP-JIA) untersucht. Ergebnisse: Die elf eingeschlossenen T21-JIA Patienten (6 weibl./5 mannl.) hatten bei Diagnosestellung JIA ein mittleres Alter von 6 Jahren (1–13 Jahre). 9 T21-JIA Patienten (82%) hatten einen polyartikularen Verlauf und wurden mit MTX behandelt. T21-JIA Patienten hatten bei Diagnosestellung eine signifikant hohere Anzahl aktiver und schmerzhafter Gelenke (T-21 JIA 19,9 (± 10,9) vs. SNP-JIA 15,5 (± 6,5)) und prasentierten sich in 7 von 10 (70%) Fallen als SNP-JIA (gemas ILAR-Klassifikation, erwartet: 13–15%). Ein T21-JIA Patient hatte eine systemische, einer eine persistierende- und 2 eine extended oligoartikulare JIA. Im Verlauf entwickelten 81% der T21-JIA Patienten Gelenkskontrakturen. Kein T21-JIA Patient hatte im Verlauf eine Uveitis. Das Ansprechen auf MTX und die Frequenz von unerwunschten Arzneimittelwirkungen (UAW) war bei T21-JIA Patienten mit denen einer gematchten Vergleichstichprobe vergleichbar. Schlussfolgerung: T21-JIA Patienten zeigen gehauft einen polyartikularen Verlauf mit einer hoheren Anzahl betroffener Gelenke und ausgepragteren Bewegungseinschrankungen im Erkrankungsverlauf. Das Ansprechen und die UAW einer MTX-Therapie bei Patienten mit T21-JIA entspricht dem von JIA-Patienten mit einem normalen Karyotyp. Auch bei anderen chromosomalen Aberrationen namentlich Turner- (Monosomie XO), Klinefelter- (Poly-X, XXY) und Di George Syndrom (del 22q11.2) wird ein erhohtes Risiko fur das Auftreten einer JIA vermutet.

Zunehmend haufig werden Kinder und Jugendliche mit lokalisierten oder generalisierten muskuloskelettalen Schmerzen (kinder-)rheumatologisch vorgestellt, ohne dass eine zugrunde liegende rheumatologische Erkrankung diagnostiziert werden kann. Differenzialdiagnostisch mussen Schmerzerkrankungen bedacht werden. Eine lokalisierte chronische Schmerzsymptomatik ist seltener zu finden als die generalisierte Form. Vor allem das komplexe regionale Schmerzsyndrom (complex regional pain syndrome, CRPS) weist bei Kindern und Jugendlichen im Vergleich zum Erwachsenenalter einige Besonderheiten, nicht zuletzt bezuglich Behandlung und Prognose auf. Multimodale Therapieprogramme haben gute Erfolgsaussichten, die Therapie sollte zeitnah durch padiatrisch und schmerztherapeutisch erfahrene Behandler erfolgen, um eine Chronifizierung zu vermeiden.

In der differenzialdiagnostischen Abklarung von Arthralgien und/oder Arthropathien bei Kindern und Jugendlichen sind auch einige z. T. sehr seltene monogenetische Erkrankungen in Betracht zu ziehen. Zunachst autoinflammatorische Erkrankungen wie das Cryopyrin assoziierte periodische Syndrom (CAPS), die pyogene Arthritis mit Pyoderma gangranosum und Akne (PAPA-Syndrom) und die Infantile Sarkoidose (Blau Syndrom); daruber hinaus genetisch bedingte Veranderungen in Regulations- und Strukturgenen des Bindegewebes wie die Progressive Pseudorheumatische Arthropathie des Kindesalters (PPAC), das Camptodaktylie-Arthropathie-Coxa vara-Perikarditis-(CACP) – Syndrom, die Multizentrische Carpotarsale Osteolyse (MCTO), die Spondyloenchondrodysplasie (SPENCD) und das Camurati-Engelmann Syndrom (CAEND). Die Vorliegende Ubersicht im Rahmen des Schwerpunktheftes gibt einen Uberblick uber diese seltenen Erkrankungen.

Die Versorgung rheumaerkrankter Kinder und Jugendlicher hat in den letzten Jahren erhebliche Fortschritte gemacht. Hierbei spielen mehrere Faktoren eine Rolle: (i) Verbesserung in der medikamentosen Therapie, (ii) Strukturelle Verbesserungen in der kinderrheumatologischen Versorgung, (iii) Multidisziplinare Therapiekonzepte und strukturierte Patientenschulung, (iv) Weiterentwicklung der funktionellen Therapien. Im Folgenden werden die wesentlichen Entwicklungen am Beispiel der Behandlung der Juvenilen Idiopathischen Arthritis in einer Ubersicht zusammengefasst.

Background Systemic juvenile idiopathic arthritis (sJIA) is a complex disease with an autoinflammatory component of unknown etiology related to the innate immune system. A major role in the pathogenesis has been ascribed to proinflammatory cytokines like interleukin-6 (IL-6), and effective drugs inhibiting their signaling are being developed. This study evaluates sJIA patients treated with the IL-6 inhibitor tocilizumab (TCZ) concerning clinical response rate, disease course and adverse effects in a real-life clinical setting. Methods In 2009 a clinical and research consortium was established, including an online registry for autoinflammatory diseases (AID) (https://aid-register.de). Data for this retrospective TCZ study were documented by 13 centers. Results From 7/2009 to 4/2014, 200 patients with sJIA were recorded in the AID-registry. Out of these, 46 (19 m, 27 f, age 1–18 years) received therapy with TCZ. Long term treatment (median 23 months) has been documented in 24/46 patients who were evaluated according to Wallace criteria (active disease 6/24, inactive disease 5/24, remission 13/24 cases). Under observation co-medication were used in 40/46 cases. Adverse events were reported in 11/46 patients. The clinical response rate (no clinical manifestation, no increased inflammation parameters) within the first 12 weeks of treatment was calculated to be 35%. Conclusion Out of 200 sJIA children reported in the German AID-registry, 46 were treated with TCZ, showing a clinical response rate of 35% during the first 12 weeks, and inactive disease and/or remission under medication in 75% after one year. Adverse events were seen in 24% and severe adverse events in 4%. Trial registration The AID-Registry is funded by the BMBF (01GM08104, 01GM1112D, 01GM1512D).

OBJECTIVE: To determine whether systemic juvenile idiopathic arthritis (JIA) susceptibility loci that were identified by candidate gene studies demonstrate association with systemic JIA in the largest study population assembled to date. METHODS: Single-nucleotide polymorphisms (SNPs) from 11 previously reported systemic JIA risk loci were examined for association in 9 populations, including 770 patients with systemic JIA and 6,947 controls. The effect of systemic JIA-associated SNPs on gene expression was evaluated in silico in paired whole genome and RNA sequencing data from the lymphoblastoid cell lines (LCLs) of 373 European subjects from the 1000 Genomes Project. Responses of systemic JIA-associated SNPs to anakinra treatment were evaluated in 38 US patients for whom treatment response data were available. RESULTS: We found no association between the previously reported 26 SNPs and systemic JIA. Expanded analysis of the regions containing the 26 SNPs revealed only 1 significant association: the promoter region of IL1RN (P < 1 × 10(-4) ). Systemic JIA-associated SNPs correlated with IL1RN expression in LCLs, with an inverse correlation between systemic JIA risk and IL1RN expression. The presence of homozygous IL1RN high expression alleles correlated strongly with a lack of response to anakinra therapy (odds ratio 28.7 [95% confidence interval 3.2-255.8]). CONCLUSION: In our study, IL1RN was the only candidate locus associated with systemic JIA. The implicated SNPs are among the strongest known determinants of IL1RN and interleukin-1 receptor antagonist levels, linking low expression with increased systemic JIA risk. Homozygous high expression alleles predicted nonresponsiveness to anakinra therapy, making them ideal candidate biomarkers to guide systemic JIA treatment. This study is an important first step toward the personalized treatment of systemic JIA.

In der Rheumatologie zeigt der zunehmende Einsatz von Kombinationstherapien aus „disease modifying drugs“ (DMARDs) und Biologika auch bei schwer verlaufenden rheumatischen Grunderkrankungen im Kindes- und Jugendalter Erfolge. Diese Strategie steigert jedoch die medikamentenspezifischen infektiologischen Risiken. Zusatzlich bedingen viele Erkrankungen per se bereits ein erhohtes Infektionsrisiko. Einige Patienten weisen weitere immunologische oder organische Komorbiditaten auf, wie beispielsweise einen Komplementmangel oder eine pulmonale Gerusterkrankung, wodurch die Infektanfalligkeit zusatzlich steigt. Die hier vorgeschlagene Checkliste mit gezielten apparativen und immunologischen Vorsorgeuntersuchungen basiert auf einer „State-of-the-art-Auswertung“ der verfugbaren Literatur und eigenen Erfahrungen. Sie soll helfen, Risikofaktoren aufzudecken. Eine zusammenfassende Beurteilung von Grunderkrankung, Komorbiditaten und Wirkungsweise der Medikation ermoglicht somit 1) eine individuelle Risikostratifizierung der geplanten Immunsuppression und 2) eine Beurteilung der infektiologischen Gefahrdung des Patienten.

The goal of modern antirheumatic therapy is to achieve an optimized disease control. This is individually achieved by an intensified immunosuppression (IS) frequently combining different immunosuppressive agents. Intensified IS should be accompanied by a standardized protocol to monitor immunological changes in the patient. This should include checklists (see Part 1 Screening during intensified IS in children and adolescents). An individual risk stratification according to the planned IS allows a prediction of infectious disease risks for the patient and, thus, individual infection prophylaxis. In addition, standardized management of patients with fever while receiving intensified IS may prevent further complications.

Juvenile idiopathic arthritis (JIA) summarizes a group of inflammatory diseases of childhood. The etiology remains still unclear. In JIA, T cells have been demonstrated to play key roles in the pathogenesis. T-cell proliferation in JIA may be different in the peripheral blood (PB) and the synovial fluid (SF). The aim of this study is to demonstrate the turnover of T cells in the PB and SF of patients with persistent oligoarticular JIA (oJIA) compared to controls. Matched pairs of samples were investigated derived from PB and SF of nine patients with persistent oJIA. The cells from PB and SF were determined by flow cytometry. The majority of the PBMC and IAMC were in phase G0/G1, with fewer than 1% in S phase. In the SF, the percentage of cells in the S phase are higher than in the PB. The percentage of cells in the S phase in SF are equal to the result in the control group. In conclusion, the turnover of synovial T cells in persistent oJIA is higher than in the PB.

Impfungen stellen bei Kindern und Jugendlichen mit rheumatischen Erkrankungen ein besonderes Problem dar. Wirkungen und Nebenwirkungen von Impfungen sind fur dieses Patientenkollektiv leider nur unzureichend untersucht, und spezifische Impfempfehlungen fehlen. Die bei diesen Patienten haufig erforderliche immunsuppressive Therapie schafft zusatzliche Unsicherheit. Hinzu kommen Bedenken bezuglich impfassoziierter Reaktivierungen der Grunderkrankung. Die bestehenden Unsicherheiten im Umgang mit Impfungen fuhren zu einer erheblichen Praxisvariation unter den Kinderarzten und Impflucken bei den betroffenen Kindern und Jugendlichen. So ist jeder dritte Patient mit juveniler idiopathischer Arthritis unzureichend geimpft, was sogar Standardimpfungen mit Totimpfstoffen wie Tetanus/Diphtherie einschliest. Nach aktuellem Stand des Wissens ist der Nutzen vieler Impfungen gerade bei Patienten mit Autoimmunerkrankungen deutlich hoher als deren Risiko zu veranschlagen. Gerade Patienten mit immunsuppressiver Therapie benotigen einen besonderen Schutz vor Infektionen. Kinder und Jugendliche mit rheumatischen Erkrankungen sollten deshalb – soweit moglich – nach den STIKO-Empfehlungen geimpft werden. Dabei muss der Zeitpunkt der anstehenden Impfung sorgfaltig in Abhangigkeit von der Krankheitsaktivitat und Therapie gewahlt werden.

Chronic anterior uveitis is a serious complication of juvenile idiopathic arthritis (JIA); disease flares are highly associated with loss of vision. Leflunomide (LEF) is used successfully for JIA joint disease but its effectiveness in uveitis has not been determined. The aim of this study was to determine whether LEF improves flare rates of uveitis in JIA patients compared to preceding methotrexate (MTX) therapy.A single-centre retrospective study of consecutive children with JIA and chronic anterior uveitis was performed. All children initially received MTX and were then switched to LEF. Demographic, clinical, and laboratory data, dose and duration of MTX and LEF therapy, concomitant medications and rate of anterior uveitis flares, as determined by an expert ophthalmologist, were obtained. Flare rates were compared using a generalized linear mixed model with a negative binomial distribution.A total of 15 children were included (80% females, all antinuclear antibody positive). The median duration of MTX therapy was 51 (range 26-167) months; LEF was given for a median of 12 (range 4-47) months. Anti-tumour necrosis factor (anti-TNF-α) co-medication was given to four children while on MTX. By contrast, LEF was combined with anti-TNF-α treatment in six children. On MTX, JIA patients showed a uveitis flare rate of 0.0247 flares/month, while LEF treatment was associated with a significantly higher flare rate of 0.0607 flares/month (p = 0.008).Children with JIA had significantly more uveitis flares on LEF compared to MTX despite receiving anti-TNF-α co-medication more frequently. Therefore, LEF may need to be considered less effective in controlling chronic anterior uveitis.

Chronic anterior uveitis is a common complication of juvenile idiopathic arthritis (JIA). Leflunomide is a frequently used alternative to methotrexate in the treatment of joint manifestations of JIA. However, very little is known on the effect of leflunomide treatment on concurrent chronic uveitis in JIA.

Background Biological disease modifying antirheumatic drugs (bDMARD) had great impact on the medical management of patients with juvenile idiopathic arthritis (JIA). Many patients nowadays enter adulthood in clinical remission, with normal function and without long-term sequelae. There is little information to what extent the early use of bDMARDs affects the long-term outcome of patients with JIA. Objectives To investigate if the 10-year outcome after JIA onset is associated with the time lag between JIA disease onset and first bDMARD use. Methods Outcome variables were examined in patients prospectively observed in the national JIA biologic register BiKeR and its follow-up register JuMBO since initiation a bDMARD therapy. Analyses included patients with at least one visit in JuMBO. Assessed parameters were JADAS3–10, C-HAQ, joint surgery (replacements, synovectomies), eye surgery and patient-reported outcomes. To analyze the influence of the time lag between JIA onset and first use of bDMARD, patients were assigned to one of the following three groups (G1: ≤2 year = early therapy, G2: intermediate, G3: ≥5 years = late). A general propensity score was estimated to adjust for baseline differences between the three groups. Mixed models were used to determine the association of the three groups and outcomes. Surgeries were analyzed by Cox regression analyses. Results 609 patients were ever treated with a bDMARD and successfully transferred to JuMBO. Most (91%) patients were enrolled in BiKeR on etanercept followed by adalimumab (6%), 93% had previously received a conventional synthetic (cs) DMARD. 27.9% had RF negative polyarthritis and 19.5% enthesitis-related arthritis. The first csDMARD was started 0.4 years after disease onset in the early bDMARD group (n=142), and 1.2 and 3.1 years after JIA onset in the in-between group and late group (n=274), respectively. At their last follow-up (10.2±6.2 years after JIA onset), the patients9 mean age was 21.2 years. The clinical outcome 10 years after disease onset could be investigated in 478 patients. Patients with early biologic treatment were significantly more often in drug-free JADAS remission (15%) for at least 12 months, had more often an inactive disease (JADAS3–10≤1, 27.6%) and no functional limitations (58.6%) compared to late treatment start. There was no significant difference in the patient-reported outcome measures. Among all 609 patients, 35 (5.8%) patients had undergone joint replacement, 100 (16.4%) synovectomy and 19 (3.2%) eye surgery. Patients on bDMARD in follow-up had a lower likelihood for joint replacement (HR=0.25, p=0.003) or synovectomy (HR=0.26, p Conclusions Patients who started with cs and bDMARDs within the first two years of disease are significantly more often in drug-free remission in adulthood and have less sequelae than those who started later. The data emphasize the importance of a fast disease activity control and may support the idea of a window of opportunity for JIA. Disclosure of Interest None declared

Background Since the approval of first biologics for JIA, such treatments in Germany are monitored prospectively by the BiKER registry. Methods sJIA pts documented in BIKER exposed to Etanercept (ETA), Tocilizumab (TOC) or IL-1inhibitors were identified. A 6-month therapy period was chosen as a meaningful time for early efficacy judgement. Intention to treat analysis (ITT) of JADAS10 was performed. Discontinuation due to inefficacy/intolerance was calculated as non-response. Results 205 sJIA patients (51% male) received 269 treatment courses with biologics (TOC 71, Anakina 36, Canakinumab 19, ETA 143). Median age and disease duration (ETA 3.3;TOC 3.3;IL-1i 3.0) were comparable. The choice of drug was influenced by the availability. ETA was started in 80% of pts before 2008 while in the TOC cohort all pts and in the IL-1i cohort 74% started therapy after 2008. Pre-treatment consisted of steroids in all pts, MTX in the ETA/TOC/IL-1i cohort in 88%/83%/76% and biologics preexposure was used in 2%/66%/86%. Concomitant treatment with systemic steroids was significantly less frequent with TOC (44%, p Systemic manifestations were present at baseline in: 8% ETA, 96% TOC and 38% IL-1i cohort. The mean±SD baseline JADAS was higher in the ETA cohort (20.7±9.1) than in the TOC cohort (16.2±10.6) or IL-1i cohort (7.8±8.9). At month 6, a marked decrease of the JADAS was noted in all cohorts. ITT analysis revealed a significant advantage of TOC and Il-1i over ETA (table). Significantly more pts reached a JADAS-Remission (JADAS≤1) upon TOC (OR/95CI 3.85/1.68–8.83/p Conclusions A high proportion of pts showed a significant response to treatment especially with TOC or with IL-1i. After 6 months on treatment JADAS remission criteria were reached by up to 50% of patients while 60% to 65% reached JADAS minimal disease activity desoite much less steroids and DMARD used with TOC or IL-1i. ETA has been used in earlier times but it is less effective and it9s use in sJIA has markedly decreased in Germany. Disclosure of Interest None declared

Background High plasticity was described for Th1 and Th17 cells depending on the local cytokine milieu and regulation by Tregs. Pathogen-induced human Th17 cells and Tregs are strongly regulated by IL-1beta. So far, the influence of IL-1beta on FoxP3 methylation and stability of the Treg lineage has not been investigated. Further, whether inhibition of IL-1beta and its receptor is able to promote FoxP3 demethylation and to conserve Treg functions, such as suppression of Th17 and Th1 functions, has not been assessed in healthy humans, as well as in patients with autoimmune arthritis. Objectives Thus, the present study aimed to investigate in vitro nTreg and iTreg functions in lymphocytes obtained from stored routine blood samples of patients with juvenile idiopathic arthritis (JIA) or rheumatoid arthritis (RA) in different disease activity states. Methods Proportions of peripheral nTregs and cultured iTregs from stored routine blood samples taken from JIA, RA patients and healthy, age-matched controls (HC) and intracellular cytokine production were analyzed by flow cytometry. Suppressive function of iTregs under in vitro inhibition of IL-1beta was studied by suppression assays. FOXP3 expression and methylation were analyzed by quantitative PCR and bisulfite pyrosequencing. Results Lower proportions of nTregs were found in samples of JIA patients with acute disease flare (mean 2.3% of CD4+ T cells) compared to HC (4.1%) (p Conclusions Induction of Tregs seems to be different depending on disease activity status in autoimmune arthritis. DNA methylation at the FOXP3 promoter and enhancer regions may influence expression of FoxP3 in Tregs and, thus, modify their phenotype. Although IL-10 was not markedly influenced by IL-1beta-dependent mechanisms, our findings indicate that suppressive iTreg functions may be restored by selective blockade of IL-1beta. Disclosure of Interest None declared

Background Since the approval of first biologics for treatment of JIA, surveillance in Germany is monitored prospectively by the BIKER registry. Objectives To evaluate the safety of Tocilizumab (TOC), IL-1 inhibitors (Anakinra & Canakinumab) and Etanercept (ETA). Methods Safety assessments were based on adverse events reports. Results 205 sJIA pts received 269 treatment courses with biologics (TOC 71, Anakina 36, Canakinumab 19, ETA 143 and 57 pts. received MTX only. Median age was lower In the MTX cohort (4.8y) than with ETA (8.2); TOC (9.6); IL-1i (8.2) as was the disease duration. ETA was started in 80% of pts before 2008 while in the TOC cohort all pts and in the IL-1i cohort 74% started therapy after 2008. Pre-treatment consisted of systemic steroids in 75% starting MTX and in all patients starting biologics. Initial concomitant treatment with systemic steroids was significantly less frequent with TOC (44%, p Conclusions Higher rates of safety signals, especially infections were noted upon treatment with TOC and IL-1i. Beside infections, disease reactivation and MAS, further adverse events were rare and overall tolerability was acceptable. However, steroids were markedly spared upon IL6- and Il-1 inhibitors. Disclosure of Interest G. Horneff Grant/research support from: Abbvie, Roche, Chugai, Pfizer, A. Schultz: None declared, A. Hospach: None declared, G. Ganser: None declared, I. Foeldvari: None declared, A. Thon: None declared, R. Trauzeddel: None declared, F. Weller: None declared, K. Minden: None declared, J. Haas: None declared

Control of disease activity and recovery of function are major issues in the treatment of children and adolescents suffering from juvenile idiopathic arthritis (JIA). Functional therapies including physiotherapy are important components in the multidisciplinary teamwork and each phase of the disease requires different strategies. While in the active phase of the disease pain alleviation is the main focus, the inactive phase requires strategies for improving motility and function. During remission the aim is to regain general fitness by sports activities. These phase adapted strategies must be individually designed and usually require a combination of different measures including physiotherapy, occupational therapy, massage as well as other physical procedures and sport therapy. There are only few controlled studies investigating the effectiveness of physical therapies in JIA and many strategies are derived from long-standing experience. New results from physiology and sport sciences have contributed to the development in recent years. This report summarizes the basics and main strategies of physical therapy in JIA.

performed with infrared cameras and the Plug-in-Gait Model. Analyses focused spatio-temporal and kinematic parameters in the sagittal plane. Mann-Whitney-UTests (p

A total of 94 patients with juvenile chronic arthritis (JCA) was tested for HLA class I by serology and for class II by RFLP typing. Early onset JCA (EOPA) is associated with HLA-A2, DR5 and DR8 in both males and females. The combination (joint occurrence) of these JCA associated alleles (A2, DR5, DR8) is frequently seen in patients with chronic iridocyclitis. Late onset pauciarticular disease has an increased frequency of HLA-B27, especially in males. Our data confirm that polyarticular JCA with early childhood onset (or = 4 years) is associated with DR5 and DR8 and has a different immunogenetic background from polyarticular JCA with later childhood (4 years) onset (associated with DR4).

Vaccinations represent a special problem in children and adolescents with inflammatory rheumatic diseases. There are very limited data on the safety and efficacy of vaccines in these patients, and guidelines for immunization are missing. The immunosuppressive therapy often necessary for these patients gives rise to additional uncertainty. In addition, many colleagues consider vaccination to increase the risk of relapse of the rheumatic illness. As a consequence, there are substantial variations in practicing vaccination in these patients, resulting in insufficient vaccination coverage rates. For example, every third patient with juvenile idiopathic arthritis is incompletely vaccinated; this even includes toxoid vaccines for tetanus and diphtheria. The benefit of vaccinations, which far outweighs their potential risks, is well recognized even in patients with autoimmune diseases. These patients in particular require a special protection from infections due to their immunosuppressive therapies. Therefore, children and adolescents with rheumatic diseases should be immunized according to the Standing Immunization Commission of the Robert Koch Institute recommendations whenever possible. However, the time of vaccination must be carefully selected, taking disease activity and treatment into account.

Systemic juvenile idiopathic arthritis (SJIA) is regarded as an autoinflammatory disease (AID) of unknown etiology related to abnormalities of the innate immune system. A major role in the pathogenesis has been ascribed to proinflammatory cytokines as interleukin (IL)-6 and IL-1.

Background Methotrexate (MTX) is the mainstay treatment in the therapy of children with juvenile idiopathic arthritis (JIA) and can lead to prolonged remission and improved quality of life. However JIA patients frequently develop intolerance to MTX, with anticipatory and associative gastrointestinal adverse effects before drug intake, arising as a conditioned response. Parents frequently try to alleviate these symptoms with a variety of countermeasures against nausea. Objectives The objective of this study was to investigate the course of MTX intolerance in pediatric patients over a period of 6 months, as well as the effect of countermeasures by parents on the severity of MTX intolerance. Methods Consecutive patients admitted to the German Center for Pediatric and Adolescent Rheumatology from October 2012 until April 2014 were included in this study. MTX intolerance was measured using the validated Methotrexate Intolerance Severity Score (MISS) questionnaire. Inclusion criteria were 1) diagnosis of JIA, 2) treatment with MTX for at least 3 months prior to inclusion, and 3) confirmation of MTX intolerance by a MISS value of ≥6. Exclusion criteria were other diseases leading to nausea and/or abdominal complaints, and concomitant medications possibly inducing nausea (excepting biologics and non-steroidal anti-inflammatory drugs). Methotrexate dose, MISS and countermeasures instituted by the parents were determined at 4 time points (at inclusion, at 6 weeks, 3 months and 6 months). Countermeasures were classified into 4 criteria: antiemetic drugs, covert dosing, taste masking and complementary medicine. Results were analyzed using descriptive statistics and non-parametric testing (Wilcoxon signed rank test). Results 38 patients were included (63% female, median age at inclusion 11.7 years, median disease duration 7.1 years). Average MISS at inclusion was 10.8±4.1, and after 6 months 12.2±7.2 (p=0.316). In 6/38 patients (16%), MTX was reduced or discontinued during the study. In 89 time intervals between study visits, 40 countermeasures were introduced by the parents. Conclusions If MTX intolerance is present, symptoms will not decrease over the course of 6 months. Various modalities used by the parents as countermeasures against nausea by the parents show no discernible effect. Acknowledgements This study was supported by the “Stiftung Hilfe fur das rheumakranke Kind e.V.” Disclosure of Interest None declared

Background Juvenile idiopathic arthritis (JIA) is the most common arthritic disease of childhood and is caused by a combination of genes and environment. In the last few years great advances have been made in dissecting the genetic basis of JIA with now 17 confirmed susceptibility loci identified. One of these loci, the MHC region, has been established for many years but the complexity and the broad linkage disequilibrium across the region has rendered fine-mapping associations challenging. Novel imputation strategies can now be utilized to impute HLA classical alleles and amino acids across the region. Objectives The aim of this work was to gain a greater understanding of the associations across the HLA region in all JIA subtypes. Methods Using the dense genotype data obtained from the analysis of the Illumina ImmunoChip in 4574 JIA cases (not including the systemic-onset cases) and 14412 controls, we imputed HLA classical alleles (2-digit and 4-digit resolution) and amino acids across the MHC region (Chr6:29-34Mb) using the SNP2HLA algorithm and a large reference panel. We performed univariate analysis for all markers across the region and tested all amino acids in HLA-DRB1 by performing an omnibus test of amino acid residues for each position. Conditional analysis, including the most significant marker as a covariate, was performed to identify independent effects. Analysis was repeated in the individual subtypes (persistent oligoarthritis (pO) n=1751, extended oligoarthritis (eO) n=658, RF negative polyarthritis (RF-P) n=1525, RF positive polyarthritis (RF+P) n=337, enthesitis related arthritis (ERA) n=183, psoriatic arthritis (jPsA) n=112). Results The omnibus test for all amino acids across HLA-DRB1 showed most significant association at HLA-DRB1 amino acid (AA) 67 and conditioning on all residues at AA 67 found significant association remaining at HLA-DRB1 AA 13 (the glycine residue most associated), suggesting two independent effects in HLA-DRB1. There was evidence for further effects in HLA-DRB1. Conditioning on all alleles of HLA-DRB1 found additional independent effects at HLA-DPB1-0201 and HLA-A AA 95. These associations hold across RF-P and both pO and eO subtypes, HLA-DRB1 AA 13 is most strongly associated in RF+P with the histidine residue driving the association. In the ERA subtype HLA-B27 showed the strongest association. For jPsA no HLA markers reached genome-wide significance. Conclusions Analysis of the MHC region in the largest cohort of JIA cases and controls studied to date has found the strongest association with the HLA-DRB1 region, with additional multiple independent effects. Acknowledgements Juvenile Arthritis Consortium for Immunochip (JACI) Disclosure of Interest None declared

Background Methotrexate (MTX) is the drug used most frequently in the therapy of juvenile idiopathic arthritis (JIA). However, long-term treatment in children frequently leads to intolerance, with marked revulsion and refusal of treatment. Mutations in the gene for methylenetetrahydrofolate reductase (MTHFR) can lead to increased toxicity of MTX and could possibly represent an initial stimulus for this conditioned response. Objectives The objective of this study was to investigate the relation of common mutations in the MTHFR gene and occurrence of MTX intolerance in pediatric patients with juvenile idiopathic arthritis treated with MTX. Methods Consecutive patients admitted to the German Center for Pediatric and Adolescent Rheumatology from October 2012 until April 2014 included in this study. Inclusion criteria were 1) diagnosis of JIA and 2) treatment with MTX for at least 3 months prior to inclusion. Exclusion criteria were other diseases leading to nausea and/or abdominal complaints, and concomitant medications possibly inducing nausea (excepting biologics and non-steroidal anti-inflammatory drugs). Intolerance to MTX was determined using the validated Methotrexate Intolerance Severity Score (MISS) questionnaire; presence of MTX intolerance was assumed for MISS values of ≥6. Presence of the two most common mutations in the MTHFR gene (C677T and A1298C) was tested using a polymerase chain reaction assay, as described previously. Results were analyzed using descriptive statistics and chi square testing. Results 114 patients were included (71% female, age at inclusion (median) 12.6 years, disease duration (median) 4.1 years). Of those, 49 (43%) showed MTX intolerance. 42% of patients were heterozygous, and 7% homozygous for the C677T mutation of the MTHFR gene, 45% of patients were heterozygous, and 12% homozygous for the A1298C mutation; both are comparable to published allele frequencies. Compared to the homozygous wild type, MTX intolerance was not found significantly more frequent in patients with hetero- and homozygous (p=1.000) or homozygous (p=0.125) C677T mutations, nor in patients with hetero- and homozygous (p=0.775) or homozygous (p=0.444) A1298C mutations. Compound heterozygous mutations for C677T and A1298C were also not found significantly more frequently in patients with MTX intolerance (p=0.809). Conclusions Mutations in the MTHFR gene are not found significantly more frequently in JIA patients with intolerance to MTX. Toxicity associated with the MTHFR gene does not seem to be causally related to the development of MTX intolerance. Acknowledgements This study was supported by the “Stiftung Hilfe fur das rheumakranke Kind e.V.” Disclosure of Interest None declared

Background Uveitis is one of the most threatening complications in juvenile idiopathic arthritis (JIA). It occurs in approximately 10% of all JIA patients. Whether the frequency of uveitis in JIA has decreased over time as a result of the widespread use of immunosuppressive substances, is still an open question. Few data on the occurrence of JIA-associated uveitis and related secondary complications are available from population-based studies. Objectives To determine the change in uveitis prevalence and related secondary complications in patients with JIA between 2002 and 2013. Methods Data source for this study was the National Paediatric Rheumatological Database (NPRD). Uveitis onset, disease characteristics and details on treatment were provided by rheumatologists once a year. Ophthalmologists reported about uveitis characteristics such as eye involvement, uveitis activity and eye complications in detail in a specific uveitis add-on module. Data from the years 2002 to 2013 were used to determine the annual prevalence of uveitis and frequency of secondary complications. Two-level random effect models were used for investigating the change between 2002 and 2013. Results A total of 60 centers included 18,555 JIA patients, which were recorded in the NPRD between 2002 and 2013. The mean age of the patients was 11.4±4.6 years, their mean disease duration 4.4±3.7 years. 66.9% were female and 51.7% ANA positive. Patients9 mean age at arthritis onset was 6.9±4.5 years. In a multivariable regression analysis, the following risk factors for uveitis were identified: oligoarthritis (OR=4.21, p Conclusions Uveitis prevalence and the frequency of secondary complications significantly decreased between 2002 and 2013. Both were correlated with a more frequent use of DMARDs. Acknowledgements The study was supported by a grant from Pfizer Pharma GmbH Germany (Forschungsforderung Rheumatologie). The national pediatric database is financially supported by the Children9s Arthritis Foundation (Kinder-Rheumastiftung). Disclosure of Interest J. Klotsche: None declared, K. Minden: None declared, S. Schenck: None declared, M. Niewerth: None declared, T. Hospach Speakers bureau: Pfizer, Abbvie, J.-P. Haas: None declared, R. Berendes: None declared, G. Ganser Grant/research support from: Abbott, Actelion, Pfizer, A. Heiligenhaus Grant/research support from: AbbVie, Pfizer, Novartis, and Deutsche Forschungsgemeinschaft, and has received study fees from AbbVie, Alimera Sciences, Allergan, Santen, and XOMA., C. Tappeiner Grant/research support from: Swiss Foundation for Grants in Biology and Medicine (SFGBM), Swiss National Science Foundation (SNSF) and Novartis.

Background Rituximab (RTX) is used in refractory paediatric rheumatic diseases (PRD). Data regarding the effects of RTX on the immune system in children and safety in PRD is scarce. Objectives To prospectively evaluate indicators of humoral immunity before and until 2 yrs after RTX administration. Methods 20 patients (pts) with PRD (4 SLE, 3 MCTD, 3 JIA, 2 eosinophilic fasciitis, 2 juvenile dermatomyositis, 2 Sjogren-syndrome, 2 GPA (Wegener), 1 MPA, 1 PM/Scl-overlap) after exclusion of common variable immunodeficiency (CVID) received at least 1 standard dose RTX cycle (some pts up to 3 cycles). Additional treatment consisted of prednisolone (10), hydroxychloroquin (10), mycophenolate mofetil (9), methotrexate (6), leflunomide (4), abatacept (2), everolimus (2), cyclosporin (1) and antiinflammatory doses of intravenous immunoglobulin (IVIG) (3). Lymphocyte subpopulations, IgA, IgG, IgM and IgE levels, IgG subclasses, isoagglutinin titers, IgG levels to tetanus toxin, H. influenzae type B (Hib), pneumococcus and measles, spleen size, presence of Howell-Jolly bodies and throat culture were obtained 6, 12 and 24 months (mos) after RTX. IgG levels and vaccine titers in pts receiving IVIG were not included. The continuous variables at time points 6, 12 and 24 mos were compared by paired T test to time point 0 mo (prior to RTX). Results All pts achieved complete B cell depletion. B cells repopulated in all pts with a median of 8.5 mos. IgG and IgM levels were as follows (median [interquartile] mg/dl at 0, 6, 12, 24 mos): IgG 1302 [898;1993], 1172 [839;1409], 902 [732;1248], 1165 [805;1580]; IgM 100 [73;174], 55 [39;85], 33 [28;59], 44 [35;51]. Significant reductions were observed for IgG (6/12 mos), IgM (6/12/24 mos), IgA (6/12/24 mos) and IgE (24 mos). Overall, 7/17 (41%) of patients received IVIG substitution based on predefined threshold levels (3/4 after 3rd cycle of RTX). 1 pt developed low IgG2/3, IgA and IgM levels at 24 mos after one cycle of RTX. 2 pts developed low IgG4 levels. Tetanus toxin IgG decreased significantly at 12 mos but not below a protective threshold. There was a non-significant decrease in pneumococcal antibodies at 12 and 24 mos. Measles IgG levels decreased significantly at 12 and 24 mos but not below a protective threshold. Isoagglutinin titers were present in all pts throughout 24 mos ruling out CVID. There was a remittent non-significant decrease in spleen size. However transient Howell-Jolly bodies indicating temporary hyposplenism were observed in 8 pts. Throat culture following RTX demonstrated colonization with C. albicans in 12, S. aureus in 3, Hib in 2, both P. aeruginosa and S. marcescens in 1, E. coli in 1 and Enterobacter in 1 pts. There were no pneumonias requiring hospitalization. Conclusions Transient IgG-/IgM-deficiency occasionally occurs after RTX treatment of PRDs, especially after repeated treatment cycles, whereas protracted humoral immunodeficiency is very rare. Preventive strategies, including IVIG substitution and/or antibiotic prophylaxis informed by immunologic studies are effective in preventing serious invasive infections. Therefore, we suggest at least 2 yrs of surveillance for acquired humoral immunodeficiency and one-time immunization titers after RTX treatment in PRD. Acknowledgements Supported by a grant from “Verein Hilfe fur das rheumakranke Kind”. Disclosure of Interest None declared

Background Juvenile Idiopathic Arthritis (JIA) patients have arthritis onset of unknown cause that lasts >6 weeks in the inflamed joints of children younger than 16 years. JIA is a complex genetic trait with established increased familial risk and robustly replicated genetic associations (e.g. HLA, PTPN2 ). Multiple single nucleotide polymorphisms (SNPs) in the 22q13.1 locus have reached genome-wide significance in recent genetic association studies using the Immunochip. The 22q13.1 locus contains both IL2RB and RAC2 which are attractive candidates to influence JIA pathology and have respective roles in IL-2 signaling and cell migration. Objectives To identify the statistically, bioinformatically and experimentally most plausible causal SNPs associated with risk of JIA in the 22q13 region. Methods We fine mapped the 22q13.1 locus using data from large scale genotyping projects of a European ancestry cohort of subjects with (3,905) and without JIA (14,388) to predict variants most likely causal at the 22q13.1 locus. Logistic regression conditional analysis was used to define regions of association followed by Bayesian analysis to define variants with large posterior probabilities. Transcription factor binding predictions were used to identify variants for experimental testing by electrophoretic mobility shift assay (EMSA). We limited our investigation to polyarticular RF - and oligoarticular JIA cases to reduce phenotypic heterogeneity. Results Conditional analyses showed independent associations to JIA in both the IL2RB and RAC2 loci. We identified two SNPs that can account for all of the JIA genetic association in this region. Using a Bayesian analysis we identified the SNPs that explained 95% of the posterior probability in the region and are the most likely to be causal. Altered nuclear extract binding was observed with risk and non-risk alleles in the IL2RB locus but not RAC2. These experimental data are consistent with the predicted alteration in transcription factor binding. Conclusions Polymorphic variants in the RAC2 and the nearby IL2RB locus are independent JIA risk loci. Use of the statistical and bioinformatics approach to produce candidates for laboratory validation is an important strategy in defining the function of risk variants in JIA. Disclosure of Interest None declared

Background Varicella zoster virus (VZV) infection is a serious preventable infection in patients receiving immunosuppression. The safety of varicella vacination (VV) in patients with paediatric rheumatic disease (PRD) while receiving immunosuppression (IS) has been debated. Objectives To evaluate the safety of 1st and/or 2nd dose varicella vaccine (VV) in patients (pts) with PRDs receiving IS after passing a pre-vaccination check list of immunologic criteria. Methods In this single centre study, 21 VZV-susceptible pts with clinically inactive PRDs, including different categories of juvenile idiopathic arthritis and connective tissue diseases between the ages of 2–18 years on low-intensity IS (LIIS) (methotrexate [MTX] ≤15mg/m 2 /week and/or prednisolone 15mg/m 2 /week, leflunomide, mycophenolate mofetil [MMF], etanercept, tocilizumab, anakinra, abatacept, or a combination thereof) were included in this study. Prior to vaccination, pts were screened according to an immunologic checklist with predefined cut-offs (for pts on LIIS: WBC>3000/μl, ALC>1200/μl, IgG>500mg/dl, IgM>0, Tetanus toxin-IgG >0,10IU/ml; in addition, for pts on HIIS: CD4 >200/μl [if>5 yrs] or CD4 >500/μl [if 1-5 yrs] and positive T cell reactivity to mitogen or antigen, e.g. via TB-EliSpot positive control. Pts meeting these safety criteria received either a 1st and/or 2nd dose of VV without suspension of IS. VZV-IgG levels were measured before applying VV and after each dose. VZV cellular mediated immunity (CMI) was measured after VV. Potential side effects and PRD flares were monitored. Results Out of 9 pts receiving LIIS and 12 pts receiving HIIS none failed the immunologic checklist. 8 pts (2 LIIS, 6 HIIS) had already received their 1 dose of VV prior to this study and received a 2nd/booster dose of VV only. 13 pts (7 LIIS, 6 HIIS) received their 1st dose of VV within the study and 7 of these 13 pts received a 2nd dose of VV. 11/13 pts demonstrated VZV-IgG levels of >150 IU/ml after the 1st dose of VV, and 5/7 pts of those receiving a 2nd dose of VV achieved levels of >500 IU/ml. 1 pt (on MMF) did not achieve protective VZV-IgG levels and 1 pt (on leflunomide and abatacept) did just achieve a VZV-IgG level of exactly 150 IU/ml, despite 2 doses of VV and adequate humoral and cellular immunity. Of those 8 pts receiving a booster dose only, all exceeded VZV-IgG levels of >500 IU/ml by far. There was no difference in either the mean absolute or relative increase (Δ) in VZV-IgG between pts on LIIS vs. HIIS (after 1st dose of VZV Δ341 IU/ml vs. Δ378 IU/ml and 4.7-fold vs. 4.2-fold, respectively; after 2nd dose Δ745 IU/ml vs. Δ1001 IU/ml and 6.9-fold vs. 6.4-fold, respectively). Data on VZV-CMI were pending at the time of abstract submission. There was no evidence of VV-induced varicella or other VV-associated complications. None of the pts developed a PRD flare and no change in the IS regimen was required in any pt during a minimum follow-up of 4 wks. 7 pts had transient arthralgias of unclear association with VV administration. Conclusions After meeting easy-to-obtain immunologic criteria, the VV could safely be applied to a diverse cohort of pts with clinically inactive PID on IS with excellent response in the majority of pts. Acknowledgements Supported by a grant from “Verein Hilfe fur das rheumakranke Kind”. Disclosure of Interest None declared

Background Patients with polyarticular Juvenile Idiopathic Arthritis (JIA) suffer from functional impairments caused by inflammation [1]. While medical treatment leads to an improvement of disease activity in JIA [2], little is known about the effects on conditional or on coordinative abilities. Both are very important in daily living. Objectives The aim of this work is to verify the balance control of JIA patients before and after 9.8 (Q25: 8.5/Q75: 11.3) months with initial adjustment to an anti-TNF-α therapy combined with functional treatment (e.g. physiotherapy) in comparison to healthy peers. Methods Longitudinal effects on balance control of twenty-six patients with polyarticular JIA were analysed before (T0) and after ten months (T1) with an anti-TNF-α therapy combined with functional treatment (median for duration of disease: T0 6.8yr). In addition, a healthy age matched control group (CG; n=26) was included in the study. The balance control was measured with the S3-Check (TST, Groshoeflein). This is a validated measurement system for functional evaluation of stability and sensorimotor ability of the body [3]. The board has one axis of rotation, which enables an alternation up to an overturning of 12° from left to right. The subjects stand barefoot on the S3-Check with an arbitrary arm position. They had the announcement to keep the board for 30 seconds as horizontal as possible. The best results of the stability and sensory indices after three trials were compared with the Wilcoxon signed-rank and Mann-Whitney-U test (p Results JIA patients had significantly lower stability and sensory indices compared to the healthy peers. The balance indices of the patients did not differ between T0 and T1. In anthropometric characteristics no significant differences could be found between the patients and controls. All results are presented in table 1. Conclusions Lower balance indices of the S3-Check demonstrate that the JIA patients had a significantly better stability and motor control than controls. The patients are able to react better to variable positions of the balance board. As all JIA patients included suffered from bad controlled polyarticular JIA, daily compensatory movements in consequence of polyarticular joint pain might have a positive effect on balance control. Additionally an increased body-awareness of patients by long-term functional physiotherapy could further amplify this effect. An anti-TNF-α therapy of ten months did not further improve coordinative ability. The positive results emphasize the significance of functional treatment in polyarticular JIA patients. References Hartmann M et al. (2010). Int J Pediatrics Vol 2010. Minden K et al. (2013). Z Rheumatol 72(4): 339-46. Raschner C et al. (2008). Sportverl Sportschad 22:100-5. Acknowledgements The authors want to thank Pfizer Inc., the “Deutsche Kinderrheuma-Stiftung” and “Ironman-Hilfe Kinderrheuma” for supporting this study. Disclosure of Interest None declared

Background Comorbidities can have a significant influence on presentation, course and prognosis of JIA. Objectives The aim of this study is to analyse the occurrence of comorbidities in a large JIA cohort. Methods JIA patients starting treatment with biologics or methotrexate were followed by the BIKER registry. This database was screened for comorbid conditions reported at baseline. Differences were analyzed by χ 2 test. Results 3427 pts (67.6% female) were admitted. The median [IQR] age at onset was 7.1 y. [3.1; 11.3], at inclusion was 11.8 y. [7.3-14.9] and the median disease duration was 2.1 y. [0,7-5.2]. 1517 (44.3%) pts started MTX. 1916 (55.7%) pts started a biologic. A total of 1327 comorbidities were reported in 959 pts (up to 4 per pts). Uveitis (327) was the most common followed by asthma (53), short stature (47), atopic dermatitis (44), Hashimoto thyreoiditis (29), obesity (28), heart defects (20), arterial hypertension (20), Psoriasis (25), pain amplification syndrome (19), attention-deficit hyperactivity disorder (19), diabetes mellitus type 1 (18), epilepsies (14) and cushingoid syndrome (14). Thus with the exception of uveitis, comorbidities are rarely reported. On interest, the rate of obesity reported is the same as the rate calculated (BMI SDS>3 according to WHO), the rate of short stature reported is much lower than calculated (n=234, length SDS Conclusions Apart from uveitis comorbidities are rare, but there were marked gender related differences. Gender specific aspects should be taken into account considering the diagnostics and treatment of JIA. The limitation of these analyses is the voluntary reporting of comorbidities in BIKER. Disclosure of Interest None declared

Background Methotrexate (MTX) is the most widely used DMARD in JIA. MTX is regarded to be a safe drug, effective in around 70% of JIA cases. Due to the frequent reoccurrence of disease after discontinuing drug therapy, MTX is often prescribed to patients over an extended period of time. However, little is known about its tolerability in long-term use in JIA. Objectives To determine the frequency of adverse events in JIA patients on MTX and the frequency of drug discontinuation due to MTX intolerance. Methods Patients treated with MTX and prospectively followed in the JIA biologic registers BiKeR and JuMBO were considered for this analysis. Adverse events (AEs) were categorized on the basis of MedDRA. Exposure-adjusted rates for AEs were calculated. MTX intolerance comprised defined preferred terms, representing well-known MTX-induced symptoms, such as nausea, vomiting, and abdominal pain, and direct reports of adverse drug reactions or refusal of MTX. Only events reported by physicians to have at least a possible causal relationship were considered as MTX-related. Results Out of 848 JIA patients followed into adulthood, 725 patients were treated with MTX during the mean observation period of 7.3 years (6,188 patient-years of observation). During this period, patients had been exposed to MTX for a total of 2,762 years (exposure-years [EY]). At enrollment into the register, 687 patients were on MTX (61% of these in combination with a biologic), while at the last follow-up at which patients had a mean age of 21.7 years, only 296 patients were still on MTX (62% in combination with a biologic DMARD). Reasons for MTX discontinuation were provided for 323 cases. MTX was discontinued most frequently because of an AE (39%). Remission was the second most common reason (37%), followed by request from the patient in 22%, inefficacy was the least common reason in 9%. One in three patients received more than one course of MTX, with the first course being the longest with a median treatment duration of 2.6 years (second and third course 1.2 and 1.1 years, respectively). During MTX exposure, 435 AEs (17.7/100 EY) and 50 serious AEs (1.8/100 EY) were considered by the physicians as causally related to MTX. Among these, intolerance dominated with 204 events (7.39/100 EY), followed by infections (n=68, 2.46/100 EY) and hepatotoxicity (n=29, 1.05/100 EY). The frequency of intolerance did not decrease, if patients received further courses of MTX; the exposure-adjusted intolerance rate was 4.3/100 EY during the first MTX course, 11.2, 5.6 and 14.3 during the second, third and fourth course of MTX, respectively. Conclusions These results reflect the major problem of MTX intolerance in the long-term care of JIA patients. Intolerance is the leading cause of MTX discontinuation. Assuming that the request from the patient to stop MTX is related to symptoms experienced during drug exposure, about half of the cases discontinue MTX after almost 3 years due to intolerance. Re-exposure to the drug seems to further increase the intolerance rate of MTX. Acknowledgements BiKeR and JuMBO are funded by unconditional grants from Abbvie, Pfizer, Roche. Disclosure of Interest K. Minden Grant/research support from: Pfizer, Abbvie, Consultant for: Pfizer, Chugai, J. Klotsche: None declared, M. Niewerth: None declared, A. Zink Grant/research support from: AbbVie, BMS, GKS, Medac, MSD, Mundipharma, Roche, Sanofi, Pfizer, UCB, E. Seipelt: None declared, J.-P. Haas Grant/research support from: Pfizer, Novartis, G. Ganser: None declared, G. Horneff Grant/research support from: Pfizer, Abbvie, Roche/Chugai, Consultant for: Pfizer, Chugai

Background In Juvenile idiopathic arthritis (JIA) accompanying pain leads to mal-positioning or compensatory movements [1], increasing the risk for osteoarthritis in long-lasting disease courses. In Germany about 1/3 of JIA patients (JIA-P) with polyarticular affection are treated with biologics [2]. This has led to substantial improvement according to disease activity [3]. Still there are hardly any objective analyses on the longitudinal development of functional effects of JIA on joint limitations, especially under treatment with biologics. Objectives The aim of this work is to analyse the longitudinal effects of a combined treatment of JIA including anti-TNF-α therapy and functional therapies (e.g. physiotherapy) on walking abilities of JIA-P. Methods In a prospective longitudinal study 37 polyarticular JIA-P were included and treated with an anti-TNF-α therapy plus regular physiotherapy. JIA-P performed a 3D- gait analysis (8 infrared cameras (Vicon), 2 ground reaction force (GRF) plates (AMTI)) including the Plug in Gait body model. The cohort diminished the size of participants because of lost to follow up (n=15), drop-out (n=1) and investigator-caused discontinuation (n=1). Finally 15 JIA-P (♀: 8; ♂: 7) were analysed according therapeutic effects at all three time-points: (i) before initial anti-TNF-α therapy (T0: 13.7±3.2yr; 1.58±0.17m; 49.8±18.6kg), (ii) after 3.7±0.7 months (T1) and (iii) after 9.9±2.9 months (T2). The results were compared to matched healthy controls (CG) (n=15, ♀=11; ♂=4; 13.5±4.1yr, 1.55±0.12m, 46.5±12.9kg). Because of multilevel affection in JIA-P, both legs of each participant were included. Additionally the Ped-ACR70 score was determined for 13 JIA-P. For statistics the one-way ANOVA with Dunnett Post-hoc test was used (p Results The results demonstrate that the gait function was significantly limited in the JIA-P at T0. JIA-P showed a reduced walking velocity, a not significant decreased hip range of motion (ROM), less power in the ankle at push-off and a reduced load in the vertical GRF (Fz) in single support phase (Table 1). While the ankle power reached a normal size already in T1, the other parameters: walking velocity, hip ROM and Fz load reduction recovered much more slower, reaching values compatible to CG at T2. ACR70/remission were achieved by 62/62% at T1 and by 46/54% at T2. Limitation: 2 JIA-Ps had a relapse between T1 and T2. Conclusions The results of the 3D gait analysis show that functional limitations in JIA-P with polyarticular affection are not completed even when patients under treatment already show good results according to remission criteria. These findings demonstrate the importance of functional therapies, as physiotherapy which should be continued after the regain of clinical inactivity precisely. References Hartmann, M., et al. Int J Pediatr, 2010. Minden, K., et al. Z Rheumatol, 2013. 72(4): p. 339-46. Hashkes, P.J., et al. Nat Rev Rheumatol, 2010. 6(10): p. 561-71. Acknowledgements The authors want to thank Pfizer Inc., the “Deutsche Kinderrheuma-Stiftung” and “Ironman-Hilfe Kinderrheuma” for supporting this study. Disclosure of Interest None declared

Background Children with trisomy 21 have an increased risk of developing polyarticular arthritis. Traditionally, these patients receive a diagnosis of juvenile idiopathic arthritis (JIA) and are treated accordingly. However, very little data exists regarding presentation and treatment response in these patients. Objectives To determine joint activity and distribution pattern in patients with trisomy 21 and JIA and their response to methotrexate compared to patients with seronegative polyarticular JIA. Methods Retrospective case-control study from database of the German Center for Pediatric and Adolescent Rheumatology. Patients with trisomy 21 (T21, confirmed by karyotyping) and JIA were searched including patients with visits within the last 5 years. As a control group two randomly selected patients with rheumatoid-factor negative polyarticular JIA (SNP-JIA) matching with age and gender were extracted for each T21-patient. A retrospective chart survey was used to extract the following data: affected joints at any time and first visit, extraarticular manifestations, and for patients with polyarticular disease: total joint count. As these data result from a historical database only erythrocyte sedimentation rate, adverse events and total active joint count (TJC) at initiation and 1 year after start of Methotrexate were used to determine the response to MTX. Analyses were performed using descriptive statistics, Spearman9s correlation to compare response to methotrexate. Results 11 T21 patients were included in the study (6 female/5 male), with a median age at diagnosis of 6 years (range 1-13 years). Median follow-up was 6 years (range 1-17 years). 9/11 (82%) showed a polyarticular course of arthritis, and all of these were treated with methotrexate. There was no different prevalence of adverse events under MTX in both groups. T21 patients with SNP-JIA showed a significantly higher total joint count of active and painful arthritis at time of diagnosis (mean, n=27) compared with SNP-JIA patients (mean, n=15,5). Initially 8 of 11 (73%) T21-JIA patients presented with SNP-JIA, which is a not expected distribution in ILAR subgroups (expected percentage: SNP 13 -15%). One T21 patient had S-JIA and two an extended Oligo-JIA. Follow up shows a decreased range of motion in at least one joint in more than 81% of T21-JIA patients. We found a significantly higher rate of hypothyreosis in T21 JIA patients (73%) than in Down–syndrome overall (35%). Notably there was no T21-JIA patient with JIA associated uveitis. Conclusions There is a difference in distribution of subtypes of JIA in trisomy-21 patients with a predominant polyarticular pattern. T21-JIA patients show a significantly higher joint count of active arthritis at time of diagnosis and a decreased range of motion in course of the disease, but no difference in MTX tolerance as compared to SNP-JIA patients. Therefore we propose the early initiation of MTX as efficacious and safe therapy, in patients with Trisomy 21 and Juvenile Idiopathic Arthritis. Disclosure of Interest None declared

Background Reduced immunogenicity and efficacy of vaccinations and waning of vaccine-antigen-specific immunity were reported for patients with rheumatic diseases with immunosuppressive therapy or biologics. So far, the persistence of the humoral and cellular immune response against tick-born-encephalitis-virus (TBEV) vaccine was not analyzed in immunocompromised patients with Juvenile Idiopathic Arthritis (JIA). Objectives Thus, the TBEV-specific humoral and cellular immunity was investigated in 64 patients with JIA and 38 age-matched healthy controls who had received at least three dosages of TBEV-vaccine in the past. Methods Antibody concentrations and avidities were measured by adapted ELISAs, TBEV-specific cellular reactivity by ELISPOT assays in spot forming units (SFUs) per 100.000 cells. Results Positive IgG-anti-TBEV antibody concentrations (>165 VIEU/ml) were found in 59 JIA patients (92.2%) compared to 100% of healthy controls. Forty-one JIA patients (64.1%) had high antibody concentrations >1000 VIEU/ml compared to 34 HC (89.5%). Relative avidity index (RAI) was high in JIA patients (82.9%). Significantly higher SFUs were seen in HC (mean 780 SFU) than in JIA (500 SFU). So far, no correlations between TBEV-specific antibody concentrations, avidities or SFU were found. Conclusions Although lower TBEV-specific antibody concentrations and SFU were demonstrated by JIA patients, a sufficient TBEV-specific humoral and cellular immune response was presented even several years after primary TBEV-vaccination in those patients. Whether TBEV-specific immunity may be influenced by age, therapeutic regimens and disease activity and will wane faster in JIA patients with need for earlier booster doses requires proof by longitudinal studies. Disclosure of Interest None declared

Severe pancytopenia due to azathioprine (AZA) toxicity in patients with autoimmune diseases is not uncommon. We describe a 14-year-old girl with HLA-B27+ spondylarthritis who was treated with AZA 3 mg/kg/day and who suddenly developed severe pancytopenia in the seventh week of treatment. Analysis of the catabolic pathway of AZA revealed a homozygous deficiency of thiopurine methyltransferase (TPMT) on the basis of a combined 2-point mutation at nucleotide positions 460 and 719 in the gene for TPMT, causing a toxic level of the metabolic active 6-thioguanine nucleotides (6-TGN) (2,394 pmoles/8 x 10(8) red blood cells). The patient was transfusion dependent and finally recovered 8 weeks after the development of the pancytopenia. At that time, 6-TGN had already returned to normal therapeutic levels. Family studies revealed another homozygous deficiency in the mother, while the other family members were heterozygous.