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Association of the autoimmunity locus 4q27 with juvenile idiopathic arthritis

OBJECTIVEnJuvenile idiopathic arthritis (JIA) is characterized by chronic arthritis and an autoimmune etiology. In several autoimmune diseases, including rheumatoid arthritis (RA), an association with the 4q27 locus has been reported. We undertook this study to investigate the possible role of the 4q27 locus in JIA.nnnMETHODSnA case-control association study was conducted, with a total of 655 Caucasian JIA patients and 791 healthy controls divided into 2 independent sample sets. The rs6822844 marker in the 4q27 locus was genotyped.nnnRESULTSnIn the first and larger sample set, a 5% decrease in T allele frequency was observed in patients compared with controls (allelic odds ratio [OR] 0.72 [95% confidence interval 0.55-0.95], P = 0.019), and in the second set, a 3% decrease was observed (allelic OR 0.81 [95% confidence interval 0.61-1.09], P = 0.169). The combined data set generated an OR of 0.76 (95% confidence interval 0.62-0.93, P = 7.08 x 10(-3)). When the different JIA subtypes were analyzed individually, significant decreases were seen in the subtypes with a polyarticular course of disease (extended oligoarthritis [P = 0.019] and rheumatoid factor-negative polyarthritis [P = 0.038]).nnnCONCLUSIONnOur findings suggest that the 4q27 locus, previously reported to be associated with RA, type 1 diabetes mellitus, celiac disease, and psoriatic arthritis, is also associated with susceptibility to JIA.

Resetting the Adaptive Immune System After Autologous Stem Cell Transplantation: Lessons from Responses to Vaccines

Autologous stem cell transplantation (ASCT) to treat autoimmune diseases (AID) is thought to reset immunological memory directed against autoantigens. This hypothesis can only be studied indirectly because the exact nature of the pathogenetic autoantigens is unknown in most AID. Therefore, 19 children with juvenile idiopathic arthritis (JIA) or systemic lupus erythematodes (SLE) and 10 adults with multiple sclerosis (MS) were vaccinated with the T-cell-dependent neoantigen rabies and the recall antigen tetanus toxoid after, respectively before, bone marrow harvest. Both vaccinations were repeated after ASCT. All except two of the responders mounted a primary antibody response to rabies after revaccination, and 44% of the responders mounted a primary antibody response to tetanus boost after ASCT. These data show that immunological memory to a neoantigen is lost in most patients with AID after immunoablative pretreatment; however, memory to a recall antigen boosted before bone marrow harvest is only lost in part of the patients. Disease progression was arrested in all patients with JIA/SLE except one, but only in a minority of MS patients. Clinical outcome on a per case basis was not associated with the profile of the immune response toward the vaccination antigens after ASCT.

Anticarbamylated protein (anti-CarP) antibodies are present in sera of juvenile idiopathic arthritis (JIA) patients

In juvenile idiopathic arthritis (JIA) patients there is a lack of markers that predict severe disease. Although anticitrullinated protein antibodies (ACPA) have contributed substantially to the understanding of rheumatoid arthritis (RA),1 their detection in JIA has not been equally useful as incidence rates in JIA patients are low2 and merely confined to the polyarticular immunoglobulin (Ig)M-rheumatoid factor (RF)-positive category resembling RA. Recently, anticarbamylated protein (anti-CarP) antibodies were detected in 45% of RA patients and importantly also in 16%–20% ACPA-negative patients.3–5 Within the ACPA-negative patients, anti-CarP antibodies were associated with more severe radiographic progression.3 Since most JIA patients are ACPA-negative we investigated whether anti-CarP antibodies are present in the sera of JIA patients and how they are related to ACPA and IgM-RF.nnJIA patients from three Dutch sources were included: the BeSt for Kids trial (NTR 1574, a treatment strategy study) (n=33), a previously described cohort6 (n=48) and the Arthritis and Biologicals in Children (ABC) register7 (n=153). Healthy controls (n=107) (mean age/range 11/(2–20)) are stem-cell graft …

CD226 (DNAM-1) is associated with susceptibility to juvenile idiopathic arthritis

Objectives Juvenile idiopathic arthritis (JIA) is considered a complex genetic autoimmune disease. We investigated the association of genetic variants previously implicated in JIA, autoimmunity and/or immunoregulation, with susceptibility to JIA. Methods A genetic association study was performed in 639 JIA patients and 1613 healthy controls of northwest European descent. Ninety-three single nucleotide polymorphisms (SNP) were genotyped in a candidate gene approach. Results of the entire JIA patient group (all subtypes) were compared with results obtained, alternatively, with a clinically homogeneous patient group including only oligoarticular and rheumatoid factor (RF) negative polyarticular JIA patients (n=493). Meta-analyses were performed for all SNPs that have been typed in other Caucasian JIA cohorts before. Results SNPs in or near PTPN22, VTCN1, the IL2-IL21 region, ANKRD55 and TNFA were confirmed to be associated with JIA (p<0.05), strengthening the evidence for involvement of these genes in JIA. In the majority of these replicated SNPs, effect sizes were larger when analysing a homogeneous patient cohort than when analysing all subtypes. We identified two novel associations with oligoarticular and RF-negative polyarticular JIA: CD226 rs763361 (OR 1.30, 95% CI 1.12 to 1.51, p=0.0006) and CD28 rs1980422 (OR 1.29, 95% CI 1.07 to 1.55, p=0.008). Meta-analyses including reported studies confirmed the association of both SNPs with susceptibility to JIA (OR 1.16, p=0.001 and OR 1.18, p=0.001, for rs763361 and rs1980422, respectively). Conclusions The CD226 gene has been identified as novel association with JIA, and a SNP near CD28 as a suggestive association. Both genes are probable candidate risk factors, since they are involved in costimulation of T cells.

Genetic variation in VTCN1 (B7-H4) is associated with course of disease in juvenile idiopathic arthritis

Objective The course of disease in juvenile idiopathic arthritis (JIA) is unpredictable with episodes of activity and remission. In order to identify predictive factors, 93 SNPs, JIA subtype, age at onset and ANA status were studied in relation to disease course. Methods Genetic and clinical parameters were analysed in a cohort of 272 Caucasian patients with persistent oligoarthritis (n=129), extended oligoarthritis (n=57) and rheumatoid factor negative polyarthritis (n=86). Categories of disease course (remitting (n=65), intermediate (n=96) and unremitting (n=111)) were designed based on the cumulative time spent in active disease in the first 2u2005years. Results Univariate analysis revealed association of the course of disease with JIA subtype (p=5.7*10–5) and three SNPs; VTCN1 rs10u2005923u2005223 (p=4.4*10−5), VTCN1 rs12u2005046u2005117 (p=0.017) and CDK6 rs42u2005041 (p=0.038). In a subsequent multivariate ordinal logistic regression analysis, VTCN1 rs10u2005923u2005223 (OR 0.41, 95%-CI 0.26 to 0.63) and JIA subtype (OR 3.8, 95%-CI 2.0 to 7.2; OR 2.5, 95%-CI 1.4 to 4.2, for extended oligoarthritis and RF-negative polyarthritis vs persistent oligoarthritis, respectively) were the strongest independent factors for course of disease. Conclusions This study provides evidence that VTCN1, encoding B7-H4, is associated with course of disease in selected subtypes of JIA. VTCN1 might be useful in predicting the course of disease.

A comparison of three treatment strategies in recent onset non-systemic Juvenile Idiopathic Arthritis: initial 3-months results of the BeSt for Kids-study

BackgroundCombination therapy with prednisone or etanercept may induce earlier and/or more improvement in disease activity in Disease Modifying Anti Rheumatic Drug (DMARD) naïve non-systemic Juvenile Idiopathic Arthritis (JIA) patients. Here we present three months clinical outcome of initial treatments of the BeSt-for-Kids study.MethodsIncluded patients were randomized to either: 1. initial DMARD-monotherapy (sulfasalazine (SSZ) or methotrexate (MTX)), 2. Initial MTX / prednisolone-bridging, 3. Initial combination MTX/etanercept. Percentage inactive disease, adjusted (a) ACR Pedi30, 50 and 70 and JADAS after 6 and 12xa0weeks of treatment (intention to treat analysis) and side effects are reported.Results94 patients (67% girls, 32 (arm 1), 32 (arm 2) and 30 (arm 3) with median (InterQuartileRange) age of 9.1 (4.7-12.9) years were included. 38% were ANA positive, 10 had oligo-articular disease, 68 polyarticular JIA and 16 psoriatic arthritis. Baseline median (IQR) ACRpedi-scores: VAS physician 49 (40-58) mm, VAS patient 54 (37-70) mm, ESR 6.5 (2-14.8)mm/hr, active joint count 8 (5-12), limited joint count 3 (1-5), CHAQ score 0.88 (0.63-1.5). In arm 1, 17 started with MTX, 15 with SSZ.After 3xa0months, aACR Pedi 50 was reached by 10/32 (31%), 12/32(38%) and 16/30 (53%) (pu2009=u20090.19) and aACR Pedi 70 was reached by 8/32 (25%), 6/32(19%) and 14/30(47%) in arms 1-3 (pu2009=u20090.04). Toxicity was similar. Few serious adverse events were reported.ConclusionAfter 3xa0months of treatment in a randomized trial, patients with recent-onset JIA achieved significantly more clinical improvement (aACRPedi70) on initial combination therapy with MTX / etanercept than on initial MTX or SSZ monotherapy.Trial registrationNTR1574. Registered 3 December 2008.

Oligoarticular and Polyarticular Juvenile Idiopathic Arthritis

Abstract Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in children. Diagnosis is made in a child with arthritis lasting longer than 6 weeks and by excluding other causes. In current classification seven categories are recognized. Increasing knowledge in various aspects (genetics, imaging, pathophysiology) of the disease has improved care for JIA patients. Improvement in treatment options expanded with the introduction of biologicals, which are available since the beginning of the 21st century. The goal of reaching inactive disease has come closer but is still not always feasible for nonsystemic JIA patients. This chapter summarizes aspects of pathophysiology, clinical manifestations, diagnostic investigations, differential diagnosis, treatment, and outcome measures of nonsystemic JIA.

PReS-FINAL-2109: Genetic variations in patients with juvenile idiopathic arthritis and uveitis

Juvenile Idiopathic Arthritis (JIA) is accompanied by uveitis in approximately 20% of the cases. This is a serious complication with risk of impaired vision or even blindness. Both conditions are considered to be autoimmune diseases. Since uveitis is often asymptomatic, frequent ophthalmologic checks are needed to diagnose this complication at an early stage. Identification of risk factors for uveitis (besides presence of antinuclear antibodies (ANA)) could contribute to understanding of the pathogenesis of both diseases, and could be used as prognostic tool in an individual patient.

OP0297 Trends in Prescription of Biologics and Outcomes of Juvenile Idiopathic Arthritis; Results of the Dutch National Arthritis and Biologicals in Children Register

Background Treatment of juvenile idiopathic arthritis (JIA) has changed dramatically since the introduction of biologics in 1999. Because of more insight in the immunological and biological pathways involved in the development of JIA the number of available biologic agents increased. Together with the introduction of these new drugs, also new insights in the optimal treatment of JIA indicate that earlier and more aggressive therapy is associated with better outcomes. Whether these new insights with regard to biologic treatment have been adopted in daily practice and resulted in better patients’ outcomes is not yet reported. Objectives o evaluate trends in prescription of biologics and influence on outcomes of Dutch JIA patients that started their first biologic between 1999 and 2010. Methods The Arthritis and Biologicals in Children register (a multicenter prospective observational study) aims to include all JIA patients in the Netherlands who use or used biologic agents since 1999. Patients were divided in time periods according to the year of introduction of first biologic agent. Trends in characteristics of patients before introduction of first biologic and effectiveness of the first biologic were analyzed over a 12 year period. Results 343 non-systemic and 86 systemic JIA patients started at least 1 biologic agent between 1999 and 2010. Etanercept remained biologic of first choice for non-systemic JIA and anakinra has become first choice for systemic JIA. The use of systemic prednisone and synthetic disease-modifying anti-rheumatic drugs (besides methotrexate) prior to biologics decreased. During these 12 years of observation, biologics were prescribed after shorter disease durations; the proportion of patients with less than 1.5 years of disease duration before start of the first biologic agent increased from zero in the years 1999-2001 to 31% in 2008-2010. Disease activity and acquired sequelae at baseline decreased with regard to number of joints with arthritis (median of 18 active joints in 1999-2001 to 5 in 2008-2010), number of joints with limited motion (median of 12 limited joints in 1999-2001 decreased to 3 in 2008-2010) and functional disability scores (median CHAQ score of 1.8 in 1999-2001 decreased to 1.1 in 2008-2010). For systemic JIA, prescription patterns changed towards introduction in patients with higher ESR values. These changes for both systemic and non-systemic JIA resulted in more patients with inactive disease and less joints with limited motion after 3 and 15 months of treatment. Conclusions Biologics are prescribed increasingly, are introduced earlier during the disease course and in JIA patients with lower disease activity. These changes are subsequently accompanied by better short-term disease outcomes. Etanercept remains biologic of first choice for non-systemic JIA and anakinra has become first choice for systemic JIA. Disclosure of Interest M. Otten Grant/research support from: Abbott, Novartis, Roche, Pfizer, Consultant for: Roche, J. Anink: None Declared, F. Prince Grant/research support from: Abbott, Bristol-Myers Squibb, Novartis, Tevapharma, and Pfizer, Consultant for: Roche, M. Twilt: None Declared, S. Vastert: None Declared, R. ten Cate Grant/research support from: Pfizer, Consultant for: Pfizer, E. Hoppenreijs: None Declared, W. Armbrust: None Declared, S. Gorter: None Declared, P. van Pelt: None Declared, S. Kamphuis Grant/research support from: Pfizer, K. Dolman: None Declared, J. Swart: None Declared, J. van den Berg: None Declared, Y. Koopman-Keemink: None Declared, M. van Rossum: None Declared, N. Wulffraat Grant/research support from: Pfizer, Novartis and Roche, L. van Suijlekom-Smit Grant/research support from: Dutch Board of Health Insurances, Dutch Arthritis Association, Pfizer, Abbott, Consultant for: Roche, Novartis

Association of the CD226 ( DNAM-1 ) Gly307Ser polymorphism with juvenile idiopathic arthritis

Background Recent genetic studies have reported an association of the Gly307Ser single nucleotide polymorphism (SNP) in the CD226 gene with susceptibility to multiple autoimmune diseases. CD226 or DNAM-1 is a type 1 membrane protein belonging to the Ig-superfamily and is involved in the adhesion and co-stimulation of T cells and NK cells. A trend towards association of this SNP with Juvenile Idiopathic Arthritis (JIA) was recently reported, but was not statistically significant (p=0.13) (Genes Immun. 2010 Mar;11(2):194-8).