Ssm Kamphuis

Time to treatment as an important factor for the response to methotrexate in juvenile idiopathic arthritis

OBJECTIVEnMethotrexate (MTX) is the most commonly used disease-modifying antirheumatic drug in juvenile idiopathic arthritis (JIA). Currently, individual response to MTX cannot be reliably predicted. Identification of clinical and genetic factors that influence the response to MTX could be helpful in realizing the optimal treatment for individual patients.nnnMETHODSnA cohort of 128 JIA patients treated with MTX were studied retrospectively. Eleven clinical parameters and genotypes of 6 single nucleotide polymorphisms in 5 genes related to the mechanism of action of MTX were compared between MTX responders and nonresponders using a multivariate regression analysis.nnnRESULTSnThe time from diagnosis to start of MTX treatment, physicians global assessment at baseline, and the starting dose were significantly associated with the response to MTX at 6 months after initiation. Patients with a shorter time from diagnosis to start of MTX and a higher disease activity according to the physician but with a lower MTX dose showed an increased response. The effect of the starting dose on MTX response seemed to be mainly due to the influence of the systemic JIA subtype. The time from diagnosis to start of MTX treatment and physicians global assessment at baseline were highly correlated. Therefore, the precise effect size of each independent variable could not be determined.nnnCONCLUSIONnIn children with JIA, the time from diagnosis to start of MTX appears to be an important factor for MTX response. Our results suggest that an earlier start of MTX treatment will lead to an increased response.

Clinical course and prognostic value of disease activity in the first two years in different subtypes of juvenile idiopathic arthritis

Juvenile idiopathic arthritis (JIA) is a heterogeneous disease involving chronic arthritis. The clinical course is characterized by a fluctuating pattern of active and inactive disease. We have described in detail the clinical course in different JIA subtypes during the first 2 years after diagnosis and studied its relationship to disease activity in the following years.

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.

PReS-FINAL-2146: Trends in prescription of biologics and outcomes of juvenile idiopathic arthritis; results of the Dutch national arthritis and biologicals in children register.

Treatment of juvenile idiopathic arthritis (JIA) has changed dramatically since the introduction of biologics in 1999. Because of more insight in the cytokines involved in JIA the number of available biologic agents increased. Together with the introduction of these new drugs, new insights in the optimal treatment of JIA indicate that earlier and more aggressive therapy is associated with better outcomes. Whether these developments with regard to biologic treatment have resulted in better patients outcomes in daily practice is not yet reported.

OR7-002 – Pyrin 577 mutations in dominant autoinflammation

Autoinflammatory disorders are disorders of the innate immune system. Standard genetic testing provided no correct diagnosis in a female patient from a non-consanguineous family of British descent with a colchicine-responsive autosomal dominant periodic fever syndrome.

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

Development of a web-based register for the Dutch national study on biologicals in juvenile idiopathic arthritis: http://www.abc-register.nl

Address: 1Erasmus MC Sophia Childrens Hospital, Rotterdam, Netherlands, 2UMCG Beatrix Childrens Hospital, Groningen, Netherlands, 3Leiden University Medical Centre, Leiden, Netherlands, 4Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands, 5Hagaziekenhuis Juliana Childrens Hospital, Den Haag, Netherlands, 6AMC Emma Childrens Hospital, Amsterdam, Netherlands and 7Academic Hospital Maastricht, Maastricht, Netherlands * Corresponding author