Abstract
Clinical response to methotrexate (MTX) treatment for children with juvenile idiopathic arthritis (JIA) displays considerable heterogeneity. Currently, there are no reliable predictors to identify non-responders: earlier identification could lead to targeted treatment. We genotyped 759 JIA cases from the UK, Netherlands and Czech Republic. Clinical variables were measured at baseline and 6 months after start of treatment. In Phase I analysis samples were analysed for association with MTX response using ordinal regression of ACR-pedi categories and linear regression of change in clinical variables, and identified 31 genetic regions (P<0.001). Phase II analysis increased SNP density in the most strongly associated regions, identifying 14 regions (P<1×10−5): three contain genes of particular biological interest (ZMIZ1, TGIF1 and CFTR). These data suggest a role for novel pathways in MTX response and further investigations within associated regions will help reach our goal of predicting response to MTX in JIA.
Highlights
Juvenile idiopathic arthritis (JIA) is a heterogeneous condition with a variable outcome and considerable ongoing disease burden.[1]
A cohort of children was recruited for the SPARKS-CHARM (CHildhood Arthritis Response to Medication) Study, which has the overall aim to improve understanding of the variability in response to treatment observed in children with JIA and define a multifactorial model of response outcomes,[14] and through the CHARMS-JIA GWAS International Consortium
Recent developments in treatments and management of childhood arthritis have lead to increased expectations from clinicians, parents and patients for complete control of disease and consequent reduction of long-term adverse health outcomes.[4,5,33]
Summary
Juvenile idiopathic arthritis (JIA) is a heterogeneous condition with a variable outcome and considerable ongoing disease burden.[1] Studies indicate that functional disability and complications due to JIA are still common in many teenagers and young people with JIA, and that the effects of early, uncontrolled inflammation may cause irreversible damage to joints and other tissues.[2,3,4] improving long-term outcomes of children with JIA remains a critical challenge. Recent studies in JIA have indicated that early control of joint inflammation correlates with much improved outcomes, suggesting an early ‘window of opportunity’ when disease control can translate to profound long-term benefit.[5] It is known that not all children respond well to any given therapy. Despite increasing availability of new therapeutic options for treating inflammation in JIA, clinicians have no validated tools to help predict likelihood of good response to a particular drug. The current treatment strategy is to offer diseasemodifying drugs in a sequential approach, with choices typically driven more by cost or safety profile than by scientific evidence
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