Identifying Pharmacogenomic Predictors of Methotrexate Response and Metabolite Biotransformation in JIA

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Project Summary: Methotrexate (MTX), a folate antagonist and has been the most widely used disease- modifying anti-rheumatic drug (DMARD) in the treatment of Juvenile Idiopathic Arthritis (JIA) over the last 25 years. However, there is vast variability in drug efficacy that is unpredictable at the onset of therapy. Although the majority of pediatric rheumatologists use MTX as their first line agent to treat polyarticular JIA, it is a slow acting drug leaving clinicians in the difficult position of exposing patients to a therapy they will not know is ultimately effective for several months. With mounting evidence of an early “window of opportunity” to treat inflammatory arthritis, many clinicians have resorted to initiating additional biologic (anti-TNFalpha) therapies in conjunction with MTX early in the treatment course to minimize the chance of permanent joint damage, disability, and poor long-term outcomes. Predictors of MTX response would personalize therapy by focusing the early administration of biologic agents to patients unlikely to respond to MTX, thus avoiding delays in adequate therapy and poor long term outcomes. Alternatively, in patients predicted to respond to MTX, escalation to biologic therapies could be avoided thereby minimizing additional risk and expense. MTX is not currently included in the >100 FDA approved drugs that include pharmacogenetics in their label. However, recent genome-wide and candidate gene studies and mounting evidence of the genetic influences on important cellular biomarkers of MTX metabolism warrant the identification of pharmacogenomic predictors of MTX response, which is the overall goal of this project. To accomplish this goal, we will leverage existing patient cohorts, a group of collaborators with aligned research interests, the infrastructure of the Childhood Arthritis Rheumatology Research Alliance (CARRA) and the Pediatric Rheumatology Care and Outcomes Improvement Network (PR-COIN) for prospective patient recruitment to assemble a large well-phenotyped cohort of JIA patients treated with MTX. We will use this cohort to test our overall hypothesis that: “methotrexate response in JIA is dependent on genetic variation influencing drug metabolism and drug bioavailability” by addressing the following aims: • Aim 1. To determine the genetic contribution to clinical drug response. • Aim 2: To understand the genetic contribution to cellular biomarkers of drug response. • Aim 3: To develop a predictive tool to inform methotrexate use in the clinic. This project provides the opportunity to understand the genetic basis for MTX response both at a clinical and cellular level and represents a truly translational approach that draws on the expertise and collaboration of multiple investigators to combine resources and strategies to personalize medicine for children with JIA. Knowledge gained from this work will translate directly into the clinical setting to guide early treatment for JIA and will also impact other diseases treated with MTX and conditions where folate metabolism and regulation is critical to growth and development.