The Effectiveness of Methotrexate to Prevent Extension of Early Limited JIA

DESCRIPTION (provided by applicant): Juvenile idiopathic arthritis (JIA) is a heterogeneous collection of inflammatory arthritides of childhood with many clinical phenotypes, the most common of which is arthritis involving 4 or fewer joints (limited JIA). The initial treatment for limited JIA typically consists of non-steroidal anti-inflammatory drugs (NSAIDs) and glucocorticoid intra-articular injections. With the use of usual therapies, more than 50% of children with limited JIA will eventually develop extension of their disease, manifested either by arthritis involving 5 or more joints (polyarthritis) or anterior uveitis. Children who experience extension of existing arthritis have suboptimal clinical outcomes. Despite the prevalence of limited JIA and the potential for poor clinical outcomes, no large placebo- controlled studies of therapeutic agents have been performed in this patient population, and it is not known if early treatment with disease modifying agents commonly used in the treatment of polyarthritis (i.e., methotrexate) may prevent subsequent disease extension. In addition, the natural history of limited JIA and the prognostic factors for extension of disease remain incompletely understood. A cohesive team of pediatric rheumatologists with broad expertise and experience working productively together, as well as experts in clinical trial methods, will finalize the preparation nd planning sufficient to conduct a successful randomized, placebo-controlled, blinded clinical trial using the existing Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry infrastructure. The proposed trial's primary hypothesis is that methotrexate plus usual care is more effective than usual care alone in reducing the proportion of children who subsequently experience extension of their disease, as manifested by polyarthritis or uveitis. This will be the first trial to evaluate methotrexate for preventive therapy for JIA and the first large randomized placebo-controlled trial for the treatment of limited JIA, the most common form of the condition. Secondary hypotheses to be tested include the identification of predictors of disease extension, including clinical factors and biomarkers, both in the presence and absence of treatment with methotrexate. The team will develop a study protocol, manual of procedures, and other requisite clinical trial documents while finalizing the study population, recruitment plans, intervention, daa collection, primary and secondary outcome assessments, safety monitoring, and analysis plan. The culmination of this planning period will be the submission of a full-scale clinical trial grant proposal (UM1) with a design that optimizes the clinical applicability of our main study objectives, maximizes the generalizability of our findings through the inclusion of many CARRA site investigators and subjects, and minimizes the clinical and administrative burden of the study to the extent possible.