Project Summary Little is known about why children develop juvenile idiopathic arthritis (JIA). Research implicates microbiome imbalance (dysbiosis) of the mouth and gut in the development and activity of rheumatoid arthritis, a disease distinct from most forms of JIA. Gut dysbiosis may also mediate eye inflammation (uveitis), a common, vision-threatening complication of JIA. Some children with a less common form of JIA have evidence of dysbiosis, and antibiotics (major microbiome disrupters) are associated with new-onset JIA in large populations. The overall goal of this research is to understand the mechanisms underlying the development and course of JIA in order to develop new ways of preventing and treating this family of chronic diseases. The main objective of this study is to examine the complex relationship between antibiotics, infections, and dysbiosis in relation to JIA pathogenesis and activity. This project will focus on the most common form of JIA, oligoarticular JIA, which is associated with high rates of uveitis. The first aim will examine whether gut microbiota from children with incident oligoarticular JIA exhibit dysbiosis (primary exposure) compared with gut microbiota of matched unaffected children in a multicenter case-control study of prospectively recruited children. The second aim will prospectively follow those children with oligoarticular JIA to determine whether gut dysbiosis A) resolves with inactive disease (in a self-controlled study comparing microbiota at diagnosis and at the time of inactive disease) and/or B) increases with JIA flare (in a case-control study comparing microbiota at flare and at the time of inactive disease). Both aims will use self-collected stool samples along with clinical data, including antibiotic use (secondary exposure). Dysbiosis will be defined as having decreased gut microbial diversity and distinct overall microbial composition relative to the comparator group. The analysis will also explore differences in the relative abundance of specific species between groups as well as associations between dysbiosis and clinical features of JIA (e.g., uveitis). The third aim will test whether antibiotic use in children with JIA, particularly drugs with antianaerobic coverage, is associated with new antirheumatic drug use within 3 months as a proxy for increased JIA disease activity. This aim will use administrative claims data and a self-controlled case series design. The proposed K23 project will provide this pediatric rheumatologist with an integrated plan of mentored patient-oriented research, career development activities, and formal training in bioinformatics. Guided by expert mentors and talented collaborators, the research and training activities outlined in this application will enable the principal investigator to mature from an observational epidemiologist into an independent patient- oriented and translational researcher. These opportunities will equip this investigator with a much larger set of skills to answer important and novel questions about pediatric rheumatic diseases.

Project Narrative We do not understand well why children develop juvenile idiopathic arthritis, but some evidence suggests that antibiotics and disturbance of human bacterial communities (“the microbiome”) may play a role. This project will examine the complex relationship between antibiotics, infections, and the microbiome in relation to the development and activity of juvenile idiopathic arthritis. New insights into the mechanisms underlying juvenile idiopathic arthritis and the role of antibiotics may ultimately lead to new, less toxic ways of treating, preventing, or even curing these chronic childhood diseases.