Polyarticular juvenile idiopathic arthritis: insights from genetic studies on disease risk and pathogenesis

Genetic and multiomics studies are reshaping our understanding of polyarticular juvenile idiopathic arthritis (JIA) and shifting the field from symptom- and phenotype-based categories toward biologically informed disease definitions. We summarize recent findings on disease risk and pathogenesis while focusing on genetic contributions to disease susceptibility and pathogenic mechanisms.

Classical HLA and non-HLA studies established the polygenic immune-mediated pathogenesis of JIA with distinct, partially overlapping, genetic architectures across the International League of Associations for Rheumatology categories. Rheumatoid factor (RF)-positive polyarticular JIA is increasingly considered a childhood-onset seropositive rheumatoid arthritis, whereas oligoarticular and RF-negative polyarticular JIA, although nonidentical, share substantial immunogenetic features. Recent subtype-integrative genome-wide association studies and transcriptomic and chromatin-interaction analyses prioritized candidate genes mediating lymphocyte activation, cytokine signaling, and immune regulation. Synovial atlas and spatial transcriptomic studies have further connected genetic susceptibility to immune-cell states and organized inflammatory niches, linking inherited risk to the chronic arthritis-sustaining tissue environment.

Genetic and multiomic studies support a shift toward biologically informed disease classification, evinced in the proposed Pediatric Rheumatology International Trials Organization framework, and provide a foundation for subtype-aware risk stratification and therapeutic target discovery in JIA. The association of genetic variations with prognosis warrants future investigation.