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

PURPOSE OF REVIEW: 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. RECENT FINDINGS: 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. SUMMARY: 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.