Rheumatoid arthritis susceptibility genes show pathotype-specific expression in synovial tissue of early treatment-naive RA patients

ObjectivesRheumatoid arthritis (RA) exhibits clinical and biological heterogeneity, with synovial tissue stratified into histological pathotypes: lympho-myeloid, diffuse-myeloid, and pauci-immune fibroid. Although GWAS have uncovered RA risk loci, how genetic risk relates to synovial immunopathology remains unclear. To better understand how genetic predisposition may shape divergent early disease mechanisms, we characterised the expression patterns of GWAS-identified RA susceptibility genes and related rheumatic diseases across the synovial pathotypes. MethodsRNA-sequencing data from synovium of 87 treatment-naive, early RA patients from the Pathobiology of Early Arthritis Cohort. Differential gene expression between pathotypes and pathway enrichment analyses were performed using susceptibility genes for RA, osteoarthritis (OA), ankylosing spondylitis, psoriatic arthritis and systemic lupus erythematosus. ResultsRA susceptibility gene expression in synovial tissue separated patients by pathotype and correlated with markers of disease activity. RA susceptibility genes were significantly enriched among genes upregulated in lympho-myeloid synovium and linked to lymphocyte activation and differentiation pathways. In contrast, OA susceptibility genes were upregulated in diffuse-myeloid and fibroid synovium. Both patterns were most pronounced in ACPA-positive and directionally consistent in ACPA-negative patients. ConclusionRA genetic susceptibility is not evenly distributed across synovial pathotypes but is strongly biased toward the lympho-myeloid pathotype, indicating that current GWAS signals preferentially capture immune-driven disease mechanisms. Enrichment of OA susceptibility genes in diffuse-myeloid and fibroid pathotypes, even among ACPA-positive patients, suggests shared biological features between auto-immune and non-inflammatory degenerative joint diseases in certain RA subtypes. Synovial pathotype stratification is therefore essential for interpreting genetic risk and understanding disease heterogeneity. Key messagesO_ST_ABSWhat is already known on this topicC_ST_ABS- Rheumatoid arthritis (RA) is clinically and biologically heterogeneous, and its affected synovial tissue can be stratified into distinct immunohistological pathotypes. - GWAS have identified numerous genetic risk loci for RA and related rheumatic and inflammatory diseases. - It remains poorly understood how RA genetic risk relates to synovial tissue heterogeneity. What this study adds- GWAS-identified RA susceptibility genes show strong, pathotype-specific expression in synovial tissue, with marked enrichment in the lympho-myeloid pathotype. - OA susceptibility genes are primarily upregulated in diffuse-myeloid and pauci-immune fibroid RA synovium, indicating shared fibroblast- and remodelling-related pathways. - These gene expression patterns are most pronounced in ACPA-positive RA but remain directionally consistent in ACPA-negative RA. How this study might affect research, practice or policy- Synovial pathotype stratification should be incorporated into genetic studies of RA. - Pathotype-aware genetic studies may improve patient stratification and guide development of more targeted therapeutic strategies.