Annals of the rheumatic diseases · 2026
Rheumatoid arthritis susceptibility genes show pathotype-specific expression in synovial tissue of patients with early treatment-naïve RA.
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den Hond Inez C, Reinders Marcel J T, Lewis Myles J, Rivellese Felice, Pitzalis Costantino, Wong Soon Wei, Wechalekar Mihir D, Knevel Rachel, van den Akker Erik B
Аннотация
OBJECTIVES: Rheumatoid arthritis (RA) exhibits clinical and biological heterogeneity, with synovial tissue stratified into histological pathotypes: lympho-myeloid, diffuse-myeloid, and pauci-immune fibroid. Although genome-wide association studies (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.
METHODS: Synovial RNA sequencing of patients with early RA (Pathobiology of Early Arthritis Cohort [PEAC] [N = 87] and Flinders [N = 18]) was used for differential gene expression between pathotypes, and pathway enrichment analyses were performed using GWAS-identified susceptibility genes for RA, osteoarthritis (OA), ankylosing spondylitis, psoriatic arthritis, and systemic lupus erythematosus.
RESULTS: RA 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 anticitrullinated protein antibody (ACPA)-positive and directionally consistent in ACPA-negative patients.
CONCLUSION: Expression of RA susceptibility genes is not evenly distributed across synovial pathotypes but is strongly biased towards 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 autoimmune and noninflammatory degenerative joint diseases in certain RA subtypes. Synovial pathotype stratification is therefore essential for interpreting genetic risk and understanding disease heterogeneity.
METHODS: Synovial RNA sequencing of patients with early RA (Pathobiology of Early Arthritis Cohort [PEAC] [N = 87] and Flinders [N = 18]) was used for differential gene expression between pathotypes, and pathway enrichment analyses were performed using GWAS-identified susceptibility genes for RA, osteoarthritis (OA), ankylosing spondylitis, psoriatic arthritis, and systemic lupus erythematosus.
RESULTS: RA 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 anticitrullinated protein antibody (ACPA)-positive and directionally consistent in ACPA-negative patients.
CONCLUSION: Expression of RA susceptibility genes is not evenly distributed across synovial pathotypes but is strongly biased towards 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 autoimmune and noninflammatory degenerative joint diseases in certain RA subtypes. Synovial pathotype stratification is therefore essential for interpreting genetic risk and understanding disease heterogeneity.