P2X7R of synovial fibroblasts is a potential therapeutic target associated with refractory rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovitis. Synovial fibroblasts (SF) are the predominant cellular components in the inflamed synovium. Recent studies have shown increased expression of P2X7 receptor (P2X7R) in RA SF. However, its precise expression patterns and its contribution to inflammatory arthritis remain unclear. We demonstrate that P2X7R is robustly expressed in RA synovium, correlating with increased synovitis and systemic inflammation. Single-cell transcriptome analysis indicated that P2X7R was enriched in specific SF associated with refractory RA. Then, we applied a highly selective human P2X7R antagonist, EVT-401, which promoted apoptosis and induced cell cycle arrest in RA SF, reduced the production of proinflammatory and joint-destructive mediators, and mitigated aggressive phenotypes. Furthermore, we demonstrated that EVT-401 markedly reduced synovial inflammation and arthritis severity in a nonhuman primate model of autoimmune arthritis. Together, these findings suggest that P2X7R is involved in synovial inflammation and its inhibition may represent a potential therapeutic strategy for refractory RA.