Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by persistent synovitis, progressive joint destruction, and diverse extra-articular complications. Increasing evidence indicates that RA pathogenesis is not driven by isolated inflammatory events, but by a tightly interconnected network involving immune dysregulation, metabolic reprogramming, and aberrant mechanotransduction. This review synthesizes recent advances in these three pathogenic dimensions and proposes an integrated framework for understanding RA as a systemic, self-reinforcing disease process. We highlight how inflammatory circuits, particularly the IL-6/STAT3 and TNF-α/NF-κB axes, interact with autoantibody- and neutrophil extracellular trap-mediated immune propagation beyond the synovium. We further discuss how glycolytic rewiring, succinate accumulation, and microbiota-derived metabolites amplify inflammatory signaling and tissue remodeling. In parallel, altered extracellular matrix stiffness and activation of the integrin-FAK-YAP/TAZ pathway sustain pathogenic fibroblast behavior through mechano-epigenetic coupling. Collectively, these pathways form a feed-forward loop that links local synovial inflammation with systemic organ involvement. A systems-level understanding of these interactions may provide a stronger foundation for biomarker-guided stratification and the development of multi-target, mechanism-based therapeutic strategies in RA.
Xu et al. (2026) studied this question.