Curr Opin Immunol. 2026 Feb 11;99:102735. doi: 10.1016/j.coi.2026.102735. Online ahead of print.

ABSTRACT

The clinical heterogeneity of rheumatoid arthritis (RA) reflects a series of dynamic immunological imbalances rather than a single dominant mechanism. In this review, we propose that RA progression is best understood as a sequence of three functional balances. The first contrasts pathogenic and protective autoantibody functions, determining whether systemic autoimmunity remains subclinical or evolves into inflammatory disease. The second opposes cytokine-driven inflammation to autoantibody-mediated cytokine regulation, including neutralization or facilitation, thereby shaping the intensity and therapeutic responsiveness of synovitis. The third and ultimate balance opposes stromal persistence to tissue repair and dictates structural outcome, even when inflammation appears clinically controlled. By reinterpreting key immunological mechanisms through this framework, we clarify why clinical remission may not prevent joint damage, why functional properties of autoantibodies matter beyond antigen specificity, and why tissue context must be integrated into therapeutic strategies. This tripartite model repositions RA as a disease of evolving equilibria, with implications for prevention, precision stratification, and the restoration of immune-stromal homeostasis.

PMID:41678865 | DOI:10.1016/j.coi.2026.102735