Figure 1.

Evolution of RA and development of autoimmunity. Note: The graph summarizes current evidence and prominent hypotheses linking development of autoimmunity and clinical symptoms in patients with rheumatoid arthritis. The first signs of the pathological process manifest years before the disease onset in the form of autoantibody positivity, including anti‐citrullinated protein antibodies (ACPA), anti‐carbamylated protein antibodies, and rheumatoid factor. The autoantibodies are class‐switched, which suggests T cell help, however, autoantibody positivity does not necessarily lead to disease onset. Close to disease onset, the ACPA response matures and accumulates more variable domain glycosylation sites. This process seemingly depends on HLA and T cells with some role for HLA shared epitope (HLA‐SE) and HLA‐DR13. In established disease, the ACPA response remains stable, while B cell depletion is clinically effective