Figure 1.

Depicting the sequence of events leading to the development of clinically detectable rheumatoid arthritis – at least two potential models are depicted. In model A, a pre-RA phase comprises early generation of autoantibodies (ACPAs) that can bind post-translationally modified self-proteins, particularly via citrullination. This is followed by amplification of the range of specificities of ACPA and by the elaboration of cytokines and chemokines, complement, and metabolic disturbance in the months prior to clinical development of disease. A transition event that requires a ‘second hit’, as yet poorly understood permits the development of synovitis. The latter is characterized by frank inflammation, stromal compartment changes and tissue modification leading to articular damage. In model B, which is not mutually exclusive, there is an early interaction between innate immune activation and stromal factors that lead to stromal cell alteration, including epigenetic modifications that initiate a cycle of inflammatory stromal mediated damage. Autoimmunity can arise as a result of these interactions that in turn can conrtibtue directly or in an amplification loop to disease perpetuation.