[The vicious circle that leads to rheumatoid arthritis; experimental evidence of the steps involved in this circle]

Rheumatoid arthritis (RA) is characterized by chronic inflammation of the joints and the presence of anti-citrullinated protein autoantibodies (ACPA). ACPA are very specific for RA and are involved in its pathophysiology. Five steps, all of which are supported by experimental evidence, can be distinguished during the development of the chronic inflammation in RA. Step 1: During inflammation a large influx of inflammatory cells takes place. These cells will ultimately die via apoptosis. When the dying cells are not cleared efficiently, citrullinated proteins and citrullinating enzymes are released into the extracellular space. Step 2: Extracellular proteins are citrullinated by these enzymes. Step 3: Only individuals with a certain genetic background produce ACPA. Step 4: Arthritis is induced by the formation of immune complexes of ACPA and citrullinated proteins. Step 5: These immune complexes stimulate the inflammation, which leads to the recruitment of new inflammatory cells. This establishes a vicious cycle, the RA cycle.