It has been suggested that anti–citrullinated protein antibodies (ACPAs) play an important role in the pathogenesis of rheumatoid arthritis (RA). To exert their pathologic effects, ACPAs must recruit immune effector mechanisms such as activation of the complement system. Mouse models of RA have shown that, surprisingly, arthritogenic antibodies activate the alternative pathway of complement rather than the expected classical pathway. This study was undertaken to investigate whether human anti–cyclic citrullinated peptide (anti‐CCP) antibodies activate the complement system in vitro and, if so, which pathways of complement activation are used.

We set up novel assays to analyze complement activation by anti‐CCP antibodies, using cyclic citrullinated peptide–coated plates, specific buffers, and normal and complement‐deficient sera as a source of complement.

Anti‐CCP antibodies activated complement in a dose‐dependent manner via the classical pathway of complement, and, surprisingly, via the alternative pathway of complement. The lectin pathway was not activated by anti‐CCP antibodies. Complement activation proceeded in vitro up to the formation of the membrane attack complex, indicating that all activation steps, including the release of C5a, took place.

Our findings indicate that anti‐CCP antibodies activate the complement system in vitro via the classical and alternative pathways but not via the lectin pathway. These findings are relevant for the design of interventions aimed at inhibition of complement‐mediated damage in RA.