The role of anti-citrullinated protein antibodies (ACPA) in the pathogenesis of rheumatoid arthritis

Abstract

The most specific autoimmunity known for rheumatoid arthritis (RA) is reflected by generation of anti-citrullinated protein antibodies (ACPA). Presence of ACPA in established RA is associated with disease severity, while generation of ACPA at early developmental phases of RA can have a strong predictive value for progressing to the full-blown disease. Hence, development of ACPA may be of crucial importance to the pathogenesis of RA. Therefore, a lot of effort has been put recently to investigate the feature of ACPA at early developmental stages of RA (before disease onset) and functional activities of these autoantibodies. Results of these studies enlarged the knowledge about the nature of ACPA, which is essential for planning the therapeutic or preventive strategies interfering with their development and pathogenic functions. In this review we describe recent evidence for a role of ACPA in the etiopathogenesis of RA and indicate key unresolved issues regarding ACPA biology that need to be clarified in the future.

Keywords: anti-citrullinated protein antibodies; pathogenesis; rheumatoid arthritis.

Fig. 1

Phases of development of RA. Left panel: In prospective studies individuals are described as having genetic risk factors for RA (Phase A), environmental risk factors for RA (Phase B), systemic autoimmunity associated with RA (Phase C), non-specific symptoms such as arthralgia and morning stiffness without clinical arthritis (Phase D), undifferentiated arthritis – UA (Phase E) and, ultimately RA (Phase F). The term “arthritis” describes clinically apparent soft tissue swelling or fluid. The term “pre-clinical RA” indicates any phase up to phase D when the arthritis cannot be detected on physical examination. Time of systemic ACPA appearance is depicted. The qualitative and quantitative changes of ACPA over the period from their systemic appearance up to RA onset are listed

Fig. 2

Evidence for pathogenic effects of ACPA gathering during in vitro and in vivo studies. The in vivo studies concern the investigation of animal models of RA as well as clinical observations of humans developing RA. A detailed description is given in the text. NET – neutrophil intracellular trap