The Clinical Value of Autoantibodies in Rheumatoid Arthritis

Abstract

Rheumatoid arthritis (RA) is a highly heterogeneous syndrome in terms of clinical presentation, progression, and response to therapy. In such a complicated context, the identification of disease-related biomarkers would be undoubtedly helpful in assisting tailored approaches for every patient. Despite remarkable efforts, however, progress in new biomarker development and validation is dramatically slow. At present, none of the candidate genetic, cellular, or molecular biomarker has yet surpassed the clinical value of RA-specific autoantibodies, including rheumatoid factor (RF) and anti-citrullinated protein autoantibodies (ACPA). Rather, recent years have witnessed significant advancements in our understanding of the multiple roles that RF and ACPA play in RA pathophysiology. This has helped clarifying the mechanistic basis of the clinical associations of autoantibodies in RA. In this short review, we will briefly summarize the effector functions of RF and ACPA, and analyse how autoantibodies may help subclassifying RA patients in terms of clinical presentation and response to therapy.

Keywords: anti-citrullinated protein antibodies; autoantibodies; remission; rheumatoid arthritis; rheumatoid factor.

Figure 1

Pro-inflammatory and osteoclastogenic roles of autoantibodies in rheumatoid arthritis. The multiple effects of anti-citrullinated protein antibodies (ACPA) and rheumatoid factor (RF) on macrophages (A) and osteoclasts (B) are shown. Collectively, ACPA are able to stimulate cytokine production by macrophages both through the interaction of their Fc tail with stimulating Fcγ receptors, and through Fab-mediated recognition of membrane citrullinated proteins such as GRP78. Pentameric class M RF potentiates ACPA-induced inflammation likely via activation of the complement cascade (A). ACPA are also able to promote osteoclast differentiation and activation through similar mechanisms mediated by their Fc and Fab portions. Again, clinical studies indicate that RF, especially at high titres, amplifies ACPA-mediate bone damage (B).

Figure 2

The possible value of autoantibodies as biomarkers in rheumatoid arthritis. The graph represents the possible trajectories of disease activity over time in patients with rheumatoid arthritis (RA): persistently high disease activity despite methotrexate (MTX) treatment (blue); satisfactory control of disease activity with a disease activity score indicative of low disease (red); achievement of remission, which is however unstable at follow-up (green); achievement of sustained remission (purple). Accurate prediction of such trajectories in every patient is currently an unmet need. The analysis of the fine characteristics of the autoantibody response in course of RA, including autoantibody levels, avidity, classes, subclasses and biochemical properties might generate useful biomarkers capable of answering critical questions such as: (Q1) the identification of those patients more likely to respond to first-line treatment with methotrexate (MTX); (Q2) the choice of second-line drug, among several mechanisms of actions available, in MTX-failures; (Q3) the possibility of tapering/stopping medications in patients achieving remission.