ACPA-negative rheumatoid arthritis: From immune mechanisms to clinical translation

The presence of anti-citrullinated protein autoantibodies (ACPA) is a hallmark feature of rheumatoid arthritis (RA), which causes chronic joint destruction and systemic inflammation. Based on ACPA status, RA patients can be sub-grouped into two major subsets: ACPA-positive RA (ACPA⁺ RA) and ACPA-negative RA (ACPA^- RA). Accumulating evidence have suggested that ACPA⁺ RA and ACPA^- RA are two distinct disease entities with different underlying pathophysiology. In contrast to the well-characterized pathogenic mechanisms of ACPA⁺ RA, the etiology of ACPA^- RA remains largely unknown. In this review, we summarized current knowledge about the primary drivers of ACPA^- RA, particularly focusing on the serological, cellular, and molecular aspects of immune mechanisms. A better understanding of the immunopathogenesis in ACPA^- RA will help in designing more precisely targeting strategies, and paving the road to personalized treatment. In addition, identification of novel biomarkers in ACPA^- RA will substantially promote early treatment and improve the outcomes.