From Rheumatoid Factor to Anti-Citrullinated Protein Antibodies and Anti-Carbamylated Protein Antibodies for Diagnosis and Prognosis Prediction in Patients with Rheumatoid Arthritis

Abstract

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease mainly involving synovial inflammation and articular bone destruction. RA is a heterogeneous disease with diverse clinical presentations, prognoses and therapeutic responses. Following the first discovery of rheumatoid factors (RFs) 80 years ago, the identification of both anti-citrullinated protein antibodies (ACPAs) and anti-carbamylated protein antibodies (anti-CarP Abs) has greatly facilitated approaches toward RA, especially in the fields of early diagnosis and prognosis prediction of the disease. Although these antibodies share many common features and can function synergistically to promote disease progression, they differ mechanistically and have unique clinical relevance. Specifically, these three RA associating auto-antibodies (autoAbs) all precede the development of RA by years. However, while the current evidence suggests a synergic effect of RF and ACPA in predicting the development of RA and an erosive phenotype, controversies exist regarding the additive value of anti-CarP Abs. In the present review, we critically summarize the characteristics of these autoantibodies and focus on their distinct clinical applications in the early identification, clinical manifestations and prognosis prediction of RA. With the advancement of treatment options in the era of biologics, we also discuss the relevance of these autoantibodies in association with RA patient response to therapy.

Keywords: anti-carbamylated protein antibodies; anti-citrullinated protein antibodies; rheumatoid arthritis; rheumatoid factors.

Figure 1

Evolution of rheumatoid arthritis (RA) and its correlation with RA-associated autoantibodies. Among at-risk populations, antigen exposure from the mucosal area helps form T-cells and assists in the induction of RA-associated autoantibodies many years before the onset of RA. The development of RA, however, requires further autoantibody maturation, including epitope spreading, isotype switching, avidity maturation and antibody glycosylation, before they are pathogenically transformed. As our understanding of autoantibodies advances, the application of the autoantibodies may be utilized to assist in RA diagnosis, to predict disease course, to guide treatment and possibly to prevent or delay RA development before its onset.

Figure 2

Schematic diagram illustrating the exposure of RF epitopes and posttranslational modification of peptide targets for autoantibody interactions in rheumatoid arthritis. (A) The epitopes of RFs reside in the Fc portion of IgG mostly in the CH2/CH3 or the CH3/CH3 groove. Recent evidence has suggested that conformational changes via altered Fc glycosylation, physicochemical treatment, antigen binding, or physical adsorption onto a hydrophobic surface promote the exposure of RF epitopes on circulating IgGs. (B) Citrullinated peptides are generated by the enzymatic activity of peptidylarginine deiminase (PAD), converting arginine to citrulline in the presence of calcium. (C) Carbamylation is the conversion of a lysine to homocitrulline upon the binding of cyanate in the form of isocyanic acid to lysine, without enzymatic catabolism. Urea and thiocyanate catabolized by myeloperoxidase (MPO) are important sources of cyanate.