Role of Anti-Carbamylated Protein Antibodies Compared to Anti-Citrullinated Protein Antibodies in Indigenous North Americans With Rheumatoid Arthritis, Their First-Degree Relatives, and Healthy Controls

Objective. Rheumatoid arthritis (RA) is characterized by the presence of autoantibodies, including seropositivity for rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPAs). In addition, antibodies to carbamylated proteins (anti-CarP) are present in patients with RA and are associated with joint damage. This study was undertaken to assess the presence of anti-CarP antibodies in indigenous North Americans (First Nations [FN] populations) with RA compared to their at-risk first-degree relatives (FDRs) and healthy controls. Methods. Anti-CarP IgG and ACPAs (specifically, anti-cyclic citrullinated peptide [anti-CCP] antibodies) were measured by enzyme-linked immunosorbent assay in the sera of FN patients with RA (n=95), their unaffected FDRs (n=109), and healthy FN controls (n=85). Antibodies to additional citrullinated peptides were measured using a multiplex ACPA array, and the number of peptides recognized was reported as an ACPA score. Groups were compared using the chi-square test and Mann-Whitney U test. Associations between RA and seropositivity for RF, ACPAs, and anti-CarP antibodies were determined by logistic regression. Results. Anti-CarP antibodies were more frequent in FN patients with RA (44.3%) compared to FDRs (18.3%) and FN controls (4.7%) (both P<0.0001 versus RA). Moreover, anti-CarP antibodies were more frequent in FDRs than in FN controls (P=0.008). The ACPA score was higher in anti-CCP-positive FN patients with RA than in anti-CCP-positive FN FDRs (median score 7 [interquartile range (IQR) 7] versus median score 1 [IQR 4]; P=0.04). The association with RA was strongest when all 3 autoantibodies (RF, anti-CCP, and anti-CarP) were present in the patients' serum (odds ratio 194, 95% confidence interval 23-1,609, P<0.0001). Conclusion. Anti-CarP antibodies are prevalent in FN patients with RA and also more common in their at-risk FDRs compared to healthy controls. The results indicate an association of RF, ACPAs, and anti-CarP with RA that is strongest when all 3 autoantibodies are present. These findings may provide new insights into the evolution of autoimmunity in preclinical RA.