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

Abstract

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 5 95), their unaffected FDRs (n 5 109), and healthy FN controls (n 5 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 5 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 5 0.04). The association with RA was strongest when all 3 autoantibodies (RF, anti-CCP, and antiCarP) 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.Indigenous North Americans have some of the highest prevalence rates of rheumatoid arthritis (RA) worldwide (1,2). These indigenous peoples, particularly

Antibodies against carbamylated proteins and cyclic citrullinated peptides in systemic lupus erythematosus: results from two well-defined European cohorts

“…While a positive anti-CCP test in RA is typically citrulline-dependent [7], it has been suggested that anti-CCP in other conditions is generally not, and thus, also reacts with the corresponding cyclic arginine peptide (anti-CAP) [8, 9]. During the last years, it has been repeatedly shown that antibodies targeting carbamylated proteins (anti-CarP) may occur in anti-CCP/rheumatoid factor (RF) negative cases [10–12]. Like RF and anti-CCP, anti-CarP antibodies can also be detected many years before the onset of RA [13–15].…”

“…Inflammation, smoking and renal failure have been reported to increase the non-enzymatic post-translational modification in which cyanate binds to molecules containing primary amine or thiol groups and forms carbamyl groups [16]. Carbamylation of proteins can lead to the loss of tolerance with formation of antibodies directed against carbamylated proteins (anti-CarP antibodies) in susceptible individuals [10–12]. …”

Autoantibodies and B Cells: The ABC of rheumatoid arthritis pathophysiology

“…The value of determining various autoantibodies appears to be remarkably different depending on what phase of the disease is studied. In at‐risk individuals without arthralgia, triple positivity for autoantibodies (RF, ACPA, and anti‐CarP) has a higher association with disease development . Moreover, in a meta‐analysis investigating various cohorts of presymptomatic individuals, triple positivity resulted in high specificity (98%‐100%), but low sensitivity (11%‐39%) for prediction of RA development .…”

“…In at-risk individuals without arthralgia, triple positivity for autoantibodies (RF, ACPA, and anti-CarP) has a higher association with disease development. 83 Moreover, in a meta-analysis investigating various cohorts of presymptomatic individuals, triple positivity resulted in high specificity (98%-100%), but low sensitivity (11%-39%) for prediction of RA development. 84 However, in individuals who have already progressed to the stage of arthralgia, anti-CarP did not have an additive value to ACPA and RF in predicting arthritis onset.…”

Identification of Lifelines participants at high risk for development of rheumatoid arthritis

“…Other described predictive markers like the acute-phase reactants erythrocyte sedimentation rate and C reactive protein and additional markers can be incorporated in the development of prediction models. Indeed, recent insight into the specificity of the combined presence of ACPA, rheumatoid factor and anticarbamylated protein antibodies provides interesting possibilities in further narrowing down persons at risk 7 8…”