Background and Objectives In rheumatoid arthritis (RA), the presence of antibodies to citrullinated proteins (ACPA) is strongly associated with certain genetic risk factors and smoking. The recently identified antibodies against carbamylated proteins (anti-CarP) are present in part of ACPA-positive, but also ACPA-negative RA patients. This raised the question whether the presence of anti-CarP may be associated with specific risk factors, which could provide clues about the pathogenesis of ACPA-negative RA. In this study we have therefore analysed the relationship between anti-CarP antibodies, ACPA, genetic risk factors (HLA-DRB1 alleles and PTPN22) and smoking in RA.
Materials and Methods Presence of antibodies to carbamylated fetal calf serum (CarP-FCS) and fibrinogen (CarP-Fib) was determined by in-house ELISAs in the Leiden Early Arthritis Cohort (EAC) and in the Swedish Epidemiological Investigation of RA (EIRA) cohort. Odds ratios for associations with different HLA-DRB1 alleles, PTPN22 genotypes and smoking were calculated separately for each cohort as well as in a combined meta-analysis, in RA subsets defined by anti-CarP and anti-cyclic citrullinated peptide (CCP) antibody status.
Results In both cohorts,anti-CarP antibodies were mainly detected in the anti-CCP-positive population, but also in the anti-CCP-negative population. No strong associations between anti-CarP antibodies and specific HLA-DRB1 alleles, including shared epitope alleles, could be identified, with the exception of a consistent association between anti-CarP FCS and HLA-DRB1*03. Further analyses did not reveal any specific associations between anti-CarP antibodies and PTPN22 genotypes or smoking.
Conclusions Anti-CarP antibodies were present in both ACPA-positive and ACPA-negative RA patients in the two separate cohorts. Except for a modest association with HLA-DRB1*03, there were no strong associations between anti-CarP antibodies and other HLA-DRB1 alleles, PTPN22 or smoking. Although it cannot be excluded that risk factors not investigated here may be importance for anti-CarP-positive disease, the lack of association found here suggests a possible fundamentally different biological mechanism for anti-CarP antibody formation compared with anti-CCP antibody formation.