Search

Objective: Previously, only the HLA–DRB1 alleles have been assessed in rheumatoid arthritis (RA). The aim of the present study was to identify the key major histocompatibility complex (MHC) susceptibility factors showing a significant association with anti–carbamylated protein antibody–positive (anti‐CarP+) RA. Methods: Analyses were restricted to RA patients who were anti–cyclic citrullinated peptide antibody negative (anti‐CCP−), because the anti‐CCP status dominated the results otherwise. Therefore, we studied samples from 1,821 anti‐CCP− RA patients and 6,821 population controls from Spain, Sweden, and the Netherlands. The genotypes for ~8,000 MHC biallelic variants were assessed by dense genotyping and imputation. Their association with the anti‐CarP status in RA patients was tested with logistic regression and combined with inverse‐variance meta‐analysis. Significance of the associations was assessed according to a study‐specific threshold of P < 2.0 × 10−5. Results: The HLA–B*08 allele and its correlated amino acid variant Asp‐9 showed a significant association with anti‐CarP+/anti‐CCP− RA (P < 3.78 × 10−7; I2 = 0). This association was specific when assessed relative to 3 comparator groups: population controls, anti‐CarP−/anti‐CCP− RA patients, and anti‐CCP− RA patients who were positive for other anti–citrullinated protein antibodies. Based on these findings, anti‐CarP+/anti‐CCP− RA patients could be separated from other antibody‐defined subsets of RA patients in whom an association with the HLA–B*08 allele has been previously demonstrated. No other MHC variant remained associated with anti‐CarP+/anti‐CCP− RA after accounting for the presence of the HLA–B*08 allele. Specifically, the reported association of HLA–DRB1*03 was observed at a level comparable to that reported previously, but it was attributable to linkage disequilibrium. Conclusion: These results identify HLA–B*08 carrying Asp‐9 as the MHC locus showing the strongest association with anti‐CarP+/anti‐CCP− RA. This knowledge may help clarify the role of the HLA in susceptibility to specific subsets of RA, by shaping the spectrum of RA autoantibodies. [ABSTRACT FROM AUTHOR]

The initial management of rheumatoid arthritis (RA) has a high impact on disease prognosis. Therefore, we need to select the most appropriate treatment as soon as possible. This goal requires biomarkers of disease severity and prognosis. One such biomarker may be the presence of anti-carbamylated protein antibodies (ACarPA) because it is associated with adverse long term outcomes as radiographic damage and mortality. Here, we have assessed the ACarPA as short-term prognostic biomarkers. The study was conducted in 978 prospective early arthritis (EA) patients that were followed for two years. Our results show the association of ACarPA with increased levels of all the disease activity measures in the first visit after arthritis onset. However, the associations were more significant with the high levels in local measures of inflammation and physician assessment than with the increases in systemic inflammation and patient-reported outcomes. More notably, disease activity was persistently increased in the ACarPA positive patients during the two years of follow-up. These differences were significant even after accounting for the presence of other RA autoantibodies. Therefore, the ACarPA could be considered short-term prognostic biomarkers of increased disease activity in the EA patients.