Background Rheumatoid Arthritis (RA) is characterized by the expression of auto-antibodies, including Anti-citrullinated peptide (ACPA) and Rheumatoid Factor. We have shown that both RA prevalence and baseline-level of auto-antibodies are higher in Canadian First Nations (FN) compared to the Caucasian population. (Peschken et al. 2010, El-Gabalawy et al. 2012) We have established a large longitudinal study among FN to collect data of both RA-patients and their First Degree Relatives (FDR) to investigate the development of RA. Recently, the presence of Anti-Carbamylated protein (Anti-CarP) antibodies in patient sera has been described and correlated to joint damage (Shi et al. 2011); their presence in FN RA-patients and FDR has not been studied.
Objectives The primary objective of this study was to determine the presence and distribution of Anti-CarP-antibodies among FN controls, FN RA-patients and FN FDR, and to examine the relationship between Anti-CarP, ACPA, and RF in this population.
Methods An in-house developed ELISA was used to measure Anti-CarP IgG. (Shi et al. 2011) Four different groups were measured: Caucasian control (n=38), FN Controls (n=86), FN RA patients (n=109) and unaffected FDR of FN RA patients (n=128). Individuals in both control groups had no known autoimmune disease or family history. The presence of ACPA and RF in these study populations was determined using commercially available assays. In addition, recognition of specific ACPA peptides was determined using a multiplex ACPA array as previously described. (Sokolove et al. 2012) An aggregate ACPA score was determined based on a sum of the total number of ACPA peptides recognized in each serum sample. A cutoff level for each ACPA peptide was established based on the mean plus 2 standard deviations in the control samples tested.
Results FDR were more often positive for anti-CarP-antibodies as compared to controls. Likewise, the FN-RA patients were more often positive for anti-CarP-antibodies as compared to FN-controls (p<0,001; OR=11,30; CI 4,54-28,10) and FN-FDR (p=0,002; OR=2,89; CI 1,65-5,06). The presence of anti-CarP-antibodies did not correlate with the number of citrullinated epitopes recognized. Intriguingly, anti-CarP-positivity was often found together with anti-CCP in the patients but not in FDR. During follow-up, 11 FDR cases developed RA. Epitope spreading of the ACPA response was detected in most of these individuals as evidenced by a progressive increase in the ACPA score over time. Interestingly, there was little correlation between the ACPA scores and the evolution of the Anti-carP response, with some individuals being Anti-CarP negative throughout follow-up, some being positive throughout follow-up and some changing from negative to positive just prior to disease onset.
Conclusions As with ACPA and RF, Anti-CarP are prevalent in FN RA patients, although with incomplete overlap. Anti-carP are also detected at a higher frequency in the FDR of FN RA patients compared to unrelated FN controls. The observed association between Anti-carP and ACPA in FN RA patients, but not FDR provides new insights into to how autoimmunity may evolve in the preclinical period, ultimately culminating in RA onset.
Disclosure of Interest None declared
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