Antibodies to citrullinated alpha-enolase peptide in rheumatoid arthritis

Abstract

Antibodies to cyclic citrullinated peptides (CCP) are diagnostically specific for rheumatoid arthritis (RA) and provide valuable prognostic information. The antigens recognised in vivo by these antibodies are still a matter of investigation and the candidates include citrullinated α-enolase. This thesis describes the identification of an immunodominant epitope, citrullinated α-enolase peptide 1 (CEP-1) . Antibodies to CEP-1 showed a diagnostic specificity of 97%, and sensitivity of 38%. A quantitative CEP-1 ELISA was developed and tested in multiple cohorts of early and established RA with a sensitivity of 25-60%. The relationship of anti-CEP-1 antibodies with the major risk factors for RA, the HLA-DRB1 'shared epitope' (SE), PTPN22 and smoking, were examined in 1497 patients and 872 controls in a collaborative study involving patients from Sweden and the UK. A previously described association between SE and anti-CCP antibodies was found to be strongest in the subset that was also positive for anti-CEP-1 antibodies. In the Swedish case-control analysis, the combination of SE, PTPN22 and smoking was preferentially associated with this subset (odds ratio 37 versus 2 for the anti-CEP-1-/anti-CCP+ subset). A novel gene association with this subset, Bromodomain-containing protein 2, was also detected by dense SNP mapping of the MHC region. The prognostic value of anti-CEP-1 antibodies was examined in 680 patients from two early RA cohorts. Only a weak predictive value for clinical outcomes was found, with no significant differences when comparing anti-CCP antibody positive patients with and without anti-CEP-1 antibodies. Furthermore, no predictive value for response to anti-TNF agents was demonstrated in 450 patients from the British Society of Rheumatology Biologics Register. These findings suggest that autoimmunity to at least one epitope on citrullinated α-enolase is a powerful probe for the aetiology of RA (genes and environment), but not for the downstream results of pathogenesis such as clinical outcome and response to treatment.