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Title: Antibodies to citrullinated alpha-enolase peptide in rheumatoid arthritis
Author: Fisher, Benjamin Alexis Charles
ISNI:       0000 0004 2699 4752
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2011
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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.
Supervisor: Venables, Patrick ; Taylor, Peter Sponsor: Schering-Plough UK ; Arthritis Research Campaign
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral