The fibrin-derived citrullinated peptide β60–74Cit60,72,74 bears the major ACPA epitope recognised by the rheumatoid arthritis-specific anticitrullinated fibrinogen autoantibodies and anti-CCP2 antibodies

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Abstract

Objectives

To evaluate the proportions of rheumatoid arthritis (RA) sera containing anticitrullinated proteins autoantibodies (ACPA) reactive to α36–50Cit38,42 and/or β60–74Cit60,72,74, two peptides identified as bearing the immunodominant epitopes of their major target, citrullinated fibrin. To analyse the relationships of anti-α36–50Cit38,42 and anti-β60–74Cit60,72,74 autoantibodies with autoantibodies reactive to the complete citrullinated human fibrinogen molecule (AhFibA) and with anti-CCP2 antibodies.

Methods

617 sera from 181 patients with established RA and 436 with non-RA rheumatic diseases were tested by ELISA for AhFibA, anti-CCP2, anti-α36–50Cit38,42, anti-β60–74Cit60,72,74 autoantibodies, and by nephelometry for rheumatoid factor (RF). Diagnostic indexes, correlations and concordances between tests were analysed. Crossreactivity of anti-α36–50Cit38,42 and anti-β60–74Cit60,72,74 autoantibodies was assessed in competition experiments.

Results

At a diagnostic specificity of 95%, the diagnostic sensitivity of AhFibA (83%) was significantly higher than that of all other tests. The diagnostic sensitivity of anti-β60–74Cit60,72,74 (71%) was significantly higher than that of anti-α36–50Cit38,42 autoantibodies (51%) but similar to that of anti-CCP2 (74%). Titres of RF, anti-α36–50Cit38,42 and anti-β60–74Cit60,72,74 autoantibodies were weakly correlated with each other, whereas titres of anti-β60–74Cit60,72,74 were strongly correlated with those of AhFibA (r=0.633) and anti-CCP2 (r=0.634). Anti-α36–50Cit38,42 and anti-β60–74Cit60,72,74 mainly corresponded to two non-crossreactive subfamilies of ACPA. More than 90% of AhFibA-positive or anti-CCP2-positive sera recognised the α36–50Cit38,42 and/or the β60–74Cit60,72,74 peptide.

Conclusions

Autoantibodies reactive to α36–50Cit38,42 and β60–74Cit60,72,74 form two distinct, non-overlapping subfamilies of ACPA that, together, cover practically all the ACPA reactivity to citrullinated fibrinogen and to CCP2 antigens. In established RA, anti-β60–74Cit60,72,74 autoantibodies show diagnostic indexes similar to those of anti-CCP2.

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