A Combination of Autoantibodies to Cyclic Citrullinated Peptide (CCP) and HLA-DRB1 Locus Antigens is Strongly Associated with Future Onset of Rheumatoid Arthritis

Ewa Berglin; Leonid Padyukov; Ulf Sundin; Göran Hallmans; Hans Stenlund; Walther J van Venrooij; Lars Klareskog; Solbritt Rantapää Dahlqvist


Arthritis Res Ther. 2004;6(4) 

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The sensitivity found for the presence of SE genes as a diagnostic indicator for RA in prepatients was 60% (34/57) and the specificity was 64% ( Table 1 ). The respective figures for carriers of two SE genes were 28% (16/57) and 95%. The specificity for the allele B1*0401 (74%) was higher than that for SE given either B1*0401 or B1*0404 (data not shown). The frequencies of the presence of one or both of the SE genes studied in the prepatients were significantly greater than in the controls (P = 0.003 and P = 0.0001, respectively). Of the prepatients, 37% (22/59) tested positive for anti-CCP-antibodies, with a specificity of 98%. The sensitivity for IgA-RF was 42% (25/59), for IgM-RF 22% (13/59), and for IgG-RF 17% (10/59) ( Table 1 ). The specificity was 94% for all three RF isotypes. The combination of SE gene carriage and anti-CCP antibodies increased the specificity to 99%, as did the combination of SE genes and IgG-RF ( Table 1 ). The presence of double doses of the SE genes studied, in combination with either anti-CCP-antibodies, IgA-RF, or IgM-RF, gave a specificity of 99%, and, in combination with IgG-RF, of 100% ( Table 1 ).

In a univariate logistic regression model, SE gene carriage, and particularly carriage of two SE alleles, significantly predicted RA (OR = 2.66, 95%CI 1.38–5.12 and OR = 6.89, 95%CI 2.52–18.84, respectively). In multivariate models including anti-CCP antibodies and RFs of all isotypes, single or double SE gene carriage significantly predicted RA in addition to our previously described predictive value of anti-CCP antibodies and IgA-RF.[3] The OR for SE gene carriage was 2.35 (95%CI 1.05–5.26) and for double SE gene carriage 7.31 (95%CI 2.26–23.67) (data not shown).

In a univariate logistic regression analysis, the combination of anti-CCP antibodies and SE gene carriage gave an OR of 66.8, while the presence of anti-CCP-antibodies alone gave an OR of 25.1 for the risk of developing RA compared with not having any of these factors ( Table 2 ). The calculation on the SE allele B1*0401 selectively in the same model gave essentially the same results (data not shown). Furthermore, in the same type of analysis, SE gene carriage and IgA-RF showed similar results but at a lower level ( Table 2 ). However, in the analysis including IgM-RF and SE, only SE gene carriage separately or in combination with IgM-RF significantly predicted RA; the same pattern was found for combinations of IgG-RF and SE ( Table 2 ).

Except for a borderline significant association between the SE allele B1*0401 and anti-CCP-antibodies (P = 0.051), no significant association between SE gene carriage and the expression of anti-CCP-antibodies or RFs could be demonstrated (data not shown). As previously reported,[3] anti-CCP antibodies and RFs were associated (data not shown).

When the prepatients were diagnosed after having developed RA, the sensitivity for anti-CCP antibodies was 71%, for IgG-RF 45%, for IgM-RF 73%, and for IgA-RF 71%. As regards SE, a significant association was found only between the presence of anti-CCP antibodies and B1*0401 (P = 0.027), and not between SE and any of the RFs.


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