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A combination of autoantibodies to cyclic citrullinated peptide (CCP) and HLA-DRB1 locus antigens is strongly associated with future onset of rheumatoid arthritis

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Abstract

Antibodies against cyclic citrullinated peptide (CCP) and rheumatoid factors (RFs) have been demonstrated to predate the onset of rheumatoid arthritis (RA) by years. A nested case–control study was performed within the Northern Sweden Health and Disease study cohort to analyse the presence of shared epitope (SE) genes, defined as HLA-DRB1*0404 or DRB1*0401, and of anti-CCP antibodies and RFs in individuals who subsequently developed RA. Patients with RA were identified from among blood donors whose samples had been collected years before the onset of symptoms. Controls matched for age, sex, and date of sampling were selected randomly from the same cohort. The SE genes were identified by polymerase chain reaction sequence-specific primers. Anti-CCP2 antibodies and RFs were determined using enzyme immunoassays. Fifty-nine individuals with RA were identified as blood donors, with a median antedating time of 2.0 years (interquartile range 0.9–3.9 years) before presenting with symptoms of RA. The sensitivity for SE as a diagnostic indicator for RA was 60% and the specificity was 64%. The corresponding figures for anti-CCP antibodies were 37% and 98%, and for RFs, 17–42% and 94%, respectively. In a logistic regression analysis, SE (odds ratio [OR] = 2.35), anti-CCP antibodies (OR = 15.9), and IgA-RF (OR = 6.8) significantly predicted RA. In a combination model analysis, anti-CCP antibodies combined with SE had the highest OR (66.8, 95% confidence interval 8.3–539.4) in predicting RA, compared with anti-CCP antibodies without SE (OR = 25.01, 95% confidence interval 2.8–222.2) or SE without anti-CCP antibodies (OR = 1.9, 95% confidence interval 0.9–4.2). This study showed that the presence of anti-CCP antibodies together with SE gene carriage is associated with a very high relative risk for future development of RA.

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Abbreviations

CCP:

cyclic citrullinated peptide

CI:

confidence interval

IQR:

interquartile range

NSHDS:

Northern Sweden Health and Disease Study

OR:

odds ratio

RA:

rheumatoid arthritis

RF:

rheumatoid factor

SD:

standard deviation

SE:

shared epitope.

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Acknowledgements

We gratefully acknowledge the technical assistance of Mrs Lisbeth Ärlestig, Solveig Linghult, and Margareta Holmgren, Department of Public Health and Clinical Medicine, Rheumatology and Nutritional Research Divisions. We also thank Dr Olle Olerup for providing us with HLA typing kits, Miss Diab Diab for technical assistance with HLA typing, and Mr Ben de Jong for technical assistance with serum analyses. The work was supported by grants from The Swedish Research Council (K2003-74XD-14705-01A, SRD); Konung Gustaf V's 80-års fund; the Swedish Rheumatism Association; and the Medical Faculty, Umeå University, Umeå, Västerbottens läns landsting (Spjutspets), University Hospital, Umeå, Sweden. The work undertaken in Nijmegen (WJvV) was supported by the Netherlands Organization for Scientific Research in the Medical Sciences and Het Nationaal Reumafonds (Dutch League against Rheumatism) (NWO-MW grant 940-35-037) and by the Council for Chemical Sciences of the Netherlands Organization for Scientific Research (NWO-CW), with financial aid from the Netherlands Technology Foundation (STW grant 349-5077).

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Authors and Affiliations

  1. Department of Public Health and Clinical Medicine, Division of Rheumatology, University Hospital, Umeå, Sweden

    Ewa Berglin & Solbritt Rantapää Dahlqvist

  2. Department of Rheumatology, Karolinska Hospital, Stockholm, Sweden

    Leonid Padyukov & Lars Klareskog

  3. Department of Clinical Immunology, Huddinge University Hospital, Stockholm, Sweden

    Ulf Sundin

  4. Department of Nutritional Research, University Hospital, Umeå, Sweden

    Göran Hallmans

  5. Department of Epidemiology, University Hospital, Umeå, Sweden

    Hans Stenlund

  6. Department of Biochemistry 161, University of Nijmegen, Nijmegen, The Netherlands

    Walther J van Venrooij

Authors
  1. Ewa Berglin
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  2. Leonid Padyukov
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  3. Ulf Sundin
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  4. Göran Hallmans
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  5. Hans Stenlund
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  6. Walther J van Venrooij
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  7. Lars Klareskog
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  8. Solbritt Rantapää Dahlqvist
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Correspondence to Solbritt Rantapää Dahlqvist.

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None declared.

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Berglin, E., Padyukov, L., Sundin, U. et al. A combination of autoantibodies to cyclic citrullinated peptide (CCP) and HLA-DRB1 locus antigens is strongly associated with future onset of rheumatoid arthritis. Arthritis Res Ther 6, R303 (2004). https://doi.org/10.1186/ar1187

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  • DOI: https://doi.org/10.1186/ar1187

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