Combination of antibodies to CCP and HLA-DRB1 locus antigens strongly associated with future RA

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Arthritis Research & Therapy

11 May 2004

Research article

A combination of autoantibodies to cyclic citrullinated peptide (CCP)

and HLA-DRB1 locus antigens is strongly associated with future onset of

rheumatoid arthritis

Ewa Berglin1, Leonid Padyukov2, Ulf Sundin3, Göran Hallmans4, Hans

Stenlund5, Walther J van Venrooij6, Lars Klareskog2 and Solbritt

Rantapää Dahlqvist1

1Department of Public Health and Clinical Medicine, Division of

Rheumatology, University Hospital, Umeå, Sweden

2Department of Rheumatology, Karolinska Hospital, Stockholm, Sweden

3Department of Clinical Immunology, Huddinge University Hospital,

Stockholm, Sweden

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

5Department of Epidemiology, University Hospital, Umeå, Sweden

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

Netherlands

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.

http://arthritis-research.com/content/6/4/r303/abstract

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