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) 

In This Article

Abstract and Introduction

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.

Autoimmune diseases, such as rheumatoid arthritis (RA), are believed to develop as a result of dysregulation of the immune system, leading ultimately, in RA, to the clinical features of inflammation and destruction in several joints.[1] The aetiology of RA has been suggested to be an interaction between genetic and environmental factors. To date, it has not been possible to identify individuals at early stages of this dysregulation, i.e. before presentation with clinically obvious polyarthritis. If methods were available to predict future development of RA, a better understanding of the events triggering the disease would be achieved, thereby creating the possibility of developing and testing preventive measures and of instituting therapy at earlier stages of disease development than is current practice.

Previous studies have demonstrated that the presence of rheumatoid factors (RFs) of IgM, IgG, and IgA class[2,3] predict the development of rheumatoid arthritis and in a case–control study we found that antibodies against cyclic citrullinated peptide (CCP), as well as RFs, predated the onset of RA by several years.[3] Both anti-CCP antibodies and IgA-RF predicted the development of RA, with the highest predictive value for anti-CCP antibodies, indicating that citrullination and production of anti-CCP antibodies and RF are early processes in the development of RA.[3] The HLA-DRB1 locus has been shown to be linked to and associated with RA, with an especially high risk in individuals with compound heterozygosity for shared epitope (SE) genes.[4] However, there are no previous reports of studies combining serological and genetic factors in order to optimise the prediction of a future risk of developing RA. In the present study, we have evaluated the significance of the presence of SE genes, defined as DRB1*0404 or DRB1*0401, in relation to anti-CCP antibodies and RFs in individuals who subsequently developed RA.


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