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


This study shows a greatly increased OR for the development of RA in individuals with the combination of SE gene carriage and anti-CCP antibodies or an RF of any isotype, in comparison with individuals not having any of the factors or having any one of them separately. In particular, the combination of SE gene carriage and the presence of anti-CCP antibodies appeared to be prognostic for the future development of RA. Previous studies by us[3] and others[2] have demonstrated that an increased production of autoantibodies may precede the development of RA. However, this is the first report in which autoantibody analyses have been combined with genotyping to show a remarkably high predictive value for the future development of RA. The main methodological strength of the current study is that the blood sampling of individuals who later developed RA and their controls was population based.

The results do not support the notion that there is a direct association between SE gene carriage and the occurrence of antibodies directed to CCP (or RFs) leading to the development of RA, but rather suggest that there is a synergistic interaction between these factors. Our knowledge about what triggers the production of anti-CCP antibodies in healthy individuals is limited, as is the role of SE genes in this context. The conversion of arginine to citrulline in HLA-DRB1*0401 transgenic mice has been demonstrated to significantly increase activation of CD4+ T cells.[6] In a previous study of patients with early RA, a significant association between anti-CCP antibodies and expression of B1*0401/0101 was reported.[7] This finding suggests that individuals carrying the SE genes may have more sustained T- and B-cell responses to citrullinated antigens than noncarriers. Taken together, these data suggest that in individuals carrying one or two SE genes, a specific T-cell-dependent immune response to citrullinated peptides may contribute to the occurrence of RA. In the prepatient cohort, there appeared to be a weak association, with borderline statistical significance, between the presence of anti-CCP antibodies and B1*0401. This association was strengthened when the prepatients had developed RA and when the number of individuals with anti-CCP antibodies had increased. However, there does not seem to be an absolute requirement for SE genes to develop anti-CCP antibodies.[8] The ORs for predicting RA were high for anti-CCP antibodies and for RFs but comparatively low for SE gene carriage. The overriding reason for this difference is the relatively high frequency among controls of the SE gene, which is also evident from the relatively low specificity of SE gene carriage in the prepatients.

A quite contradictory suggestion is that HLA antigens do not predispose to the autoimmune disease per se but rather fail to provide protection. Abnormal T-cell regulation associated with certain HLA haplotypes leads to the loss of self-tolerance followed by polyclonal activation of T and B cells and the subsequent production of autoantibodies.[9] This mechanism could be applicable to autoantibodies assessed in this study and would, therefore, explain the findings.

In a recent report on the genetic control of RF production in a rat model of RA, it was shown that the antibody response is controlled by several other genetic regions in addition to the defined arthritis loci.[10] The strength of the genetic association between HLA-DR4 and RA is reported to vary according to disease severity and the population studied.[11] The HLA gene locus has been calculated to contribute to one-third of the genetic risk for developing RA.[12,13] It is, therefore, apparent that other, non-HLA linked genes contribute to the risk of RA.[14] Two recent reports presented numerous single-nucleotide polymorphisms in the peptidyl arginine deiminase enzyme 4, i.e. the enzyme converting peptidylarginine to peptidylcitrulline, several of which are strongly associated with RA.[15,16] Carriers of the susceptibility haplotype had antibodies against citrullinated proteins significantly more often than noncarriers.[15,16]

The limitation of this study is the sample size, which resulted in a relatively low number of individuals in each group when the data were stratified for individuals positive or negative for a given antibody. Furthermore, we emphasise that this is a population-based case–control study, which makes it possible to establish associations between the outcome and the factors studied but precludes calculation of the probability of being a case, given certain values on the analysed factors. In this study, calculations are based on the combination of SE and the analysed autoantibodies. This is because anti-CCP antibodies and RFs are significantly associated, and consequently prediction of RA is only marginally increased when they are considered in combination.


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