Antibodies to citrullinated proteins and differences in clinical progression of rheumatoid arthritis

Autoantibodies directed to citrullinated proteins (e.g. anti-cyclic-citrullinated peptide [anti-CCP] antibodies) are highly specific serological markers for rheumatoid arthritis (RA) that are thought to be directly involved in the disease pathogenesis [1]. Citrullinated proteins are not exclusively located in synovial tissue of RA patients, but can also be found in synovium samples of patients with other inflammatory joint diseases [2] – suggesting that the specificity of anti-CCP antibodies for RA is not due to the expression of citrullinated proteins, but might be the result of an abnormal humoral response. Intriguingly, this antibody response may occur years before any clinical symptoms, as shown by the presence of anti-CCP antibodies several years before the clinical onset of arthritis [3,4]. Furthermore, a proportion of RA patients do not harbour anti-CCP antibodies, suggesting that the presence of anti-CCP antibodies is not obligatory for the development of arthritis or that the pathogenic mechanisms underlying anti-CCP-positive RA and anti-CCP-negative RA are different.These observations inspired subsequent research addressing the question of whether RA patients with anti-CCP antibodies are different from those who are anti-CCP-negative. We very recently demonstrated in two independent Caucasian populations that the shared epitope encoding HLA-DBR1 alleles is associated with RA in patients with anti-CCP antibodies but not in patients without these antibodies (unpublished data, [5]). These findings are important as they indicate that the shared epitope alleles are not associated with RA as such, but rather with a particular phenotype of the disease.Given the findings suggesting a pathophysiological role for anti-CCP antibodies in RA and the reported immunogenetic differences between anti-CCP-positive and anti-CCP-negative patients, it is conceivable that anti-CCP-positive RA and anti-CCP-negative RA are different disease entities and thus have different phenot