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The excellent commentary by Levesque et al. provides much-needed context to the history of anti-cyclic citrullinated peptide (CCP) antibody tests and the role of these assays in clinical rheumatology.1 Questions that remain, however, relate to the origin of the epitopes that are recognized by anti-mutant (modified) citrullinated vimentin (MCV) antibodies and how this process might theoretically provide more specificity than standard anti-CCP antibody tests. Studies by Burmester and colleagues showed that the citrullinated peptides in modified vimentin purified from rheumatoid arthritis (RA) patients are mutated and contain non-conserved amino acid substitutions.2 Antigenicity of vimentin could, therefore, be enhanced by two “hits”, i.e., the presence of citrulline in combination with an epitope containing different amino acid.
How might this occur? Several studies demonstrated that somatic mutations are present in the synovium of patients with RA. While the data are most robust for the p53 tumor suppressor gene,3,4,5 microsatellite instability and mutations in HPRT and mitochondrial DNA have also been identified.6,7,8 DNA damage due to relaxed DNA mismatch repair mechanisms in the presence of abundant reactive oxygen and nitrogen probably account for the point mutations. In fact, fibroblasts exposed to reactive oxygen in vitro produce similar mutant vimentin proteins.2 Increased specificity of anti-MCV antibodies in RA compared with anti-CCP antibodies observed in some studies is theoretically because somatic mutations are much less common in other types of arthritis.
The recent study of the Leiden Early Arthritis Clinic Cohort suggests that anti-MCV is not more specific than anti-CCP.9 This is a bit puzzling from two perspectives. First, we had previously thought that somatic mutations occur mainly in longstanding disease after a significant burden of mutations accumulates rather than in early synovitis. Second, the presence of these antibodies in individuals that do not progress to RA suggests that the amount of oxidative damage in synovitis is greater than originally thought. It is possible that examining the cohort as patients progress to chronic disease might permit more separation between RA and non-RA when the likelihood for creating greater amounts of MCV in the former increases.
In any case, the anti-MCV antibody studies show how basic science can contribute to understanding clinical science. Observations over the last dozen years demonstrating that DNA damage could alter genes in the rheumatoid synovium and synoviocytes provide an explanation for the creation of neo-epitopes in RA. In addition, it could also explain increased specificity of the antibody responses to mutated proteins in patients with longstanding disease.