Journal Scan: Rheumatology

The following four articles on the topic of anti-cyclic citrullinated peptide antibodies and the timely diagnosis of rheumatoid arthritis are presented as a group. Context: The progression of rheumatoid arthritis can be slowed by disease modifying antirheumatic drugs (DMARDs). Accordingly, it is important to identify cases of early synovitis syndromes (< 1 year duration) which have the potential to progress to erosive rheumatoid arthritis. Traditional approaches to diagnosis, including the American College of Rheumatology 1987 classification criteria for RA and measurement of rheumatoid factor, do not perform well in evaluating undifferentiated early synovitis syndromes. The discovery of antibodies to citrullinated peptides has provided a new serologic tool for identification of patients who should be referred early to a rheumatologist for treatment. Citrullination refers to the process in which a terminal nitrogen atom in an arginine molecule on a protein chain is replaced by oxygen, thereby creating the amino acid citrulline. Citrullination occurs in the normal apoptosis of cells, but environmental factors, such as cigarette smoking, may stimulate it. The process is controlled by an enzyme peptidylarginine deiminase (PAD), of which specific haplotypes have been associated with rheumatoid arthritis. The development of an immune response to citrulline, namely anti-cyclic citrullinated peptide (anti-CCP) antibodies, is thought to be a critical step in the pathogenesis of rheumatoid arthritis. Anti-CCP antibodies are detectable months to years before the onset of clinical disease, and their detection provides an opportunity to identify rheumatoid arthritis at a stage where treatment will have the greatest impact. A new model for an etiology of rheumatoid arthritis: smoking may trigger HLA-DR (shared epitope)—restricted immune reactions to autoantigens modified by citrullination. Klareskog L, Stolt, P, Lundberg K, Kallberg H, Bengtsson C, Grunewald J, Ronnelid J, Harris HE, Ulfgren AK, Rantapaa-Dahlqvist S, Eklund A, Padyukov L, Alfredsson L. Arthritis Rheum. 2006;54:38–46. Study Design and Results: This was a case control study of patients with recent-onset rheumatoid arthritis (disease duration < 12 months), with control subjects taken from the same geographic areas in Sweden. Investigators evaluated the hypothesis that the environmental risk factor of cigarette smoking influences the production of anti-CCP antibodies and interacts with the genetic risk factor of the HLA-DR “shared epitope” (SE). In addition, patients had bronchoscopic evaluation for citrullinated proteins in bronchoalveolar lavage cells. Results showed that there is a dose-dependent association of smoking and the presence of anti-CCP antibodies in patients with rheumatoid arthritis. In addition there is an interaction between smoking and double copies of the HLA-DR SE genes leading to a 21-fold increased risk for RA compared with nonsmokers without SE genes. In CCP negative RA, these risk factors were not present. The BAL results revealed citrullinated proteins staining cells in smokers but not in nonsmokers. Conclusions: This is an important study revealing the interaction of an environmental risk factor, namely smoking exposure, with the underlying genetic substrate for rheumatoid arthritis leading to the production of anti-CCP antibodies. Furthermore, the results show that the clinical illness of rheumatoid arthritis is likely a spectrum of diseases with differing environmental and genetic risk factors. Interaction between smoking, the shared epitope, and anti-cyclic citrullinated peptide. Lee HS, Irigoyen P, Kern M, Lee A, Batliwalla F, Khalili H, Wolfe F, Lum RF, Massarotti E, Weisman M, Bombardier C, Karlson EW, Criswell LA, Vlietinck R, Gregersen PK. Arthritis Rheum. 2007;56:1745–1753. Study Design and Results: This is a case analysis of 2476 North American patients with RA from three research cohorts evaluating the association of smoking, anti-CCP antibodies, and HLA-DR shared epitope alleles. Although an association between the presence of anti-CCP antibodies and the shared epitope alleles was confirmed, only weak evidence between smoking and CCP antibody formation was found in one cohort. Conclusions: The authors hypothesize that other environmental factors such as air pollution may have a greater influence in North American patients, masking a measurable impact of tobacco. The role of anti-cyclic citrullinated peptide antibodies in predicting progression of palindromic rheumatism to rheumatoid arthritis. Russell AS, Devani AL, Maksymowych WP. J Rheumatol. 2006;33:1240–1242. Study Design and Results: This is a retrospective cohort design evaluating the presence of anti-CCP antibodies in patients followed at one Canadian center with palindromic rheumatism. (A palindrome is a word or phrase that reads the same in both directions: “Madam, I’m Adam” and “mom” are examples. So-called “palindromic rheumatism” follows a symmetric course of flare up and recession—episodic attacks of synovitis last 1 to 3 days, ending as rapidly as they began.) Testing was performed on serum stored at the first evaluation or within 1 year of initial presentation. After a mean followup of 5.4 years, 83% of the patients who were CCP positive had persistent rheumatoid arthritis. The positive predictive value of the CCP antibody was 71 compared with 60 for a positive rheumatoid factor. The presence of both antibodies increased the PPV to 81. The performance of anti-cyclic citrullinated peptide antibodies in predicting the severity of radiographic damage in inflammatory polyarthritis. Bukhari M, Thomson W, Naseem H, Bunn D, Silman A, Symmons D, Barton A. Arthritis Rheum. 2007;56:2929–2935. Study Design and Results: Valuable observations regarding the natural history of early inflammatory arthritis syndromes (two or more swollen joints present for at least 4 weeks) have come from the Norfolk Arthritis Register population of community-based primary care patients in the UK. Previous studies from this group confirmed the utility of rheumatoid factor in predicting the risk of progressive erosive arthritis in patients with early arthritis. Now the group presents comparative longitudinal observations over 5 years comparing the value of the rheumatoid factor versus CCP antibody detection. The CCP antibody was found to be a better predictor of erosive disease at presentation and at 5 years followup than the rheumatoid factor. The group of patients in whom CCP antibody detection had the greatest value was in those with rheumatoid factor negative arthritis. The authors emphasize the CCP antibody status by itself should not determine treatment decisions, as some patients with a negative assay do have erosive disease develop with time. Conclusions: These studies of very early inflammatory arthritis reveal that the anti-cyclic citrullinated peptide antibody is a highly useful serologic marker for the risk of progression in patients with rheumatoid arthritis. Comments: The discovery and the diagnostic evaluation of anti-CCP antibodies have provided a serologic tool for identifying very early stages of the clinical illness. Moreover, the study if these antibodies offer clues regarding potential environmental and genetic risk factors in the etiology of RA. Although these studies illustrate a risk of disease progression in patients who lack the CCP antibody, the identification of the antibody in a patient with either relapsing or early persistent limited synovitis should lead to early rheumatology referral. Pearls: DMARDs are powerful drugs which offer great clinical benefits, but because of their power (and potential side effects) they cannot be used indiscriminately. Assessing patients for the presence of the anti-CCP antibody may be a useful step in evaluating early synovitis syndromes where the standard rheumatoid factor is negative.