Evidence from animal models further supports the potential contribution of anticitrulline antibodies to the pathogenesis of inflammatory arthritis. Recent studies in the collagen induced arthritis model have demonstrated that anticitrulline autoantibodies are induced by immunization with collagen and that establishing tolerance to citrullinated peptides blocks development of disease.23 Perhaps more compelling evidence for the pathogenic role of these antibodies is the ability to passively transfer anticitrulline antibodies to mice with subclinical arthritis and initiate robust symmetric inflammatory synovitis. Interestingly, passive transfer of anticitrulline antibodies into mice without any inflammatory stimulus does not elicit arthritis, and citrullination of joint tissue proteins is evident in mice with subclinical collagen-induced arthritis (CIA).
Taken together, these observations suggest a new disease model where the combination of anticitrulline antibodies and inflammation-induced citrullination of tissue proteins can conspire to induce an autoimmune inflammatory arthritis.9 The clinical utility of testing for anti-CCP versus RF is summarized in Table 1 (below). The anti-CCP test, while having similar sensitivity for the presence of RA, has much greater specificity. In addition, antibodies to CCP are rarely found in patients with other rheumatic conditions and infectious diseases where RF is more frequently found. Anti-CCP is even found frequently before the diagnosis of RA. These observations suggest that the anti-CCP test may be more useful for the diagnosis of RA than are RF tests—or that it at least should be part of the diagnostic algorithm.
Recently, my colleagues and I have examined a large cohort of patients with early arthritis who were followed for at least six months.26 The substitution of anti-CCP for the ACR classification criteria subcutaneous nodules and erosions improved on the ACR classification criteria for the earlier identification and classification of those patients who eventually developed RA. On the basis of these findings, we recommend that, if one suspects that a patient has RA, one should test for both RF and anti-CCP.
What do we do with these results in our Arthritis Center? We have observed a gradual trend for earlier and more aggressive treatment with disease-modifying antirheumatic drugs (DMARDs) in the patient who presents with a symmetric polyarthritis, and sometimes even a monoarthritis, who has a positive anti-CCP test. This approach is in marked contrast with the way the RF test was used, due to the lower specificity of this test in early arthritis in predicting RA. However, we rarely add a biological (e.g., TNF blocker) to the treatment regimen unless the patient has failed two DMARDs, clearly has inflammation, and is felt clinically to probably have RA. However, more carefully constructed clinical trials are needed to guide us on when and how to treat the early arthritis patient, because not all of them develop RA.
Summary
What does the future hold? First, in respect to antinuclear antibodies (ANAs, covered in Part One of this series), I predict that testing will become more automated, based on both economic pressures and improvement in solid-phase immunoassays. I suspect this will be coupled with the recognition that systemic lupus erythematosus, scleroderma, and Sjögren’s each represent a spectrum of related disorders. I predict that the combination of good clinical description, genetic markers, and assays for biomarkers via proteomics, will better divide up related subsets, resulting in better testing as well as therapy.
