A study appearing in the Journal of Rheumatology provides evidence that the presence of rheumatoid factor (RF) along with antibodies to cyclic citrullinated peptide (CCP) in patients with very early inflammatory arthropathy can predict which patients will go on to develop rheumatoid arthritis (RA).¹

The need for diagnostic criteria that can detect early disease has become urgent in light of recent findings indicating that aggressive treatment with biologic agents can effectively stem the course of RA progression. "There is increasing interest in the concept that the very early phase of clinically apparent RA -- within the first 3 months of symptom onset -- may represent a therapeutic window of opportunity," lead investigator Karim Raza, PhD, MRCP, senior lecturer at the Medical School of the University of Birmingham in the UK, told CIAOMed.

Currently, diagnosis of RA is largely made using clinical rather than laboratory criteria. Tests for RF, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) can help confirm diagnoses, but cannot be relied on in isolation of a clear clinical presentation.

In recent studies, antibodies recognizing CCP have been noted for their close association with early RA and the diagnostic utility of tests for these antibodies in known RA patients has been strongly supported.^{2, 3} The presence of CCP antibodies is associated with sensitivity values up to 81% for detection of RA and high specificity that is usually measured at greater than 90%. Tests for RF, while very sensitive, usually exhibit a somewhat lower specificity that has limited their utility. The two tests can be effectively complementary, however, and analysis of both parameters simultaneously improves the detection of RA, especially at very early stages.

Drawing on these tools, the present study sought to determine whether serological RF and anti-CCP status could predict progression to RA in patients with very early, nonspecific inflammatory arthritis. An initial cross-sectional study of 124 patients revealed that anti-CCP and RF were detected in only 4% of patients with non-RA inflammatory disease and in no patients with noninflammatory disease. Additionally, a longitudinal study over 72 weeks of 96 patients with early synovitis of ��3 months revealed that the combined measure had a 63% sensitivity, 97% specificity, 86% positive predictive value, and 91% negative predictive value for development of chronic RA.

"The ability to predict, at a very early stage, which patients with synovitis will develop RA is important, as it will allow clinical studies of aggressive therapy in such patients to determine whether it is possible to switch off the rheumatoid disease process during this early phase of disease," Dr. Raza emphasized. "The data thus suggest that we need to conduct clinical studies�cin patients who are seropositive for rheumatoid factor and anti-CCP antibody -- before these patients necessarily fulfill current formal classification criteria for RA."

As is the case for most autoantibodies observed in rheumatic disease, the origin of antibodies to CCP and their significance to RA pathology remains unclear. The atypical amino acid citrulline is generated through the posttranslational modification of arginine residues by protein arginine deiminases (PADI). Although the process that leads to immunological intolerance of citrullinated proteins in RA is not entirely clear, it has been suggested that modification by PADI causes denaturation of targeted proteins and a dramatic change in their antigenicity.⁴

References

1. Raza K, Breese M, Nightingale P, et al. Predictive value of antibodies to cyclic citrullinated peptide in patients with very early inflammatory arthritis. J Rheumatol. 2005;32:231-238.

2. Araki C, Hayashi N, Moriyama M, et al. [Usefulness of anti-cyclic citrullinated peptide antibodies (anti-CCP) for the diagnosis of rheumatoid arthritis]. Rinsho Byori. 2004;52:966-972.

3. Girelli F, Foschi FG, Bedeschi E, Calderoni V, Stefanini GF, Martinelli MG. Is anti cyclic citrullinated peptide a useful laboratory test for the diagnosis of rheumatoid arthritis? Allerg Immunol (Paris). 2004;36:127-130.

4. Yamada R, Suzuki A, Chang X, Yamamoto K. Citrullinated proteins in rheumatoid arthritis. Front Biosci. 2005;10:54-64.