Should I order an anti-CCP antibody test to diagnose rheumatoid arthritis?

STUDIES COMPARING THE TWO TESTS

Several studies have evaluated the utility and validity of anti-CCP antibody testing vs rheumatoid factor testing.

In a study of 826 US veterans with RA,⁶ 75% tested positive for anti-CCP antibody and 80% were positive for rheumatoid factor. It was found that a higher anti-CCP antibody titer was associated with increased disease activity and inversely correlated with remission, especially in those also positive for rheumatoid factor.⁶

In another study,¹ in which blood samples from 79 patients with RA who had been blood donors were analyzed, 39 patients (49.4%) were positive for either rheumatoid factor or anti-CCP antibody, or both, a median of 4.5 years (range 0.1 to 13.8 years) before the onset of RA symptoms; 32 patients (40.5%) became positive for anti-CCP antibody before symptom onset.

Whiting et al,⁷ in a systematic review of 151 studies, showed that anti-CCP antibody testing had greater specificity than rheumatoid factor testing (96% vs 86%), with similar sensitivity (56% vs 58%)—most notably in eight cohort studies of patients with early RA.⁷ In the 15 cohort studies analyzed, the test was found to have a positive likelihood ratio of 12.7 and a negative likelihood ratio of 0.45, supporting this as a test of high positive predictive value for RA.

In view of the evidence from these studies, it is not surprising that the 2010 collaborative classification of RA of the American College of Rheumatology and the European League Against Rheumatism places equal weight on anti-CCP antibody testing and rheumatoid factor testing in the early diagnosis of RA.⁵

GENETICS AND THE PROGNOSIS OF RHEUMATOID ARTHRITIS

In recent years, there has been a growing recognition that the pathogenesis of RA in patients who are seropositive for rheumatoid factor or anti-CCP antibody is different from the pathogenesis of RA in patients who are seronegative for rheumatoid factor and anti-CCP antibody. This may help us guide therapy.

Patients positive for rheumatoid factor or anti-CCP antibody who have a specific allelic subset of a region of the immune-response gene DRB1*04 appear to be highly vulnerable to smoking as an environmental trigger or to worsening RA.⁸

Patients positive for anti-CCP antibody tend also to have severe joint destruction and, hence, have a worse prognosis. Kaltenhäuser et al⁹ found that determining the presence of the shared epitope (an RA-specific genetic marker) and positivity for anti-CCP antibody facilitates prediction of the disease course and prognosis.⁹

Studies have shown that patients with confirmed RA who test positive for anti-CCP antibody may also have more-severe extraarticular manifestations. Recent studies have found anti-CCP antibody positivity in 15.7% to 17.5% of patients with psoriatic arthritis and in 85% of patients with RA. Patients with psoriatic arthritis who were positive for anti-CCP antibody had more joints that were tender and swollen, erosive arthritis, deformities, and functional impairment of peripheral joints.^10,11

THE COST DIFFERENCE IS TRIVIAL IN THE LONG RUN

Cost is the major differentiating factor between rheumatoid factor testing and anti-CCP antibody testing. Rheumatoid factor testing costs around $43, and anti-CCP antibody testing costs $102 in the reference laboratory at Cleveland Clinic. However, the difference in cost is trivial, since this is only a one-time cost, whereas the information anti-CCP antibody testing provides can have a major impact on predicting the prognosis and determining the choice of therapy for a disease associated with high direct and indirect costs over a lifetime. Also, Medicare and other insurers would likely reimburse for anti-CCP antibody testing as long as it was associated with a related diagnosis such as arthralgia or arthritis.

Given that there will be a small number of patients with confirmed RA who will be negative for rheumatoid factor yet positive for anti-CCP antibody, one can support ordering both tests in tandem in a patient whom you strongly suspect of having RA. Or, at $100, one could make the argument that it would be cost-effective to order anti-CCP antibody testing only if rheumatoid factor testing is negative.

Testing for rheumatoid factor and anti-CCP antibody should not be done serially to assess treatment response or disease activity in these patients: these markers do not vary with inflammatory activity or disappear with clinical “remission.”