AntiCyclic Citrullinated Peptide Antibodies in the Diagnosis of Rheumatoid Arthritis: Bayes Clears the Haze

In this issue, Nishimura and colleagues review the value of testing for anticyclic citrullinated peptide (CCP) antibodies in the diagnosis of rheumatoid arthritis (1). Their well-done meta-analysis confirms that the presence of anti-CCP antibody is more specific than rheumatoid factor for diagnosing rheumatoid arthritis and thereby corroborates the results of 2 published systematic reviews (2, 3). The biology of this putative biomarker of rheumatoid arthritis is intriguing. Anti-CCP antibodies may be important in the pathoetiology of rheumatoid arthritis. A specific interaction between smoking and certain HLA-DR4 genes exists in patients with rheumatoid arthritis who test positive for anti-CCP antibodies (4), and anti-CCP antibodies worsened arthritis in a murine model of arthritis (5). Healthy persons with anti-CCP antibodies are more likely than those without these antibodies to develop rheumatoid arthritis (6, 7). Rheumatoid arthritis varies phenotypically, from mild joint inflammation at 1 end of the spectrum to progressive, severe joint destruction with extra-articular manifestations, such as the Felty syndrome, keratoconjunctivitis sicca, interstitial lung disease, and rheumatoid vasculitis, at the other. Anti-CCP antibodies seem to define a rheumatoid arthritis phenotype that is characterized by extensive structural joint damage (1, 2), functional impairment (8), and disease that is more likely to benefit from very early antirheumatic therapy (9). Once viewed as inexorably progressive, rheumatoid arthritis has become a potentially curable disease with early, aggressive use of disease-modifying antirheumatic drugs (DMARDs). Therefore, early and accurate diagnosis has become increasingly important (10). The rationale for early DMARD therapy is the existence of a critical period, a therapeutic window of opportunity, in which antirheumatic therapy is more effective than later in the course of the disease (11). Early DMARD therapy also appears to have a durable effect, modifying the disease permanently (12). We have no direct evidence about the width of this therapeutic window. A meta-analysis found that delaying DMARD therapy for as little as 9 months after disease onset resulted in significantly worse long-term outcomes (12). Information on the average delay in diagnosis of rheumatoid arthritis is sparse: In the United States, patients with inflammatory polyarthritis saw a physician, on average, within 4 weeks of symptom onset, but a median of 8 to 9 months elapsed before rheumatoid arthritis was definitively diagnosed (13). Biological antirheumatic therapies may enable us to change the natural course of the disease by starting aggressive therapy early in the course of disease (14, 15). Therefore, diagnosing rheumatoid arthritis as soon and as accurately as possible has become a high-stakes undertaking and necessitates better diagnostic tests. The diagnosis of rheumatoid arthritis has been primarily clinical. The gold standard for the classification of rheumatoid arthritis is the American College of Rheumatology (ACR) criteria (16). Although these criteria are explicitly intended as a case definition for epidemiologic purposes and not for clinical diagnosis, they are often used for the latter. The presence of rheumatoid factor is the only criterion that is a laboratory variable, and radiographic appearance of erosive disease is the only morphologic criterion. All other items are symptoms and physical findings: prolonged morning stiffness, soft-tissue swelling (arthritis) of 3 or more joint areas, arthritis involving the hand or wrist joints, symmetrical arthritis, and rheumatoid nodules. Signs and symptoms must last for 6 weeks or more to meet the ACR criteria (16), which means that the criteria apply only to patients with subacute or chronic disease. For new-onset rheumatoid arthritis, the sensitivity of the ACR criteria is 62% to 90% (1719); in the most rigorous study of the ACR criteria, the sensitivity and specificity were only 62% and 50%, respectively. The poor discrimination of these criteria in early rheumatoid arthritis may contribute to delayed diagnosis (13). Incorporating anti-CCP antibody testing into the standard evaluation of patients with early inflammatory polyarthritis might improve our ability to diagnose early rheumatoid arthritis and therefore make better treatment decisions in the therapeutic window. Nishimura and colleagues conclude that anti-CCP antibody testing is more useful than rheumatoid factor in predicting whether patients with recent-onset arthritis will develop rheumatoid arthritis or erosive disease (1). They recommend that positivity for anti-CCP antibodies be added to the ACR classification criteria of rheumatoid arthritis. Although this recommendation is sound, it may be premature because other biomarkers, such as genotypes, C-reactive protein, cytokine, and chemokine profilesin combination, in series, and with or without anti-CCP antibodiesmay yet be shown to improve predictive accuracy. Nishimura and colleagues do not provide definitive evidence about the sensitivity and specificity of anti-CCP antibodies in diagnosing very early rheumatoid arthritis. They define early as less than 1 year of disease. The therapeutic window in rheumatoid arthritis may be too narrow to allow even 1 year of symptoms to pass, given the imperative of early, aggressive drug management. Ideally, to fully understand the usefulness of positivity for anti-CCP antibodies, we should know its sensitivity and specificity (and those of other tests for rheumatoid arthritis) in disease of less than 3 months' duration. Two studies of anti-CCP antibodies in presymptomatic rheumatoid arthritis suggest that the sensitivity and specificity of anti-CCP antibody positivity are the same in rheumatoid arthritis of less than 3 months' duration as in rheumatoid arthritis of less than 1 year's duration (6, 7). Two scenarios show the clinical utility of anti-CCP antibodies in diagnosing rheumatoid arthritis in patients with recent-onset undifferentiated arthritis. A 25-year-old man with an 8-week history of symmetrical arthritis of the knees, morning stiffness, a moderately elevated C-reactive protein level (<50 mg/L), and no rheumatoid factor is at low risk for rheumatoid arthritis within the next year (estimated probability, 0% to 6%) (20). In this patient, positivity for anti-CCP antibodies will not increase considerably his likelihood of developing rheumatoid arthritis (estimated probability, approximately 7%) (20). In contrast, a 50-year-old woman with an 8-week history of tender and swollen metacarpophalangeal joints of only the left hand, moderate morning stiffness, a moderately elevated C-reactive protein level (<50 mg/L), and no rheumatoid factor has a likelihood of developing rheumatoid arthritis within the next year of approximately 26% (20). If she tests positive for anti-CCP antibodies, however, her risk jumps to 67% (20). These examples demonstrate the major implication of the Bayes' theorem: The probability of disease after a test result is critically dependent on the prior probability of disease in the individual patient. Anti-CCP antibodies are an important addition to our diagnostic armamentarium, but we must interpret their presence in light of the pretest probability of rheumatoid arthritis. Estimating the pretest probability requires expert clinical judgment and a careful clinical assessment of the patient. The requirement for these clinical skills is especially important in rheumatoid arthritis because treatment is most effective in the early stages of disease, when the clinical diagnosis is most difficult.