This study is the first to show that the likelihood of persistent arthritis increases with the levels of IgM RF and anti-CCP. We also demonstrate an added predictive value in testing for both biomarkers in patients with very early undifferentiated arthritis. Several studies have assessed anti-CCP and/or RF as predictors of persistent arthritic disease in patients with undifferentiated arthritis [7
] but none of these investigated the influence of antibody level on diagnostic outcome. The association between levels of these serologic markers and outcome also supports the new American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria for RA which provide different points in the classification system according to level of anti-CCP or RF. (Aletaha D, et al
. The 2010 American College of Rheumatology/European League Against Rheumatism Classification Criteria for Rheumatoid Arthritis. Arthritis Rheum/Ann Rheum Dis
When working with prediction models, the challenge of circularity arises when the predictive factor is a part of diagnostic or classification criteria. Presence of the factor of interest can bias the physician to label or diagnose a patient (for example, rheumatoid factor or anti-CCP and RA) [13
]. This challenge can be overcome by using alternative definitions of the outcome, like persistent joint swelling or erosive disease, which are examples of more objective outcomes in early arthritis patients. Their determination relies solely on the presence of physical features, and therefore is less likely to be biased. Moreover, 17 patients who fulfilled the 1987 ARA criteria for RA at baseline turned out to have self-limiting disease after one year (Table ), which is in line with previous early arthritis studies demonstrating the low specificity of these criteria [10
As evidence of the superior specificity and similar sensitivity of anti-CCP as compared to RF as a predictor of an adverse outcome in inflammatory arthritis has increased [3
], the question of whether one should stop testing for RF has been raised [29
]. The overlap between RF and anti-CCP positivity may be greater in established RA (93% in a study of 784 RA patients, mean disease duration 18 years) [30
], than in early arthritis (50 to 80% in different studies) [5
]. In the present study only 58% (37/64) of antibody positive patients with persistent arthritis were positive for both RF and anti-CCP. Testing for both markers increased sensitivity for persistent arthritis from about 30% to 37%. Our results support that each of these antibodies should be evaluated when making risk assessments in early arthritis, especially if the one first tested is negative.
We also investigated the benefits and drawbacks of lowering the threshold for defining a positive antibody status. Although lowering the threshold resulted in a rather steep loss of specificity for IgM RF, we found some, but limited, added predictive value of lowering the threshold for anti-CCP positivity to 10 units/ml. This is in line with the findings in a recent study [18
]. We believe that the clinician should be aware of the potential value also of low levels of anti-CCP when evaluating early arthritis patients, but we cannot recommend a change in the current threshold for positivity based on our findings.
Is there a dose-response relationship
between antibody level and likelihood of developing persistent arthritis? Kudo-Tanaka and colleagues reported a higher mean level of anti-CCP2 (Axis-Shield Diagnostics Ltd., Dundee, Scotland, cut-off 4.6 U/ml for positive status) in patients developing RA (167 U/ml) than in patients developing other arthropathies or persistent UA (55 U/ml) in a study of 146 anti-CCP positive UA patients [32
]. A Dutch study of patients with arthralgia demonstrated higher median levels of ACPA and IgM RF in patients developing arthritis than in patients who did not [33
]. Our findings support that patients with very high levels of anti-CCP or rheumatoid factor are more prone to enter a serious disease course than individuals with low positive levels. This study is the first to demonstrate the effect of levels of anti-CCP and IgM RF on the likelihood of persistent disease, although the numbers of patients with a positive antibody status is moderate and the confidence intervals for the point estimates are wide. A dose-response relationship could support the theory of a pathophysiologic role for anti-CCP antibodies in the development of RA and persistent arthritic diseases, but further studies are needed to shed more light on this complex issue. Importantly, our study supports that presence of high antibody levels give more points than low levels in the new ACR/EULAR classification criteria for RA.
We have shown in this and a previous report [23
] that anti-CCP is the most important predictor of an adverse outcome in early arthritis. However, as most patients who developed persistent disease were antibody negative, it is important to bear in mind that early referral and assessment is needed in all patients with significant inflammatory arthritis.