Autoantibodies to cyclic citrullinated peptide 2 (CCP2) are superior to other potential diagnostic biomarkers for predicting rheumatoid arthritis in early undifferentiated arthritis

Abstract

We evaluated the diagnostic value of anti-cyclic citrullinated peptide 2 (anti-CCP2) antibodies and other potential diagnostic biomarkers (IgM rheumatoid factor, anti-agalactosyl IgG antibodies, matrix metalloproteinase 3, C-reactive protein) for predicting early development of rheumatoid arthritis (RA). Patients were defined as having recent-onset undifferentiated arthritis (UA) if they had developed arthritis in two or more joints within the previous 2 years and could not be classified with a well-defined arthropathy. Baseline levels of biomarkers were measured in blood samples collected at the entry of the study and the patients were followed for 1 year to monitor development of RA. Diagnoses of RA and non-RA arthropathies were made according to individual standard diagnostic criteria. A total of 146 patients were enrolled in the study. In the follow-up year, 18 patients developed RA, 54 developed non-RA arthropathies, and 60 remained in the UA category. The sensitivity and specificity of the presence of anti-CCP2 antibodies for the diagnosis of RA were 83.3 and 93.0%, respectively. The positive predictive value (PPV), negative predictive value (NPV), and diagnostic accuracy of anti-CCP2 antibodies for RA (65.2, 97.2, and 91.7%, respectively) were higher than for any other biomarker. Combination of anti-CCP2 with any other biomarker only slightly improved each diagnostic value compared to the presence of anti-CCP2 alone. Among the anti-CCP2-positive patients, the average titer was significantly higher in those with RA than in non-RA or UA patients (163.7 +/- 138.4 vs 55.2 +/- 72.0 U/ml, p = 0.017). Anti-CCP2 antibodies are superior to any other single biomarker for predicting early development of RA in patients with recent-onset UA and the diagnostic value of anti-CCP2 alone is similar to that for biomarker combinations. Moreover, the anti-CCP2 antibody titer is useful to discriminate between patients at high risk for early developing RA from those at risk of developing non-RA arthropathies.

Interpreting Studies of Diagnostic Accuracy

“…Their results seem to be at odds with previous findings, which have shown the high diagnostic accuracy of anti-CCP tests for differential diagnosis of RA 2,3 . It is important, therefore, to consider how to appropriately interpret studies of diagnostic accuracy and assess generalizability.…”

The status of serum vitamin D in patients with rheumatoid arthritis and undifferentiated inflammatory arthritis compared with controls

“…The presence of these antibodies in UIA may be a marker of B-cell activation and progression to early RA [22]. The ability of autoantibodies such as anti-cyclic-citrullinated antibody, antinuclear antibodies, and rheumatoid factor in predicting the outcome of patients with UIA was shown in a number of previous studies [23][24][25][26][27]. A positive results for anti-CCP and RF in patients with UIA could be a useful indicator of the presence of future RA [23,24,26].…”

Value of anti–modified citrullinated vimentin and third‐generation anti–cyclic citrullinated peptide compared with second‐generation anti–cyclic citrullinated peptide and rheumatoid factor in predicting disease outcome in undifferentiated arthritis and rheumatoid arthritis

“…In the subgroup of patients with early arthritis, no diagnosis can be established according to existing classification criteria, and the presence of RF or anti-CCP-2 indicates an increased risk of RA development (15,16). Thus far, the PPVs and NPVs for the risk of developing RA in patients with UA have not been studied using anti-CCP-3 or anti-MCV, and the 4 autoantibodies have not been subjected to a head-to-head comparison.…”