Background/Purpose: We sought to establish the diagnostic performances of rheumatoid factor isotypes (IgM and IgA) and anti-citrullinated peptide antibodies (ACPAs: anti-mutated citrullinated vimentin [anti-MCV] and anti-cyclic citrullinated peptide antibodies [antiCCP]) in a large population of patients with rheumatoid arthritis (RA) and other rheumatic diseases.

Methods: 1140 subjects were from the United States and informed consent was obtained from all patients.  The group of 703 RA patients (78% females, age was 60.0±14 yrs) consisted of 452 patients diagnosed using the 1987 ACR criteria and 251 patients diagnosed using the 2010 ACR criteria.  A total of 113 RA patients (16.1%) presented with disease duration lower than 2 years. Alternatively, the group of 387 patients with other diseases (83% females, age 44.6±15.0, mean±SD) consisted of 271 patients with Systemic lupus erythematosus and 116 patients with other autoimmune diseases. An additional 50 normal healthy volunteers were also enrolled. IgM RF, IgA RF, anti-CCP were measured using fluoroenzyme immunoassays (Phadia, Uppsala, Sweden) and anti-MCV was determined using enzyme linked immunosorbent assays (Orgentec, Mainz, Germany). Statistical analyses utilized area under receiver operating characteristic (ROC) curves, and calculations of diagnostic sensitivity, specificity, positive likelihood ratio (LR+) and interval LR. Cutoffs used for positivity were 5 U/ml for IgM RF, 20 U/ml for IgA RF, 10 U/ml for anti-CCP and 35 U/ml for anti-MCV.

Results: The area under the ROC curve was 0.857±0.022 for IgM RF, 0.724±0.031 for IgA RF, 0.828±0.025 for anti-CCP and 0.805±0.025 for anti-MCV. Sensitivity and specificity against other rheumatic diseases were 71% and 85% for IgM RF (positive LR=4.8), 41% and 90% for IgA RF (LR+=4.1), 70% and 96% for anti-CCP (LR+=18.0) and 62% and 92% for anti-MCV (LR=7.3).  Specificity ranged from 94-100% against normal healthy individuals for all markers. A scoring system combining positivity for ACPA (anti-CCP and anti-MCV) and RF isotypes was calculated. Interval likelihood ratio increased from 0.3 among ACPA negative patients, to 126.1 among patients positive for both ACPAs and IgA RF (Figure). Interval LR differences when compared by disease duration and diagnostic criteria were not statistically significant.

Conclusion:  An assay panel combining ACPAs (anti-CCP with anti-MCV) with RF isotopes can help in differentiating RA from other rheumatic diseases.