Background/Purpose: Novel antibody systems including anti-carbamylated protein antibody (anti-CarP IgG) and anti-peptidyl arginine deiminase antibody (anti-PAD4 IgG) are emerging as independent diagnostic and prognostic biomarkers for rheumatoid arthritis (RA) and may add value to rheumatoid factor (IgM) and anti-citrullinated peptide antibody (ACPA IgG), the hallmark antibodies in RA. We evaluated the diagnostic performance of these markers in combination.

Methods: The cohort consisted of 638 consented subjects with RA (fulfilling  the 1987 or 2010 ACR classification criteria, mean age: 59.8±0.5 years [SEM], 80% females) and a control group of 775 subjects (mean age: 44.7±0.5 years, 85% females, including systemic lupus erythematosus [n=369], primary Sjogren’s syndrome [n=64], primary fibromyalgia [n=85], other connective tissue diseases [n=63], and a group of normal healthy donors [n=194]). Autoantibodies titers from serum were measured using fluoroenzyme immunoassays (IgM RF and anti-CCP [IgG]; Phadia, Upsala Sweden), ELISA (anti-CarP [IgG], research use only [RUO], Inova Diagnostics, San Diego) and bead-based Aptiva^TM technology (anti-PAD4 [IgG], RUO, Inova Diagnostics) in a clinical laboratory accredited by the College of American Pathologists. For each positive antibody (above each cutoff) a score of 1 was assigned and the cumulative presence of the 4 antibodies was determined [range 0-4].  The ability of the biomarkers to distinguish RA from controls was calculated using sensitivity, specificity and interval likelihood ratio (LR). Predictive value (PPV) was estimated at 10% pre-test probability. Statistics consisted of Mann-Whitney and Chi-square test.

Results: In this cohort anti-CarP ( >20 Units) yielded 33.5% sensitivity and 77.9% specificity. Anti-PAD4 ( >1000 Units) yielded 35.0% sensitivity and 95.0% specificity. RF IgM ( >5 Units/ml) and anti-CCP ( >10 Units/ml) were 67.4% and 66.5% sensitive, respectively (87.5% and 97.0% specific, respectively). RA presented 5-fold higher 4-antibody system scores (2.02±0.05) than controls (0.42±0.02) (p< 0.01). Scores greater than 2 yielded 42% sensitivity and 98.8% specificity. A total of 82 subjects presented with full-house 4 antibodies (score = 4) and 81 of them had RA (99.9% specific). Interval LR and PV for each of the 4-antibody score are presented in the Table. There was no difference in the 4-antibody score between RA who fulfilled the 1987 ACR or 2010 ACR criteria (1.99±0.07 vs 2.08±0.09; p=0.40). In the subset of subjects newly diagnosed (less than one year), average 4-antibody system score for RA (n=33) was 1.72±0.22 (36.3% with score greater than 2) and 0.58±0.12 for other diseases (0% with score greater than 2, 100% specific) (p< 0.01).

Conclusion: This cumulative combination of antibody systems targeting citrullinated, carbamylated, PAD4 and RF is highly specific for RA.  It may be useful in diagnosing and classifying RA even in symptomatic patients who present early in the course of disease.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/antibody-systems-targeting-citrullinated-carbamylated-and-peptidyl-arginine-deaminase-autoantigens-distinguish-rheumatoid-arthritis-in-combination-with-rheumatoid-factors/