Peptidylarginine deiminase 4 (PAD4) activity in early rheumatoid arthritis

Objectives: Peptidylarginine deiminases (PADs) are a family of calcium-dependent enzymes catalysing the conversion of arginine residues to citrulline, which may constitute a risk factor in rheumatoid arthritis (RA) pathogenesis. We investigated PAD activation by serum (PAD(Act)) in early RA, and the associations between PAD activation and disease characteristics, treatment response, and progression of radiographic damage. Method: Sera from disease-modifying anti-rheumatic drug (DMARD)-naive early RA patients (n = 225), classified according to the 2010 American College of Rheumatology/European League Against Rheumatism criteria, and healthy controls (n = 63) were analysed for PAD4 activating capacity at 0, 3, 12, and 24 months using a high-performance liquid chromatography fluorometric method. Associations for PAD(Act) were evaluated by Mann-Whitney U and chi-squared tests. Changes in PAD(Act) levels were compared using the Wilcoxon signed-rank test. Results: PAD(Act) positivity occurred in 42% (n = 95) of the patients and was more prevalent in anti-citrullinated protein antibody (ACPA)-positive vs ACPA-negative patients (47% vs 20%, p = 0.002), but not in rheumatoid factor (RF)-positive vs RF-negative patients (44% vs 38%, p = 0.49). PAD(Act)-positive were younger than PAD(Act)-negative patients [mean +/- sd 48.7 +/- 13.5 vs 53.2 +/- 13.7 years, p = 0.011]. Median [25th, 75th percentile] PAD(Act) levels were higher in patients than in controls (8768 [7491, 11 393] vs 7046 [6347, 7906], p < 0.0001) and decreased after initiation of DMARD treatment, but were not associated with treatment response or progression of radiographic damage after 2 years of follow-up. Conclusion: Serum capacity to activate PAD4 was associated with ACPA and RF positivity and earlier disease onset in early RA patients, and decreased after initiation of DMARD treatment, indicating that anti-PAD treatment could potentially be beneficial in RA.