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 (PADAct) 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)-naïve 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 PADAct were evaluated by Mann-Whitney U and chi-squared tests. Changes in PADAct levels were compared using the Wilcoxon signed-rank test. Results: PADAct 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). PADAct-positive were younger than PADAct-negative patients [mean ± sd 48.7 ± 13.5 vs 53.2 ± 13.7 years, p = 0.011]. Median [25th, 75th percentile] PADAct 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.

中文翻译：

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类风湿关节炎早期的肽基精氨酸脱亚氨酶4（PAD4）活性。

目的：肽基精氨酸脱亚氨酶（PADs）是一类钙依赖性酶，可催化精氨酸残基向瓜氨酸的转化，这可能是类风湿关节炎（RA）发病的危险因素。我们调查了早期RA中血清（PADAct）对PAD的激活，以及PAD激活与疾病特征，治疗反应和放射线损伤进展之间的关联。方法：根据2010年美国风湿病学会/欧洲风湿病联盟标准对未患疾病的抗风湿药（DMARD）早期RA患者（n = 225）的血清进行分类，并采用健康对照（n = 63）。使用高效液相色谱荧光法分析了0、3、12和24个月时PAD4的活化能力。通过Mann-Whitney U和卡方检验评估PADAct的关联。使用Wilcoxon符号秩检验比较PADAct水平的变化。结果：PADAct阳性发生在42％（n = 95）的患者中，抗瓜氨酸化蛋白抗体（ACPA）阳性的患者比ACPA阴性的患者更为普遍（47％vs 20％，p = 0.002），但没有类风湿因子（RF）阳性与RF阴性患者的比例分别为（44％vs 38％，p = 0.49）。PADAct阳性的患者比PADAct阴性的患者年轻[平均±标准偏差48.7±13.5 vs 53.2±13.7岁，p = 0.011]。DMARD治疗开始后，患者中PADAct的中位数[第25、75％]高于对照组（8768 [7491，11 393]对7046 [6347，7906]，p <0.0001），并且降低了，但与随访2年后的治疗反应或放射线损伤进展无关。结论：早期RA患者的血清激活PAD4的能力与ACPA和RF阳性以及疾病的早期发作有关，并且在开始DMARD治疗后降低，这表明抗PAD治疗可能对RA有益。