Introduction The second generation anticycliccitrullinated peptide (anti-CCP2) assay detects the majority but not all anticitrullinated protein/peptide antibodies (ACPA). Anti-CCP2-positive rheumatoid arthritis (RA) is associated with HLA-DRB1* shared epitope (SE) alleles and smoking. Using a multiplex assay to detect multiple specific ACPA, we have investigated the fine specificity of individual ACPA responses and the biological impact of additional ACPA reactivity among anti-CCP2-negative patients. Methods We investigated 2825 patients with RA and 551 healthy controls with full data on anti-CCP2, HLA-DRB1* alleles and smoking history concerning reactivity against 16 citrullinated peptides and arginine control peptides with a multiplex array. Results The prevalence of the 16 ACPA specificities ranged from 9% to 58%. When reactivity to arginine peptides was subtracted, the mean diagnostic sensitivity increased by 3.2% with maintained 98% specificity. Of the anti-CCP2-negative patients, 16% were found to be ACPA positive. All ACPA specificities associated with SE, and all but one with smoking. Correction for arginine reactivity also conveyed a stronger association with SE for 13/16 peptides. Importantly, when all ACPA specificities were analysed together, SE and smoking associated with RA in synergy among ACPA positive, but not among ACPA-negative subjects also in the anti-CCP2-negative subset. Conclusions Multiplexing detects an enlarged group of ACPA-positive but anti-CCP2-negative patients with genetic and environmental attributes previously assigned to anti-CCP2-positive patients. The individual correction for arginine peptide reactivity confers both higher diagnostic sensitivity and stronger association to SE than gross ACPA measurement.

中文翻译：

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抗瓜氨酸蛋白/肽抗体多路复用定义了具有不同遗传和环境决定因素的 ACPA 阳性类风湿性关节炎患者的扩展组

简介 第二代抗环瓜氨酸肽 (anti-CCP2) 检测可检测大部分但不是所有的抗瓜氨酸蛋白/肽抗体 (ACPA)。抗 CCP2 阳性类风湿性关节炎 (RA) 与 HLA-DRB1* 共享表位 (SE) 等位基因和吸烟有关。我们使用多重分析检测多个特定的 ACPA，研究了个体 ACPA 反应的精细特异性以及抗 CCP2 阴性患者中额外 ACPA 反应性的生物学影响。方法 我们研究了 2825 名 RA 患者和 551 名健康对照者，并使用多重阵列研究了关于抗 CCP2、HLA-DRB1* 等位基因和吸烟史的完整数据，这些数据涉及对 16 种瓜氨酸化肽和精氨酸对照肽的反应性。结果 16 项 ACPA 特异性的流行率为 9% 至 58%。当减去对精氨酸肽的反应性后，平均诊断灵敏度增加了 3.2%，特异性保持在 98%。在抗 CCP2 阴性患者中，发现 16% 为 ACPA 阳性。与 SE 相关的所有 ACPA 特性，以及与吸烟相关的所有特性。精氨酸反应性的校正也传达了与 13/16 肽的 SE 更强的关联。重要的是，当所有 ACPA 特异性一起分析时，SE 和吸烟与 RA 在 ACPA 阳性之间具有协同作用，但在 ACPA 阴性受试者中和抗 CCP2 阴性子集中也没有。结论 多重检测可检测到一组扩大的 ACPA 阳性但抗 CCP2 阴性患者，这些患者具有先前分配给抗 CCP2 阳性患者的遗传和环境属性。