OBJECTIVE Exaggerated neutrophil activation and formation of neutrophil extracellular traps (NETs) are linked to inflammation and autoimmunity, including rheumatoid arthritis (RA). However, whether NETs are present in the circulation of RA patients and contribute to inflammation and disease progression has not been carefully addressed. We undertook this study to assess markers of neutrophil activation and NET formation in plasma samples, investigating whether they add clinical value in improving the determination of prognosis and monitoring in RA patients. METHODS Markers of neutrophil activation (calprotectin) and cell death (NETs) were analyzed, using enzyme-linked immunosorbent assay, in serum and plasma obtained from patients in 3 cross-sectional RA cohorts and sex-matched healthy controls. A longitudinal inception cohort (n = 247), seen for a median follow-up of 8 years, was used for predictive analyses. RESULTS Markers of neutrophil activation and cell death were increased in RA patients compared to healthy individuals (P < 0.0001). Calprotectin levels correlated with the Clinical Disease Activity Index (r = 0.53, P < 0.0001) and could be used to distinguish between patients with disease in remission and those with active disease, an observation not seen when examining C-reactive protein levels. A biomarker panel consisting of anti-citrullinated protein antibody and calprotectin could predict erosive disease (odds ratio [OR] 7.5, P < 0.0001) and joint space narrowing (OR 4.9, P = 0.001). NET levels were associated with markers of inflammation (P = 0.0002). Furthermore, NETs and a "neutrophil activation signature" biomarker panel had good predictive value in identifying patients who were developing extraarticular nodules (OR 5.6, P = 0.006). CONCLUSION Neutrophils undergo marked activation and cell death in RA. Neutrophil biomarkers can provide added clinical value in the monitoring and prognosis of RA patients and may allow for early preventive treatment intervention.

中文翻译：

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中性粒细胞激活生物标志物组用于类风湿关节炎患者的预后和监测。


目的 中性粒细胞过度活化和中性粒细胞胞外陷阱 (NET) 的形成与炎症和自身免疫相关，包括类风湿性关节炎 (RA)。然而，NETs 是否存在于 RA 患者的循环中并导致炎症和疾病进展尚未得到仔细解决。我们进行这项研究是为了评估血浆样本中中性粒细胞活化和 NET 形成的标志物，调查它们是否在改善 RA 患者预后判断和监测方面具有临床价值。方法 使用酶联免疫吸附测定法，对从 3 个横断面 RA 队列患者和性别匹配的健康对照中获得的血清和血浆中的中性粒细胞活化（钙卫蛋白）和细胞死亡（NET）标志物进行分析。中位随访时间为 8 年的纵向起始队列 (n = 247) 用于预测分析。结果 与健康个体相比，RA 患者中性粒细胞活化和细胞死亡标志物增加 (P < 0.0001)。钙卫蛋白水平与临床疾病活动指数相关（r = 0.53，P < 0.0001），可用于区分疾病缓解期患者和活动期患者，这是在检查 C 反应蛋白水平时未观察到的观察结果。由抗瓜氨酸蛋白抗体和钙卫蛋白组成的生物标志物组可以预测糜烂性疾病（比值比 [OR] 7.5，P < 0.0001）和关节间隙狭窄（OR 4.9，P = 0.001）。 NET 水平与炎症标志物相关（P = 0.0002）。此外，NET 和“中性粒细胞激活特征”生物标志物组在识别出现关节外结节的患者方面具有良好的预测价值（OR 5.6，P = 0.006）。 结论 RA 中中性粒细胞经历显着的激活和细胞死亡。中性粒细胞生物标志物可以为 RA 患者的监测和预后提供附加的临床价值，并可能允许早期预防性治疗干预。