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Abstract：
BACKGROUND: This study assesses the accuracy of neutrophil activation markers, including neutrophil extracellular traps (NETs) and calprotectin, as biomarkers of disease activity in patients with established rheumatoid arthritis (RA). We also analyse the relationship between NETs and various types of therapies as well as their association with autoimmunity.
METHODS: Observational cross-sectional study of patients with RA receiving treatment with biological disease-modifying antirheumatic drugs or Janus kinase inhibitors (JAK-inhibitors) for at least 3 months. Plasma calprotectin levels were measured using an enzyme-linked immunosorbent assay test kit and NETs by measuring their remnants in plasma (neutrophil elastase-DNA and histone-DNA complexes). We also assessed clinical disease activity, joint ultrasound findings and autoantibody status [reumatoid factor (RF), anti-citrullinated peptide/protein antibodies (ACPAs) and anti-carbamylated protein (anti-CarP)]. Associations between neutrophilic biomarkers and clinical or ultrasound scores were sought using correlation analysis. The discriminatory capacity of both neutrophilic biomarkers to detect ultrasound synovitis was analysed through receiver-operating characteristic (ROC) curves.
RESULTS: One hundred fourteen patients were included. Two control groups were included to compare NET levels. The active control group consisted of 15 patients. The second control group consisted of 30 healthy subjects. Plasma NET levels did not correlate with clinical disease status, regardless of the clinic index analysed or the biological therapy administered. No significant correlation was observed between NET remnants and ultrasound synovitis. There was no correlation between plasma NET and autoantibodies. In contrast, plasma calprotectin positively correlated with clinical parameters (swollen joint count [SJC] rho = 0.49; P < 0.001, Clinical Disease Activity Index [CDAI] rho = 0.30; P < 0.001) and ultrasound parameters (rho > 0.50; P < 0.001). Notably, this correlation was stronger than that observed with acute phase reactants.
CONCLUSIONS: While NET formation induced by neutrophils may play a role in RA pathogenesis, our study raises questions about the utility of NET remnants in peripheral circulation as a biomarker for inflammatory activity. In contrast, this study strongly supports the usefulness of calprotectin as a biomarker of inflammatory activity in patients with RA.
METHODS: Observational cross-sectional study of patients with RA receiving treatment with biological disease-modifying antirheumatic drugs or Janus kinase inhibitors (JAK-inhibitors) for at least 3 months. Plasma calprotectin levels were measured using an enzyme-linked immunosorbent assay test kit and NETs by measuring their remnants in plasma (neutrophil elastase-DNA and histone-DNA complexes). We also assessed clinical disease activity, joint ultrasound findings and autoantibody status [reumatoid factor (RF), anti-citrullinated peptide/protein antibodies (ACPAs) and anti-carbamylated protein (anti-CarP)]. Associations between neutrophilic biomarkers and clinical or ultrasound scores were sought using correlation analysis. The discriminatory capacity of both neutrophilic biomarkers to detect ultrasound synovitis was analysed through receiver-operating characteristic (ROC) curves.
RESULTS: One hundred fourteen patients were included. Two control groups were included to compare NET levels. The active control group consisted of 15 patients. The second control group consisted of 30 healthy subjects. Plasma NET levels did not correlate with clinical disease status, regardless of the clinic index analysed or the biological therapy administered. No significant correlation was observed between NET remnants and ultrasound synovitis. There was no correlation between plasma NET and autoantibodies. In contrast, plasma calprotectin positively correlated with clinical parameters (swollen joint count [SJC] rho = 0.49; P < 0.001, Clinical Disease Activity Index [CDAI] rho = 0.30; P < 0.001) and ultrasound parameters (rho > 0.50; P < 0.001). Notably, this correlation was stronger than that observed with acute phase reactants.
CONCLUSIONS: While NET formation induced by neutrophils may play a role in RA pathogenesis, our study raises questions about the utility of NET remnants in peripheral circulation as a biomarker for inflammatory activity. In contrast, this study strongly supports the usefulness of calprotectin as a biomarker of inflammatory activity in patients with RA.
摘要：
背景：这项研究评估了中性粒细胞活化标志物的准确性，包括中性粒细胞胞外陷阱（NET）和钙卫蛋白，作为类风湿关节炎（RA）患者疾病活动的生物标志物。我们还分析了NETs与各种类型疗法之间的关系以及它们与自身免疫的关联。
方法：RA患者接受生物疾病缓解抗风湿药或Janus激酶抑制剂（JAK抑制剂）治疗至少3个月的观察性横断面研究。使用酶联免疫吸附测定测试试剂盒和NETs通过测量血浆中的残留物（中性粒细胞弹性蛋白酶-DNA和组蛋白-DNA复合物）来测量血浆钙卫蛋白水平。我们还评估了临床疾病活动，联合超声检查结果和自身抗体状态[肿瘤样因子（RF），抗瓜氨酸肽/蛋白质抗体（ACPAs）和抗氨基甲酰化蛋白质（抗CarP）]。使用相关性分析寻找嗜中性粒细胞生物标志物与临床或超声评分之间的关联。通过受试者操作特征（ROC）曲线分析了两种嗜中性粒细胞生物标志物检测超声滑膜炎的判别能力。
结果：纳入了114例患者。包括两个对照组以比较NET水平。主动对照组由15名患者组成。第二对照组由30名健康受试者组成。血浆NET水平与临床疾病状态无关，无论分析的临床指数或给予的生物治疗。NET残留物与超声滑膜炎之间没有显着相关性。血浆NET与自身抗体之间无相关性。相比之下,血浆钙卫蛋白与临床参数（肿胀关节计数[SJC]rho=0.49；P<0.001，临床疾病活动指数[CDAI]rho=0.30；P<0.001）和超声参数（rho>0.50；P<0.001）呈正相关。值得注意的是,这种相关性强于急性期反应物。
结论：虽然中性粒细胞诱导的NET形成可能在RA发病机制中起作用，我们的研究提出了有关外周循环中NET残留物作为炎症活动生物标志物的效用的问题.相比之下,这项研究强烈支持钙卫蛋白作为RA患者炎症活性生物标志物的有效性.
方法：RA患者接受生物疾病缓解抗风湿药或Janus激酶抑制剂（JAK抑制剂）治疗至少3个月的观察性横断面研究。使用酶联免疫吸附测定测试试剂盒和NETs通过测量血浆中的残留物（中性粒细胞弹性蛋白酶-DNA和组蛋白-DNA复合物）来测量血浆钙卫蛋白水平。我们还评估了临床疾病活动，联合超声检查结果和自身抗体状态[肿瘤样因子（RF），抗瓜氨酸肽/蛋白质抗体（ACPAs）和抗氨基甲酰化蛋白质（抗CarP）]。使用相关性分析寻找嗜中性粒细胞生物标志物与临床或超声评分之间的关联。通过受试者操作特征（ROC）曲线分析了两种嗜中性粒细胞生物标志物检测超声滑膜炎的判别能力。
结果：纳入了114例患者。包括两个对照组以比较NET水平。主动对照组由15名患者组成。第二对照组由30名健康受试者组成。血浆NET水平与临床疾病状态无关，无论分析的临床指数或给予的生物治疗。NET残留物与超声滑膜炎之间没有显着相关性。血浆NET与自身抗体之间无相关性。相比之下,血浆钙卫蛋白与临床参数（肿胀关节计数[SJC]rho=0.49；P<0.001，临床疾病活动指数[CDAI]rho=0.30；P<0.001）和超声参数（rho>0.50；P<0.001）呈正相关。值得注意的是,这种相关性强于急性期反应物。
结论：虽然中性粒细胞诱导的NET形成可能在RA发病机制中起作用，我们的研究提出了有关外周循环中NET残留物作为炎症活动生物标志物的效用的问题.相比之下,这项研究强烈支持钙卫蛋白作为RA患者炎症活性生物标志物的有效性.
