Krasselt Marco, Gruz Natalya, Pierer Matthias, Baerwald Christoph, Wagner Ulf
Medical Clinic III, Endocrinology, Nephrology and Rheumatology, Leipzig University, Liebigstr. 21, 04103 Leipzig, Germany.
J Pers Med. 2022 Jun 19;12(6):1003. doi: 10.3390/jpm12061003.
(1) Background: To date, the response of patients with rheumatoid arthritis (RA) to the various biologic DMARD available cannot be predicted due to a lack of reliable biomarkers. Based on our preliminary work on tmTNF reverse signaling, we developed a whole-blood assay measuring tmTNF crosslinking-induced IL-10 production to predict the response to TNF inhibitor (TNFi) therapy. (2) Methods: This prospective study included patients with active RA. Depending on the clinical judgment of the attending rheumatologist, either therapy with a TNF or JAK inhibitor was initiated. Clinical parameters and blood samples were obtained at baseline and after 8 weeks of therapy. The blood samples were collected using a newly developed whole-blood assay based on the principle of tmTNF reverse signalling. Subsequently, IL-10 was measured via enzyme-linked immunosorbent assay (ELISA) technique. (3) Results: 63 patients with RA were enrolled. In fifteen patients, TNFi therapy was initiated, while eight patients started a JAKi treatment. The cross-sectional analysis of all patients showed a positive correlation between tmTNF crosslinking-induced IL-10 and parameters of disease activity (CRP [r = 0.4091, = 0.0009], DAS28 [r = 0.3303, = 0.0082]) at baseline. In the TNFi treatment study, IL-10 was found to be significantly higher in EULAR responders than in non-responders ( = 0.0033). After initiation of JAKi treatment, in contrast, IL-10 induction was not linked to response. Longitudinal analysis of the TNFi-treated patients revealed IL-10 to decrease in responders ( = 0.04), but not in non-responders after 8 weeks of therapy. Of importance, the IL-10 production at baseline correlated inversely with TNFi response determined by ΔDAS28 in patients with TNFi treatment (r = -0.5299, = 0.0422) while no such link was observed under JAKi therapy ( = 0.22). Receiver operation characteristics (ROC) analysis demonstrated a high performance of tmTNF/crosslinking-induced IL-10 in predicting a TNFi therapy response according to the EULAR criteria (AUC = 0.9286, 95% Confidence interval 0.7825-1.000, = 0.0055). (4) Conclusions: In this pilot investigation, we demonstrated the feasibility of a whole-blood assay measuring tmTNF-induced IL-10 to predict clinical response to TNF inhibitor treatment. This approach might support rheumatologists in their decision for an individually tailored RA therapy.
（1）背景：迄今为止，由于缺乏可靠的生物标志物，类风湿关节炎（RA）患者对现有各种生物性改善病情抗风湿药（DMARD）的反应无法预测。基于我们对跨膜肿瘤坏死因子（tmTNF）反向信号传导的初步研究，我们开发了一种全血检测方法，用于测量tmTNF交联诱导的白细胞介素-10（IL-10）产生，以预测对肿瘤坏死因子抑制剂（TNFi）治疗的反应。（2）方法：这项前瞻性研究纳入了活动期RA患者。根据主治风湿病学家的临床判断，启动TNF或JAK抑制剂治疗。在基线和治疗8周后获取临床参数和血样。血样采用基于tmTNF反向信号传导原理新开发的全血检测方法采集。随后，通过酶联免疫吸附测定（ELISA）技术测量IL-10。（3）结果：63例RA患者入组。15例患者开始TNFi治疗，8例患者开始JAK抑制剂治疗。对所有患者的横断面分析显示，基线时tmTNF交联诱导的IL-10与疾病活动参数（C反应蛋白[CRP，r = 0.4091，P = 0.0009]、28个关节疾病活动评分[DAS28，r = 0.3303，P = 0.0082]）之间呈正相关。在TNFi治疗研究中，发现欧洲抗风湿病联盟（EULAR）反应者的IL-10显著高于无反应者（P = 0.0033）。相比之下，在启动JAK抑制剂治疗后，IL-10诱导与反应无关。对接受TNFi治疗患者的纵向分析显示，治疗8周后，反应者的IL-10下降（P = 0.04），而无反应者则未下降。重要的是，在接受TNFi治疗的患者中，基线时IL-10产生与由DAS28变化量（ΔDAS28）确定的TNFi反应呈负相关（r = -0.5299，P = 0.0422），而在JAK抑制剂治疗下未观察到这种关联（P = 0.22）。受试者工作特征（ROC）分析表明，tmTNF/交联诱导的IL-10在根据EULAR标准预测TNFi治疗反应方面具有高性能（曲线下面积[AUC] = 0.9286，95%置信区间0.7825 - 1.000，P = 0.0055）。（4）结论：在这项初步研究中，我们证明了一种测量tmTNF诱导的IL-10的全血检测方法预测TNF抑制剂治疗临床反应的可行性。这种方法可能有助于风湿病学家为个体化定制RA治疗做出决策。
