Diallo Katy, Degboé Yannick, Baron Michel, Bellin-Robert Anaïs, Boyer Jean-Frédéric, Ruyssen-Witrand Adeline, Constantin Arnaud, Rauwel Benjamin, Cantagrel Alain, Davignon Jean-Luc
Institut Toulousain des Maladies Infectieuses et Inflammatoires (INFINITY), INSERM UMR1291, 31024 Toulouse, France.
Faculty of Health, CHU Toulouse, University of Toulouse, 31059 Toulouse, France.
Diagnostics (Basel). 2025 May 14;15(10):1232. doi: 10.3390/diagnostics15101232.
(1) : TNF inhibitors (TNFis) have revolutionized the treatment of rheumatoid arthritis (RA). However, 30-40% of RA patients do not respond adequately to those biologics. In addition to neutralizing soluble TNF, TNFis have the ability to bind the transmembrane form of TNF, tmTNF. Importantly, tmTNF can act itself as a receptor that induces "Reverse Signaling" (RS) in cells. We previously showed that certolizumab, a Fab' TNFi, activates RS in human primary monocytes, at least in part through the transcription factor Nrf2 that is known to regulate the expression of genes involved in anti-inflammatory response and oxidative stress. (2) : Here, we have developed an assay for the prediction of clinical response of RA patients to TNF inhibitors. This assay is based on mRNA quantitation of CD36 activation and of six genes induced by Nrf2 following tmTNF RS in fresh monocytes. (3) : We could predict the response to anti-TNF monoclonal antibodies (mAbs) with 93.3% accuracy. However, our method was not suitable for the prediction of the response to TNF soluble receptor etanercept. (4) : We have developed a rather simple, short-term test that can be standardized. Predicting the response to TNF mAbs will help physicians offer the best available treatment and provide patients with personalized medicine.
(1)：肿瘤坏死因子抑制剂（TNFis）彻底改变了类风湿关节炎（RA）的治疗方式。然而，30%至40%的类风湿关节炎患者对这些生物制剂反应不佳。除了中和可溶性肿瘤坏死因子外，肿瘤坏死因子抑制剂还能够结合肿瘤坏死因子的跨膜形式，即tmTNF。重要的是，tmTNF自身可作为一种受体，在细胞中诱导“反向信号传导”（RS）。我们之前表明，赛妥珠单抗，一种Fab'肿瘤坏死因子抑制剂，至少部分通过已知可调节参与抗炎反应和氧化应激的基因表达的转录因子Nrf2，在人原代单核细胞中激活反向信号传导。(2)：在此，我们开发了一种用于预测类风湿关节炎患者对肿瘤坏死因子抑制剂临床反应的检测方法。该检测方法基于新鲜单核细胞中tmTNF反向信号传导后CD36激活以及由Nrf2诱导的六个基因的mRNA定量。(3)：我们能够以93.3%的准确率预测对抗肿瘤坏死因子单克隆抗体（mAbs）的反应。然而，我们的方法不适用于预测对肿瘤坏死因子可溶性受体依那西普的反应。(4)：我们开发了一种相当简单的短期检测方法，该方法可以标准化。预测对抗肿瘤坏死因子单克隆抗体的反应将有助于医生提供最佳可用治疗方案，并为患者提供个性化医疗。
