Zhang Cai-Bin, Tang Jian, Wang Xue-Ding, Lyu Kun-Sheng, Huang Min, Gao Xiang
Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China.
Department of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China.
Gastroenterol Rep (Oxf). 2020 Dec 29;9(5):427-434. doi: 10.1093/gastro/goaa070. eCollection 2021 Oct.
Infliximab (IFX) is the first-line treatment for patients with Crohn's disease (CD) and is noted for its relatively high cost. The therapeutic efficacy of IFX has noticeable individual differences. Known single-gene polymorphisms (SNPs) are inadequate for predicting non-response to IFX. In this study, we aimed to identify new genetic factors associated with IFX-therapy failure and to predict non-response to IFX by developing a multivariate predictive model.
In this retrospective study, we collected and analysed the data of Chinese patients with CD who received IFX therapy at one hospital between June 2013 and June 2019. Primary non-response (PNR) and non-durable response (NDR) were evaluated using a simple endoscopic score for CD (SES-CD). A total of 125 SNPs within 44 genes were genotyped. A multivariate logistic-regression model was established to predict non-response to IFX. An area-under-the-receiver-operating-characteristics curve (AUROC) was applied to evaluate the predictive model performance.
Forty-two of 206 (20.4%) patients experienced PNR and 15 of 159 (9.4%) patients experienced NDR. Nine SNPs were associated with PNR ( < 0.05). A PNR predictive model was established, incorporating 2-week high-sensitivity C-reactive protein (hs-CRP), rs61886887, rs61740234, rs357291, rs2269330, and rs111504845, and the AUROC on training and testing data sets were 0.818 ( < 0.001) and 0.888 ( < 0.001), respectively. At week 14, hs-CRP levels ≥ 2.25 mg/L were significantly associated with NDR (AUROC = 0.815, < 0.001). PNR-associated SNPs were not mutually associated with NDR, suggesting distinct mechanisms between PNR and NDR.
Genetic polymorphisms are significantly associated with response to IFX among Chinese CD patients.
英夫利昔单抗（IFX）是克罗恩病（CD）患者的一线治疗药物，但其成本相对较高。IFX的治疗效果存在显著的个体差异。已知的单基因多态性（SNP）不足以预测对IFX无反应的情况。在本研究中，我们旨在识别与IFX治疗失败相关的新遗传因素，并通过建立多变量预测模型来预测对IFX的无反应情况。
在这项回顾性研究中，我们收集并分析了2013年6月至2019年6月期间在一家医院接受IFX治疗的中国CD患者的数据。使用简单的CD内镜评分（SES-CD）评估原发性无反应（PNR）和非持续性反应（NDR）。对44个基因中的125个SNP进行基因分型。建立多变量逻辑回归模型以预测对IFX的无反应情况。应用受试者操作特征曲线下面积（AUROC）评估预测模型的性能。
206例患者中有42例（20.4%）出现PNR，159例患者中有15例（9.4%）出现NDR。9个SNP与PNR相关（<0.05）。建立了一个PNR预测模型，纳入了2周高敏C反应蛋白（hs-CRP）、rs61886887、rs61740234、rs357291、rs2269330和rs111504845，训练数据集和测试数据集的AUROC分别为0.818（<0.001）和0.888（<0.001）。在第14周时，hs-CRP水平≥2.25mg/L与NDR显著相关（AUROC = 0.815，<0.001）。与PNR相关的SNP与NDR没有相互关联，表明PNR和NDR之间存在不同的机制。
基因多态性与中国CD患者对IFX的反应显著相关。
