克罗恩病患者英夫利西单抗相关基因多态性与血药浓度及疗效关联性研究

目的：探讨克罗恩病（CD）患者英夫利西单抗（IFX）相关基因多态性与血药浓度、免疫原性及疗效之间的关联性，以期为优化CD患者IFX治疗方案提供参考。方法：前瞻性收集2017年9月至2019年9月在本院使用IFX治疗的CD患者相关临床资料，给药前采用多重PCR技术结合高通量测序技术的靶向测序法测得患者TNF-α-308、TNF-α-238、TNF-α-857、TNFRSF1B、ABCB1、FCGR3A基因型，借助酶联免疫吸附法检测维持期IFX谷浓度。利用SPSS 20.0软件进行统计分析，并绘制ROC曲线求临床疗效及抗体（ATI）产生的浓度阈值。结果：研究共纳入111例患者，携带TNF-α-238突变基因的患者IFX谷浓度显著低于野生型（0.55±0.52） vs. （1.75±1.46）μg/mL（P=0.003），而TNF-α-308、TNF-α-857、TNFRSF1B、ABCB1、FCGR3A不同基因型间IFX谷浓度差异无统计学意义。TNFRSF1B突变型（TG+GG）临床应答率显著高于野生型（TT）（75.0%vs. 42.3%）（P=0.001），其他基因不同基因型患者间临床疗效差异无统计学意义（P>0.05）。IFX治疗克罗恩病的疗效及ATI的产生与谷浓度显著相关（P<0.01）。预测治疗后生物学反应及临床反应的IFX谷浓度最佳阈值分别为1.33、0.85 μg/mL；谷浓度≤0.51 μg/mL作为指标预测ATI产生的特异性为91.0%，敏感性66.7%。结论：TNF-α-238、TNFRSF1B基因多态性可分别影响IFX治疗CD患者的谷浓度与临床反应。未发现TNF-α-308、TNF-α-857、ABCB1、FCGR3A基因多态性明显影响IFX治疗CD的浓度或疗效。IFX谷浓度>1.33 μg/mL对生物学反应具一定的预测意义，而谷浓度≤0.51 μg/mL可作为ATI产生的预测指标。

Correlation of infliximab related genetic polymorphism,serum trough concentration and efficacy in patients with Crohn's disease

AIM: To investigate the correlations of genetic polymorphisms, infliximab(IFX) serum trough concentration, immunogenicity and clinical outcome in patients with Crohn's disease(CD) to provide reference for optimizing IFX treatment in CD patients. METHODS: The clinical data of CD patients treated with IFX in our hospital from September 2017 to September 2019 were prospectively collected. The genotypes TNF-α-308, TNF-α-238, TNF-α-857, TNFRSF1B, ABCB1, FCGR3A were detected by targeted sequencing using multiple PCR combined with high throughput sequencing before administration. The IFX steady-state concentration was determined by ELISA. SPSS 20.0 software was used for statistical analysis and ROC curve was drawn for clinical efficacy and antibody threshold. RESULTS: A total of 111 patients were included in the study, the IFX trough concentration of patients with TNF-α-238GA was significantly lower than that of GG (0.55±0.52) vs. (1.75±1.46) μg/mL (P=0.003), while there was no significant difference in IFX trough concentration among TNF-α-308, TNF-α-857, TNFRSF1B, ABCB1, FCGR3 Agenotypes. Clinical response rate of TNFRSF1B (TG+GG) was significantly higher than that of the wild type (TT) (75.0% vs. 42.3%) (P=0.001), and there was no statistically significant difference in clinical efficacy among patients with different genotypes of other genes (P>0.05). The efficacy of IFX in the treatment of CD and the production of antibody to IFX were significantly correlated with maintenance trough concentration (P<0.01). The optimal IFX trough concentration thresholds for predicting CPR≤5 mg/L and clinical response after treatment were 1.33, 0.85 μg/mL, respectively. Trough concentration ≤0.51 μg/mL was used as an indicator to predict the generation of antibody. CONCLUSION: Polymorphisms of TNF-α-238 and TNFRSF1B can affect the maintenance trough concentration and clinical response of IFX in CD patients, respectively. The trough concentration at IFX maintenance stage >1.33 μg/mL had certain predictive significance for biological response, while ≤0.51 μg/mL can be used as a predictor of antibody production.