英夫利西单抗治疗药物监测在克罗恩病治疗中的临床应用价值

Value of therapeutic drug monitoring of infliximab in Crohn s disease

目的分析英夫利西单抗(infliximab,IFX)治疗的克罗恩病(CD)患者诱导治疗后和维持期的两次治疗药物监测(TDM),与随访中原发无应答(PNR)、继发失应答(SLR)、内镜黏膜愈合(MH)、急性输液反应以及停药的关系。方法回顾性纳入2018年6月至2022年9月在南京鼓楼医院治疗的中重度CD患者47例,均为生物制剂初治。诱导治疗后第14周时行首次TDM,检测IFX谷浓度和抗肿瘤坏死因子药物抗体(ATI)的滴度,IFX谷浓度≥3μg/mL判断为达标,根据检测结果允许药物调整优化,维持期第二次行TDM。分析14周IFX谷浓度达标(n=25)和不达标组(n=22)组间及维持期IFX谷浓度不同亚组间的PNR、SLR、MH、急性输液反应和停药的差别,并分析不同IFX谷浓度与ATI阳性率的关系。结果14周达标组和不达标组在(32±4)周时的MH率分别是80.0%和31.8%,差异有统计学意义(χ^(2)=11.113,P<0.01)。14周达标组中,二次达标和不达标组亚组间的ATI率、输液反应率、停药率差异均有统计学意义(P<0.01)。14周不达标组中,二次谷浓度达标和不达标组亚组间的ATI率差异有统计学意义(P<0.05)。极低IFX谷浓度亚组(<1.0μg/mL)的ATI阳性率高达53.9%,显著高于其他浓度亚组(P<0.05)。结论14周IFX谷浓度与CD患者治疗后首次内镜复查MH有密切关系,维持期IFX谷浓度与ATI产生、输液反应、停药均有关,期待经济、便捷的主动TDM以保持药物疗效。

Objective To analyze the associations of therapeutic drug monitoring(TDM)after induction therapy and during maintenance period with primary non-response(PNR),secondary lost response(SLR),endoscopic mucosal healing(MH),acute infusion reaction and drug withdrawal in the patients with Crohn s disease(CD)treated with infliximab(IFX).Methods Forty-seven moderate-severe CD patients were enrolled for a respective analysis,who were admitted to Nanjing Drum Tower Hospital from June 2018 to September 2022 and were initially treated with biological agents.At the 14th week after induction therapy,the first TDM was performed to detect IFX trough concentration(TC)and anti-tumor necrosis factor drug antibody titers(anti-TNF antibody,ATI).IFX TC≥3μg/mL was defined as up-to-standard,and drug dosing optimization was allowed based on TDM results.In the maintenance treatment,the second TDM was conducted.The differences of PNR,SLR,MH,acute infusion reaction and drug withdrawal between 14-week IFX TC up-to-standard group(n=25)and substandard group(n=22)and among different subgroups of IFX TC during maintenance period were analyzed,and the relationship between different IFX TC and ATI positive rate was analyzed.Results At(32±4)weeks,there was a significant difference in MH rate between 14-week up-to-standard group and substandard group(80.0%vs 31.8%,χ^(2)=11.113,P<0.01).In the 14-week up-to-standard group,there were significant differences in the incidences of ATI,infusion reaction and drug withdrawal between second up-to-standard subgroup and second substandard subgroup(P<0.01).In 14-week substandard group,there was significant difference in the rate of ATI between the two subgroups(P<0.05).The ATI positive rate of extremely low IFX TC group(<1.0μg/mL)was 53.9%,which was significantly higher than other groups(P<0.05).Conclusion IFX TC at 14-week after induction therapy is closely related to the first endoscopic reexamination of MH in CD patients,and IFX TC during the maintenance period is related to ATI,infusion reaction and drug withdrawal.More economical and convenient proactive TDM strategy is expected to maintain drug efficacy in CD patients.