基于美国FDA不良事件报告系统数据库的伊匹木单抗不良事件风险信号挖掘

Adverse event risk signal mining of ipilimumab based on the US FDA Adverse Event Reporting System

目的挖掘伊匹木单抗不良事件(AE)风险信号,为临床安全使用该药提供参考。方法检索美国FDA不良事件报告系统数据库,收集2011年3月1日至2022年9月30日以伊匹木单抗为首要怀疑药物的AE报告。采用《国际医学用语词典》26.0版首选术语(PT)和系统器官分类(SOC)对AE进行标准化和分类,采用报告比值比(ROR)法挖掘伊匹木单抗AE风险信号,报告数≥3、ROR≥2且其95%置信区间(CI)下限>1的AE定义为风险信号,对相关PT进行描述性分析。结果纳入分析的AE报告共12329例,涉及1915个PT,采用ROR法获得268个风险信号(PT),涉及21个SOC。报告数居前10位的PT为腹泻、结肠炎、皮疹、发热、垂体炎、肾上腺功能不全、食欲下降、甲状腺功能减退、肝脏疾病、脱水,均为说明书中常见AE。信号强度居前10位的PT为垂体炎、淋巴细胞垂体炎、免疫介导性皮炎、免疫介导的肾上腺功能不全、垂体功能减退、免疫介导的肝脏疾病、促肾上腺皮质激素缺乏、免疫介导性脑炎、自身免疫性结肠炎和免疫介导性甲状腺功能亢进,涉及的SOC分别为内分泌系统疾病、皮肤及皮下组织类疾病、肝胆系统疾病、胃肠系统疾病、神经系统疾病。共36个PT在药品说明书中未收录,信号强度居前5位的PT为颅内肿瘤出血、放射性坏死、恶性胸腔积液、肺部肉芽肿、苔藓样角化病。结论伊匹木单抗的主要AE为腹泻、结肠炎、皮疹等。该药还可能导致颅内肿瘤出血、放射性坏死、恶性胸腔积液等说明书未记载的不良反应,临床实践中应予警惕。

Objective To mine the risk signals of ipilimumab‑related adverse events(AEs)and provide reference for the safe use in clinical practice.Methods AE reports with ipilimumab as the primary suspect drug were collected from US FDA Adverse Event Reporting System database during March 1,2011 to September 30,2022.AEs were standardized and classified according to the preferred term(PT)and system organ class(SOC)in Medical Dictionary for Regulatory Activites version 26.0.The AE risk signals of ipilimumab were mined using reporting odds ratio(ROR)method.An AE with reports≥3,ROR≥2,95%confidence interval(CI)lower limit of ROR>1 was defined as a risk signal.Risk signals were analyzed using descriptive method.Results A total of 12329 AE reports were entered in the analysis,involving 1915 PTs.Two hundred and sixty‑eight risk signals(PTs)were obtained using ROR method,involving 21 SOCs.The top 10 PTs in report number were diarrhea,colitis,rash,fever,hypophysitis,adrenal insufficiency,decreased appetite,hypothyroidism,liver disease,and dehydration,all of which were common AEs in the labels.The top 10 PTs in signal intensity were hypophysitis,lymphocytic hypophysitis,immune‑mediated dermatitis,immune‑mediated adrenal insufficiency,hypopituitarism,immune‑mediated liver disease,adrenocorticotropic hormone deficiency,immune‑mediated encephalitis,autoimmune colitis,and immune‑mediated hyperthyroidism.The SOCs involved were endocrine system diseases,skin and subcutaneous tissue diseases,hepatobiliary system diseases,gastrointestinal system diseases,and nervous system diseases.A total of 36 PTs were not included in the labels,and the top 5 in signal intensity were intracranial tumor hemorrhage,radiation necrosis,malignant pleural effusion,pulmonary granuloma,and lichenoid keratosis.Conclusions The main AEs of ipilimumab are diarrhea,colitis,rash,etc.In addition,ipilimumab might cause adverse reactions such as intracranial tumor hemorrhage,radiation necrosis,and malignant pleural effusion that are not recorded in label,which should be vigilant in clinical practice.