免疫检查点抑制剂引起肠炎研究进展

Progress in study on enteritis caused by immune checkpoint inhibitors

摘要

免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)是肿瘤免疫治疗的核心,但易诱发免疫相关不良反应(immune-related adverse events,irAEs),其中ICIs相关肠炎是胃肠道最常见且重要的irAEs,占致命性irAEs的37%,严重影响患者治疗与预后。其发生率具有药物差异:细胞毒性T淋巴细胞相关抗原4(cytotoxic T-lymphocyte-associated antigen 4,CTLA-4)抑制剂单药发生率为7.7%~15%,程序性死亡受体1/配体1(programmed cell death 1/programmed death-ligand 1,PD-1/PD-L1)抑制剂单药仅为1%~2%,联合治疗升至13.9%~40%;发生时间上,CTLA-4抑制剂更早(1~3个月),PD-1/PD-L1抑制剂较晚(3~6个月)。风险因素包括高剂量ICIs、联合治疗、既往炎症性肠病(inflammatory bowel disease,IBD)史、肠道菌群失调、非甾体抗炎药(non-steroidal anti-inflammatory drugs,NSAIDs)使用及遗传多态性。临床表现以腹泻为核心,可致肠穿孔等并发症;诊断需结合多种手段,生物标志物如粪便钙卫蛋白具有重要意义;治疗依分级进行,生物制剂可改善难治病例,多数患者发生肠炎后预后更优。

Abstract

Immune checkpoint inhibitors (ICIs) are the core of tumour immunotherapy, but they are prone to induce immune-associated adverse events (irAEs). ICIs-associated enterocolitis is the most common and important irAE in the gastrointestinal tract, accounting for 37% of the fatal irAEs, which seriously affects the treatment and prognosis of patients. The incidence varies by drug: 7.7%~15% for cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitors, 1%~2% for programmed death-ligand 1(PD-1/PD-L1) inhibitors single therapy, rising to 13.9%~40% for combination therapy. The time of onset is earlier for CTLA-4 inhibitors (1~3 months) and later for PD-1/PD-L1 inhibitors (3~6 months). Risk factors include high-dose ICIs, combination therapy, previous history of IBD, intestinal dysbiosis, NSAIDs use, and genetic polymorphisms. Clinical manifestations are centered on diarrhiea, which can lead to complications such as intestinal perforation. The diagnosis is multifactorial, with biomarkers such as fecal calproteatin being important. The treatment is graded, with biologics improving difficult-to-treat cases, and the majority of patients with enterocolitis have a better prognosis.

关键词

免疫检查点抑制剂 / 肠炎 / 免疫相关不良事件 / 免疫治疗

Key words

immune checkpoint inhibitors / enterocolitis / immune-related adverse events / immunotherapy

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基金资助

国家自然科学基金青年科学基金资助项目(82504778);北京慢性病防治与健康教育研究会2024年药学专项科研课题资助项目(MBZX0082024001)