免疫检查点抑制剂致孤立性促肾上腺皮质激素缺乏症患者的临床特征分析

Clinical characteristics of patients with isolated adrenocorticotropic hormone deficiency caused by immune checkpoint inhibitors

目的:探讨免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)导致孤立性促肾上腺皮质激素缺乏症(isolated adrenocorticotropic hormone deficiency,IAD)患者的临床特征,为早期发现ICIs导致的内分泌免疫相关不良事件提供理论依据。方法:通过截至2022年7月检索万方、维普、中国知网、PubMed、Web of Science、Embase、Cochrane Library数据库,共纳入文献54篇,收集的70例患者中男性51例、女性19例,年龄为34~87岁,平均年龄(64.17±11.33)岁,收集使用ICIs导致IAD患者的临床资料进行统计学分析。结果:与IAD最相关的肿瘤类型为非小细胞肺癌35.7%(25/70),其次为恶性黑色素瘤24.3%(17/70)。最常见导致IAD的ICIs为程序性细胞死亡-1(programmed cell death-1,PD-1)抑制剂87.1%(61/70)。使用PD-1、程序性细胞死亡-1配体(programmed cell death-ligand 1,PD-L1)、PD-1联合细胞毒性T淋巴细胞抗原-4(cytotoxic T lymphocyte antigen 4,CTLA-4)抑制剂诊断IAD的中位时间分别为180.0、364.0、87.5天。IAD患者最常见的实验室指标异常为低钠血症、嗜酸性粒细胞升高。IAD患者行糖皮质激素替代治疗后临床症状均得到改善。结论:PD-1联合CTLA-4抑制剂导致IAD的发生时间最短,ICIs治疗过程中及停药后均需监测皮质醇、促肾上腺皮质激素水平,使用ICIs治疗的患者,尤其是男性患者,若出现低钠血症、嗜酸性粒细胞升高,需警惕IAD的可能性。

Objective:To investigate the clinical characteristics of patients with isolated adrenocorticotropic hormone deficiency(IAD)caused by immune checkpoint inhibitors(ICIs)and provide a theoretical basis for the early detection of endocrine immune-related adverse events caused by ICIs.Methods:Clinical data reported till July 2022 were obtained from the Wanfang,VIP,CNKI,PubMed,Web of Science,Embase,and Cochrane Library databases,with 54 studies for a total of 70 IAD patients(51 males and 19 females)analyzed.The age of these patients ranged between 34–87 years,with an average age of(64.17±11.33)years.The clinical data of these patients with IAD due to ICIs were statistically analyzed.Results:We found that the tumor type most closely associated with IAD is non-small cell lung cancer[35.7%(25/70)],followed by malignant melanoma[24.3%(17/70)].Furthermore,the ICI most frequently causing IAD was PD-1 inhibitor[87.1%(61/70)].The median diagnostic time of PD-1,PD-L1,and PD-1 combined with CTLA-4 inhibitor was 180.0,364.0,and 87.5days,respectively.Moreover,the most common abnormal laboratory indicators in IAD patients were hyponatremia and eosinophilia.The clinical symptoms of these patients improved following glucocorticoid replacement therapy.Conclusions:In this study,we established that PD-1 combined with CTLA-4 inhibitor is associated with the shortest time of IAD onset.This indicates that the cortisol and adrenocorticotropic hormone levels of patients should be monitored during and after ICI treatment.Notably,for those patients treated with ICIs,particularly males,hyponatremia and eosinophilia occurring can cause IAD,and thus such patients should be closely monitored.