Clinical characteristics of patients with isolated adrenocorticotropic hormone deficiency caused by immune checkpoint inhibitors
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摘要:
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。 Abstract: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 87.5 days, 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. -
表 1 70例IAD患者的一般情况
项目 例数(%) 国籍 日本 44(62.9) 中国 9(12.9) 美国 6(8.6) 葡萄糖 2(2.9) 意大利 2(2.9) 泰国 1(1.4) 比利时 1(1.4) 西班牙 1(1.4) 德国 1(1.4) 土耳其 1(1.4) 爱尔兰 1(1.4) 希腊 1(1.4) 肿瘤类型 非小细胞肺癌 25(35.7) 恶性黑色素瘤 17(24.3) 肾细胞癌 9(12.9) 头颈部鳞癌 4(5.7) 输尿管癌 2(2.9) 胃癌 2(2.9) 原发性肝癌 2(2.9) 尿路上皮癌 2(2.9) 肾盂癌 1(1.4) 胆管癌 1(1.4) 恶性间皮瘤 1(1.4) 乳腺癌 1(1.4) 舌和下咽癌 1(1.4) 喉癌 1(1.4) 盲肠癌 1(1.4) 药物类型 纳武利尤单抗 45(64.3) 帕博利珠单抗 12(17.2) 卡瑞丽珠单抗 1(1.4) 替雷利珠单抗 1(1.4) 信迪利单抗 1(1.4) HX008 1(1.4) 阿替利珠单抗 3(4.3) 纳武利由单抗+伊匹木单抗 5(7.2) 帕博利珠单抗+伊匹木单抗 1(1.4) 表 2 不同分组情况下70例IAD患者的临床特征
项目 单药治疗组 联合治疗组(n=6) PD-1抑制剂组(n=61) PD-L1抑制剂组(n=3) 性别 男性 46(75.4) 3(100) 2(33.3) 女性 15(24.6) 0(0) 4(66.7) 肿瘤类型 非小细胞肺癌 22(36.1) 2(66.7) 1(16.7) 恶性黑色素瘤 12(19.7) 0(0) 5(83.3) 肾细胞癌 9(14.8) 0(0) 0(0) 其他 18(29.4) 1(33.3) 0(0) IAD发生时间 治疗中 50(82.0) 2(66.7) 6(100) 停药后 11(18.0) 1(33.3) 0(0) ()内单位为% 表 3 70例IAD患者的临床表现
临床表现 例数(%) 乏力、疲劳 57(81.4) 恶心、呕吐、纳差、食欲减退 49(70.0) 体质量下降 6(8.6) 发热 5(7.1) 肌肉、关节疼痛 5(7.1) 腹痛、腹泻 4(5.7) 情绪低落、抑郁、失眠 4(5.7) 嗜睡、意识障碍 4(5.7) 头痛、头晕 4(5.7) 全身不适 3(4.3) 呼吸困难 2(2.9) -
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