Cui Kai, Wang Ziqi, Zhang Qianqian, Zhang Xiaoju
Academy of Medical Science, Zhengzhou University, Zhengzhou, China.
Department of Respiratory and Critical Care Medicine, Zhengzhou University People's Hospital & Henan Provincial People's Hospital, Zhengzhou, China.
Ann Transl Med. 2022 Mar;10(5):251. doi: 10.21037/atm-21-7006.
Adrenal insufficiency (AI) represents a rare, yet potentially life-threatening immune checkpoint inhibitor (ICI)-related adverse event. The clinical characteristics of ICI-induced AI are still poorly defined due to its low incidence but need to be comprehensively understood.
We systematically retrieved and screened the PubMed/Medline, Embase, Web of Science, and Cochrane Library databases for all articles published on AI related to anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4), anti-programmed cell death protein-1 (PD-1) receptor or its ligand (PD-L1), or combination ICI therapy. The retrieved articles were reviewed and selected in accordance with the exclusion criteria. The detailed data of individual cases were then collected and analyzed.
We identified 206 ICI-induced AI patients, comprising 11 (5.3%) primary AI patients, 191 (92.7%) secondary AI patients, and 4 (1.9%) mixed-type AI patients. The subclassification of the secondary AI patients, comprising 108 isolated adrenocorticotropic hormone (ACTH) insufficiency (IAD) and 83 multiple pituitary hormone deficiency (MPHD) patients, revealed that 56.5% of secondary AIs were related to IAD. Fatigue, anorexia/loss of appetite, headache, and nausea/vomiting were the most prevalent symptoms, and MPHD patients had a significantly higher rate of headache than primary AI patients and IAD patients (67.2% 9.1% 10.2%; P=0.000). Further, anti-PD-1-induced AI patients showed more complex and poorer clinical manifestations than anti-CTLA-4-induced patients, including a higher rate of emergency admission (28.7% 4.9%; P=0.003), tachycardia (30.4% 0; P=0.014), hypotension (50.0% 8.6%; P=0.000), hypoglycemia (19.5% 2.6%; P=0.014), hyponatremia (64.2% 33.3%; P=0.002), and a prolonged median duration from ICI initiation to symptom onset (26 9 weeks; P=0.000).
The ICI-induced AI events could be primary, secondary, or mixed-type, and IAD was the most common reason for such events. The symptoms were usually unspecific and could be complex. AI should be excluded in a timely manner, and the patients should be followed-up with and receive extra attention for AI events even after the discontinuation of ICI treatment. Additionally, the discrepancy in relation to clinical characteristics between anti-PD-1- and anti-CTLA4-induced AI events warrants further exploration.
肾上腺功能不全（AI）是一种罕见但可能危及生命的免疫检查点抑制剂（ICI）相关不良事件。由于其发病率低，ICI诱导的AI的临床特征仍不清楚，但需要全面了解。
我们系统检索和筛选了PubMed/Medline、Embase、Web of Science和Cochrane图书馆数据库中所有发表的与抗细胞毒性T淋巴细胞抗原4（CTLA-4）、抗程序性细胞死亡蛋白1（PD-1）受体或其配体（PD-L1）或联合ICI治疗相关的AI文章。根据排除标准对检索到的文章进行审查和筛选。然后收集并分析个别病例的详细数据。
我们确定了206例ICI诱导的AI患者，包括11例（5.3%）原发性AI患者、191例（92.7%）继发性AI患者和4例（1.9%）混合型AI患者。继发性AI患者的亚分类包括108例孤立性促肾上腺皮质激素（ACTH）不足（IAD）和83例多垂体激素缺乏（MPHD）患者，显示56.5%的继发性AI与IAD有关。疲劳、厌食/食欲不振、头痛和恶心/呕吐是最常见的症状，MPHD患者头痛发生率明显高于原发性AI患者和IAD患者（67.2%对9.1%对10.2%；P = 0.000）。此外，抗PD-1诱导的AI患者比抗CTLA-4诱导的患者表现出更复杂和更差的临床表现，包括更高的急诊入院率（28.7%对4.9%；P = 0.003）、心动过速（30.4%对0；P = 0.014）、低血压（50.0%对8.6%；P = 0.000）、低血糖（19.5%对2.6%；P = 0.014）、低钠血症（64.2%对33.3%；P = 0.002）以及从ICI开始到症状出现的中位持续时间延长（26对9周；P = 0.000）。
ICI诱导的AI事件可能是原发性、继发性或混合型，IAD是此类事件最常见的原因。症状通常不具特异性且可能很复杂。应及时排除AI，即使在停止ICI治疗后，也应对患者进行随访并对AI事件给予额外关注。此外，抗PD-1和抗CTLA-4诱导的AI事件在临床特征方面的差异值得进一步探索。
