OBJECTIVE Immune checkpoint inhibitors have introduced a new and heterogeneous class of immune-related adverse effects, with the endocrine system being a predominant target for autoimmunity. Autoimmune hypothalamic-pituitary-adrenal axis (HPA) diseases induced by checkpoint inhibitors are being increasingly recognized. We aimed to characterize the spectrum of checkpoint associated hypothalamic-pituitary-adrenal axis endocrinopathies. DESIGN A retrospective cohort study of a tertiary cancer center. METHODS Patients were characterized for HPA axis abnormalities based on clinical and pituitary axes evaluation. The risk for developing HPA endocrinopathies was compared by log- rank test, by the time since checkpoint inhibitors initiation. Additionally, the risk for developing HPA endocrinopathies after adjusting for covariates was assessed using multivariable logistic regression analysis. RESULTS Among 1615 patients, fourteen (0.87%) patients developed isolated adrecocorticotrophic hormone deficiency (IAD), six (0.37%) - hypophysitis and no case of adrenalitis was identified. IAD presented with mild and non-specific symptoms, mainly asthenia. In multivariable analysis, exposure to both PD-1/PD-L1 and Ipilimumab and female gender were associated with an increased odds ratio (OR) for developing IAD (6.98 [95% CI 2.38-20.47, p < .001] and 3.67 [95% CI 1.13-11.84, p = .03]), respectively. CONCLUSIONS IAD, a rare disease before the immunotherapy era, has become a predominant checkpoint related HPA axis autoimmune injury. Despite its life threatening potential, IAD may be missed due to its subtle presentation. Patients exposed to Ipilimumab and PD-1/PD-L1 in combination or sequentially and women have an increased risk for developing IAD.

中文翻译：

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孤立的自身免疫性促肾上腺皮质激素缺乏症：从罕见疾病到与检查点抑制剂相关的肾上腺功能不全的主要原因。

目的免疫检查点抑制剂已引入一类新的异类免疫相关不良反应，内分泌系统是自身免疫的主要靶标。由检查点抑制剂引起的自身免疫性下丘脑-垂体-肾上腺轴（HPA）疾病已得到越来越多的认识。我们旨在表征检查点相关的下丘脑-垂体-肾上腺轴内分泌病变的频谱。设计对三级癌症中心的回顾性队列研究。方法根据临床和垂体轴评估对患者的HPA轴异常进行表征。通过对数秩检验比较自检查点抑制剂启动以来的时间发展HPA内分泌病的风险。此外，使用多变量logistic回归分析评估调整协变量后发生HPA内分泌病变的风险。结果在1615例患者中，有14例（0.87％）患上孤立的肾上腺皮质营养激素缺乏症（IAD），有6例（0.37％）患有垂体炎，未发现肾上腺炎病例。IAD表现为轻度和非特异性症状，主要是乏力。在多变量分析中，暴露于PD-1 / PD-L1和伊匹木单抗以及女性与IAD发生的比值比（OR）升高相关（6.98 [95％CI 2.38-20.47，p <.001]和3.67 [ 95％CI 1.13-11.84，p = .03]。结论IAD是免疫治疗时代之前的一种罕见疾病，已经成为与HPA轴自身免疫损伤相关的主要检查点。尽管有威胁生命的潜力，由于其微妙的表现，IAD可能会被错过。合并或顺序暴露于伊匹木单抗和PD-1 / PD-L1的患者和女性患IAD的风险增加。