Department of Endocrinology, Diabetes and Nutrition, University of Bordeaux, USN Haut Leveque, Bordeaux, France.
Pharmacovigilance Unit, Department of Pharmacology, Unité de Cardio-Oncologie Sorbonne Université-Groupe de Recherche Clinique en Cardio-Oncologie (UNICO-GRECO), INSERM Centre d'Investigation Clinique (CIC)-1901, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.
Oncologist. 2020 Aug;25(8):696-701. doi: 10.1634/theoncologist.2019-0555. Epub 2020 May 17.
Immune checkpoint inhibitors (ICIs) have transformed cancer therapy but may also trigger autoimmune adverse drug reactions (ADRs) referred to as immune-related adverse events (irAEs). Although endocrinopathies are among the most common form of irAEs, primary adrenal insufficiency (PAI) is infrequent and has only been published in case reports. The aim of this study was to identify and characterize the main features of PAI-irAE.
Suspected PAI-irAE cases were identified using VigiBase, the World Health Organization's pharmacovigilance database of individual case safety reports.
From September 2, 2008, through October 5, 2018, a total of 50,108 ICI-associated ADRs were reported. Since 2008, there were 451 cases of PAI-irAE identified of which 45 were "definite PAI" and 406 "possible PAI." Patients were mainly male (58.1%) with a median age of 66 years (range, 30-95). Indications of ICI were predominantly for melanoma (41.2%) and lung cancer (28.6%). The majority of patients were treated with ICI monotherapy (nivolumab: 44.3%, pembrolizumab: 11.7%, ipilimumab: 23.6%), and 17.9% were treated with ICI combination therapy. These events occurred with a median time to onset of 120 days (range, 6-576). ICI-associated PAI was associated with significant morbidity (≥90% severe) and mortality (7.3%). Fatality rates were similar in the subgroups of combination therapy versus monotherapy. There were no relevant differences in clinical or demographical characteristics and outcomes between "definite" versus "possible" PAI group.
Our study represents the largest clinical description and characterization of PAI-irAE. Although ICI-associated PAI is a rare adverse event, early recognition is important to implement corticosteroid treatment. Further studies are required to elucidate risk factors and reversibility of this rare but severe irAE. Clinical trial identification number. NCT03492242 IMPLICATIONS FOR PRACTICE: Immune checkpoint inhibitor (ICI)-associated primary adrenal insufficiency (PAI) is a rare adverse event that is important to recognize because it may be severe and life-threatening, requiring emergent and often lifelong hormonal replacement therapy. Awareness regarding this ICI-related endocrinopathy is strongly encouraged among clinicians in addition to patient education about common PAI symptoms that should prompt urgent medical evaluation. In clinical practice, close monitoring and investigation for PAI is crucial to allow for early management and to further define the pathophysiology and prognosis of ICI-PAI. Corticotrophin (adrenocorticotrophic hormone) circulating level evaluation may be often lacking but should be considered as part of the diagnostic workup to differentiate PAI from secondary (central) adrenal insufficiency.
免疫检查点抑制剂（ICIs）改变了癌症治疗方法，但也可能引发被称为免疫相关不良事件（irAEs）的自身免疫性药物不良反应。虽然内分泌疾病是最常见的 irAE 之一，但原发性肾上腺功能不全（PAI）较为罕见，仅在病例报告中发表过。本研究旨在确定和描述 PAI-irAE 的主要特征。
使用世界卫生组织个体病例安全报告药物警戒数据库 VigiBase 来识别疑似 PAI-irAE 病例。
自 2008 年 9 月 2 日至 2018 年 10 月 5 日，共报告了 50108 例与 ICI 相关的 ADR。自 2008 年以来，共发现 451 例 PAI-irAE，其中 45 例为“明确的 PAI”，406 例为“可能的 PAI”。患者主要为男性（58.1%），中位年龄为 66 岁（范围为 30-95 岁）。ICI 的适应证主要为黑色素瘤（41.2%）和肺癌（28.6%）。大多数患者接受 ICI 单药治疗（nivolumab：44.3%，pembrolizumab：11.7%，ipilimumab：23.6%），17.9%接受 ICI 联合治疗。这些事件的中位发病时间为 120 天（范围为 6-576 天）。与 ICI 相关的 PAI 与显著的发病率（≥90%严重）和死亡率（7.3%）相关。联合治疗组与单药治疗组的病死率相似。在“明确”与“可能”的 PAI 组之间，临床或人口统计学特征和结局没有明显差异。
本研究代表了对 PAI-irAE 的最大临床描述和特征描述。尽管与 ICI 相关的 PAI 是一种罕见的不良事件，但早期识别非常重要，因为它可能很严重且危及生命，需要紧急且通常需要终身激素替代治疗。强烈鼓励临床医生了解这种罕见但严重的 irAE，此外还需要患者了解常见的 PAI 症状，以便在出现症状时及时就医。在临床实践中，密切监测和调查 PAI 至关重要，以便能够进行早期管理，并进一步确定 ICI-PAI 的病理生理学和预后。循环促肾上腺皮质激素（ACTH）水平的评估可能经常缺乏，但应作为诊断工作的一部分考虑，以将 PAI 与继发性（中枢）肾上腺功能不全区分开来。
