Deharo François, Carvelli Julien, Cautela Jennifer, Garcia Maxime, Sarles Claire, Maues de Paula Andre, Bourenne Jérémy, Gainnier Marc, Bichon Amandine
Marseille Public University Hospital System, 13005 Marseille, France.
J Clin Med. 2022 Sep 23;11(19):5611. doi: 10.3390/jcm11195611.
Immune checkpoint inhibitors (ICIs) are a major breakthrough in cancer treatment. Their increasingly frequent use leads to an uprising incidence of immune-related adverse events (irAEs). Among those, myocarditis is the most reported fatal cardiovascular irAE, frequently associated with ICI-related myositis.
Here, we report three cases of ICI-induced myocarditis/myositis with an extremely severe myasthenia gravis-like (MG-like) presentation, highlighting the main challenges in irAEs management. These patients were over 60 years old and presented an ongoing melanoma, either locally advanced or metastatic, treated with ICI combinations. Shortly after the first or second ICI infusion, they were admitted in an intensive care unit (ICU) for grade 3 ICI-induced MG-like symptoms leading to acute respiratory failure (ARF) requiring invasive mechanical ventilation (IMV). The initial misdiagnosis was later corrected to severe ICI-induced seronegative myocarditis/myositis upon biological results and histopathology from muscular/endomyocardial biopsies. All of them received urgent high-dose corticosteroids pulses. The oldest patient died prematurely, but the two others received targeted therapies leading to complete recovery for one of them.
These cases highlight the four main challenges of irAEs, encompassing the lack of knowledge among physicians, the risk of misdiagnosis due to numerous and non-specific symptoms, the frequent overlapping forms of irAEs, and the extremely rare MG-like misleading presentation of myocarditis/myositis. The exact pathophysiology of irAEs remains unclear, although a major involvement of the lymphoid compartment (specifically T lymphocytes) was evidenced. Therapeutic management is based on urgent high-dose corticosteroids. For the severest forms of irAEs, case-by-case targeted immunosuppressive therapies should be urgently administered upon multidisciplinary meetings.
These cases highlight the lack of knowledge of irAEs among physicians, aggravated by misleading overlapping forms, requiring specific management in trained units and multidisciplinary care. Severe MG-like presentation of irAEs constitutes an absolute therapeutic emergency with high-dose corticosteroids and targeted immunosuppressive therapy.
免疫检查点抑制剂（ICIs）是癌症治疗领域的一项重大突破。其使用频率日益增加，导致免疫相关不良事件（irAEs）的发生率不断上升。其中，心肌炎是报告最多的致命性心血管irAE，常与ICI相关的肌炎相关。
在此，我们报告3例ICI诱导的心肌炎/肌炎，伴有极其严重的重症肌无力样（MG样）表现，突出了irAEs管理中的主要挑战。这些患者均超过60岁，患有持续的黑色素瘤，为局部晚期或转移性，接受ICI联合治疗。在首次或第二次ICI输注后不久，他们因3级ICI诱导的MG样症状导致急性呼吸衰竭（ARF）而入住重症监护病房（ICU），需要有创机械通气（IMV）。最初的误诊后来根据肌肉/心内膜活检的生物学结果和组织病理学纠正为严重的ICI诱导的血清阴性心肌炎/肌炎。他们均接受了紧急大剂量糖皮质激素冲击治疗。年龄最大的患者过早死亡，但另外两名患者接受了靶向治疗，其中一名完全康复。
这些病例突出了irAEs的四个主要挑战，包括医生知识的缺乏、由于症状众多且无特异性导致的误诊风险、irAEs常见的重叠形式，以及心肌炎/肌炎极其罕见的MG样误导性表现。尽管已证明淋巴系统（特别是T淋巴细胞）起主要作用，但irAEs的确切病理生理学仍不清楚。治疗管理基于紧急大剂量糖皮质激素。对于最严重形式的irAEs，应在多学科会议后紧急给予逐案靶向免疫抑制治疗。
这些病例突出了医生对irAEs知识的缺乏，因误导性的重叠形式而加剧，这需要在有经验的单位进行特殊管理和多学科护理。irAEs的严重MG样表现构成了使用大剂量糖皮质激素和靶向免疫抑制治疗的绝对治疗紧急情况。
