Immune Checkpoint Inhibitor-Induced Myositis/Myocarditis with Myasthenia Gravis-like Misleading Presentation: A Case Series in Intensive Care Unit

Abstract

Introduction: 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. Case series: 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. Discussion: 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. Conclusion: 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.

Peripheral nervous system adverse events associated with immune checkpoint inhibitors

“…Notably, four out of six patients with MG/myositis presented with concurrent myocarditis. The association of immune-related MG, myositis, and myocarditis has been identified as a specific overlap syndrome (IM3OS) [ 26 ], characterized by a short latency of onset from ICI initiation—on average after one dose—and an abrupt and clinical deterioration, often requiring admission to intensive care unit [ 27 ]. The co-occurrence of myocarditis [ 28 ] and the elevation of serum troponin [ 29 ] have been identified as predictors of poor prognosis in patients with ir-MG/myositis and IM3OS is characterized by a high mortality (up to 60% of cases) [ 30 ], which can occur due to both cardiac (i.e., arrythmia) and neuromuscular (i.e., respiratory failure) involvement.…”

“…Notably, four out of six patients with MG/myositis presented with concurrent myocarditis. The association of immunerelated MG, myositis, and myocarditis has been identified as a specific overlap syndrome (IM3OS) [26], characterized by a short latency of onset from ICI initiation-on average after one dose-and an abrupt and clinical deterioration, often requiring admission to intensive care unit [27].…”

Immunotherapy-Induced Overlap Syndrome: Myositis, Myasthenia Gravis, and Myocarditis—A Case Series

“…Additionally, ICIs deplete regulatory T cells, thereby activating anergic self-reactive T cells. Tere appears to be an expansion of T cell clonal cells in both tumour and muscle cells leading to a role of molecular mimicry [1,5]. Tere is an increased incidence of MG in anti-PD1 therapy compared to anti-CTLA-4 therapy.…”

“…Myocarditis is the most common and fatal cardiotoxicity, leading to death in 25-50% of cases [5]. Myasthenia gravis (MG) is the most commonly reported neuromuscular irAE, with 40-50% requiring ventilatory support, seven times higher than in typical MG [3].…”

Two Cases of Immune Checkpoint Inhibitor-Induced Myocarditis With Complete Atrioventricular Block

“…There is no consensus on the use of steroids in cases of ICIM complicated with both CAVB and myasthenia gravis. However, in previous case reports of similar cases, some patients were treated with steroid pulse therapy, prioritizing the treatment of myocarditis [11][12][13][14]. In these reports, atrioventricular conduction improved after steroid pulse therapy.…”