Title

Immune Checkpoint Inhibitor-Induced Myocarditis, Myositis, and Myasthenia Gravis Overlap Syndrome: Lessons from a Multidisciplinary Approach

Authors

Mohammad R. Salah, DO and Liza Icayan, MD

Introduction

Immune checkpoint inhibitors (ICI) have revolutionized the treatment of malignancies, offering improved survival for many patients with advanced cancers. However, their use has introduced a new set of immune-related adverse events which can be devastating. We present a case of ICI-induced myocarditis, myositis, and myasthenia gravis overlap syndrome (IM3OS), a very rare immunotherapy-related complication.

Case Presentation

A 71-year-old woman with newly diagnosed invasive ductal carcinoma (IDC) of the right breast established care with an oncologist and a cardio-oncologist who initiated combined treatment with chemotherapy (paclitaxel/carboplatin) and immunotherapy (pembrolizumab). Approximately 1 month after starting therapy, including 2 doses of chemotherapy and 1 dose of immunotherapy, the patient presented to her oncologist's office for her next treatment cycle but endorsed bilateral ptosis, vision changes, myalgia, fatigue, and generalized weakness, prompting referral to the emergency department. Laboratory evaluation revealed a markedly elevated troponin (1,246 ng/L), creatine kinase (12,984 U/L), and acetylcholine receptor antibodies. Electrocardiogram showed a new incomplete right bundle branch block and ST-segment elevations in the precordial and inferior leads. This constellation of findings raised concern for myocarditis, myositis, and myasthenia gravis overlap syndrome secondary to immune checkpoint inhibitor therapy. A multidisciplinary team involving cardiology, neurology, and oncology initiated treatment with high-dose corticosteroids, intravenous immunoglobulin, and abatacept. The clinical course was complicated by new-onset neck weakness, dysphagia, and lethargy followed by hemodynamic instability requiring ICU admission for emergent intubation, plasmapheresis, and vasopressor support. Despite the severity of her critical condition, timely intervention led to gradual improvement in muscle strength and respiratory effort. Ultimately, the patient required tracheostomy with mechanical ventilation and percutaneous endoscopic gastrostomy before being deemed stable for discharge to a long-term acute care facility.

Discussion

This case underscores the potential for severe, life-threatening immune-mediated toxicities associated with immune checkpoint inhibitors and highlights the critical need for prompt recognition and intervention. The incidence of ICI-related neurotoxicity is estimated to be between 3.8% and 6.1%, with severe neurotoxicity, including myositis and/or myasthenia gravis, reported in less than 1% of cases¹. The median time to symptom onset is approximately 4 weeks, typically occurring after the first or second dose². Immune-mediated myositis overlapping syndrome often presents with symptoms such as ptosis, diplopia, dyspnea, and fatigue, with most requiring supplemental oxygen and prolonged hospitalization². As the use of ICIs continues to grow, maintaining a high index of suspicion for immune-related adverse events is crucial to improving patient outcomes. This is particularly important in cases involving multi-organ toxicity, such as IM3OS, where mortality rates have been reported as high as 60% in systematic reviews³. In this complex case, multidisciplinary collaboration was key for timely diagnosis and implementation of effective treatment, including immunosuppressive therapy with corticosteroids, ultimately contributing to a favorable outcome.

References

1. Bryan J. Schneider et al., Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update. JCO 39, 4073-4126(2021). DOI:10.1200/JCO.21.01440 2. Lipe DN, Galvis-Carvajal E, Rajha E, Wechsler AH, Gaeta S. Immune checkpoint inhibitor-associated myasthenia gravis, myositis, and myocarditis overlap syndrome. Am J Emerg Med. 2021;46:51-55. 3. Pathak R, Katel A, Massarelli E, Villaflor VM, Sun V, Salgia R. Immune Checkpoint Inhibitor-Induced Myocarditis with Myositis/Myasthenia Gravis Overlap Syndrome: A Systematic Review of Cases. Oncologist. 2021 Dec;26(12):1052-1061