Case Presentation: A 75-year-old man with advanced urothelial carcinoma on enfortumab vedotin and pembrolizumab presented with new muscle weakness. His weakness began two weeks prior as cramping in his lower extremities and progressed upwards, leading to difficulty raising his head. He also noted progressive dyspnea on exertion and lower extremity edema. On exam, he had bilateral ptosis which worsened with sustained upward gaze, fatigable muscle weakness, and bilateral pitting edema. He had symmetrically diminished bicep reflexes and absent lower-extremity reflexes. His troponin T was 3,852 ng/L (normal range < 19ng/L), creatine kinase was 3,355 U/L (normal 22-250U/L), and NT-pro B-type natriuretic peptide 2,468 pg/mL (normal < 125pg/mL). Electrocardiogram showed new diffuse T-wave inversions. Multiple EMG studies with and without pyridostigmine were non-diagnostic for myasthenia gravis and antibody testing for myasthenia gravis antibodies returned negative. Cardiac magnetic resonance imaging (MRI) findings were consistent with myocarditis. Muscle biopsy demonstrated necrotizing myopathy. Based on the clinical constellation of myocarditis, myositis, and myasthenia gravis, triple M overlap syndrome was diagnosed. Initial therapy with high-dose methylprednisone, pyridostigmine, and intravenous immunoglobulin (IVIG) yielded minimal improvement, and worsening respiratory status culminated in requiring Bilevel Positive Airway Pressure (BiPAP) for respiratory depression. Addition of IV abatacept led to mild, gradual clinical improvement and ruxolitinib was added, correlating with a subsequent decrease in cardiac enzymes. Along with his clinical improvement from dose optimization of medications, the patient was discharged.
Discussion: Immune checkpoint inhibitor therapy (ICI) is used to treat many malignancies but can be associated with a wide spectrum of immune-related adverse events. With the expanding use of ICIs, it is essential for clinicians to recognize these manifestations and intervene early. Triple M Overlap Syndrome (TMOS) is a rare and severe complication of ICIs, consisting of a combination of myocarditis, myositis, and myasthenia gravis, with in-hospital mortality reported at 40–60% [1][2]. While ICI-associated TMOS has been described, optimal management is not known. This underscores the need for comprehensive evaluation when immune toxicity is suspected. Although TMOS is rare, there are high rates of co-occurrence between ICI mediated myocarditis, myositis, and myasthenia gravis thus it is important to screen for the triad when one entity is identified. Patients with suspected TMOS warrant aggressive immunosuppressive therapy and urgent negative inspiratory force (NIF) trending due to the high risk of sudden respiratory failure.
Conclusions: Patients frequently present to the hospital with immune mediated reactions, emphasizing the central role hospitalists often play in recognition of these patients. Optimal management includes timely recognition of the disease and early collaboration with a multidisciplinary team. Although rare, recognizing TMOS and adapting management accordingly can substantially improve prognosis.
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