Myocarditis-myositis-myasthenia gravis overlap syndrome

Myocarditis-myositis-myasthenia gravis overlap syndrome, abbreviated IM3OS, is a rare immune-related adverse event in which immune checkpoint inhibitors provoke inflammation of heart muscle, skeletal muscle and the neuromuscular junction at the same time.

It is among the most lethal forms of checkpoint-inhibitor toxicity, with in-hospital mortality of about 60 per cent in published case series, and it usually appears within the first few months of treatment.

Terminology and classification

• Myocarditis-myositis-myasthenia gravis overlap syndrome is a severe immune-related adverse event in which checkpoint inhibitor therapy triggers inflammation of the heart, skeletal muscle and neuromuscular junction at the same time.
• The condition is also called immune checkpoint inhibitor-associated myocarditis with myositis and myasthenia gravis overlap, and abbreviations such as IM3OS, IMMMO and IM3O appear in the literature.
• Overlap here means that two or more immune-related syndromes occur together or in sequence, not that a separate histological disease entity has been defined.
• No ICD-10 or ICD-11 rubric exists for the overlap syndrome, so morbidity coding requires separate codes for myocarditis, myositis and myasthenia gravis.
• The first widely recognised cases were reported in 2016 after combined nivolumab and ipilimumab, and the overlap pattern was named and systematically reviewed in 2021.
• It differs from isolated checkpoint inhibitor myocarditis because skeletal muscle and neuromuscular junction involvement dominate the clinical picture and respiratory failure is common.
• The syndrome is best regarded as an oncological emergency that requires joint management by oncology, cardiology, neurology and intensive care rather than as a mild extension of ordinary myalgia.

History

• Ipilimumab was approved in 2011 and programmed cell death protein 1 inhibitors followed in 2014, which rapidly expanded the population at risk of immune-related adverse events.
• In 2016 Johnson and colleagues described two patients with fulminant myocarditis after combined checkpoint blockade, and both had concurrent myositis and myasthenia-like weakness and both died.
• Between 2017 and 2020, single cases and small series established that myocarditis, myositis and myasthenia gravis can present together, often after only one or two infusions.
• Pathak and colleagues published a systematic review of 60 cases in 2021, which defined the demographic, clinical and outcome profile that most later reviews still cite.
• Siu and colleagues reviewed the overlap syndrome in 2022 and emphasised that early recognition and aggressive immunosuppression can change the otherwise fatal course.
• National and society guidelines now list myocarditis as a high-grade immune-related adverse event, and they recommend urgent evaluation of any patient on checkpoint therapy who develops weakness or dyspnoea.
• The overlap syndrome also changed practice because it showed that a single immune-related adverse event should prompt active search for involvement of other organs, especially muscle and the neuromuscular junction.

Epidemiology

• The syndrome is rare, and checkpoint inhibitor myocarditis itself occurs in less than one percent of treated patients, with the overlap pattern representing a subset of those cases.
• The 2021 systematic review identified 60 cases from case reports and small series, which is likely to underestimate the true frequency because mild or atypical cases are not published.
• In that review the median age was 71 years and 67 percent of patients were male, which partly reflects the demographics of melanoma and lung cancer treated with checkpoint inhibitors.
• Melanoma accounted for about 38 percent of cases, and lung cancer, renal cell carcinoma and other tumour types made up the remainder.
• The median number of doses before onset was one, and most cases occurred after the first or second infusion rather than after months of treatment.
• Many patients with checkpoint inhibitor myocarditis also have myositis or myasthenia gravis, and the combination is common enough that myocarditis should prompt neuromuscular assessment.
• Incidence is higher with combination checkpoint blockade than with monotherapy, and the growing use of adjuvant and perioperative regimens may increase the number of exposed patients.

Pathophysiology

• The leading explanation is shared antigen expression across striated muscle, cardiac muscle and thymic tissue, which allows one T-cell response to attack several organs simultaneously.
• Blockade of PD-1, PD-L1 or CTLA-4 releases autoreactive T cells from peripheral tolerance, and clonal expansion then produces tissue infiltration and myocyte necrosis.
• Endomyocardial biopsies typically show lymphocytic infiltration with macrophage and CD8-positive T-cell predominance, and conduction tissue may be involved even when the ejection fraction is normal.
• Acetylcholine receptor and muscle-specific kinase antibodies are positive in only a minority of patients, so seronegative myasthenia is common and a negative antibody test does not exclude the syndrome.
• HLA associations and other genetic predispositions have been reported but not consistently replicated, and no routine genetic test is currently recommended.
• Cytokine release, myokine leakage from damaged muscle and systemic inflammation may amplify cardiac injury and contribute to the rapid haemodynamic deterioration seen in some patients.
• The overlap may also reflect the shared embryological origin of cardiac and skeletal muscle and the role of the thymus in selecting T cells that react with striated muscle antigens.

Clinical features

• Fatigue, muscle weakness and myalgia are the most common presenting complaints, and weakness is often proximal and rapidly progressive over days.
• Cardiac involvement causes palpitations, chest pain, dyspnoea, syncope or cardiogenic shock, and arrhythmias or conduction block may be the first sign.
• Ocular and bulbar myasthenic features include ptosis, diplopia, dysphagia, dysarthria and head drop, and they may precede overt myocardial symptoms.
• Respiratory failure can arise from diaphragmatic myositis, from myasthenic weakness of respiratory muscles or from both, and it may require urgent intubation.
• Creatine kinase is usually markedly elevated with a mean around 9600 units per litre in the 2021 review, while troponin is elevated in most patients with cardiac involvement.
• Left ventricular ejection fraction is preserved in about 80 percent of patients, so a normal echocardiogram does not exclude myocarditis and should not delay further investigation.
• The course may be fulminant, with rapid progression to complete heart block, ventricular arrhythmia, cardiogenic shock or respiratory arrest within hours of the first symptom.

Diagnosis

• The diagnosis should be suspected in any patient receiving checkpoint inhibitors who develops new weakness, myalgia, ptosis, dyspnoea, chest pain or unexplained fatigue.
• Initial tests include electrocardiography, troponin, creatine kinase, renal and liver function, and continuous cardiac monitoring when arrhythmia is suspected.
• Echocardiography, cardiac magnetic resonance imaging and endomyocardial biopsy are used when myocarditis is suspected, and biopsy may be needed to exclude other causes of fulminant heart failure.
• Electromyography and nerve conduction studies show myopathic or mixed changes, and repetitive nerve stimulation or single-fibre electromyography may support a neuromuscular junction disorder.
• Acetylcholine receptor, muscle-specific kinase and anti-striated muscle antibodies should be sent, but treatment must not wait for results when the clinical picture is severe.
• Forced vital capacity, negative inspiratory force and bedside swallowing assessment are essential because respiratory and bulbar weakness can deteriorate rapidly.
• The differential includes acute coronary syndrome, pulmonary embolism, sepsis, electrolyte disturbance, statin myopathy and isolated checkpoint inhibitor myocarditis without overlap.

Management

• Checkpoint inhibitor therapy should be withheld immediately when the syndrome is suspected, and decisions about permanent discontinuation are usually made after recovery.
• High-dose glucocorticoids should be started without delay, typically intravenous methylprednisolone at one to two milligrams per kilogram or a one-gram pulse daily.
• Intravenous immunoglobulin or plasma exchange is added for myasthenic or myositic components, especially when respiratory weakness or bulbar dysfunction is present.
• Second-line immunosuppression with mycophenolate, tacrolimus, cyclophosphamide, rituximab or alemtuzumab has been used in steroid-refractory cases, but evidence comes from case reports.
• Cardiac support may require temporary pacing for complete heart block, mechanical circulatory support for cardiogenic shock and mechanical ventilation for respiratory failure.
• Patients require monitoring for infections, hyperglycaemia, gastrointestinal bleeding and other complications of intensive immunosuppression, and antimicrobial prophylaxis is often considered.
• Management is best delivered by a multidisciplinary team that includes oncology, cardiology, neurology, intensive care, pharmacy and rehabilitation, because organ involvement changes quickly.

Research and controversies

• In-hospital mortality was about 60 percent in the 2021 systematic review, and death often resulted from cardiogenic shock, ventricular arrhythmia or respiratory failure.
• Survivors may recover cardiac and muscle function, but residual weakness, conduction abnormalities and dependence on immunosuppression have been reported.
• No randomised trial exists, and current recommendations are based on case series, expert opinion and extrapolation from other immune-related adverse events.
• Whether routine electrocardiography, troponin or creatine kinase screening before each dose improves outcomes remains unknown and is being evaluated in prospective studies.
• Rechallenge with checkpoint inhibitors after recovery is controversial, and the decision depends on cancer prognosis, severity of the event and availability of alternative therapy.
• The absence of a specific ICD code hampers epidemiological research, and registries and standardised case definitions are needed to compare incidence and outcomes across centres.
• Biomarkers such as cardiac and skeletal microRNAs, HLA typing, autoantibody profiles and imaging markers are being studied to identify patients at highest risk before severe injury occurs.