Immune Checkpoint Inhibitor Myocarditis

Immune checkpoint inhibitor (ICI) myocarditis is an immune related adverse event of antibodies directed against PD-1 (nivolumab, pembrolizumab, cemiplimab), PD-L1 (atezolizumab, durvalumab, avelumab) or CTLA-4 (ipilimumab, tremelimumab), in which T cells infiltrate the myocardium and conduction system.

It affects about 0.5 to 1% of treated patients, and about 2% on combined PD-1 and CTLA-4 therapy, with mortality of about 25 to 50%. It usually appears within the first 3 months, most often after the first 1 to 3 doses (median onset about 30 days, range days to over a year).

Risk factors are combination therapy, pre-existing autoimmune disease, diabetes, obesity, and chronic kidney disease.

About a quarter to a half of patients also have myositis, myasthenia gravis like weakness or both (the myocarditis, myositis and myasthenia overlap), which raises mortality, and other immune related events (hepatitis, colitis, pneumonitis, thyroiditis) may coexist.

Pathophysiology. Loss of the PD-1 and CTLA-4 checkpoints releases autoreactive CD4 and CD8 T cells and macrophages against antigens shared between tumour and cardiac or skeletal muscle (for example alpha myosin). The result is patchy inflammation and necrosis of the myocardium, conduction system and skeletal muscle.

Loss of PD-1 signalling in animal models produces autoimmune cardiomyopathy.

• Fatigue, myalgia, dyspnoea, chest pain, palpitations, syncope and oedema. Often subtle at the start.
• Ptosis, diplopia, dysphagia, proximal weakness and respiratory muscle weakness (myositis and myasthenic overlap).
• ECG abnormality in most: atrioventricular block, bundle branch block, ventricular arrhythmia, ST-T change. Ventricular function is preserved in about half, so a normal ejection fraction does not exclude the diagnosis.
• Heart failure, cardiogenic shock and sudden death.

Red flags.

• New troponin rise during or after ICI therapy
• Atrioventricular block, new bundle branch block or ventricular tachycardia
• Concurrent myositis, ptosis or respiratory weakness
• Combination ICI therapy or earlier autoimmune disease
• Falling ejection fraction or reduced global longitudinal strain
• Hypotension or rising lactate

• Baseline and surveillance. ECG and troponin before starting ICI therapy, and repeated before each of the next 3 doses (doses 2 to 4), particularly in high risk patients.
• Troponin. High sensitivity troponin I is preferred, because troponin T can rise from concurrent myositis. Also CK (raised in myositis), natriuretic peptide, CRP, aldolase, liver enzymes, thyroid function, and a cortisol level.
• ECG and telemetry.
• Echocardiography with global longitudinal strain.
• Cardiac MRI. Oedema and late gadolinium enhancement, but enhancement is absent in many cases, so a normal study does not exclude disease and should not delay treatment.
• Coronary angiography or CT coronary angiography in patients with ischaemic features, to exclude acute coronary syndrome.
• Endomyocardial biopsy. Confirms the diagnosis (T-cell and macrophage infiltrate with myocyte necrosis) when the diagnosis is uncertain or the response is poor. Do not delay steroids for it.
• Neuromuscular tests when weakness is present: acetylcholine receptor antibody, anti-striated muscle antibody, electromyography, and spirometry (forced vital capacity and negative inspiratory force).

The diagnosis rests on a new troponin rise with a new ECG, echocardiographic or MRI abnormality after ICI exposure, with acute coronary syndrome and other myocarditis excluded. Biopsy proves it.

Differential diagnosis.

• Acute coronary syndrome and takotsubo syndrome
• Viral myocarditis
• ICI pericarditis, myositis or myasthenia without myocarditis
• Tumour progression or cardiac metastasis
• Cardiotoxicity from other cancer drugs (anthracyclines, trastuzumab, fluoropyrimidine vasospasm)
• Radiation heart disease
• Sepsis and pulmonary embolism
• Thyroid dysfunction and adrenal insufficiency (hypophysitis)
• Giant cell and eosinophilic myocarditis

Start treatment within 24 hours of suspicion, in a monitored unit. Delay increases cardiac events.

• Hold the ICI at once. Withdraw permanently for any clinically significant myocarditis. Rechallenge is considered only after complete recovery, for a clear oncological need, with a PD-1 or PD-L1 antibody alone, and by joint cardio oncology decision.
• Methylprednisolone 500 to 1,000 mg intravenously once daily for 3 to 5 days, then prednisolone 1 mg/kg orally once daily (maximum 80 mg). Begin the taper only when troponin has fallen steadily and symptoms and ECG have improved, then over at least 4 to 6 weeks (for example reduce by 10 mg weekly to 20 mg daily, then more slowly). If troponin rises on tapering, return to the previous dose. Add calcium and vitamin D, a proton pump inhibitor, and glucose and blood pressure monitoring. Co-trimoxazole 960 mg orally three times weekly (or 480 mg once daily; halve at creatinine clearance 15 to 30 mL/min and avoid under 15 mL/min) when steroids are expected for over 4 weeks.
• Steroid refractory disease (no fall in troponin within 24 to 72 hours, worsening function, or new arrhythmia): add a second agent in a specialist unit.
  • Abatacept 500 mg intravenously every 2 weeks for up to 5 doses (some centres use weight adjusted doses). Check for infection first.
  • Mycophenolate mofetil 500 to 1,000 mg orally or intravenously twice daily (maximum 3 g daily). Contraindicated in pregnancy. Monitor full blood count. Avoid adding azathioprine.
  • Rabbit antithymocyte globulin 1.5 mg/kg intravenously once daily for 3 to 5 days, with premedication and CD3 monitoring, for refractory fulminant cases.
  • Intravenous immunoglobulin 2 g/kg in total over 2 to 5 days, or plasma exchange, for refractory disease or overlap with myasthenia (evidence is limited). Intravenous immunoglobulin carries a risk of thrombosis, haemolysis and renal injury.
  • Tocilizumab 8 mg/kg intravenously once (maximum 800 mg) in refractory cases, with infection screening. Avoid infliximab at doses over 5 mg/kg, because it can worsen heart failure.
  • Evidence for second line agents is from case series.
• Arrhythmia and conduction block. Telemetry for at least 72 hours. Defibrillation for unstable ventricular arrhythmia, and amiodarone 150 mg intravenously over 10 minutes, repeated for recurrence, then 1 mg/min for 6 hours, then 0.5 mg/min for 18 hours, maximum 2.2 g in 24 hours. Temporary pacing for high grade block, then permanent pacing if it persists, because block often resolves. Defibrillator after recovery for persistent ventricular arrhythmia.
• Heart failure and shock. Give noradrenaline 0.05 microgram/kg/min intravenously, titrated to a mean pressure of 65 mm Hg (usual maximum 0.5 microgram/kg/min), and early venoarterial extracorporeal membrane oxygenation for refractory shock. Heart failure drugs once stable.
• Myasthenia and myositis overlap. Monitor forced vital capacity and negative inspiratory force every 4 to 6 hours with bulbar or respiratory symptoms. Avoid drugs that worsen myasthenia (macrolides, fluoroquinolones, aminoglycosides, magnesium infusions, beta blockers). Intravenous immunoglobulin 2 g/kg in total over 2 to 5 days or plasma exchange in a specialist unit, and mechanical ventilation for ventilatory failure.
• Coexisting immune related events (hepatitis, colitis, pneumonitis): treat with the steroid course used for the myocarditis (methylprednisolone 500 to 1,000 mg intravenously once daily for 3 to 5 days, then prednisolone 1 mg/kg orally once daily, maximum 80 mg) and the relevant specialist.

Special groups. Kidney impairment: avoid nephrotoxic combinations, and adjust mycophenolate and antibiotic prophylaxis. Pregnancy: avoid mycophenolate and plan with an obstetric team.

Monitoring. Troponin and ECG daily until the peak has passed, then every 2 to 3 days until normal and during the taper. Echocardiography at baseline, at 1 to 2 weeks and at 3 months, and cardiac MRI at 3 months. CK in overlap disease. Glucose, blood pressure, full blood count, creatinine and liver enzymes while on immunosuppression. Heart failure follow up for 12 months.

Referral and escalation. Admit to a cardiac care unit and involve cardio oncology, the treating oncologist and neurology for overlap. Escalate at once for arrhythmia, shock, respiratory weakness or failure to respond within 24 to 72 hours.