Immune checkpoint inhibitor-associated myocarditis

Immune checkpoint inhibitor-associated myocarditis or immune checkpoint-induced myocarditis is a form of immune-mediated myocarditis associated with immune checkpoint inhibitor therapy.

Epidemiology

Although myocarditis can occur with immune checkpoint inhibitor monotherapy it is more common with combination therapy and a prevalence of more than ~1% has been reported if immune checkpoint inhibitors are used in combination ¹.

Diagnosis

A proposal for the diagnosis of myocarditis in the setting of immune checkpoint inhibitor was made ^2,3:

• definite:

  • pathology proven myocarditis

  • diagnostic cardiac MRI in conjunction with typical symptoms positive electrocardiogram (ECG) or cardiac biomarkers

  • wall motion abnormalities on echocardiography with typical symptoms, positive ECG and biomarkers as well as exclusion of coronary artery disease on invasive angiography

• probable:

  • diagnostic cardiac MRI without typical symptoms, positive biomarkers or ECG

  • suggestive cardiac MRI with either only typical symptoms, positive ECG or biomarkers

  • wall motion abnormalities on echocardiography with typical symptoms positive ECG or cardiac biomarkers

  • any possible clinical scenario with a positive PET scan not explained otherwise

• possible:

  • suggestive cardiac MRI with no symptoms or other criteria

  • wall motion abnormalities on echocardiography with symptoms or ECG only

  • elevated biomarkers with symptoms or ECG and no alternative diagnosis

Clinical presentation

There is a spectrum of clinical findings in the setting of immune checkpoint inhibitor-associated myocarditis ranging from mild to severe disease. Correspondingly, clinical symptoms can vary from asymptomatic patients with abnormal cardiac biomarkers, to life-threatening conditions including heart failure, ventricular tachycardia, high-grade atrioventricular block or cardiogenic shock.

Symptoms can occur early after the first dose with a reported median time of around 30 days after initiation of therapy ^4,5.

Classification

A clinical classification proposed by the American Society of Clinical Oncology ²:

• grade 1: abnormal biomarkers or electrocardiogram

• grade 2: mild clinical symptoms with abnormal biomarkers or ECG

• grade 3:

  • reduced LVEF <50% or regional wall motion abnormalities on echocardiography

  • cardiac MRI suggesting myocarditis

• grade 4: life-threatening disease with appropriate findings from the lower grades

Pathology

Immune checkpoint inhibitor-associated myocarditis is characterized by a multifocal lymphohistiocytic infiltration of the myocardium ⁷. Inhibition of CTLA-4 and PD-1 plays a major role in the pathophysiology ^4,5.

Microscopic appearance

Histopathologic features of  immune checkpoint inhibitor-associated myocarditis include the following ⁷:

• prominent interstitial inflammatory changes consisting of histiocytes and intermingled lymphocytes

• evidence of myocyte necrosis and destruction

• no histologic evidence of myocardial fibrosis

Immunophenotype

Immunohistochemistry stains are usually positive for CD163, CD3, CD8, Granzyme B, PD1 and PD-L1 ⁷.

Radiographic features

Echocardiography

Echocardiographic findings are nonspecific and variable and might include regional wall motion abnormalities, pericardial effusion, diastolic impairment, decreased systolic function (LVEF <50%) or left ventricular dilatation ².

MRI

Cardiac MRI involves the Lake Louise criteria for the diagnosis of myocardial inflammation ^2,7,8 which include two main criteria, myocardial edema and myocardial injury as well as two supportive criteria, pericarditis and left ventricular dysfunction, with the main criteria supporting the diagnosis with high specificity if both are found, but also if only one can be found in the correct clinical setting or if supportive criteria are present ^2,8,9.

Radiology report

The radiology report should include a description of the following:

• morphology and functional analysis

• systolic dysfunction (LVEF <50%)

• wall motion abnormalities

MRI

• myocardial tissue properties including abnormal T1 and T2 mapping values and late gadolinium enhancement

• specifically:

  • presence and location of myocardial edema

  • presence and pattern of myocardial injury

  • presence of supportive criteria (pericarditis, wall motion abnormalities)

Treatment and prognosis

Management includes close cooperation between cardiologists and oncologists. The mainstay in the treatment is considered high-dose intravenous corticosteroids and the withdrawal of immune checkpoint inhibitors with immunosuppressive agents and a CTLA-4 agonist as a second-line concept ⁵. Additionally, management should include symptomatic cardiac treatment for heart failure and arrythmias as recommended by guidelines ².

Generally, the outcome is poor with up to 50% of patients dying ^4,5 and the fatality rate is higher with immune checkpoint inhibitor combination therapy ⁴.

History and etymology

Two cases of fulminant myocarditis associated with immune checkpoint inhibitors were first described by the American hematologist and oncologist Douglas B Johnson, the cardio-oncologist Javid J Moslehi and their multicenter study group of numerous colleagues in 2016 ².

Differential diagnosis

The differential diagnosis include the following conditions:

• acute coronary syndrome

• takotsubo cardiomyopathy

• other causes of myocarditis