What is the management of myositis and cardiac involvement in patients treated with immune checkpoint inhibitors (ICIs)?

Immune Checkpoint Inhibitor-Related Myositis with Cardiac Involvement

Any evidence of myocardial involvement in ICI-related myositis mandates permanent discontinuation of the checkpoint inhibitor, immediate high-dose corticosteroids (1-2 mg/kg methylprednisolone IV), and urgent cardiology consultation, as this represents a life-threatening emergency with high mortality risk. 1

Critical Recognition: The "Terrible Triad"

ICI-related myositis frequently overlaps with myocarditis and myasthenia gravis, creating a potentially fatal syndrome that requires immediate recognition 2, 3. This overlap occurs in approximately 40% of myositis cases and carries significantly higher mortality than isolated myositis 4. The cardiac component is the most dangerous element, with complications ranging from cardiogenic shock to sudden death 5.

Key Diagnostic Pitfalls

Ocular involvement is frequently misdiagnosed - non-fluctuating ptosis and diplopia may be mistaken for myasthenia gravis rather than recognized as myositis 4. Brain MRI can reveal initially missed signs of extraocular muscle inflammation 4.

Troponin elevation is more sensitive than CK - troponin-T was elevated in 12/12 patients and troponin-I in 7/9 tested patients, while CK was elevated in only 8/15 patients in one institutional series 4. This means you cannot rule out myocarditis based on normal CK alone 1.

Grade-Based Management Algorithm

Grade 1 (Mild weakness ± pain)

• Continue ICI only if no cardiac involvement 1
• Check CK, troponin, ESR, CRP 1
• If CK elevated with muscle weakness, treat as Grade 2 1
• Analgesia with acetaminophen or NSAIDs 1

Grade 2 (Moderate weakness limiting instrumental ADLs)

• Hold ICI immediately 1
• Permanently discontinue if any evidence of myocardial involvement 1
• Obtain troponin, ECG, echocardiogram 1
• Complete autoimmune myositis panel, EMG, MRI of proximal limbs 1
• Early referral to rheumatology or neurology 1

If CK ≥3x normal:

• Initiate prednisone 0.5-1 mg/kg 1
• May require permanent ICI discontinuation with objective findings (elevated enzymes, abnormal EMG, abnormal MRI or biopsy) 1

May resume ICI only if:

• Symptoms controlled
• CK normalized
• Prednisone <10 mg
• No cardiac involvement 1

Grade 3-4 (Severe weakness limiting self-care ADLs)

Immediate Actions:

• Permanently discontinue ICI if any myocardial involvement 1
• Consider hospitalization for severe weakness 1
• Urgent rheumatology/neurology referral 1

Corticosteroid Dosing:

• Standard: Prednisone 1 mg/kg or equivalent 1
• Severe compromise (cardiac, respiratory, dysphagia, severe mobility limitation): Methylprednisolone 1-2 mg/kg IV or higher-dose bolus 1
• For refractory cases, consider cardiac transplant rejection doses (methylprednisolone 1 g daily) 1

Additional Immunosuppression:

• Consider plasmapheresis 1
• Consider IVIG therapy 1
• If no improvement or worsening after 4-6 weeks: add methotrexate, azathioprine, or mycophenolate mofetil 1
• Rituximab: use with caution given long biologic duration 1
• For severe refractory cases with complement deposition on biopsy, consider eculizumab 6
• Infliximab or antithymocyte globulin may be considered for cardiac involvement, though infliximab is contraindicated in moderate-severe heart failure 1

Cardiac-Specific Management

All grades of cardiac involvement warrant immediate work-up and intervention 1:

• Immediate transfer to coronary care unit for elevated troponin or conduction abnormalities 1
• Cardiology consultation mandatory 1
• ECG, cardiac biomarkers (BNP, troponin), echocardiogram 1
• High-dose corticosteroids (1-2 mg/kg methylprednisolone IV) initiated rapidly 1
• Manage according to ACC/AHA guidelines with cardiology guidance 1

Essential Diagnostic Work-Up

Initial evaluation for suspected myositis:

• CK, AST, ALT, LDH, aldolase 1
• Troponin (mandatory to evaluate myocardial involvement) 1
• ESR, CRP 1
• Autoimmune myositis panel 1
• ECG, echocardiogram if any cardiac symptoms or troponin elevation 1

For Grade 2 and higher:

• EMG, MRI of affected proximal limbs 1
• Consider muscle biopsy if diagnosis uncertain or to guide targeted therapy 1, 6
• Paraneoplastic autoantibody testing for myositis and myasthenia gravis 1

Critical Timing and Prognosis

Myocarditis typically occurs early - often after the first or second ICI infusion 3, 5. The true incidence is likely underestimated (reported 0.06%-1%) due to lack of specificity in clinical presentation and diagnostic challenges 5.

Combination immunotherapy carries higher risk - particularly ipilimumab-nivolumab combinations 2, 4, 5.

With early recognition, ICI discontinuation, and adequate immunosuppressive treatment, neurological and cardiological outcomes are generally good 4. However, delayed recognition or inadequate treatment of the cardiac component can be fatal 3, 5.