What is the preferred treatment regimen for cardiac sarcoidosis, comparing prednisone (corticosteroid) vs methotrexate (immunosuppressant)?

Treatment of Cardiac Sarcoidosis: Prednisone vs. Methotrexate

Corticosteroids (prednisone) are the first-line therapy for cardiac sarcoidosis, with methotrexate recommended as a second-line agent for patients who cannot tolerate corticosteroids or who continue to worsen despite corticosteroid treatment. 1

First-Line Treatment: Corticosteroids

Evidence Base and Recommendations

• Corticosteroids are the mainstay of therapy for cardiac sarcoidosis, with a strong level of consensus (Level of Evidence B) 1
• The American Heart Association (AHA) specifically recommends corticosteroids to suppress inflammation and granuloma formation in cardiac sarcoidosis 1
• The European Respiratory Society (ERS) guidelines favor glucocorticoid treatment for clinically relevant cardiac sarcoidosis, especially given the high risk of death associated with cardiac sarcoidosis, particularly in those with reduced left ventricular function 1

Dosing Approach

• Initial prednisone dosing typically ranges from 20-40 mg daily 1
• Dose adjustments are recommended for patients with comorbidities:
  • Diabetes
  • Psychosis
  • Osteoporosis 1
• Corticosteroids are commonly initiated at a high dose and tapered off slowly over months if clinical and imaging features remain stable or improve 1

Second-Line Treatment: Methotrexate and Other Immunosuppressants

When to Consider Methotrexate

Methotrexate should be considered in the following scenarios:

• Patients who cannot tolerate corticosteroids
• Patients who continue to worsen clinically despite treatment with corticosteroids 1
• High risk for steroid toxicity
• When long-duration therapy is anticipated 1

Evidence for Methotrexate

• A single-center retrospective study comparing methotrexate plus prednisone versus prednisone alone suggested improved ejection fraction and brain natriuretic peptide after 5 years of treatment 1
• The CHASM CS-RCT (NCT03593759) is currently evaluating whether a low-dose prednisone/methotrexate combination has non-inferior efficacy to standard dose prednisone while resulting in better quality of life 2

Treatment Algorithm

1. Initial Assessment:

   • Confirm diagnosis of cardiac sarcoidosis through appropriate imaging (cardiac MRI, PET) and/or biopsy
   • Assess severity based on prognostic variables:
     • Left ventricular ejection fraction <40%
     • NYHA Functional Class III or IV
     • Ventricular tachycardia
     • Cardiac inflammation on imaging 1

2. First-Line Treatment:

   • Begin prednisone at 20-40 mg daily 1
   • Lower starting dose for patients with diabetes, psychosis, or osteoporosis 1
   • Continue for 3-6 months to allow for therapeutic response 1

3. Treatment Monitoring:

   • Follow-up at 3-6 month intervals 1
   • Assess response using cardiac imaging (MRI or PET)
   • Monitor for steroid-related side effects

4. Treatment Adjustment Based on Response:

   • If improved: Decrease steroid dose to find lowest effective dose 1
   • If stable: Consider dose reduction 1
   • If worsening: Add adjunctive therapy (methotrexate) and re-evaluate diagnosis 1

5. Second-Line Treatment:

   • Methotrexate is the preferred initial non-biologic therapy 1
   • Oral administration is generally favored 1
   • Consider subcutaneous administration for patients with gastrointestinal side effects 1

Important Considerations and Caveats

• Evidence Quality: The level of evidence supporting treatment approaches for cardiac sarcoidosis is very low, with multiple potential confounders and biases in available studies 1
• Treatment Duration: The optimal duration of treatment remains unclear, but withdrawal of glucocorticoids after initiation, regardless of clinical improvement, has been associated with worse outcomes 1
• Disease Recurrence: A study examining immunosuppression discontinuation found radiologic relapse in 8 of 9 patients after immunosuppression cessation, suggesting the need for ongoing surveillance 3
• Newer Approaches: Some evidence suggests that regimens containing infliximab may be superior to those containing prednisone alone or prednisone plus methotrexate in terms of achieving lower effective prednisone doses 4
• Cardiac Transplantation: Should be considered for patients with advanced heart failure or intractable arrhythmias in the absence of significant extracardiac sarcoidosis 1

Despite the lack of randomized clinical trials, the high mortality risk associated with cardiac sarcoidosis warrants aggressive treatment with corticosteroids as first-line therapy, with early consideration of steroid-sparing agents like methotrexate to minimize corticosteroid toxicity.