How to select between methotrexate (MTX), azathioprine (AZA), and mycophenolate mofetil (MMF) in the treatment of myositis?

Selection Between Methotrexate, Azathioprine, and MMF in Myositis Treatment

No trials have shown the superiority of one agent (methotrexate, azathioprine, or mycophenolate mofetil) over the others in the treatment of myositis, and the choice should be based on patient-specific factors including comorbidities, potential side effects, and organ involvement. 1

Initial Treatment Approach

• All patients with newly diagnosed idiopathic inflammatory myopathy (IIM) should receive high-dose corticosteroids (prednisone 0.5-1 mg/kg/day) combined with a steroid-sparing agent 1, 2
• Steroid-sparing agents are typically slow-acting and may take 3-6 months to reach full efficacy 1
• The three most commonly used steroid-sparing agents are methotrexate (MTX), azathioprine (AZA), and mycophenolate mofetil (MMF) 1, 2

Medication-Specific Considerations

Methotrexate (MTX)

• Start at 15 mg orally once weekly with 1 mg/day folic acid supplementation 1
• Target dose is 25 mg once weekly within 3-6 months 1
• Preferred in patients without significant lung disease 1
• Contraindications/cautions:
  • Interstitial lung disease (relative contraindication) 1
  • Liver disease (requires baseline liver function tests and hepatitis screening) 1
  • Pregnancy (teratogenic) 1
• Common side effects: GI symptoms, stomatitis, hepatotoxicity 1

Azathioprine (AZA)

• Check thiopurine methyltransferase (TPMT) level before starting to screen for enzyme deficiency 1
• Start at 25-50 mg/week with increments of 25-50 mg/week 1
• Target dose is 2 mg/kg of ideal body weight in divided doses 1
• May be preferred in patients with interstitial lung disease 1
• Common side effects: nausea, diarrhea, fever, liver toxicity, myelosuppression 1

Mycophenolate Mofetil (MMF)

• Start at 500 mg twice daily and increase by 500 mg weekly 1
• Target dose is 1000 mg twice daily (2 g/day), occasionally up to 3 g/day 1
• Particularly effective for patients with severe skin disease in dermatomyositis 1
• Contraindications/cautions:
  • Pregnancy (teratogenic - requires two forms of birth control) 1
• Common side effects: nausea, diarrhea, leukopenia, transaminitis 1

Selection Algorithm Based on Clinical Presentation

1. For patients with significant lung involvement (ILD):

   • Prefer MMF or AZA over MTX 1, 3
   • MTX has been associated with pneumonitis, though it's not an absolute contraindication 1

2. For patients with predominant skin disease in dermatomyositis:

   • Consider MMF as first choice 1
   • Several case series have shown efficacy in severe dermatomyositis skin disease 1

3. For patients with liver disease or abnormal liver function:

   • Prefer AZA or MMF over MTX 1
   • Monitor liver function closely regardless of agent chosen 1

4. For women of childbearing potential:

   • Prefer AZA if pregnancy is a possibility 1
   • Both MTX and MMF are teratogenic and require reliable contraception 1

5. For patients with renal impairment:

   • Prefer MTX or AZA with dose adjustments over MMF 4

Monitoring and Follow-up

• Regular assessment of muscle strength, skin disease, and major organ involvement 1
• Monitor appropriate lab tests:
  • MTX: CBC, liver function tests 1
  • AZA: CBC, liver function tests 1
  • MMF: CBC, liver function tests 1
• Consider switching agents if:
  • Inadequate response after 3-6 months 1
  • Intolerable side effects 1
  • Development of new organ involvement 1

Treatment for Refractory Disease

• If first-line treatment fails, consider:
  • Switching to another steroid-sparing agent 1
  • Adding IVIG (especially for severe weakness or dysphagia) 1
  • Consider rituximab, cyclosporine, or cyclophosphamide for severe refractory disease 1, 4

Common Pitfalls

• Delaying initiation of steroid-sparing agents (should be started concurrently with steroids) 2
• Inadequate initial dosing of corticosteroids 2
• Failing to screen for TPMT deficiency before starting azathioprine 1
• Not providing folic acid supplementation with methotrexate 1
• Tapering steroids too quickly before steroid-sparing agents take full effect 1