What is the preferred initial immunosuppressive therapy, mycophenolate mofetil (MMF) or azathioprine (AZA), in the treatment of fibrotic chronic hypersensitivity pneumonitis?

Mycophenolate Mofetil vs Azathioprine in Fibrotic Chronic Hypersensitivity Pneumonitis

Mycophenolate mofetil (MMF) is preferred over azathioprine (AZA) as initial immunosuppressive therapy for fibrotic chronic hypersensitivity pneumonitis due to its superior diffusion capacity improvement and better safety profile. While both medications can be used as steroid-sparing agents in fibrotic hypersensitivity pneumonitis (fHP), the evidence suggests MMF offers specific advantages.

Efficacy Comparison

Lung Function Effects

• MMF Advantages:

  • Significantly improves DLCO by 4.2% after 1 year of treatment 1
  • Recent 2025 data shows MMF stabilizes FVC% and significantly improves DLCO% (p=0.004) 2
  • Associated with reduced dyspnea and decreased corticosteroid requirements 2

• AZA Considerations:

  • Similar to MMF in stabilizing FVC decline
  • Less robust evidence for DLCO improvement specifically in fHP

Disease Progression

Both agents appear to alter the slope of monthly FVC decline (0.7% vs 0.2%; p=0.001) when used as prednisone-sparing therapy 3. However, neither medication has demonstrated clear superiority in preventing overall FVC% decline over extended periods.

Safety Profile

Adverse Events

• MMF Advantages:

  • 66% fewer treatment-emergent adverse events compared to prednisone alone (p=0.002) 4
  • Associated with more infections but less hepatotoxicity than azathioprine 3
  • Recent data shows only 5.5% of patients discontinue due to severe adverse effects 2

• AZA Considerations:

  • 54% fewer treatment-emergent adverse events compared to prednisone alone (p=0.04) 4
  • Higher risk of hepatotoxicity compared to MMF 3
  • Requires TPMT/NUDT15 genotype testing to avoid severe toxicity in deficient patients

Special Considerations

Patient Selection

• Predictors of poor MMF response:
  • Male gender
  • History of tuberculosis 2

Specific Situations Where AZA May Be Preferred:

• Pregnancy (AZA is preferred for pregnant patients) 3
• Patients with total thiopurine S-methyltransferase deficiency should avoid AZA 3
• Cost considerations (AZA is considerably less expensive than MMF) 3

Treatment Algorithm

1. First-line approach: Complete antigen avoidance (most important intervention)
2. When immunosuppression is indicated:
   • For non-pregnant patients without contraindications: Start MMF at 1000-2000 mg/day
   • For pregnant patients or those with MMF contraindications: Use AZA 75-150 mg/day
3. Monitoring:
   • Assess pulmonary function tests (FVC and DLCO) every 3-6 months
   • Monitor for adverse effects, particularly infections with MMF and hepatotoxicity with AZA
   • Aim to reduce corticosteroid dose gradually

Important Caveats

• Response to immunosuppression varies by antigen type - patients with unknown causative antigens may have worse outcomes with immunosuppression 5
• Neither medication has been shown to definitively improve survival in fHP 4
• Patients who don't receive immunosuppressive therapy generally have better survival, but this likely reflects selection bias (less severe disease) 4
• Consider antifibrotic medications as second-line therapy for progressive fibrotic HP despite immunosuppression 6

In conclusion, while both MMF and AZA can be used as steroid-sparing agents in fibrotic chronic hypersensitivity pneumonitis, MMF should generally be preferred due to its superior DLCO improvement and better safety profile, unless specific contraindications exist.