Can methotrexate (Disease-Modifying Antirheumatic Drug (DMARD)) cause fibrosis, specifically pulmonary fibrosis?

Methotrexate Can Cause Pulmonary Fibrosis

Yes, methotrexate can cause pulmonary fibrosis, which is one of the most severe manifestations of methotrexate toxicity and can be potentially fatal. 1, 2

Pulmonary Toxicity of Methotrexate

Methotrexate can cause several types of pulmonary toxicity:

• Acute or chronic interstitial pneumonitis is a potentially dangerous complication that may occur at any time during therapy, even at low doses 2
• Pulmonary fibrosis is a severe manifestation that must be ruled out in patients presenting with new pulmonary symptoms such as cough 1
• Of 164 reported methotrexate-associated fatalities, 30 were caused by pulmonary fibrosis, making it the second most common cause of methotrexate-related death after myelosuppression 1

Risk Factors and Incidence

• Pulmonary fibrosis appears to be more common in patients with rheumatoid arthritis than in those with psoriasis 1
• Risk factors for increased pulmonary toxicity include:
  • Renal impairment 1
  • Advanced age 1
  • Pre-existing pulmonary disease 1
  • Concomitant use of other pulmonary toxic drugs 3

Clinical Presentation and Diagnosis

• Patients may present with:

  • Dry, nonproductive cough 1
  • Dyspnea 2
  • Fever 4
  • Progressive shortness of breath 4

• Diagnostic findings may include:

  • Bilateral basal interstitial involvement on imaging 4
  • Diffuse ground glass opacities on high-resolution CT 4
  • Reduced diffusion capacity on pulmonary function tests 1

Management

When pulmonary symptoms develop in a patient on methotrexate:

• Immediately discontinue methotrexate therapy 2, 4
• Perform appropriate diagnostic workup including imaging and pulmonary function tests 1
• Consider corticosteroid therapy, although response may be variable 4, 5
• Patients with pulmonary diseases (asthma, chronic cough) may not be candidates for methotrexate therapy 1
• Consider pulmonary function studies in consultation with a pulmonologist prior to initiating therapy in high-risk patients 1

Monitoring and Prevention

• Obtain a baseline chest x-ray for all patients starting methotrexate 1
• Monitor for pulmonary symptoms at each visit 1
• Pulmonary fibrosis may occur with short or long-term use of methotrexate 1
• The condition is not always fully reversible and fatalities have been reported 2
• Folate supplementation may reduce some methotrexate toxicities, though its specific effect on preventing pulmonary toxicity is not well established 1

Pathophysiology

The mechanism of methotrexate-induced pulmonary fibrosis appears to involve:

• Alveolar epithelial cell injury and apoptosis 6
• Loss of integrity of the alveolar-capillary barrier basement membranes 6
• Recruitment and proliferation of myofibroblasts 6
• Deposition of collagen 6

Important Considerations

• Pulmonary toxicity can occur unpredictably and may be fatal despite prompt intervention 4
• Some studies suggest that low-dose methotrexate may not be associated with increased risk of chronic interstitial lung disease compared to control patients with rheumatoid arthritis 7
• Drug interactions may increase the risk of pulmonary toxicity, as seen with combinations like methotrexate and nitrofurantoin 3

Methotrexate-induced pulmonary fibrosis remains a serious concern that requires vigilant monitoring and prompt intervention when suspected.