Can methotrexate cause pulmonary (lung) injury?

Methotrexate and Lung Injury

Yes, methotrexate can definitely cause lung injury, with interstitial pneumonitis being the most common and potentially serious pulmonary complication. 1

Types of Methotrexate-Induced Lung Injury

Methotrexate can cause several forms of pulmonary toxicity:

1. Acute/Subacute Interstitial Pneumonitis

   • Most common pulmonary toxicity
   • Characterized by dry cough, dyspnea, fever, and hypoxemia 2
   • Can develop at any time during therapy, even at low doses 1
   • Not always fully reversible; fatalities have been reported 1

2. Pulmonary Fibrosis

   • Can occur with long-term use
   • May develop without preceding symptoms 1

3. Opportunistic Infections

   • Increased susceptibility, particularly to Pneumocystis carinii pneumonia 1, 3
   • Can be potentially fatal 1

4. Noncardiogenic Pulmonary Edema

   • Rare but reported after intrathecal administration 4

Risk Factors

Several factors increase the risk of methotrexate-induced lung toxicity:

• Pre-existing lung disease 2
• Cigarette smoking 2
• Older age (>40 years) 2
• Psoriatic arthritis (in patients with psoriasis) 2

Incidence and Timing

• Incidence ranges from 0.5% to 14% in patients receiving low-dose methotrexate 5
• Can occur at any time during treatment, regardless of cumulative dose 1, 6
• Hypersensitivity pneumonitis typically occurs within the first 5 months of treatment 6

Clinical Presentation and Diagnosis

Patients typically present with:

• Dry, nonproductive cough
• Progressive dyspnea
• Fever
• Hypoxemia
• Bibasilar crackles on examination 5

Diagnostic findings include:

• Bilateral interstitial or mixed infiltrates on chest X-ray, often with basal predominance
• Ground-glass opacities, interstitial infiltrates, or consolidation on CT scan
• Restrictive pattern on pulmonary function tests
• Cellular interstitial infiltrates on lung biopsy 5

Management

When methotrexate-induced lung injury is suspected:

1. Discontinue methotrexate immediately 1, 5
2. Consider corticosteroid therapy for severe cases 7, 5
3. Rule out infectious causes through appropriate testing 5

Monitoring and Prevention

To minimize risk:

• Baseline assessment: Inquire about respiratory symptoms and history of pulmonary disease before starting methotrexate 2
• Chest X-ray: Obtain baseline imaging in patients >40 years, smokers, or those with respiratory risk factors 2
• Regular monitoring: Assess for new respiratory symptoms at follow-up visits 2
• Patient education: Instruct patients to report new respiratory symptoms promptly 1

Prognosis

• Most cases resolve with drug discontinuation and appropriate treatment 5
• However, some cases can be fatal, particularly if diagnosis is delayed 1, 6
• Mortality has been reported in up to 17% of cases 6

Important Caveats

• Symptoms of methotrexate-induced pneumonitis can mimic infection or worsening of underlying lung disease
• The risk of methotrexate-induced pneumonitis must be weighed against its efficacy as an anchor treatment in conditions like rheumatoid arthritis 2
• Patients with pre-existing lung disease should be informed of their increased risk before starting methotrexate 2

Despite these risks, methotrexate is still conditionally recommended over alternative DMARDs for patients with mild and stable airway or parenchymal lung disease who have moderate-to-high disease activity requiring treatment 2.