What lung disease can be caused by methotrexate in patients with or without a history of lung disease?

Methotrexate-Induced Lung Disease

Methotrexate can cause interstitial pneumonitis (also called hypersensitivity pneumonitis), which is a potentially fatal pulmonary complication that presents with dry nonproductive cough, progressive dyspnea, and fever. 1, 2

Clinical Presentation and Timing

• The classic triad consists of dry nonproductive cough, progressive dyspnea, and fever, typically developing within the first 32 weeks of treatment, though it can occur at any time during therapy—even after 30 years of use 1, 3
• The presentation is not dose-dependent, meaning it can occur with low-dose weekly therapy (7.5-15 mg/week) used for rheumatoid arthritis, not just high-dose regimens 1, 4
• Symptoms are nonspecific and can easily be mistaken for infection, particularly pneumonia—infection must always be excluded before attributing respiratory symptoms to methotrexate toxicity 1
• Physical examination typically reveals fever, tachycardia, bilateral basal crackles, and hypoxemia 3

Diagnostic Features

• Chest imaging shows bilateral interstitial or mixed interstitial-alveolar infiltrates with predilection for the bases on chest X-ray, and ground-glass opacities, interstitial infiltrates, or widespread consolidation on CT scan 4
• Laboratory findings may include peripheral eosinophilia (present in approximately one-third of cases), elevated erythrocyte sedimentation rate, and normal or mildly elevated white blood cell count 3, 4
• Pulmonary function tests reveal restrictive ventilatory defect and/or impaired gas exchange with decreased carbon monoxide diffusing capacity 5, 4
• Bronchoalveolar lavage may help rule out infectious etiology and support the diagnosis, though it is not always necessary 4

Mortality and Risk Factors

• This is a potentially fatal complication with a mortality rate of approximately 17.2-17.6% once pulmonary toxicity develops 1
• Pre-existing pulmonary disease significantly increases the risk of methotrexate-induced pulmonary toxicity 1, 2
• Additional risk factors include:
  • Rheumatoid arthritis (higher rates than psoriasis patients) 1
  • Cigarette smoking 1, 6
  • Age >40 years (advanced age is an independent risk factor) 1
  • Male sex 6
  • Renal impairment 1

Incidence

• The incidence of interstitial pneumonitis in rheumatoid arthritis patients on low-dose methotrexate (7.5-15 mg/week) is approximately 1% in controlled trials 2
• Overall pulmonary toxicity occurs in 0.5% to 14% of patients receiving low-dose methotrexate, depending on the population studied 4

Management Algorithm

When methotrexate-induced pneumonitis is suspected:

1. Immediately discontinue methotrexate 1, 2, 4
2. Rule out infection through appropriate cultures, viral testing, and consideration of opportunistic infections (particularly Pneumocystis carinii pneumonia) 2
3. Initiate corticosteroid therapy (typically prednisone 60 mg daily orally) for moderate to severe cases, which accelerates resolution and improves prognosis 3, 4, 6
4. Provide supportive care including supplemental oxygen as needed 7

Prognosis

• The prognosis is usually favorable if the condition is recognized early and methotrexate is promptly withdrawn 4, 7
• Corticosteroid treatment improves outcomes, particularly in severe or fulminant cases 4, 6
• Discontinuation of methotrexate does not always result in complete recovery, and chronic changes can persist 2
• Clinical and radiologic improvement typically occurs within 4 weeks of stopping methotrexate and initiating corticosteroids 3

Prevention and Monitoring

• Enquiry regarding respiratory symptoms should be made at every visit to avoid missing methotrexate-induced pulmonary toxicity 1
• Patients with preexisting lung disease should be informed of their potentially increased risk prior to initiating treatment 8
• When pulmonary symptoms develop, the possibility of Pneumocystis carinii pneumonia should be considered, as this is the most common opportunistic infection in methotrexate-treated patients 2

Other Pulmonary Manifestations

Beyond interstitial pneumonitis, methotrexate can cause:

• Respiratory fibrosis and chronic interstitial obstructive pulmonary disease with prolonged use 2
• Airway hyperreactivity and air trapping 4
• Respiratory failure in severe cases 2

Critical Pitfall to Avoid

Do not assume that long-term tolerance to methotrexate confers immunity from pulmonary toxicity—cases have been documented after 30 years of continuous use, emphasizing that vigilance must be maintained throughout the entire treatment duration 3