Methotrexate (MTX) is a folate antagonist used to treat conditions ranging from severe psoriasis and rheumatoid arthritis to certain types of cancer. While effective for managing chronic inflammatory and proliferative diseases, MTX has potential side effects. One serious, though relatively uncommon, adverse effect is pulmonary toxicity, which involves damage or inflammation in the lung tissue. This complication, which can range from mild inflammation to life-threatening respiratory failure, is estimated to occur in about 0.3% to 7.5% of patients taking the drug.
The Mechanism of Methotrexate-Induced Lung Injury
The exact process by which methotrexate causes lung damage is not fully understood, but evidence points toward an immune-mediated or hypersensitivity reaction in most cases. MTX functions by inhibiting the enzyme dihydrofolate reductase, disrupting DNA and RNA synthesis. This mechanism slows the growth of rapidly dividing cells and calms the overactive immune system in autoimmune diseases.
In the lungs, this cellular interference appears to trigger an inflammatory cascade rather than direct, dose-dependent damage, especially at the lower doses used for autoimmune conditions. The resulting inflammation is characterized by an accumulation of immune cells, including lymphocytes, histiocytes, and eosinophils, within the lung tissue. This suggests the immune system is overreacting to the drug or its metabolites, though some evidence also suggests the possibility of direct toxicity to the alveolar epithelial walls.
Types of Pulmonary Complications
Methotrexate-induced pulmonary toxicity encompasses several distinct forms of lung injury. The most frequent complication is Methotrexate Pneumonitis, typically characterized as a subacute hypersensitivity reaction. This involves inflammation of the lung tissue and the interstitium (the space between the air sacs), usually presenting within the first year of starting the medication. Pneumonitis, when identified promptly, is generally reversible and often resolves after the drug is stopped and treatment with corticosteroids is initiated.
Another, less common, but more concerning complication is Pulmonary Fibrosis, which involves the scarring and thickening of the lung tissue. Fibrosis is a chronic condition where the damage becomes permanent, impairing the lungs’ ability to transfer oxygen. While pneumonitis can sometimes progress to a fibrotic stage, the link between long-term, low-dose MTX and the development of chronic pulmonary fibrosis is debated. Rarer manifestations of MTX lung injury include organizing pneumonia and the development of pulmonary nodules.
Identifying Symptoms and When to Seek Help
Recognizing the symptoms of methotrexate-induced lung injury is challenging because they are often vague and can mimic other common conditions, such as a respiratory infection or a flare-up of the underlying disease. The most characteristic symptoms are a persistent, non-productive dry cough and increasing shortness of breath (dyspnea). These respiratory complaints are often accompanied by systemic symptoms like fever, fatigue, and malaise.
These symptoms may develop suddenly, but more typically they have an insidious, progressive onset over several weeks. Patients must contact their prescribing physician immediately if any new or worsening respiratory symptoms appear. If symptoms include severe difficulty breathing, emergency medical care should be sought immediately. A clinician will likely perform a chest X-ray and possibly a CT scan to look for characteristic findings like ground-glass opacities, and will rule out infection. If MTX lung toxicity is suspected, the drug will be temporarily discontinued, and high-dose corticosteroids may be administered to reduce inflammation in severe cases.
Risk Factors and Monitoring Protocols
While pulmonary toxicity is a risk for anyone taking methotrexate, certain patient characteristics increase the probability of developing the complication. Individuals with a pre-existing lung condition, such as prior pulmonary involvement from rheumatoid arthritis, face a higher risk. Other associated factors include older age, the presence of diabetes, and low serum albumin levels. Unlike some other drug toxicities, the risk of developing lung injury is generally not correlated with the weekly dose or the total amount of methotrexate received over time, especially in low-dose regimens.
To proactively manage this risk, healthcare providers often recommend baseline testing before starting MTX therapy. This typically includes a chest X-ray and sometimes Pulmonary Function Tests (PFTs) to establish a benchmark of lung health. Routine, long-term monitoring with serial PFTs or chest imaging is not universally recommended due to the unpredictable nature of the hypersensitivity reaction. Regular clinical assessment remains the standard of care, and patients are educated about potential symptoms so they can report them quickly, allowing for timely investigation and cessation of the drug if toxicity is suspected.