Drug-induced pneumonitis: the role of methotrexate

Methotrexate (MTX) is a folate antagonist used in several chronic inflammatory and neoplastic conditions. Pulmonary toxicity occurs in 0.5% to 14% of patients receiving low-dose MTX. Manifestations of pulmonary toxicity are protean and include parenchymal inflammation, pneumonia, airway hyperreactivity, air trapping and possibly neoplasm. We performed an exhaustive review of the English literature and identified 189 cases of methotrexate-induced pneumonitis (MIP). Rheumatoid arthritis (RA) was the most frequent underlying disease. In most patients, symptoms present subacutely with progression over several weeks. Most patients present with dyspnea, dry cough, fever, and bibasilar crackles. Peripheral eosinophilia has been cited in one third of cases. The chest radiograph may be normal, but more commonly reveals bilateral interstitial or mixed, interstitial and alveolar infiltrates with a predilection for the bases. Chest computed tomography (CT) scans demonstrate ground-glass opacities, interstitial infiltrates, septal lines or widespread consolidation. Pulmonary function studies reveal a restrictive ventilatory defect and/or impaired gas exchange. Bronchoalveolar lavage (BAL) may be helpful in ruling out an infectious etiology and in supporting the diagnosis of MIP. Cellular interstitial infiltrates, granulomas, fibrosis, atypical epithelial cells, and diffuse alveolar damage (DAD) are the main histologic features. Once MIP is suspected, the MTX should be withdrawn. Corticosteroids may accelerate resolution and are recommended in severe or fulminant cases. The prognosis of MIP is usually favorable, but occasionally the outcome may be fatal.