Methotrexate is an analogue of the vitamin folic acid; it inhibits cellular proliferation by inducing an acute intracellular deficiency of certain folate coenzymes (figure 1) [1-3]. This impairs the intracellular trafficking of single carbon groups and results in impaired synthesis of thymidine, deoxyribonucleic acid (DNA), and ribonucleic acid (RNA) [1,4]. In addition to its antiproliferative effects, methotrexate has antiinflammatory and immunomodulating properties [2,3,5-7]. It is used to treat a variety of malignancies, connective tissue diseases, and also psoriasis. Serious toxicity from methotrexate may affect the lungs, liver, and bone marrow [1,2,8-11].
This topic review will review the pulmonary injury that may result from methotrexate use. Other side effects of methotrexate therapy and an approach to pulmonary toxicity associated with antineoplastic agents are discussed separately. (See "Major side effects of low-dose methotrexate" and "Hepatotoxicity associated with chronic oral methotrexate for nonmalignant disease" and "Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation, diagnosis, and treatment" and "Therapeutic use and toxicity of high-dose methotrexate", section on 'Overview of adverse effects' and "Use of methotrexate in the treatment of rheumatoid arthritis", section on 'Mechanism of action'.)
Lung toxicity most often occurs after weeks to months of low-dose oral methotrexate therapy, but can occur following relatively short term use of intravenous or intrathecal high-dose administration [10,12-14]. In a literature review of 123 cases of methotrexate pneumonitis, about one-half arose in patients receiving therapy for rheumatoid arthritis (range 2.5 to 15 mg weekly), about 20 percent arose during intensification/consolidation treatment for leukemia (doses approximately 20 to 80 mg weekly), and 8 percent were in patients treated for other malignancies (weekly doses ranging from 15 to 1400 mg) (table 1) .
The precise frequency with which methotrexate pulmonary toxicity occurs is difficult to assess as some reports have included patients who were receiving other cytotoxic medications, had ongoing infectious diseases, or had underlying disease processes capable of involving the lungs and pleura . In addition, impure preparations of methotrexate may have played a role in some of the earlier reports of toxicity . Most series estimate that acute pulmonary toxicity develops in 1 to 8 percent of patients receiving methotrexate for rheumatologic condition, including rheumatoid arthritis, but some reports suggest an incidence as high as 33 percent [11,14-25]. Whether all of these cases are attributable to methotrexate is unclear. In a systematic literature review of 3463 patients with rheumatoid arthritis who were receiving methotrexate, there were 84 reported cases of pneumonitis, only 15 of which were felt to be directly attributable to methotrexate (incidence 0.43 percent) .
PATHOGENESIS AND PATHOLOGY
Pulmonary complications of methotrexate may be classified as inflammatory, infectious, and lymphoproliferative .