Methotrexate-induced lung injury
- Robert A Balk, MD
Robert A Balk, MD
- Professor of Medicine
- Rush-University Medical Center
- Section Editors
- Kevin R Flaherty, MD, MS
Kevin R Flaherty, MD, MS
- Section Editor — Interstitial Lung Disease
- Associate Professor of Medicine
- University of Michigan Health System
- James R Jett, MD
James R Jett, MD
- Section Editor — Lung Cancer
- Professor of Medicine Emeritus
- National Jewish Health
- Deputy Editors
- Helen Hollingsworth, MD
Helen Hollingsworth, MD
- Deputy Editor — Pulmonary, Critical Care, and Sleep Medicine
- Associate Professor of Medicine
- Boston University School of Medicine
- Diane MF Savarese, MD
Diane MF Savarese, MD
- Senior Deputy Editor — UpToDate
- Deputy Editor — Oncology and Palliative Care
- Clinical Instructor of Medicine
- Harvard Medical School
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 low-dose 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 (as is typically used for non-malignant disease), but can occur following relatively short term use of intravenous or intrathecal administration of higher doses [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 . Many 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 [14-22]. On the other hand, others suggest that rates are much lower because not all cases of pneumonitis occurring in patients treated with methotrexate are directly attributable to the drug. The following examples show the frequency of pneumonitis among patients who received methotrexate for rheumatoid arthritis or other inflammatory diseases:
●In a systematic literature review of 3463 patients with rheumatoid arthritis who were receiving methotrexate, 84 patients (2 percent) had some type of lung toxicity, but only 15 were felt to be definitive cases of pneumonitis attributable to methotrexate (0.43 percent) . The mean duration of methotrexate use was 36.5 months and the average dose was 8.8 mg/week.
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- PATHOGENESIS AND PATHOLOGY
- Inflammatory and fibrotic lung disease
- Pulmonary infections
- Pulmonary lymphoproliferative disease
- RISK FACTORS
- CLINICAL MANIFESTATIONS
- DIFFERENTIAL DIAGNOSIS
- DIAGNOSTIC EVALUATION
- Laboratory testing
- Pulmonary function testing
- Lung biopsy
- Making the diagnosis
- Initial management
- SUMMARY AND RECOMMENDATIONS
- Clinical manifestations and diagnostic evaluation