Methotrexate lung disease

Last revised by Liz Silverstone on 26 Jul 2023

Methotrexate lung disease is a specific etiological type of drug-induced lung disease. It can occur due to the administration of methotrexate, which is an antimetabolite, commonly prescribed to treat rheumatoid arthritis. It is also given alone or in combination with other chemotherapeutic agents to treat a wide variety of malignancies including lung, breast, and head and neck epidermoid cancers, non-metastatic osteosarcoma, and advanced-stage non-Hodgkin lymphoma.

It is thought to occur in ~5% (range 0.3-10%) of patients treated with methotrexate 1-2.

The typical clinical symptoms include progressive shortness of breath and cough, often associated with fever 6. Hypoxemia and tachypnea are always present and crackles are frequently audible. Symptoms typically manifest within months of starting therapy). There appears to be no correlation between the development of drug toxicity and the duration of therapy or total cumulative dose) 1. Anaphylaxis and anaphylactoid reactions are reported.

There can be several manifestations of methotrexate-related lung changes:

Previously, methotrexate was thought to cause pulmonary fibrosis, however, more recent evidence (c. 2021) has not established a causative effect 10-12.

BAL may show an excess proportion of lymphocytes.

CT features can be variable and included diffuse parenchymal opacification, reticular opacities, and centrilobular nodules 2. An NSIP pattern is considered the most common manifestation of methotrexate-induced lung disease 1.

Overall prognosis would depend on the exact form of the disease. In general, the prognosis is considered good, with most patients improving despite the continuation of therapy. Patients with lung fibrosis at presentation may have worse prognosis 2.

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Cases and figures

  • Case 1: NSIP
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  • Case 2: obliterative bronchiolitis
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  • Case 3: hypersensitivity pneumonitis
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