Methotrexate lung disease

Methotrexate lung disease is a specific aetiological 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.

Epidemiology

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

Clinical presentation

The typical clinical symptoms include progressive shortness of breath and cough, often associated with fever ⁶. Hypoxaemia and tachypnoea 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.

Pathology

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

• non-immunosuppresive

  • methotrexate-induced pneumonitis: 1% of rheumatoid arthritis patients starting methotrexate ¹⁰. NSIP pattern and granuloma formation

  • pleural effusion / pleuritis ¹⁵ but also reported in rheumatoid arthritis in general ¹⁴

  • organising pneumonia: has been associated with methotrexate use but can also occur in the setting of new diagnosis rheumatoid arthritis ¹³

  • ARDS

• immunosupressive

  • superimposed pulmonary infection ¹⁰

  • pulmonary lymphoproliferative disease ¹⁶

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.

Radiographic features

CT

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.

Treatment and prognosis

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.

Differential diagnosis

• rheumatoid arthritis associated interstitial lung disease ¹⁰

  • more common

  • fibrotic pattern

• non-fibrotic hypersensitivity pneumonitis ¹⁰

See also

• pulmonary manifestations of rheumatoid arthritis