The long-term administration of low-dose methotrexate (MTX) to treat autoimmune disorders can be associated with the risk of serious, and potentially irreversible, side effects, including chronic hepatotoxicity or pulmonary fibrosis.
Hepatic and pulmonary side effects after the long-term administration of low-dose methotrexate
Incident data |
Description |
|---|---|
| Year: 2010 Age group: elderly Sex: female Active substance: Methotrexate (MTX) Indication: Rheumatoid arthritis ADR: Pulmonary fibrosis Latency period: ~ 13 years Outcome: Not recovered, recovering |
An elderly female patient with rheumatoid arthritis and type 2 non-insulin-dependent diabetes mellitus was treated with MTX (10 mg up to max. 20 mg once a week). After taking this treatment for 13 years, she developed breathing difficulties, which ultimately led to the diagnosis of pulmonary fibrosis. The MTX was stopped. As well as a possible side effect of the MTX treatment, an extra-articular organ manifestation of rheumatoid arthritis was also considered in the differential diagnosis. |
| Year: 2010 Age group: elderly Sex: female Active substance: Methotrexate (MTX) Indication: Rheumatoid arthritis ADR: Liver cirrhosis, pulmonary fibrosis Latency period: ~ 12 years Outcome: Not recovered (both ADRs) |
During a hospital stay due to a fall, a CT scan revealed incidental findings of pulmonary fibrosis, liver cirrhosis with signs of portal hypertension, and partial portal vein thrombosis. The elderly patient had been taking MTX for about 12 years for rheumatoid arthritis (10 mg once a week, cumulative dose > 6 g). The MTX was discontinued, whereupon the elevated liver enzyme levels returned to normal. After an extensive diagnostic process (history of tuberculous pleuritis, evidence of restrictive syndrome with severe hypoxaemia, endoscopic evidence of oesophageal varices, exclusion of hepatitis B / C), the most likely diagnosis was assumed to be methotrexate-associated hepatotoxicity and pulmonary toxicity. |
Summary and recommendation
MTX-induced acute or chronic lung disease and pleural effusion, can occur acutely at any stage of the treatment and have been reported even at doses as low as 7.5 mg per week. These conditions were not always fully reversible, and fatal cases have been reported. In the event of typical symptoms, such as a dry, irritating cough, immediate discontinuation of treatment and careful investigation should be considered [1].
An MTX-associated chronic hepatotoxicity usually occurs after prolonged administration (≥ two years) and a cumulative total dose ≥ 1.5 g. The risk is influenced by factors such as excessive alcohol consumption, obesity, diabetes mellitus, long-term treatment, age (> 60 years), renal insufficiency and pre-existing liver disease [1]. Since histological changes, fibrosis and more rarely liver cirrhosis may not be preceded by abnormal liver function tests, non-invasive diagnostic methods should also be considered for monitoring purposes [1]. US guidelines recommend non-invasive fibrosis testing at the start of treatment and then annually for patients with risk factors [2].
The administration of folic or folinic acid (at the earliest 24 hours after MTX administration) can significantly reduce the incidence of toxic methotrexate-induced gastrointestinal, haematological and hepatic side effects in patients with autoimmune diseases [3, 4]. However, folic acid administration has no effect on the pulmonary side effects [5].
Statutory duty of healthcare professionals to report adverse drug reactions (ADRs)
In Switzerland, healthcare professionals who are authorised to dispense or administer medicinal products are obligated to report severe and/or previously unknown side effects. Reports to Swissmedic can be entered and sent in the Electronic Vigilance Reporting Portal “ElViS” (ElViS login).
References
- [1] Product information for Jylamvo® (AIPS – individual search)
- [2] Fontana, R. J., Liou, I., Reuben, A., Suzuki, A., Fiel, M. I., Lee, W., & Navarro, V. (2023). AASLD practice guidance on drug, herbal, and dietary supplement-induced liver injury. Hepatology (Baltimore, Md.), 77(3), 1036–1065. https://doi.org/10.1002/hep.32689
- [3] Liu, L., Liu, S., Wang, C., Guan, W., Zhang, Y., Hu, W., Zhang, L., He, Y., Lu, J., Li, T., Liu, X., Xuan, Y., & Wang, P. (2019). Folate Supplementation for Methotrexate Therapy in Patients With Rheumatoid Arthritis: A Systematic Review. Journal of clinical rheumatology : practical reports on rheumatic & musculoskeletal diseases, 25(5), 197–202. https://doi.org/10.1097/RHU.0000000000000810
- [4] Shea, B., Swinden, M. V., Tanjong Ghogomu, E., Ortiz, Z., Katchamart, W., Rader, T., Bombardier, C., Wells, G. A., & Tugwell, P. (2013). Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis. The Cochrane database of systematic reviews, 2013(5), CD000951. https://doi.org/10.1002/14651858.CD000951.pub2
- [5] Onda, K., Honma, T., & Masuyama, K. (2023). Methotrexate-related adverse events and impact of concomitant treatment with folic acid and tumor necrosis factor-alpha inhibitors: An assessment using the FDA adverse event reporting system. Frontiers in pharmacology, 14, 1030832. https://doi.org/10.3389/fphar.2023.1030832
Reporting adverse drug reactions
Electronic reports via the ElVis portal
Note for marketing authorisation holders
If articles in this section refer to individual cases, these cases are already recorded in the Swiss spontaneous reporting system and have been transmitted to all responsible institutions. We ask affected marketing authorisation holders not to report these cases again (“back report”) to Swissmedic.