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You are here: Home / Articles / Low-Dose Methotrexate Can Cause Adverse Effects

Low-Dose Methotrexate Can Cause Adverse Effects

February 19, 2020 • By Will Boggs, MD

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NEW YORK (Reuters Health)—Low-dose methotrexate can be associated with gastrointestinal, pulmonary, infectious, hematologic and other adverse effects, according to an analysis of the Cardiovascular Inflammation Reduction Trial (CIRT).

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“Methotrexate is not a benign drug, even at dosages used for rheumatic diseases,” Daniel H. Solomon, MD, MPH of Brigham and Women’s Hospital, Boston, tells Reuters Health by email. “However, the currently understood side effect profile is relatively accurate. Laboratory monitoring plays a useful role.”

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Low-dose methotrexate has been associated with many toxicities during its decades of clinical use. Observational data have also suggested associations with certain cancers.

In CIRT, patients with cardiovascular disease and either type 2 diabetes or metabolic syndrome who tolerated low-dose methotrexate (up to 20 mg/week) during a run-in period were randomly assigned to continue on it or receive placebo instead. To evaluate toxicities from the drug, Dr. Solomon and colleagues conducted a prespecified secondary analysis of the resulting data.

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In the study, 2,391 participants were assigned to low-dose methotrexate and 2,395 to placebo. Everyone also received folic acid supplementation.

During follow up (median: 23 months), the relative rate of an adverse effect of interest was 17% higher for those assigned to methotrexate.

Compared with placebo, low-dose methotrexate (median dosage: 15 mg/week) was associated with 23% higher risk of gastrointestinal adverse effects, 42% higher risk of pulmonary adverse effects, 15% higher risk of infectious adverse effects and 22% higher risk of hematologic adverse effects, all significant increases.

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Low-dose methotrexate was associated with a 2.04-fold increased risk of skin cancer, also a significant increase, although the absolute risk was low (2.2% with low-dose methotrexate vs. 1.1% with placebo), researchers report in Annals of Internal Medicine.1

There were five cases of cirrhosis in the low-dose methotrexate group vs. none in the placebo group. All patients who developed cirrhosis had diabetes and three had metabolic syndrome. All cases had at least one liver test abnormality (none of them severe) before the diagnosis of cirrhosis.

Six patients (0.3%) in the methotrexate group had possible pneumonitis, compared with one patient (0.04%) in the placebo group, but there was insufficient evidence to determine whether their cases could be considered probable or definite.

Renal adverse effect rates were 15% lower in the low-dose methotrexate group, driven primarily by trends in estimated glomerular filtration rate.

The findings “should better inform decision making between patients and clinicians,” Dr. Solomon says. “We have many effective treatments for rheumatoid arthritis, and now we know more about the safety of methotrexate. This facilitates a more informed discussion between patients and clinicians.”

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Filed Under: DMARDs & Immunosuppressives, Drug Updates Tagged With: adverse events, Methotrexate

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