Low-Dose Methotrexate Associated With Small Increase in Adverse Events

February 26, 2020

Use of low-dose methotrexate is associated with small to moderate elevations in risks for skin cancer and gastrointestinal, infectious, pulmonary, and haematologic adverse events, according to a study published in the Annals of Internal Medicine.

Methotrexate is the most commonly used drug for systemic rheumatic diseases worldwide, however, robust data on the rates of side effects of the drug are lacking. Observational studies have suggested that methotrexate may elevate a person’s risk of a variety of adverse events, including liver toxicity, anaemia, and difficulty breathing, but the magnitude of risk has been unknown.

“Methotrexate is a cornerstone drug for a variety of inflammatory diseases, especially for rheumatoid arthritis,” said Daniel H. Solomon, MD, Brigham and Women’s Hospital, Boston, Massachusetts. “Over the decades, we have learned about the side effects but only from small studies. Questions for both physicians and patients have lingered about the drug’s safety. Our study offers a detailed side effect profile that I think will help us prescribe methotrexate in an informed way.”

To determine the rates of adverse events for people taking methotrexate, Dr. Solomon and colleagues looked at data on 4,786 individuals who were randomised to receive low-dose methotrexate (≤20 mg weekly) with folate (1 mg daily, 6 days per week) or a placebo.

The researchers found that of the 2,391 participants assigned to low-dose methotrexate, 87% had an adverse event of interest compared with 81.5% of those assigned to placebo (hazard ratio [HR] = 1.17; 95% confidence interval [CI], 1.10-1.25).

The relative hazards of gastrointestinal (HR = 1.91; 95% CI, 1.75-2.10), pulmonary (HR = 1.52; 95% CI, 1.16-1.98), infectious (HR = 1.15; 95% CI, 1.01-1.30), and haematologic (HR = 1.15; 95% CI, 1.07-1.23) adverse events were elevated for low-dose methotrexate versus placebo.

According to Dr. Solomon, the most surprising finding was a doubling of risk of skin cancer for participants taking methotrexate (HR = 2.05; 95% CI, 1.28-3.28). This result may be particularly important because patients with psoriatic arthritis are already at increased risk of skin cancer.

The treatment groups did not differ in risk for other cancer or mucocutaneous, neuropsychiatric, or musculoskeletal adverse events, and renal adverse events were reduced in the low-dose methotrexate group (HR = 0.85; 95% CI, 0.78-0.93).

“We now have real numbers we can share with patients when talking about side effects,” concluded Dr. Solomon. “We definitely would not suggest this drug is too dangerous to give, but having a clear side effect profile allows us to [prescribe] it with eyes wide open and better balances the risks and benefits of an age-old drug.”

Reference: http://doi.org/10.7326/M19-3369

SOURCE: Brigham and Women’s Hospital