Study Confirms Skin Cancer Risk with Methotrexate

February 19, 2020

A double-blind, placebo-controlled, randomized clinical trial has confirmed that low-dose methotrexate is associated with an increased risk of skin cancer, according to a study published this week in the Annals of Internal Medicine.

A double-blind, placebo-controlled, randomized clinical trial has confirmed that low-dose methotrexate is associated with an increased risk of skin cancer, according to a study published this week in the Annals of Internal Medicine.

The study, which was led by David H. Solomon, M.D., MPH, a rheumatologist and clinical scientist at Brigham and Women's Hospital at Harvard Medical School, and, Harvard colleague Paul M. Ridker, M.D., found small to moderate elevations in risks for skin cancer, and gastrointestinal, infectious, pulmonary, and hematologic adverse events. It confirms the findings of previous observational studies on adverse events associated with methotrexate.

Methotrexate is the most commonly used medication for rheumatic conditions. The American College of Rheumatology recommends that it be used as first-line therapy for rheumatoid arthritis and it is also used in combination with biologic agents. It has long been known to be associated with the development of skin cancer and non-Hodgkin's lymphoma.

"We did this study because methotrexate is a widely used drug across the globe. About 5 million people take it weekly for rheumatoid arthritis. Even after three to four decades of its use, we're still a bit uncertain about its side effect profile," Dr. Solomon said in a video news release.

"The story of methotrexate really goes back about three to four decades in rheumatology, but five to six decades overall. It started in pediatric oncology with Dr. Sidney Farber using methotrexate in children with pediatric leukemia. It was found to be very effective. Over the next several decades it moved from dermatology into rheumatology. And, now, fast forward to 2020, we have a randomized, placebo-controlled trial with several thousand patients to better understand the safety of methotrexate," he said.

This study was a secondary analyses of a double-blind, placebo-controlled, randomized trial of adults with cardiovascular disease and diabetes or metabolic syndrome. Methotrexate was not effective in reducing cardiovascular-related inflammation in that study, but the secondary analysis of adverse events confirmed an increased risk of cancer.

It included 6,158 patients of which 4,786 (81.2% male, 65.7 years median age, 31.5 kg/m2 median BMI) were randomly assigned to a group. The median follow-up was 23 months and the median dosage was 15 mg/wk. Each patient also received folic acid, 1 mg per day for six days per week.

Of 2,391 participants assigned to low-dose methotrexate, 2,080 (87.0%) experienced an adverse event compared to 1,951 of 2,395 (81.5%) patients assigned to placebo (hazard ratio [HR], 1.17 [95% CI, 1.10 to 1.25]).

The risk of all-cause adverse events for this well-established treatment was about 30 percent more for patients receiving low-dose methotrexate compared to the placebo group. Liver function abnormality was about two-fold more common in the treatment group; nausea, vomiting and diarrhea was 50 percent more prevalent; pulmonary adverse events of any type were increased; interstitial pneumonitis increased seven-fold in the treatment group and anemia was more common in the treatment group.

With the exception of increased risk for skin cancer (HR, 2.05 [CI, 1.28 to 3.28]), the treatment groups did not differ in risk for other cancer or mucocutaneous, neuropsychiatric, or musculoskeletal AEs. Renal AEs were reduced in the LD-MTX group (HR, 0.85 [CI, 0.78 to 0.93]).

REFERENCE

Solomon DH, Glynn RJ, Karlson EW, et al. "Adverse Effects of Low-Dose Methotrexate: A Randomized Trial,"Annals of Internal Medicine. EPub Feb. 18, 2020. DOI: 10.7326/M19-3369