Low-dose Methotrexate May Lower Comorbidity Risk in Rheumatic Disease


Patients with rheumatic disease are at higher risk for skin cancer, gastrointestinal infectious, pulmonary disease, and hematologic conditions. A new study finds that taking low-dose methotrexate may lower the risk of developing these conditions.


Low-dose methotrexate is associated with a small to moderate increased risk of skin cancer, infections and gastrointestinal, pulmonary and hematologic adverse events, a large placebo-controlled trial has confirmed, but not any greater risk of renal adverse events.

While low-dose methotrexate is the first-line treatment for rheumatoid arthritis and the drug has been used for the condition for more than 30 years, data on the side-effect profile at low doses has been lacking. These decades of experience have indicated that low dose methotrexate is associated with a wide variety of adverse events, but few data on specific risks and their ratees have come from randomized, placebo-controlled trials of low doses of the drug. Those trials that have taken place have tended to be small, short in duration and not involved prescription of folic acid. Routine prescription of folic acid alongside methotrexate has been the norm since the 1990s.

Data on adverse events has also come from adverse event reporting, observational studies and studies looking at use of much higher doses of methotrexate than used for rheumatoid arthritis, including for cancer and transplant patients.

The latest data on use of low doses comes from the CIRT (Cardiovascular Inflammation Reduction Trial), which is a more recent placebo-controlled trial that assessed the potential for low dose methotrexate to reduce cardiovascular events and deaths. The trial was never completed, because it was halted in April 2018 because it failed to achieve its primary outcomes, so researchers at Brigham and Women's Hospital, Boston accessed the data and analysed the adverse events reported.

Dr Daniel H. Solomon, Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Boston, said: “This was a very large placebo controlled trial with excellent follow up for adverse events. Those aspects of our study are unlike prior investigations.”

CIRT began enrolling patients in April 2013. After a 5-8 week run in period, where all patients received low dose methotrexate uptitrated from 5 to 15 mg/week, patients were randomly assigned to receive either oral low dose methotrexate (15mg to 20mg) or placebo. Patients in the active treatment were given methotrexate on one day per week and 1mg folic acid on the other six days.

A total of 4786 patients were randomised and followed for a median of 23 months.

The analysis of the adverse events data, published in the Annals of Internal Medicine, show that patients taking low dose methotrexate were 17% more likely to have an adverse event of interest.[i] Of the 2391 participants in the low dose methotrexate group, 2156 (90.2%) had an adverse event and 2080 (87.0%) had an adverse event of interest, in comparison2076 of the 2395 patients in the placebo group(86.7%) had an adverse event and the event was of interest in 1951 patients (81.5%).

Patients treated with low-dose methotrexate were more likely to have gastrointestinal, pulmonary and hematologic adverse events and infections than the placebo group (at 23%, 42%, 22% and 15% greater risk respectively). And while the overall risk of cancer did not differ between the two groups, patients prescribed low dose methotrexate had double the risk of skin cancer, in particular the risk of squamous cell skin cancer which was more than trebled.

Adverse hepatic effects were also more common in the low dose methotrexate group with five cases of cirrhosis (0.11 cases per 100 person years) recorded in patients given the drug compared to none in the placebo group.

There were 15% fewer renal adverse events were reported in the low dose methotrexate group compared with than the placebo group

Dr Solomon said that the high incidences of skin cancer and the low risk of renal events were particularly surprising. “While immunosuppressive use has been associated with skin cancer in transplant populations, the data around methotrexate at low doses was less clear, so that was one surprise. We also found no risk of renal toxicity. The data around renal toxicity and low dose methotrexate has been mixed so this was very reassuring.

“Finally the risk associated with hematologic toxicity was very low. Reductions in hemoglobin and white blood cell count were real but very small.”

The key message for rheumatologists using methotrexate for their patients is that low-dose methotrexate users experience frequent minor side effects but only rarely have more serious toxicities, he said. “The potential is real and needs to be monitored, especially liver issues. We found some cases of cirrhosis with very minor elevations in liver tests, so clinicians need to take liver test abnormalities that are chronic very seriously.”



Solomon DH, Glynn RJ, Karlson EW, et al. "Adverse Effects of Low-Dose Methotrexate: A Randomized Trial." Ann Intern Med. 2020;172(6):369-380. doi:10.7326/M19-3369

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