Methotrexate Increases Risk of Adverse Events Compared with Placebo

Daniel Solomon, MD, MPH

Investigators found associations between methotrexate and small-to-moderate elevations in risks for skin cancer, gastrointestinal, infectious, lung, and blood adverse events, according to new findings of a prespecified secondary analyses of a double-blind, placebo-controlled, randomized trial.

Conversely, renal adverse events were decreased.

Daniel Solomon, MD, MPH, and a team of investigators analyzed data from more than 4700 patients in the Cardiovascular Inflammation Reduction Trial (CIRT) to determine rates of adverse events for patients taking methotrexate, the most commonly used drug for systemic rheumatic diseases worldwide. The team compared the difference between methotrexate and placebo.

Solomon, a rheumatologist in the Division of Rheumatology, Inflammation and Immunology at Brigham and Women’s Hospital, used the randomized CIRT cohort as the primary study population in addition to participants from the active low dose methotrexate run-in phase. Eligible patients were required to have had a known myocardial infarction or multi-vessel obstructive coronary artery disease, along with type 2 diabetes or metabolic syndrome. The patients included did not have rheumatoid arthritis or other rheumatic diseases.

Patients who met the criteria entered into an active run-in period of 5-8. During this time, all participants were given low dose methotrexate. The dose increased from 5-15 mg per week during the period. Each patient was seen after 2-3 weeks to be assessed for possible adverse events and a laboratory assessment at the end of the timeframe to determine the patient’s tolerability of the drug.

Participants who had limited adverse evets and sufficient adherence to the drug were randomly assigned to receive either oral low dose methotrexate or placebo. The weekly dosage was 15 mg on 1 day per week and 1 mg of folic acid on the 6 other days. After 16 weeks, dosage was upped to 20 mg per week.

The investigators identified adverse events of interest, which were identified from routine visit and adverse event case report forms, reasons given by the site for a temporary or permanent withdrawal of the study drug, and central laboratory monitoring values. Adverse events included gastrointestinal; pulmonary; infectious; hematologic; malignant; mucocutaneous; renal; neuropsychiatric; and musculoskeletal.

Among the 2391 patients randomized to the methotrexate group, 2156 (90.2%) had an adverse event and 2080 (87%) had an adverse event of interest. In the placebo group of 2395 patients, 2076 (86.7%) had an adverse event and 1951 (81.5%) had an event of interest. The rate of an adverse event of interest was 17% higher for those who took the drug (HR, 1.17; 95% CI, 1.1-1.25) compared with placebo.

Relative rates of gastrointestinal (HR, 1.23; CI, 1.03-1.47), pulmonary (HR, 1.42; CI, 1.14-1.77), infectious (HR, 1.15; CI, 1.01-1.30), and hematologic (HR, 1.22; CI, 1.11-1.34) adverse events were higher for patients who took low dose methotrexate compared to placebo. The groups did not differ in risk for overall cancer, but 53 patients (2.2%) in the methotrexate group and 26 (1.1%) in the placebo group had skin cancer (HR, 2.04; 95% CI, 1.28-3.26).

Hepatic pathology was more common in the drug group, and 5 cases of cirrhosis were seen in the primary, modified analysis (rate, .11 cases; CI, .01-.2 cases) per 100 person-years vs none in the placebo group; P = .032).

The results can be shared with patients when talking about side effects, Solomon said.

“We definitely wouldn’t suggest this drug is too dangerous to give,” he said in a statement. “But having a clear side-effect profile allows us to give it with eyes wide open and better balances the risks and benefits of an age-old drug.”

The study, “Adverse Effects of Low-Dose Methotrexate,” was published online in the journal Annals of Internal Medicine.