Low-Dose Methotrexate Associated With Increased Risk for Certain Adverse Events

Researchers investigated rates, risk, and risk differences of adverse events in patients receiving low-dose methotrexate compared with placebo.

Low-dose methotrexate use may be associated with increased risk for gastrointestinal, infectious, pulmonary, and hematologic adverse events, as well as skin cancer, according to study results published in Annals of Internal Medicine.1

Low-dose methotrexate has been previously associated with a number of toxicities, but a detailed analysis of adverse effects related to its use has been lacking. In this prespecified secondary analysis of the randomized placebo-controlled Cardiovascular Inflammation Reduction Trial (CIRT; ClinicalTrials.gov Identifier: NCT01594333), investigators evaluated the rates of adverse events associated with low-dose methotrexate use.

Study participants had a diagnosis of cardiovascular disease and metabolic syndrome or diabetes and underwent an initial active run-in period in which they received low-dose methotrexate. Participants who completed the run-in period were randomly assigned 1:1 to receive oral low-dose methotrexate (maximum, 20 mg/wk) or placebo. During the 5-year follow-up, adverse events — adjudicated by appropriate medical professionals — were recorded and classified as gastrointestinal, pulmonary, infectious, hematologic, malignant, mucocutaneous, renal, neuropsychiatric, or musculoskeletal.

Of the 4786 patients in this analysis, 2391 received low-dose methotrexate (19.3% women) and 2395 received placebo (18.2% women). Any adjudicated adverse events occurred in 87.0% of low-dose methotrexate users and 81.5% of participants receiving placebo (hazard ratio [HR], 1.17; 95% CI, 1.10-1.25).

Patients who received low-dose methotrexate vs placebo were at increased risk for gastrointestinal (HR, 1.23; 95% CI, 1.03-1.47), pulmonary (HR, 1.42; 95% CI, 1.14-1.77), infectious (HR, 1.15; 95% CI, 1.01-1.30), and hematologic (HR, 1.22; 95% CI, 1.11-1.34) events. Risks for anemia (HR, 1.36; 95% CI, 1.22-1.52) and leukopenia (HR, 1.46; 95% CI, 1.19-1.80) were also elevated in participants receiving low-dose methotrexate vs placebo.

Although there was no significant difference in the risk for cancer overall between treatment groups, participants who received low-dose methotrexate vs placebo were at increased risk for squamous cell skin cancer (HR, 3.31; 95% CI, 1.63-6.71). No difference in risk was observed for any other malignant, mucocutaneous, neuropsychiatric, or musculoskeletal events. However, risk for renal events was lower in low-dose methotrexate users compared with those who received placebo (HR, 0.85; 95% CI, 0.78-0.93).

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“The data presented here provide an important source of new evidence to improve the monitoring guidelines and safe prescribing of LD-MTX,” noted the investigators. “[Low-dose methotrexate] users had increased risk for any [adverse events], as well as for hematologic, skin cancer, gastrointestinal, liver, infectious, and pulmonary [adverse events].” However, investigators also noted that patients enrolled in CIRT did not have systemic rheumatic disease, which may limit the generalizability of results to patients with rheumatic disease.1

In an accompanying editorial, Vivian P. Bykerk, MD, associate attending rheumatologist at the Hospital for Special Surgery and associate professor of medicine, Weill Cornell Medical College in New York City, New York echoed these concerns, noting that “[p]atients with [rheumatoid arthritis] differ from the CIRT participants in that they are younger, are predominantly women, and have lower rates of diabetes and obesity.”2 However, Dr Bykerk also noted that the results of this work “[remind] us that [methotrexate] use has inherent risks and warrants vigilance for symptomatic, laboratory, and infrequent but clinically serious [adverse events].”

Disclosure: Several authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of disclosures.


  1. Solomon DH, Glynn RJ, Karlson EW, et al. Adverse effects of low-dose methotrexate: A randomized trial [published online February 18, 2020]. Ann Intern Med. doi:10.7326/M19-3369
  2. Bykerk VP. A call to systematically monitor for adverse events in users of low-dose methotrexate therapy [published online February 18, 2020]. Ann Intern Med. doi:10.7326/M20-0435

This article originally appeared on Rheumatology Advisor