NEW YORK (Reuters Health)—Low-dose methotrexate can be associated with gastrointestinal, pulmonary, infectious, hematologic and other adverse effects, according to an analysis of the Cardiovascular Inflammation Reduction Trial (CIRT).
“Methotrexate is not a benign drug, even at dosages used for rheumatic diseases,” Daniel H. Solomon, MD, MPH of Brigham and Women’s Hospital, Boston, tells Reuters Health by email. “However, the currently understood side effect profile is relatively accurate. Laboratory monitoring plays a useful role.”
Low-dose methotrexate has been associated with many toxicities during its decades of clinical use. Observational data have also suggested associations with certain cancers.
In CIRT, patients with cardiovascular disease and either type 2 diabetes or metabolic syndrome who tolerated low-dose methotrexate (up to 20 mg/week) during a run-in period were randomly assigned to continue on it or receive placebo instead. To evaluate toxicities from the drug, Dr. Solomon and colleagues conducted a prespecified secondary analysis of the resulting data.
In the study, 2,391 participants were assigned to low-dose methotrexate and 2,395 to placebo. Everyone also received folic acid supplementation.
During follow up (median: 23 months), the relative rate of an adverse effect of interest was 17% higher for those assigned to methotrexate.
Compared with placebo, low-dose methotrexate (median dosage: 15 mg/week) was associated with 23% higher risk of gastrointestinal adverse effects, 42% higher risk of pulmonary adverse effects, 15% higher risk of infectious adverse effects and 22% higher risk of hematologic adverse effects, all significant increases.
Low-dose methotrexate was associated with a 2.04-fold increased risk of skin cancer, also a significant increase, although the absolute risk was low (2.2% with low-dose methotrexate vs. 1.1% with placebo), researchers report in Annals of Internal Medicine.1
There were five cases of cirrhosis in the low-dose methotrexate group vs. none in the placebo group. All patients who developed cirrhosis had diabetes and three had metabolic syndrome. All cases had at least one liver test abnormality (none of them severe) before the diagnosis of cirrhosis.
Six patients (0.3%) in the methotrexate group had possible pneumonitis, compared with one patient (0.04%) in the placebo group, but there was insufficient evidence to determine whether their cases could be considered probable or definite.
Renal adverse effect rates were 15% lower in the low-dose methotrexate group, driven primarily by trends in estimated glomerular filtration rate.
The findings “should better inform decision making between patients and clinicians,” Dr. Solomon says. “We have many effective treatments for rheumatoid arthritis, and now we know more about the safety of methotrexate. This facilitates a more informed discussion between patients and clinicians.”
“The current treatment paradigm for rheumatoid arthritis should not change based on these data,” he adds.
Shaye Kivity, MD, of The Chaim Sheba Medical Center, Ramat-Gan, Israel, who has studied the toxicity of low-dose methotrexate used in systemic inflammatory disease, says the new research “emphasizes the need for tight surveillance in patients treated with methotrexate. Yet it should be noted that the patients in this study were not the same patients we treat in our daily practice with methotrexate. We treat patients with immune-mediated rheumatic disease, and they benefit from immunosuppression.”
“Clinicians should be encouraged to continue to use methotrexate, and patients should not be intimidated,” he tells Reuters Health by email. “Under the supervision of an experienced clinician and careful monitoring, life-threatening adverse effects are exceedingly rare.”
“Symptomatic adverse effects that are often most concerning to patients with rheumatoid arthritis and inflammatory arthritis include alopecia, nausea, malaise, and diarrhea,” writes Vivian P. Bykerk, MD, of the Hospital for Special Surgery and Weill Cornell Medical College, New York, in a linked editorial.2 “Given their subjective nature, these were not separately addressed in this study. Over 3 decades of methotrexate use in rheumatoid arthritis and inflammatory arthritis, strategies to minimize these effects also include coprescription of folinic acid, split methotrexate dosing and switching to parenteral methotrexate.”
“These data provide objective estimates of risk for adverse effects, reminding us that methotrexate use has inherent risks and warrants vigilance for symptomatic, laboratory, and infrequent but clinically serious adverse effects—particularly skin cancer and hepatic, pulmonary, and hematologic toxicity,” she says. “The authors of this preplanned safety analysis from the CIRT study should be commended for providing estimates of adverse effects that can inform improved systematic monitoring of patients using methotrexate.”
References
- Solomon DH, Glynn RJ, Karlson EW, et al. Adverse effects of low-dose methotrexate: A randomized trial. Ann Intern Med. 2020 Feb 18. [Epub ahead of print]
- Bykerk VP. A call to systematically monitor for adverse events in users of low-dose methotrexate therapy. Ann Intern Med. 2020 Feb 18. [Epub ahead of print]
