In the Journals

Low-dose methotrexate linked to skin cancer, various adverse events

Photo of Daniel H. Solomon
Daniel H. Solomon

Low-dose methotrexate — the most commonly used drug for systemic rheumatic diseases — was associated with small to moderate increased risks for skin cancer along with gastrointestinal, infectious, pulmonary and hematologic adverse events, according to a study published in the Annals of Internal Medicine.

“Clinicians should continue to prescribe low-dose methotrexate, but they can now have a more detailed and evidence-based conversation with patients weighing the pros and cons of the drug,” Daniel H. Solomon, MD, MPH, a rheumatologist in the division of rheumatology, inflammation and immunology at Brigham and Women’s Hospital, told Healio Primary Care.

“The adverse events that we observed are not substantially different from our prior understanding of the drug, but clinicians now have better information about how often specific adverse events occur and some of the predictors of these events,” he continued.

Solomon and colleagues conducted a prespecified secondary analyses of the Cardiovascular Inflammation Reduction Trial (CIRT), a double-blind, placebo controlled randomized trial that investigated whether the anti-inflammatory effects of methotrexate could reduce the risk for CV events. As Healio previously reported, results from the trial showed that methotrexate did not reduce the risk for CV events and was associated with an elevated risk for nonbasal-cell skin cancers.

The analysis included participants with a known myocardial infarction, a multi-vessel obstructive coronary artery disease, type 2 diabetes or a metabolic syndrome. They were enrolled into an active run-in period for 5 to 8 weeks, in which they were given low-dose methotrexate with dosages increasing from 5 mg to 15 mg per week. After the run-in phase, participants were randomly assigned to receive placebo or 15 mg of oral low-dose methotrexate once per week and 1 mg folic acid the other 6 days of the week. Participants who met safety criteria had methotrexate doses increased to 20 mg per week after 16 weeks.

Researchers recorded a wide range adverse events experienced by participants during the study period, including gastrointestinal, pulmonary, infectious, hematologic, malignant and musculoskeletal adverse events.

A total of 6,158 participants were enrolled after the run-in period and 4,786 were randomly assigned to low-dose methotrexate (n = 2,391) or placebo (n = 2,395). The median follow-up period was 23 months with a median dosage of 15 mg per week.

Among participants, adverse events of interest occurred in 87% of the methotrexate group, compared with 81.5% of the placebo group (HR = 1.17; 95% CI, 1.1-1.25).

Researchers found that the relative hazards for many adverse events were elevated in the methotrexate group, including gastrointestinal (HR = 1.91; 95% CI, 1.75-2.1), pulmonary (HR = 1.52; 95% CI, 1.16-1.98), infectious (HR = 1.15; 95% CI, 1.01-1.3) and hematologic events (HR = 1.15; 95% CI, 1.07-1.23).

Although Solomon and colleagues identified a significantly increased risk for skin cancer in the methotrexate group compared with the placebo group (HR = 2.05; 95% CI, 1.28-3.28), there was not an association with increased risks for other cancers or for mucocutaneous, neuropsychiatric or musculoskeletal adverse events.

Compared with the placebo group, researchers discovered that the methotrexate group had a reduced risk for renal adverse events (HR = 0.85; 95% CI, 0.78-0.93).

In an editorial accompanying the study, Vivian P. Bykerk, MD, a rheumatologist at the Hospital for Special Surgery and associate professor of medicine at Weill Cornell Medical College, explained that although the typical patient with inammatory arthritis and rheumatoid arthritis differs from those in the CIRT population, the risk estimates identified in the study are largely consistent with those in patients with rheumatic diseases who were treated with methotrexate.

“These data provide objective estimates of risk for [adverse events], reminding us that [methotrexate] use has inherent risks and warrants vigilance for symptomatic, laboratory, and infrequent but clinically serious [adverse events] — particularly skin cancer and hepatic, pulmonary, and hematologic toxicity,” she wrote. – by Erin Michael

Disclosures: Bykerk reports receiving personal fees from Amgen, BMS, Genzyme Corporation, Gilead, Pfizer, Regeneron Pharmaceuticals and United Chemicals of Belgium; please see the editorial for all other relevant financial disclosures. Solomon reports receiving grants from the National Heart, Lung, and Blood Institute during the conduct of the study; grants from AbbVie, Amgen, Corrona, Janssen and Pzer outside the submitted work; and royalties for writing a chapter on nonsteroidal anti-inammatory drugs in UpToDate. Please see the study for all other authors’ relevant financial disclosures.

Photo of Daniel H. Solomon
Daniel H. Solomon

Low-dose methotrexate — the most commonly used drug for systemic rheumatic diseases — was associated with small to moderate increased risks for skin cancer along with gastrointestinal, infectious, pulmonary and hematologic adverse events, according to a study published in the Annals of Internal Medicine.

“Clinicians should continue to prescribe low-dose methotrexate, but they can now have a more detailed and evidence-based conversation with patients weighing the pros and cons of the drug,” Daniel H. Solomon, MD, MPH, a rheumatologist in the division of rheumatology, inflammation and immunology at Brigham and Women’s Hospital, told Healio Primary Care.

“The adverse events that we observed are not substantially different from our prior understanding of the drug, but clinicians now have better information about how often specific adverse events occur and some of the predictors of these events,” he continued.

Solomon and colleagues conducted a prespecified secondary analyses of the Cardiovascular Inflammation Reduction Trial (CIRT), a double-blind, placebo controlled randomized trial that investigated whether the anti-inflammatory effects of methotrexate could reduce the risk for CV events. As Healio previously reported, results from the trial showed that methotrexate did not reduce the risk for CV events and was associated with an elevated risk for nonbasal-cell skin cancers.

The analysis included participants with a known myocardial infarction, a multi-vessel obstructive coronary artery disease, type 2 diabetes or a metabolic syndrome. They were enrolled into an active run-in period for 5 to 8 weeks, in which they were given low-dose methotrexate with dosages increasing from 5 mg to 15 mg per week. After the run-in phase, participants were randomly assigned to receive placebo or 15 mg of oral low-dose methotrexate once per week and 1 mg folic acid the other 6 days of the week. Participants who met safety criteria had methotrexate doses increased to 20 mg per week after 16 weeks.

Researchers recorded a wide range adverse events experienced by participants during the study period, including gastrointestinal, pulmonary, infectious, hematologic, malignant and musculoskeletal adverse events.

A total of 6,158 participants were enrolled after the run-in period and 4,786 were randomly assigned to low-dose methotrexate (n = 2,391) or placebo (n = 2,395). The median follow-up period was 23 months with a median dosage of 15 mg per week.

Among participants, adverse events of interest occurred in 87% of the methotrexate group, compared with 81.5% of the placebo group (HR = 1.17; 95% CI, 1.1-1.25).

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Researchers found that the relative hazards for many adverse events were elevated in the methotrexate group, including gastrointestinal (HR = 1.91; 95% CI, 1.75-2.1), pulmonary (HR = 1.52; 95% CI, 1.16-1.98), infectious (HR = 1.15; 95% CI, 1.01-1.3) and hematologic events (HR = 1.15; 95% CI, 1.07-1.23).

Although Solomon and colleagues identified a significantly increased risk for skin cancer in the methotrexate group compared with the placebo group (HR = 2.05; 95% CI, 1.28-3.28), there was not an association with increased risks for other cancers or for mucocutaneous, neuropsychiatric or musculoskeletal adverse events.

Compared with the placebo group, researchers discovered that the methotrexate group had a reduced risk for renal adverse events (HR = 0.85; 95% CI, 0.78-0.93).

In an editorial accompanying the study, Vivian P. Bykerk, MD, a rheumatologist at the Hospital for Special Surgery and associate professor of medicine at Weill Cornell Medical College, explained that although the typical patient with inammatory arthritis and rheumatoid arthritis differs from those in the CIRT population, the risk estimates identified in the study are largely consistent with those in patients with rheumatic diseases who were treated with methotrexate.

“These data provide objective estimates of risk for [adverse events], reminding us that [methotrexate] use has inherent risks and warrants vigilance for symptomatic, laboratory, and infrequent but clinically serious [adverse events] — particularly skin cancer and hepatic, pulmonary, and hematologic toxicity,” she wrote. – by Erin Michael

Disclosures: Bykerk reports receiving personal fees from Amgen, BMS, Genzyme Corporation, Gilead, Pfizer, Regeneron Pharmaceuticals and United Chemicals of Belgium; please see the editorial for all other relevant financial disclosures. Solomon reports receiving grants from the National Heart, Lung, and Blood Institute during the conduct of the study; grants from AbbVie, Amgen, Corrona, Janssen and Pzer outside the submitted work; and royalties for writing a chapter on nonsteroidal anti-inammatory drugs in UpToDate. Please see the study for all other authors’ relevant financial disclosures.