From the Journals

Low-dose methotrexate trial pins down adverse event rates



A new study has found an elevated risk of some adverse events in patients treated with low-dose methotrexate, compared with patients treated with placebo.

“The data presented here provide an important source of new evidence to improve the monitoring guidelines and safe prescribing of LD-MTX [low-dose methotrexate],” wrote Daniel H. Solomon, MD, of Brigham and Women’s Hospital and Harvard Medical School in Boston, and coauthors. The study was published in Annals of Internal Medicine.

Dr. Daniel H. Solomon, Brigham and Women's Hospital, Boston

Dr. Daniel H. Solomon

To determine the rates of adverse events (AEs) among LD-MTX users, along with assessing the risks of certain predefined AEs, the researchers enrolled 6,158 patients in the Cardiovascular Inflammation Reduction Trial (CIRT) and randomized 4,786 of those patients to two groups: those receiving LD-MTX (n = 2,391) and those receiving placebo (n = 2,395). The median dose was 15 mg per week, and median follow-up was 23 months. All participants in CIRT had a history of cardiovascular disease, along with diabetes or metabolic syndrome. Just over 81% of the participants were male, and nearly 85% were white. Their median age was nearly 66 years.

Of the participants in the LD-MTX group, 2,156 (90.2%) had an AE and 2,080 (87.0%) had an AE of interest, which included infectious, hematologic, pulmonary, hepatic, cancerous, and gastrointestinal AEs. Of the participants in the placebo group, 2,076 (86.7%) had an AE and 1,951 (81.5%) had an AE of interest. As such, the relative rate of an AE of interest was 17% higher in the LD-MTX group (hazard ratio, 1.17; 95% confidence interval, 1.10-1.25).

In regard to specific types of AEs, the rates of 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) were higher for participants in the LD-MTX group. Five cases of cirrhosis were found in the LD-MTX group, compared with none in the placebo group; none of the patients with cirrhosis had severe liver test abnormalities before their diagnosis. While the risk of cancer overall was not elevated in the LD-MTX group, 53 participants in that group developed skin cancer, compared with 26 in the placebo group (HR, 2.04; 95% CI, 1.28-3.26). Renal AEs were among the few that decreased in LD-MTX users (HR, 0.85; 95% CI, 0.78-0.93).

“Methotrexate has become the standard of care for RA patients,” Dr. Solomon said in an interview, “and because it worked so well, we accepted it without large placebo-controlled trials and without a precise understanding of the risk factors for AEs. Until this study, our evidence basis for the side-effect profile was relatively weak.

“We had a limited data set but decades of experience,” he added. “Now we have better evidence, for example, that methotrexate is associated with elevations in liver function tests. We even found five cases of cirrhosis. And the people who developed cirrhosis didn’t have severe test abnormalities; just minor ones over many months. So now we have a better understanding of the potential impact of minor, yet chronic abnormalities.”

Dr. Solomon and coauthors acknowledged their study’s limitations, including CIRT not including patients with systemic rheumatic disease and the possibility that participants did not report AEs that occurred in between routine study visits. In addition, although the median follow-up of nearly 2 years was longer than in other LD-MTX trials, they noted that “it may still be too short to observe some AEs that require long-term exposure.”

Dr. Solomon and colleagues should be commended for undertaking a long-awaited randomized, placebo-controlled trial that adds much-needed insight into how and when to monitor patients being treated with MTX, Vivian P. Bykerk, MD, of the Hospital for Special Surgery and Weill Cornell Medical College in New York, wrote in an editorial (Ann Intern Med. 2020 Feb 17. doi: 10.7326/M20-0435).

Dr. Vivian P. Bykerk, director of the Inflammatory Arthritis Center of Excellence, Hospital for Special Surgery, New York

Dr. Vivian P. Bykerk

Dr. Bykerk noted that although the results may not be applicable to patients with RA and other inflammatory arthritides who are treated with MTX – RA patients in particular are younger, more often female, have lower rates of diabetes, and usually receive higher doses than those used in CIRT — the risk estimates from the CIRT study are “largely congruent with those expected in MTX-treated patients with rheumatic diseases.”

Regardless, she emphasized that this is a step in a much-needed direction, reminding physicians that “MTX use has inherent risks” and that its AEs, although infrequent, are clinically serious.

The National Institutes of Health funded the study. Various authors reported receiving grants from the National Heart, Lung, and Blood Institute, along with grants, research support, and personal fees from numerous pharmaceutical companies before and during the study. Dr. Bykerk reported receiving personal fees, grants, and nonfinancial support from pharmaceutical companies, foundations, and the NIH.

SOURCE: Solomon DH et al. Ann Intern Med. 2020 Feb 17. doi: 10.7326/M19-3369.

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