Methotrexate no better than placebo for prevention of ulcerative colitis relapse

Parenteral methotrexate did not outperform placebo in the prevention of ulcerative colitis relapse among patients who attained steroid-free response during induction therapy, according to a recent study published in Gastroenterology.

“Parenteral methotrexate induces clinical remission but not endoscopic improvement of mucosal inflammation in patients with ulcerative colitis (UC),” wrote authors led by Hans Herfarth, MD, PhD, Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina, Chapel Hill, NC.

Although methotrexate’s ability to induce and maintain remission in patients with steroid-dependent Crohn’s disease has been established, its role in treating UC is contentious, with study results mixed.

To that end, Dr. Herfarth and colleagues performed a randomized, placebo-controlled trial to assess the efficacy of parenteral methotrexate in maintaining steroid-free response or remission in patients with UC following induction therapy with methotrexate and steroids.

The investigators screened 256 patients at 37 US clinical sites between February 2012 and May 2016 for inclusion in this 48-week trial. In total, 179 patients between ages 18 and 70 years with active UC were included in the 16-week methotrexate open-label induction period.

The initial induction period was followed by a 32-week double-blind placebo-controlled maintenance period. Induction consisted of once-weekly subcutaneous doses of 25 mg methotrexate, as well as a 12-week steroid taper. At week 16, the team randomized the steroid-free responders to either continue with methotrexate treatment or to take placebo through week 48. Additionally, 29% of patients attained steroid-free clinical remission by week 16.

The primary outcome for this study was relapse-free survival without the need for other UC therapies such as steroids, immunosuppressants, or biologics. The team compared methotrexate maintenance vs placebo by assessing the number of patients who remained relapse-free at week 48 without the need for other UC therapies.

In total, 24 of 40 placebo patients (60%) and 29 of 44 methotrexate patients (66%) relapsed during the maintenance period (P=0.75). At week 48, 12 of 40 placebo patients (30%) and 12 of 44 methotrexate patients (27%) sustained steroid-free remission (P=0.86). The team observed no new adverse events associated with methotrexate treatment.

Overall, the team observed that at week 48, remission did not differ between the methotrexate and placebo maintenance groups (P=0.78). Importantly, the results of the current study concurred with findings of previous trials.

“Whereas MTX [methotrexate] may have a limited efficacy to induce steroid-free response or remission in combination with a standardized steroid taper, MTX did not show better efficacy as a maintenance treatment than placebo in preventing relapse in patients with UC,” concluded the researchers.

Dr. Herfarth and colleagues conceded that their investigation had limitations. For instance, the study was powered to detect only a 25% difference between placebo and methotrexate, which means that methotrexate could have yielded a treatment effect between 10% and 15%. The team would have needed to include between 500 and 700 patients to test this possibility.

This study was funded by the National Institute of Diabetes and Digestive Kidney Diseases.