Findings from a landmark clinical trial in pediatric Crohn’s disease show a clear benefit of adding methotrexate to treatment with the tumor necrosis factor inhibitor (TNFi) adalimumab (Humira), but not to infliximab therapy.
Children initiating treatment with adalimumab plus a low dose of methotrexate experienced a twofold reduction in treatment failure, note the authors of the largest, double-blind, randomized trial to date in pediatric Crohn’s disease. However, children initiating infliximab, another TNFi, had similar outcomes with or without methotrexate.
“We believe these results are practice changing,” principal investigator Michael Kappelman, MD, MPH, professor of pediatrics at University of North Carolina, Chapel Hill, told Medscape Medical News.
Dr Michael Kappelman
All patients with pediatric Crohn’s disease starting on adalimumab, and their parents, should be informed that combining the drug with low-dose oral methotrexate improves treatment effectiveness, he said.
“Those without contraindications should be offered combination therapy, and shared decision-making should be incorporated into final treatment decisions. In contrast, most patients starting infliximab are not likely to experience added benefits from low-dose oral methotrexate,” Kappelman added.
The study was published online March 31 in Gastroenterology and will be presented in early May at Digestive Disease Week 2023.
“This is an important study, published in a very high-ranking journal, that will have a huge impact on how we practice,” Jacob Kurowski, MD, Department of Pediatric Gastroenterology, Hepatology and Nutrition, Cleveland Clinic Children’s, Cleveland, Ohio, who wasn’t involved in the study, told Medscape Medical News.
Treatment with a TNFi, including infliximab and adalimumab, is a mainstay of pediatric Crohn’s disease therapy. However, not all patients achieve remission, and many lose response over time.
The current trial compared the effectiveness and safety of adding a low-dose of oral methotrexate to adalimumab or infliximab vs TNFi therapy alone in 297 children with Crohn’s disease. The mean age was 13.9 years, and about two thirds were boys. None had a prior history of TNFi therapy.
Participants initiating infliximab or adalimumab were randomly allocated (1:1) to oral methotrexate or placebo. Of them, 110 infliximab initiators and 46 adalimumab initiators received methotrexate, while 102 infliximab initiators and 39 adalimumab initiators were given placebo. Methotrexate was administered as a weekly dose of 15 mg for children weighing 40 kg or more, 12.5 mg for children 30 to <40 kg, and 10 mg for children 20 to <30 kg. All participants received pretreatment with ondansetron 4 mg (or placebo) to prevent nausea and folic acid (1 mg per day). Participants were followed for 12-36 months.
The primary outcome was a failure to achieve or maintain steroid-free remission defined by occurrence of any of the following:
Short Pediatric Crohn’s Disease Activity Index (SPCDAI) score of less than 15 by week 26
Failure to complete a steroid taper by week 16
SPCDAI score of 15 or higher as a result of active Crohn’s disease at two or more consecutive visits beyond week 26
Hospitalization or surgery for Crohn’s disease beyond week 26
Use of corticosteroids for Crohn’s disease for 10 or more weeks cumulatively beyond week 16
Discontinuation of anti-TNF and/or study drug for lack of effectiveness or toxicity
Overall, 88 of 297 children (30%) experienced treatment failure, including 57 of 212 (27%) on infliximab and 31 of 85 (36%) on adalimumab. Overall, 40 of 156 children (26%) on combination therapy and 48 of 141 (34%) on monotherapy experienced treatment failure.
Kaplan Meier analysis of the overall population showed a nonsignificant trend toward lower event rates with combination therapy (hazard ratio [HR] 0.69; 95% CI, 0.45 – 1.05; P = .08).
After stratification by TNFi, there was no difference in time to treatment failure among infliximab initiators between combination and monotherapy (HR, 0.93; 95% CI, 0.55 -1.56; P = .78). In contrast, among adalimumab initiators, combination therapy was significantly associated with a longer time to treatment failure (HR, 0.40; 95% CI 0.19 – 0.81; P = .01).
There was a nonsignificant trend toward lower development of anti-drug antibodies with combination therapy (risk ratio 0.72 with infliximab and 0.71 with adalimumab). This trend is in line with adult studies and adds substantially to the pediatric literature on this topic, the researchers note.
No differences in patient-reported outcomes were observed. There were slightly more adverse events with combination therapy, as expected, but fewer serious adverse events.
Kappelman noted that the study was not designed to answer the question of which is better — adalimumab plus methotrexate or infliximab alone.
“This is an area for future research. At this point, we believe it is an individualized decision, and appropriate counseling is needed to support shared decision-making,” he told Medscape Medical News.
Nor was the trial designed to evaluate the role of proactive therapeutic drug monitoring (TDM). However, proactive TDM is endorsed in the ImproveCareNow Model IBD Care guidelines and was considered standard of care at the 35 study sites.
The findings “suggest strong consideration of using combination therapy for pediatric Crohn’s disease patients initiating adalimumab, but not infliximab,” Kappelman and colleagues say.
“Dissemination and implementation of these findings should lead to improved outcomes in this patient population, including consideration of de-implementation of combination therapy in infliximab treated patients,” they add.
The decision about which approach to use is still very dependent on patients and their providers, Kurowski told Medscape Medical News.
“The study shows that you can safely use infliximab as monotherapy, with low risk of antibody formation, while utilizing proactive therapeutic drug monitoring and dose optimization,” he said. “The study also shows that adalimumab in combination with low-dose methotrexate can be strongly considered when needed.”
The researchers’ standardization of methotrexate doses by weight “is another significant contribution and provides a guide for clinicians,” Kurowski added.
The study was funded by grants from the Patient-Centered Outcomes Research Institute, the Helmsley Charitable Trust, and National Institute of Arthritis and Musculoskeletal and Skin Diseases. Kappelman has consulted for AbbVie, Janssen, Pfizer, Takeda, and Lilly; holds shares in Johnson & Johnson; and has received research support from Pfizer, Takeda, Janssen, AbbVie, Lilly, Genentech, Boehringer Ingelheim, Bristol-Myers Squibb, Celtrion, and Arena Pharmaceuticals. Kurowski reports no relevant financial relationships.
Gastroenterology. Published online March 31, 2023. Abstract
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