Comparative Effectiveness of Anti-TNF in Combination With Low-Dose Methotrexate vs Anti-TNF Monotherapy in Pediatric Crohn's Disease: A Pragmatic Randomized Trial

Michael D. Kappelman, Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. Electronic address: michael_kappelman@med.unc.edu.
David A. Wohl, Institute of Global Health and Infectious Diseases, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Hans H. Herfarth, Division of Gastroenterology and Hepatology, University of North Carolina, Chapel Hill, North Carolina.
Ann M. Firestine, Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Jeremy Adler, Susan B. Meister Child Health Evaluation and Research Center and Division of Pediatric Gastroenterology, University of Michigan, Ann Arbor, Michigan.
Rana F. Ammoury, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Children's Hospital of The King's Daughters, Norfolk, Virginia.
Jeanine E. Aronow, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Dorsey M. Bass, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Stanford University School of Medicine, Lucile Packard Children's Hospital, Palo Alto, California.
Julie A. Bass, Department of Pediatrics, School of Medicine, University of Missouri Kansas City, Division of Gastroenterology, Children's Mercy Kansas City, Kansas City, Missouri.
Keith Benkov, Division of Pediatric Gastroenterology, Icahn School of Medicine at Mt Sinai, New York, New York.
Catalina Berenblum Tobi, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina.
Margie E. Boccieri, Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Brendan M. Boyle, Division of Gastroenterology, Hepatology, and Nutrition, Nationwide Children's Hospital, Columbus, Ohio.
William B. Brinkman, Department of Pediatrics, University of Cincinnati College of Medicine, Division of General and Community Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Jose M. Cabera, Division of Pediatric Gastroenterology, Department of Pediatrics, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee, Wisconsin.
Kelly Chun, Esoterix Specialty Laboratory, Labcorp, Calabasas, California.
Richard B. Colletti, Division of Gastroenterology, Department of Pediatrics, University of Vermont, Burlington, Vermont.
Cassandra M. Dodds, James M. Anderson Center for Health Systems Excellence, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Jill M. Dorsey, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Nemours Children's Health, Jacksonville, Florida.
Dawn R. Ebach, Division of Pediatric Gastroenterology, Hepatology, Pancreatology, and Nutrition, University of Iowa, Iowa City, Iowa.
Edurne Entrena, Progenika Biopharma, a Grifols Company, Derio, Bizkaia, Spain.
Christopher B. Forrest, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Philadelphia.
Joseph A. Galanko, Center for Gastrointestinal Biology and Disease, Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
John E. Grunow, University of Oklahoma Children's Physicians, Pediatric Gastroenterology, Oklahoma City, Oklahoma.
Ajay S. Gulati, Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Anastasia Ivanova, Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Traci W. Jester, Department of Pediatrics, Division of Gastroenterology, University of Alabama at Birmingham, Birmingham, Alabama.
Jess L. Kaplan, Division of Pediatric Gastroenterology, Mass General for Children and Harvard Medical School, Boston, Massachusetts.
Subra Kugathasan, Department of Pediatrics, Emory University, Atlanta, Georgia.
Mark E. Kusek, Division of Pediatric Gastroenterology, University of Nebraska Medical Center, Omaha, Nebraska.
Ian H. Leibowitz, Division of Gastroenterology, Hepatology and Nutrition, Children's National Medical Center, Department of Pediatrics, George Washington University, Washington, District of Columbia.
Tiffany M. Linville, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Levine Children's Hospital, Charlotte, North Carolina.

Document Type

Journal Article

Publication Date

7-1-2023

Journal

Gastroenterology

Volume

165

Issue

1

DOI

10.1053/j.gastro.2023.03.224

Keywords

Adalimumab; Anti-Tumor Necrosis Factor–α; Children; Crohn’s Disease; Infliximab; Methotrexate

Abstract

BACKGROUND & AIMS: Tumor necrosis factor inhibitors, including infliximab and adalimumab, are a mainstay of pediatric Crohn's disease therapy; however, nonresponse and loss of response are common. As combination therapy with methotrexate may improve response, we performed a multicenter, randomized, double-blind, placebo-controlled pragmatic trial to compare tumor necrosis factor inhibitors with oral methotrexate to tumor necrosis factor inhibitor monotherapy. METHODS: Patients with pediatric Crohn's disease initiating infliximab or adalimumab were randomized in 1:1 allocation to methotrexate or placebo and followed for 12-36 months. The primary outcome was a composite indicator of treatment failure. Secondary outcomes included anti-drug antibodies and patient-reported outcomes of pain interference and fatigue. Adverse events (AEs) and serious AEs (SAEs) were collected. RESULTS: Of 297 participants (mean age, 13.9 years, 35% were female), 156 were assigned to methotrexate (110 infliximab initiators and 46 adalimumab initiators) and 141 to placebo (102 infliximab initiators and 39 adalimumab initiators). In the overall population, time to treatment failure did not differ by study arm (hazard ratio, 0.69; 95% CI, 0.45-1.05). Among infliximab initiators, there were no differences between combination and monotherapy (hazard ratio, 0.93; 95% CI, 0.55-1.56). Among adalimumab initiators, combination therapy was associated with longer time to treatment failure (hazard ratio, 0.40; 95% CI, 0.19-0.81). A trend toward lower anti-drug antibody development in the combination therapy arm was not significant (infliximab: odds ratio, 0.72; 95% CI, 0.49-1.07; adalimumab: odds ratio, 0.71; 95% CI, 0.24-2.07). No differences in patient-reported outcomes were observed. Combination therapy resulted in more AEs but fewer SAEs. CONCLUSIONS: Among adalimumab but not infliximab initiators, patients with pediatric Crohn's disease treated with methotrexate combination therapy experienced a 2-fold reduction in treatment failure with a tolerable safety profile. CLINICALTRIALS: gov, Number: NCT02772965.

Department

Pediatrics

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