Inflamm Bowel Dis. 2024 Oct 17:izae239. doi: 10.1093/ibd/izae239. Online ahead of print.

Jonathan Moses ¹, Jeremy Adler ^2 3, Shehzad A Saeed ⁴, Ann M Firestine ⁵, Joseph A Galanko ⁵, Rana F Ammoury ⁶, Dorsey M Bass ¹, Julie A Bass ⁷, Monique Bastidas ⁸, Keith J Benkov ⁹, Athos Bousvaros ¹⁰, José M Cabrera ¹¹, Kelly Y Chun ⁸, Jill M Dorsey ¹², Dawn R Ebach ¹³, Ajay S Gulati ¹⁴, Hans H Herfarth ¹⁵, Anastasia Ivanova ¹⁶, Traci W Jester ¹⁷, Jess L Kaplan ¹⁸, Mark E Kusek ¹⁹, Ian H Leibowitz ²⁰, Tiffany M Linville ²¹, Peter A Margolis ²², Phillip Minar ²³, Zarela Molle-Rios ²⁴, Barbara Joanna Niklinska-Schirtz ²⁵, Kelly K Olano ²⁶, Lourdes Osaba ²⁷, Pablo J Palomo ²⁸, Dinesh S Pashankar ²⁹, Lisa Pitch ³⁰, Charles M Samson ³¹, Kelly C Sandberg ³², Steven J Steiner ³³, Jennifer A Strople ³⁴, Jillian S Sullivan ³⁵, Jeanne Tung ³⁶, Prateek Wali ³⁷, David A Wohl ³⁸, Mike Zikry ⁸, Brendan M Boyle ³⁹, Michael D Kappelman ⁵

Author information

¹Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Stanford Medicine Children's Health, Palo Alto, CA, USA.

²Division of Gastroenterology, Hepatology, and Nutrition, C.S. Mott's Children's Hospital, Ann Arbor, MI, USA.

³Susan B. Meister Child Health Evaluation and Research Center, University of Michigan, Ann Arbor, MI, USA.

⁴Department of Medical Affairs, Dayton Children's Hospital and Wright State University, Dayton, OH, USA.

⁵Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

⁶Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Children's Hospital of The King's Daughters, Norfolk, VA, USA.

⁷Department of Gastroenterology, Hepatology, and Nutrition, Children's Mercy Kansas City, Kansas City, MO, USA.

⁸Esoterix Specialty Laboratory, Labcorp, Calabasas, CA, USA.

⁹Division of Pediatric Gastroenterology, Icahn School of Medicine at Mt Sinai, New York, NY, USA.

¹⁰Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA, USA.

¹¹Division of Pediatric Gastroenterology, Department of Pediatrics, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee, WI, USA.

¹²Pediatric Gastroenterology, Hepatology, and Nutrition, Nemours Children's Specialty Care, Jacksonville, FL, USA.

¹³Division of Pediatric Gastroenterology, Hepatology, Pancreatology, and Nutrition, Department of Pediatrics, University of Iowa, Iowa City, IA, USA.

¹⁴Department of Pediatrics and Pathology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

¹⁵Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

¹⁶Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

¹⁷Department of Pediatrics, Division of Gastroenterology, University of Alabama at Birmingham, Birmingham, AL, USA.

¹⁸Division of Pediatric Gastroenterology, Mass General for Children and Harvard Medical School, Boston, MA, USA.

¹⁹Division of Pediatric Gastroenterology, University of Nebraska Medical Center, Omaha, NE, USA.

²⁰Division of Gastroenterology, Hepatology and Nutrition, Children's National Medical Center, Department of Pediatrics, George Washington University, Washington, D.C., USA.

²¹Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Levine Children's Hospital, Charlotte, NC, USA.

²²Cincinnati Children's Research Foundation Chair in Improvement Science, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.

²³Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.

²⁴Division of Pediatric Gastroenterology, Nemours Children's Hospital, Wilmington, DE, USA.

²⁵Division of Pediatric Gastroenterology, Department of Pediatrics, Emory University School of Medicine & Children's Healthcare of Atlanta, Atlanta, GA, USA.

²⁶Division of Biostatistics and Epidemiology, Children's Hospital Medical Center, Cincinnati, OH, USA.

²⁷Progenika Biopharma, a Grifols Company, Derio, Bizkaia, Spain.

²⁸Division of Pediatric Gastroenterology, Nemours Children's Hospital, Orlando, FL, USA.

²⁹Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA.

³⁰ImproveCareNow Inc., Essex Junction, VT, USA.

³¹Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Washington University School of Medicine, St Louis, MO, USA.

³²Division of Gastroenterology, Hepatology, and Nutrition, Dayton Children's Hospital, Dayton, OH, USA.

³³Division of Pediatric Gastroenterology, Hepatology & Nutrition, Indiana University School of Medicine, Indianapolis, IN, USA.

³⁴Division of Gastroenterology, Hepatology and Nutrition, Ann and Robert H. Lurie Children's Hospital of Chicago, Department of Pediatrics, Northwestern Feinberg School of Medicine, Chicago, IL, USA.

³⁵The University of Vermont Children's Hospital and Department of Pediatrics, Larner College of Medicine, The University of Vermont, Burlington, VT, USA.

³⁶University of Oklahoma Children's Physicians, Pediatric Gastroenterology, Oklahoma City, OK, USA.

³⁷Division of Pediatric Gastroenterology, Hepatology, and Nutrition, State University of New York, Upstate Medical University, Syracuse, NY, USA.

³⁸Division of Infectious Diseases, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

³⁹Division of Gastroenterology, Hepatology, and Nutrition, Nationwide Children's Hospital, Columbus, OH, USA.

Abstract

Background: Higher drug levels and combination therapy with low-dose oral methotrexate (LD-MTX) may reduce anti-tumor necrosis factor (TNF) treatment failure in pediatric Crohn's disease. We sought to (1) evaluate whether combination therapy with LD-MTX was associated with higher anti-TNF levels, (2) evaluate associations between anti-TNF levels and subsequent treatment failure, and (3) explore the effect of combination therapy on maintenance of remission among patients with therapeutic drug levels (>5 µg/mL for infliximab and >7.5 µg/mL for adalimumab).

Methods: We conducted a post hoc analysis of the COMBINE trial, which compared anti-TNF monotherapy to combination therapy with LD-MTX. We included participants who entered maintenance therapy and provided a serum sample approximately 4 months from randomization.

Results: Among 112 infliximab and 41 adalimumab initiators, median drug levels were similar between combination therapy and monotherapy (infliximab: 8.8 vs 7.5 μg/mL [P = .49]; adalimumab: 11.1 vs 10.5 μg/mL [P = .11]). Median drug levels were lower in patients experiencing treatment failure (infliximab: 4.2 vs 9.6 μg/mL [P < .01]; adalimumab: 9.1 vs 12.3 μg/mL [P < .01]). Among patients treated with infliximab with therapeutic drug levels, we observed no difference in treatment failure between participants assigned monotherapy or combination therapy. Among patients treated with adalimumab, a trend towards reduced treatment failure in the combination therapy arm was not statistically significant (P = .14).

Conclusions: LD-MTX combination was not associated with higher drug levels, but higher drug levels were associated with reduced risk of treatment failure. Among patients with therapeutic drug levels, we observed no benefit of LD-MTX for patients treated with infliximab. A nonsignificant trend towards reduced treatment failure with the addition of LD-MTX patients treated with adalimumab warrants further investigation.