Low Anti-Tumor Necrosis Factor Levels During Maintenance Phase Are Associated With Treatment Failure in Children With Crohn's Disease

Jonathan Moses, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Stanford Medicine Children's Health, Palo Alto, CA, USA.
Jeremy Adler, Division of Gastroenterology, Hepatology, and Nutrition, C.S. Mott's Children's Hospital, Ann Arbor, MI, USA.
Shehzad A. Saeed, Department of Medical Affairs, Dayton Children's Hospital and Wright State University, Dayton, OH, USA.
Ann M. Firestine, Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Joseph A. Galanko, Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Rana F. Ammoury, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Children's Hospital of The King's Daughters, Norfolk, VA, USA.
Dorsey M. Bass, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Stanford Medicine Children's Health, Palo Alto, CA, USA.
Julie A. Bass, Department of Gastroenterology, Hepatology, and Nutrition, Children's Mercy Kansas City, Kansas City, MO, USA.
Monique Bastidas, Esoterix Specialty Laboratory, Labcorp, Calabasas, CA, USA.
Keith J. Benkov, Division of Pediatric Gastroenterology, Icahn School of Medicine at Mt Sinai, New York, NY, USA.
Athos Bousvaros, Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA, USA.
José M. Cabrera, Division of Pediatric Gastroenterology, Department of Pediatrics, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee, WI, USA.
Kelly Y. Chun, Esoterix Specialty Laboratory, Labcorp, Calabasas, CA, USA.
Jill M. Dorsey, Pediatric Gastroenterology, Hepatology, and Nutrition, Nemours Children's Specialty Care, Jacksonville, FL, USA.
Dawn R. Ebach, Division of Pediatric Gastroenterology, Hepatology, Pancreatology, and Nutrition, Department of Pediatrics, University of Iowa, Iowa City, IA, USA.
Ajay S. Gulati, Department of Pediatrics and Pathology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Hans H. Herfarth, Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Anastasia Ivanova, Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Traci W. Jester, Department of Pediatrics, Division of Gastroenterology, University of Alabama at Birmingham, Birmingham, AL, USA.
Jess L. Kaplan, Division of Pediatric Gastroenterology, Mass General for Children and Harvard Medical School, Boston, MA, USA.
Mark E. Kusek, Division of Pediatric Gastroenterology, University of Nebraska Medical Center, Omaha, NE, USA.
Ian H. Leibowitz, Division of Gastroenterology, Hepatology and Nutrition, Children's National Medical Center, Department of Pediatrics, George Washington University, Washington, D.C., USA.
Tiffany M. Linville, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Levine Children's Hospital, Charlotte, NC, USA.
Peter A. Margolis, Cincinnati Children's Research Foundation Chair in Improvement Science, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Phillip Minar, Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Zarela Molle-Rios, Division of Pediatric Gastroenterology, Nemours Children's Hospital, Wilmington, DE, USA.
Barbara Joanna Niklinska-Schirtz, Division of Pediatric Gastroenterology, Department of Pediatrics, Emory University School of Medicine & Children's Healthcare of Atlanta, Atlanta, GA, USA.
Kelly K. Olano, Division of Biostatistics and Epidemiology, Children's Hospital Medical Center, Cincinnati, OH, USA.
Lourdes Osaba, Progenika Biopharma, a Grifols Company, Derio, Bizkaia, Spain.
Pablo J. Palomo, Division of Pediatric Gastroenterology, Nemours Children's Hospital, Orlando, FL, USA.
Dinesh S. Pashankar, Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA.
Lisa Pitch, ImproveCareNow Inc., Essex Junction, VT, USA.

Document Type

Journal Article

Publication Date

10-17-2024

Journal

Inflammatory bowel diseases

DOI

10.1093/ibd/izae239

Keywords

biologics; inflammatory bowel disease; pediatrics; therapeutic drug monitoring

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.

Department

Pediatrics

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