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

Jonathan Moses; Jeremy Adler; Shehzad A Saeed; Ann M Firestine; Joseph A Galanko; Rana F Ammoury; Dorsey M Bass; Julie A Bass; Monique Bastidas; Keith J Benkov; Athos Bousvaros; José M Cabrera; Kelly Y Chun; Jill M Dorsey; Dawn R Ebach; Ajay S Gulati; Hans H Herfarth; Anastasia Ivanova; Traci W Jester; Jess L Kaplan; Mark E Kusek; Ian H Leibowitz; Tiffany M Linville; Peter A Margolis; Phillip Minar; Zarela Molle-Rios; Barbara Joanna Niklinska-Schirtz; Kelly K Olano; Lourdes Osaba; Pablo J Palomo; Dinesh S Pashankar; Lisa Pitch; Charles M Samson; Kelly C Sandberg; Steven J Steiner; Jennifer A Strople; Jillian S Sullivan; Jeanne Tung; Prateek Wali; David A Wohl; Mike Zikry; Brendan M Boyle; Michael D Kappelman

doi:10.1093/ibd/izae239

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

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

Authors

Jonathan Moses¹, Jeremy Adler^{2

3}, Shehzad A Saeed⁴, Ann M Firestine⁵, Joseph A Galanko⁵, Rana F Ammoury⁶, Dorsey M Bass¹, Julie A Bass⁷, Monique Bastidas⁸, Keith J Benkov⁹, Athos Bousvaros¹⁰, José M Cabrera¹¹, Kelly Y Chun⁸, Jill M Dorsey¹², Dawn R Ebach¹³, Ajay S Gulati¹⁴, Hans H Herfarth¹⁵, Anastasia Ivanova¹⁶, Traci W Jester¹⁷, Jess L Kaplan¹⁸, Mark E Kusek¹⁹, Ian H Leibowitz²⁰, Tiffany M Linville²¹, Peter A Margolis²², Phillip Minar²³, Zarela Molle-Rios²⁴, Barbara Joanna Niklinska-Schirtz²⁵, Kelly K Olano²⁶, Lourdes Osaba²⁷, Pablo J Palomo²⁸, Dinesh S Pashankar²⁹, Lisa Pitch³⁰, Charles M Samson³¹, Kelly C Sandberg³², Steven J Steiner³³, Jennifer A Strople³⁴, Jillian S Sullivan³⁵, Jeanne Tung³⁶, Prateek Wali³⁷, David A Wohl³⁸, Mike Zikry⁸, Brendan M Boyle³⁹, Michael D Kappelman⁵

Affiliations

¹ Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Stanford Medicine Children's Health, Palo Alto, CA, USA.
² Division of Gastroenterology, Hepatology, and Nutrition, C.S. Mott's Children's Hospital, Ann Arbor, MI, USA.
³ Susan B. Meister Child Health Evaluation and Research Center, University of Michigan, Ann Arbor, MI, USA.
⁴ Department of Medical Affairs, Dayton Children's Hospital and Wright State University, Dayton, OH, USA.
⁵ Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁶ Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Children's Hospital of The King's Daughters, Norfolk, VA, USA.
⁷ Department of Gastroenterology, Hepatology, and Nutrition, Children's Mercy Kansas City, Kansas City, MO, USA.
⁸ Esoterix Specialty Laboratory, Labcorp, Calabasas, CA, USA.
⁹ Division of Pediatric Gastroenterology, Icahn School of Medicine at Mt Sinai, New York, NY, USA.
¹⁰ Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA, USA.
¹¹ Division of Pediatric Gastroenterology, Department of Pediatrics, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee, WI, USA.
¹² Pediatric Gastroenterology, Hepatology, and Nutrition, Nemours Children's Specialty Care, Jacksonville, FL, USA.
¹³ Division of Pediatric Gastroenterology, Hepatology, Pancreatology, and Nutrition, Department of Pediatrics, University of Iowa, Iowa City, IA, USA.
¹⁴ Department of Pediatrics and Pathology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹⁵ Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹⁶ Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹⁷ Department of Pediatrics, Division of Gastroenterology, University of Alabama at Birmingham, Birmingham, AL, USA.
¹⁸ Division of Pediatric Gastroenterology, Mass General for Children and Harvard Medical School, Boston, MA, USA.
¹⁹ Division of Pediatric Gastroenterology, University of Nebraska Medical Center, Omaha, NE, USA.
²⁰ Division of Gastroenterology, Hepatology and Nutrition, Children's National Medical Center, Department of Pediatrics, George Washington University, Washington, D.C., USA.
²¹ Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Levine Children's Hospital, Charlotte, NC, USA.
²² Cincinnati Children's Research Foundation Chair in Improvement Science, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
²³ Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
²⁴ Division of Pediatric Gastroenterology, Nemours Children's Hospital, Wilmington, DE, USA.
²⁵ Division of Pediatric Gastroenterology, Department of Pediatrics, Emory University School of Medicine & Children's Healthcare of Atlanta, Atlanta, GA, USA.
²⁶ Division of Biostatistics and Epidemiology, Children's Hospital Medical Center, Cincinnati, OH, USA.
²⁷ Progenika Biopharma, a Grifols Company, Derio, Bizkaia, Spain.
²⁸ Division of Pediatric Gastroenterology, Nemours Children's Hospital, Orlando, FL, USA.
²⁹ Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA.
³⁰ ImproveCareNow Inc., Essex Junction, VT, USA.
³¹ Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Washington University School of Medicine, St Louis, MO, USA.
³² Division of Gastroenterology, Hepatology, and Nutrition, Dayton Children's Hospital, Dayton, OH, USA.
³³ Division of Pediatric Gastroenterology, Hepatology & Nutrition, Indiana University School of Medicine, Indianapolis, IN, USA.
³⁴ Division 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.
³⁵ The University of Vermont Children's Hospital and Department of Pediatrics, Larner College of Medicine, The University of Vermont, Burlington, VT, USA.
³⁶ University of Oklahoma Children's Physicians, Pediatric Gastroenterology, Oklahoma City, OK, USA.
³⁷ Division of Pediatric Gastroenterology, Hepatology, and Nutrition, State University of New York, Upstate Medical University, Syracuse, NY, USA.
³⁸ Division of Infectious Diseases, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
³⁹ Division of Gastroenterology, Hepatology, and Nutrition, Nationwide Children's Hospital, Columbus, OH, USA.

PMID: 39418336
DOI: 10.1093/ibd/izae239

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.

Keywords: biologics; inflammatory bowel disease; pediatrics; therapeutic drug monitoring.

Plain language summary

For children with Crohn’s disease treated with biologic medications, with and without low-dose methotrexate, the role of drug levels on treatment failure in a recent prospective trial is unclear. These data suggest patients on infliximab with therapeutic drug levels are more likely to continue any therapy, and the effect on patients treated with adalimumab requires more investigation.

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Abstract

Plain language summary

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