Journal article
Low Anti-Tumor Necrosis Factor Levels During Maintenance Phase Are Associated With Treatment Failure in Children With Crohn's Disease
Inflammatory bowel diseases, Vol.31(7), pp.1841-1850
07/07/2025
DOI: 10.1093/ibd/izae239
PMID: 39418336
Abstract
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).BACKGROUNDHigher 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).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.METHODSWe 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.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).RESULTSAmong 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).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.CONCLUSIONSLD-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.
Details
- Title: Subtitle
- Low Anti-Tumor Necrosis Factor Levels During Maintenance Phase Are Associated With Treatment Failure in Children With Crohn's Disease
- Creators
- Jonathan Moses - Stanford MedicineJeremy Adler - University of MichiganShehzad A Saeed - Wright State UniversityAnn M Firestine - University of North Carolina at Chapel HillJoseph A Galanko - University of North Carolina at Chapel HillRana F Ammoury - Children's Hospital of The King's DaughtersDorsey M Bass - Stanford MedicineJulie A Bass - Children's Mercy HospitalMonique Bastidas - LabCorpKeith J Benkov - Icahn School of Medicine at Mount SinaiAthos Bousvaros - Boston Children's HospitalJosé M Cabrera - Children's Hospital of WisconsinKelly Y Chun - LabCorpJill M DorseyDawn R Ebach - University of IowaAjay S Gulati - University of North Carolina at Chapel HillHans H Herfarth - University of North Carolina at Chapel HillAnastasia Ivanova - University of North Carolina at Chapel HillTraci W Jester - University of Alabama at BirminghamJess L Kaplan - Massachusetts General HospitalMark E Kusek - University of Nebraska Medical CenterIan H Leibowitz - Children's NationalTiffany M Linville - Levine Children's HospitalPeter A Margolis - Cincinnati Children's Hospital Medical CenterPhillip Minar - University of CincinnatiZarela Molle-RiosBarbara Joanna Niklinska-Schirtz - Children's Healthcare of AtlantaKelly K Olano - Cincinnati Children's Hospital Medical CenterLourdes Osaba - GrifolsPablo J Palomo - Nemours Children's ClinicDinesh S Pashankar - Yale UniversityLisa PitchCharles M Samson - Washington University in St. LouisKelly C Sandberg - Dayton Children's HospitalSteven J Steiner - Indiana UniversityJennifer A Strople - Lurie Children's HospitalJillian S Sullivan - University of Vermont Children’s HospitalJeanne Tung - University of OklahomaPrateek Wali - SUNY Upstate Medical UniversityDavid A Wohl - University of North Carolina at Chapel HillMike Zikry - LabCorpBrendan M Boyle - Nationwide Children's HospitalMichael D Kappelman - University of North Carolina at Chapel Hill
- Resource Type
- Journal article
- Publication Details
- Inflammatory bowel diseases, Vol.31(7), pp.1841-1850
- DOI
- 10.1093/ibd/izae239
- PMID
- 39418336
- NLM abbreviation
- Inflamm Bowel Dis
- ISSN
- 1536-4844
- eISSN
- 1536-4844
- Publisher
- OXFORD UNIV PRESS INC
- Grant note
- Patient Centered Outcomes Research Institute: PCS-1406-18643 Helmsley Charitable Trust
This study was funded by grants from the Patient Centered Outcomes Research Institute (PCS-1406-18643) and the Helmsley Charitable Trust. Biosample supplies, shipping costs, and laboratory testing were provided in kind by Progenika Biopharma, a Grifols Company. Laboratory testing was also provided in kind by Esoterix Specialty Laboratory, Labcorp.
- Language
- English
- Electronic publication date
- 10/17/2024
- Date published
- 07/07/2025
- Academic Unit
- Stead Family Department of Pediatrics; Gastroenterology, Hepatology, Pancreatology, and Nutrition
- Record Identifier
- 9984736611102771
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