Randomized Controlled Trial

. 2025 May 1;120(5):1076-1086.

doi: 10.14309/ajg.0000000000003135. Epub 2024 Oct 18.

HLA DQA1*05 and Risk of Antitumor Necrosis Factor Treatment Failure and Anti-Drug Antibody Development in Children With Crohn's Disease

Jeremy Adler^{1

2}, Joseph A Galanko³, Rana Ammoury⁴, Keith J Benkov⁵, Athos Bousvaros⁶, Brendan Boyle⁷, José M Cabrera⁸, Kelly Y Chun⁹, Jill Dorsey¹⁰, Dawn R Ebach¹¹, Ann M Firestine¹², Ajay S Gulati^{3

12}, Hans H Herfarth¹³, Traci W Jester¹⁴, Jess L Kaplan¹⁵, Ian Leibowitz¹⁶, Tiffany M Linville¹⁷, Peter A Margolis¹⁸, Phillip Minar¹⁸, Zarela Molle-Rios¹⁹, Jonathan Moses²⁰, Kelly Olano²¹, Dinesh S Pashankar²², Lisa Pitch²³, Shehzad A Saeed²⁴, Charles M Samson²⁵, Kelly Sandberg²⁴, Steven J Steiner²⁶, Jennifer A Strople²⁷, Jillian S Sullivan²⁸, Prateek D Wali²⁹, Michael D Kappelman³

Affiliations

¹ Division of Pediatric Gastroenterology, C.S. Mott's Children's Hospital, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA.
² Susan B. Meister Child Health Evaluation and Research Center, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA.
³ Department of Pediatrics, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
⁴ Department of Pediatrics, Children's Hospital of the King's Daughters, Norfolk, Virginia, USA.
⁵ Icahn School of Medicine at Mount Sinai, New York, New York, USA.
⁶ Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, Massachusetts, USA.
⁷ Division of Gastroenterology, Hepatology and Nutrition, Nationwide Children's Hospital, Columbus, Ohio, USA.
⁸ Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
⁹ LabCorp Diagnostics, Burlington, North Carolina, USA.
¹⁰ Nemours Children's Health, Jacksonville, Florida.
¹¹ Division of Pediatric Gastroenterology, University of Iowa, Iowa City, Iowa, USA.
¹² Department of Pathology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
¹³ Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina, Chapel Hill, North Carolina, USA.
¹⁴ Division of Gastroenterology, Hepatology and Nutrition, University of Alabama at Birmingham, Children's of Alabama, Birmingham, Alabama, USA.
¹⁵ Division of Pediatric Gastroenterology, Mass General for Children, Harvard Medical School, Boston, Massachusetts, USA.
¹⁶ George Washington University School of Medicine, Children's National Medical Center, Washington, District of Columbia, USA.
¹⁷ Atrium Health Levine Children's Hospital, Charlotte, North Carolina, USA.
¹⁸ Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
¹⁹ Nemours Children's Health, Wilmington, North Carolina, USA.
²⁰ Division of Pediatric Gastroenterology, Hepatology, and Nutrition, UH Rainbow Babies and Children's Hospital, Cleveland, Ohio, USA.
²¹ Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
²² Department of Pediatrics (Gastroenterology), Yale University School of Medicine, New Haven, Connecticut, USA.
²³ ImproveCareNow Inc., Essex Junction, Vermont, USA.
²⁴ Department of Gastroenterology, Dayton Children's Hospital, Boonshoft School of Medicine, Wright State University, Dayton, Ohio, USA.
²⁵ Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Washington University in St. Louis School of Medicine, St. Louis, Missouri, USA.
²⁶ Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, Indiana, USA.
²⁷ Ann & Robert H. Lurie Children's Hospital of Chicago, Department of Pediatrics, Northwestern Feinberg School of Medicine, Chicago, Illinois, USA.
²⁸ Larner College of Medicine at the University of Vermont, Burlington, Vermont, USA.
²⁹ Division of Pediatric Gastroenterology, Hepatology, and Nutrition, State University of New York, Upstate Medical University, Syracuse, New York, USA.

PMID: 40315028
DOI: 10.14309/ajg.0000000000003135

Randomized Controlled Trial

HLA DQA1*05 and Risk of Antitumor Necrosis Factor Treatment Failure and Anti-Drug Antibody Development in Children With Crohn's Disease

Jeremy Adler et al. Am J Gastroenterol. 2025.

. 2025 May 1;120(5):1076-1086.

doi: 10.14309/ajg.0000000000003135. Epub 2024 Oct 18.

Authors

Affiliations

¹ Division of Pediatric Gastroenterology, C.S. Mott's Children's Hospital, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA.
² Susan B. Meister Child Health Evaluation and Research Center, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA.
³ Department of Pediatrics, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
⁴ Department of Pediatrics, Children's Hospital of the King's Daughters, Norfolk, Virginia, USA.
⁵ Icahn School of Medicine at Mount Sinai, New York, New York, USA.
⁶ Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, Massachusetts, USA.
⁷ Division of Gastroenterology, Hepatology and Nutrition, Nationwide Children's Hospital, Columbus, Ohio, USA.
⁸ Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
⁹ LabCorp Diagnostics, Burlington, North Carolina, USA.
¹⁰ Nemours Children's Health, Jacksonville, Florida.
¹¹ Division of Pediatric Gastroenterology, University of Iowa, Iowa City, Iowa, USA.
¹² Department of Pathology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
¹³ Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina, Chapel Hill, North Carolina, USA.
¹⁴ Division of Gastroenterology, Hepatology and Nutrition, University of Alabama at Birmingham, Children's of Alabama, Birmingham, Alabama, USA.
¹⁵ Division of Pediatric Gastroenterology, Mass General for Children, Harvard Medical School, Boston, Massachusetts, USA.
¹⁶ George Washington University School of Medicine, Children's National Medical Center, Washington, District of Columbia, USA.
¹⁷ Atrium Health Levine Children's Hospital, Charlotte, North Carolina, USA.
¹⁸ Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
¹⁹ Nemours Children's Health, Wilmington, North Carolina, USA.
²⁰ Division of Pediatric Gastroenterology, Hepatology, and Nutrition, UH Rainbow Babies and Children's Hospital, Cleveland, Ohio, USA.
²¹ Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
²² Department of Pediatrics (Gastroenterology), Yale University School of Medicine, New Haven, Connecticut, USA.
²³ ImproveCareNow Inc., Essex Junction, Vermont, USA.
²⁴ Department of Gastroenterology, Dayton Children's Hospital, Boonshoft School of Medicine, Wright State University, Dayton, Ohio, USA.
²⁵ Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Washington University in St. Louis School of Medicine, St. Louis, Missouri, USA.
²⁶ Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, Indiana, USA.
²⁷ Ann & Robert H. Lurie Children's Hospital of Chicago, Department of Pediatrics, Northwestern Feinberg School of Medicine, Chicago, Illinois, USA.
²⁸ Larner College of Medicine at the University of Vermont, Burlington, Vermont, USA.
²⁹ Division of Pediatric Gastroenterology, Hepatology, and Nutrition, State University of New York, Upstate Medical University, Syracuse, New York, USA.

PMID: 40315028
DOI: 10.14309/ajg.0000000000003135

Abstract

Introduction: Human leukocyte antigen (HLA) DQA1*05 has been associated with the development of anti-drug antibodies (ADA) to tumor necrosis factor antagonists (anti-TNFα) and treatment failure among adults with Crohn's disease (CD). However, findings from other studies have been inconsistent with limited pediatric data.

Methods: We analyzed banked serum from patients with CD aged <21 years enrolled in clinical outcomes of Methotrexate Binary Therapy in practice, a multicenter, prospective randomized trial of anti-TNFα monotherapy vs combination with methotrexate. The primary outcome was a composite of factors indicative of treatment failure. The secondary outcome was ADA development.

Results: A trend toward increased treatment failure among HLA DQA1*05-positive participants was not significant (hazard ratio 1.58, 95% confidence interval [CI] 0.95-2.62; P = 0.08). After stratification by HLA DQA1*05 and by methotrexate vs placebo, patients who were HLA DQA1*05 negative and assigned to methotrexate experienced less treatment failures than HLA DQA1*05-positive patients on placebo (hazard ratio 0.31, 95% CI 0.13-0.70; P = 0.005). A trend toward increased ADA development among HLA DQA1*05-positive participants was not significant (odds ratio 1.96, 95% CI 0.90-4.31, P = 0.09). After further stratification, HLA DQA1*05-negative participants assigned to methotrexate were less likely to develop ADA relative to HLA DQA1*05-positive patients on placebo (odds ratio 0.12, 95% CI 0.03-0.55; P = 0.008).

Discussion: In a randomized trial of children with CD initiating anti-TNFα, 40% were HLA DQ-A1*05 positive, which was associated with a trend toward increased risk of both treatment failure and ADA. These risks were mitigated, but not eliminated, by adding oral methotrexate. HLA DQ-A1*05 is an important biomarker for prognosis and risk stratification.

Keywords: drug persistence; genotype; loss of response; pediatric.

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References

1. Herzog D, Fournier N, Buehr P, et al. Prevalence of intestinal complications in inflammatory bowel disease: A comparison between paediatric-onset and adult-onset patients. Eur J Gastroenterol Hepatol 2017;29(8):926–31.
1. Chaparro M, Garre A, Ricart E, et al. Differences between childhood- and adulthood-onset inflammatory bowel disease: The CAROUSEL study from GETECCU. Aliment Pharmacol Ther 2019;49(4):419–28.
1. Kugathasan S, Denson LA, Walters TD, et al. Prediction of complicated disease course for children newly diagnosed with Crohn's disease: A multicentre inception cohort study. Lancet 2017;389(10080):1710–8.
1. Walters TD, Kim MO, Denson LA, et al. Increased effectiveness of early therapy with anti-tumor necrosis factor-α vs an immunomodulator in children with Crohn's disease. Gastroenterology 2014;146(2):383–91.
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PCS-1406-18643/Gary and Rachel Glick Charitable Fund, Patient-Centered Outcomes Research Institute, Leona M. and Harry B. Helmsley Charitable Trust

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HLA DQA1*05 and Risk of Antitumor Necrosis Factor Treatment Failure and Anti-Drug Antibody Development in Children With Crohn's Disease

Affiliations

HLA DQA1*05 and Risk of Antitumor Necrosis Factor Treatment Failure and Anti-Drug Antibody Development in Children With Crohn's Disease

Authors

Affiliations

Abstract

References

Publication types

MeSH terms

Substances

Supplementary concepts

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Research Materials