HLA DQA1*05 and Risk of Antitumor Necrosis Factor Treatment Failure and Anti-Drug Antibody Development in Children With Crohn's Disease.
Kelly Olano, Prateek D Wali, Kelly Y Chun, Keith J Benkov, Rana Ammoury, Michael D Kappelman, Jennifer A Strople, Athos Bousvaros, Jeremy Adler, Lisa Pitch, Phillip Minar, Joseph A Galanko, Zarela Molle-Rios, Brendan Boyle, Jonathan Moses, Shehzad A Saeed, Ann M Firestine, Peter A Margolis, Ian Leibowitz, Jill Dorsey, Hans H Herfarth, Ajay S Gulati, Dinesh S Pashankar, Jess L Kaplan, Jillian S Sullivan, José M Cabrera, Kelly Sandberg, Steven J Steiner, Charles M Samson, Tiffany M Linville, Traci W Jester, Dawn R Ebach
Journal: The American journal of gastroenterology
2025;120(5):1076-1086
PMID: 40315028
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.
Copyright © 2024 by The American College of Gastroenterology.
Address:
Division of Pediatric Gastroenterology, C.S. Mott's Children's Hospital, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA.; Susan B. Meister Child Health Evaluation and Research Center, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA.; Department of Pediatrics, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.; Department of Pediatrics, Children's Hospital of the King's Daughters, Norfolk, Virginia, USA.; Icahn School of Medicine at Mount Sinai, New York, New York, USA.; Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, Massachusetts, USA.; Division of Gastroenterology, Hepatology and Nutrition, Nationwide Children's Hospital, Columbus, Ohio, USA.; Medical College of Wisconsin, Milwaukee, Wisconsin, USA.; LabCorp Diagnostics, Burlington, North Carolina, USA.; Nemours Children's Health, Jacksonville, Florida.; Division of Pediatric Gastroenterology, University of Iowa, Iowa City, Iowa, USA.; Department of Pathology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.; Department of Pediatrics, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.; Department of Pathology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.; Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina, Chapel Hill, North Carolina, USA.; Division of Gastroenterology, Hepatology and Nutrition, University of Alabama at Birmingham, Children's of Alabama, Birmingham, Alabama, USA.; Division of Pediatric Gastroenterology, Mass General for Children, Harvard Medical School, Boston, Massachusetts, USA.; George Washington University School of Medicine, Children's National Medical Center, Washington, District of Columbia, USA.; Atrium Health Levine Children's Hospital, Charlotte, North Carolina, USA.; Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.; Nemours Children's Health, Wilmington, North Carolina, USA.; Division of Pediatric Gastroenterology, Hepatology, and Nutrition, UH Rainbow Babies and Children's Hospital, Cleveland, Ohio, USA.; Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.; Department of Pediatrics (Gastroenterology), Yale University School of Medicine, New Haven, Connecticut, USA.; ImproveCareNow Inc., Essex Junction, Vermont, USA.; Department of Gastroenterology, Dayton Children's Hospital, Boonshoft School of Medicine, Wright State University, Dayton, Ohio, USA.; Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Washington University in St. Louis School of Medicine, St. Louis, Missouri, USA.; Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, Indiana, USA.; Ann & Robert H. Lurie Children's Hospital of Chicago, Department of Pediatrics, Northwestern Feinberg School of Medicine, Chicago, Illinois, USA.; Larner College of Medicine at the University of Vermont, Burlington, Vermont, USA.; Division of Pediatric Gastroenterology, Hepatology, and Nutrition, State University of New York, Upstate Medical University, Syracuse, New York, USA.
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MeSH Terms:
Humans,
Crohn Disease,
Methotrexate,
Male,
Female,
Child,
Adolescent,
Treatment Failure,
HLA-DQ alpha-Chains,
Tumor Necrosis Factor-alpha,
Prospective Studies,
Drug Therapy, Combination,
Adalimumab,
Immunosuppressive Agents,
Antibodies,
Young Adult