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©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
HLA-C*03:04:01 and HLA-B*15:18:01 but not HLA-DQA1*05 associated with anti- tumor necrosis factor antibody formation in Taiwanese inflammatory bowel disease patients
Meng-Tzu Weng, Chi-Yuan Yao, Wei-Chen Lin, Sheng-Kai Lai, Chien-Chih Tung, Chun-Ying Wang, Jau-Min Wong, Pei-Lung Chen, Shu-Chen Wei
Meng-Tzu Weng, Jau-Min Wong, Pei-Lung Chen, Shu-Chen Wei, Department of Internal Medicine, National Taiwan University Hospital, Taipei 100, Taiwan
Meng-Tzu Weng, Chun-Ying Wang, Department of Medical Research, National Taiwan University Hospital, Hsin-Chu Branch, Hsinchu 302, Taiwan
Chi-Yuan Yao, Department of Laboratory Medicine, National Taiwan University Hospital, Taipei 100, Taiwan
Wei-Chen Lin, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mackay Memorial Hospital, Taipei 10449, Taiwan
Sheng-Kai Lai, Pei-Lung Chen, Department of Medical Genetics, National Taiwan University Hospital, Taipei 100, Taiwan
Chien-Chih Tung, Department of Integrated Diagnostics and Therapeutics, National Taiwan University Hospital, Taipei 100, Taiwan
Pei-Lung Chen, Graduate Institute of Medical Genomics and Proteomics, National Taiwan University, Taipei 100, Taiwan
Author contributions: Wei SC and Chen PL contributed to important intellectual content and led the study; Weng MT contributed to study design; Wei SC, Lin WC, Tung CC, and Weng MT contributed to recruited the subjects; Yao CY and Lai SK contributed to performed the sequencing analysis; Yao CY and Wang CY contributed to interpreted the sequencing results and conducted statistical analyses; Wong JM contributed to supervised the study; Wei SC and Weng MT drafted the manuscript. All authors reviewed, revised, and approved the final version of the manuscript.
Supported by Ministry of Science and Technology, Taiwan, No. MOST 111-2314-B-002-226; National Taiwan University Hospital, Hsin-Chu Branch, No. 112-BIH017; and The Liver Disease Prevention and Treatment Research Foundation, Taiwan.
Institutional review board statement: The study was reviewed and approved by the Institutional Review Board of National Taiwan University Hospital, No. 202112095RIND.
Informed consent statement: All involved patients gave their written informed consent prior to study inclusion.
Conflict-of-interest statement: Dr. Wei reports consultancy fees from AbbVie, Celltrion, Ferring Pharmaceuticals Inc., Janssen, Pfizer Inc, Takeda, and Tanabe, and speaker fees from AbbVie, Celltrion, Excelsior Biopharma Inc., Ferring Pharmaceuticals Inc., Pfizer Inc, Janssen, Takeda and Tanabe, outside the submitted work.
STROBE statement: The authors have read the STROBE Statement-checklist of items, and the manuscript was prepared and revised according to the STROBE Statement-checklist of items.
Data sharing statement: Dataset available from the corresponding author.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
https://creativecommons.org/Licenses/by-nc/4.0/ Corresponding author: Shu-Chen Wei, MD, PhD, Professor, Department of Internal Medicine, National Taiwan University Hospital, No. 7 Chung-Shan South Road, Taipei 100, Taiwan.
shuchenwei@ntu.edu.tw
Received: July 11, 2025
Revised: August 12, 2025
Accepted: September 28, 2025
Published online: November 7, 2025
Processing time: 121 Days and 3.1 Hours
BACKGROUND
Anti-drug antibodies (ADAs) can reduce the effectiveness of biologics. While human leukocyte antigen (HLA)-DQA1*05 allele is linked to ADA formation in European Crohn’s disease patients, its relevance in non-European populations remains unclear.
AIM
To investigate HLA genotypes associated with the development of ADAs in Taiwanese inflammatory bowel disease (IBD) patients treated with biologics.
METHODS
In this multicenter study, IBD patients treated with anti-tumor necrosis factor (TNF), anti-integrin, or anti-interleukin (IL)-12/23 therapies from April 2022 to June 2024 were enrolled. All participants underwent next-generation sequencing for HLA genotyping. ADA levels were measured via enzyme linked immunosorbent assay. HLA allele frequencies were compared between ADA-positive and ADA-negative groups, and against general Taiwanese population data.
RESULTS
Ninety-five IBD patients were included: 58 received anti-TNF therapy (38 infliximab, 20 adalimumab), 27 anti-integrin, and 10 anti-IL-12/23. ADAs occurred only in the anti-TNF group (n = 22): 19 infliximab (50%) and 3 adalimumab (15%). No ADAs developed in patients on anti-integrin or anti-IL-12/23 agents. HLA-C*03:04:01 was significantly associated with anti-infliximab ADAs (31.6% vs 0%, P = 0.02), and HLA-B*15:18:01 with anti-adalimumab ADAs (66.7% vs 0%, P = 0.016). HLA-DQA1*05 was not associated with ADA formation. Frequencies of HLA-C*03:04:01 (8.4% vs 10.5%) and HLA-B*15:18:01 (1.6% vs 0.6%) in IBD patients were comparable to those in the general population. ADA titers were inversely correlated with serum drug levels.
CONCLUSION
In Taiwanese IBD patients, HLA-C*03:04:01 and HLA-B*15:18:01 were significantly associated with ADA development to infliximab and adalimumab, respectively. HLA-DQA1*05 was not predictive, highlighting ethnic differences in genetic predisposition to immunogenicity.
Core Tip: The development of anti-drug antibodies (ADA) compromises the effectiveness of biologic therapies in treating inflammatory bowel disease. In European inflammatory bowel disease patients receiving anti-tumor necrosis factor therapy, the human leukocyte antigen (HLA)-DQA1*05 allele has been strongly associated with increased ADA formation. However, this association does not appear to hold in Taiwanese patients. Instead, distinct HLA variants have emerged: HLA-C*03:04:01 is linked to ADA formation in those treated with infliximab, while HLA-B*15:18:01 is associated with immunogenicity to adalimumab. Notably, in the Taiwanese cohort, HLA-DQA1*05 does not predict ADA development during anti-tumor necrosis factor treatment.
