HLA-DQA1∗05 Genotype and Immunogenicity to Tumor Necrosis Factor-α Antagonists: A Systematic Review and Meta-analysis

Virginia Solitano; Antonio Facciorusso; Dermot P B McGovern; Tran Nguyen; Ruben J Colman; Lily Zou; Brigid S Boland; Silje W Syversen; Kristin Kaasen Jørgensen; Christopher Ma; Alessandro Armuzzi; Aze Wilson; Vipul Jairath; Siddharth Singh

doi:10.1016/j.cgh.2023.03.044

HLA-DQA1∗05 Genotype and Immunogenicity to Tumor Necrosis Factor-α Antagonists: A Systematic Review and Meta-analysis

Clin Gastroenterol Hepatol. 2023 Nov;21(12):3019-3029.e5. doi: 10.1016/j.cgh.2023.03.044. Epub 2023 Apr 13.

Authors

Affiliations

¹ Division of Gastroenterology, Department of Medicine, Western University, London, Ontario, Canada; Department of Biomedical Sciences, Humanitas University, Milan, Italy.
² Department of Medical Sciences, University of Foggia, Foggia, Italy.
³ F. Widjaja Inflammatory Bowel Research Institute, Cedars-Sinai Medical System, Los Angeles, California.
⁴ Division of Gastroenterology, Department of Medicine, Western University, London, Ontario, Canada.
⁵ Division of Paediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Stanford University School of Medicine, Stanford, California.
⁶ Department of Statistics and Actuarial Sciences, University of Waterloo, Waterloo, Ontario, Canada.
⁷ Center for Treatment of Rheumatic and Musculoskeletal Diseases (REMEDY), Diakonhjemmet Hospital, Oslo, Norway.
⁸ Department of Gastroenterology, Akershus University Hospital, Oslo, Norway.
⁹ Division of Gastroenterology and Hepatology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada.
¹⁰ Department of Biomedical Sciences, Humanitas University, Milan, Italy; IBD Center, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.
¹¹ Division of Gastroenterology, Department of Medicine, Western University, London, Ontario, Canada; Division of Clinical Pharmacology, Department of Medicine, Western University, London, Ontario, Canada; Department of Physiology and Pharmacology, Western University, London, Ontario, Canada.
¹² Division of Gastroenterology, Department of Medicine, Western University, London, Ontario, Canada; Department of Epidemiology and Biostatistics, Western University, London, Ontario, Canada.
¹³ Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, California; Division of Biomedical Informatics, Department of Medicine, University of California San Diego, La Jolla, California. Electronic address: sis040@ucsd.edu.

PMID: 37061107
DOI: 10.1016/j.cgh.2023.03.044

Abstract

Background & aims: Identifying patients at high risk of immunogenicity is important when selecting tumor necrosis factor (TNF)-α antagonists in patients with immune-mediated inflammatory diseases (IMIDs). We evaluated the association HLA-DQA1∗05 genotype and risk of immunogenicity with TNF-α antagonists.

Methods: Through a systematic review through July 14, 2022, we identified studies in patients with IMIDs treated with TNF-α antagonists, which reported the risk of immunogenicity and/or secondary loss of response in patients with HLA-DQA1∗05 variants. Primary outcome was risk of immunogenicity. We performed random effects meta-analysis and used GRADE to appraise certainty of evidence.

Results: On meta-analysis of 13 studies (3756 patients; median follow-up, 12 months; 41% with variants), HLA-DQA1∗05 variants were associated with 75% higher risk of immunogenicity compared with non-carriers (relative risk, 1.75; 95% confidence interval, 1.37-2.25) with considerable heterogeneity (I² = 62%) (low certainty evidence). Positive and negative predictive values of HLA-DQA1∗05 variants for predicting immunogenicity were 30% and 80%, respectively. Proactive therapeutic drug monitoring, but not concomitant use of IMMs, IMIDs, and TNF-α antagonist-type, modified this association. Patients with HLA-DQA1∗05 variants experienced 2.2-fold higher risk of secondary loss of response (6 cohorts; relative risk, 2.24; 95% confidence interval, 1.67-3.00; I² = 0%) (moderate certainty evidence).

Conclusion: Variants in HLA-DQA1∗05 are associated with an increased risk in immunogenicity and secondary loss of response in patients with IMIDs treated with TNF-α antagonists. However, the positive and negative predictive value is moderate, and decisions on concomitant use of IMMs to prevent immunogenicity should be individualized based on all factors that influence drug clearance.

Keywords: Biologics; Crohn’s Disease; Pharmacogenomics; Rheumatoid Arthritis.

Publication types

Meta-Analysis
Systematic Review
Review
Research Support, N.I.H., Extramural

MeSH terms

Genotype
Humans
Immunomodulating Agents
Tumor Necrosis Factor Inhibitors*
Tumor Necrosis Factor-alpha*

Substances

Tumor Necrosis Factor-alpha
HLA-DQA1 antigen
Tumor Necrosis Factor Inhibitors
Immunomodulating Agents

Abstract

Publication types

MeSH terms

Substances

Grants and funding