TY - JOUR
T1 - HLA-DQA1∗05 Genotype and Immunogenicity to Tumor Necrosis Factor-α Antagonists
T2 - A Systematic Review and Meta-analysis
AU - Solitano, Virginia
AU - Facciorusso, Antonio
AU - McGovern, Dermot P. B.
AU - Nguyen, Tran
AU - Colman, Ruben J.
AU - Zou, Lily
AU - Boland, Brigid S.
AU - Syversen, Silje W.
AU - Jørgensen, Kristin Kaasen
AU - Ma, Christopher
AU - Armuzzi, Alessandro
AU - Wilson, Aze
AU - Jairath, Vipul
AU - Singh, Siddharth
N1 - Funding Information: Funding Siddarth Singh is supported by National Institute of Diabetes and Digestive and Kidney Diseases K23DK117058 and R03DK129631 . The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Publisher Copyright: © 2023 AGA Institute
PY - 2023/11
Y1 - 2023/11
N2 - 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.
AB - 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.
KW - Biologics
KW - Crohn's Disease
KW - Pharmacogenomics
KW - Rheumatoid Arthritis
UR - http://www.scopus.com/inward/record.url?scp=85160062866&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.cgh.2023.03.044
DO - https://doi.org/10.1016/j.cgh.2023.03.044
M3 - Review article
C2 - 37061107
SN - 1542-3565
VL - 21
SP - 3019-3029.e5
JO - Clinical Gastroenterology and Hepatology
JF - Clinical Gastroenterology and Hepatology
IS - 12
ER -