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

BACKGROUND & AIMS: Identifying patients at high risk of immunogenicity is important when selecting tumor necrosis factor (TNF)-a antagonists in patients with immune-mediated inflammatory diseases (IMIDs). We evaluated the association HLA-DQA1*05 genotype and risk of immunogenicity with TNF-a antagonists. METHODS: Through a systematic review through July 14, 2022, we identified studies in patients with IMIDs treated with TNF-a 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-a 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-a 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.