HLA-DQA1*05 Genotype and Immunogenicity to Tumor Necrosis Factor-a 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.

Automated summary

This study evaluated the association between HLA-DQA1*05 genotype and the risk of immunogenicity with TNF-a antagonists in patients with IMIDs. The meta-analysis showed that patients with HLA-DQA1*05 variants had a 75% higher risk of immunogenicity compared to non-carriers. The study also found that patients with HLA-DQA1*05 variants had a higher risk of secondary loss of response.