HLA-DQA1*05 correlates with increased risk of anti-drug antibody development and reduced response to infliximab in Chinese patients with Crohn’s disease

Abstract

Background: The efficacy of anti-TNF therapy in Crohn’s disease (CD), such as infliximab, is often compromised by the development of anti-drug antibodies (ADAs). The genetic variation HLA-DQA1*05 has been linked to the immunogenicity of biologics, influencing ADA formation. This study investigates the correlation between HLA-DQA1*05 and ADA formation in CD patients treated with infliximab in a Chinese Han population and assesses clinical outcomes. Methods: In this retrospective cohort study, 345 infliximab-exposed CD patients were genotyped for HLADQ A1*05A > G (rs2097432). We evaluated the risk of ADA development, loss of infliximab response, adverse events, and treatment discontinuation among variant and wild-type allele individuals. Results: A higher percentage of patients with ADAs formation was observed in HLA-DQA1*05 G variant carriers compared with HLADQA1*05 wild-type carriers (58.5% vs 42.9%, P ¼ 0.004). HLA-DQA1*05 carriage significantly increased the risk of ADAs development (adjusted hazard ratio ¼ 1.65, 95% CI 1.18–2.30, P ¼ 0.003) and was associated with a greater likelihood of infliximab response loss (adjusted HR ¼ 2.55, 95% CI 1.78–3.68, P < 0.0001) and treatment discontinuation (adjusted HR ¼ 2.21, 95% CI 1.59–3.06, P < 0.0001). Interestingly, combined therapy with immunomodulators increased the risk of response loss in HLA-DQA1*05 variant carriers. Conclusions: HLA-DQA1*05 significantly predicts ADAs formation and impacts treatment outcomes in infliximab-treated CD patients. Pre-treatment screening for this genetic factor could therefore be instrumental in personalizing anti-TNF therapy strategies for these patients.