Abstract
Abstract Background Anti-drug antibodies (ADAs) are a primary factor in the loss of response to infliximab and other adverse drug reactions. The genetic variant HLA-DQA1*05 has been associated with infliximab antibody development in Crohn’s disease (CD) among European populations. This study aims to assess the relationship between HLA genotypes and ADA formation in non-European inflammatory bowel disease (IBD) patients receiving anti-tumor necrosis factor (TNF), anti-integrin, or anti-IL-12/23 therapies. Methods This prospective cohort study enrolled patients with IBD receiving anti-TNF, anti-integrin, or anti-IL-12/23 therapy between January 2022 and March 2024. NGS-based HLA genotyping was performed for all participants. The occurrence of ADAs was assessed, and the frequencies of specific HLA alleles were compared between patients who developed ADAs and those who did not. Additionally, HLA allele frequencies in ADA-positive patients were analyzed against the general population in Taiwan. Results A total of 95 patients with IBD were included in the study, along with HLA genotype data from 1,097 control individuals obtained from the Taiwan Biobank. Among the IBD patients, 58 received anti-TNF therapy, 27 underwent anti-integrin therapy, and 10 were treated with anti-IL-12/23 therapy. According to the reimbursement criteria in Taiwan, all patients have to be treated with conventional therapy and when with inadequate response or with adverse effects, then biologics would be reimbursed. Therefore, all the 95 patients were under the biologics and immunosuppressive agents (either thiopurine or methotrexate) combination therapy. No ADA development was observed in patients treated with anti-integrin or anti-IL-12/23 therapies. However, among the 58 patients treated with anti-TNF therapy (38 with infliximab and 20 with adalimumab), 21 developed ADAs (18 infliximab-related and 3 adalimumab-related). A comparison of patients with and without ADAs revealed a significant association between the HLA-C*03:04:01 allele and ADA development (33.3% vs. 10.8%, p=0.035), whereas the HLA-DQA1*05 allele showed no association (52.3% vs. 51.4%, p=0.940). The frequency of the HLA-C*03:04:01 allele was comparable between IBD patients and the broader Taiwanese population (16.8% vs. 11.2%, p=0.0915). Conclusion This study demonstrated that the different HLA locus associated with ADA development among different ethnics. While HLA-DQA1*05 was found in European cohort, our data showed that HLA-C*03:04:01 was significantly associated with an increased risk of anti-TNF antibodies formation in Taiwanese IBD patients.
Published Version
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