1. Carriage of the HLA-DQA1*05 allele is significantly associated with the development of antibodies against anti-TNF agents.
Evidence Rating Level: 2 (Good)
Anti-tumor necrosis factor (anti-TNF) therapies are the most widely used biologics for treating immune-mediated diseases. However, repeated administration can lead to the formation of anti-drug antibodies (immunogenicity), which can contribute to treatment failure. Thus, there is a critical need for methods to identify patients at an increased risk of immunogenicity to better inform treatment decisions. In this prospective cohort study, a genome-wide association study was performed on 1,240 biologic-naïve patients with active luminal Crohn’s disease starting infliximab or adalimumab to identify genomic variants associated with time to development of anti-drug antibodies. Immunogenicity was defined as an anti-drug antibody titer ≥10 AU/ml in a drug-tolerant ELISA assay. Significant association signals were confirmed in a replication cohort of 178 patients with inflammatory bowel disease. Researchers found that within the first 12 months, 44% of patients developed anti-drug antibodies (95% CI 41% to 48%), and 62% of patients did so within 36 months (95% CI 57% to 67%). After correcting for immunomodulator use, the rate of immunogenicity was greater in patients treated with infliximab (n=742) than adalimumab (n=498) (HR 3.21, 95% CI 2.61 to 3.95, p=1.18×10-28). Researchers also identified a short nucleotide polymorphism (SNP) on chromosome 6, rs2097432, which falls within the major histocompatibility complex (MHC) region, that is significantly associated with time to development of immunogenicity (b38_pos: 6:32622994; HR 1.70, 95% CI 1.48 to 1.94, p=4.24×10-13). This association was replicated in the independent cohort (HR 1.69, 95% CI, 1.26 to 2.28, p=8.80×10-4). At the human leukocyte antigen (HLA) allele group level, the HLA-DQA1*05 allele achieved genome-wide significance (HR 1.90, 95% CI 1.60 to 2.25, p=5.88×10-13). Fine-mapping and confirmatory sequencing of the HLA identified that the specific alleles HLA-DQA1*05:01 and HLA DQA1*05:05 mediated most of this risk. Concordantly, the highest rates of immunogenicity, 92% at 1 year, were observed in patients treated with infliximab monotherapy who carried HLA-DQA1*05. Conversely, the lowest rates of immunogenicity, 10% at 1 year, were observed in patients treated with adalimumab combination therapy who did not carry HLA-DQA1*05. This finding was confirmed in the replication cohort (HR 2.00, 95% CI 1.35 to 2.98, p=6.60×10-4). This association was consistent for patients treated with adalimumab (HR 1.89, 95% CI 1.32 to 2.70) or infliximab (HR 1.92, 95% CI 1.57 to 2.33). Overall, this study suggests that pre-treatment genetic testing for HLA-DQA1*05 may help personalize the choice of anti-TNF therapy and the need for combination therapy with an immunomodulator. However, due to the wide variation in the frequency of HLA-DQA1*05 across ethnic groups, further studies are required to assess the contribution of HLA-DQA1*05 to immunogenicity across populations.
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