Identifying Genetic Factors Influencing the Development of Anti-Drug Antibodies in Inflammatory Bowel Disease: A...

Biologic therapies such as infliximab and adalimumab have transformed the management of inflammatory bowel disease. However, many patients experience primary or secondary loss of response, often due to the development of anti-drug antibodies. The cause of anti-drug antibody formation is thought to be influenced by genetic variations, with human leukocyte antigen alleles-particularly HLA-DQA1*05-emerging as consistent risk factors for immunogenicity, but other candidate variants may also be of importance. To explore the role of genetic predictors in anti-drug antibody development, we systematically reviewed the literature. A search of Medline, Embase, and the Cochrane Library identified 1944 records, of which 27 studies met inclusion criteria. Across these studies, HLA-DQA1*05 carriage was repeatedly associated with higher antibody formation, lower drug levels, treatment failure, and secondary loss of response. Other HLA alleles and FCGR3A variants were also linked to increased risk, while some haplotypes appeared protective. Findings varied depending on the drug, genetic background, and patient population. The role of concomitant immunomodulator therapy was inconsistent, though some genotypes appeared to benefit. Overall, HLA-DQA1*05 and FCGR3A variants are the most reliable predictors of immunogenicity, particularly in infliximab-treated patients. Future work should prioritize large, multi-ethnic prospective studies with standardized antibody measurements and integrated pharmacogenomic approaches to establish clinical utility.