Ethnic divergence in human leukocyte antigen-linked immunogenicity in inflammatory bowel disease

Abstract

Inflammatory bowel disease (IBD), encompassing both Crohn’s disease and ulcerative colitis, poses significant treatment challenges due to its complex etiology and variable therapeutic responses. Anti-tumor necrosis factor biologic therapies have substantially reduced corticosteroid dependence, hospitalization rates, and the need for surgery in moderate-to-severe IBD, yet their clinical utility is frequently compromised by the development of anti-drug antibodies (ADAs) which reduce drug trough levels, diminish therapeutic response, and accelerate treatment failure. Concomitant immunomodulator co-therapy attenuates ADA formation by approximately 47%, but introduces competing risks that necessitate individualized benefit-risk assessment. While the genetic determinants of immunogenicity have been characterized extensively in European populations – most notably the human leukocyte antigen (HLA)-DQA1*05 allele – a clinically consequential gap persists in non-European ethnic groups. This opinion review critically evaluates the work, which identified HLA class I alleles HLA-C*03:04:01 and HLA-B*15:18:01 as ethnic-specific predictors of ADA formation in Taiwanese IBD patients, challenging the presumed universality of HLA-DQA1*05. We place these findings within the broader context of a shifting global IBD epidemiological burden, newly refined four-digit allele subtype evidence in European and East Asian populations, the mechanistic basis of HLA class I-driven immunogenicity, the complementary roles of immunomodulator co-therapy and therapeutic drug monitoring, and the broader precision pharmacogenomics agenda in IBD. We propose that pre-treatment ethnically calibrated HLA-based stratification, integrated with therapeutic drug monitoring-guided monitoring, represents the next frontier in biologic optimization and immunologic safety in IBD.

Keywords: Inflammatory bowel disease; Anti-drug antibodies; Human leukocyte antigen genotyping; Immunogenicity; Precision medicine; Therapeutic drug monitoring; Crohn’s disease; Ulcerative colitis

Core Tip: This opinion review contextualizes the landmark findings, which identified human leukocyte antigen (HLA)-C*03:04:01 and HLA-B*15:18:01 as ethnic-specific risk alleles for anti-drug antibody formation in Taiwanese inflammatory bowel disease (IBD) patients receiving infliximab and adalimumab, respectively, challenging the universality of HLA-DQA1*05 as a pharmacogenomic predictor of anti-tumor necrosis factor immunogenicity. We integrate these findings within: (1) The shifting global IBD epidemiology; (2) Four-digit allele subtype behavior in European and East Asian populations; (3) Mechanistic pathways including cross-presentation, peptide-groove structural specificity, and killer cell immunoglobulin-like receptor-mediated tolerance regulation; (4) The complementary roles of immunomodulator co-therapy and therapeutic drug monitoring; and (5) The broader precision pharmacogenomics agenda in IBD. Global multi-ethnic collaboration to validate allele-immunogenicity associations is an ethical and clinical imperative.