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

Table 1 Summary of human leukocyte antigen alleles associated with anti-drug antibody formation across ethnic groups in inflammatory bowel disease

HLA allele	Class	Ethnic group	Biologic	Key finding/ADA risk	Ref.
HLA-DQA1*05 (group)	II	European	IFX, ADA	HR = 1.90 (95%CI: 1.60-2.25); 92% ADA rate at 1 year with IFX monotherapy in carriers	Sazonovs et al[10]
HLA-DQA1*05:01	II	European	IFX	Specifically shortens time-to-LoR to infliximab; actionable by switching to adalimumab monotherapy	Hodges et al[13]; Ternette et al[14]
HLA-DQA1*05:05	II	European	IFX, ADA	Shortens time-to-LoR to both IFX and ADA; mitigated by concomitant immunomodulator (number needed to treat approximately 5 to prevent one drug-clearing ADA)	Hodges et al[13], Ternette et al[14]
HLA-DQB1*03:01	II	Japanese	IFX	HR = 2.03 (P = 9.42 × 10-5) for IFX discontinuation; subsumes DQA1*05:05 information in Japanese patients	Osaka et al[15]
HLA-C*03:04:01	I	Taiwanese	IFX	31.6% of ADA-positive vs 0% of ADA-negative patients (P = 0.02); prior autoimmune associations	Weng et al[19]
HLA-B*15:18:01	I	Taiwanese	ADA	66.7% of ADA-positive vs 0% of ADA-negative patients (P = 0.016); linked to Drug-Induced Liver Injury and aplastic anaemia outcomes	Weng et al[19]
HLA-DQA1*05 (group)	II	Taiwanese (25.3% allele frequency)	IFX, ADA	No significant association with ADA formation despite comparable carriage frequency; fails to predict in this cohort	Weng et al[19]; Pascual-Oliver et al[7]

ADA: Anti-drug antibodies; HLA: Human leukocyte antigen; HR: Hazard ratio; IFX: Infliximab; LoR: Loss of response.

Table 2 Proposed ethnically stratified clinical decision framework integrating human leukocyte antigen genotype and therapeutic drug monitoring for biologic therapy in inflammatory bowel disease

Clinical scenario	HLA genotype	TDM strategy	Recommended biologic approach	Ref.
European patient, anti-TNF naïve	HLA-DQA1*05:01 carrier	Proactive TDM post-induction; monitor trough levels	Adalimumab monotherapy; avoid infliximab entirely	Hodges et al[13]; Chanchlani et al[9]
European patient, anti-TNF naïve	HLA-DQA1*05:05 carrier	Proactive TDM; monitor ADA titers from induction	IFX or ADA with concomitant immunomodulator; number needed to treat approximately 5 to prevent drug-clearing ADA	Hodges et al[13]; Papamichael et al[28]
Japanese patient, anti-TNF naïve	HLA-DQB1*03:01 carrier	Proactive TDM from induction; closely monitor IFX persistence	IFX + concomitant immunomodulator; consider alternative class if monotherapy required	Osaka et al[15]
Taiwanese patient, naïve to IFX	HLA-C*03:04:01 carrier	Reactive TDM with early ADA titer surveillance	Prefer adalimumab, ustekinumab, or vedolizumab over infliximab	Weng et al[19]; Ashraf et al[51]
Taiwanese patient, naïve to ADA	HLA-B*15:18:01 carrier	Reactive TDM; early switch protocol if ADA detected	Avoid adalimumab; use IFX + immunomodulator or ustekinumab	Weng et al[19]; Atreya and Neurath[6]
Any patient with secondary loss of response	Any relevant allele (or unknown)	Reactive TDM (drug trough + ADA titers)	Dose-optimise for pharmacokinetic failure; switch biologic class for high-titer immunological failure	Chanchlani et al[9]; Sazonovs et al[10]

ADA: Adalimumab; HLA: Human leukocyte antigen; IFX: Infliximab; TDM: Therapeutic drug monitoring; TNF: Tumor necrosis factor.