590 - HLA-DQA1 Contributes to the Development of Antibodies to Anti-TNF Therapy in Crohn's Disease

Sazonovs, Aleksejs; Kennedy, Nicholas A.; Bewshea, Claire; Moutsianas, Loukas; Walker, Gareth; Lange, Katrina De; Goodhand, James; Anderson, Carl W.; Barrett, Jeffrey C.; Ahmad, Tariq; Consortium, PANTS

doi:10.1016/s0016-5085(18)30843-6

Cited by 38 publications

(68 citation statements)

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“…The translation of genetic data into functional science and then into clinical application poses both a challenge and an opportunity to IBD researchers, as can be seen in the recent association between anti‐TNF therapy antibody formation in patients with specific HLA‐DQA alleles . Common pathways between autoimmune conditions, including IBD, may reveal additional treatment options amongst existing medications and present novel pathways for new therapies to target.…”

Section: Discussionmentioning

confidence: 99%

“…This effect was constant with (HR 2.0) or without (HR 1.75) concurrent immunosuppression, with up to 92% of patients treated with anti‐TNF monotherapy carrying the HLA‐DQA1*05 having antibody formation at one year. However, importantly, the study did not associate this increase in antigenicity with an increased loss of response to anti‐TNF therapies . Clinical testing for this genotype is heavily limited by the lack of impact on disease outcome, however the PANTS data do provide a clear roadmap for future utility of HLA genotyping to personalise therapy, including targeted use of monotherapy, combination therapy and new generation monoclonals.…”

Section: Implication Of Hla In Medication Response and Reactionmentioning

confidence: 94%

“…Recent data from the PANTS study, focusing on the genetic factors effecting response to anti‐TNF therapy, reported the HLA‐DQA1*05 genotype as being significantly associated with higher rates of antibody formation against both infliximab (hazard ratio, HR 1.91) and adalimumab (HR 1.89) . This is a common genotype in Northern European individuals having an allele frequency ~0.25 .…”

Section: Implication Of Hla In Medication Response and Reactionmentioning

confidence: 99%

“…However, importantly, the study did not associate this increase in antigenicity with an increased loss of response to anti-TNF therapies. 110 Clinical testing for this genotype is heavily limited by the lack of impact on disease outcome, however the PANTS data do provide a clear roadmap for future utility of HLA genotyping to personalise therapy, including targeted use of monotherapy, combination therapy and new generation monoclonals.…”

Section: Anti-tnf Monoclonal Antibodiesmentioning

confidence: 99%

“…118 The translation of genetic data into functional science and then into clinical application poses both a challenge and an opportunity to IBD researchers, as can be seen in the recent association between anti-TNF therapy antibody formation in patients with specific HLA-DQA alleles. 110 Common pathways between autoimmune conditions, including IBD, may reveal additional treatment options amongst existing medications and present novel pathways for new therapies to target. Beyond the classical genes discussed in this review the 420+ additional coding regions of the extended MHC region may also harbour risk or causative genes, either independently or epistatically with classical HLA genotypes.…”

Section: Anti-tnf Monoclonal Antibodiesmentioning

confidence: 99%

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Review article: the genetics of the human leucocyte antigen region in inflammatory bowel disease

Ashton

Latham

Beattie

et al. 2019

Aliment Pharmacol Ther

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Summary Background The human leucocyte antigen (HLA) complex, located at chromosome 6p21.3 is a highly polymorphic region containing the classical class I and II HLA genes. The region is highly associated with inflammatory bowel disease (IBD), largely through genome‐wide association studies (GWAS). Aims To review the role of HLA in immune function, summarise data on risk/protective HLA genotypes for IBD, discuss the role of HLA in IBD pathogenesis, treatment and examine limitations that might be addressed by future research. Methods An organised search strategy was used to collate articles describing HLA genes in IBD, including Crohn's disease and ulcerative colitis. Results All classical HLA genes with variation (including HLA‐A, B, C, DRB1, DQA1, DQB1, DPA1 and DPB1) harbour IBD‐associated genotypes. The most implicated gene is HLA‐DRB1, with HLA‐DRB1*03:01 the most associated risk allele in both Crohn's disease and ulcerative colitis. Elucidating precise disease associations is challenging due to high linkage disequilibrium between HLA genotypes. The mechanisms by which risk alleles cause disease are multifactorial, with the best evidence indicating structural and electrostatic alteration impacting antigen binding and downstream signalling. Adverse medication events have been associated with HLA genotypes including with thiopurines (pancreatitis) and anti‐TNF agents (antibody formation). Conclusions The HLA complex is associated with multiple risk/protective alleles for IBD. Future research utilising long‐read technology, ascertainment of zygosity and integration in disease modelling will improve the functional understanding and clinical translation of genetic findings.

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Section: Discussionmentioning

confidence: 99%

Section: Implication Of Hla In Medication Response and Reactionmentioning

confidence: 94%

Section: Implication Of Hla In Medication Response and Reactionmentioning

confidence: 99%

Section: Anti-tnf Monoclonal Antibodiesmentioning

confidence: 99%

Section: Anti-tnf Monoclonal Antibodiesmentioning

confidence: 99%

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Review article: the genetics of the human leucocyte antigen region in inflammatory bowel disease

Ashton

Latham

Beattie

et al. 2019

Aliment Pharmacol Ther

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Effectiveness of strategies to suppress antibodies to infliximab in pediatric inflammatory bowel disease

Jagt,

Holleman,

Benninga

et al. 2023

J. pediatr. gastroenterol. nutr.

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ObjectivesAntibodies to infliximab (ATIs) are associated with loss of response in children with inflammatory bowel disease (IBD). We aimed to describe the effectiveness of strategies for treatment modification following ATI development in pediatric IBD: (1) treatment escalation; and (2) switching to another anti‐TNF agent.MethodsThis multicenter retrospective study included children with IBD (4–18 years) on infliximab. Therapeutic drug monitoring (TDM) < 6 months and corticosteroid‐free remission following each strategy were evaluated for low ATI titers (≤30 AU/mL) and high ATI titers (>30 AU/mL).ResultsAnti‐infliximab antibodies were detected in 52/288 patients (18%) after a median of 15.3 months. Three of 52 ATI‐positive patients were excluded due to alternative treatments. Of the remaining 49 patients, 19 had low titers and 30 had high titers. Of 19 low‐ATIs, 16 (84%) underwent treatment escalation with infliximab (IFX). Of 13 patients with TDM available, seven (54%) achieved ATI suppression at subsequent TDM and 12 (92%) at any time point. Among 30 patients with high‐ATIs, 17 (57%) continued with IFX; immunomodulators were started in seven patients. Of 14 patients with TDM, seven (50%) achieved ATI suppression at subsequent TDM and 10 (71%) at any time point. At 24 months of follow‐up, 73% of low‐ATI patients and 50% of high‐ATI patients could continue with IFX without steroids. Thirteen of 30 high‐ATI patients (43%) switched to another anti‐TNF agent, of whom 54% and 46% had clinical response at 6 and 24 months, respectively.ConclusionsDose optimization and/or adding an immunomodulator seem effective in suppressing low ATI titers. This strategy could also be considered in high ATI titers before switching.

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Precision nutrition in pediatric IBD: A position paper from the ESPGHAN special interest group for basic science and translational research, the IBD Porto group, and allied health professionals

Gerasimidis,

Russell,

Giachero

et al. 2023

J. pediatr. gastroenterol. nutr.

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Stratified and precision nutrition refers to disease management or prevention of disease onset, based on dietary interventions tailored to a person's characteristics, biology, gut microbiome, and environmental exposures. Such treatment models may lead to more effective management of inflammatory bowel disease (IBD) and reduce risk of disease development. This societal position paper aimed to report advances made in stratified and precision nutritional therapy in IBD. Following a structured literature search, limited to human studies, we identified four relevant themes: (a) nutritional epidemiology for risk prediction of IBD development, (b) food‐based dietary interventions in IBD, (c) exclusive enteral nutrition (EEN) for Crohn's disease (CD) management, and (d) pre‐ and probiotics for IBD management. There is scarce literature upon which we can make recommendations for precision or stratified dietary therapy for IBD, both for risk of disease development and disease management. Certain single‐nucleotide polymorphisms related to polyunsaturated fatty acid (PUFA) metabolism may modify the effect dietary PUFA have in increasing the risk of IBD development. Non‐colonic CD, mild‐to‐moderate CD, and high microbiota richness may predict success of EEN and may be used both for prediction of treatment continuation, but also for early cessation in nonresponders. There is currently insufficient evidence to make recommendations for precision or stratified dietary therapy for patients with established IBD. Despite the great interest in stratified and precision nutrition, we currently lack data to support conclusive recommendations. Replication of early findings by independent research groups and within structured clinical interventions is required.

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590 - HLA-DQA1 Contributes to the Development of Antibodies to Anti-TNF Therapy in Crohn's Disease

Cited by 38 publications

References 0 publications

Review article: the genetics of the human leucocyte antigen region in inflammatory bowel disease

Review article: the genetics of the human leucocyte antigen region in inflammatory bowel disease

Effectiveness of strategies to suppress antibodies to infliximab in pediatric inflammatory bowel disease

Precision nutrition in pediatric IBD: A position paper from the ESPGHAN special interest group for basic science and translational research, the IBD Porto group, and allied health professionals

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