Genetic Susceptibilities and Prediction Modeling of Carbamazepine and Allopurinol-Induced Severe Cutaneous Adverse Reactions in Vietnamese

Nguyen, Dinh Van; Chu, Hieu Chi; Vidal, Christopher; Fulton, Richard B.; Nguyen, Nguyet Nhu; Quynh, Nga Thi; Tran, Tu Linh; Nguyen, Thuy Van; Nguyen, Ha Thi Thu; Chu, Hanh Hong; Thuc, Huyen Thi Thanh; Le, Huong Thi; Nunen, Sheryl van; Anderson, Janet; Fernando, Suran L.

doi:10.2217/pgs-2019-0146

Cited by 17 publications

(10 citation statements)

References 48 publications

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“…In 2018, the allopurinol drug label was updated to include pharmacogenetic guidance, however, despite the evidence supporting the association, replication across different races/ancestries, and guidance from medical societies, testing is recommended rather than required. Since this update, studies have also confirmed the HLA‐B*58:01‐ allopurinol association in Vietnamese, 72 Brazilian, 73 and Malaysian patients 74 . Notably, the 2020 ACR gout treatment guideline update added an additional recommendation for HLA‐B*58:01 screening in African Americans 75 …”

Section: Human Leukocyte Antigen: the Untapped Hotspot For Pharmacogenomic Actionability?mentioning

confidence: 89%

Translational Pharmacogenomics: Discovery, Evidence Synthesis and Delivery of Race‐Conscious Medicine

Davis

Limdi

2021

Clin Pharma and Therapeutics

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Response to medications, the principal treatment modality for acute and chronic diseases, is highly variable, with 40–70% of patients exhibiting lack of efficacy or adverse drug reactions. With ~ 15–30% of this variability explained by genetic variants, pharmacogenomics has become a valuable tool in our armamentarium for optimizing treatments and is poised to play an increasing role in clinical care. This review presents the progress made toward elucidating genetic underpinnings of drug response including discovery of race/ancestry‐specific pharmacogenetic variants and discusses the current evidence and evidence framework for actionability. The review is framed in the context of changing demographics and evolving views related to race and ancestry. Finally, it highlights the vital role played by cohort studies in elucidating genetic differences in drug response across race and ancestry and the informal collaborations that have enabled the field to bridge the “bench to bedside” translational gap.

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Section: Human Leukocyte Antigen: the Untapped Hotspot For Pharmacogenomic Actionability?mentioning

confidence: 89%

Translational Pharmacogenomics: Discovery, Evidence Synthesis and Delivery of Race‐Conscious Medicine

Davis

Limdi

2021

Clin Pharma and Therapeutics

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“…Both allopurinol and lenalidomide were possible causes for DRESS in patient 9. Allopurinol is one of the leading causes of DRESS globally [ 25 ] with few cases associated with lenalidomide to date [ 26 ]. Surprisingly, the patient had a positive XTT–LTT to lenalidomide and not allopurinol or its metabolite oxypurinol [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

Development and initial validation of a modified lymphocyte transformation test (LTT) assay in patients with DRESS and AGEP

Weir

Fulton

et al. 2022

Allergy Asthma Clin Immunol

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Background The lymphocyte transformation test (LTT) is an in vitro assay used to diagnose drug induced hypersensitivity reactions by detecting the activation and expansion of drug-specific memory T cells to the suspected implicated drug. Traditionally radiolabelled thymidine (3H-thymidine) has been used but requires the handling and disposal of radioactive materials. Objective To examine safe alternatives to 3H-thymidine, test assay modifications for improved assay sensitivity and evaluate the modified LTT in patients with DRESS and AGEP. Methods Four proliferation detection assays (BRDU, CyQUANT™, MTT and XTT) were screened for LTT sensitivity. XTT the most sensitive and practical was selected for further evaluation Modifications like autologous serum (AS) and regulatory T cell depletion (T-REG) were tested for improved assay sensitivity. Finally, an initial evaluation of the XTT–LTT was performed in 8 patients with DRESS and 2 with AGEP including cytokine testing. Results Of the non-radioactive alternatives we tested, XTT a colorimetric assay was the most sensitive and practical to move to evaluation. The addition of AS increased background signal. Depletion of T-REGs improved sensitivity but cell sorting time and risk of contamination limited benefit. Of eight patients diagnosed with DRESS and 2 with AGEP tested with XTT–LTT assay results showed our assay matched clinical findings of implicated drugs in 8/10 patients when using a stimulation index (SI) ≥ 2 and 8/10 with analysis by ANOVA. All ten patients were correctly diagnosed by either analysis. Conclusion XTT appears to be a safe, viable alternative to 3H-thymidine, with high sensitivity and allowing direct cytokine quantification on specific patient cells.

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“…Both allopurinol and lenalidomide were possible causes for DRESS in patient 9. Allopurinol is one of the leading causes of DRESS globally (25) with few cases associated with lenalidomide to date(26). Surprisingly, the patient had a positive XTT-LTT to lenalidomide and not allopurinol or its metabolite oxypurinol (27).…”

Section: Discussionmentioning

confidence: 99%

Development and initial validation of a modified LTT assay in patients with DRESS and AGEP

Weir¹,

Fulton

et al. 2022

Preprint

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BackgroundThe lymphocyte transformation test (LTT) is an in vitro assay used to diagnose drug induced hypersensitivity reactions by detecting the activation and expansion of drug-specific memory T cells to the suspected implicated drug. Traditionally radiolabelled thymidine (3H-thymidine) has been used but requires the handling and disposal of radioactive materials.ObjectiveTo examine safe alternatives to 3H-thymidine, test assay modifications for improved assay sensitivity and validate the modified LTT in patients with DRESS and AGEP.MethodsFour proliferation detection assays (BRDU, CyQUANT™, MTT and XTT) were screened for LTT sensitivity. XTT the most sensitive and practical was selected for further validation. Modifications like autologous serum (AS) and regulatory T cell depletion (T-REG) were evaluated for improved assay sensitivity. Finally, an initial validation of the XTT-LTT was performed in 8 patients with DRESS and 2 with AGEP including cytokine testing.ResultsOf the non-radioactive alternatives we tested, XTT a colorimetric assay was the most sensitive and practical to move to validation. The addition of AS increased background signal. Depletion of T-REGs improved sensitivity but cell sorting time and risk of contamination limited benefit.Of eight patients diagnosed with DRESS and 2 with AGEP tested with XTT-LTT assay results showed our assay matched clinical findings of implicated drugs in 8/10 patients when using a stimulation index (SI) ≥2 and 8/10 with analysis by ANOVA. All ten patients were correctly diagnosed by either analysisConclusionXTT appears to be a safe, viable alternative to 3H-thymidine, with high sensitivity and allowing direct cytokine quantification on specific patient cells.

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Genetic Susceptibilities and Prediction Modeling of Carbamazepine and Allopurinol-Induced Severe Cutaneous Adverse Reactions in Vietnamese

Cited by 17 publications

References 48 publications

Translational Pharmacogenomics: Discovery, Evidence Synthesis and Delivery of Race‐Conscious Medicine

Translational Pharmacogenomics: Discovery, Evidence Synthesis and Delivery of Race‐Conscious Medicine

Development and initial validation of a modified lymphocyte transformation test (LTT) assay in patients with DRESS and AGEP

Development and initial validation of a modified LTT assay in patients with DRESS and AGEP

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