Genetic predictors of Stevens–Johnson syndrome and toxic epidermal necrolysis induced by aromatic antiepileptic drugs among the Chinese Han population

Wang, Wei; Hu, Fayun; Wu, Xintong; An, Dongmei; Yan, Bo; Zhou, Dong

doi:10.1016/j.yebeh.2014.05.025

Cited by 24 publications

(14 citation statements)

References 30 publications

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“…However, we did observe an association between SMX immunogenicity and Mamu-DRB1 genotype. This is intriguing, since allelic variants in the orthologous gene in humans (HLA-DRB1) increase the risk of idiosyncratic drug reactions to nevirapine in HIV-infected patients, as well as to asparaginase, lapatinib, amoxicillin/clavulanate, and aromatic antiepileptics in immunocompetent populations (Cornejo Castro et al, 2015; Fernandez et al, 2014; Parham et al, 2015; Wang et al, 2014; Yip et al, 2015). Screening macaques for this genotype might strengthen the power of this model to detect SMX hypersensitivity.…”

Section: Discussionmentioning

confidence: 99%

Immunogenicity of trimethoprim/sulfamethoxazole in a macaque model of HIV infection

Wong

Rakasz²,

Gasper

et al. 2016

Toxicology

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Background Sulfonamide hypersensitivity has a high incidence in HIV infection and correlates with low CD4+ counts, but the mechanisms are not understood. The aims of this study were to determine whether trimethoprim/sulfamethoxazole (TMP/SMX) led to SMX adduct formation, immunogenicity, or signs of drug hypersensitivity in SIV-infected rhesus macaques, and whether differences in antioxidants, pro-inflammatory mediators, or SMX disposition were predictive of drug immunogenicity. Methods Nine macaques chronically infected with SIVmac239 and 7 non-infected controls were studied. Baseline blood ascorbate, glutathione, IFN-γ, LPS, sCD14, and cytochrome b5 reductase measurements were obtained, macaques were dosed with TMP/SMX (120 mg/kg/day p.o. for 14 days), and SMX metabolites, lymph node drug adducts, drug-responsive T cells, and anti-SMX antibodies were measured. Results Four of 9 of SIV-positive (44%), and 3 of 7 SIV negative (43%) macaques had drug-responsive T cells or antibodies to SMX. Two macaques developed facial or truncal rash; these animals had the highest levels of lymph node drug adducts. Antioxidants, pro-inflammatory mediators, and SMX metabolites were not predictive of drug immunogenicity; however, the Mamu DRB1*0401/0406/0411 genotype was significantly over-represented in immune responders. Conclusions Unlike other animal models, macaques develop an immune response, and possible rash, in response to therapeutic dosages of TMP/SMX. Studying more animals with CD4+ counts < 200 cells/µl, along with moderately restricted ascorbate intake to match deficiencies seen in humans, may better model the risk of SMX hypersensitivity in HIV-infection. In addition, the role of Mamu-DRB1 genotype in modeling drug hypersensitivity in retroviral infection deserves further study.

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Section: Discussionmentioning

confidence: 99%

Immunogenicity of trimethoprim/sulfamethoxazole in a macaque model of HIV infection

Wong

Rakasz²,

Gasper

et al. 2016

Toxicology

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“…This seminal study showed that the HLA‐B*15:02 allele was present in 100% of SJS/TEN cases, but in only 3% of carbamazepine‐tolerant controls and 8.6% of drug naïve controls, equating to 97% specificity and 100% sensitivity (Table ). Over the past decade, numerous studies have corroborated this association not only in Han Chinese populations, but also in Thai, Indian, Vietnamese, Malaysian, Spanish Romani, Javanese/Sudanese and other populations (Table ). Conversely, investigations of HLA‐B*15:02 ‐restricted carbamazepine‐induced SJS/TEN in European and Japanese studies failed to find a significant association (Table ), which is not surprising given the relatively low frequency of this HLA allele in these populations (Table ).…”

Section: Pharmacogenomic Identification Of Genetic Risk Factors In Aementioning

confidence: 85%

“…Whilst, phenytoin has been associated with SJS/TEN in the Han Chinese, 24,48 Thai 34 and Malaysian 50 populations, no significant association was found in two additional Thai studies 51,52 (Table 1). There is also a lack of evidence linking lamotrigine-induced SJS/TEN to HLA-B*15:02 carriage in patients of Han Chinese descent 24,27,48 (Table 1). This absence of association is mainly attributed to small sample sizes in these reports, therefore larger cohort studies are needed to determine whether this HLA allele confers risk in lamotrigine-induced SJS/TEN.…”

Section: Aed-induced Sjs/ten and Hla-b*15:02mentioning

confidence: 99%

HLA‐associated antiepileptic drug‐induced cutaneous adverse reactions

Mullan

Anderson

Illing

et al. 2019

HLA

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Adverse drug reactions (ADRs) are a common cause of hospital admissions (up to 19%), with the majority of cases due to off‐target predictable drug effects (type A reactions). However, idiosyncratic drug‐induced immune activated (type B) reactions contribute to a range of hypersensitivity reactions, with T‐cell‐mediated type IV hypersensitivity reactions mainly manifesting as cutaneous ADRs (cADRs). Aromatic antiepileptic drugs (AEDs), used in the treatment of epilepsy as well as bipolar disorder or neuropathic pain, have been implicated as culprit drugs in a spectrum of pathologies ranging from mild maculopapular exanthema (MPE) to severe and life‐threatening conditions including drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens‐Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). These AED‐induced cADRs are unpredictable based on pharmacological and clinical factors alone, thereby prompting investigations into genomic contributors mediating risk of pathology. The most strongly associated risk genes identified are from the human leukocyte antigen (HLA) class I alleles, which play a critical role in adaptive immunity by flagging either infected or aberrant cells for recognition by surveying T‐cells. In the setting of drug hypersensitivity, the immunogenicity of HLA molecules and their peptide cargo can be modulated by interactions with small drug molecules that drive inappropriate T‐cell responses. This review discusses the current understanding of HLA class I molecules in modifying risk of AED‐induced cADRs.

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“…The HLA-B*15:02 allele belongs to the HLA-B75 serotype, and other alleles belonging to the same serotype, such as HLAB*15:08, HLA-B*15:11 and HLA-B*15:18, have been associated with an increased risk of carbamazepine-induced SJS/TEN [52] . By contrast, some HLA alleles have been reported to be potentially protective against the risk of carbamazepine-induced SJS/TEN, such as HLA-B*40:01, HLA-B*07:02, HLAB* 58:01, HLA-A*33:03, HLA-B*4001, HLA-B*4601 and HLA-DRB1*03:01 [66,67] .…”

Section: Adverse Drug Reactionmentioning

confidence: 97%

Personalized medicine in epilepsy patients

Orsini¹,

Esposito²,

Perna³

et al. 2018

JTGG

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The large number of different syndromes and seizure types together with an interindividual variable response to antiepileptic drugs (AEDs) make the treatment of epilepsy challenging. Fortunately, the last few years have been characterized by a huge interest in epilepsy genetics and two methods, genome-wide analyses and next-generation sequencing, have definitely given the possibility to write a new chapter in the book of treatment of epilepsy, the chapter on precision medicine. Epilepsy offers a good opportunity for the personalization of therapy if we consider that at least one third of epileptic patients do not achieve complete seizure control with the currently available pharmacological treatments, treatment is still often empirical and precise therapy, based on the pathogenesis and the mechanism of each AED is not generally possible because this mechanism often remains incompletely known. In addition, new drugs are often not targeted but developed using in vivo seizure models, to be potentially used by the largest number of patients. This method leads to a therapy aimed at treating the symptoms and the seizures rather than the single pathogenic mechanism of each seizure type or syndrome. In this narrative review, we summarize the established evidence regarding pharmacogenomics in epilepsy and discuss the basis of precision medicine.

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Genetic predictors of Stevens–Johnson syndrome and toxic epidermal necrolysis induced by aromatic antiepileptic drugs among the Chinese Han population

Cited by 24 publications

References 30 publications

Immunogenicity of trimethoprim/sulfamethoxazole in a macaque model of HIV infection

Immunogenicity of trimethoprim/sulfamethoxazole in a macaque model of HIV infection

HLA‐associated antiepileptic drug‐induced cutaneous adverse reactions

Personalized medicine in epilepsy patients

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