Systemic and skin-limited delayed-type drug hypersensitivity reactions associate with distinct resident and recruited T cell subsets.

Delayed-type drug hypersensitivity reactions are major causes of morbidity and mortality. The origin, phenotype, and function of pathogenic T cells across the spectrum of severity require investigation. We leveraged recent technical advancements to study skin-resident memory T cells (TRMs) versus recruited T cell subsets in the pathogenesis of severe systemic forms of disease, Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS), and skin-limited disease, morbilliform drug eruption (MDE). Microscopy, bulk transcriptional profiling, and single-cell RNA-sequencing (scRNA-Seq) plus cellular indexing of transcriptomes and epitopes by sequencing (CITE-Seq) plus T cell receptor sequencing (TCR-Seq) supported clonal expansion and recruitment of cytotoxic CD8+ T cells from circulation into skin along with expanded and nonexpanded cytotoxic CD8+ skin TRM in SJS/TEN. Comparatively, MDE displayed a cytotoxic T cell profile in skin without appreciable expansion and recruitment of cytotoxic CD8+ T cells from circulation, implicating TRMs as potential protagonists in skin-limited disease. Mechanistic interrogation in patients unable to recruit T cells from circulation into skin and in a parallel mouse model supported that skin TRMs were sufficient to mediate MDE. Concomitantly, SJS/TEN displayed a reduced Treg signature compared with MDE. DRESS demonstrated recruitment of cytotoxic CD8+ T cells into skin as in SJS/TEN, yet a pro-Treg signature as in MDE. These findings have important implications for fundamental skin immunology and clinical care.

Dermatomyositis-like skin eruptions under hydroxyurea therapy conceal TP53-mutated atypical keratinocytes: A histopathologic and molecular pathologic case series.

Hydroxyurea is an antimetabolite that inhibits DNA synthesis and is used as a treatment option in chronic myeloproliferative disorders. Rarely, "dermatomyositis (DM)-like" skin lesions are observed after long-term therapy. In this case series, five skin biopsies of four patients were evaluated by histology, immunohistochemistry, and next-generation sequencing of the TP53 gene locus. All biopsies showed focal basal pleomorphic keratinocytes and suprabasal aberrant p53 expression as well as sparse to severe vacuolar interface dermatitis. Histopathologically, "DM-like" skin lesions can be clearly distinguished from DM by marked subepidermal fibrosis, vascular proliferation, and the absence of dermal mucin deposits. In 75% of the specimens multiple, partly inactivating and/or pathogenic point mutations of TP53 were found in low frequencies. "DM-like" skin eruptions as a long-term consequence of hydroxyurea therapy are possibly not chemotherapy-associated benign toxic changes, but rather inflammatory reactions to complex keratinocyte alterations that clinically mimic the picture of DM. Synergistic mutagenic effects of hydroxyurea and sunlight might be responsible for this unique drug side effect and could provide a pathogenic link to the known increased risk of skin cancer in these patients.

Fixed drug eruption in a patient of HLA-B*58:01 negative after allopurinol administration: A case report.

WHAT IS KNOWN AND OBJECTIVE: Allopurinol is widely used for hyperuricemia and gouty arthritis, but is associated with cutaneous adverse drug reactions (CADRs). HLA-B*58:01 is a highly specific and effective genetic marker for the detection of allopurinol-induced CADRs, especially for Asian descents. CASE SUMMARY: A 60-year-old Chinese Han male patient took allopurinol for lowering uric acid after the negative result from HLA-B*58:01 testing. Then, he experienced episodes of well-demarcated pruritic erythematous patches on the whole body that developed into blisters and pustular eruption. Fixed drug eruption (FDE) was diagnosed by skin biopsy and improved with withdrawal and hormone treatments. WHAT IS NEW AND CONCLUSION: It should be kept in mind that cutaneous drug eruption might occur after allopurinol administration in Asians of HLA-B*58:01 negative. Awareness among medical practitioners about FDE can lead to correct diagnosis, treatment and decreased damage as well as lower therapeutic costs.

ACC1-expressing pathogenic T helper 2 cell populations facilitate lung and skin inflammation in mice.

T cells possess distinguishing effector functions and drive inflammatory disorders. We have previously identified IL-5-producing Th2 cells as the pathogenic population predominantly involved in the pathology of allergic inflammation. However, the cell-intrinsic signaling pathways that control the pathogenic Th2 cell function are still unclear. We herein report the high expression of acetyl-CoA carboxylase 1 (ACC1) in the pathogenic CD4+ T cell population in the lung and skin. The genetic deletion of CD4+ T cell-intrinsic ACC1 dampened eosinophilic and basophilic inflammation in the lung and skin by constraining IL-5 or IL-3 production. Mechanistically, ACC1-dependent fatty acid biosynthesis induces the pathogenic cytokine production of CD4+ T cells via metabolic reprogramming and the availability of acetyl-CoA for epigenetic regulation. We thus identified a distinct phenotype of the pathogenic T cell population in the lung and skin, and ACC1 was shown to be an essential regulator controlling the pathogenic function of these populations to promote type 2 inflammation.

A Young Boy With Hemophagocytic Lymphohistiocytosis Presenting With Vaccine-Related Granulomatous Dermatitis: A Case Report and Literature Review.

ABSTRACT: Cutaneous eruptions associated with hemophagocytic lymphohistiocytosis (HLH) have been reported in 6%-63% of patients. Clinical findings of these skin lesions vary widely and include maculopapular rashes, ulcers, and violaceous nodules. Corresponding histologic findings are also variable and are considered nonspecific. We report the case of a 4-year-old boy who initially developed a widespread popular-pustular rash 2 weeks after his 12-month measles, mumps, and rubella vaccinations. These resolved with scarring then recurred following his 24-month vaccinations. Multiple skin biopsies were negative for infectious organisms and showed a granulomatous infiltrate with perforation and necrobiosis. The differential diagnosis included perforating granuloma annulare, infection, or rheumatoid nodules. At the age of 4, he developed fever, hepatosplenomegaly, pancytopenia and other laboratory abnormalities, requiring hospitalization. A number of studies were performed including biopsies of bone marrow and liver. Molecular testing revealed 2 mutations in UNC13D known to be associated with familial HLH. His prior cutaneous lesions were likely caused by immune dysregulation exacerbated by immunizations because of underlying familial HLH. This case illustrates the importance of recognizing an unusual cutaneous manifestation of a rare disease to arrive at an earlier diagnosis in a pediatric patient. Although cutaneous eruptions usually develop concurrently with other systemic symptoms of HLH, preceding unusual skin lesions may be the first indication of this rare disease.

Diagnostic Tools and Biomarkers for Severe Drug Eruptions.

In accordance with the development of human technology, various medications have been speedily developed in the current decade. While they have beneficial impact on various diseases, these medications accidentally cause adverse reactions, especially drug eruption. This delayed hypersensitivity reaction in the skin sometimes causes a life-threatening adverse reaction, namely Stevens-Johnson syndrome and toxic epidermal necrolysis. Therefore, how to identify these clinical courses in early time points is a critical issue. To improve this problem, various biomarkers have been found for these severe cutaneous adverse reactions through recent research. Granulysin, Fas ligands, perforin, and granzyme B are recognized as useful biomarkers to evaluate the early onset of Stevens-Johnson syndrome and toxic epidermal necrolysis, and other biomarkers, such as miRNAs, high mobility group box 1 protein (HMGB1), and S100A2, which are also helpful to identify the severe cutaneous adverse reactions. Because these tools have been currently well developed, updates of the knowledge in this field are necessary for clinicians. In this review, we focused on the detailed biomarkers and diagnostic tools for drug eruption and we also discussed the actual usefulness of these biomarkers in the clinical aspects based on the pathogenesis of drug eruption.

Spectrum of cutaneous adverse reactions to aromatic antiepileptic drugs and human leukocyte antigen genotypes in Thai patients and meta-analysis.

Aromatic antiepileptic drugs (AEDs)-induced cutaneous adverse drug reactions (cADRs) add up to the limited use of the AEDs in the treatment and prevention of seizures. Human leukocyte antigen-B (HLA-B) alleles have been linked to AEDs-induced cADRs. We investigated the association between cADRs (including Stevens-Johnson syndrome; SJS/toxic epidermal necrolysis; TEN, drug reaction with eosinophilia and systemic symptoms; DRESS, and Maculopapular eruption; MPE) caused by AEDs (phenytoin, carbamazepine, lamotrigine, phenobarbital and oxcarbazepine) and HLA-B alleles in Thai population. Through the case-control study, 166 patients with AEDs-induced cADRs, 426 AEDs-tolerant patients (AEDs-tolerant controls), and 470 healthy subjects (Thai population) were collected. The HLA genotypes were detected using the polymerase chain reaction-sequence specific oligonucleotide probe (PCR-SSOP) method. We also performed a meta-analysis with these data and other populations. The carrier rate of HLA-B*15:02 was significantly different between AEDs-induced cADRs group and AEDs-tolerant group (Odds ratio; OR 4.28, 95% Confidence interval; CI 2.64-6.95, p < 0.001), AEDs-induced cADRs group and Thai population (OR 2.15, 95%CI 1.41-3.29, p < 0.001). In meta-analysis showed the strong association HLA-B*15:02 with AEDs-induced cADRs (OR 4.77, 95%CI 1.79-12.73, p < 0.001). Furthermore, HLA-B*15:02 was associated with SJS/TEN induced by AEDs (OR 10.28, 95%CI 6.50-16.28, p < 0.001) Phenytoin (OR 4.12, 95%CI 1.77-9.59, p = 0.001) and carbamazepine (OR 137.69, 95%CI 50.97-371.98, p < 0.001). This study demonstrated that genetic association for AEDs-induced cADRs was phenotype-specific. A strong association between HLA-B*15:02 and AEDs-induced SJS/TEN was demonstrated with an OR of 10.79 (95%CI 5.50-21.16, p < 0.001) when compared with AEDs-tolerant group. On the other hand, the carrier rates of HLA-B*08:01, HLA-B*13:01, and HLA-B*56:02 were significantly higher in the DRESS group compared with the AEDs-tolerant group (p = 0.029, 0.007, and 0.017, respectively). The HLA-B*15:02 allele may represent a risk factor for AEDs-induced cADRs.

Genotyping HLA alleles to predict the development of Severe cutaneous adverse drug reactions (SCARs): state-of-the-art.

Introduction: Pharmacogenomics has great potential in reducing drug-induced severe cutaneous adverse drug reactions (SCARs). Pharmacogenomic studies have revealed an association between HLA genes and SCARs including acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN).Areas covered: Pharmacogenomics-guided therapy could prevent severe drug hypersensitivity reactions. The US Food and Drug Administration (FDA), Clinical Pharmacogenetics Implementation Consortium (CPIC), and Dutch Pharmacogenetics Working Group (DPWG) provided guidelines in the translation of clinically relevant and evidence-based SCARs pharmacogenomics research into clinical practice. In this review, we intended to summarize the significant HLA alleles associated with SCARs induced by different drugs in different populations. We also summarize the SCARs associated with genetic and non-genetic factors and the cost-effectiveness of screening tests.Expert opinion: The effectiveness of HLA screening on a wider scale in clinical practice requires significant resources, including state-of-the-art laboratory; multidisciplinary team approach and health care provider education and engagement; clinical decision support alert system via electronic medical record (EMR); laboratory standards and quality assurance; evidence of cost-effectiveness; and cost of pharmacogenomics tests and reimbursement.

Extracellular Vesicles from Human Plasma Show a Distinctive Proteome and miRNome Profile in Patients with Severe Cutaneous Adverse Reactions.

Cutaneous drug-induced reactions are immune-mediated responses that can lead to life-threatening diseases such as drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome, and toxic epidermal necrolysis, collectively known as severe cutaneous adverse reactions (SCARs). Unfortunately, they cannot be predicted during drug development, and, at present, a prognostic biomarker is not available nor are validated in vitro assays for diagnosis. Thus, by using proteomic and microarray miRNA analysis, the cargo of extracellular vesicles obtained from SCARs patients was analyzed and correlated with the severity of the reaction. Confirmatory assays using Western blot and qRT-PCR were performed to validate findings, and bioinformatic tools were used to establish the correlation between protein and miRNAs expression between groups. The proteomic analysis showed an increase in the amount of pro-inflammatory proteins, von Willebrand factor, and C-reactive protein and a decrease in anti-inflammatory and protective proteins in the SCARs group compared with the control group. Additionally, histone protein H2A was enriched in DRESS patients. APO1 and SERPINA4 proteins, highly increased in the control group but absent in the SCARs group, are the target of several overexpressed miRNAs, suggesting that the regulation of these proteins might involve gene silencing and protein repressing mechanisms in the severe patients. According with previous reports showing its presence in plasma and T-cells, microRNA miR-18 was upregulated in extracellular vesicles obtained from the most severe patients. Determination of the unique cargo associated with different disease conditions will help to understand the pathophysiology of these complex reactions and might help to develop novel biomarkers for life-threatening iatrogenic cutaneous disease.

Real-world evidence of population differences in allopurinol-related severe cutaneous adverse reactions in East Asians: A population-based cohort study.

Allopurinol-related severe cutaneous adverse reactions (SCARs) are strongly associated with HLA-B*58:01, the allele frequency (AF) of which is largely different among East Asians. However, evidence of population differences in SCAR development and relevance of genetic and/or other risk factors in the real-world remain unelucidated. This study aimed to evaluate population differences in allopurinol-related SCAR incidence related to genetic and/or other risk factors among East Asians in the real-world. A population-based cohort study was conducted using claims databases from Taiwan, Korea, and Japan. New users of allopurinol (311,846; 868,221; and 18,052 in Taiwan, Korea, and Japan, respectively) were followed up to 1 year. As control drugs, phenytoin and carbamazepine were used. The crude incidence rate ratios (IRRs) of SCARs for allopurinol against phenytoin or carbamazepine were the highest in Taiwan (IRR, 0.62 and 1.22; 95% confidence interval [CI], 0.54-0.72 and 1.01-1.47, respectively), followed by Korea (IRR, 0.34 and 0.82; 95% CI, 0.29-0.40 and 0.77-0.87), and the lowest in Japan (IRR, 0.04 and 0.16; 95% CI, 0.02-0.08 and 0.09-0.29). This order was accordant with that of AF ratios (AFRs) reported of HLA-B*58:01 against alleles responsible for phenytoin- or carbamazepine-related SCARs. The IRRs were higher in patients with chronic kidney disease, females, and elderly. This study demonstrated population differences in the risk of allopurinol-related SCAR development among East Asians based on genetic and other common risk factors. This finding will help to promote appropriate risk management for allopurinol-related SCARs based on ethnic origins. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THIS TOPIC? Allopurinol-related severe cutaneous adverse reactions (SCARs) are strongly associated with HLA-B*58:01, the allele frequency of which is largely different among East Asians. However, there is no direct real-world evidence of population differences in SCAR development and the influence of genetic factors and/or other risk factors. WHAT QUESTION DID THIS STUDY ADDRESS? Do population differences in development of allopurinol-related SCARs, depending on genetic factors and/or other risk factors, exist among three East Asians in the real-world? WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? The current analysis, based on comparisons of relative risks of SCAR incidence, provides real-world evidence of population differences in allopurinol-related SCAR development risk among East Asians, which was consistent with differences in reported HLA-B*58:01 frequencies, as well as identifying chronic kidney disease, female gender, and old age as common risk factors. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? This study helps to promote appropriate risk management strategies for allopurinol-related SCARs in the real-world considering risk factors based on the patients' ethnicity. Our approach is useful for evaluating population differences in the real-world.

Genetic Predictors of Severe Skin Toxicity in Patients with Stage III Colon Cancer Treated with Cetuximab: NCCTG N0147 (Alliance).

BACKGROUND: Cetuximab, an EGFR inhibitor used to treat multiple cancer types, including colon cancer, causes severe skin toxicity in 5%-20% of patients, leading to decreased quality of life and treatment delays. Our understanding of which patients have an increased risk of severe toxicities is limited. We conducted a genome-wide association study to identify germline variants predictive of cetuximab-induced severe skin toxicity. METHODS: Our study included 1,209 patients with stage III colon cancer randomized to receive cetuximab plus 5-fluorouracil and oxaliplatin as part of the NCCTG N0147 (Alliance) clinical trial. Skin toxicity outcomes were collected using the Common Toxicity Criteria for Adverse Events version 3.0. We performed genotyping, evaluating approximately 10 million genetic variants. We used logistic regression to evaluate the association of each genetic variant and severe (grade ≥ 3) skin toxicity, adjusting for age, sex, and genetic ancestry. Genome-wide significance was defined as P < 5 × 10-8. RESULTS: Participants were predominantly middle-aged white men; 20% (n = 243) experienced severe skin toxicity. Two genetic variants in the retinoic acid receptor alpha (RARA) gene were significantly associated with severe skin toxicity [OR, 3.93; 95% confidence interval (CI), 2.47-6.25; P < 7.8 × 10-9]. Functional annotations indicate these variants are in the RARA promoter. Additional significantly associated variants were identified in chromosome 2 intergenic regions. CONCLUSIONS: Identified variants could represent a potential target for risk stratification of patients with colon cancer receiving cetuximab. IMPACT: Retinoids have shown promise in the treatment of cetuximab-induced skin toxicity, so follow-up work could evaluate whether individuals with the RARA variant would benefit from retinoid therapy.

HLA-A∗24:02 associated with lamotrigine-induced cutaneous adverse drug reactions: A systematic review and meta-analysis.

BACKGROUND: Several studies demonstrated a connection between human leukocyte antigen (HLA)-B∗1502 and lamotrigine (LTG)-induced cutaneous adverse drug reactions (cADRs). The correlation between the HLA-A∗24:02 and LTG-cADRs remains controversial. To examine the associations between HLA-A∗24:02 and LTG-cADRs, we conducted a systematic review and meta-analysis. METHODS: We performed a comprehensive search of the literature in several electronic database systems including Cochrane Library, EMBASE and PubMed from inception to January 2020. Review Manager was used to compare the frequencies of HLA-A∗24:02 carriers between the subgroups. RESULTS: A total of 5 studies were eligible, including 197 LTD-cADRs, 396 LTD-tolerant controls, and 2068 population controls. Compared with the LTG-tolerant controls, there was a statistically significant association between the HLA-A∗24:02 allele and LTG-induced cADRs (odds ratios: 1.94, 95% confidence intervals 1.06-3.54; P = .03). Compared with the general population, the relationship between the HLA-A∗24:02 genotype and LTG-induced cADRs was statistically significant (summary odds ratios: 2.12, 95% confidence intervals 1.04-4.30; P = .04). CONCLUSIONS: HLA-A∗24:02 may be a risk factor for LTG-cADRs.

Histopathologic Characterization of Mogamulizumab-associated Rash.

Rash is one of the most common adverse events observed with mogamulizumab, an anti-C-C chemokine receptor 4 monoclonal antibody approved for previously treated mycosis fungoides (MF) and Sezary syndrome (SS). Given the nonspecific clinical presentations of this rash, histopathologic distinction from MF/SS is critical for informing clinical management. We performed a comprehensive characterization of the histopathologic findings in mogamulizumab-associated rash (MAR) with the integration of high-throughput sequencing of T-cell receptor (TCR) genes. Fifty-two biopsy specimens from 19 patients were evaluated retrospectively. Three major histologic reaction patterns were identified: spongiotic/psoriasiform dermatitis (33/52), interface dermatitis (11/52), and granulomatous dermatitis (8/52). Almost half of the specimens (21/52) showed at least 2 of these reaction patterns concurrently. Dermal eosinophils were not a consistent feature, being present in only half (27/52) of specimens and prominent in only 3. Features mimicking MF/SS, including lymphocyte exocytosis, lamellar fibroplasia, and adnexal involvement, were commonly seen but tended to be focal and mild. In 38/43 specimens with available immunohistochemistry, intraepidermal lymphocytes demonstrated a CD4:CD8 ratio ≤1 : 1. Low background levels of the patient's previously identified MF/SS-associated TCR sequence(s) were demonstrated in 20/46 specimens analyzed by high-throughput sequencing of TCR. We conclude that MAR may demonstrate diverse histologic features. Findings that may distinguish MAR from MF/SS include the inverted or normalized CD4:CD8 ratio within intraepidermal lymphocytes and demonstration of absent or nondominant levels of disease-associated TCR sequences. Correlation with the clinical findings and immunohistochemical and molecular characterization of the patient's MF/SS before mogamulizumab, when possible, may facilitate recognition of MAR.

Gene expression profiling in allopurinol-induced severe cutaneous adverse reactions in Vietnamese.

Aim: To examine gene expression in different clinical phenotypes of allopurinol-induced severe cutaneous adverse reactions (SCARs). Materials & methods: Gene expression profiling was performed using microarray on 11 RNA samples (four controls, three hypersensitivity syndrome/drug rash with eosinophilia and systemic symptoms, four Stevens-Johnson syndrome/toxic epidermal necrolysis) followed by quantitative real-time PCR in a total of 11 SCARs patients and 11 controls. Results: The biological pathways which were significantly enriched in differentially expressed genes in Stevens-Johnson syndrome/toxic epidermal necrolysis compared with hypersensitivity syndrome/drug rash with eosinophilia and systemic symptoms patients included; cell surface interactions at the vascular wall, immunoregulatory interactions at the immunological synapse and MyD88 signaling pathways. Overexpression of miR146a occurred in allopurinol-tolerant HLA-B*58:01 carriers. Conclusion: Biological pathways are identified which appear to be implicated in determining clinical phenotypes in allopurinol-induced SCARs. Overexpression of miR146a is potentially important for allopurinol tolerance in HLA-B*58:01 carriers.

Association between HLA genotype and antiseizure medications (ASMs)-induced maculopapular eruption among epilepsy patients in Xinjiang, China.

PURPOSE: To determine genetic associations between antiseizure medications (ASMs)-induced maculopapular eruption (MPE) and human leukocyte antigen (HLA) variants in Xinjiang, China. METHODS: A total of 409 patients were enrolled in this study, including 36 subjects with ASMs-induced MPE (case group) and 373 ASMs-tolerant patients (control group). We detected the whole sequence of the HLA alleles in the 409 Uighur patients using next-generation sequencing (NGS). The carried rate of HLA alleles were compared between the case group, the control group, and the general Chinese population. RESULTS: The carried rate of HLA-A*03:01, HLA-B*07:02, HLA-C*01:02, and HLA-DRB1 *06:09 allele was significantly higher in the ASMs-MPE group when compared with both the ASMs-tolerant group (p = 0.000, odds ratio (OR) = 23.92, 95 % confidence interval (CI) = 3.96-74.84; p = 0.000, OR = 21.40, 95 % CI = 3.55-67.52; p = 0.030, OR = 4.69, 95 % CI = 0.90-61.73 and p = 0.000, OR = 18.94, 95 % CI = 3.15-60.58; respectively), and the general Chinese population (p = 0.000, OR = 21.34, 95 % CI = 3.31-38.98; p = 0.000, OR = 23.92, 95 % CI = 3.96-74.84; p = 0.019, OR = 5.53, 95 % CI = 0.14-19.86 and p = 0.000, OR = 21.67, 95 % CI = 3.68-11.73; respectively). Moreover, the carried rate of the HLA-B*4001 allele was significantly higher in the ASMs-tolerant group when compared with the ASMs-MPE group (p = 0.024, OR = 5.13, 95 % CI = 1.01-9.99). CONCLUSIONS: In this study, we identified for the first time that the carried rate of HLA-A*03:01, HLA-B*07:02, HLA-C*01:02, and HLA-DRB1 *06:09 allele was significantly higher in the ASMs-MPE group when compared with the ASMs-tolerant group.

HLA-B*58: 01 association in allopurinol-induced severe cutaneous adverse reactions: the implication of ethnicity and clinical phenotypes in multiethnic Malaysia.

OBJECTIVE: The association between human leukocyte antigen (HLA)-B*58:01 and risk of allopurinol-induced severe cutaneous adverse reactions (AIS) was observed across different populations. We explore the association between HLA-B*58:01 and AIS risk in multiethnic Malaysian population. The HLA-B*58:01 risk for different AIS clinical phenotypes and ethnicity was determined. METHODS: We performed a case-control association study by genotyping the HLA-B alleles of 55 patients with AIS [11 toxic epidermal necrolysis (TEN), 21 Steven Johnson syndrome (SJS) 22 drug reaction wit eosinophilia and systemic symptoms (DRESS) and one acute generalized exanthematous pustulosis (AGEP)] and 42 allopurinol-tolerant controls (ATC). RESULTS: HLA-B*58:01 was positive in 89.1 and 14.3% of the AIS and ATC study groups [odds ratio (OR) = 49.0, 95% confidence interval (CI) = 14.6-164.4, P < 0.0001)], respectively. Our data showed that 93.8% of the AIS-SJS/TEN patients and 86.4% of the AIS-DRESS patients were HLA-B*58:01 positive (AIS-SJS/TEN, OR = 90, 95% CI = 16.9-470.1, P < 0.0001 and AIS-DRESS OR = 38, 95% CI = 8.5-169.2, P < 0.0001). Stratification by ethnicity and clinical phenotypes revealed a significant increased risk between HLA-B*58:01 and Chinese-AIS patients (OR = 137.5, 95% CI = 11.3-1680.2, P < 0.0001), in particular Chinese patients with AIS-SJS/TEN phenotype (100% HLA-B*58:01 positive). HLA-B*58:01 was positive in 90.9% Chinese AIS-DRESS (P < 0.0001). Highly significant associations of HLA-B*58:01 were observed in Malay AIS-SJS/TEN (OR = 78, 95% CI = 9.8-619.9, P < 0.0001) and Malay AIS-DRESS (OR = 54, 95% CI = 6.6-442.9, P < 0.0001). Although the number of Indian-AIS patients was relatively small (n = 2), both were HLA-B*58:01 positive. CONCLUSION: Our data suggest strong associations between HLA-B*58:01 and AIS in Malaysian population with Chinese and Malays ethnicity. The strong association was also observed in three different clinical phenotypes of AIS, mainly the AIS-SJS/TEN.

Associations of CYP2C9 and CYP2C19 Pharmacogenetic Variation with Phenytoin-Induced Cutaneous Adverse Drug Reactions.

The role of cytochrome P450 (CYP)2C9 and CYP2C19 genetic variation in risk for phenytoin-induced cutaneous adverse drug events is not well understood independently of the human leukocyte antigen B (HLA-B)*15:02 risk allele. In the multi-ethnic resource for Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort, we identified 382 participants who filled a phenytoin prescription between 2005 and 2017. These participants included 21 people (5%) who self-identified as Asian, 18 (5%) as black, 29 (8%) as white Hispanic, and 308 (81%) as white non-Hispanic. We identified 264 (69%) CYP2C9*1/*1, 77 (20%) CYP2C9*1/*2, and 29 (8%) CYP2C9*1/*3. We also determined CYP2C19 genotypes, including 112 with the increased activity CYP2C19*17 allele. Using electronic clinical notes, we identified 32 participants (8%) with phenytoin-induced cutaneous adverse events recorded within 100 days of first phenytoin dispensing. Adjusting for age, sex, daily dose, and race/ethnicity, participants with CYP2C9*1/*3 or CYP2C9*2/*2 genotypes were more likely to develop cutaneous adverse events compared with CYP2C9*1/*1 participants (odds ratio 4.47; 95% confidence interval 1.64-11.69; P < 0.01). Among participants with low-intermediate and poor CYP2C9 metabolizer genotypes, eight (22%) who also had extensive and rapid CYP2C19 metabolizer genotypes experienced cutaneous adverse events, compared with none of those who also had intermediate CYP2C19 metabolizer genotypes (P = 0.17). Genetic variation reducing CYP2C9 metabolic activity may increase risk for phenytoin-induced cutaneous adverse events in the absence of the HLA-B*15:02 risk allele.