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1.
Hum Genet ; 138(11-12): 1267-1274, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31642954

RESUMO

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare severe cutaneous adverse reactions to drugs. Granulysin (GNLY) plays a key role in keratinocyte apoptosis during SJS/TEN pathophysiology. To determine if GNLY-encoding mutations might be related to the protein's functional disturbances, contributing to SJS/TEN pathogenesis, we performed direct sequencing of GNLY's coding region in a group of 19 Colombian SJS/TEN patients. A GNLY genetic screening was implemented in a group of 249 healthy individuals. We identified the c.11G > A heterozygous sequence variant in a TEN case, which creates a premature termination codon (PTC) (p.Trp4Ter). We show that a mutant protein is synthesised, possibly due to a PTC-readthrough mechanism. Functional assays demonstrated that the mutant protein was abnormally located in the nuclear compartment, potentially leading to a toxic effect. Our results argue in favour of GNLY non-synonymous sequence variants contributing to SJS/TEN pathophysiology, thereby constituting a promising, clinically useful molecular biomarker.


Assuntos
Antígenos de Diferenciação de Linfócitos T/genética , Queratinócitos/patologia , Proteínas Mutantes/metabolismo , Mutação , Necrose , Síndrome de Stevens-Johnson/genética , Síndrome de Stevens-Johnson/patologia , Adolescente , Adulto , Apoptose , Biomarcadores/metabolismo , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Predisposição Genética para Doença , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Proteínas Mutantes/genética , Adulto Jovem
2.
Cochrane Database Syst Rev ; 7: CD010891, 2019 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-31314143

RESUMO

BACKGROUND: Drug-induced skin reactions present with a range of clinical symptoms, from mild maculopapular skin rashes to potentially fatal blistering skin rashes - such as Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) - which may result in death. Milder reactions may be troublesome and lead to low drug compliance. The pathogenesis of these drug reactions is not yet fully understood; however, there is evidence that pretreatment genetic testing may help to predict and prevent these reactions in some cases. OBJECTIVES: To assess the effects of prospective pharmacogenetic screening to reduce drug-associated skin reactions in a patient population. SEARCH METHODS: We searched the following databases up to July 2018: the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase and LILACS. We also searched five trials registers, and checked the reference lists of included studies and relevant reviews for further references to relevant randomised controlled trials (RCTs). SELECTION CRITERIA: We included RCTs of participants who had prospective pharmacogenetic screening to determine genetic variants associated with hypersensitivity reactions, compared with those who did not have prospective pharmacogenetic screening. We included participants in any setting, who were of any age, gender, and ethnicity, who had been prescribed drugs known to cause delayed type hypersensitivity reactions. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. To assess studies for inclusion, two review authors independently screened all of the titles and abstracts of publications identified by the searches. Because there was only one included study, many of the planned data analyses were not applicable to the review. We used GRADE to assess the quality of the included study.The review's primary outcomes were the incidence of severe skin rashes with systemic symptoms (such as fever and multiple organ involvement), and long-term effects (such as scarring of eyelids or lung tissue). Secondary outcomes were hospitalisation for drug-induced skin reactions, blistering skin reactions (such as SJS, hypersensitivity (HSS) syndrome), and death. MAIN RESULTS: One study, which was a randomised, double-blind, controlled, multicentre trial, fulfilled our inclusion criteria. The trial included 1956 adult participants (74% men, with a mean age of 42 years) across 265 centres (medical centres, hospitals, outpatient clinics) in 19 countries around the world who were infected with HIV-type 1 and who had not received abacavir previously. The participants, who had a clinical need for treatment with an antiretroviral-drug regimen containing abacavir, were randomly assigned to undergo prospective human leukocyte antigen (HLA) Class I, locus B, allele 57:01 (HLA-B*57:01) screening (prospective-screening group) before this treatment, or to undergo a standard-care approach of abacavir use without prospective HLA-B*57:01 screening (control group). Participants who tested positive for HLA-B*57:01 were not given abacavir; instead, they received antiretroviral therapy that did not include abacavir. The control group did have retrospective HLA-B*57:01 pharmacogenetic testing. The trial duration was six months. Each participant was observed for six weeks. Assessments were performed at the time of study entry, at baseline (day one of abacavir treatment), and at weeks one, two and six. This study was funded by the manufacturer of abacavir, GlaxoSmithKline.The study did not assess any of our primary outcomes, and it measured none of our secondary outcomes in isolation. However, it did assess an outcome of (characteristically severe) hypersensitivity reaction which included (but was not limited to) our secondary outcomes of HSS and SJS/TEN.The study demonstrated that prospective HLA-B*57:01 screening probably reduces the incidence of hypersensitivity reaction to abacavir. The incidence of clinically diagnosed HSS reaction to abacavir was lower in the screening arm (risk ratio (RR) 0.43, 95% confidence interval (CI) 0.28 to 0.67; 1650 participants; moderate-quality evidence), as was immunologically confirmed HSS reaction (RR 0.02, 95% 0.00 to 0.37; 1644 participants; moderate-quality evidence). A positive result from an epicutaneous patch test performed six to ten weeks after clinical diagnosis provided immunological confirmation.Overall, the study demonstrates a low risk of bias across five out of seven domains. There was a high risk of detection bias because hypersensitivity reactions were diagnosed by the principal investigator at the recruitment site without the use of predefined clinical criteria. Although there was also high risk of attrition bias due to excluding participants with incomplete follow-up from analyses, the authors did undertake a series of sensitivity analyses based on the intention-to-treat population, which demonstrated consistent results with the primary analysis. We rated the study quality as moderate-quality using GRADE criteria. AUTHORS' CONCLUSIONS: Prospective screening for HLA-B*57:01 probably reduces severe hypersensitivity skin reactions to abacavir in patients positive for HIV-type 1. However, these results are only based on one study, which was at high risk of attrition and detection bias.Our primary outcomes (incidence of severe skin rashes with systemic symptoms, and long-term effects) were not assessed by the trial, and only one of the review's secondary outcomes was measured (hypersensitivity reaction); thus, we found no evidence relating to hospitalisation, death, or long-term conditions resulting from drug injury.We found no eligible evidence on genetic testing for severe drug-induced skin rash in relation to different drugs and classes of drugs. Further clinical trials based on other drugs, and in different patient populations, would be useful for advising policy changes for improving the prevention of adverse skin reactions to drug treatments.


Assuntos
Exantema/genética , Exantema/prevenção & controle , Testes Genéticos , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Síndrome de Stevens-Johnson/genética , Síndrome de Stevens-Johnson/prevenção & controle
3.
Medicine (Baltimore) ; 98(19): e15553, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31083216

RESUMO

RATIONALE: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are 2 rare but life-threatening diseases characterized by detachment of epidermis, bullous skin lesions, and mucous membrane erosions. Drugs are highly suspected to be the causative agents. We report a case of SJS/TEN induced by oseltamivir, which is a very rare event. PATIENT CONCERNS: A 9-year-old girl with upper respiratory tract infections presented with generalized maculopapular rash the second day after taking oseltamivir. DIAGNOSIS: The diagnosis of SJS/TEN was made based on cytotoxic skin lesions and mucous membrane involvement. INTERVENTIONS: After discontinuing of the drug and combination therapy of corticosteroid and human immunoglobulin initiation, the lesions were improved. Human leukocyte antigen (HLA) gene sequencing was done. OUTCOMES: The girl was followed-up for 1 year. The skin and mucous membranes symptoms were relieved. LESSONS: We report this case to attract attention to the rare but serious side effect of this antiviral drug.


Assuntos
Antivirais/efeitos adversos , Oseltamivir/efeitos adversos , Síndrome de Stevens-Johnson/etiologia , Antivirais/uso terapêutico , Criança , Feminino , Antígeno HLA-A2/genética , Humanos , Oseltamivir/uso terapêutico , Infecções Respiratórias/tratamento farmacológico , Síndrome de Stevens-Johnson/diagnóstico , Síndrome de Stevens-Johnson/genética , Síndrome de Stevens-Johnson/terapia
4.
Br J Ophthalmol ; 103(8): 1015-1023, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31023710

RESUMO

BACKGROUND: Stevens-Johnson syndrome (SJS), a blistering disorder of the skin and mucous membrane, leads to ocular morbidity in >60% of cases. Retinoids are vital micronutrients for vision, regulating corneal and conjunctival cell proliferation, differentiation and immune function. This prospective case-control study probed for alterations in retinoid metabolism by evaluating retinoic acid receptor signalling in the conjunctival cells of patients with SJS. METHODS: Imprints were collected from the bulbar conjunctiva of patients with chronic SJS. The gene expression of retinoic acid receptors, namely, RXRA, RARA, RARG, RORA; the fibrosis marker TGFß and its receptor TGFßRII; the transcription factors PPAR-γ, STRA6 and Stat3; the enzymes aldehyde dehydrogenase (ALDH1a1), alpha-1 antitrypsin (A1AT); and the Cyp genes Cyp26a1 and Cyp26b1 were assessed by quantitative PCR in patients with SJS pre-mucous (n = 34) and post-mucous membrane graft (MMG) intervention (n=19) in comparison with age-matched/sex-matched healthy controls (n=20). Western blot analysis of ALDH1a1, RARA and RARG were done in the conjunctival imprint cells. RESULTS: The transcript levels of ALDH1a1, RXRA, RORA, STRA6, Cyp26a1 and Cyp26b1 were decreased around 4, 26, 17, 129, 9 and 8 folds, respectively, and RARA, RARG, PPAR-γ, TGFß, TGFßRII were increased by 12, 15, 51, 16 and 87 folds, respectively, in SJS conjunctiva at the pre-MMG stage. The changes in RORA, Cyp26a1, Cyp26b1, RARA and Stat3 were statistically significant (p<0.05). Changes in protein expression of ALDH1a1, RARA and RARG supported the gene expression changes. CONCLUSIONS: The study provides the first experimental insight into the role of retinoid metabolism in the ocular sequelae of chronic SJS.


Assuntos
Túnica Conjuntiva/patologia , Córnea/patologia , Oftalmopatias/etiologia , Regulação da Expressão Gênica , Retinoides/genética , Síndrome de Stevens-Johnson/genética , Adolescente , Adulto , Western Blotting , Estudos de Casos e Controles , Doença Crônica , Oftalmopatias/genética , Oftalmopatias/metabolismo , Feminino , Seguimentos , Humanos , Masculino , Estudos Prospectivos , Retinoides/biossíntese , Síndrome de Stevens-Johnson/complicações , Síndrome de Stevens-Johnson/metabolismo , Adulto Jovem
5.
Br J Ophthalmol ; 103(4): 573-576, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30705045

RESUMO

BACKGROUND/AIMS: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are a spectrum of diseases that cause an acute vesiculobullous reaction in the skin and mucous membranes. The occurrence of these diseases is associated with various drugs, a large proportion of which is comprised cold medicines (CM). We try to investigate the association between human leucocyte antigen (HLA) class I genes and CM-related SJS/TEN (CM-SJS/TEN) with severe ocular complications (SOC) in the Korean population. METHODS: This multicentre case-control study enrolled 40 Korean patients with CM-SJS/TEN with SOC and 120 age-matched and sex-matched Korean healthy volunteers between January 2012 and May 2014. HLA genotyping was performed using PCR followed by hybridisation with sequence-specific oligonucleotide probes. RESULTS : The carrier frequency and gene frequency of HLA-A*02:06 were 37.5 % and 20.0 %, respectively, in patients, and 16.7 % and 9.6 %, respectively, in controls (p=0.018). The carrier frequency of HLA-C*03:04 was 30 % in patients and 10.8 % in controls, and gene frequency of HLA-C*03:04 was 15 % in patients and 5.4 % in controls (p=0.003). The carrier frequency and gene frequency of HLA-C*03:03 were 2.5 % and 1.3 %, respectively, in patients, and 20 % and 10.4 %, respectively, in controls (p=0.006). CONCLUSIONS : As per our results, we suggest that HLA-A*02:06 and HLA-C*03:04 might be positive markers for CM-SJS/TEN with SOC, and HLA-C*03:03 might be an indicator of protection against CM-SJS/TEN with SOC in the Korean population.


Assuntos
Oftalmopatias/etiologia , Genes MHC Classe I/genética , Polimorfismo de Nucleotídeo Único , Síndrome de Stevens-Johnson/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Criança , Pré-Escolar , Oftalmopatias/epidemiologia , Oftalmopatias/genética , Feminino , Frequência do Gene , Predisposição Genética para Doença , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Prognóstico , República da Coreia/epidemiologia , Síndrome de Stevens-Johnson/complicações , Síndrome de Stevens-Johnson/epidemiologia , Adulto Jovem
6.
Mol Immunol ; 106: 170-177, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30623817

RESUMO

Stevens-Johnson syndrome (SJS) /toxic epidermal necrolysis (TEN) are life-threatening severe cutaneous adverse drug reactions characterized by widespread epidermal necrosis. Recent studies have indicated that SJS/TEN is a specific immune reaction regulated by T cells. Certain drug serves as foreign antigens that are presented by major histocompatibility complex (MHC) and recognized by T cell receptors (TCRs), inducing adaptive immune responses. However, few studies have performed detailed characterization of TCR repertoire in SJS/TEN, and it remains unclear whether the particular types of TCRs expanded clonally are drug-specific, which would provide a potential underlying mechanism of SJS/TEN. In this study, using high-throughput sequencing, we comprehensively assessed the diversity, composition and molecular characteristics of the TCRß repertoires in 17 SJS/TEN patients associated with three different causative drugs including methazolamide (MZ), carbamazepine (CBZ) and allopurinol (ALP). Systematic analysis of the TCRß sequences revealed that SJS/TEN patients had more highly expanded clones and less TCR repertoire diversity, and the TCR repertoire diversity of these patients showed certain associations with the clinical severity of disease. Similar predominant clonotypes, shared-usage TRBV/TRBJ subtypes and combinations thereof were observed among different subjects with the same causative agent. Our observations provide enhanced understanding of the role of T lymphocytes in the pathogenesis of SJS/TEN and enumerate potential therapeutic targets.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Síndrome de Stevens-Johnson/genética , Alopurinol/administração & dosagem , Alopurinol/efeitos adversos , Carbamazepina/administração & dosagem , Carbamazepina/efeitos adversos , Feminino , Humanos , Masculino , Metazolamida/administração & dosagem , Metazolamida/efeitos adversos , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Síndrome de Stevens-Johnson/imunologia , Síndrome de Stevens-Johnson/patologia
7.
Pharmacogenomics J ; 19(3): 286-294, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30242287

RESUMO

Methazolamide-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are life-threatening adverse drug reactions. Based on previous studies, HLA genotypes may play an important role in methazolamide-induced SJS/TEN. Therefore, to identify the associations between HLA genotypes and methazolamide-induced cutaneous adverse drug reactions (cADRs) (i.e., SJS/TEN and hypersensitivity syndrome), a systematic review and meta-analysis were performed. Two studies (one study in Korean and another in Han Chinese) met the inclusion criteria. The studies included 13 patients with methazolamide-induced SJS/TEN, 30 methazolamide-tolerant, and 768 population controls. Associations between HLA-B*5901, HLA-B*5901-Cw*0102 haplotype, and methazolamide-induced SJS/TEN were identified in methazolamide-tolerant and population controls. Overall ORs were 305.0 (95% CI = 11.3-8, 259.4) in methazolamide-tolerant and 715.3 (95% CI = 83.1-6,158.5) in population control. In addition, statistically significant associations between the HLA-Cw*0102 and methazolamide-induced SJS/TEN were found in methazolamide-tolerant (OR = 12.1; 95% CI = 1.3-111.7) and population control (OR = 17.5; 95% CI = 3.2-96.6). Since HLA-B*5901 and HLA-B*5901-Cw*0102 haplotype are associated with methazolamide-induced SJS/TEN, genetic screening prior to methazolamide therapy in Asian populations is warranted.


Assuntos
Predisposição Genética para Doença/genética , Antígenos HLA-B/genética , Metazolamida/efeitos adversos , Síndrome de Stevens-Johnson/etiologia , Síndrome de Stevens-Johnson/genética , Grupo com Ancestrais do Continente Asiático/genética , Síndrome de Hipersensibilidade a Medicamentos/genética , Genótipo , Humanos
8.
Clin Pharmacol Ther ; 105(1): 112-120, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29569740

RESUMO

Specific ethnic genetic backgrounds are associated with the risk of Stevens-Johnson syndrome / toxic epidermal necrolysis (SJS/TEN) especially in Asians. However, there have been no large cohort, multiple-country epidemiological studies of medication risk related to SJS/TEN in Asian populations. Thus, we analyzed the registration databases from multiple Asian countries who were treated during 1998-2017. A total 1,028 SJS/TEN cases were identified with the algorithm of drug causality for epidermal necrolysis. Furthermore, those medications labeled by the US Food and Drug Administration (FDA) as carrying a risk of SJS/TEN were also compared with the common causes of SJS/TEN in Asian countries. Oxcarbazepine, sulfasalazine, COX-II inhibitors, and strontium ranelate were identified as new potential causes. In addition to sulfa drugs and beta-lactam antibiotics, quinolones were also a common cause. Only one acetaminophen-induced SJS was identified, while several medications (e.g., oseltamivir, terbinafine, isotretinoin, and sorafenib) labeled as carrying a risk of SJS/TEN by the FDA were not found to have caused any of the cases in the Asian countries investigated in this study.


Assuntos
Grupo com Ancestrais do Continente Asiático , Rotulagem de Medicamentos/normas , Síndrome de Stevens-Johnson/diagnóstico , Síndrome de Stevens-Johnson/epidemiologia , United States Food and Drug Administration/normas , Alopurinol/efeitos adversos , Anti-Infecciosos/efeitos adversos , Anti-Inflamatórios não Esteroides/efeitos adversos , Anticonvulsivantes/efeitos adversos , Antipsicóticos/efeitos adversos , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Coortes , Depuradores de Radicais Livres/efeitos adversos , Humanos , Sistema de Registros , Fatores de Risco , Síndrome de Stevens-Johnson/genética , Estados Unidos/epidemiologia
9.
Genet Med ; 21(2): 382-390, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-29858578

RESUMO

PURPOSE: The Veterans Health Administration (VHA) Clinical Pharmacogenetics Subcommittee is charged with making recommendations about whether specific pharmacogenetic tests should be used in healthcare at VHA facilities. We describe a process to inform VHA pharmacogenetic testing policy. METHODS: After developing consensus definitions of clinical validity and utility, the Subcommittee identified salient drug-gene pairs with potential clinical application in VHA. Members met monthly to discuss each drug-gene pair, the evidence of clinical utility for the associated pharmacogenetic test, and any VHA-specific testing considerations. The Subcommittee classified each test as strongly recommended, recommended, or not routinely recommended before drug initiation. RESULTS: Of 30 drug-gene pair tests reviewed, the Subcommittee classified 4 (13%) as strongly recommended, including HLA-B*15:02 for carbamazepine-associated Stevens-Johnston syndrome and G6PD for rasburicase-associated hemolytic anemia; 12 (40%) as recommended, including CYP2D6 for codeine toxicity; and 14 (47%) as not routinely recommended, such as CYP2C19 for clopidogrel dosing. CONCLUSION: Only half of drug-gene pairs with high clinical validity received Subcommittee support for policy promoting their widespread use across VHA. The Subcommittee generally found insufficient evidence of clinical utility or available, effective alternative strategies for the remainders. Continual evidence review and rigorous outcomes research will help promote the translation of pharmacogenetic discovery to healthcare.


Assuntos
Clopidogrel/efeitos adversos , Farmacogenética/estatística & dados numéricos , Síndrome de Stevens-Johnson/epidemiologia , Saúde dos Veteranos/estatística & dados numéricos , Clopidogrel/uso terapêutico , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2D6/genética , Genótipo , Glucosefosfato Desidrogenase/genética , Antígeno HLA-B15/genética , Humanos , Testes Farmacogenômicos , Síndrome de Stevens-Johnson/genética , Estados Unidos , United States Department of Veterans Affairs/estatística & dados numéricos , Veteranos
10.
J Allergy Clin Immunol ; 143(1): 66-73, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30573342

RESUMO

Controversies exist with regard to in vivo approaches to delayed immunologically mediated adverse drug reactions, such as exanthem (maculopapular eruption), drug reaction with eosinophilia and systemic symptoms, acute generalized exanthematous pustulosis, Stevens-Johnson syndrome/toxic epidermal necrolysis, and fixed drug eruptions. In particular, widespread differences exist between regions and practice on the availability and use of intradermal and patch testing, the standard drug concentrations used, the use of additional drugs in intradermal and patch testing to help determine cross-reactivity, the timing of testing in relation to the occurrence of the adverse drug reaction, the use of testing in specific phenotypes, and the use of oral challenge in conjunction with delayed intradermal and patch testing to ascertain drug tolerance. It was noted that there have been advances in the science of delayed T cell-mediated reactions that have shed light on immunopathogenesis and provided a mechanism of preprescription screening in the case of HLA-B*57:01 and abacavir hypersensitivity and HLA-B*15:02 and carbamazepine Stevens-Johnson syndrome/toxic epidermal necrolysis in Southeast Asian subjects. Future directions should include the collaboration of large international networks to develop and standardize in vivo diagnostic approaches, such as skin testing and patch testing, combined with ex vivo and in vitro laboratory approaches.


Assuntos
Antígenos HLA-B , Antígeno HLA-B15 , Síndrome de Stevens-Johnson , Animais , Grupo com Ancestrais do Continente Asiático , Carbamazepina/efeitos adversos , Carbamazepina/uso terapêutico , Didesoxinucleosídeos/efeitos adversos , Didesoxinucleosídeos/uso terapêutico , Antígenos HLA-B/genética , Antígenos HLA-B/imunologia , Antígeno HLA-B15/genética , Antígeno HLA-B15/imunologia , Humanos , Testes Cutâneos/normas , Síndrome de Stevens-Johnson/genética , Síndrome de Stevens-Johnson/imunologia , Síndrome de Stevens-Johnson/patologia
11.
Invest Ophthalmol Vis Sci ; 59(14): DES183-DES191, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30481825

RESUMO

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are acute inflammatory vesiculobullous reactions of the mucosa of the ocular surface, oral cavity, and genitals, and of the skin. Severe ocular complications (SOC) are present in about half of SJS/TEN patients diagnosed by dermatologists. We review our group's findings on the genetic predisposition for and the etiology of SJS/TEN with SOC. We suspected that abnormal innate mucosal immunity, resulting in an anomalous response to commensal bacteria that usually do not elicit such a response, contributes to the ocular surface inflammation seen in SJS/TEN with SOC. We found that cold medicines, including multi-ingredient cold medications and nonsteroidal anti-inflammatory drugs, were the main causative drugs especially in patients with SJS/TEN with SOC. Cold medicine-related SJS/TEN (CM-SJS/TEN) with SOC was strongly associated with HLA-A*02:06 in the Japanese populations, and significantly associated with HLA-B*44:03 in the Japanese and in Indian and Brazilian populations. Single nucleotide polymorphism association analysis showed that the Toll-like receptor 3 (TLR3), prostaglandin-E receptor 3 (PTGER3), and IKZF1 gene were significantly associated with CM-SJS/TEN with SOC and that they could regulate mucocutaneous inflammation including that of the ocular surface. As we found several HLA-SNP sets with a high odds ratio, we postulated that they may help to predict the possible development of SJS/TEN with SOC. From our findings we suggest that besides microbial infection and cold medicines, a combination of multiple gene polymorphisms and their interactions contribute strongly to the onset of CM-SJS/TEN with SOC.


Assuntos
Síndromes do Olho Seco/genética , Fator de Transcrição Ikaros/genética , Ceratoconjuntivite/genética , Polimorfismo de Nucleotídeo Único , Receptores de Prostaglandina E Subtipo EP3/genética , Síndrome de Stevens-Johnson/genética , Receptor 3 Toll-Like/genética , Animais , Anti-Inflamatórios não Esteroides/efeitos adversos , Predisposição Genética para Doença , Antígenos HLA/imunologia , Humanos , Imunidade Inata , Imunidade nas Mucosas , Síndrome de Stevens-Johnson/etiologia
13.
BMJ Case Rep ; 20182018 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-30018035

RESUMO

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are two related mucocutaneous disorders with different severities. Although the incidence is low, SJS and TEN are life-threatening and predominantly drug-induced conditions. There is a strong relationship between the HLA-B*1502 allele and carbamazepine-induced SJS and TEN in different Southeast Asian populations. Here, we report a case of Filipino with SJS/TEN overlap probably induced by carbamazepine. The condition was treated with hydrocortisone followed by prednisone. The HLA-B*1502 allele was not found in this case. The patient tested positive for the HLA-B75 serotype, suggesting that carbamazepine-induced SJS/TEN may be serotype specific. Establishing the genotype before initiation of the drug may be advantageous for some patients and will aid physicians in determining the optimal drug therapy. Prevention of adverse drug reactions (ADR) may be done if pharmacists and other healthcare professionals work as a multidisciplinary ADR team to ensure that safe medication practices are realised.


Assuntos
Antimaníacos/efeitos adversos , Carbamazepina/efeitos adversos , Antígenos HLA-B/sangue , Transtornos Mentais/tratamento farmacológico , Síndrome de Stevens-Johnson/etiologia , Adulto , Humanos , Masculino , Síndrome de Stevens-Johnson/genética
14.
Mol Cell ; 70(5): 920-935.e7, 2018 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-29883609

RESUMO

Receptor-interacting protein kinase-3 (RIP3 or RIPK3) is a central protein in necroptosis, but posttranslational processes that regulate RIP3 activity and stability remain poorly understood. Here, we identify pellino E3 ubiquitin protein ligase 1 (PELI1) as an E3 ligase that targets RIP3 for proteasome-dependent degradation. Phosphorylation of RIP3 on T182 leads to interaction with the forkhead-associated (FHA) domain of PELI1 and PELI1-mediated K48-linked polyubiquitylation of RIP3 on K363. This same phosphorylation event is also important for RIP3 kinase activity; thus, PELI1 preferentially targets kinase-active RIP3 for degradation. PELI1-mediated RIP3 degradation effectively prevents cell death triggered by RIP3 hyperactivation. Importantly, upregulated RIP3 expression in keratinocytes from toxic epidermal necrolysis (TEN) patients is correlated with low expression of PELI1, suggesting that loss of PELI1 may play a role in the pathogenesis of TEN. We propose that PELI1 may function to control inadvertent activation of RIP3, thus preventing aberrant cell death and maintaining cellular homeostasis.


Assuntos
Queratinócitos/enzimologia , Proteínas Nucleares/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Síndrome de Stevens-Johnson/enzimologia , Ubiquitina-Proteína Ligases/metabolismo , Animais , Morte Celular , Fibroblastos/enzimologia , Fibroblastos/patologia , Células HEK293 , Células HT29 , Células HeLa , Humanos , Queratinócitos/patologia , Camundongos , Proteínas Nucleares/genética , Fosforilação , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Proteólise , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Transdução de Sinais , Síndrome de Stevens-Johnson/genética , Síndrome de Stevens-Johnson/patologia , Ubiquitina-Proteína Ligases/genética , Ubiquitinação
15.
J Antimicrob Chemother ; 73(8): 2137-2140, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29762688

RESUMO

Objectives: Nevirapine is used in developing countries for the treatment of HIV infection, but its use is associated with rare serious adverse reactions such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Recently, an association between rs5010528 in the human leucocyte antigen (HLA)-C locus and SJS/TEN susceptibility has been described in sub-Saharan populations. Our aim was to verify this association in a population of nevirapine-treated patients from Mozambique. Methods: The rs5010528 SNP was analysed by direct sequencing in 27 patients who had developed SJS/TEN and 75 patients who did not develop adverse reactions after nevirapine treatment. A case-control association study was conducted. A multivariate analysis was performed in order to evaluate the role of HLA-C also in relation to other susceptibility genetic factors (CYP2B6, TRAF3IP2, HCP5, PSORS1C1 and GSTM1 genes). Results: rs5010528 was significantly associated with a higher risk of developing SJS/TEN; the variant allele was more frequent in cases than in controls, conferring a high risk of developing this adverse reaction in carriers (OR = 5.72 and P = 0.0002 at genotype level, OR = 3.51 and P = 0.0002 at allelic level). The multivariate analysis showed that the HLA-C SNP, CYP2B6 (rs28399499), TRAF3IP2 (rs76228616) and GSTM1 (null genotype) can explain 25% of the susceptibility to this reaction, with the HLA-C SNP as the most significant contributor (P = 0.02 and OR = 5.64). Conclusions: Our study confirmed the association of the rs5010528 SNP in the HLA-C region with susceptibility to developing SJS/TEN in a population from Mozambique, suggesting that it could be a good genomic biomarker for SJS/TEN susceptibility in different sub-Saharan populations.


Assuntos
Fármacos Anti-HIV/efeitos adversos , Infecções por HIV/tratamento farmacológico , Antígenos HLA-C/genética , Nevirapina/efeitos adversos , Síndrome de Stevens-Johnson/genética , Adulto , Alelos , Fármacos Anti-HIV/uso terapêutico , Estudos de Casos e Controles , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Moçambique , Análise Multivariada , Nevirapina/uso terapêutico , Polimorfismo de Nucleotídeo Único
16.
Br J Ophthalmol ; 102(9): 1303-1307, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29706602

RESUMO

BACKGROUND: Polymorphisms in human leucocyte antigen (HLA) class I genes have been found to be associated with cold medicine (CM)-related Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) with severe ocular complications (SOC). Because ethnic differences in genetic predisposition to SJS/TEN among different populations have been proposed, we focused on Thai patients and investigated the association between HLA class I genotypes and CM-SJS/TEN with SOC. METHODS: This multicentre case-control study was conducted between September 2014 and August 2017. Seventy-one Thai patients with SJS/TEN with SOC and 159 healthy Thai controls were enrolled. HLA typing was performed. Genetic relationships were analysed using Fisher's exact test. RESULTS: Of 71 patients with SJS/TEN with SOC (28 male, 43 female), 49 (69%) had a history of taking cold medications prior to SJS/TEN onset. The mean age of onset was 26.7±17.1 years (range, 2-77 years). HLA-B*44:03 (OR, 7.2, p=5.5×10-6, pc=1.1×10-4) and HLA-C*07:01 (OR, 6.1, p=7.1×10-6, pc=1.1×10-4) showed significant positive associations with Thai patients with CM-SJS/TEN with SOC. Additionally, 17 of 49 patients with CM-SJS/TEN with SOC (34.7%) significantly harboured the HLA-B*44:03 and HLA-C*07:01 haplotype compared with only 11 of 159 healthy controls (6.9%) (OR=7.1, p=5.5×10-6). CONCLUSIONS: HLA-B*44:03-HLA-C*07:01 haplotype is a potential risk factor for CM-SJS/TEN with SOC in the Thai population. This study supports that HLA-B*44:03 might be a common marker for CM-SJS/TEN with SOC in Eurasia populations, including European, Indian, Japanese and Thai.


Assuntos
Oftalmopatias/etiologia , Antígenos HLA-B/genética , Antígenos HLA-C/genética , Polimorfismo Genético , Síndrome de Stevens-Johnson/genética , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Criança , Pré-Escolar , Oftalmopatias/epidemiologia , Oftalmopatias/genética , Feminino , Predisposição Genética para Doença , Genótipo , Haplótipos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Síndrome de Stevens-Johnson/complicações , Tailândia/epidemiologia , Adulto Jovem
17.
Annu Rev Genomics Hum Genet ; 19: 329-353, 2018 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-29652519

RESUMO

The Global Genomic Medicine Collaborative, a multinational coalition of genomic and policy experts working to implement genomics in clinical care, considers pharmacogenomics to be among the first areas in genomic medicine that can provide guidance in routine clinical practice, by linking genetic variation and drug response. Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe life-threatening reactions to medications with a high incidence worldwide. Genomic screening prior to drug administration is a key opportunity and potential paradigm for using genomic medicine to reduce morbidity and mortality and ultimately eliminate one of the most devastating adverse drug reactions. This review focuses on the current understanding of the surveillance, pathogenesis, and treatment of SJS/TEN, including the role of genomics and pharmacogenomics in the etiology, treatment, and eradication of preventable causes of drug-induced SJS/TEN. Gaps, unmet needs, and priorities for future research have been identified for the optimal management of drug-induced SJS/TEN in various ethnic populations. Pharmacogenomics holds great promise for optimal patient stratification and theranostics, yet its clinical implementation needs to be cost-effective and sustainable.


Assuntos
Farmacogenética , Síndrome de Stevens-Johnson/etiologia , Nanomedicina Teranóstica , Humanos , Síndrome de Stevens-Johnson/genética
18.
JAMA Neurol ; 75(7): 842-849, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29610831

RESUMO

Importance: Carbamazepine, a commonly used antiepileptic drug, is one of the most common causes of cutaneous adverse drug reactions (cADRs) worldwide. The allele HLA-A*31:01 is reportedly associated with carbamazepine-induced cADRs in Japanese and European populations; however, the clinical utility of HLA-A*31:01 has not been evaluated. Objective: To assess the use of HLA-A*31:01 genetic screening to identify Japanese individuals at risk of carbamazepine-induced cADRs. Design, Setting, and Participants: This cohort study was conducted across 36 hospitals in Japan from January 2012 to November 2014 among 1202 patients who had been deemed suitable to start treatment with carbamazepine. Preemptive HLA-A*31:01 genetic screening was performed for 1187 participants. Patients who did not start treatment with carbamazepine or alternative drugs were excluded. Participants were interviewed once weekly for 8 weeks to monitor the development of cADRs. Data analysis was performed from June 8, 2015, to December 27, 2016. Exposures: Neuropsychiatrists were asked to prescribe carbamazepine for patients who tested negative for HLA-A*31:01 and alternative drugs for those who tested positive for HLA-A*31:01. Main Outcomes and Measures: Incidence of carbamazepine-induced cADRs. Results: Of the 1130 included patients who were prescribed carbamazepine or alternative drugs, the mean (range) age was 37.4 (0-95) years, 614 (54.3%) were men, and 198 (17.5%) were positive for HLA-A*31:01. Expert dermatologists identified 23 patients (2.0%) who had carbamazepine-induced cADRs, of which 4 patients required hospitalization. Drug-induced hypersensitivity syndrome was observed for 3 patients, maculopapular eruption for 9 patients, erythema multiforme for 5 patients, and an undetermined type of cADR for 6 patients. No patient developed Stevens-Johnson syndrome or toxic epidermal necrolysis. Compared with historical controls, the incidence of carbamazepine-induced cADRs was significantly decreased (for BioBank Japan data: incidence, 3.4%; odds ratio, 0.60; 95% CI, 0.36-1.00; P = .048; for the Japan Medical Data Centre claims database: incidence, 5.1%; odds ratio, 0.39; 95% CI, 0.26-0.59; P < .001). Conclusions and Relevance: Preemptive HLA-A*31:01 genetic screening significantly decreased the incidence of carbamazepine-induced cADRs among Japanese patients, which suggests that it may be warranted in routine clinical practice.


Assuntos
Anticonvulsivantes/efeitos adversos , Carbamazepina/efeitos adversos , Hipersensibilidade a Drogas/epidemiologia , Testes Farmacogenômicos/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Erupção por Droga/epidemiologia , Erupção por Droga/genética , Erupção por Droga/prevenção & controle , Hipersensibilidade a Drogas/genética , Hipersensibilidade a Drogas/prevenção & controle , Síndrome de Hipersensibilidade a Medicamentos/epidemiologia , Síndrome de Hipersensibilidade a Medicamentos/genética , Síndrome de Hipersensibilidade a Medicamentos/prevenção & controle , Feminino , Antígenos HLA-A/genética , Humanos , Incidência , Lactente , Recém-Nascido , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Síndrome de Stevens-Johnson/epidemiologia , Síndrome de Stevens-Johnson/genética , Síndrome de Stevens-Johnson/prevenção & controle , Adulto Jovem
19.
J Immunol Res ; 2018: 2780272, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29546073

RESUMO

The HLA-B∗15:02 allele has been reported to have a strong association with carbamazepine-induced Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) in Thai patients. The HLA-B alleles associated with carbamazepine-induced maculopapular exanthema (MPE) and the drug reaction with eosinophilia and systemic symptoms (DRESS) among the Thai population have never been reported. The aim of the present study was to carry out an analysis of the involvement of HLA-B alleles in carbamazepine-induced cutaneous adverse drug reactions (cADRs) in the Thai population. A case-control study was performed by genotyping the HLA-B alleles of Thai carbamazepine-induced hypersensitivity reaction patients (17 MPE, 16 SJS/TEN, and 5 DRESS) and 271 carbamazepine-tolerant controls. We also recruited 470 healthy Thai candidate subjects who had not taken carbamazepine. HLA-B∗15:02 showed a significant association with carbamazepine-induced MPE (P = 0.0022, odds ratio (OR) (95% confidence interval [CI]) = 7.27 (2.04-25.97)) and carbamazepine-induced SJS/TEN (P = 4.46 × 10-13; OR (95% CI) = 70.91(19.67-255.65)) when compared with carbamazepine-tolerant controls. Carbamazepine-induced SJS/TEN also showed an association with HLA-B∗15:21 allele (P = 0.013; OR (95% CI) = 9.54 (1.61-56.57)) when compared with carbamazepine-tolerant controls. HLA-B∗58:01 allele was significantly related to carbamazepine-induced MPE (P = 0.007; OR (95% CI) = 4.73 (1.53-14.66)) and DRESS (P = 0.0315; OR (95% CI) = 7.55 (1.20-47.58)) when compared with carbamazepine-tolerant controls. These alleles may serve as markers to predict carbamazepine-induced cADRs in the Thai population.


Assuntos
Carbamazepina/efeitos adversos , Erupção por Droga/genética , Síndrome de Hipersensibilidade a Medicamentos/genética , Genótipo , Antígenos HLA-B/genética , Antígeno HLA-B15/genética , Síndrome de Stevens-Johnson/genética , Adolescente , Adulto , Alelos , Carbamazepina/uso terapêutico , Estudos de Casos e Controles , Criança , Feminino , Frequência do Gene , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Pele/patologia , Tailândia , Adulto Jovem
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