Research Directions in Genetic Predispositions to Stevens-Johnson Syndrome / Toxic Epidermal Necrolysis.
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ABSTRACT:
SUBMITTER: Manolio TA
PROVIDER: S-EPMC5805563 | biostudies-literature | 2018 Mar
REPOSITORIES: biostudies-literature
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Research Directions in Genetic Predispositions to Stevens-Johnson Syndrome / Toxic Epidermal Necrolysis.
Manolio Teri A TA Hutter Carolyn M CM Avigan Mark M Cibotti Ricardo R Davis Robert L RL Denny Joshua C JC Grenade Lois La L Wheatley Lisa M LM Carrington Mary N MN Chantratita Wasun W Chung Wen-Hung WH Dalton Andrea D AD Hung Shuen-Iu SI Lee Ming Ta Michael MTM Leeder J Steven JS Lertora Juan J L JJL Mahasirimongkol Surakameth S McLeod Howard L HL Mockenhaupt Maja M Pacanowski Michael M Phillips Elizabeth J EJ Pinheiro Simone S Pirmohamed Munir M Sung Cynthia C Suwankesawong Wimon W Trepanier Lauren L Tumminia Santa J SJ Veenstra David D Yuliwulandari Rika R Shear Neil H NH
Clinical pharmacology and therapeutics 20171106 3
Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is one of the most devastating of adverse drug reactions (ADRs) and was, until recently, essentially unpredictable. With the discovery of several risk alleles for drug-induced SJS/TEN and the demonstration of effectiveness of screening in reducing incidence, the stage is set for implementation of preventive strategies in populations at risk. Yet much remains to be learned about this potentially fatal complication of commonly used drug ...[more]
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Project description:Stevens-Johnson syndrome (SJS) is an acute inflammatory vesiculobullous reaction of the skin and mucosa, such as the ocular surface, oral cavity, and genitals. In patients with extensive skin detachment and a poor prognosis, the condition is called toxic epidermal necrolysis (TEN). Severe ocular complications (SOCs) appear in some-but not all-SJS/TEN patients who are diagnosed by dermatologists, and cold medicines including multi-ingredient cold medications and nonsteroidal anti-inflammatory drugs are the main causative drugs particularly for SJS/TEN with SOCs and all SJS and TEN. In this review, we focus on the genetic predisposition of cold medicine-related SJS/TEN (CM-SJS/TEN) with SOCs. CM-SJS/TEN with SOCs was strongly associated with HLA-A*02:06 and significantly associated with HLA-B*44:03 in Japanese individuals, significantly associated with HLA-B*44:03 in Indian and Brazilian individuals, and associated with HLA-A*02:06 in Korean individuals. In the first genome-wide association study (GWAS), we found an association between the prostaglandin E receptor 3 (PTGER3) gene and SJS/TEN with SOCs. In this study, we focused on CM-SJS/TEN with SOCs and found that the association of CM-SJS/TEN with SOCs became stronger than all SJS/TEN with SOCs. In the second GWAS, we found an association between the IKZF1 gene and CM-SJS/TEN with SOCs not only in Japanese, but also in Korean and Indian populations. Moreover, we found that TSHZ2 gene single nucleotide polymorphisms (SNPs) also showed especially low p values in the Japanese population; however, this association was not found in the Korean population. Furthermore, we investigated the interaction between susceptibility genes, and found multiplicative interactions of HLA-A*02:06 and TLR3 SNPs and additive interactions of HLA-A*02:06 and PTGER3 SNPs.
| S-EPMC5525617 | biostudies-literature
Project description:Epidermal necrolysis, the unifying term for Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), is a severe cutaneous drug reaction associated with high morbidity and mortality. Given the rarity of this disease, large-scale prospective research studies are limited. Significant institutional and geographical variations in treatment practices highlight the need for standardization of clinical assessment scores and prioritization of research outcome measures in epidermal necrolysis. At the present, clinical assessment is typically simplified to total body surface area (BSA) involvement, with little focus on morphology. Validated clinical scoring systems are used as mortality prognostication tools, with SCORTEN being the best-validated tool thus far, although the ABCD-10 has also been recently introduced. These tools are imperfect in that they tend to either overestimate or underestimate mortality in certain populations and are not designed to monitor disease progression. Although mortality is often used as a primary endpoint for epidermal necrolysis studies, this outcome fails to capture more nuanced changes in skin disease such as arrest of disease progression while also lacking a validated skin-directed inclusion criterion to stratify patients based on the severity of skin disease at study entry. In addition to mortality, many studies also use BSA stabilization or time to re-epithelialization as endpoints, although these are not clearly defined morphologically, and inter- and intra-rater reliability are unclear. More specific, validated cutaneous assessment scores are necessary in order advance therapeutic options for epidermal necrolysis. In this review, we summarize the strengths and weaknesses of current clinical assessment practices in epidermal necrolysis and highlight the need for standardized research tools to monitor cutaneous involvement throughout the hospitalization.
| S-EPMC9245022 | biostudies-literature
Project description:Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening mucocutaneous adverse drug reactions characterized by massive epidermal detachment. Cytotoxic T cells and associated effector molecules are known to drive SJS/TEN pathophysiology, but the contribution of innate immune responses is not well understood. We describe a mechanism by which neutrophils triggered inflammation during early phases of SJS/TEN. Skin-infiltrating CD8+ T cells produced lipocalin-2 in a drug-specific manner, which triggered the formation of neutrophil extracellular traps (NETs) in early lesional skin. Neutrophils undergoing NETosis released LL-37, an antimicrobial peptide, which induced formyl peptide receptor 1 (FPR1) expression by keratinocytes. FPR1 expression caused keratinocytes to be vulnerable to necroptosis that caused further release of LL-37 by necroptotic keratinocytes and induced FPR1 expression on surrounding keratinocytes, which likely amplified the necroptotic response. The NETs-necroptosis axis was not observed in less severe cutaneous adverse drug reactions, autoimmune diseases, or neutrophil-associated disorders, suggesting that this was a process specific to SJS/TEN. Initiation and progression of SJS/TEN keratinocyte necroptosis appear to involve a cascade of events mediated by innate and adaptive immune responses, and understanding these responses may contribute to the identification of diagnostic markers or therapeutic targets for these adverse drug reactions.
| S-EPMC9392155 | biostudies-literature
Project description:BackgroundLittle is known about the epidemiology of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in children.ObjectiveWe sought to determine the morbidity, mortality, and comorbid health conditions of SJS and TEN in US children.MethodsThis was a cross-sectional study of the 2009 to 2012 Nationwide Inpatient Sample, which contains a representative 20% sample of all US hospitalizations. Sociodemographics, inflation-adjusted cost, length of stay, comorbidities, and mortality were analyzed using descriptive statistics and multivariate regression analyses.ResultsThe incidences of SJS, SJS-TEN, and TEN were a mean 5.3, 0.8, and 0.4 cases per million children per year in the US, respectively. Prolonged length of stay and higher costs of care (SJS: 9.4 ± 0.6 days, $24,947 ± $3171; SJS-TEN: 15.7 ± 1.5 days, $63,787 ± $8014; TEN: 20.4 ± 6.3 days, $102,243 ± $37,588) were observed compared with all other admissions (4.6 ± 0.1 days, $10,496 ± $424). Mortality was 0% for SJS, 4% for SJS-TEN, and 16% for TEN. In regression models, predictors of mortality included renal failure (adjusted OR [aOR] 300.28, 95% confidence interval [CI] 48.59->999.99), malignancy (aOR 54.33, 95% CI 9.40-314.22), septicemia (aOR 30.45, 95% CI 7.91-117.19), bacterial infection (aOR 20.38, 95% CI 5.44-76.36), and epilepsy (aOR 5.56, 95% CI 1.37-26.2).LimitationsData regarding treatment were not available. Date of diagnosis of comorbidities was not present, precluding temporal analysis.ConclusionsPediatric SJS/TEN poses a substantial health burden in the United States.
| S-EPMC5502094 | biostudies-literature
Project description:Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening diseases characterized by detachment of the epidermis and mucous membrane. SJS/TEN are considered to be on the same spectrum of diseases with different severities. They are classified by the percentage of skin detachment area. SJS/TEN can also cause several complications in the liver, kidneys, and respiratory tract. The pathogenesis of SJS/TEN is still unclear. Although it is difficult to diagnose early stage SJS/TEN, biomarkers for diagnosis or severity prediction have not been well established. Furthermore, optimal therapeutic options for SJS/TEN are still controversial. Several drugs, such as carbamazepine and allopurinol, are reported to have a strong relationship with a specific human leukocyte antigen (HLA) type. This relationship differs between different ethnicities. Recently, the usefulness of HLA screening before administering specific drugs to decrease the incidence of SJS/TEN has been investigated. Skin detachment in SJS/TEN skin lesions is caused by extensive epidermal cell death, which has been considered to be apoptosis via the Fas-FasL pathway or perforin/granzyme pathway. We reported that necroptosis, i.e. programmed necrosis, also contributes to epidermal cell death. Annexin A1, released from monocytes, and its interaction with the formyl peptide receptor 1 induce necroptosis. Several diagnostic or prognostic biomarkers for SJS/TEN have been reported, such as CCL-27, IL-15, galectin-7, and RIP3. Supportive care is recommended for the treatment of SJS/TEN. However, optimal therapeutic options such as systemic corticosteroids, intravenous immunoglobulin, cyclosporine, and TNF-? antagonists are still controversial. Recently, the beneficial effects of cyclosporine and TNF-? antagonists have been explored. In this review, we discuss recent advances in the pathophysiology and management of SJS/TEN.
| S-EPMC7308994 | biostudies-literature
Project description:BackgroundStevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are two of the most severe dermatologic emergencies. Although pregnant women comprise a subset of individuals at risk for SJS and TEN development, little is known with regard to outcomes and treatment.ObjectiveThis study aimed to conduct a systematic review to characterize the risk factors, outcomes, and treatment of SJS and TEN in pregnant patients and newborns.MethodsA primary literature search was conducted using PubMed in September 2019, using the following search terms entered in separate pairs: pregnant or pregnancy and stevens-johnson or SJS or toxic epidermal necrolysis. Reviews, studies in a language other than English, and articles not including pregnant patients were excluded.ResultsTwenty-six articles were included for review, including a total of 177 patients. The average maternal age for a reaction was 29.9 years, gestational age was 24.9 weeks, and time to reaction after drug initiation was 27.5 days. Approximately 85% of pregnant women in this review were infected with HIV. The most common causative medications were antiretroviral therapy (90% of all cases), antibiotics (3%), and gestational drugs (2%). Of the 94 cases in which outcome data were available, the survival rates of pregnant women and newborns after delivery were 98% and 96%, respectively. Withdrawal of the offending agent and supportive care was often sufficient for treatment, but antibiotics, steroids, and intravenous immunoglobulin were implemented in some cases. Complications included preterm labor, vaginal stenosis, and vaginal adhesions.ConclusionGiven the predominance of studies focusing on the subset of pregnant patients who are infected with HIV, SJS and TEN is most commonly reported in young patients after antiretroviral therapy, primarily nevirapine. Overall mortality is lower than that of the general population, but similar to the expected mortality rates of younger adults. Early recognition and withdrawal of the offending agent is essential to mitigate the distinct consequences of these conditions in the pregnant population.
| S-EPMC7522894 | biostudies-literature
Project description:BACKGROUND: Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) are rare but extremely severe cutaneous adverse drug reactions in which drug-specific associations with HLA-B alleles were described. OBJECTIVES: To investigate genetic association at a genome-wide level on a large sample of SJS/TEN patients. METHODS: We performed a genome wide association study on a sample of 424 European cases and 1,881 controls selected from a Reference Control Panel. RESULTS: Six SNPs located in the HLA region showed significant evidence for association (OR range: 1.53-1.74). The haplotype formed by their risk allele was more associated with the disease than any of the single SNPs and was even much stronger in patients exposed to allopurinol (OR(allopurinol) = 7.77, 95%CI = [4.66; 12.98]). The associated haplotype is in linkage disequilibrium with the HLA-B*5801 allele known to be associated with allopurinol induced SJS/TEN in Asian populations. CONCLUSION: The involvement of genetic variants located in the HLA region in SJS/TEN is confirmed in European samples, but no other locus reaches genome-wide statistical significance in this sample that is also the largest one collected so far. If some loci outside HLA play a role in SJS/TEN, their effect is thus likely to be very small.
| S-EPMC3173287 | biostudies-literature
Project description:BackgroundStevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are acute, life-threatening, severe drug reactions. Randomized studies on these diseases are difficult to perform.Aims and objectivesThe purpose of this study was to summarize the demographic and clinical characteristics of patients with SJS and TEN in a tertiary hospital in Turkey.Materials and methodsWe evaluated the records of 33 patients with SJS and TEN who were followed in our clinic or examined between January 2008 and June 2019, retrospectively. Age, sex, time of admission to hospital, causative drug, presence of concomitant disease, skin findings, mucosal involvement, the severity-of-illness score for TEN, the medication used, antibiotic use, transfer to intensive care, development of complications, and death or discharge status were noted.ResultsOf the 33 patients, 11 (33.3%) had SJS, 3 (9.1%) had SJS/TEN overlap, and 19 (57.6%) had TEN. The majority (60.6%) of the patients were female. Nineteen (57.6%) patients had one, and 13 (39.4%) had more than one suspected drug exposure in their history. The most commonly suspected drugs were antibiotics. Twelve (36.4%) patients had intensive care unit hospitalization. Ten (30.3%) patients died.ConclusionThe demographic data of our study were consistent with the literature. Similar to the literature, antibiotics were the most common reaction-causing drugs. However, antiepileptic drugs, which were more frequently reported in other studies, were identified as suspicious in only one patient. We believe that our study will contribute to the determination of characteristics of this rare disease with real-life data.
| S-EPMC9154133 | biostudies-literature
Project description:BackgroundStevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) carry a high mortality risk. While identifying clinical and genetic risk factors for these conditions has been hindered by their rarity, large electronic health databases hold promise for identifying large numbers of cases for study, especially with the introduction in 2008 of ICD-9 codes more specific for these conditions.ObjectiveThe objective of this study is to estimate the validity of ICD-9 codes for ascertaining SJS/TEN in 12 collaborating research units in the USA, covering almost 60 million lives.MethodsFrom the electronic databases at each site, we ascertained potential cases of SJS/TEN using ICD-9 codes. At five sites, a subset of medical records was abstracted and standardized criteria applied by board-certified dermatologists to adjudicate diagnoses. Multivariate logistic regression was used to identify factors independently associated with validated SJS/TEN cases.ResultsA total of 56 591 potential cases of SJS/TEN were identified. A subset of 276 charts was selected for adjudication and 39 (of the 276) were confirmed as SJS/TEN. Patients with the ICD-9 codes introduced after 2008 were more likely to be confirmed as cases (OR 3.32; 95%CI 0.82, 13.47) than those identified in earlier years. Likelihood of case status increased with length of hospitalization. Applying the probability of case status to the 56 591 potential cases, we estimated 475-875 to be valid SJS/TEN cases.ConclusionNewer ICD-9 codes, along with length of hospitalization, identified patients with a high likelihood of SJS/TEN. This is important for identification of subjects for future pharmacogenomics studies.
| S-EPMC7105169 | biostudies-literature
Project description:PurposeTo report a novel technique to facilitate amniotic membrane transplantation (AMT) for acute stage Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN).DesignLaboratory investigation and retrospective, single-center case series.MethodsThe polylactic acid (PLA) amniotic fornical ring (AFR) have been successfully manufactured by three-dimensional (3D) printing technology for AMT. This study retrospectively analyzed the medical records of 5 SJS/TEN patients at the acute stage between 2019 and 2023. Patients were surgically treated with AFR or sutured amniotic membrane transplant (SAMT). Epidemiology, best-corrected visual acuity (BCVA), acute ocular severity score, operative duration, epithelial healing time, amniotic dissolution and follow-up time were evaluated.ResultsOf all five patients, three patients (6 eyes) received AFR/AMT (Group A), and 2 patients (4 eyes) received SAMT (Group B). There were no significant differences between two groups in the mean preoperative days and vision changes. The mean operation duration was 11.7 ± 3.8 mins in group A. Compared with the SAMT (48.8 ± 5.3 mins), the operation duration was reduced by 76.02%. The mean times for epithelial healing were 32.5 ± 29.2 days in group A and 12.0 ± 0.0 days in group B. In addition, there were no significant side effects of 3D-printed sterile AFR on the eyes.Conclusions3D-printed PLA scaffolds could be used as an AFR device for acute SJS/TEN. In addition, personalized 3D-printed AFR is superior to conventional SAMT in operation duration.
| S-EPMC10432697 | biostudies-literature