The Fas Signaling Pathway Is a Common Genetic Risk Factor for Severe Cutaneous Drug Adverse Reactions Across Diverse Drugs.
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ABSTRACT:
SUBMITTER: Park HW
PROVIDER: S-EPMC6082816 | biostudies-literature | 2018 Sep
REPOSITORIES: biostudies-literature
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Project description:Epilepsy is one of the most common neurologic disorders in dogs and life-long treatment with antiepileptic drugs (AED) is frequently required. Adverse events of AED targeting the skin are only rarely reported in veterinary medicine and the true incidence and spectrum of cutaneous reactions in epileptic dogs remains unknown. In this study, we hypothesized that cutaneous reactions commonly occur in epileptic dogs and are related to AED treatment. A retrospective case review of 185 dogs treated for epilepsy identified 20.0% with simultaneous appearance of dermatologic signs. In a subsequent prospective case investigation (n?=?137), we identified newly appearing or distinct worsening of skin lesions following initiation of AED therapy in 10.9% of dogs treated for epilepsy (95% CI 6.8-17.7%). Cutaneous lesions were classified as probably drug-induced in 40.0% of these cases. Patch testing and intradermal testing were further investigated as potential diagnostic methods to confirm AED hypersensitivity. They were of high specificity but sensitivity and positive predictive value appeared inappropriate to recommend their routine use in clinical practice.
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Project description:PurposeAnti-tuberculosis drugs (ATDs) can cause severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS). Underlying tuberculous infection and co-administration of multiple drugs may contribute to the complexity of ATD-related SCARs. This study aimed to investigate the clinical characteristics and outcomes of ATD-related SCARs.MethodsWe analyzed ATD-related SCAR cases in 2010-2015, selected from a web-based Database of the Korean Registry of SCAR.ResultsAmong 783, 53 patients with ATD-induced SCARs were enrolled, including 12 with SJS/TEN (22.6%) and 41 with DRESS (77.4%). When comparing the ATD and non-ATD groups, the prevalence of DRESS patients was higher in the ATD group than in the non-ATD group (77.4% vs. 45.8%, P < 0.001). Among patients with ATD-related SCARs, those with SJS/TEN were significantly older, had higher intensive care unit admissions, and had higher mortality than those with DRESS (70.5 vs. 50.0 years, P < 0.001; 41.7% vs. 6.1%, P = 0.010; and 33.3% vs. 2.5%, P = 0.003, respectively). ATDs were challenged in 14 cases. The ATD associated most often with SCAR cases was rifampin (81.8%), followed by isoniazid (66.7%), ethambutol (50.0%), pyrazinamide (33.3%). Six patients (42.9%) had hypersensitivity reactions to 2 or more drugs.ConclusionsDRESS was more common among the ATD-related SCAR cases. Although treatment with most ATDs carries the risk of SCAR development, the use of rifampin was most frequently involved in the occurrence of SCARs. Multiple hypersensitivity was frequently observed in ATD-related SCARs.
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Project description:PURPOSE:Nonsteroidal anti-inflammatory drugs (NSAIDs) are common cause of severe cutaneous adverse reactions (SCARs). The present study aimed to investigate the characteristics of SCARs induced by NSAIDs in the Korean SCAR registry. METHODS:A retrospective survey of NSAID-induced SCARs recorded between 2010 and 2015 at 27 university hospitals in Korea was conducted. Clinical phenotypes of SCARs were classified into Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), SJS-TEN overlap syndrome and drug reaction with eosinophilia and systemic symptoms (DRESS). Causative NSAIDs were classified into 7 groups according to their chemical properties: acetaminophen, and propionic, acetic, salicylic, fenamic and enolic acids. RESULTS:A total of 170 SCARs, consisting of 85 SJS, 32 TEN, 17 SJS-TEN overlap syndrome and 36 DRESS reactions, were induced by NSAIDs: propionic acids (n=68), acetaminophen (n=38), acetic acids (n=23), salicylic acids (n=16), coxibs (n=8), fenamic acids (n=7), enolic acids (n=5) and unclassified (n=5). Acetic acids (22%) and coxibs (14%) accounted for higher portions of DRESS than other SCARs. The phenotypes of SCARs induced by both propionic and salicylic acids were similar (SJS, TEN and DRESS, in order). Acetaminophen was primarily associated with SJS (27%) and was less involved in TEN (10%). DRESS occurred more readily among subjects experiencing coxib-induced SCARs than other NSAID-induced SCARs (62.5% vs. 19.7%, P = 0.013). The mean time to symptom onset was longer in DRESS than in SJS or TEN (19.1 ± 4.1 vs. 6.8 ±1.5 vs. 12.1 ± 3.8 days). SCARs caused by propionic salicylic acids showed longer latency, whereas acetaminophen- and acetic acid-induced SCARs appeared within shorter intervals. CONCLUSIONS:The present study indicates that the phenotypes of SCARs may differ according to the chemical classifications of NSAIDs. To establish the mechanisms and incidences of NSAID-induced SCARs, further prospective studies are needed.
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Project description:Drug hypersensitivity such as severe cutaneous adverse reactions (SCAR), including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), could be life-threatening. Here, we enroll SCAR patients to investigate the T cell receptor (TCR) repertoire by next-generation sequencing. A public αβTCR is identified from the cytotoxic T lymphocytes of patients with carbamazepine-SJS/TEN, with its expression showing drug/phenotype-specificity and an bias for HLA-B*15:02. This public αβTCR has binding affinity for carbamazepine and its structural analogs, thereby mediating the immune response. Adoptive transfer of T cell expressing this public αβTCR to HLA-B*15:02 transgenic mice receiving oral administration of carbamazepine induces multi-organ injuries and symptoms mimicking SCAR, including hair loss, erythema, increase of inflammatory lymphocytes in the skin and blood, and liver and kidney dysfunction. Our results not only demonstrate an essential role of TCR in the immune synapse mediating SCAR, but also implicate potential clinical applications and development of therapeutics.
| S-EPMC6687717 | biostudies-literature
Project description:Epidemiologic investigation of cutaneous adverse drug reactions (cADRs) is important in order to evaluate their impact on dermatology and health care in general as well as their burden on affected patients. Few epidemiologic studies have been performed on frequent non-life-threatening cADR, including reactions of both delayed and immediate hypersensitivity, such as maculopapular exanthema (MPE), fixed drug eruption, and urticaria. Concerning rare but life-threatening severe cutaneous adverse reactions, e.g., toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), acute generalized exanthematous pustulosis (AGEP), and drug reaction with eosinophilia and systemic symptoms (DRESS), several epidemiologic studies have been performed to date, some of which are still ongoing. Such studies enable the calculation of reliable incidence rates and demographic data, and also allow researchers to perform risk estimation for drugs. The spectrum of drugs causing cADR differs substantially when separating the various clinical conditions. Whereas antibiotics are by far the most frequent inducers of milder cADRs, like MPE, they have a much lower risk of inducing SJS/TEN, for which "high-risk" drugs are anti-infective sulfonamides, allopurinol, certain anti-epileptic drugs, nevirapine, and non-steroidal anti-inflammatory drugs (NSAIDs) of the oxicam-type. In contrast, AGEP is predominantly caused by the antibiotics pristinamycin and aminopenicillins, followed by quinolones, (hydroxy-)chloroquine, and sulfonamides. DRESS can be induced by a number of drugs known to cause SJS/TEN, such as certain antiepileptics and allopurinol, but also other medications (e.g., minocyclin).
| S-EPMC6039997 | biostudies-other
Project description:PurposeSevere cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) to antiepileptic drug (AED), are rare, but result in significant morbidity and mortality. We investigated the major culprit drugs, clinical characteristics, and clinical course and outcomes of AED-induced SCARs using a nationwide registry in Korea.MethodsA total of 161 patients with AED-induced SCARs from 28 referral hospitals were analyzed. The causative AEDs, clinical characteristics, organ involvements, details of treatment, and outcomes were evaluated. We compared the clinical and laboratory parameters between SJS/TEN and DRESS according to the leading causative drugs. We further determined risk factors for prolonged hospitalization in AED-induced SCARs.ResultsCarbamazepine and lamotrigine were the most common culprit drugs causing SCARs. Valproic acid and levetiracetam also emerged as the major causative agents. The disease duration and hospital stay in carbamazepine-induced SJS/TEN were shorter than those in other AEDs (P< 0.05, respectively). In younger patients, lamotrigine caused higher incidences of DRESS than other drugs (P= 0.045). Carbamazepine, the most common culprit drug for SCARs, was associated with a favorable outcome related with prolonged hospitalization in SJS (odds ratio, 0.12; 95% confidence interval, 0.02-0.63, P= 0.12), and thrombocytopenia was found to be a risk factor for prolonged hospitalization in DRESS.ConclusionThis was the first large-scale epidemiological study of AED-induced SCARs in Korea. Valproic acid and levetiracetam were the significant emerging AEDs causing SCARs in addition to the well-known offending AEDs such as carbamazepine and lamotrigine. Carbamazepine was associated with reduced hospitalization, but thrombocytopenia was a risk factor for prolonged hospitalization. Our results suggest that the clinical characteristics and clinical courses of AED-induced SCARs might vary according to the individual AEDs.
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Project description:Severe cutaneous adverse reactions (SCAR) are rare but life-threatening drug reactions mediated by human leukocyte antigen (HLA) class I-restricted CD8+ T-cells. To obtain an unbiased assessment of SCAR cellular immunopathogenesis, we performed single-cell (sc) transcriptome, surface proteome, and TCR sequencing (5' scRNA-TCR-CITE-seq, 10x Genomics) on unaffected skin, affected skin, and blister fluid from diverse SCAR patients.
2024-09-18 | GSE275871 | GEO
Project description:Severe cutaneous adverse reactions (SCARs), such as Stevens-Johnson syndrome/toxic epidermal necrolysis and drug-induced hypersensitivity syndrome, are rare and occasionally fatal. However, it is difficult to detect SCARs at the drug development stage, necessitating a new approach for prediction. Therefore, in this study, using the chemical structure information of SCAR-causative drugs from the Japanese Adverse Drug Event Report (JADER) database, we tried to develop a predictive classification model of SCAR through deep learning. In the JADER database from 2004 to 2017, we defined 185 SCAR-positive drugs and 195 SCAR-negative drugs using proportional reporting ratios as the signal detection method, and the total number of reports. These SCAR-positive and SCAR-negative drugs were randomly divided into the training dataset for model construction and the test dataset for evaluation. The model performance was evaluated in the independent test dataset inside the applicability domain (AD), which is the chemical space for reliable prediction results. Using the deep learning model with molecular descriptors as the drug structure information, the area under the curve was 0.76 for the 148 drugs of the test dataset inside the AD. The method developed in the present study allows for utilizing the JADER database for SCAR classification, with potential to improve screening efficiency in the development of new drugs. This method may also help to noninvasively identify the causative drug, and help assess the causality between drugs and SCARs in postmarketing surveillance.
| S-EPMC7993315 | biostudies-literature
Project description:BackgroundSeveral type B adverse drug reactions (ADRs), especially severe cutaneous adverse reactions (SCARs), are associated with particular human leukocyte antigen (HLA) genotypes. However, pre-stored HLA information obtained from other clinical workups has not been used to prevent ADRs. We aimed to simulate the preemptive use of pre-stored HLA information in electronic medical records to evaluate whether this information can prevent ADRs.MethodsWe analyzed the incidence and the risk of ADRs for selected HLA alleles (HLA-B*57:01, HLA-B*58:01, HLA-A*31:01, HLA-B*15:02, HLA-B*15:11, HLA-B*13:01, HLA-B*59:01, and HLA-A*32:01) and seven drugs (abacavir, allopurinol, carbamazepine, oxcarbazepine, dapsone, methazolamide, and vancomycin) using pre-stored HLA information of transplant patients based on the Pharmacogenomics Knowledge Base guidelines and experts' consensus.ResultsAmong 11,988 HLA-tested transplant patients, 4092 (34.1%) had high-risk HLA alleles, 4583 (38.2%) were prescribed risk drugs, and 580 (4.8%) experienced type B ADRs. Patients with HLA-B*58:01 had a significantly higher incidence of type B ADR and SCARs associated with allopurinol use than that of patients without HLA-B*58:01 (17.2% vs. 11.9%, odds ratio [OR] 1.53 [95% confidence interval {CI} 1.09-2.13], p = 0.001, 2.3% versus 0.3%, OR 7.13 [95% CI 2.19-22.69], p < 0.001). Higher risks of type B ADR and SCARs were observed in patients taking carbamazepine or oxcarbazepine if they had one of HLA-A*31:01, HLA-B*15:02, or HLA-B*15:11 alleles. Vancomycin and dapsone use in HLA-A*32:01 and HLA-B*13:01 carriers, respectively, showed trends toward increased risk of type B ADRs.ConclusionUtilization of pre-stored HLA data can prevent type B ADRs including SCARs by screening high-risk patients.
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Project description:Despite their being uncommon, severe cutaneous adverse drug reactions (SCARs) result in a very great burden of disease. These reactions not only carry with them a high mortality (10%-50%) and high morbidity (60%) with severe ocular complications, alopecia, oral and dental complications and development of autoimmune diseases, but also create a substantial economic burden for patients' families and society. SCARs are, therefore, an important medical problem needing a solution in many countries, especially in Asia. The clinical spectrum of SCARs comprises Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS (drug rash with eosinophilia and systemic symptoms) (also known as drug hypersensitivity syndrome or drug-induced hypersensitivity syndrome) and acute generalised exanthematous pustulosis. Recent crucial advances in determining genetic susceptibility and understanding how T cells recognise certain medications or their metabolites via the major histocompatibility complex and the effects of cofactors, have led to the implementation of cost-effective screening programs enabling prevention in a number of countries, and to further understanding of the patho-mechanisms involved in SCARs and their significance. In this review, we document comprehensively the journey of SCARs from bedside to bench and outline future perspectives in SCARs research.
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