Drug-induced Toxic Epidermal Necrolysis Research Articles

Drug-induced Stevens Johnson syndrome and toxic epidermal necrolysis: Interpreting the systematic reviews on immunomodulatory therapies.

Drug-induced Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are non-immunoglobulin E-mediated severe cutaneous adverse reactions with a high risk of morbidity, mortality, and physical and mental health impact. These are associated with certain high-risk drugs, human leukocyte antigen (HLA)-specific genotypes and ethnicities. HLA class I-restricted oligoclonal CD8 cytotoxic T-cell responses occur at the tissue level in SJS/TEN. Cytotoxic T cells are the T effector cells that result in keratinocyte apoptosis (cell death) mediated by T effector molecules granzyme B, perforin, granulysin, gamma interferon, tumor necrosis factor-alpha, and lipocalin-2. The clinical hallmarks of SJS/TEN include fever, ≥2 mucosal involvements (ocular, oral, and genital), and positive Nikolsky sign with epidermal detachment. Systematic reviews on immunomodulatory treatments remain limited by the paucity of randomized controlled trials, heterogeneity of studies, and non-standardization of outcome measures. Preventive HLA genotype screening before the prescription of carbamazepine and allopurinol may further reduce the incidence of SJS/TEN. The role of immunomodulatory treatments in SJS/TEN is at present not supported by robust evidence from systematic reviews given the lack of randomized controlled trials. The evidence for improved survival with off-label use of corticosteroids plus intravenous immunoglobulins, ciclosporin plus intravenous immunoglobulins, and ciclosporin alone has not been demonstrated by network meta-analyses and meta-regression. In the real-world clinical setting, systemic corticosteroids (in SJS and overlap SJS/TEN), ciclosporin, and etanercept (in TEN) appear to be the off-label treatments currently most widely used.

Management of Drug-Induced Epidermal Necrolysis (DEN) in Pediatric Patients: Moving from Drug-Induced Stevens-Johnson Syndrome, Overlap and Toxic Epidermal Necrolysis to a Single Unifying Diagnosis of DEN.

Pediatric Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but life-threating blistering diseases triggered by medications that affect the skin and mucosae. Drug-induced epidermal necrolysis is a better term for medication-triggered cases because there is a spectrum of disease severity that otherwise is divided into the separate entities of SJS, overlap SJS/TEN, and TEN. This manuscript reviews the management of drug-induced epidermal necrolysis (DEN), including diagnosis, investigations to exclude differential diagnoses, and treatment. Diagnosis of DEN relies on clinical features and a detailed medication history. The primary differential diagnosis is reactive infectious mucocutaneous eruption, which can be clinically distinguished by its disproportionate mucous membrane involvement relative to (sparse or absent) skin lesions. Identification and discontinuation of culprit medications is the mainstay of treatment of DEN. Early initiation of immunomodulatory therapy may prevent progression, reducing maximal disease severity and the risk of sequelae. A checklist approach to detailed management of DEN is proposed.

Clinical and Epidemiological Features of Patients with Drug-Induced Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis in Iran: Different Points of Children from Adults.

Background Different epidemiologic aspects of drug-induced Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in children are scarce. Aim To compare the clinical and epidemiological features of patients with drug-induced SJS and TEN in children and adults. Method This retrospective study was conducted at two academic referral centers (Isfahan, Iran) over 5 years. SJS and TEN were clinically diagnosed and confirmed by skin biopsy as needed. Results One hundred one patients (31 children and 70 adults) with a female to male ratio of 1.1 : 1 was identified in the present study. SJS was more commonly diagnosed in both pediatric and adult patients. The most frequent reason for drug administration identified was the infection (45.2%) and seizure (45.2%) in children and infection (34.3%) and psychiatry disorder (27.1%) in adults (P = 0.001). The most common culprit drugs in the pediatric were phenobarbital (9/31), cotrimoxazole (4/31), and amoxicillin (4/31); however, in the adult group, the most common drugs were carbamazepine (11/70) and lamotrigine (9/70). Fever was significantly more common in adults (44.3%) compared to pediatric patients (22.6%) (P = 0.03). Multiple logistic regression models showed that pediatric patients had significantly lower odds of hospitalization (OR [odds ratio]: 0.14; 95% CI 0.02, 0.67). In addition, patients with SCORTEN 1 had significantly higher odds of hospitalization (OR: 6.3; 95% CI: 1.68, 23.79) compared to patients with SCORTEN 0. Conclusions The present study showed several differences between the pediatric and adult patients with SJS and TEN, including the reason for drug administration, culprit drugs, length of hospital stay, presence of fever, and final diagnosis of disease.

Single-cell multi-omic approaches define common molecular and cellular signals of dominant antigen-driven cells at the site of drug-induced Stevens Johnson Syndrome and Toxic Epidermal Necrolysis (SJS/TEN) tissue damage

Human leukocyte antigen (HLA)-restricted CD8+ T-cells expressing dominant T-cell receptor (TCR) clonotypes are recently implicated drivers of keratinocyte cell death, cutaneous blistering, and mortality in drug-induced Stevens Johnson Syndrome/Toxic epidermal necrolysis (SJS/TEN). Signatures of these effector population(s) remain undefined in affected tissue but hold utility for early diagnosis and targeted therapy.

Agreement Among Different Scales for Causality Assessment in Drug-Induced Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis.

Identification of the offending drug is crucial and challenging in cases of severe cutaneous adverse drug reactions (CADR) like Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Poor reproducibility and varying levels of agreement have been observed among different causality assessment tools (CATs) in assessing severe CADRs. This study was conducted to examine the agreement among four different CATs in assessing cases of drug-induced SJS, TEN and SJS/TEN overlap. All cases of drug-induced SJS, TEN and SJS/TEN overlap, which were reported between January 2012 and January 2020, were identified from the ADR register at an ADR monitoring centre. Causality assessment was done in these reported cases using the following CATs: The World Health Organization-Uppsala Monitoring Centre (WHO-UMC) scale, Naranjo algorithm, Liverpool algorithm and Algorithm of drug causality for epidermal necrolysis (ALDEN). Weighted kappa (κw) test was used to evaluate the agreement among four CATs. A total of 30 cases of drug-induced SJS, TEN and SJS/TEN overlap were included in our analyses. The most common offending groups of drugs were anticonvulsants (46.7%), antimicrobials (40%) and nonsteroidal anti-inflammatory drugs (13.3%). Of the anticonvulsants, phenytoin (13.3%), carbamazepine (10%), and valproate (10%) were the commonly reported offending drugs. Poor agreement was observed among the four different causality assessment scales. Discrepancies were observed among four different CATs in assessing drug-induced SJS and TEN. A CAT, which is more specific to drug-induced SJS and TEN, simple, user-friendly with limited subjective interpretation, incorporating new immunological and pharmacogenetic markers, is necessary.

Clinical characteristics of drug-induced Stevens-Johnson syndrome and toxic epidermal necrolysis: A single-center study.

BackgroundStevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe adverse cutaneous reactions, most commonly triggered by medications, characterized by extensive necrosis and detachment of the epidermis.ObjectiveWe investigated the differences in clinical characteristics of drug-induced SJS/TEN depending on the type of drug in a single center.MethodsThe relevance of sex, age, culprit drugs, clinical features, courses, treatment options, and follow-up results were retrospectively evaluated in patients diagnosed with drug-induced SJS/TEN at Pusan National University Hospital between 2008 and 2019.ResultsNinety-two patients with a mean age of 58.7 ± 20.2 years (range, 10–93 years) were included in the study. Those aged 60–80 years accounted for the largest number of patients (42.4%). Patients with drug-induced SJS/TEN comprised 40 women (43.5%) and 52 men (56.5%). We categorized drug-induced SJS/TEN cases by culprit drugs into 6 groups: antibiotics, allopurinol, antiepileptic (AED), nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, and other drugs. The rate of NSAID-induced disease significantly increased from SJS to TEN (p = 0.016). Among the patients in the NSAID group, the proportion of TEN (40%) was higher than that in the other groups (p = 0.021). The mean body surface area was significantly lower in the AED group than in the non-AED groups (7.1 ± 9.8 vs. 23.1 ± 27.3, p = 0.020) and higher in the NSAID group than in the non-NSAID groups (47.5 ± 39.5 vs. 15.7 ± 20.0, p = 0.010).ConclusionThis study showed that the clinical characteristics of each causative drug group may be different in drug-induced SJS/TEN. Our findings may help clinicians better understand drug-induced SJS/TEN.

Toxic epidermal necrolysis and coronavirus disease 2019: A rare association

Cutaneous manifestations of Coronavirus disease 2019 (COVID-19) are variable. We report a 57-year-old woman who developed toxic epidermal necrolysis (TEN) in association with COVID-19. The patient had not received any drugs prior to the onset of TEN. She responded to treatment with cylosporine. Previous authors have suggested a better prognosis for TEN associated with COVID-19 in comparison to drug-induced TEN.

Association of antinuclear antibodies with toxic epidermal necrolysis – A novel manifestation

Toxic epidermal necrolysis (TEN) is a potentially life-threatening dermatologic disorder characterized by widespread erythema, necrosis, and bullous detachment of the epidermis of skin and mucous membranes, resulting in exfoliation and possible sepsis and/or morbidity/mortality. Exact diagnosis of lesions is very important in terms of therapeutic intervention as well as outcome. As cutaneous hypersensitivity reactions are known to occur with increased frequency in connective tissue disease, differentiating lesions of systemic lupus erythematosus that simulate drug-induced TEN is a challenge in the practical scenario. In this case series, we discuss about three patients aged between 24 and 67 years, who presented with vesiculobullous lesions all over the body and oral mucosal ulcerations. Each of them was initially admitted in the Critical Care Unit with a provisional diagnosis of TEN. Two of the three patients recovered well and were discharged. However, the third patient, who was the oldest and had multiple comorbidities, could not be saved and succumbed after 75 days of hospital stay.

重组人Ⅱ型肿瘤坏死因子受体-抗体融合蛋白治疗中毒性表皮坏死松解症的临床疗效观察

重组人Ⅱ型肿瘤坏死因子受体-抗体融合蛋白治疗中毒性表皮坏死松解症的临床疗效观察

TEN in a Case of SLE - A case based review

Systemic lupus erythematosus (SLE) is a complex autoimmune disorder of unknown etiology. Cutaneous manifestations in SLE are common, results in significant morbidity and helpful in diagnosis of underlying systemic disease. Vesiculobullous lesions in SLE are uncommon but present a diagnostic challenge. It can be a manifestation of SLE-specific or nonspecific pathology. It can also result from unrelated etiology such as drug-induced toxic epidermal necrolysis (TEN). Clinically, it is challenging to differentiate TEN-like acute cutaneous lupus erythematosus from classical TEN. We hereby present a case of TEN in SLE and discuss approach to vesiculobullous lesions in SLE.

Toxic epidermal necrolysis occurring with immune checkpoint inhibitors

Nivolumab and ipilimumab are immune checkpoint inhibitors (ICIs) used in the management of advanced malignancies including malignant melanoma. Although several cutaneous adverse events have been reported with these immunotherapy agents, toxic epidermal necrolysis (TEN) secondary to ICIs is rare. We report a 67-year-old man with TEN occurring during nivolumab and ipilimumab co-therapy and review published cases to highlight the challenges in recognizing and managing these patients. ICI-induced TEN can present atypically with delayed onset in comorbid, immunosuppressed patients with an associated high mortality rate. Prompt recognition and drug withdrawal are essential to improve outcomes. High dose systemic corticosteroid has also been recommended for the management of ICI-induced TEN, unlike other drug-induced TEN for which optimal immunomodulatory treatment is still debated.

Toxic Epidermal Necrolysis-like Subacute Cutaneous Lupus Erythematosus: a Case Report

Abstract Cutaneous lupus erythematosus (LE) encompasses a wide spectrum of dermatologic manifestations, including toxic epidermal necrolysis (TEN)-like presentations of acute or subacute cutaneous lupus erythematosus (TEN-like ACLE/SCLE). Although the clinical characteristics and histological features of these rare entities may closely mimic TEN, several subtle differences can help in differentiation between these conditions. We report a case of a patient with SCLE which developed drug unrelated TEN-like blisters after prolonged, intensive sun exposure and focus on a discussion of distinctive features that can be used to differentiate drug-induced TEN and TEN-like presentation of ACLE/SCLE.

Drug-induced toxic epidermal necrolysis with secondary aspergillus fumigatus infection: a case report

Among the various drug induced dermatological entities toxic epidermalnecrolysis (TEN) and Stevens-Johnson syndrome (SJS) occupy a primary place in terms of mortality. Toxic epidermal necrolysis also known as Lyell's syndrome was first described by Lyell in 1956. Drugs are by far the most common cause of toxic epidermal necrolysis, in which large sheets of skin are lost from the body surface making redundant the barrier function of the skin, with its resultant complications. Drug-induced toxic epidermal necrolysis are severe adverse cutaneous drug reactions to various precipitating agents that predominantly involve the skin and mucous membranes. Toxic epidermal necrolysis is rare but considered medical emergencies as they are potentially fatal. Drugs are the most common cause accounting for about 65%-80% of the cases. The most common offending agents are sulfonamides, NSAIDs, butazones and hydrantoins. An immune mechanism is implicated in the pathogenesis, but its nature is still unclear. There is a prodormal phase in which there is burning sensation all over the skin and conjunctivae, along with skin tenderness, fever, malaise and arthralgias. Early sites of cutaneous involvement are the presternal region of the trunk and the face, but also the palms and soles, rapidly spread to their maximum extent, the oral mucosa and conjunctiva being affected. Initial lesions are macular, followed by desquamateion, or may be from atypical targets with purpuriccenters that coalesce, from bullae, then slough. The earlier a causative agent is withdrawn the better is the prognosis. Several treatment modalities given in addition to supportive care are reported in the literature, such as systemicsteroids, high-dose intravenous immunoglobulins, ciclosporin, TNF antagonists. Recovery is slow over a period of 14-28 days and relapses are frequent. Mortality is 25%-50% and half the deaths occur due to secondary infection. Here we report a 50-year-old female of drug-induced toxic epidermal necrolysis. She was admitted to the dermatology ward with extensive peeling of skin over the trunk and limbs. She had taken alamotrigine for epilepsy. A week after taking the tablets, the patient developed a severe burning sensation all over the body and followed by a polymorphic erythematous dermatitis and widespread peeling of skin. We treated this patient with high dose corticosteroids, high-dose intravenous immunoglobulins and etanercept, but eventually she died of secondary aspergillus fumigatus infection.

Correction to: Adverse drug reaction causality assessment tools for drug-induced Stevens-Johnson syndrome and toxic epidermal necrolysis: room for improvement.

The correct name of the 9th Author is David J. Margolis. The original article was corrected.

A review and guide to drug-associated oral adverse effects-Oral mucosal and lichenoid reactions. Part 2.

Dental practitioners and other health professionals commonly encounter and manage adverse medicine effects that manifest in the orofacial region. Numerous medicines are associated with a variety of oral adverse effects. However, due to lack of awareness and training, these side effects are not always associated with medicine use and are underreported to pharmacovigilance agencies by dentists and other health professionals. This article aims to inform health professionals about the various oral adverse effects that can occur and the most commonly implicated drugs to improve the management, recognition and reporting of adverse drug effects. This article follows on from Part 1; however, the focus here is on lichenoid reactions and oral mucosal disorders including oral aphthous-like ulceration, mucositis and bullous disorders such as drug-induced pemphigus, pemphigoid, Stevens-Johnson syndrome and toxic epidermal necrolysis.

Drug-induced toxic epidermal necrolysis: A rare case report

Drug-induced toxic epidermal necrolysis: A rare case report - JOOO- Print ISSN No: - 2395-6186 Online ISSN No:- 2395-6194 Article DOI No:- 10.18231/j.jooo.2019.008, Journal of Oral Medicine, Oral Surgery, Oral Pathology and Oral Radiology-J Oral Med Oral Surg Oral Pathol Oral Radiol

Drug-induced Stevens-Johnson syndrome and toxic epidermal necrolysis: Proportion and determinants of underreporting to pharmacovigilance

Drug-induced Stevens-Johnson syndrome and toxic epidermal necrolysis: Proportion and determinants of underreporting to pharmacovigilance

Drug-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in vietnamese spontaneous adverse drug reaction database: A subgroup approach to disproportionality analysis.

Despite the numerous studies investigating drug-induced Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), the understanding and quantitative data in developing countries remain limited. The study aimed to describe and quantify the drug-related risk of SJS/TEN in a resource-limited context using the Vietnamese spontaneous reporting database (VSRD) of adverse drug reactions. Spontaneous reports relating to medium- and late-onset severe cutaneous adverse reactions (MLOSCAR) and SJS/TEN recorded in the VSRD from 2010 to 2015 were retrospectively analysed. The demographic characteristics and drug information were described and compared between SJS/TEN and other MLOSCAR reports. The drug-induced SJS/TEN signals were estimated using subgrouped disproportionality analysis with calculation of the reporting odds ratio (ROR) and the respective 95% confidence interval (CI). The VSRD received 2,849 MLOSCAR reports, 136 of which focus on SJS/TEN over a 6-year period. About 60% of SJS/TEN patients were male, and the majority of them were adults (mean age 42.5±22.9). Up to 91.8% of drugs induced SJS/TEN within 1-28days, and 45% SJS/TEN cases were evaluated as life-threatening. Positive signals were generated with carbamazepine (n=25, ROR [95% CI]=11.99 [7.07-19.92]), allopurinol (n=15, ROR [95% CI]=4.2 [2.20-7.59]), traditional/herbal medicines (n=7, ROR [95% CI]=2.76 [1.12-5.86]), colchicine (n=4, ROR [95% CI]=6.22 [1.69-18.72]), valproic acid (n=3, ROR [95% CI]=8.71 [1.89-30.19]) and meloxicam (n=3, ROR [95% CI]=7.09 [1.55-24.29]), which are well known for SJS/TEN. Cefixime (n=5, ROR [95% CI]=3.34 [1.13-8.00]) and paracetamol (n=22, ROR [95% CI]=5.23 [3.10-8.49]) also generated positive signals despite their popularity in Vietnam. This first Vietnamese population-based study has highlighted original characteristics and signals of drug-induced SJS/TEN, which are relatively consistent with other worldwide data and typical for a developing country.

Infection and drug-induced toxic epidermal necrolysis: A case report

Lyell’s syndrome or toxic epidermal necrolysis is a dermatological disease with severe evolution, and cutaneous-mucosal lesions involving more than 30% of body surface area. The following are the most commonly involved in triggering TEN: antibiotics, anti-inflammatory drugs, chemotherapeutic agents, antivirals, and anticonvulsants drugs. The evolution is accompanied by local complications (superinfections, vicious scars), or general complications (sepsis, multiple organ failure). We present the case of a patient with infectious-induced Lyell’s syndrome associated with exposure to two classes of drugs at risk of inducing Lyell’s syndrome (antibiotics and nonsteroidal anti-inflammatory drugs). Supportive therapy, associated with the treatment of cutaneous mucosal lesions, and the treatment of sepsis, were the most important elements that led to a favourable evolution of our case.

Association between infection and severe drug adverse reactions: an analysis using data from the Japanese Adverse Drug Event Report database.

It has been reported recently that immune reactions are involved in the pathogenesis of certain types of adverse drug reactions (ADRs). We aimed to determine the associations between infections and drug-induced interstitial lung disease (DILD), rhabdomyolysis, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), or drug-induced liver injury (DILI) using a spontaneous adverse drug event reporting database in Japan. The reported cases were classified into three categories (anti-infectious drug group, concomitant infection group, and non-infection group) based on the presence of anti-infectious drugs (either as primary suspected drug or concomitant drug) and infectious disease. We assessed the association between four severe ADRs and the presence and seriousness of infection using logistic regression analysis. We identified 177,649 cases reported in the study period (2009-2013). Logistic regression analysis showed significant positive associations between infection status and onset of SJS/TEN or DILI (SJS/TEN: anti-infectious drug group: odds ratio (OR) 2.04, 95% CI [1.85-2.24], concomitant infection group: OR 2.44, 95% CI [2.21-2.69], DILI: anti-infectious drug group: OR 1.27, 95% CI [1.09-1.49], concomitant infection group: OR 1.25, 95% CI [1.04-1.49]), compared to the non-infection group. By contrast, there were negative or no associations between infection and DILD or rhabdomyolysis. A significantly positive association between infection and SJS/TEN seriousness (OR 1.48, 95% CI [1.10-1.98]) was observed. This study suggested that infection plays an important role in the development of SJS/TEN and DILI. For the patients with infection and/ or anti-infectious drugs, careful monitoring for severe ADRs, especially SJS/TEN, might be needed.