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INTRODUCTION The distinction between epidermal necrolysis [EN; including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and overlap syndrome] and erythema multiforme major (EMM) in children is confusing. We aimed to better describe and compare these entities. MATERIALS AND METHODS This French retrospective multicentre study included children ≤18 years old referred for EN or EMM between 1 January 2008 and 1 March 2019. According to pictures, children were reclassified into TEN/overlap, SJS or EMM/unclassified (SJS/EMM) groups and compared for epidemiological and clinical data, triggers, histology and follow-up. RESULTS We included 62 children [43 boys, median age 10 years (range 3-18)]: 16 with TEN/overlap, 11 SJS and 35 EMM. The main aetiologies were drugs in EN and infections (especially Mycoplasma pneumoniae) in EMM (P

BACKGROUND: Among dermatologic adverse events induced by immune checkpoint inhibitors (ICI), bullous life-threatening reactions are rare. OBJECTIVES: To better define the clinical and histological features, treatment and prognosis of ICI-related severe blistering cutaneous eruptions. METHODS: This retrospective case series was conducted between 2014/05/15 to 2021/04/15 by the dermatology departments of four international registries involved in drug reactions. Inclusion criteria were age ≥ 18 years-old, skin eruption with blisters and/or detachment covering ≥ 1% body surface area and at least one mucous membrane involved, available pictures, and ICI as suspect drug. Autoimmune bullous disorders were excluded. Each participant medical team gave his own diagnosis conclusion: epidermal necrolysis (EN), severe lichenoid dermatosis (LD) or unclassified dermatosis (UD). After a standardized review of pictures, cases were reclassified by 4 experts in EN or LD/UD. Skin biopsies were blindly reviewed. RESULTS: Thirty-two patients were included. Median time to onset was 52 days [3–420]. Cases were originally diagnosed as EN in 21 cases and LD/UD in 11 cases. After review by experts, 10/21 EN were reclassified as LD/UD. The following manifestations were more frequent or severe in EN: fever, purpuric macules, blisters, ocular involvement, maximal detachment. Most patients were treated with topical and/or systemic corticosteroids. Eight patients (25%) died in the acute phase. The culprit ICI was not resumed in 92% of cases. In three patients, another ICI was given with a good tolerance. Histology did not reveal significant differences between groups. CONCLUSIONS: Severe blistering cutaneous drug reactions induced by ICI are often overdiagnosed as EN. Consensus for management is pending.

Epidermal necrolysis (EN, including Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN)) is mostly induced by drugs. Prevalence of lupus erythematosus (LE) is higher in EN than in general population (1.2 to 2%).1,2 Furthermore, flares of LE may present as EN (TEN-like LE).3-5 We aimed to describe EN in patients with clinical or biological LE to better characterize the relation between both diseases.

Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) represents the spectrum of skin lesions characterized by rashes, exfoliation, and sloughing usually following drug intake. Occasionally, TEN-like cutaneous manifestations have also been described with systemic lupus erythematosus. Recognition of lupus in a child presenting with TEN-like skin changes is clinically challenging and requires a high degree of suspicion. We describe the case of a child who had epidermal necrolysis as the presenting feature of lupus and had severe neurological complications. TEN-like skin changes in association with severe neurological complications in pediatric lupus are uncommon. Lupus must be considered in the differential diagnosis of a child presenting with epidermal necrolysis with no provocative risk factors such as a history of exposure to medications.

Toxic epidermal necrolysis is a rapidly progressive exfoliating dermatosis which simulates second degree burns. The authors describe a fatal case reported as due to burns. Around 95% of the deceased’s total body surface area was affected, with epidermolysis over face, chest, abdomen, limbs and associated with mucosal involvement. Histopathological findings revealed epidermal necrolysis and confirmed the autopsy suspicion. Because of its sudden onset and rapid progression, toxic epidermal necrolysis often arises suspicion of burns by investigators. We emphasise the differentiating features between toxic epidermal necrolysis and burns and its implications.

BACKGROUND Because of its rarity, the exact incidence of and mortality from epidermal necrolysis (Stevens-Johnson syndrome/toxic epidermal necrolysis) is difficult to establish and closely depends on the size and type of the data source. OBJECTIVES To estimate the incidence of and mortality due to epidermal necrolysis in France over a 14-year period. METHODS Data from four national databases were analysed. A capture-recapture analysis was performed. RESULTS A total of 2635 incident cases of epidermal necrolysis were recorded in at least one of the four databases during the study period [males: 47·9%; median age: 52 (interquartile range 25-72) years]. On capture-recapture analysis, the estimated total number of cases was 5686, for an overall estimated annual incidence of 6·5 (95% confidence interval 4·1-8·9) cases per million inhabitants. The estimated annual incidence rates were 4·1 (0·3-7·9) cases per million inhabitants < 20 years of age, 3·9 (1·5-6·3) cases per million inhabitants aged 20-64 years and 13·7 (5·4-22·0) cases per million inhabitants ≥ 65 years of age. The estimated overall annual mortality rate from epidermal necrolysis was 0·9 (0·1-1·8) case per million inhabitants. It was 0·6 (0·1-1·5) case per million inhabitants aged 20-64 years and 2·8 (0·9-6·6) cases per million inhabitants ≥ 65 years of age (deaths in people < 20 years old were too rare to provide an accurate estimate). CONCLUSIONS The annual incidence of epidermal necrolysis is higher than the one to five cases per million inhabitants usually reported. Such estimations could be helpful in establishing appropriate healthcare plans for people with epidermal necrolysis, in particular the need for specialized care units. What's already known about this topic? Few data are available regarding incidence of and mortality from epidermal necrolysis in the general population. Experts in epidermal necrolysis have recently proposed an annual incidence of one to five cases per million individuals. The overall mortality rate is usually reported to be between 10% and 20%. What does this study add? Using a four-source capture-recapture method and data from a 14-year period (2003-16), the annual incidence of and mortality from epidermal necrolysis were estimated to be 6·5 (95% confidence interval 4·1-8·9) and 0·9 (0·1-1·8) cases per million French inhabitants, respectively. Such estimations could be helpful in establishing appropriate healthcare plans, in particular the need for specialized care units.

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Background Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are associated with various sequelae. Chronic pain, one of these sequelae, has never been systematically evaluated. Objectives and methods To assess the persistence of pain in a single-centre cohort of 113 consecutive patients with SJS/TEN. From this cohort, 81 patients were interviewed more than 1 year after the initial episode and included in the study. Data were collected according to standardized questionnaires. Results From the 81 interviewed patients, 52 patients (64%) were painless and 29 patients (36%) were painful. Chronic pain syndrome was associated with a more severe initial acute phase of the disease (larger extent of detachment, higher SCORTEN, increased rate of admission in ICU and complications, and longer hospital stay). Pain was mainly located at the level of eyes (55%), mouth and lower limbs (38-41%), with a moderate daily intensity on average (4.7/10). The 'affective' descriptors prevailed over the 'sensory' descriptors, with the exception of burning and itching sensations. Finally, regarding provoked pain, mechanical allodynia (to brushing and pressure) was more marked than thermal allodynia. Discussion The persistence of chronic pain after SJS/TEN is a common phenomenon. Sensory descriptors are consistent with sensitization of both small-diameter nerve fibres (burning and itching sensations) and large-diameter nerve fibres (mechanical allodynia), but the affective-emotional components of pain largely predominate. Conclusions Complex mechanisms lead to persistent pain as long-term sequela of SJS/TEN, among which mechanisms, psychological factors related to post-traumatic stress disorder probably play a key role.

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Toxic epidermal necrolysis (TEN) is a severe autoimmune idiosyncratic reaction, which is mostly caused by drugs, involves for more than 30% of the body surface and affects the entire mucosa, and is characterized by extensive epidermal loss. The worldwide incidence of TEN is estimated to be 0.4-1.3 million. The mortality rate of TEN is between 30-50%, and primary death cause is septicemia and multiple organ failure. The Scorten Mortality Scoring is widely used in assay of mortality and morbidity and gives substantially correct results. Since lesions are similar with burns and the possibility of sepsis in TEN, their follow-up in the burn intensive care unit (BICU) is widely accepted. In this case report, a 30-year-old male patient who developed TEN on the third day of cefuroxime axetil oral use due to upper respiratory tract infection was presented in the BICU follow-up, in company with the literature data.

Qin Xiang Ng,1,2 Michelle Lee Zhi Qing De Deyn,3 Nandini Venkatanarayanan,4 Collin Yih Xian Ho,2 Wee-Song Yeo,5 1Department of Medicine, National University Hospital, National University Health System, Singapore; 2MOH Holdings Pte Ltd, Singapore; 3Department of Medicine, James Cook University Hospital, Middlesbrough, UK; 4Department of Medicine, Nottingham University Hospitals NHS Trust, Queen’s Medical Centre, Nottingham, UK; 5Department of Paediatrics, National University Hospital, National University Health System, Singapore Background: Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are dermatologic emergencies with high morbidity and mortality risk. Cyclosporine, an immunomodulatory agent, is sometimes used off-label, and its role continues to be debated. This meta-analysis aimed to provide an update of current evidence and to clarify the role of cyclosporine in SJS/TEN treatment better.Methods: Using the keywords [cyclosporine OR cyclosporine OR ciclosporin OR CsA] AND [Steven-Johnson OR SJS OR toxic epidermal OR epidermal necrolysis OR TEN OR hypersensitivity OR dermatologic OR burns], a preliminary search on the PubMed, Ovid, Web of Science, and Google Scholar Database yielded 615 papers published in English between January 1, 1960 and July 1, 2017. The inclusion criteria for this review were: 1) published retrospective or prospective study (excluding single case reports); 2) patients with clinical diagnosis of SJS or TEN; 3) trial of cyclosporine treatment; and 4) available survival/mortality data.Results: A total of 12 studies, with a total of 358 SJS/TEN patients were reviewed. Two studies were excluded from the meta-analysis as they did not report SCORe of toxic epidermal necrosis/predicted mortality data; one was excluded because of possible data irregularities. Meta-analysis of nine studies revealed a significant reduction in mortality risk with cyclosporine therapy (standardized mortality ratio 0.320; 95% CI: 0.119–0.522; P=0.002). Cyclosporine was also generally well tolerated with little adverse effects or increased infection, albeit the patients tended to be critically ill. Publication bias was observed in the funnel plot and Egger test (P=0.0467).Conclusion: Currently available evidence are predominantly open trials and retrospective studies with a significant risk of bias, perhaps owing to the rarity and life-threatening nature of the condition. Given its immunomodulatory actions, cyclosporine could be a potential treatment option for SJS/TEN in addition to best supportive measures. Further confirmation with robust randomized, controlled trials or larger case series is necessary and should be encouraged. Keywords: SJS, TEN, epidermal necrolysis, cyclosporine, CsA, meta-analysis

In-hospital mortality for epidermal necrolysis (EN) has been well-characterized, but less is known about the long-term complications. Marxer et al. (2020) report mortality rates of 7.4% during the initial hospitalization, 4.8% within 90 days, and 7.6% after 91 days. Compared with that of matched controls, long-term mortality was not increased, highlighting the importance of understanding the long-term sequelae of EN survivors.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe adverse reactions to drugs that cause a life-threatening eruption of mucocutaneous blistering and epithelial sloughing. While the acute complications of SJS/TEN are well described, it is increasingly recognized that survivors may develop delayed sequelae, some of which can be associated with significant morbidity. Studies of long-term SJS/TEN outcomes mostly focus on mucocutaneous and ocular complications. However, other internal organs, such as the respiratory tract and gastrointestinal tract, can be affected. Psychological sequelae are also frequent following the trauma of widespread epidermal necrolysis. An appreciation of the 'chronic' phase of SJS/TEN is needed by clinicians caring for individuals who have survived the acute illness. This review aims to provide an update on the breadth and range of sequelae that can affect patients in the months and years following an acute episode of SJS/TEN.

Background/Objectives Epidermal necrolysis (Stevens–Johnson syndrome and toxic epidermal necrolysis) includes immune-mediated, life-threatening inflammatory blistering disorders that can affect children. The Score of Toxic Epidermal Necrosis (SCORTEN) tool has accurately predicted the outcome of these disorders in adults but has not been tested in children. Methods We performed a retrospective chart review to compare the accuracy of the adult SCORTEN tool with that of two modifications tailored to children in predicting disease outcome. Results The longer the patient's median length of hospital stay was, the higher the adult and two proposed pediatric SCORTENs were. In addition, all patients who died had SCORTENs greater than 4. Conclusion The pediatric-modified tools were not superior to the adult SCORTEN, which accurately predicted outcome.

Drug-induced severe cutaneous adverse reactions (SCARs) include acute generalized exanthematous pustulosis, drug reaction with eosinophilia and systemic symptoms (DRESS), and epidermal necrolysis (Stevens-Johnson syndrome [SJS], toxic epidermal necrolysis). The identification of the causal drug is crucial in order to avoid further exposure, but making the right differential diagnosis of the type of SCAR is equally important since treatment, follow-up, and prognosis of different SCARs are not the same. These syndromes are distinct entities with different clinical, biological, and histological patterns, but sometimes the early distinction between 2 SCARs can be extremely challenging, and overlapping conditions could therefore be taken into consideration, although true overlapping SCARs are very rare when using strict diagnostic criteria (described by the RegiSCAR group). Only a better understanding of the physiopathology of the SCARs could possibly explain these ambiguities and overlaps. We report a case of SCAR in an 86-year-old patient probably induced by allopurinol and simultaneously fulfilling the diagnostic criteria for DRESS and SJS, thus considered as an overlapping case of SCARs.

Palmar plantar erythrodysesthesia (hand-foot syndrome, HFS) is a common adverse event of treatment with cytostatic chemotherapeutics such as capecitabine. Histopathological findings are nonspecific and may even include generalized epidermal necrolysis. A total of 50 patients were examined before and after the intake of capecitabine to assess if HFS may result in relevant changes of the palmar epidermal ridge configurations with possible consequences for the patients who want to travel abroad. In total, 14 of the 50 patients developed HFS (28%) with HFS grades 1-3 observed. HFS grade 4 was not observed. HFS of grade 2 and 3 was associated with a temporary macroscopic loss of the epidermal ridges. No dactyloscopic changes that might have led to a false identification were seen in those cases. Patients with a risk of HFS development who want to travel abroad should carry a medical pass of the chemotherapeutic treatment to prevent them from difficulties in identification controls.

Stevens–Johnson syndrome (SJS) and toxic epidermolysis necrosis (TEN) are rare, severe adverse cutaneous reactions that are often due to drugs with high morbidity and mortality. Certain risk factors make patients at higher risk of this disorder such as being a slow acetylator, immunocompromised hosts, concurrent use of radiotherapy and anticonvulsants, specific human leukocyte antigen (HLA) alleles, and ethnicity. Epidermal necrolysis starts with painful ill-defined erythematous coalescing macules and patches and central purpura. These lesions evolve into extensive areas of detached epidermis within a week. Management is multidisciplinary and involves supportive care with intravenous fluids and feeding, dressing, observation for sepsis, as well as active medication such as etanercept, cyclosporine, and/or methylprednisolone. Patient and family should be counseled before discharge and followed up by dermatologist, ophthalmologist, and gynecologist/urologist to monitor and manage chronic complications.

Epidermal necrolysis (EN), encompassing the spectrum of Stevens-Johnson syndrome and toxic EN, is a rare, severe cutaneous drug reaction with an estimated mortality in modern cohorts of 15% to 23%.1-3 The rarity of the disease makes rigorous prospective clinical research difficult, highlighting the need for multicenter, multinational collaborations as well as iterative efforts to validate and build on prior work.

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Sixty years after its original description by Sir Alan Lyell, epidermal necrolysis (from Stevens-Johnson syndrome to toxic epidermal necrolysis) seems finally amenable to a specific treatment in addition to essential symptomatic measures in specialized settings. A recently published systematic review and an article by Gonzales-Herrada et al. strongly suggest that cyclosporine is effective in reducing the risk of death.

Several immunomodulatory agents are used in the treatment of epidermal necrolysis, but evidence of their efficacy is limited. The Autonomous Community of Madrid has two reference burn units to which all patients with epidermal necrolysis are referred. One burn unit has mostly used cyclosporine (CsA), and the other has used non-CsA therapies (mainly high-dose intravenous immunoglobulin). The allocation of patients to one or the other burn unit was mainly based on proximity, resembling a random assignment. Thus, we took advantage of this “natural experiment” to estimate the mortality risk ratio (MRR) of CsA (n = 26) compared with non-CsA (n = 16) treatment using hospital as an instrumental variable over the period from 2001 to 2015. We also computed the observed versus expected (O/E) MRR in a case series of 49 CsA-treated patients (including 23 patients from other regions treated in Madrid), and using the Score for Toxic Epidermal Necrolysis (i.e., SCORTEN) scale to estimate the expected values. The instrumental variable-based MRR of CsA versus non-CsA was 0.09 (95% confidence interval = 0.00–0.49). The O/E analysis also showed a reduction in mortality risk (MRROE = 0.42; 95% confidence interval = 0.14–0.99). We identified five other case series of CsA-treated patients providing MRROE and meta-analyzed their results. The pooled MRROE (including from this study) was 0.41 (95% confidence interval = 0.21–0.80). All three approaches consistently show that CsA reduces the mortality in epidermal necrolysis patients. Ministerio de Economía, Industria y Competitividad (#PI12/02267) 6.448 JCR (2017) Q1, 3/64 Dermatology 2.282 SJR (2017) Q1, 48/457 Biochemistry No data IDR 2017 UEM

Toxic epidermal necrolysis is an idiosyncratic drug reaction which manifests with extensive epidermal detachment due to the massive keratinocyte apoptosis, mucous membrane involvement, and potentially lethal outcome. It is caused by adverse reactions to drugs, mostly idiosyncratic, unpredictable and independent of the applied dose, which develops 7-21 days after initiation of the drug, and is most commonly caused by the following drugs: sulfonamides, allopurinol, carbamazepine, phenobarbitone, phenytoin and oxycam group of nonsteroidal anti-inflammatory drugs. The treatment outcome depends on several factors, while older age, multiple drug use, late exclusion of the drug inducing toxic epidermal necrolysis, raised serum levels of urea, creatinine and cytopenia are poor prognostic indicators which are rated in SCORTEN scoring which proved to be of great help in the assessment of disease outcome. The basic approach to the treatment is early diagnosis, immediate suspension of the probable inducing drug, and emergency transport to the closest burn center, since treatment in burn units is associated with a lower risk of infection and mortality of these patients. Exclusion of the drug that induced toxic epidermal necrolysis, and supportive therapy, is the first and only therapy for which there is a consensus in different centers. Various forms of adjuvant therapy are also applied: in France, supportive therapy is a standard of care, in Germany it is short-term use of high-dose corticosteroids, while in USA, in the last decade high-dose intravenous immunoglobulins are the most widely accepted treatment modalities. Case reports and small patients’ series described therapeutic effects of plasmapheresis, cyclosporine and other immunosuppressants. In conclusion, elimination of the possible causal agent, rapid transport to the burn unit, and multidisciplinary approach to treatment are of utmost importance for favorable outcome of the disease with 20-30% mortality rate. An update on diagnosis and the treatment of toxic epidermal necrolysis is provided in this review.

Toxic epidermal necrolysis is an extremely severe drug reaction, manifesting itself by widespread apoptosis of keratinocytes, generally considered to result from Fas/CD95-FasLigand interaction, but of unknown primary mechanism. We looked at the role of cells present in the skin blisters as probable effectors of this immune reaction. In a patient suffering from cotrimoxazole-induced toxic epidermal necrolysis, blister fluid cells were phenotyped by FACS and tested without prior restimulation for cytotoxicity on autologous and allogeneic cells in the presence of the drug. Blister fluid lymphocytes were predominantly CD8+, DR+, CLA+, CD56+ T lymphocytes, perforin positive and expressing preferentially two Vbeta chains of the T cell receptor repertoire. These lymphocytes were cytotoxic only in the presence of the drug towards autologous EBV transformed lymphocytes and towards allogeneic cells sharing HLA-Cw4. Cytotoxicity occurred in the presence of either cotrimoxazole, sulfamethoxazole, or the nitroso metabolite of sulfamethoxazole, but not with the hydroxylamine metabolite of sulfamethoxazole. The lysis was blocked by an anti-MHC class I monoclonal antibody. It was abolished by EGTA and CMA, but neither by anti-fas, brefeldin A, nor by anti-TRAIL receptor monoclonal antibodies, strongly suggesting perforin/granzyme-mediated cytotoxicity, without implication of Fas or TRAIL at this stage. This is direct evidence that T lymphocytes present within the lesions of toxic epidermal necrolysis may exhibit, without any re-stimulation, a drug-specific cytotoxicity against autologous cells. Harboring the markers of classical CTL and MHC class I restriction these lymphocytes reacted against the parent drug and one of its reactive metabolites. These results challenge several current concepts and could support new therapeutic approaches.

Toxic epidermal necrolysis (TEN) is a rare but life-threatening adverse drug reaction. Implicated drugs are sulfonamides, anticonvulsants, allopurinol, and pyrazolone derivatives. Recently, advances in pathogenesis have been made in two directions. It is now known that (1) most patients with TEN have an abnormal metabolism to the culprit drug; and (2) the mechanism leading to epidermal necrolysis seems to be a cell-mediated cytotoxic reaction. The treatment remains symptomatic.

Auteur(s) : Yumi Aoyama, Keiko Kouchi, Yuko Hiramitsu, Hiroaki Iwata, Yasuo Kitajima Department of Dermatology, Gifu University School of Medicine, Yanagido, 1-1, Gifu City, 501-1194, Japan Occupational exposure to chemicals can cause severe cutaneous reactions similar to erythema multiforme (EM), Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN). We report an occupational dermatitis associated with thiourea dioxide, manifesting as histopathologic epidermal necrolysis. A [...]