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Background
Erythema multiforme is part of a spectrum of diseases beginning with a self-limited rash of the skin and mucous membranes which may progress to a disseminated blistering and sometimes fatal disorder known as Stevens-Johnson syndrome (SJS). Older classification systems divided the disease into erythema multiforme minor and major. The major variant is associated with fever, systemic symptoms, and severe oral lesions. These severe cases were sometimes termed SJS and were usually associated with drugs while the minor form was associated with herpes and other infections. At the extreme end is toxic epidermal necrolysis (TEN) which is the most advanced form of Stevens-Johnson syndrome and erythema multiforme. One clinical distinction uses the diagnosis of TEN if greater than 30% of the total body surface area is involved by blisters and peeling and SJS when mucosal lesions are present and the blisters involve less than 30% of the total body surface area.
Working Classification System
Bullous erythema multiforme
Recurrent erythema multiforme
Persistent erythema multiforme
Stevens-Johnson syndrome
Overlap Stevens-Johnson syndrome/toxic epidermal necrolysis (epidermal detachment between 10-30%)
Toxic epidermal necrolysis with spots (widespread purpuric macules or target lesions)
Toxic epidermal necrolysis without spotsThe recurrent form has been associated herpes simplex virus infection. The persistent form has been associated with underlying malignancies and Epstein-Barr virus.
The disease is a lichenoid interface dermatitis. See the outline below for detailed information.
TEN may present with generalized erythema rapidly progressing to blisters and shedding of skin. Mortality may be up to 35%. Unlike erythema multiforme, drugs are implicated in the majority of cases. The list is extensive and includes sulfonamides, anticonvulsants, NSAIDs, allopurinol, clindamycin, chloroquine, and ranitidine. The reactive metabolites of the drugs adhere to the keratinocytes leading to an immune reponse.
OUTLINE
DISEASE ASSOCIATIONS CHARACTERIZATION ALLOPURINOL
Department of Dermatology, Soroka University Medical Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
BACKGROUND: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare severe cutaneous adverse reactions.
OBJECTIVES: We sought to update knowledge on the causes of SJS or TEN with a focus on the rate of allopurinol-associated cases and to identify risk factors for allopurinol-associated SJS or TEN.
METHODS: We conducted a multinational case-control study.
RESULTS: In all, 379 patients with severe cutaneous adverse reactions validated as SJS or TEN and 1505 matched hospitalized control subjects were enrolled. Allopurinol was the drug most frequently associated with SJS or TEN, with 66 exposed patients (17.4%) and 28 exposed control subjects (1.9%) (adjusted odds ratio = 18, 95% confidence interval: 11-32). Allopurinol use was greater than in a previous case-control European study. Daily doses equal to or greater than 200 mg were associated with a higher risk (adjusted odds ratio = 36, 95% confidence interval: 17-76) than lower doses (adjusted odds ratio = 3.0, 95% confidence interval: 1.1-8.4). The risk was restricted to short-term use (<or=8 weeks). The use of comedications did not increase the risk.
LIMITATIONS: Nonsystematic recording of the indications for allopurinol use was a limitation.
CONCLUSIONS: Results of this multinational study (EuroSCAR) revealed that allopurinol is the drug most commonly associated with SJS or TEN. The incidence of allopurinol-associated SJS or TEN has increased possibly because of increased use and dosages of this drug.DRUG ASSOCIATED Stevens-Johnson syndrome caused by the antiretroviral drug nevirapine J Am Acad Dermatol 2001;44:354-7
Nevirapine is a non-nucleoside reverse transcriptase inhibitor widely used in combination with other antiretroviral agents for the treatment of HIV infection
This describes 2 cases of SJS related to nevirapine use
LUPUS
Lupus-associated toxic epidermal necrolysis: A novel manifestation of lupus?Mandelcorn R, Shear NH.
Division of Dermatology, Department of Medicine, University of Toronto.
J Am Acad Dermatol 2003 Apr;48(4):525-9 Abstract quote BACKGROUND: Toxic epidermal necrolysis is an acute mucocutaneous reaction characterized by extensive cutaneous and mucosal sloughing and systemic involvement. It is generally associated with drug ingestion.
Objective and Methods: We describe 2 patients who developed typical clinical and histopathologic features of toxic epidermal necrolysis with unusual subacute progression, absence of systemic involvement or high-risk drug ingestion, and features of lupus erythematosus.
CONCLUSION: We propose that this constellation of features represents a new entity not previously described. This entity may represent a more severe variant of Rowell's syndrome or, alternatively, a novel manifestation of lupus erythematosus
HISTOLOGICAL TYPES CHARACTERIZATION General Mild infiltrate of lymphocytes whicc may obscure the dermoepidermal junction Prominent cell death with basal vacuolar change and individual cell necrosis
Severe cases may have papillary dermal edema with secondary subepidermal vesicular change
VARIANTS TOXIC EPIDERMAL NECROLYSIS
Department of Dermatology, Mount Sinai School of Medicine, New York, New York, USA.
Toxic epidermal necrolysis (TEN) is an unpredictable, life-threatening drug reaction associated with a 30% mortality. Massive keratinocyte apoptosis is the hallmark of TEN. Cytotoxic T lymphocytes appear to be the main effector cells and there is experimental evidence for involvement of both the Fas-Fas ligand and perforin/granzyme pathways.
Optimal treatment for these patients remains to be clarified. Discontinuation of the offending drug and prompt referral to a burn unit are generally agreed upon steps. Beyond that, however, considerable controversy exists. Evidence both pro and con exists for the use of IVIG, systemic corticosteroid, and other measures. There is also evidence suggesting that combination therapies may be of value. All the clinical data, however, is anecdotal or based on observational or retrospective studies. Definitive answers are not yet available.
Given the rarity of TEN and the large number of patients required for a study to be statistically meaningful, placebo controlled trials are logistically difficult to accomplish. The absence of an animal model further hampers research into this condition. This article reviews recent data concerning clinical presentation, pathogenesis and treatment of TEN.
LEARNING OBJECTIVES: At the conclusion of this learning activity, participants should have acquired a more comprehensive knowledge of our current understanding of the classification, clinical presentation, etiology, pathophysiology, prognosis, and treatment of TEN.
- Uncovering histologic criteria with prognostic significance in toxic epidermal necrolysis.
Quinn AM, Brown K, Bonish BK, Curry J, Gordon KB, Sinacore J, Gamelli R, Nickoloff BJ.
Departments of Pathology, Surgery, Internal Medicine, and Preventive Medicine and Epidemiology, Loyola University, Maywood, IL 60153, USA.
Arch Dermatol. 2005 Jun;141(6):683-7. Abstract quote
OBJECTIVE: To identify histologic criteria and prognostic significance in patients with toxic epidermal necrolysis (TEN), a frequently lethal disease that usually represents an adverse drug reaction.
DESIGN: Retrospective analysis of clinical records and histologic material from a 10-year period (1994-2004). Two investigators blinded to clinical data reviewed hematoxylin-eosin-stained sections.
SETTING: North American tertiary care, university-based burn unit.Patients Thirty-seven patients treated for TEN between 1994 and 2004 who had sloughing of 30% or more of their total body surface area and who underwent skin punch biopsies immediately following admission.Main Outcome Measure The degree of dermal mononuclear (DM) inflammation was graded (sparse, moderate, or extensive) at least 2 high-power fields (HPF) away from the perimeter of epidermal detachment, and the mean number of DM cells/5 HPF was quantified for each patient. Clinical records were reviewed and the following data extracted: age, history of cancer, percentage of total body surface area slough, heart rate, and serum glucose, bicarbonate, and serum urea nitrogen values on admission. Severity scores for TEN (SCORTEN) were calculated, and clinical outcome was recorded as survived or died during hospitalization.
RESULTS: Extent of inflammation was assessed by categorizing the mean +/- SD DM cell counts as follows: sparse, 161 +/- 36 cells/HPF (n = 15); moderate, 273 +/- 76 cells/HPF (n = 15); and extensive, 392 +/- 124 cells/HPF (n = 7). There was good concordance between observer ratings (P<.001). While 73% of patients (n = 11) with sparse inflammation survived, only 47% (n = 7) with moderate and 29% (n = 2) with extensive inflammation survived. The accuracy in predicting patient outcome was 65% using grade of inflammation, 68% with mean cell count, and 71% with SCORTEN.
CONCLUSIONS: There is a histologic spectrum with TEN that ranges from sparse to extensive DM inflammation, and degree of inflammation predicts clinical outcome approximately as well as SCORTEN. Future clinical trials should consider the possibility that various patient subsets exist within the TEN population, and a role for immunocytes needs to be critically reevaluated in this devastating disease.
SPECIAL STAINS/
IMMUNOPEROXIDASECHARACTERIZATION Direct immunofluorescence (DIF) Intrapidermal degenerating keratinocytes surrounded with IgM and C3
G ranular staining for C3 along the dermoepidermal junctionIndirect immunofluorescence (IIF)
PROGNOSIS AND TREATMENT CHARACTERIZATION TEN
Dokumentation-szentrum schwerer Hautreaktionen, University Medical Center Freiburg, Freiburg, Germany.
BACKGROUND: No treatment modality has been established as standard for patients with Stevens-Johnson syndrome and toxic epidermal necrolysis.
OBJECTIVE: We sought to evaluate the effect of treatment on mortality in a large cohort of patients with Stevens-Johnson syndrome or toxic epidermal necrolysis.
METHODS: Data on therapy were retrospectively collected from patients in France and Germany enrolled in EuroSCAR, a case-control study of risk factors.
RESULTS: Neither intravenous immunoglobulins nor corticosteroids showed any significant effect on mortality in comparison with supportive care only. Compared with supportive care, odds ratios for death were 1.4 (95% confidence interval: 0.6-4.3) for intravenous immunoglobulins in France and 1.5 (0.5-4.4) in Germany, and 0.4 (0.1-1.7) for corticosteroids in France and 0.3 (0.1-1.1) in Germany.
LIMITATIONS: Such an observational study with retrospective data collection has obvious limitations, including heterogeneity between the countries, supportive care, treatment doses, and durations.
CONCLUSIONS: We found no sufficient evidence of a benefit for any specific treatment. The trend for a beneficial effect of corticosteroids deserves further exploration.
Analysis of Intravenous Immunoglobulin for the Treatment of Toxic Epidermal Necrolysis Using SCORTEN: The University of Miami Experience.Trent JT, Kirsner RS, Romanelli P, Kerdel FA.
University of Miami Department of Dermatology, PO Box 016250, Miami, FL 33136.
Arch Dermatol 2003 Jan;139(1):39-43 Abstract quote BACKGROUND: Toxic epidermal necrolysis (TEN) is a rare, life-threatening condition caused by certain medications. Keratinocytes affected by TEN have been found to undergo apoptosis mediated by Fas-FasL interactions. Treatment with intravenous immunoglobulin (IVIG) has been proposed to inhibit this interaction.
OBJECTIVE: To demonstrate the effectiveness of IVIG therapy in reducing mortality in patients with TEN.
DESIGN: A retrospective analysis of 16 consecutive patients with TEN who were treated with IVIG. The SCORTEN system, a validated predictor of TEN mortality, was used to analyze the data of these patients. Using SCORTEN, we compared the predicted mortality of our patient population with observed mortality.
SETTING: Dermatology inpatient unit at a university-affiliated hospital.
INTERVENTION: All 16 patients received IVIG treatment daily for 4 days. Fifteen patients received 1 g/kg per day and 1 patient received 0.4 g/kg per day.
MAIN OUTCOME MEASURES: For each patient, causes of TEN and other medical problems were documented prior to IVIG therapy, as were the 7 independent SCORTEN risk factors. RESULTS: One patient died. Based on the SCORTEN system, 5.81 patients were expected to die. These mortality rates were compared using the standardized mortality ratio (SMR) analysis ([Sigma observed deaths/Sigma expected deaths] x 100) to determine the efficacy of this treatment, which showed that patients with TEN treated with IVIG were 83% less likely to die than those not treated with IVIG (SMR = 0.17; 95% confidence interval, 0.0-0.96). CONCLUSION: Based on comparison of our observed mortality rate with the SCORTEN-predicted mortality rate, treatment with IVIG significantly decreased mortality in patients with TEN.
Intravenous immunoglobulin treatment for stevens-johnson syndrome and toxic epidermal necrolysis: a prospective noncomparative study showing no benefit on mortality or progression.Bachot N, Revuz J, Roujeau JC.
Service de Dermatologie, Hopital Henri Mondor, 49010 Creteil CEDEX, France.
Arch Dermatol 2003 Jan;139(1):33-6 Abstract quote BACKGROUND: It has been proposed that Fas-Fas ligand interaction was responsible for the apoptosis of epidermal cells in Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) and that high doses of intravenous immunoglobulin (IVIG) could help patients by blocking the apoptosis.
OBJECTIVE: To study the effects of IVIG on SJS and TEN.
DESIGN: Prospective open trial.
SETTING: Referral center of a university hospital.
PATIENTS: Thirty-four consecutive patients admitted for SJS (n = 9), SJS-TEN (n = 5), or TEN (n = 20) a mean of 4.3 days after onset.
INTERVENTION: A dose of 2 g/kg of IVIG was administered within 2 days (half doses or full doses over a longer period for patients with low creatinine clearance).
MAIN OUTCOME MEASURES: Detached plus detachable proportions of the total body surface area measured before and after treatment and predicted death rate estimated on admission with a validated prognostic score.
RESULTS: Epidermal detachment involved a mean +/- SD 19% +/- 16% of the total body surface area on admission and 32% +/- 26% after IVIG treatment (progression in 22 of 34 cases, including most patients referred early). The prognostic score predicted 8.2 deaths (24%); 11 were observed (32%; 95% confidence interval, 17%-51%). Most deaths occurred in elderly patients who had initially impaired renal function.
CONCLUSIONS: The confidence interval of the observed death rate excludes a dramatic decrease in mortality. No measurable effect was observed on the progression of detachment or on the speed of reepidermalization. These results do not support the routine use of IVIG treatment for patients with SJS or TEN, especially in cases of impaired renal function.
Treatment of toxic epidermal necrolysis with high-dose intravenous immunoglobulins: multicenter retrospective analysis of 48 consecutive cases.Prins C, Kerdel FA, Padilla RS, Hunziker T, Chimenti S, Viard I, Mauri DN, Flynn K, Trent J, Margolis DJ, Saurat JH, French LE.
Dermatology Department, Geneva University Hospital, 1211 Geneva 14, Switzerland.
Arch Dermatol 2003 Jan;139(1):26-32 Abstract quote OBJECTIVE: To evaluate the effect of high-dose intravenous immunoglobulin (IVIG) in toxic epidermal necrolysis (TEN), parameters that may affect response to treatment, and the effect of different IVIG batches on Fas-mediated cell death.
DESIGN: Multicenter retrospective analysis of 48 consecutive TEN patients treated with IVIG.
SETTING: Fourteen university hospital dermatology centers in Europe and the United States.
PATIENTS: Forty-eight patients with TEN (skin detachment >10% of their body surface [mean, 44.8%; range, 10%-95%]).
INTERVENTIONS: Infusion of IVIG in all patients (range, 0.8-5.8 g/kg), and analysis of the ability of different IVIG batches to inhibit Fas-mediated cell death.
MAIN OUTCOME MEASURES: Objective response to IVIG treatment, final outcome at day 45, parameters that may affect response to IVIG treatment, and tolerance.
RESULTS: Infusion of IVIG (mean total dose, 2.7 g/kg [range, 0.65-5.8 g/kg]; mean consecutive days, 4 [range, 1-5 days]) was associated with a rapid cessation (mean, 2.3 days [range, 1-6 days]) of skin and mucosal detachment in 43 patients (90%) and survival in 42 (88%). Patients who responded to IVIG had received treatment earlier in the course of disease and, on average, higher doses of IVIG. Furthermore, analysis of 35 IVIG batches revealed significant batch-to-batch variations in the capacity of IVIG to inhibit Fas-mediated cell death in vitro.
CONCLUSIONS: Early infusion of high-dose IVIG is safe, well tolerated, and likely to be effective in improving the survival of patients with TEN. We recommend early treatment with IVIG at a total dose of 3 g/kg over 3 consecutive days (1 g/kg per day for 3 days).
Long-term consequences of toxic epidermal necrolysis in children.Sheridan RL, Schulz JT, Ryan CM, Schnitzer JJ, Lawlor D, Driscoll DN, Donelan MB, Tompkins RG.
Shriners Burns Hospital, Boston, Massachusetts, USA.
Pediatrics 2002 Jan;109(1):74-8 Abstract quote OBJECTIVE: Toxic epidermal necrolysis (TEN) is an acute inflammatory systemic condition that involves injury not just to the skin. Historically, it has been associated with a high mortality but few long-term consequences among survivors. With improved survival, long-term consequences may be becoming more apparent. The objective of this study was to define these long-term consequences and their frequency.
METHODS: From July 1, 1991, to June 30, 2000, 11 children with severe TEN were referred to a regional pediatric burn facility. Wounds were managed with a strategy involving prevention of wound desiccation and superinfection, including the frequent use of biological wound coverings. All children survived and have been followed in the burn clinic. The records of all children were reviewed in detail.
RESULTS: Two boys and 9 girls with an average age of 7.2 +/- 1.8 years (range: 6 months-15 years) and sloughed surface area of 76 +/- 6% of the body surface (range: 50%-95%) were admitted to the burn unit for care. Antibiotics (3 children), anticonvulsants (4 children), nonsteroidals (2 children), and viral syndrome or unknown agents (2 children) were believed to have triggered the syndrome. Six (55%) children required intubation for an average of 9.7 +/- 1.8 days (range: 2-14 days). Mucosal involvement occurred in 10 (91%) and ocular involvement in 10 (91%). Lengths of stay averaged 19 +/- 3 days (range: 6-40 days). Overall follow-up averaged 14 +/- 13 months. Three children had no apparent long-term consequences of the disease and were referred to primary care follow-up after the 2-month burn clinic visit. The remaining children had follow-up averaging 23 +/- 13 months. The most common long-term morbidity involved eyes (3 children [27%]), nails (4 children [36%]), and variegated skin depigmentation (all children). One child developed vaginal stenosis from mucosal inflammation. No esophageal strictures or recurrent TEN has been diagnosed.
CONCLUSIONS: Survival has improved in children with TEN, but long-term sequelae are not infrequent. The most common long-term consequences involve the eyes, the skin, and the nails.
A multicenter review of toxic epidermal necrolysis treated in U.S. burn centers at the end of the twentieth century.Palmieri TL, Greenhalgh DG, Saffle JR, Spence RJ, Peck MD, Jeng JC, Mozingo DW, Yowler CJ, Sheridan RL, Ahrenholz DH, Caruso DM, Foster KN, Kagan RJ, Voigt DW, Purdue GF, Hunt JL, Wolf S, Molitor F.
Burn Multicenter Study Group, Shriners Hospitals for Children Northern California and University of California Davis Regional Burn Center, Sacramento, CA 95817, USA.
J Burn Care Rehabil 2002 Mar-Apr;23(2):87-96 Abstract quote Toxic epidermal necrolysis (TEN) is a potentially fatal disorder that involves large areas of skin desquamation. Patients with TEN are often referred to burn centers for expert wound management and comprehensive care.
The purpose of this study was to define the presenting characteristics and treatment of TEN before and after admission to regional burn centers and to evaluate the efficacy of burn center treatment for this disorder. A retrospective multicenter chart review was completed for patients admitted with TEN to 15 burn centers from 1995 to 2000. Charts were reviewed for patient characteristics, non-burn hospital and burn center treatment, and outcome.
A total of 199 patients were admitted. Patients had a mean age of 47 years, mean 67.7% total body surface area skin slough, and mean Acute Physiology and Chronic Health Evaluation (APACHE II) score of 10. Sixty-four patients died, for a mortality rate of 32%. Mortality increased to 51% for patients transferred to a burn center more than one week after onset of disease. Burn centers and non-burn hospitals differed in their use of enteral nutrition (70 vs 12%, respectively, P < 0.05), prophylactic antibiotics (22 vs 37.9%, P < 0.05), corticosteroid use (22 vs 51%, P < 0.05), and wound management.
Age, body surface area involvement, APACHE II score, complications, and parenteral nutrition before transfer correlated with increased mortality. The treatment of TEN differs markedly between burn centers and non-burn centers. Early transport to a burn unit is warranted to improve patient outcome.
Treatment of toxic epidermal necrolysis with intravenous immunoglobulin in children.Tristani-Firouzi P, Petersen MJ, Saffle JR, Morris SE, Zone JJ.
Department of Dermatology, University of Utah School of Medicine, Salt Lake City 84132, USA
J Am Acad Dermatol 2002 Oct;47(4):548-52 Abstract quote BACKGROUND: Toxic epidermal necrolysis (TEN) is an acute illness characterized by rapid onset of skin necrosis and high mortality. Standard treatment is primarily aimed at supportive care in a burn unit setting.
OBJECTIVE: We evaluated the outcome of 8 pediatric patients treated for TEN with intravenous immunoglobulin (IVIg) over a 3-year period.
METHODS: We performed a retrospective analysis of pediatric patients with a diagnosis of TEN between 1999 and 2001, obtained from a computerized database.
RESULTS: Mean body surface involvement of 8 patients treated with IVIg was 67%. The average length of hospitalization was 13.6 days, with an average delay in treatment of 3.2 days. The average time to arrest in progression of lesions was 2.1 days and to complete re-epithelialization, 8.1 days. The mortality rate was 0%. The majority of complications were infectious.
CONCLUSION: IVIg is a safe and effective treatment for TEN in the pediatric population. Randomized trials are needed to further evaluate the efficacy of IVIg compared with other modalities.
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Target lesions -Dusky erythematous lesions associated with central epidermal necrosis and surrounding erythema.
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