Stevens-Johnson Syndrome - Toxic Epidermal Necrolysis

17/2/22, 12:29 Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis
Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis

Overview and Recommendations
Background
● Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are febrile mucocutaneous drug
reactions that are probably part of the same disease spectrum.
● Most cases are associated with medications, especially sulfonamides, aminopenicillins, cephalosporins,
tetracyclines, quinolones, imidazole antifungals, allopurinol, and aromatic anticonvulsants.
● Skin and mucous membrane lesions begin 7-21 days after initiation of the causative drug in the setting of a
first exposure to the drug and can occur within 2 days upon reexposure.
● The amount of body surface area involvement may define classification.
⚬ SJS is diffuse and involves < 10% of body surface area.

⚬ SJS/TEN overlap syndrome involves > 10% of body surface area and < 30% of body surface area.
⚬ TEN involves > 30% of body surface area and may have purpuric macules, atypical target lesions, and/or
large epidermal sheets without any discrete lesions.
Evaluation
● SJS/TEN may present as dusky red skin macules or patches which progress to bullae, skin sloughing,
mucosal erosions, and may be accompanied by fever, conjunctivitis, dysuria, and/or uveitis which may
precede the rash by several days.
● Diagnose SJS/TEN based on clinical findings including Nikolsky sign (rubbing the skin with lateral traction
induces a blister).
● Consider involvement of mucous membranes and histopathologic findings from a skin biopsy to help
differentiate between SJS/TEN and staphylococcal scalded skin syndrome (SSSS). Graft-versus-host disease
(GVHD) may be histologically indistinguishable from SJS/TEN but can be differentiated by clinical signs and
symptoms.
Management
● Discontinue the causative drug, or all non-essential and suspected medications if the causative drug cannot
be specifically identified. Early withdrawal of the causative drug is associated with lower mortality.
● Consider supportive care as the focus of management for skin lesions (Weak recommendation), including
⚬ resuscitation, hydration, control of electrolyte imbalances, and adequate nutrition

⚬ reconstitution of the skin barrier function with nonadherent dressings such as paraffin gauze,
petrolatum impregnated gauze, xenografts, or allografts, or with newer skin substitutes
● Obtain multidisciplinary input for evaluation and management of care, including experts in dermatology or
plastic surgery for skin care, ophthalmology, and skincare nursing. Consider additional expertise as
needed, such as from pediatrics, otorhinolaryngology, pulmonology, infectious disease, gynecology,
urology, gastroenterology, psychiatry, psychology, nutrition, and social work.
● Consider lubrication and topical antibiotics for prevention and treatment of ocular manifestations (Weak
recommendation).
https://www.dynamed.com/condition/stevens-johnson-syndrome-toxic-epidermal-necrolysis 1/55
● Systemic immunomodulatory medications have been used as treatment for SJS/TEN, but their efficacy is
not well established. Consider IV immune globulin (IVIG), IV cyclosporine, IV corticosteroids, or etanercept
with specialist, multidisciplinary team supervision, and in context of clinical research or case study (Weak
recommendation).
● SJS/TEN has a high mortality rate and is associated with a high risk of long-term sequelae such as skin
scarring, hypo- or hyperpigmentation, and ocular complications. Use of the Severity of Illness Score for
Toxic Epidermal Necrolysis (SCORTEN) score, which includes age and other clinical factors on admission to
the hospital, may help predict mortality.
● After recovery, monitor patients for potential late-sequelae with periodic ophthalmologic, gynecologic,
pulmonary, dental, ear, nose and throat, and psychiatric evaluation as needed based on affected mucosal
sites, ocular symptoms, and other symptoms.
Related Topics
● Erythema Multiforme
● Staphylococcal Scalded Skin Syndrome (SSSS)
General Information
Description
● severe mucocutaneous reaction with widespread, severe blistering and sloughing of the skin 1
⚬ most commonly caused by systemic drug

⚬ Stevens-Johnson syndrome (SJS) is defined as being less severe than toxic epidermal necrolysis (TEN)
⚬ mortality with SJS is < 10%
⚬ mortality with TEN is > 30%
Also Called
● toxic epidermal necrolysis also called Lyell syndrome
Definitions
● original 1993 consensus classification for acute bullous disorders
⚬ forms of epidermal necrolysis
– bullous erythema multiforme
● detachment < 10% of the body surface area

● localized "typical targets" or "raised atypical targets"
– Stevens-Johnson syndrome
● detachment < 10% of the body surface area

● widespread erythematous or purpuric macules or flat atypical targets
– overlap Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN)
● detachment between 10% and 30% of the body surface area

● widespread purpuric macules or flat atypical targets
– toxic epidermal necrolysis with spots
● detachment > 30% of the body surface area

● widespread purpuric macules or flat atypical targets
– toxic epidermal necrolysis without spots
● detachment > 10% of the body surface area

● large epidermal sheets and without any purpuric macule or target
⚬ Reference - Arch Dermatol 1993 Jan;129(1):92

⚬ proposed modified classification
– lesions in SJS/TEN consist of flat typical targets, flat atypical targets, and macules with or without
blisters
– lesions in erythema multiforme consist of raised typical targets and raised atypical targets
– Reference - Clin Dermatol 2007 May-Jun;25(3):348
Epidemiology
Who is Most Affected
● Stevens-Johnson syndrome (SJS)/ toxic epidermal necrolysis (TEN) can affect patients of any age 2
● SJS/TEN may be more likely to recur in children 2
● mortality from SJS/TEN higher in elderly than younger patients 2
STUDY
● SUMMARY
female gender and nonwhite race/ethnicity associated with increased risk of SJS, SJS/TEN, and TEN in
adults in the United States
CROSS-SECTIONAL STUDY: J Invest Dermatol 2016 Jul;136(7):1387 | Full Text
Details
⚬ based on cross-sectional study

⚬ 3,657 adult patients with necrolytic disease (SJS, SJS-TEN, or TEN) between 2009 and 2012 identified from
Nationwide Inpatient Sample (NIS) database (overall database included 23,009,584 hospital discharges)
⚬ female gender associated with increased risk for necrolytic disease odds ratio (OR) 1.27 (95% CI 1.23-
1.31)
⚬ race/ethnicity associated with increased risk for necrolytic disease relative to white patients
– Asian OR 3.27 (95% CI 3.02-3.54)

– African-American OR 2.01 (95% CI 1.92-2.1)
– Hispanic OR 1.2 (95% CI 1.13-1.28)
– multiracial/other 1.59 (95% CI 1.44-1.74)
⚬ Reference - J Invest Dermatol 2016 Jul;136(7):1387 full-text
Incidence/Prevalence
● Stevens-Johnson syndrome (SJS), Stevens-Johnson syndrome/toxic epidermal necrolysis (overlap), and toxic
epidermal necrolysis (TEN) are rare conditions 1 , 3
● estimated annual incidence from data in the 1990's ranged from 0.4 to 7 cases per million per year for
occurrence of SJS, Stevens-Johnson syndrome/toxic epidermal necrolysis (overlap), or TEN 1 , 3
STUDY
● SUMMARY
incidence of SJS in adults in the United States estimated about 9 per million per year
Details

⚬ 3,657 adult patients with SJS, SJS-TEN, or TEN between 2009 and 2012 identified from Nationwide
Inpatient Sample (NIS) database (overall database included 23,009,584 hospital discharges)
⚬ mean ages of 57.6 years for SJS, 55.8 years for SJS-TEN, and 59.6 years for TEN
⚬ estimated frequency per million adults
– 8.61-9.69 for SJS (defined as < 10% of body surface area [BSA] involved)
– 1.46-1.84 for SJS-TEN (between 10% and 30% BSA involved)
– 1.58-2.26 for TEN (> 30% BSA involved)
⚬ Reference - J Invest Dermatol 2016 Jul;136(7):1387 full-text
STUDY
● SUMMARY
incidence of SJS in children in the United States estimated about 4-6 per million per year
CROSS-SECTIONAL STUDY: J Am Acad Dermatol 2017 May;76(5):811 | Full Text
Details

⚬ 1,959 pediatric patients with SJS, SJS-TEN, or TEN between 2009 and 2012 identified from NIS database
– exclusions included newborns, patients hospitalized for < 3 days, patients with erythema multiforme
major, herpes simplex virus infection, Kawasaki disease, and Mycoplasma pneumoniae infection
– mean ages of 10.5 years for SJS, 10.4 years for SJS-TEN, and 9.3 years for TEN
⚬ estimated frequency per million children
– 4.3-5.8 for SJS

– 0.6-1.4 for SJS-TEN
– 0-0.7 for TEN
⚬ Reference - J Am Acad Dermatol 2017 May;76(5):811 full-text
Risk Factors
Medical Conditions and Cross-reactivity
● Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) appear more common in patients with
HIV/AIDS 2
● patients with brain tumors receiving irradiation and phenytoin may have increased risk of SJS/TEN 2
● cross-reactivity 2
⚬ patients with history of SJS/TEN may have increased risk of recurrence if given a different medication
within the same class of medications
– for example, beta lactam antibiotics may have cross-reactivity (penicillins and cephalosporins)
– antiepileptic drugs (carbamazepine, phenytoin, and phenobarbital) may have cross-reactivity due to
similar aromatic structures
⚬ SJS/TEN reaction does not appear to increase risk of recurrence in response to a drug from a different
class of medications
⚬ SJS/TEN reaction to a sulfonamide antibiotic may not increase risk to sulfonamide non-antibiotic drug
(for example, thiazide diuretic or COX-2 inhibitor)
Genetic Risk Factors
● human leukocyte antigens (HLA)
⚬ patients with certain HLA may be at increased risk 2 , 5
– host genetic differences in HLA may put certain individuals at higher risk of SJS/TEN in response to
certain drugs
– genotype HLA-B*5801 associated with allopurinol-related SJS/TEN
– HLA-B*1502 associated with carbamazepine-, lamotrigine-, oxcarbazepine-, phenobarbital-, and
phenytoin-related SJS/TEN
– HLA-B*1511 and HLA-B*3101 associated with carbamazepine-related SJS/TEN
⚬ HLA-B*5901 associated with methazolamide-induced SJS/TEN in Asian populations (Pharmacogenomics

J 2019 Jun;19(3):286 )
⚬ HLA-B*5801 associated with allopurinol-induced SJS and TEN in Thai population (Pharmacogenet
Genomics 2009 Sep;19(9):704 )
⚬ HLA-A*0206 and HLA-B*4403 associated with SJS and ocular complications (Cornea 2015 Nov;34 Suppl
11:S158 )
⚬ HLA-B*1502 allele associated with Stevens-Johnson syndrome and toxic epidermal necrolysis in patients
taking carbamazepine
– dangerous or even fatal skin reactions (Stevens-Johnson syndrome and toxic epidermal necrolysis)
with carbamazepine significantly more common in patients with human leukocyte antigen allele HLA-
B*1502
– HLA-B*1502 allele occurs almost exclusively in patients with Asian ancestry, including South Asian
Indians
– carbamazepine should not be used in patients testing positive for HLA-B*1502 unless expected
benefit clearly outweighs increased risk of serious skin reactions
– any patients (including those positive for HLA-B*1502) taking carbamazepine for more than few
months without skin reactions should be considered low risk
– Reference - FDA MedWatch 2007 Dec 12 , FDA Press Release 2007 Dec 12
Associated Conditions
● Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) frequently associated with other
serious medical illnesses
⚬ unclear if associations related to underlying disease processes or medications given for associated
illness or whether associated conditions are complications of critical illness
⚬ malignancies reported associated with SJS/TEN include multiple myeloma, leukemia, non-Hodgkin
lymphoma, and central nervous system cancer.
⚬ other conditions reported as associated with SJS/TEN include
– systemic lupus erythematosus (SLE)

severe infections including tuberculosis and HIV/AIDS
–
– acute and chronic kidney disease
⚬ Reference - J Invest Dermatol 2016 Jul;136(7);1387 full-text
● Drug-induced Liver Injury 5
Etiology and Pathogenesis

Causes
● Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) in adults is associated with drug exposure
in about 85% of cases, with the rest of cases ascribed to infections or unknown causes 1 , 2
● in children, SJS/TEN may be associated with drugs in 50% of cases and infection in 50% of cases (Br J
Dermatol 2019 Jul;181(1):37 )
● > 200 drugs have been associated with SJS/TEN 1 , 2
⚬ most common drugs associated with Stevens-Johnson syndrome/toxic epidermal necrolysis include
– allopurinol
– carbamazepine
– lamotrigine
– nevirapine
– oxicam nonsteroidal anti-inflammatory drugs (NSAIDs) (meloxicam, piroxicam, tenoxicam)
– phenobarbital
– phenytoin
– sulfamethoxazole and other sulfur antibiotics (sulfasalazine, sulfadiazine, sulfadoxine, sulfafurazole)
⚬ anticancer drugs associated with SJS/TEN
– traditional chemotherapeutics including bleomycin, cladribine, lenalidomide, mithramycin,

pemetrexed, tegafur-gimeracil-oteracil-potassium, and thalidomide
– targeted anticancer therapeutics including epidermal growth factor receptor (EGFR) inhibitors
(afatinib, cetuximab, gefitinib), BCR-ABL and KIT inhibitors (imatinib), and antiangiogenics (sorafenib)
– anticancer immune therapy including aldesleukin, nivolumab, and pembrolizumab
– Reference - J Immunol Res 2018;2018:5376476 full-text
⚬ SJS/TEN usually starts within 1-2 weeks of a new medication but has been reported to occur up to 8
weeks after a new medication
⚬ in children < 15 years old, drugs associated with Stevens-Johnson syndrome/toxic epidermal necrolysis
– based on pooled analysis of 2 multicenter case-control studies

– 80 cases of Stevens-Johnson syndrome/toxic epidermal necrolysis were matched to 216 controls
– comparing drug exposure in cases vs. controls (p < 0.05 for each)
● antimicrobial sulfonamides in 13% vs. 0%

● cephalosporins in 10% vs. 1%
● macrolides in 7% vs. 1%
● phenobarbital in 15% vs. 1%
● valproic acid in 9% vs. 0%
● lamotrigine in 9% vs. 0%
● carbamazepine in 5% vs. 0%
● acetaminophen in 37% vs. 7%
– Reference - Pediatrics 2009 Feb;123(2):e297
⚬ methazolamide associated with Stevens-Johnson syndrome and toxic epidermal necrolysis in individuals
with Asian ancestry (Pharmacogenomics J 2019 Jun;19(3):286 )
⚬ SJS/TEN has also been associated with vaccinations, herbal medications, and industrial chemicals and
fuels
STUDY
⚬ SUMMARY
algorithm of drug causality for epidermal necrolysis (ALDEN) score for assessment of drug causality
in Stevens-Johnson syndrome and toxic epidermal necrolysis
DIAGNOSTIC COHORT STUDY: Clin Pharmacol Ther 2010 Jul;88(1):60
Details
– based on diagnostic cohort study with validation

– drug score from -1 to 10 based on
● time delay from initial drug intake to index day of reaction onset (scored +3 to -3)
⚬ 5-28 days, score +3 (suggestive); if previous reaction to drug identified, 2-4 days
⚬ 29-56 days, score +2 (compatible)
⚬ 1-4 days, score +1 (likely); if previous reaction to drug identified, 5-56 days
⚬ > 56 days, score -1 (unlikely)
⚬ drug started on or after index day, score -3 (excluded)
● probability of drug presence in body on index day (scored 0 to -3)
⚬ drug continued up to index day or discontinued at time < 5 times the half-life for elimination of
suspected drug, scored 0 (definite)
⚬ drug discontinued at time > 5 times the half-life for elimination of suspected drug
– with suspected drug interactions or kidney or liver function alterations present, scored -1
(doubtful)
– without suspected drug interactions or kidney or liver function alterations, scored -3
(excluded)
● previous history of adverse reaction to same drug (scored 4 to -2)
⚬ SJS/TEN after use of same drug, scored +4

⚬ SJS/TEN after use of similar drug or other reaction with same drug, scored +2
⚬ other reaction after use of similar drug, scored +1
⚬ no known prior exposure to suspected drug, scored 0
⚬ no known reaction after exposure to this drug (before or after index reaction), scored -2
● presence of drug beyond the progression phase of disease (scored 0 or -2)
⚬ drug unknown or discontinued, scored 0

⚬ drug continued without harm, scored -2
● drug notoriety based on EuroSCAR trial (scored 3 to -1)
⚬ high-risk drug (strongly associated), scored +3, for drugs including, allopurinol, carbamazepine
oxicam-NSAIDs, phenobarbital, phenytoin, sulfamethoxazole-trimethoprim, and sulfonamide-
anti-infectives
⚬ definite, but lower than high-risk drug (associated), scored +2, for drugs including acetic acid
NSAIDs, aminopenicillins, cephalosporins, macrolides, quinolones, and tetracyclines
⚬ drugs with several previous reports but ambiguous results (suspected), scored +1
⚬ drugs with no evidence of association (not suspected), scored -1 for drugs including
angiotensin-converting enzyme (ACE) inhibitors, beta blockers, calcium channel blockers,
furosemide, insulin, propionic acid NSAIDs, and sulfonylurea antibiotics
● drug ranking and score calculation
⚬ calculate total intermediate score from criteria above

⚬ rank all drug scores from highest to lowest in intermediate score
⚬ if ≥ 1 drug has an intermediate score > 3, subtract 1 from scores of all other drugs and compare
candidates to causality scores below
– drug causality scores
● ≥ 6 very probable
● 4-5 probable
● 2-3 possible
● 0-1 unlikely
● < 0 very unlikely
– Reference - Clin Pharmacol Ther 2010 Jul;88(1):60 and J Allergy Clin Immunol Pract 2018 Jan
;6(1):38 full-text
● other causes of SJS/TEN 1 , 2
⚬ association with Mycoplasma pneumoniae unclear, as Mycoplasma pneumoniae also associated with
erythema multiforme
⚬ herpes virus infections have been associated with SJS/TEN
⚬ reported associated with Chlamydia infections in children (Br J Dermatol 2019 Jul;181(1):37 )
⚬ SJS/TEN may be idiopathic
Pathogenesis
● pathogenesis is uncertain, but likely combination of drug structures interacting with host metabolism and
immunity responses 1 , 2
⚬ delay of reaction by 1-3 weeks after drug exposure suggests delayed type IV hypersensitivity reaction
⚬ immune response to antigenic complex formed by reaction of drug metabolites with certain host tissues
⚬ genetic susceptibility suspected with certain human leukocyte antigen (HLA) molecules (for example,
HLA-B*5801, HLA-B*1502)
⚬ apoptosis of epithelial keratinocytes appears to be triggered by drug-induced cytotoxic T lymphocytes
(CTLs)
⚬ pro-apoptotic proteins and molecules involved in immune response may include cytokines, granulysin,
tumor necrosis factors (TNF), interferons, soluble Fas ligand, perforin, and granzyme B
⚬ epidermal necrolysis is due to massive keratinocyte cell death via apoptosis
History and Physical

History
Chief Concern (CC)
● widespread skin and mucous membrane lesions, such as purpuric macules and patches, atypical targetoid
lesions, bullae, erosions, and ulcers, with or without systemic symptoms 1
● symptoms usually begin within 1-2 weeks after the start of culprit drug
● shorter latency period from drug exposure if episode follows a repeated exposure to culprit drug
History of Present Illness (HPI)
● prodromal symptoms may precede cutaneous manifestations by 1-3 days, such as 1 , 2
⚬ fever
⚬ malaise
⚬ cough
⚬ rhinorrhea
⚬ myalgias, headache
● ulceration of mucosa generally begins within prodromal period, and about 1 day later, skin pain and lesions
appear 2
● skin lesion patterns 1 , 3 , 4
⚬ atypical targets and/or purpuric macules are earliest lesions and often start on trunk with progression
to neck, face, proximal extremities
⚬ lesion involvement may include entire body, including soles and palms, and mucosal sites
⚬ lesions may progress to flaccid bullae, erosions, and ulcerations
⚬ skin may be tender to touch and palpation may cause sloughing of skin (positive Nikolsky sign)
⚬ painful inflammation and ulcers on mucocutaneous surfaces (ocular, oral, and genital) may develop
⚬ hairy areas of scalp usually spared
⚬ widespread skin involvement develops over about 2-15 days
● ocular symptoms may include 1
⚬ keratoconjunctivitis
⚬ eyelid edema and inflammation
● constitutional symptoms may include fever, malaise, anorexia, and pharyngitis and usually are present with
toxic epidermal necrolysis and Stevens-Johnson syndrome/toxic epidermal necrolysis overlap 4
● ask about pulmonary symptoms such as dyspnea, tachypnea, hemoptysis, and hypoxemia 1 , 2
● ask about gastrointestinal symptoms such as diarrhea and abdominal distention 1
● ask about past herpes simplex virus infection and recent or past pulmonary infections 1
Medication History
● ask about any new drugs in past 8 weeks 1 , 2
● most common medications implicated with Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN)
include 1 , 2
⚬ allopurinol
⚬ carbamazepine
⚬ lamotrigine
⚬ nevirapine
⚬ oxicam nonsteroidal anti-inflammatory drugs (NSAIDs) (meloxicam, piroxicam, tenoxicam)
⚬ phenobarbital
⚬ phenytoin
⚬ sulfamethoxazole and other sulfur antibiotics (sulfasalazine, sulfadiazine, sulfadoxine, sulfafurazole)
⚬ see also Causes for other drugs associated with SJS/TEN
● ask about past drug allergies 1
Physical
General Physical
● check vital signs and oxygen saturation 1
Skin
● evaluate appearance of skin lesions and amount of body surface area (BSA) involved 1
● appearance of skin lesions 1 , 4
⚬ initially erythematous, dusky-red, or purpuric macules of irregular size and shape, and morbilliform or
atypical targetoid lesions
⚬ progresses to gray color and flaccid blisters with full-thickness necrosis within hours
Image 1 of 6
Toxic epidermal necrolysis
Drug-induced toxic epidermal necrolysis: early blisters.
Copyright© 2014, EBSCO Information Services.
Image 2 of 6
Drug-induced toxic epidermal necrolysis: hemorrhagic erosions in areas of prior blisters.
● tender skin, painful mucosal erosions, flaccid bullae (positive for Asboe-Hansen sign - lateral extension of
bullae with pressure), and necrosis with gray hue 4
● exfoliation of skin, positive for Nikolsky sign 3 , 4
⚬ < 10% of body surface area in Stevens-Johnson syndrome

⚬ 10%-30% in Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) overlap
⚬ > 30% for toxic epidermal necrolysis
● Nikolsky sign - rubbing of the skin with lateral traction induces a blister (always present in TEN but can also
be present in pemphigus vulgaris and staphylococcal scalded skin syndrome) 1
● jaundice 5
⚬ cholestatic liver disease is rare but may indicate Drug-induced Liver Injury (DILI) comorbidity
⚬ DILI associated jaundice associated with increased mortality rate (reported 45.5%)
⚬ evaluate for vanishing bile duct syndrome if cholestatic signs increase in the context of SJS-TEN
● 3 cases of mucositis without rash described in Mycoplasma pneumoniae-associated Stevens-Johnson

syndrome (Pediatrics 2007 Apr;119(4):e1002 ), commentary can be found in Pediatrics 2007
Aug;120(2):451
Mucosal Surfaces
● painful inflammation and ulcers of mucosa in 87%-100% of patients with TEN 3 , 4
⚬ in oral cavity in 71%-100%

⚬ with ocular involvement in 50%-78%
⚬ in genital mucosa in 40%-63%
⚬ in all 3 locations in 34%-50%
● SJS/TEN
⚬ may have extensive involvement of mucous membranes, including 1 , 5
– lips
– oral mucosa
– pharynx
– esophagus
– ocular involvement conjunctiva
– corneal ulcerations
– uveitis
⚬ acute ocular involvement may include 1 , 5
– conjunctivitis
– pseudomembrane formation
– corneal epithelial infiltrates, defects, and/or ulceration
– uveitis
– chemosis
⚬ in severe cases, perform complete ear, nose, and throat evaluation for nasopharyngeal mucosa and
oropharyngeal involvement, which can lead to pulmonary complications 5
Image 3 of 6
Drug-induced toxic epidermal necrolysis: severe oral involvement.
Image 4 of 6
Drug-induced toxic epidermal necrolysis: severe genital involvement.
Image 5 of 6
Drug-induced toxic epidermal necrolysis: severe lip involvement.
Image 6 of 6
Drug-induced toxic epidermal necrolysis: severe eye involvement with corneal vascularization.
Lungs
● epithelial of respiratory tract may be affected in 25% with toxic epidermal necrolysis 4
● erosion or necrosis of bronchi may cause 3
⚬ adult respiratory distress syndrome

⚬ bronchiolitis obliterans
⚬ subcutaneous emphysema
Diagnosis
Making the Diagnosis
● suspect Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) in patients with characteristic
history and physical exam 3 , 4

⚬ symptoms most commonly begin 6-14 days after initiation of the causative drug (for a reexposure to
causative drug, symptoms may occur within 2 days)
⚬ widespread erosions and necrosis of skin seen, but multiple organ systems may also be involved
including mucosal surfaces of mouth, eyes, lungs, gut, kidneys, and genitalia
⚬ typical clinical presentation may include
– fever
– malaise
– anorexia
– pharyngitis
– headache
– skin tenderness
– rash of erythematous, dusky, or violaceous macules; may be morbilliform (fine, discrete
maculopapular exanthem), or atypical targetoid macules and patches
– flaccid bullae
– skin erosions
– painful inflammation and ulceration of oral cavity
– dysuria
– inflammation, blistering, and erosions of mucosal surfaces, especially the mouth, are early and
characteristic findings
⚬ algorithm of drug causality for epidermal necrolysis (ALDEN) score may be used to determine relative
likelihood of drug causality among suspected drugs
● clinical classification of SJS and TEN is based on severity of epidermal detachment 1 , 3
⚬ SJS with epidermal detachment characterized by < 10% of body surface area with widespread
erythematous or confluent purpuric macules or atypical flat target lesions with blisters and erosions
⚬ SJS/TEN overlap characterized by epidermal detachment 10%-30% of body surface area with widespread
erythematous or purpuric macules or atypical targetoid patches
⚬ TEN with spots characterized by epidermal detachment > 30% of body surface area with widespread
erythematous or purpuric macules or atypical target lesions
⚬ TEN without spots characterized by epidermal detachment in large sheets > 10% of body surface area
with loss of large epidermal sheets without purpuric macules or target lesions
Differential Diagnosis
● erythema multiforme
⚬ characterized by typical target lesions (atypical target lesions seen in Stevens-Johnson syndrome
[SJS]/toxic epidermal necrolysis [TEN]), < 10% total body surface involved, and symmetrical pattern on
distal extremities 3
– usually self-limiting
– systemic involvement usually mild or nonexistent
– epidermal detachment usually 1%-2%
– 25%-60% mucosal involvement
– pathognomonic target lesion with 3 concentric zones
● dark dusky red center

● paler pink edematous zone
● red peripheral ring
– atypical papular lesions have round, edematous, palpable lesions in 2 zones and/or borders poorly
defined
⚬ infection is most common cause 4
● Mycoplasma pneumoniae-induced rash and mucositis (MIRM)
⚬ based on systematic review of observational studies

⚬ systematic review of 95 case series and case reports evaluating M. pneumoniae-induced mucocutaneous
disease in 202 patients
⚬ mean patient age 12 years, 66% were male

⚬ 34% had no cutaneous involvement, 47% had sparse cutaneous involvement (single or few scattered
lesions), and 19% had moderate involvement
⚬ mucosal and skin involvement
– mucosa, with oral lesions in 94%, ocular involvement in 82%, and urogenital lesions in 63%
– skin, with acral or extremity lesions in 46%, generalized lesions in 31%, and truncal lesions in 23%
⚬ lesion morphology included vesiculobullous lesions in 77%, targetoid lesions in 48%, papules in 14%,
and macules in 12%
⚬ Reference - J Am Acad Dermatol 2015 Feb;72(2):239
● methotrexate-induced epidermal necrosis (MEN)
⚬ characterized by extensive epidermal necrosis, but no target lesions

⚬ histology shows keratinocyte dystrophy
⚬ mortality of 16.7% reported in cohort study of 24 patients with MEN
⚬ older age (> 60 years), chronic kidney disease, and high initial dose of methotrexate without folic acid
supplementation may be risk factors
⚬ Reference - J Am Acad Dermatol 2017 Aug;77(2):247
● other bullous disorders, such as 1 , 4
⚬ staphylococcal scalded skin syndrome - superficial epidermal peeling and no mucositis

⚬ bullous pemphigoid
⚬ pemphigus
⚬ paraneoplastic pemphigus
⚬ drug-induced linear immunoglobulin A (IgA) dermatosis - bullae in ring-like pattern, rare mucositis
⚬ bullous lupus erythematosus (SLE)
⚬ bullous acute graft-versus-host disease (GVHD) 4
– typically occurs 2 weeks after hematopoietic stem cell transplant

– presents as symmetric acral morbilliform and sometimes lichenoid eruption; bullous eruption may
occur with oral or genital involvement
– distinguishing features may include
● acral to proximal spread

● folliculocentric spread of early eruption
● volume of diarrhea and bilirubin elevation
⚬ acute generalized exanthematous pustulosis - rare, nonerosive mucous membrane involvement

⚬ bullous generalized fixed drug reaction
● toxic shock syndrome
● Kawasaki disease
● scarlet fever
● zinc deficiency
● candidiasis
● pustular psoriasis
● subcorneal pustular dermatosis
● allergic contact dermatitis

● necrolytic migratory erythema
● other severe cutaneous adverse reactions (SCARs)
⚬ acute generalized exanthematous pustulosis (AGEP)

⚬ drug rash with eosinophilia and systemic symptoms (DRESS) syndrome
Table 1. Differential Diagnosis of Similar Severe Cutaneous Conditions
DRESS SJS/TEN AGEP Erythroder

ma
Cause(s) Drugs (most Drugs (> 100 Drugs (most – Flare of

commonly implicated, commonly preexisting
antiepileptics, most antibiotics) chronic
allopurinol, commonly skin
sulfa drugs, antibiotics, condition
antibiotics) sulfa drugs, (for
allopurinol, example,
antiepileptics) psoriasis,
seborrheic
dermatitis,
atopic
dermatitis)
– Drug
reactions
– Lymphom
a/leukemia
(for
example
mycosis
fungoides)
– Idiopathic
Onset of 2-6 weeks 1-3 weeks 48 hours 1-3 weeks

eruption
after drug
initiation
Fever Present Present Present Present

ma
Mucocutaneo – Morbillifor – Bullae/slou – Pinpoint – Erythemat

us findings m eruption ghing pustules ous
– Facial – Atypical that start plaques
edema target in – Edema
– Pustules lesions intertrigino affecting >
– Exfoliative – Mucocutan us regions 90% of
dermatitis eous – Possible total skin
– Tense erosions target surface
bullae – Skin lesions with or
– Possible tenderness – Possible without
target /pain mucosal diffuse
lesions involveme exfoliation
nt
Lymphadeno Prominent Negative Possible Possible

pathy
Hepatitis Marked Minimal-to- Minimal-to- Not

moderate moderate associated
Other organ – Interstitial – Tubular Possible Possible

involvement nephritis nephritis
– Pneumonit – Tracheobr
is onchial
– Myocarditi necrosis
s
– Thyroiditis
Neutrophils Increased Decreased Substantially Increased

increased
Eosinophils Substantially Not Increased Increased

increased commonly
changed

ma
Atypical Much more Not common Not common Common (if

lymphocytes commonly associated
seen with mycosis
fungoides)
Mortality 10% 5%-35% 5% 5%-15%
Abbreviations: AGEP, acute generalized exanthematous pustulosis; DRESS, drug reaction with
eosinophilia and systemic symptoms; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal
necrolysis.
⚬ References - J Am Acad Dermatol 2013 May;68(5):709.e1 , J Am Acad Dermatol 2015 Nov;73(5):843
● Stevens-Johnson syndrome/Toxic epidermal necrolysis-like rash associated with chikungunya fever in 21

children in India (Pediatr Dermatol 2018 May;35(3):392 )
Testing Overview
● evaluate 1 , 3 , 4
⚬ electrolytes
⚬ renal function tests
⚬ glucose
⚬ complete blood count including platelets
⚬ liver function tests
⚬ coagulation studies
⚬ erythrocyte sedimentation rate
⚬ C-reactive protein
⚬ chest X-ray
● if no drug cause identified, perform tests to identify possible infectious etiology including
⚬ wound and blood cultures

⚬ herpes simplex virus (HSV) DNA testing of swab of mucosal lesions or skin biopsy with polymerase chain
reaction (PCR)
⚬ mycoplasma testing with serology or PCR testing of throat swab (see also Erythema Multiforme)
⚬ Reference - J Allergy Clin Immunol Pract 2018 Jan ;6(1):38 full-text
● evaluate skin biopsy 1 , 2
⚬ biopsy of lesional skin, just adjacent to a blister, should be sent for routine histopathology
⚬ a second biopsy from peri-lesional skin should be sent unfixed for direct immunofluorescence to rule
out an immunobullous condition (such as bullous pemphigoid or pemphigus)
Blood Tests
● anemia and leukopenia common 3
● other common findings 3
⚬ elevated liver enzymes but may be transient

⚬ elevated blood urea nitrogen (BUN) and creatinine
● hypoalbuminemia and hyponatremia less common 3
Urine Studies
● increased microalbuminuria and renal tubular enzymes in urine may suggest acute renal insult 3
Biopsy and Pathology
● histological features may include 4
⚬ full thickness epidermal necrosis

⚬ subepidermal split
⚬ varied lymphocytic infiltrate at dermoepidermal junction
⚬ CD4+ T cells in dermis
⚬ CD8+ T cells in epidermis
⚬ endothelial apoptosis
● skin biopsy may be helpful for distinguishing staphylococcal scalded skin syndrome from toxic epidermal
necrolysis (TEN) or graft-versus-host disease (GVHD)
⚬ histology of staphylococcal scalded skin syndrome may show
– intraepidermal cleavage beneath stratum corneum

– minimal inflammatory infiltrate and no cell necrosis
⚬ TEN and GVHD are histologically indistinguishable and may show 4
– full thickness epidermal cell necrosis

– subepidermal cleavage
– basal layer vacuolar degeneration
– rare mononuclear cell infiltrate
⚬ see Staphylococcal Scalded Skin Syndrome (SSSS) for details
STUDY
● SUMMARY
degree of inflammation on histologic exam may be associated with survival
COHORT STUDY: Arch Dermatol 2005 Jun;141(6):683
Details
⚬ based on retrospective study of 37 patients treated for TEN with sloughing of ≥ 30% total body surface
area who had skin punch biopsies
⚬ survival
– 73% in 15 patients with sparse dermal mononuclear inflammation

– 47% in 15 patients with sparse moderate mononuclear inflammation
– 29% in 7 patients with extensive dermal mononuclear inflammation
⚬ Reference - Arch Dermatol 2005 Jun;141(6):683

Management
Management Overview
● discontinue any suspected causative medication immediately 1 , 2 , 4
⚬ if causative medication cannot be identified, discontinue all non-essential medications and any
suspected medications initiated within past 2 months
⚬ early withdrawal of causative drug is associated with lower mortality
● if available, intensive care unit or specialized burn unit with barrier nursing and controlled environment are
preferred settings for treatment
● a multidisciplinary team should be involved in the evaluation of care and management planning 1 , 5
⚬ include a specialist in skin failure, usually dermatology and/or plastic surgery, an intensive care
specialist, and experts in ophthalmology and skincare nursing
⚬ consider other specialists as needed, such as pediatrics, ear, nose, and throat specialists,
pulmonologists, infectious disease specialists, stomatologists, gynecologists, urologists,
gastroenterologists, psychiatrists, psychologists, dieticians, and social workers
● institute supportive care as the focus of treatment, including all of the following
⚬ resuscitation, hydration, control of electrolyte imbalances, and adequate nutrition

⚬ reconstitution of the skin barrier function with nonadherent dressings such as paraffin gauze,
petrolatum impregnated gauze, xenografts, or allografts, or with newer skin substitutes
⚬ prevention and treatment of ocular manifestations with lubrication and topical antibiotics
⚬ prevention and treatment of mucosal involvement with topical emollients to prevent scarring
⚬ monitoring for infection, but use of prophylactic antibiotics is not recommended
⚬ monitoring for and treating respiratory distress
● consider prognostic scoring with Severity of Illness Score for Toxic Epidermal Necrolysis (SCORTEN)
calculation (BAD Grade C, Level 2+) (see also DynaMed Plus calculator for SCORTEN prediction of
mortality) 1
● systemic immunomodulatory medications are often used, but their efficacy is not well established
⚬ consider use of systemic medications under specialist, multidisciplinary team supervision and in context
of clinical research or case study (BAD Grade D, Level 4)
⚬ etanercept may speed skin healing in patients with Stevens-Johnson syndrome (SJS)/toxic epidermal
necrolysis (TEN) with > 10% body surface detachment and might reduce mortality compared to steroids
DynaMed Level 2
⚬ insufficient evidence to support or refute use of other immunomodulating medications for Stevens-
Johnson syndrome/toxic epidermal necrolysis
⚬ cyclosporine associated with reduced mortality in patients with SJS/TEN DynaMed Level 2 and may be
associated with lower mortality than corticosteroids or IV immunoglobulin (IVIG) in patients with mild
SJS/TEN DynaMed Level 2
⚬ IVIG might not reduce mortality in patients with Stevens-Johnson syndrome or toxic epidermal
necrolysis DynaMed Level 2 ; uncertain if high-dose IV immunoglobulin may be associated with reduced
mortality in patients with Stevens-Johnson syndrome or toxic epidermal necrolysis DynaMed Level 2
⚬ glucocorticosteroids might be associated with reduced mortality in patients with SJS/TEN

DynaMed Level 2
● plasmapheresis associated with increased rate of recovery in patients with SJS/TEN overlap or TEN
DynaMed Level 2
● after recovery, patients should have close follow-up to screen for potential late-sequelae of ocular
symptoms and affected mucosal sites
Treatment Setting
● patients with > 10% body surface area (BSA) epidermal loss should be admitted without delay to a burn
center or to an intensive care unit (ICU) with experience in treating patients with Stevens-Johnson
syndrome (SJS)/toxic epidermal necrolysis (TEN) (BAD Grade D, Level 4) 1
⚬ employ strict barrier nursing to reduce nosocomial infection
⚬ use side room controlled for humidity, pressure-relieving mattress, and ambient temperature between
25 degrees C and 28 degrees C (77 degrees F and 82.4 degrees F)
● delays in referral to burn center of 5-7 days reported associated with increased mortality 5
Diet
● consider fluid resuscitation if needed 1
● consider enteral nutrition for acute Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)
(BAD Grade C, Level 3) 1

⚬ consider nasogastric feeding if buccal mucositis prevents oral feeding
⚬ aim for 20-25 calories/kg/day during early, catabolic phase, then 25-30 calories/kg/day during recovery
phase
Medications
Overview of Systemic Immunomodulating Medications
● recommendations from United Kingdom 2016 guidelines for the management of Stevens-Johnson
syndrome (SJS)/toxic epidermal necrolysis in adults (TEN) 1

⚬ no conclusive evidence shows benefit of any one systemic medication therapy over supportive
management, nor is there conclusive evidence of harm from systemic corticosteroids, IV
immunoglobulins (IVIGs), or cyclosporine for treatment of SJS/TEN
⚬ consider systemic medications only with specialist input and in the context of a clinical study or a case
registry (BAD Grade D, Level 4)
● recommendations from the British Association of Dermatologists' 2018 guidelines for the management of
Stevens-Johnson syndrome/toxic epidermal necrolysis in children (aged 0-17 years)
⚬ insufficient evidence to support any recommendation for systemic immunomodulating medication
⚬ no reliable evidence shows benefits or lack of benefit for medication therapy, including corticosteroids,
IVIG, anti-tumor necrosis factor (TNF) biologics, or cyclosporine
⚬ give any systemic immunomodulating medication only on supervision of a specialist in skin failure
multidisciplinary treatment and within confines of clinical research and/or case registry (BAD Strong
recommendation)
⚬ Reference - Br J Dermatol 2019 Jul;181(1):37
STUDY
● SUMMARY
limited evidence regarding treatment of SJS and TEN in children
SYSTEMATIC REVIEW: J Popul Ther Clin Pharmacol 2011;18:e121
Details
⚬ based on systematic review of 31 case series and case reports with 128 children with SJS or TEN
⚬ treatments included IVIG, steroids (prednisolone, methylprednisolone, dexamethasone), dressings with
or without surgical debridement, and supportive treatment alone
⚬ 33 patients treated with supportive care had response in 3-9 days and 2 deaths
⚬ 57 patients treated with IVIG had response in 1-3 days and 0 deaths
⚬ 20 patients treated with steroids had response in 1-4 days and 0 deaths
⚬ Reference - J Popul Ther Clin Pharmacol 2011;18:e121
Corticosteroids
● systemic corticosteroids have been used to treat SJS/TEN, but efficacy is unclear 1 , 5
EVIDENCE SYNOPSIS
Observational studies have not found evidence of a consistent benefit or harm with the use of systemic
glucocorticosteroids, including use of steroids within 2 days of admission (early use), for patients with
SJS/TEN, but there are no randomized trials evaluating systemic corticosteroids in these patients.
⚬ no randomized trials evaluating systemic glucocorticosteroids for SJS/TEN identified in systematic
review (JAMA Dermatol 2017 Jun 1;153(6):514 )
STUDY
⚬ SUMMARY
glucocorticosteroids might be associated with reduced mortality in patients with SJS/TEN
DynaMed Level 2
SYSTEMATIC REVIEW: JAMA Dermatol 2017 Jun 1;153(6):514 | Full Text
Details
– based on systematic review of mostly observational studies

– systematic review of 96 studies (1 randomized clinical trial, 1 interventional trial without control, 53
cohort studies, and 40 case series) evaluating systemic immunomodulating therapy for SJS/TEN in
3,248 patients
– overall, glucocorticosteroids included in 24.7% (IVIGs in 20.3%, no systemic immunomodulating
therapies in 34.1%, cyclosporine in < 5%, cyclophosphamide in < 5%, other treatments in < 15%)
– compared to supportive care, glucocorticosteroids associated with nonsignificant reduction in
mortality
● odds ratio [OR] 0.54 (95% CI 0.29-1.01) in analysis of 11 cohort studies with 465 patients (largest
study, the EuroSCAR study summarized below)
● similar results with patient level data in adjusted model
– Reference - JAMA Dermatol 2017 Jun 1;153(6):514 full-text

STUDY
⚬ SUMMARY
early corticosteroid treatment may not be associated with reduced mortality in patients with
COHORT STUDY: Am J Clin Dermatol 2019 Aug;20(4):579
Details
– based on retrospective cohort study

– 1,846 patients with SJS or TEN from Japanese national registry (2010-2014) treated with early
corticosteroids (≤ 2 mg/kg/day in 793 patients, > 2 mg/kg/day in 558 patients) or without early
corticosteroid treatment were evaluated for outcome and associated factors
– analyses based on propensity matching due to baseline differences between groups (332 pairs and
235 pairs for corticosteroid ≤ 2 mg/kg/day and corticosteroid > 2 mg/kg/day respective comparisons
vs. controls)
– treatment on day of or 1 day following admission defined as early treatment; patients not treated
with corticosteroids during this period were considered controls
– all-cause mortality for all patients 5% (3.3% for patients with SJS, 18.6% for patients with TEN)
– comparing early treatment with corticosteroid vs. propensity-matched controls (results confirmed
using inverse probability of treatment weighting)
● for dosing ≤ 2 mg/kg/day, all-cause, in-hospital mortality in 2.4% vs. 3.9% (relative risk [RR] 0.61,
95% CI 0.28-1.36)
● for dosing > 2 mg/kg/day, all-cause, in-hospital mortality in 4.3% vs. 5.1% (RR 0.83, 95% CI 0.37-
1.85)
– similar results seen with comparisons limited to high-dose (500 mg/day) corticosteroids vs. controls
or if early treatment definition expanded to up to 2 days following admission
– Reference - Am J Clin Dermatol 2019 Aug;20(4):579
STUDY
⚬ SUMMARY
supportive care and corticosteroids each associated with similar mortality rates in patients with
COHORT STUDY: J Am Acad Dermatol 2008 Jan;58(1):33
Details

– 281 patients from France and Germany with TEN or SJS treated with supportive care alone or
additional corticosteroids were compared
– overall mortality
● 25% with supportive care

● 18% with corticosteroids (odds ratio [OR] 0.4 [95% CI 0.1-1.7] in France and OR 0.3 [95% CI 0.1-
1.1] in Germany)
– Reference - EuroSCAR study (J Am Acad Dermatol 2008 Jan;58(1):33 )
STUDY
⚬ SUMMARY
dexamethasone IV reported to reduce mortality in patients with toxic epidermal necrolysis and
Severity of Illness Score for Toxic Epidermal Necrolysis (SCORTEN) score ≤ 3 DynaMed Level 3
CASE SERIES: J Dermatol 2016 Feb;43(2):156
Details
– based on case series

– 18 patients (mean age 49.7 years) with TEN treated with dexamethasone IV 1-1.5 mg/kg per day for
3-5 days, then changed to prednisolone orally 1 mg/kg per day and tapered as possible
– mean SCORTEN score of 2.2 (range 1-6, but no patient with SCORTEN 4) and mean body surface
area (BSA) of epidermal detachment on admission of 41% (range 30%-85%)
– duration of steroid treatment, mean 6.8 days (range 5-10 days)
– mortality outcomes
● death in 2 (11%) patients (both with SCORTEN ≥ 5)

● mortality in patients with SCORTEN 1-4 was 0% vs. 11% in patients with SCORTEN ≥ 5 (no p value
reported, but SCORTEN of 1-4 associated with predicted mortality of 3.2%-62.2%)
– Reference - J Dermatol 2016 Feb;43(2):156
Cyclosporine
● cyclosporine has been used for patients with SJS/TEN 2 , 5
⚬ dosing and duration of treatment varied in reported studies, but generally 3-5 mg/kg/day for several
days followed by tapering
⚬ adverse effects may include leukoencephalopathy, neutropenia, pneumonia, and nephropathy
EVIDENCE SYNOPSIS
Observational studies have shown some evidence of reduced mortality with cyclosporine in patients with
SJS/TEN, however these observational studies may have been limited by selection bias as some patients
treated with cyclosporine were younger and less ill than those in the comparison group. There are no
randomized trials evaluating cyclosporine in patients with SJS/TEN.
⚬ no randomized controlled trial evaluating cyclosporine for SJS/TEN identified in systematic review (J
Inflamm Res 2018;11:135 full-text )
STUDY
⚬ SUMMARY
cyclosporine associated with reduced mortality in patients with SJS/TEN DynaMed Level 2
SYSTEMATIC REVIEW: J Inflamm Res 2018;11:135 | Full Text
Details
– based on systematic review of observational studies

– systematic review of 12 observational studies evaluating cyclosporine for treatment of SJS/TEN in
358 patients
– cyclosporine associated with reduced mortality in meta-analysis of 9 studies with SCORTEN/

predicted mortality data in 255 patients
● standardized mortality ratio (SMR) 0.32 (95% CI 0.119-0.522)
● results limited by publication bias (p = 0.0467)
– Reference - J Inflamm Res 2018;11:135 full-text

– the most recent studies with > 25 patients or comparing cyclosporine to other treatments evaluated
in the above systematic review include
● cyclosporine associated with reduced mortality risk compared to supportive care in
patients with SJS/TEN
DynaMed Level 2
⚬ based on retrospective cohort study

⚬ 42 patients with SJS/TEN treated in Madrid between 2001 and 2015
⚬ 23 patients treated with cyclosporine at 1 hospital were compared to 19 patients treated
without cyclosporine at another hospital
⚬ no significant differences in baseline factors, including age, days ill prior to admission,
percentage of mucosal involvement, total body surface area involved, preexisting conditions,
or 24-hour SCORTEN values between treatment groups
⚬ mortality in 1 (4.3%) with cyclosporine vs. 6 (31.6%) with other treatment (mortality risk ratio
0.14, 95% CI 0.02-0.94)
⚬ Reference -J Invest Dermatol 2017 Oct;137(10):2092 full-text
● cyclosporine might be associated with lower mortality than supportive care in patients
with SJS/TEN
DynaMed Level 2
⚬ based on cohort study

⚬ 44 patients with SJS/TEN admitted between 2011 and 2014 were treated with cyclosporine or
supportive treatment only based on prespecified inclusion criteria
⚬ inclusion criteria to receive cyclosporine were age ≥ 18 years, admitted < 7 days from initial
blistering, and progressive disease
⚬ exclusion criteria not to receive cyclosporine included renal impairment, uncontrolled
hypertension, severe infection, active cancer, HIV, or pregnancy
⚬ cyclosporine dosing of 3 mg/kg/day enterally (by mouth or nasogastric tube) for 10 days, then
2 mg/kg/day for 10 days, then 1 mg/kg/day for 10 days
⚬ 24 patients treated with cyclosporine and 20 patients treated supportively without
immunomodulating medication
⚬ comparing cyclosporine vs. supportive treatment
– mean age 50 vs. 66 years (p = 0.009)

– comorbid cardiac disease 4% vs. 30% (p = 0.035)
– SCORTEN predicted deaths 7.2 vs. 6.9
– actual deaths 3 vs. 6
– standardized mortality ratio 0.42 (95% CI 0.09-1.22) vs. 1.02 (95% CI 0.37-2.21)
⚬ adjusted risk ratio for death with cyclosporine vs. supportive treatment 0.49 (95% CI 0.15-
1.61, p = 0.242)
⚬ Reference - J Am Acad Dermatol 2017 Jan;76(1):106
● cyclosporine associated with reduced mortality risk compared to predicted risk in

patients with SJS/TEN
DynaMed Level 2

⚬ 28 patients with SJS/TEN admitted between July 2014 and June 2015 were reviewed
⚬ 19 patients given cyclosporine 5 mg/kg/day in 3 divided doses for 10 days
⚬ 9 patients who were immunocompromised or had hypertension, elevated serum creatinine
or potassium, or malignancy had supportive treatment only
⚬ comparing cyclosporine vs. supportive treatment
– SCORTEN score 3.67 vs. 2.05 (p = 0.0008)

– SCORTEN predicted deaths 3.1 vs. 4.7
– actual deaths 1 vs. 5
– standardized mortality ratio 0.32 vs. 1.06
⚬ Reference - Indian J Dermatol Venereol Leprol 2017 May;83(3):312 full-text
STUDY
● SUMMARY
cyclosporine may be associated with lower mortality compared to IVIG in patients with SJS/TEN
DynaMed Level 2
COHORT STUDY: J Am Acad Dermatol 2014 Nov;71(5):941
Details

⚬ 52 patients with SJS/TEN treated with cyclosporine and/or IVIG were reviewed
⚬ 30% mortality reported with IVIG
– 11 of 37 patients (30%) treated with IVIG (including 2 patients also treated with cyclosporine) died
– standardized mortality ratio 1.43 compared to expected mortality of 21% based on SCORTEN score
⚬ 6% mortality reported with cyclosporine
– 1 of 17 patients (6%) treated with cyclosporine (including 2 patients also treated with IVIG) died
– standardized mortality ratio 0.42 compared to expected mortality of 14% based on SCORTEN score
⚬ Reference - J Am Acad Dermatol 2014 Nov;71(5):941
STUDY
● SUMMARY
cyclosporine may be associated with lower mortality compared to corticosteroids in patients with
COHORT STUDY: Indian J Dermatol Venereol Leprol 2013 Sep-Oct;79(5):686
Details
⚬ based on cohort study

⚬ 11 prospective patients (mean age 32 years), 5 with SJS, 3 with SJS/TEN, and 3 with TEN, were treated
with cyclosporine 3 mg/kg/day in 3 divided doses for 7 days and then tapered over 7 days
⚬ 6 retrospective patients (mean age 27 years), 3 with SJS, 1 with SJS/TEN, and 2 with TEN, were treated
with dexamethasone IV then oral prednisolone ≥ 1 mg/kg/day
⚬ all patients had < 3 on SCORTEN prognostic score
⚬ comparing cyclosporine vs. corticosteroids
– mean duration of reepithelialization 14 vs. 23 days (p = 0.01)

– mean hospital stay was 18 vs. 26 days (p = 0.026)
– death in 0 (1.1 predicted) vs. 2 (0.5 predicted) (p = 0.04)
⚬ Reference - Indian J Dermatol Venereol Leprol 2013 Sep-Oct;79(5):686
IVIG
● IVIG has been used to treat SJS/TEN, but efficacy is unclear and not well established 4
● European S1 guidelines on the use of high-dose IVIG in dermatology
⚬ consider high-dose IVIG for confirmed toxic epidermal necrolysis based on potential benefits
outweighing potential risks of IVIG
⚬ give IVIG as soon as toxic epidermal necrolysis diagnosed
⚬ give total dose of IVIG 3 g/kg in fractionated dosing over 3-5 days
⚬ Reference - J Dtsch Dermatol Ges 2017 Feb;15(2):228
● British guidelines for management of Stevens-Johnson syndrome/toxic epidermal necrolysis
⚬ insufficient evidence to support or refute benefit of IVIG for SJS/TEN in children or adults
⚬ give IVIG only with specialist input and in the context of a clinical study or a case registry
⚬ Reference - Br J Dermatol 2019 Jul;181(1):37 , Br J Dermatol 2016 Jun;174(6):1194
EVIDENCE SYNOPSIS
Observational studies have not found evidence of a consistent benefit or harm with the use of IVIG for
patients with SJS/TEN, but there are no randomized trials evaluating IVIG in these patients. There might be
benefit from use of IVIG as adjunctive therapy with steroid treatment.
⚬ no randomized trials evaluating IVIG for SJS/TEN identified in systematic reviews (JAMA Dermatol 2017
Jun 1;153(6):514 , Int J Dermatol 2015 Jan;54(1):108 , Br J Dermatol 2012 Aug;167(2):424 )
STUDY
⚬ SUMMARY
IVIG might not reduce mortality in patients with Stevens-Johnson syndrome or toxic epidermal
necrolysis DynaMed Level 2 ; uncertain if high-dose IV immunoglobulin may be associated with
reduced mortality in patients with Stevens-Johnson syndrome or toxic epidermal necrolysis
DynaMed Level 2
SYSTEMATIC REVIEW: JAMA Dermatol 2017 Jun 1;153(6):514 | Full Text

SYSTEMATIC REVIEW: Br J Dermatol 2012 Aug;167(2):424
SYSTEMATIC REVIEW: Int J Dermatol 2015 Jan;54(1):108
Details
– based on 3 systematic reviews of observational studies with wide confidence intervals that cannot
rule out benefit or harm
– systematic review of 96 studies evaluating systemic immunomodulating therapy for SJS/TEN in
3,248 patients
● overall, IVIGs included in 20.3% (glucocorticosteroids in 25.7%, no systemic immunomodulating
therapies in 34.1%, cyclosporine in < 5%, cyclophosphamide in < 5%, other treatments in < 15%)
● compared to supportive care, IVIG associated with no significant difference in mortality (odds
ratio [OR] 0.99, 95% CI 0.64-1.54) in analysis of 9 cohort studies with 380 patients (largest study,
the EuroSCAR study summarized below)
● similar results with patient level data in adjusted model
● largest study without comparison group reported 88% survival with IVIG for mean 4 days in 48
patients (summarized below)
● Reference - JAMA Dermatol 2017 Jun 1;153(6):514 full-text
– systematic review of 17 studies (cohort studies and case series) evaluating IVIG in 442 patients with
SJS or TEN
● studies varied in extent of disease and range of doses used
⚬ dose ranged from 0.5 g/kg (in children) to 2.8 g/kg

⚬ mean BSA affected by SJS/TEN ranged from 17% to 67%
● comparing IVIG to best supportive care, no significant difference in mortality (odds ratio 1, 95%
CI 0.58-1.75) in analysis of 6 comparative studies
● mean length of hospital stay 17.4 days (range 12.1-34.9 days)
● children had significantly shorter lengths of time from IVIG initiation to disease cessation and
skin healing, shorter hospital stay, and lower mortality rates compared to adults
● high-dose IVIG associated with lower mortality than low-dose IVIG in adults (19% vs. 50%), but
results not statistically significant after adjusting for other factors
● Reference - Br J Dermatol 2012 Aug;167(2):424
– systematic review of 13 observational studies reporting mortality rates in 391 patients with SJS/TEN
treated with IVIG
● SCORTEN scale used to estimate predicted mortality
● IVIG not associated with overall mortality difference compared to expected mortality
(standardized mortality ratio 0.814, 95% CI 0.617-1.076) in meta-analysis of 13 studies with 391
patients
● meta-regression analysis found strong inverse relationship between IVIG dose (using mean dose
per study) and standardized mortality ratio (results limited by possible publication bias)
● Reference - Int J Dermatol 2015 Jan;54(1):108 , comment can be found in Int J Dermatol 2017
Feb;56(2):e27
STUDY
⚬ SUMMARY
supportive care and IVIG each associated with similar mortality rates DynaMed Level 2
COHORT STUDY: J Am Acad Dermatol 2008 Jan;58(1):33
Details
– 281 patients from France and Germany with TEN or SJS treated with supportive care alone or
additional IVIG were compared
– overall mortality
● 25% with supportive care

● 25% with IVIG (odds ratio [OR] 1.4 [95% CI 0.5-3.7] in France and OR 1.5 [95% CI 0.5-4.4] in
Germany)
– Reference - EuroSCAR study (J Am Acad Dermatol 2008 Jan;58(1):33 )
STUDY
⚬ SUMMARY
IVIG reported to reduce skin and mucosal symptoms in < 3 days in patients with TEN
DynaMed Level 3
CASE SERIES: Arch Dermatol 2003 Jan;139(1):26
Details
– based on case series

– 48 patients with TEN (mean BSA 44.8%) received IVIG 0.8-5.8 g/kg (mean 2.7 g/kg) for 1-5 days
(mean 4 days)
– 90% had cessation of skin and mucosal detachment in mean 2.3 days
– 88% survived
– authors recommend early initiation with IVIG 1 g/kg/day for 3 days
– Reference - Arch Dermatol 2003 Jan;139(1):26
TNF Inhibitors
● TNF inhibitors (also known as TNF alpha antagonists) include etanercept, infliximab, and thalidomide 1 , 2 , 5
⚬ etanercept and infliximab have recently been used in some patients with SJS/TEN
⚬ thalidomide is not indicated as it increased mortality in a randomized trial of patients with SJS/TEN
STUDY
● SUMMARY
etanercept may speed skin healing in patients with SJS/TEN with > 10% body surface detachment and
might reduce mortality compared to steroids DynaMed Level 2
RANDOMIZED TRIAL: J Clin Invest 2018 Mar 1;128(3):985
Details
⚬ based on randomized trial without blinding and case series

⚬ 93 patients with Stevens-Johnson syndrome/toxic epidermal necrolysis randomized to etanercept 25 mg
(or 50 mg for weight > 65 kg) subcutaneously twice weekly vs. prednisolone 1-1.5 mg/kg/day IV until skin
healing
– 11 patients terminated inclusion in the study and 11 patients died
– outcome analyses performed with data from remaining 71 patients
– no significant difference in SCORTEN or predicted mortality between treatments
– comparing etanercept vs. prednisolone
● overall mortality 8.3% vs. 16.3% (not significant)

● in patients with ≥ 10% BSA detachment, median time to skin healing of 14 days vs. 19 days (p =
0.1)
● drug-related adverse effect of gastrointestinal bleeding in 2.6% vs. 18.2% (p = 0.03)
– compared to historical controls with mortality rate of 26%, etanercept associated with reduced
mortality (odds ratio 0.25, 95% CI 0.07-0.89)
⚬ Reference - J Clin Invest 2018 Mar 1;128(3):985 full-text
⚬ etanercept 50 mg as single subcutaneous injection reported effective in series of 10 patients (J Am Acad
Dermatol 2014 Aug;71(2):278 )
⚬ etanercept reported to induce rapid clearance of SJS in patient aged 11 years with SJS/TEN after recently
starting sulfamethoxazole-trimethoprim in case report (J Cutan Med Surg 2018 Sep/Oct;22(5):514 )
⚬ etanercept reported to not alter mortality, rates of infection, intubation, or vasopressor use in case
series of 13 patients with SJS/TEN treated with IVIG (Burns 2019 Nov;45(7):1634 )
STUDY
● SUMMARY
addition of infliximab to N-acetylcysteine (NAC) may not improve skin healing in patients with toxic
epidermal necrolysis DynaMed Level 2
RANDOMIZED TRIAL: Burns 2014 Dec;40(8):1707
Details
⚬ based on small randomized trial

⚬ 10 patients with TEN randomized to 1 dose of NAC 150mg/kg IV over 20 hours vs. 1 dose of NAC plus 1
dose of infliximab 5mg/kg IV
⚬ no significant difference in skin healing or an illness auxiliary score (IAS) of clinical severity between
treatments at 48 hours
⚬ Reference - Burns 2014 Dec;40(8):1707
● thalidomide associated with increased mortality in patients with SJS/TEN in a randomized trial (Lancet 1998
Nov 14;352(9140):1586 )
● review of TNF inhibitors for SJS/TEN can be found in J Dermatolog Treat 2019 Jan 31:1
Other Medications
● use of other medications reported in case series and case reports
⚬ granulocyte colony-stimulating factor in case report of 2 patients (Br J Dermatol 2010 Apr;162(4):860 )
⚬ IV pentoxifylline, NAC, and S-adenosyl-L-methionine (SAM) in case report (Br J Dermatol 1994
May;130(5):688 , noted in Br J Dermatol 1997 Apr;136(4):645 )
Combination Therapy
STUDY
● SUMMARY
addition of IVIG to corticosteroids might be associated with faster healing compared to corticosteroids
alone in patients with SJS/TEN DynaMed Level 2
SYSTEMATIC REVIEW: PLoS One 2016;11(11):e0167120 | Full Text
Details
⚬ based on systematic review of observational studies

⚬ systematic review of 26 observational studies evaluating corticosteroids and/or IVIG in 628 patients (age
range < 1 year old to 90 years old) with SJS/TEN
⚬ 15 studies reported parameters of healing (including time to arrest progression and hospitalization time)
for patients with SJS (4 studies), SJS/TEN (6 studies), or TEN (6 studies) (1 study reported on 2 groups)
treated with
– corticosteroids only in 317 patients
– corticosteroids plus IVIG in 311 patients
⚬ compared to corticosteroid alone, corticosteroid plus IVIG associated with
– reduced time to arrest progression (time until fever control, skin healing, and reepithelialization
begun) in meta-analysis of 12 studies
● 1.63 fewer days (95% CI 0.83-2.43 fewer days, p < 0.001) with combination vs. corticosteroid alone
● results limited by significant heterogeneity, and sensitivity analysis showed similar results for TEN
patients (vs. all patients), general population (vs. children), and Asian patients (vs. non-Asian)
– reduced hospitalization time of 3.19 fewer days (95% CI 0.08-6.3 fewer days, p = 0.045) in meta-
analysis of 14 studies (results limited by significant heterogeneity, and unreliable results after
sensitivity analysis)
⚬ impact of IVIG on actual mortality vs. expected mortality derived from SCORTEN analysis reported in 16
studies for patients with SJS/TEN (8 studies) or TEN (9 studies)
– treated with IVIG alone (effect size [ES] 0.96, 95% CI 0.69-1.35, not significant) in meta-analysis of 8
studies with 167 patients
– treated with IVIG plus corticosteroids (ES 0.74, 95% CI 0.51-1.08, not significant) in meta-analysis of 8
studies with 167 patients
– treated with IVIG alone or combined with corticosteroids (ES 32%, 95% CI 0.45-1.01, not significant) in
subgroup meta-analysis of 163 patients with TEN from 9 studies
⚬ analyses limited by potential publication bias
⚬ Reference - PLoS One 2016;11(11):e0167120 full-text
● etanercept 50 mg subcutaneously once plus IVIG 20 g for 3 days reported to induce rapid clearance of SJS in
patient aged 28 years with SJS after recently starting lamotrigine and sodium valproate, in case report
(Dermatol Ther 2019 Jul;32(4):e12832 )
Treatment of Skin Lesions
● goal of supportive care of skin lesions in patients with Stevens-Johnson syndrome (SJS)/toxic epidermal
necrolysis (TEN) includes reducing epidermal detachment and reducing risk of infection 1
⚬ monitor for infection with swabs form sloughed areas of lesional skin every other day
– take swabs from 3 areas of lesional skin

– send swabs for bacterial and candidal culture
⚬ institute systemic antibiotics only if there are clinical signs of infection (the choice of systemic antibiotic
should be guided by local microbiological advice)
● consider supportive management, including all of the following (BAD Grade D, Level 4) 1
⚬ use warm sterile water, saline, or antimicrobial, such as chlorhexidine (1/5000), to irrigate and cleanse
skin
⚬ use greasy emollient, such as 50% white soft paraffin with 50% liquid paraffin, over entire skin surface
(aerosol application may reduce shearing force of topical applications)
⚬ use topical antimicrobial agent on sloughy areas
– choice of agent based on local microbiological patterns

– consider silver-containing products or dressings, but to reduce risk of absorption, limit use of silver-
containing products if extensive areas involved
⚬ leave detached, lesional epidermis in place to act as biological covering
⚬ consider decompressing blisters with piercing and expression of fluid
⚬ use nonadherent dressings on denuded dermis
⚬ secondary foam or burn dressing may be used to absorb exudate
● for patients with TEN (> 30% BSA epidermal loss) and worsening epidermal detachment, or signs of
infection or delayed healing (BAD Grade D, Level 4) 1

⚬ transfer to burn center if possible
⚬ consider surgical management options, such as
– removal of necrotic/loose infected epidermis and cleansing of wounds under general anesthesia
– debridement with hydrosurgery (Versajet)
– closure of wounds with allograft, xenograft, or biosynthetic dressing (Biobrane)
Treatment of Ocular Manifestations
● ocular management in Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) should include all
of the following (BAD Grade D, Level 4) 1

⚬ ocular hygiene, such as removal of inflammatory debris or conjunctival adhesions, by ophthalmology
specialist
⚬ application of lubricating ointment (such as nonpreserved hyaluronate or carmellose eye drops) every 2
hours
⚬ broad-spectrum topical antibiotics to prevent infection if corneal fluorescein staining or frank ulceration,
when microbial keratitis excluded
⚬ if corneal infection suspected, use culture-guided antibiotics and/or antifungal treatment
⚬ topical steroid drops (such as nonpreserved dexamethasone 0.1%) to control inflammation
⚬ for unconscious patients, prevent corneal exposure with moisture chamber of polyethylene film and
paper tape on eyelid skin to affix chamber
● consider amniotic membrane transplantation for patients with severe ocular surface epithelial loss
refractory to conservative treatment and inability to undergo ocular hygiene without general anesthesia
(BAD Grade D, Level 3) 1
STUDY
● SUMMARY
amniotic membrane transplantation may reduce long-term complications of acute ocular Stevens-
Johnson syndrome DynaMed Level 2
RANDOMIZED TRIAL: Ophthalmology 2016 Mar;123(3):484
Details
⚬ based on small randomized trial and 2 case series
⚬ 25 patients with acute ocular Stevens-Johnson had eyes randomized to amniotic membrane
transplantation plus usual medical care vs. usual medical care alone with follow-up for 6 months
– comparing amniotic membrane transplantation plus usual medical care vs. usual medical care alone
at 6 months
● best corrected visual acuity (BCVA) 0.068 logMAR units vs. 0.522 logMAR units (p < 0.042)
● tear film breakup time 9.92 seconds vs. 6.96 seconds (p < 0.015)
● mean Schirmer test 15.4 mm vs. 8.64 mm (p < 0.001)
● conjunctival congestion in 4% vs. 44% (p = 0.03, NNT 3)
● corneal haze in 0% vs. 44% (p = 0.001, NNT 3)
⚬ Reference - Ophthalmology 2016 Mar;123(3):484

⚬ in 5 patients with 9 eyes treated with amniotic membrane transplantation for acute TEN, reported
results included reduced inflammation and ocular surface scarring, improved dry eye, and limited ocular
sequelae at 1 year (1 eye had mild symblepharon) (Eur J Ophthalmol 2014 Sep-Oct;24(5):667 )
⚬ transplantation of cryopreserved amniotic membrane for conjunctival reconstruction described in series
of 6 case reports in patients with acute SJS/TEN and 2 case series in chronic SJS/TEN (Surv Ophthalmol
2009 Nov-Dec;54(6):686 full-text )
STUDY
● SUMMARY
systemic immunomodulatory therapy may not affect risk for chronic ocular complications in patients
with SJS/TEN DynaMed Level 2
COHORT STUDY: Ophthalmology 2015 Feb;122(2):254
Details
⚬ based on small retrospective cohort study with inadequate sample size to exclude clinically relevant
differences
⚬ 43 patients admitted to 1 of 3 university hospitals in Korea for STS or TEN were followed for ≥ 6 months
(mean 29 months)
⚬ systemic immunomodulatory treatment received categorized into 5 groups: supportive care only,
systemic steroids alone, systemic pulse steroids, IV immune globulin (IVIG), or combination steroids plus
IVIG
⚬ therapy received not associated with chronic ocular surface complications score or best corrected visual
acuity at final follow-up
⚬ Reference - Ophthalmology 2015 Feb;122(2):254
Treatment of Mucosal Involvement
● management of mouth involvement in Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN)
should include all of the following (BAD Grade D, Level 4) 1

⚬ daily review of oral symptoms
⚬ use of white soft paraffin ointment to lips every 2 hours
⚬ mucoprotectant mouthwash (such as polyvinylpyrrolidone-sodium hyaluronate gel [Gelclair]) 3 times
daily
⚬ cleansing with warm saline mouthwashes or oral sponge
⚬ for mouth pain
– anti-inflammatory oral rinse or spray with benzydamine hydrochloride every 3 hours

– for severe mouth pain, consider viscous lidocaine 2% or cocaine mouthwashes 2%-5%
⚬ antiseptic oral rinse, such as 1.5% hydrogen peroxide 10 mL twice daily or 0.2% chlorhexidine
digluconate mouthwash 10 mL twice daily
⚬ if local infection suspected, obtain oral and lip swabs for bacterial or candidal culture and consider
secondary infection or reactivation of herpes simplex virus
⚬ consider corticosteroid topically; options include
– betamethasone sodium phosphate 0.5 mg in 10 mL water as a 3-minute rinse-and-spit preparation

– clobetasol propionate 0.05%, mixed in equal amounts with 20% benzocaine applied daily
● management of urogenital involvement in SJS/TEN should include all of the following (BAD Grade D, Level
4) 1
⚬ consider consult and exam by vulval specialist for women with SJS/TEN
⚬ daily review of urogenital symptoms
⚬ use of white soft paraffin ointment to urogenital skin and mucosae every 4 hours
⚬ for eroded areas of vulva and vagina, use porous, semitransparent, low-adherent wound contact layer
dressings (such as Mepitel) to prevent adhesions, including dressing-wrapped tampon or dilator in
vagina to prevent synechiae
⚬ consider topical corticosteroid ointment applied once daily to involved but noneroded areas
⚬ urinary catheter to prevent urethral strictures
Other Management
Plasmapheresis
STUDY
● SUMMARY
role of therapeutic plasma exchange (TPE) not established for refractory toxic epidermal necrolysis
(ASFA Category III, Grade 2B)
SYSTEMATIC REVIEW: J Clin Apher 2013 Jul;28(3):145
Details
⚬ based on systematic review of 11 case series (with 83 patients) and 2 case reports (with 2 patients)
⚬ suggested approach to TPE is 1-1.5 total plasma volumes (TPV) using plasma and albumin as
replacement fluids daily or every other day for 1 to > 5 procedures, discontinuation has been guided by
clinical improvement (most frequently skin healing and reepithelialization)
⚬ Reference - American Society for Apheresis (ASFA) guideline on use of therapeutic apheresis in clinical
practice (J Clin Apher 2013 Jul;28(3):145 )
STUDY
● SUMMARY
plasmapheresis associated with improvements in disease severity and increased rate of recovery in
patients with SJS/TEN overlap or TEN DynaMed Level 2
COHORT STUDY: J Crit Care 2017 Dec;42:65
Details
⚬ based on prospective cohort study
⚬ 28 patients with SJS/TEN overlap or TEN treated with or without plasmapheresis were evaluated for
severity of illness at 1, 4, 7, 10, and 20 days following admission and for speed of disease resolution
⚬ a novel 40 point severity of illness score (SIS40) used to grade changes in disease severity (higher score
corresponds to greater severity); recovery velocity index (RVI) used to evaluate speed of TEN resolution
calculated as difference in severity of illness score between discharge and admission divided by length
of hospital stay (higher score corresponds to faster resolution)
⚬ comparing plasmapheresis vs. no plasmapheresis
– SIS40 score of 12 vs. 19 on day 7 (p < 0.05)

– SIS40 score of 6.5 vs. 26 on day 10 (p < 0.001)
– SIS40 score of 2.63 vs. 20 on day 20 (p < 0.001)
– mean reduction in SIS40 score of 28.2 vs. 12.5 (p < 0.001)
– RVI of 2.49 vs. 0.88 (p < 0.001)
⚬ adverse events were not reported

⚬ Reference - J Crit Care 2017 Dec;42:65
STUDY
● SUMMARY
plasmapheresis plus cyclosporine reported to improve survival for patients with severe TEN
DynaMed Level 3
CASE SERIES: Plast Reconstr Surg Glob Open 2017 Feb;5(2):e1221 | Full Text
Details
⚬ based on case series

⚬ 12 patients with severe TEN treated between 2005 and 2015 with addition of plasmapheresis and
cyclosporine A to other supportive treatments were reviewed
– mean body surface area affected 77%
– mean SCORTEN 4.3, with predicted mortality 58.3%
⚬ plasmapheresis given every other day for total 7 cycles and cyclosporine 250 mg/day (4 mg/kg/day for
pediatric patients) IV given for 15 days
⚬ mortality in 1 patient (8.3%)
⚬ time to response (defined as halting of skin sloughing as determined by negative Nikolsky sign) of mean
4.9 days (range 4-6 days)
⚬ time to complete reepithelialization of mean 22 days (range 16-32 days)
⚬ Reference - Plast Reconstr Surg Glob Open 2017 Feb;5(2):e1221 full-text
Follow-up
● follow-up patients to screen for potential sequelae, including
⚬ ophthalmologic exam for dry eye, adhesions, symblepharon

⚬ buccal and dental exams
⚬ pulmonary exam and respiratory function testing
⚬ ear, nose, throat (ENT) exam
⚬ for women, gynecologic exam to evaluate for synechia and vulvovaginal dryness
⚬ psychiatric evaluation for posttraumatic stress disorder
⚬ Reference - Orphanet J Rare Dis 2018 Apr 10;13(1):56 full-text
● for patients with unknown culprit drug 1
⚬ routine drug hypersensitivity testing not recommended (BAD Grade D, Level 4)

⚬ consider formal drug hypersensitivity if avoidance of suspected medication may be detrimental or if
accidental exposure possible (BAD Grade D, Level 4)
⚬ testing for immunoglobulin E (IgE)-mediated immediate reactions, such as skin-prick testing and specific
IgE testing are not helpful, as mechanism of SJS/TEN appears to be delayed type IV hypersensitivity
reactions
⚬ in vitro testing with lymphocyte drug-induced interferon-γ (IFN-γ) assays may be helpful in determining
culprit drugs
● consider discharge instructions, including the following (BAD Grade D, Level 4) 1
⚬ provide patient with information about culprit drug and clear instruction to avoid culprit drug
⚬ advise MedicAlert bracelet
Complications
● acutely, the skin loss of Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) may lead to 5
⚬ fluid loss
⚬ dysphagia, which may result from esophageal manifestations including ulcerations, blistering, and
strictures
⚬ bacteremia
⚬ sepsis from increased susceptibility to skin infections
⚬ renal failure
⚬ pneumonia
⚬ acute respiratory failure
⚬ hepatitis
⚬ multiple organ failure
⚬ death
⚬ Reference - Dent Clin North Am 2005 Jan;49(1):67
STUDY
● SUMMARY
low hemoglobin, presence of cardiovascular disease, and involved body surface area > 10% may increase
risk of bacteremia in patients with SJS and TEN
COHORT STUDY: J Am Acad Dermatol 2019 Sep;81(3):686
Details

⚬ 176 patients with SJS (59 patients), SJS/TEN (51 patients), or TEN (66 patients) evaluated for bacteremia
and associated factors
⚬ overall mortality 23.9%
⚬ bacteremia in 52 (29%) and associated with worse outcomes (increased mortality, dialysis, mechanical
ventilation)
⚬ factors on admission associated with bacteremia in multivariate analysis included
– hemoglobin ≤ 10 g/dL (odds ratio [OR] 2.4, 95% CI 2.2-2.6)

– cardiovascular disease (OR 2.1, 95% CI 2-2.3)
– involved body surface area ≥ 10% (OR 14.3, 95% CI 13.4-15.2)
⚬ bacteremia risk score (BRS) derived from analysis
– hemoglobin ≤ 10 g/dL, scored as +1, cardiovascular disease, scored at +1, involved body surface area
≥ 10%, scored as +4
– risk categories that predict probability of bacteremia based on BRS score
● BRS 0-1: low risk, 3.1% probability of bacteremia

● BRS 2-4: moderate risk, 31.4% probability of bacteremia
● BRS 5: high risk, 52.4% probability of bacteremia
● BRS 6: very high risk, 71.6% probability of bacteremia
⚬ Reference - J Am Acad Dermatol 2019 Sep;81(3):686
STUDY
● SUMMARY
ocular involvement common in Stevens-Johnson syndrome and toxic epidermal necrolysis
COHORT STUDY: Arch Dermatol 2009 Feb;145(2):157
Details
⚬ based on retrospective cohort of 159 patients (mean age 50 years) with SJS or toxic epidermal necrolysis
⚬ 74% had acute ocular involvement (most commonly dry eye syndrome)
– 58% mild
– 8% moderate
– 8% severe
⚬ Reference - Arch Dermatol 2009 Feb;145(2):157
● long-term sequelae appear to develop in many patients with SJS/TEN (see Long-term sequelae in Prognosis)
Prognosis
SCORTEN Prognostic Score
● severity of illness score for toxic epidermal necrolysis (SCORTEN) 2 , 4
⚬ developed to assess illness severity and predict mortality risk in patients with toxic epidermal necrolysis
(TEN)
– scoring within 24 hours of admission and again on day 3 of hospitalization reported to optimize
usefulness
– mortality risk may be underestimated in patients with respiratory involvement
⚬ see DynaMed calculator for SCORTEN prediction of mortality

⚬ score range 0-7 points with increasing score associated with higher mortality risk
Table 2. SCORTEN Criteria (Range 0-7 Points)
Variable Point Value if Present
Variable Point Value if Present
Age > 40 years 1 point
Heart rate > 120 beats/minute 1 point
Comorbid malignancy 1 point
Epidermal detachment > 10% of body 1 point

surface are on day 1
Blood urea nitrogen > 28 mg/dL 1 point
Glucose > 252 mg/dL 1 point
Bicarbonate < 20 mEq/L 1 point
STUDY
● SUMMARY
SCORTEN prognostic score may predict mortality in patients with Stevens-Johnson syndrome
(SJS)/toxic epidermal necrolysis (TEN) DynaMed Level 2
PREDICTION RULE: J Invest Dermatol 2000 Aug;115(2):149 | Full Text
Details
⚬ based on prognostic cohort study with small validation cohort

⚬ derivation cohort included 165 patients (mean age 42 years) admitted to dermatology intensive care and
validation cohort included 75 similar patients (mean age 46 years)
– in derivation cohort, SJS in 16.3%, SJS/TEN in 41.8% and TEN in 41.8%
– in validation cohort, SJS in 45.3%, SJS/TEN in 21.3% and TEN in 33.3%
⚬ mortality 26.7% in derivation cohort and 20% in validation cohort

⚬ SCORTEN prognostic score derived with 1 point assigned for each of 7 factors significantly associated
with mortality in derivation cohort (total score 0-7 points)
– age > 40 years
– malignancy
– tachycardia (> 120 beats/minutes)
– initial surface of epidermal detachment > 10% total body surface area (BSA)
– serum urea nitrogen > 10 mmol/L (28 mg/dL)
– serum glucose > 14 mmol/L (252 mg/dL)
– bicarbonate < 20 mmol/L (20 mEq/L)
Table 3. Mortality by SCORTEN Score in Validation Cohort

SCORTEN Score Predicted Observed Mortality in Validation

Mortality Cohort
0-1 < 10% 2.6% of 38 patients
2 10% to < 20% 17.6% of 17 patients
3 20% to < 40% 0% of 7 patients
4 40% to < 60% 71% of 7 patients
≥5 ≥ 60% 100% of 6 patients
Abbreviation: SCORTEN, Severity-of-Illness

Score for Toxic Epidermal Necrolysis.
⚬ precision of mortality data in validation cohort was limited by small sample size, with very small
numbers of patients with scores ≥ 3 points (95% CIs not reported)
⚬ Reference - J Invest Dermatol 2000 Aug;115(2):149 full-text
STUDY
● SUMMARY
ABCD-10 score might help predict in-hospital mortality in patients with SJS/TEN, with performance
similar to SCORTEN prognostic score DynaMed Level 2
PREDICTION RULE: JAMA Dermatol 2019 Apr 1;155(4):448 | Full Text
Details
⚬ based on retrospective prognostic cohort study without independent validation

⚬ 370 adults (mean age 49 years) with confirmed SJS/TEN from 2000 to 2015 in 18 hospitals in United
States were assessed
⚬ median epidermal detachment was 15.5% of BSA
⚬ in-hospital mortality 15.1%
⚬ 98% had complete data and were included in model derivation
⚬ ABCD-10 score derived using 5 factors significantly associated with in-hospital mortality in derivation
cohort (total score 0-8 points)
– 3 points for dialysis prior to admission
– 2 points for presence of active cancer
– 1 point each for
● age ≥ 50 years
● epidermal detachment ≥ 10% of BSA
● serum bicarbonate level < 20 mmol/L
⚬ in-hospital mortality 15.14% overall

⚬ predicted in-hospital mortality by ABCD-10 prognostic score (observed rates by score not reported)
– 2.3% for 0 points

– 5.4% for 1 point
⚬ ABCD-10 score had strong discrimination for predicting higher vs. lower risk of in-hospital death at
admission and at 48 hours (c-statistic 0.82 for each) and good calibration of absolute risk
⚬ no significant differences in discrimination comparing ABCD-10 score vs. SCORTEN prognostic score
⚬ Reference - JAMA Dermatol 2019 Apr 1;155(4):448 full-text
Mortality
EVIDENCE SYNOPSIS
Mortality rates for Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are reported to
range between 0% and 9% for SJS, between 3.9% and 19.4% for SJS\TEN, and 15% and 23% for TEN.
STUDY
⚬ SUMMARY
annual age- and sex-adjusted in-hospital mortality of 4.8% for SJS, 19.4% for SJS/TEN, and 14.8%
for TEN
Details
– based on cross-sectional study of 3,657 adult patients with SJS, SJS-TEN, or TEN between 2009 and
2012 identified from Nationwide Inpatient Sample (NIS) database (overall database included
23,009,584 hospital discharges)
– annual age- and sex-adjusted in-hospital mortality of 4.8% for SJS, 19.4% for SJS/TEN, and 14.8% for
TEN
– increased risk of mortality associated with
● increasing age: compared with patients aged < 39 years
⚬ patients aged 60-79 years (adjusted odds ratio [OR] 2.51, 95% CI 1.9-3.25)
⚬ patients aged > 80 years (adjusted OR 2.6, 95% CI 1.92-3.42)
● tuberculosis (adjusted OR 10.12, 95% CI 6.09-16.84)

● septicemia (adjusted OR 7.8, 95% CI 6.85-8.85)
● non-Hodgkin lymphoma (adjusted OR 5.25, 95% CI 2.15-11.02), or leukemia (adjusted OR 2.19,
95% CI 1.6-3.02)
● renal failure (adjusted OR 3.92, 95% CI 3.47-4.44)
● pneumonia (adjusted OR 1.57, 95% CI 1.38-1.8)
– Reference - J Invest Dermatol 2016 Jul;136(7):1387 full-text
STUDY
⚬ SUMMARY
in pediatric patients, mortality reported as 0% for SJS, 3.9% for SJS/TEN, and 15.1% for TEN
CROSS-SECTIONAL STUDY: J Am Acad Dermatol 2017 May;76(5):811 | Full Text
Details
– based on cross-sectional study of 1,959 pediatric patients with SJS, SJS-TEN, or TEN between 2009
and 2012 identified from NIS database
– exclusions included newborns, patients hospitalized for < 3 days, patients with erythema
multiforme major, herpes simplex virus infection, Kawasaki disease, and Mycoplasma pneumoniae
infection
– mortality in 0% for SJS, 3.9% for SJS/TEN, and 15.1% for TEN
– increased risk of mortality associated with renal failure, malignancy, septicemia, any bacterial
infection, and epilepsy (p < 0.0001 for all associations)
– Reference - J Am Acad Dermatol 2017 May;76(5):811 full-text
STUDY
⚬ SUMMARY
mortality reported about 9% for patients with first episode of SJS and 23% for patients with TEN
COHORT STUDY: JAMA 2014 Jun 4;311(21):2231
Details
– based on cohort study

– 708 patients hospitalized with first episode of Stevens-Johnson syndrome (80%) or toxic epidermal
necrolysis (20%) were followed for up to 10 years
– patients included 127 children < 18 years old
– median age of 666 patients with no recurrence was 53 years and 42 years for 42 patients with
disease recurrence (p = 0.03)
– 60-day mortality was 30% (17.9% in-hospital, 7.6% within 60 days of discharge); 60-day mortality by
condition
● 23.4% in patients with toxic epidermal necrolysis
● 9% in patients with Stevens-Johnson syndrome
– 581 surviving patients were followed for median 1,283 days

– hospitalization for recurrence of Stevens-Johnson syndrome or toxic epidermal necrolysis in 7.2%
for 1 episode and 1.4% for ≥ 2 episodes
– male sex associated with increased risk of recurrence
– Reference - JAMA 2014 Jun 4;311(21):2231 , commentary can be found in JAMA 2014 Oct
15;312(15):1590
EVIDENCE SYNOPSIS
The early withdrawal of the causative drug of SJS/TEN is associated with lower mortality, and overall
mortality rates for SJS/TEN appear to be decreasing over past 20 years.
STUDY
⚬ SUMMARY
early withdrawal of causative drug associated with lower mortality
COHORT STUDY: Arch Dermatol 2000 Mar;136(3):323
Details
– based on retrospective cohort study of 113 patients admitted to hospital with TEN (74 patients) or
Stevens-Johnson syndrome (39 patients)
– 65% (74) patients had TEN and 34.5% (39) had SJS
– drug causing TEN or SJS withdrawn early in 57% (64) patients vs. late in 43% (49) patients
– 18% overall mortality: 11% for patients with early drug withdrawal, 27% for patients without
– earlier withdrawal associated with improved prognosis (adjusted odds ratio 0.69 for each day, 95%
CI 0.53-0.89)
– drugs with long half-lives associated with increased mortality (adjusted odds ratio 4.9, 95% CI 1.3-
18.9)
– Reference - Arch Dermatol 2000 Mar;136(3):323 , editorial can be found in Arch Dermatol 2000
Mar;136(3):410
STUDY
⚬ SUMMARY
mortality from SJS/TEN reported to be decreasing over time
COHORT STUDY: Br J Dermatol 2019 Jul 19:10.1111/bjd.18360
Details
– based on retrospective cohort study of 361 patients treated from 1997 to 2017
– 361 patients (median age 46 [interquartile range 31-62] years) with SJS (38%), SJS-TEN overlap (22%),
or TEN (40%) evaluated for mortality and related factors for up to 1 year after condition onset
– median baseline SCORTEN was 2 (26 patients had incomplete data on final detached body surface
area and no reported condition diagnosis)
– overall mortality 18%; for SJS mortality was 2%, for SJS/TEN overlap mortality was 12%, and for TEN
mortality was 26%
– regression and multivariate analysis indicated significant decrease in mortality over time (p < 0.05)
● introduction of cyclosporine not supported as factor responsible for mortality decrease in

separate propensity study (J Invest Dermatol 2018 Jun;138(6):1293 full-text )
● improvement in supportive care suggested by authors as responsible for decrease in mortality
over time
– Reference - Br J Dermatol 2019 Jul 19:10.1111/bjd.18360
EVIDENCE SYNOPSIS
Medical comorbidities, older age, and bacteremia or mechanical ventilation are associated with increased
risks for mortality from SJS/TEN.
STUDY
⚬ SUMMARY
bacteremia associated with poor prognosis in patients with SJS and TEN
COHORT STUDY: J Am Acad Dermatol 2019 Sep;81(3):686
Details

– 176 patients with SJS (59 patients), SJS/TEN (51 patients), or TEN (66 patients) evaluated for
bacteremia and associated factors
– overall mortality 23.9%
– bacteremia in 52 (29.5%)
– bacteremia associated with
● increased mortality (odds ratio [OR] 4.4, 95% CI 2.1-9.1)

● hemoglobin ≤ 10 g/dL (OR 2.4, 95% CI 2.2-2.6)
● increased admission to intensive care (OR 6.8, 95% CI 3.1-15)
● dialysis required (OR 18.3, 95% CI 3.9-85.3)
● mechanical ventilation required (OR 6.6, 95% CI 2.3-18.4)
– Reference - J Am Acad Dermatol 2019 Sep;81(3):686
STUDY
⚬ SUMMARY
need for mechanical ventilation treatment associated with increased cutaneous disease severity and
poor outcomes in patients with SJS/TEN
COHORT STUDY: Crit Care Med 2014 Jan;42(1):118
Details

– 221 adults with SJS, SJS/TEN, or TEN evaluated for factors associated with mechanical ventilation
treatment and outcome
– 25.3% (56 patients) were treated with mechanical ventilation for acute respiratory failure, shock,
coma, and/or cardiac arrest or general anesthesia
– outcomes comparing 56 patients requiring mechanical ventilation vs. 165 nonventilated patients
● mortality 57.1% vs. none (p < 0.0001)

● cutaneous disease severity (p < 0.0001)
⚬ SJS 1.8% vs. 36.9%

⚬ SJS/TEN 14.3% vs. 37.5%
⚬ TEN 83.9% vs. 24.8%
● renal replacement therapy 37.5% vs. none (p < 0.0001)
● pneumonia 58.9% vs. 10.9% (p < 0.0001)

● bacteremia 58.9% vs. 23% (p < 0.001)
– factors at admission associated with requirement for mechanical ventilation treatment
● detached body surface area (BSA) affected
⚬ 10% to 29% (odds ratio [OR] 3.7, 95% CI 1-13.8), compared to < 10% BSA
⚬ ≥ 30% (OR 19.7, 95% CI 4.4-87.4), compared to < 10% BSA
● serum bicarbonates < 20 mmol/L (OR 4.9, 95% CI 1.1-22.7)

● serum urea > 10 mmol/L (OR 7, 95% CI 2.2-22.8)
● white blood cell count (WBC) > 12,000 / mm3 (OR 11.6, 95% CI 2.8-48.1)
● hemoglobin < 8 g/dL (OR 8.1, 95% CI 1.2-55.2)
● pulmonary infiltrates on chest x-ray (OR 9.7, 95% CI 3.6-25.9)
– Reference - Crit Care Med 2014 Jan;42(1):118
STUDY
⚬ SUMMARY
serious comorbidity or older age but not skin disease severity associated with mortality 90 days
after condition onset in patients with SJS/TEN
COHORT STUDY: J Invest Dermatol 2013 May;133(5):1197 | Full Text
Details
– based on retrospective cohort study of patients in RegiSCAR registry and enrolled from Jan 2003 to
March 2007 with SJS/TEN
– 460 patients with SJS (50%), SJS-TEN overlap (35%), or TEN (15%) evaluated for mortality and related
factors followed for up to 1 year after condition onset
– all-cause mortality
● 104 (23%) deaths by day 42 (12% with SJS, 29% with SJS/TEN, 46% with TEN); significantly
associated with severity of skin disease and severe liver or kidney disorder
● between 42 and 90 days, additional 18 deaths, yielding 90-day mortality rate of 28% (individual
condition values not reported at 90 days); significantly associated with severity of skin disease,
severe liver disorder, and recent malignancy or infection
● between 90 and 365 days, additional 27 deaths, yielding 1-year mortality rate of 34% (24% with
SJS, 43% with SJS/TEN, 49% with TEN); significantly associated with severe liver disorder and
recent malignancy
– identification of culprit drug associated with reduced mortality hazard ratio 0.66 (95% CI 0.45-0.96)
– Reference - J Invest Dermatol 2013 May;133(5):1197 full-text
Long-term Sequelae
● long-term, chronic sequelae of skin, eyes, gastrointestinal tract, kidneys, pulmonary tract, urogenital region,
other mucosal sites, and psychosocial sequelae appear frequently in survivors of Stevens-Johnson
syndrome (SJS)/toxic epidermal necrolysis (TEN)
⚬ common cutaneous sequelae include
– postinflammatory dyspigmentation, reported in 14%-100%
– nail changes in up to 50%

– abnormal scarring, in 10%-40%
– eruptive nevi, in up to 20%
⚬ chronic ocular sequelae may affect 20%-75%, and may result in changes to vision, leading to markedly
reduced quality of life
⚬ common ocular sequelae include
– chronic photosensitivity, decreased visual acuity, lacrimal duct obstruction, and dry eyes
– ectropion, entropion, trichiasis, distichiasis, or lagophthalmos of the lids
– persistent hyperemia, symblepharon, ankyloblepharon, or forniceal shortening of the conjunctiva
– superficial punctate keratopathy, loss of palisades of Vogt, epithelial defects, corneal scarring,
neovascularization, keratinization, infectious keratitis, or corneal thinning of the cornea
⚬ oral and dental sequelae may include
– synechiae formation at the angle of lips, between the tongue and the floor of the mouth, and
between gingival surfaces and adjacent structures
– chronic ulcers
– depapillation of the tongue
– Sjögren-like sicca syndrome
– dental growth abnormalities in children
⚬ urogenital sequelae may include adhesions of the urethra or vagina

⚬ late pulmonary sequelae may include interstitial lung disease, respiratory tract obstruction,
bronchiectasis, bronchitis, and bronchiolitis obliterans
⚬ the most common gastrointestinal chronic complication reported is esophageal stricture
⚬ less common gastrointestinal sequelae include intestinal ulceration (may be associated with diarrhea
and malabsorption) and vanishing bile duct syndrome (loss of > 50% of interlobular vile ducts)
⚬ chronic renal insufficiency reported in about 20%
⚬ long-term psychiatric sequelae poorly researched, but may include fear of medications and
posttraumatic stress disorder
⚬ Reference - Br J Dermatol 2017 Oct;177(4):924
STUDY
● SUMMARY
long-term sequelae may develop in 47% of children with SJS/TEN
COHORT STUDY: Pediatrics 2011 Oct;128(4):723
Details
⚬ based on retrospective cohort study of 55 children (mean age 10 years) with SJS, TEN, or SJS/TEN overlap
syndrome diagnosed from 2000 to 2007
⚬ mortality 2% (1 child)
⚬ long-term sequelae (primarily involving skin and eyes) in 47%
– long-term skin sequelae (hypopigmentation, scarring) in 45%

– long-term ocular sequelae (uveitis, keratitis, corneal defects, chronic conjunctivitis) in 42%
⚬ recurrence of SJS following index episode in 18% (multiple recurrence in 5%)

⚬ Reference - Pediatrics 2011 Oct;128(4):723
EVIDENCE SYNOPSIS
Clinical factors that may be associated with higher risk for ocular sequelae may include younger age,
nonsteroidal anti-inflammatory drugs (NSAIDs) or cold remedies as culprit drug, and darker skin
phototype.
STUDY
⚬ SUMMARY
younger age and cold remedies as culprit drug may be associated with worse ocular symptoms in
patients with SJS/TEN DynaMed Level 2
COHORT STUDY: Am J Ophthalmol 2015 Aug;160(2):228
Details

– 87 patients diagnosed with SJS and 48 patients diagnosed with TEN between January 2005 and
December 2007 were evaluated for factors associated with ocular symptom severity
– ocular involvement graded as follows
● no ocular involvement, grade 0

● conjunctival hyperemia, grade 1 (mild)
● either ocular surface epithelial defect or pseudomembrane formation, grade 2 (severe)
● both ocular surface epithelial defect and pseudomembrane formation, grade 3 (very severe)
– no ocular involvement in 19 (21.8%) patients with SJS and in 12 (25%) patients with TEN
– greater severity of ocular involvement associated with
● younger age (odds ratio [OR] 0.98, 95% CI 0.96-0.99)

● cold remedies or NSAIDs as culprit drug (OR 2.58, 95% CI 1.26-5.29)
– severity of ocular involvement was not associated with systemic severity scoring, sex, antibiotics as
culprit drugs, or anticonvulsants as culprit drugs
– Reference - Am J Ophthalmol 2015 Aug;160(2):228
STUDY
⚬ SUMMARY
darker skin phototypes associated with higher frequency of long-term ocular sequelae in patients
with SJS/TEN DynaMed Level 2
COHORT STUDY: Br J Dermatol 2019 Jul;181(1):212
Details

– 69 patients (median age 45 years, range 17-79 years) with SJS/TEN and late ocular complications
who were seen at the ophthalmology department for specific scleral contact lenses between 2003
and 2016 were reviewed
● Fitzpatrick skin phototype I-IV (encompassing pale skin that always burns to light skin that always
tans, never burns) in 46 (67%)
● Fitzpatrick skin phototype V-VI (encompassing skin with light to dark pigmentation) in 23 (33%)
– median time from acute SJS/TEN to need for specific scleral contact lens was 6 years (range 6
months to 44 years)
– comparing ocular sequelae in skin phototype I-IV vs. V-VI
● visual acuity ≤ 20/200 in worst eye in 50% vs. 78% (p = 0.037)

● symblepharons and trichiasis/distichiasis 22% vs. 57% (p = 0.006)
● corneal ulceration in 54% vs. 70% (p = 0.05)
● corneal punctate epithelial erosion in 67% vs. 87% (not significant)
● corneal vascularization in 24% vs. 48% (not significant)
– Reference - Br J Dermatol 2019 Jul;181(1):212
Prevention and Screening

Prevention
● avoid reintroduction of causal drugs (and related compounds) in patients with history of Stevens-Johnson
syndrome 1
● for certain drugs, screening for specific human leukocyte antigen allele (HLA) types in certain populations
may be recommended to reduce risks of drug hypersensitivity and Stevens-Johnson syndrome/toxic
epidermal necrolysis (SJS/TEN)
⚬ abacavir
– screening of all patients for HLA-B*5701, prior to treatment with abacavir recommended by FDA to
avoid hypersensitivity reactions
– abacavir contraindicated in patients with HLA-B*5701
– Reference - FDA Table of Pharmacogenomic Biomarkers in Drug Labeling 2019 June
⚬ allopurinol
– American College of Rheumatology (ACR) guidelines on therapeutic approaches to hyperuricemia

recommends screening for HLA-B*5801 in selected patients including those of Korean, Han Chinese,
or Thai descent (ACR Evidence A) (Arthritis Care Res (Hoboken) 2012 Oct;64(10):1431 full-text )
– HLA-B*5801 associated with increased risk of severe cutaneous adverse reactions in patients of east
Asian descent (J Cutan Med Surg 2019 Nov/Dec;23(6):595 )
– HLA-B*5801 associated with increased risk for Stevens-Johnson syndrome in Portuguese population
in analysis of 6 patients with SJS syndrome (Br J Dermatol 2013 Sep;169(3):660 )
STUDY
– SUMMARY
HLA-B*5801 screening may decrease incidence of allopurinol-induced severe cutaneous adverse
reactions DynaMed Level 2
COHORT STUDY: BMJ 2015 Sep 23;351:h4848
Details
● based on prospective cohort study with nested case-control analysis

● 2,910 patients of Han Chinese descent with indication for allopurinol between 2009 and 2014 in
Taiwan were screened for presence of HLA-B*5801
● 19.6% of patients were HLA-B*5801 positive

● 2,339 patients negative for HLA-B*5801 had allopurinol and were followed for 2 months
● no patients negative for HLA-B*5801 were diagnosed with allopurinol-induced severe cutaneous
adverse reactions (7 cases would be expected based on incidence between 2001 and 2004)
● Reference - BMJ 2015 Sep 23;351:h4848 , commentary can be found in BMJ 2015 Sep
23;351:h5042
⚬ carbamazepine
– FDA recommends screening patients with Asian ancestry for HLA-B*1502 allele before starting
carbamazepine
● dangerous or even fatal skin reactions (Stevens-Johnson syndrome and toxic epidermal
necrolysis) with carbamazepine are significantly more common in patients with HLA-B*1502
● HLA-B*1502 allele occurs almost exclusively in patients with Asian ancestry, including South Asian
Indians
● carbamazepine should not be used in patients testing positive for HLA-B*1502 unless expected
benefit clearly outweighs increased risk of serious skin reactions
● any patients (including those positive for HLA-B*1502) taking carbamazepine for more than a few
months without skin reactions should be considered low risk
● References - FDA Table of Pharmacogenomic Biomarkers in Drug Labeling 2019 June , FDA
MedWatch 2007 Dec 12 , FDA Press Release 2007 Dec 12
– FDA states that the risks and benefits of carbamazepine therapy should be weighed before
considering carbamazepine in patients known to be positive for HLA-A*3101
● HLA-A*3101 may increase risk for SJS/TEN but it appears to have a stronger association with drug
reaction with eosinophilia and systemic symptoms (DRESS)
● approximate frequencies for HLA-A*3101 in various populations
⚬ > 15% in patients of Native American and Japanese ancestry

⚬ up to 10% in patients of Han Chinese, European, Korean, and Latin American ancestry
⚬ up to 5% in African-Americans and patients of Chinese (Hong Kong), Indian, Taiwanese, and
Thai ancestry
● References - Medical Genetics Summaries 2015 Oct 14 full-text and FDA Label Warnings
⚬ phenytoin and fosphenytoin
– FDA recommends avoiding starting phenytoin or fosphenytoin in patients with HLA-B*1502, and
avoiding phenytoin and fosphenytoin as an alternative for carbamazepine for patients positive for
HLA-B*1502
– Reference - FDA Table of Pharmacogenomic Biomarkers in Drug Labeling 2019 June
Screening
● not applicable
Guidelines and Resources

Guidelines
International Guidelines
● International Collaboration in Asthma, Allergy, and Immunology, International Consensus on drug allergy
position paper on drug hypersensitivity reactions can be found in Allergy 2014 Apr;69(4):420
United States Guidelines
● Society of Dermatology Hospitalists Supportive Care guidelines for management of Stevens-Johnson

syndrome/toxic epidermal necrolysis in adults can be found in J Am Acad Dermatol 2020 Jun;82(6):1553
● American Society for Apheresis (ASFA) guideline on the use of therapeutic apheresis in clinical practice can
be found in J Clin Apher 2019 Jun;34(3):171
● American Academy of Allergy, Asthma, and Immunology (AAAI) practical guidance for evaluation and
management of drug hypersensitivity of specific drugs can be found in J Allergy Clin Immunol Pract 2020
Oct;8(9S):S16
United Kingdom Guidelines
● British Association of Dermatologists (BAD) guidelines on management of Stevens-Johnson syndrome/toxic

epidermal necrolysis in
⚬ adults can be found in Br J Dermatol 2016 Jun;174(6):1194 full-text
⚬ children and young people can be found in Br J Dermatol 2019 Jul;181(1):37
European Guidelines
● French national diagnosis and care protocol on epidermal necrolysis can be found at Orphanet J Rare Dis
2018 Apr 10;13(1):56 full-text
● European Academy of Allergy and Clinical Immunology (EAACI) position paper on how to classify cutaneous
manifestations of drug hypersensitivity can be found in Allergy 2019 Jan;74(1):14
● European Guidelines (S1) on the use of high-dose intravenous immunoglobulin in dermatology can be
found in J Eur Acad Dermatol Venereol 2016 Oct;30(10):1657
● European Dermatology Forum Guideline Subcommittee guideline on use of high-dose intravenous

immunoglobulin in dermatology can be found in Eur J Dermatol 2009 Jan-Feb;19(1):90
● Haute Autorité de Santé (HAS) conseils sur syndromes de Stevens-Johnson et de Lyell se trouvent sur le site
Haute Autorité de Santé 2010 Jun [French]
Asian Guidelines
● Indian expert guideline on management of Stevens-Johnson syndrome/toxic epidermal necrolysis can be

found in Indian J Dermatol Venereol Leprol 2016 Nov-Dec;82(6):603 full-text
Review Articles
● review of severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic
epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS)/drug-induced
hypersensitivity syndrome (DIHS or HSS) and acute generalized exanthematous pustulosis (AGEP) can be
found in Br J Dermatol 2017 Nov;177(5):1234 full-text
● review of SJS/TEN management can be found in Indian J Dermatol 2018 Mar;63(2):117 full-text
● review can be found in Am J Clin Dermatol 2015 Dec;16(6):475
● review of toxic epidermal necrolysis can be found in Int J Mol Sci 2016 Dec 18;17(12):doi:
10.3390/ijms17122135 full-text
● review of wound care for SJS/TEN can be found in J Am Acad Dermatol 2018 Oct;79(4):764
● review of ocular manifestations and their management in Stevens-Johnson syndrome (SJS)/toxic epidermal
necrolysis (TEN) can be found in Ocul Surf 2016 Apr;14(2):168
● review of dermatologic emergencies can be found in Am Fam Physician 2010 Oct 1;82(7):773 full-text
● review of cutaneous adverse drug reactions in children can be found in Clin Dermatol 2017 Nov ;35(6):566
● review of SJS in childhood with ophthalmologic perspective can be found in Arch Soc Esp Oftalmol 2017
May;92(5):241
● review of toxic epidermal necrolysis management in Japan can be found in Allergol Int 2017 Jan;66(1):36
● review of therapeutic interventions emphasizing supportive measures for SJS/TEN can be found in Adv Ther
2017 Jun;34(6):1235 full-text
MEDLINE Search
● to search MEDLINE for (Stevens-Johnson syndrome or Toxic epidermal necrolysis) with targeted search
(Clinical Queries), click therapy , diagnosis , or prognosis
Patient Information
● handout on Stevens-Johnson syndrome from Stevens-Johnson Syndrome Foundation PDF
● handout on toxic epidermal necrolysis from DermNet NZ
● brief information on toxic epidermal necrolysis from National Organization for Rare Disorders
ICD Codes
ICD-10 Codes
● L51.1 bullous erythema multiforme
● L51.2 toxic epidermal necrolysis [Lyell]
References
General References Used
The references listed below are used in this DynaMed topic primarily to support background information and for
guidance where evidence summaries are not felt to be necessary. Most references are incorporated within the text
along with the evidence summaries.
1. Creamer D, Walsh SA, Dziewulski P, et al. U.K. guidelines for the management of Stevens-Johnson
syndrome/toxic epidermal necrolysis in adults 2016. Br J Dermatol. 2016 Jun;174(6):1194-227
2. Kohanim S, Palioura S, Saeed HN, et al. Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis--A

comprehensive review and guide to therapy. I. Systemic disease. Ocul Surf. 2016 Jan;14(1):2-19
3. Schwartz RA, McDonough PH, Lee BW. Toxic epidermal necrolysis: Part I. Introduction, history,
classification, clinical features, systemic manifestations, etiology, and immunopathogenesis. J Am Acad
Dermatol. 2013 Aug;69(2):173.e1-13
4. Schwartz RA, McDonough PH, Lee BW. Toxic epidermal necrolysis: Part II. Prognosis, sequelae, diagnosis,
differential diagnosis, prevention, and treatment. J Am Acad Dermatol. 2013 Aug;69(2):187.e1-16 ,
commentary can be found in J Am Acad Dermatol 2014 Jul;71(1):195
5. Lerch M, Mainetti C, Terziroli Beretta-Piccoli B, Harr T. Current Perspectives on Stevens-Johnson Syndrome

and Toxic Epidermal Necrolysis. Clin Rev Allergy Immunol. 2018 Feb;54(1):147-176
Recommendation Grading Systems Used
● British Association of Dermatology (BAD) grading system
⚬ strength of recommendation
– Class A
● at least 1 meta-analysis, systematic review or randomized controlled trial (RCT) rated as 1++, and
directly applicable to target population OR
● systematic review of RCTs or body of evidence consisting mostly of studies rated as 1+, directly
applicable to target population, and showing overall consistency of results
– Class B
● studies rated as 2++, directly applicable to target population, and showing overall consistency of
results OR
● extrapolated evidence from studies rated as 1++ or 1+
– Class C
● studies rated as 2+, directly applicable to target population, and showing overall consistency of
results OR
● extrapolated evidence from studies rated as 2++
– Class D
● evidence level 3 or 4 OR
● extrapolated evidence from studies rated as 2+ OR
● formal consensus
– Good Practice Point (GPP) - recommendation for best practice based on experience of guideline
development group
⚬ levels of evidence
– Level 1++ - high-quality meta-analyses, systematic reviews of RCTs, or RCTs with very low risk of bias
– Level 1+ - well-conducted meta-analyses, systematic reviews of RCTs, or RCTs with low risk of bias
– Level 1 - meta-analyses, systematic reviews of RCTs, or RCTs with high risk of bias; should not be
used as basis for making recommendations
– Level 2++ - high-quality systematic reviews of case-control or cohort studies; or high-quality case-
control or cohort studies with very low risk of confounding, bias, or chance and high probability that
relationship is casual
– Level 2+ - well-conducted case-control or cohort studies with low risk of confounding, bias, or chance
and moderate probability that relationship is casual
– Level 2 - case-control or cohort studies with high risk of confounding, bias, or chance and significant
risk that relationship is not casual; should not be used as basis for making recommendations
– Level 3 - nonanalytical studies (case reports, case series)

– Level 4 - expert opinion, formal consensus
⚬ Reference - BAD guideline on management of Stevens-Johnson syndrome/toxic epidermal necrolysis in

adults (Br J Dermatol 2016 Jun;174(6):1194 )
● BAD 2018 recommendation grading system
⚬ strength of recommendation
– Strong - benefits outweigh risks; most patients would receive the intervention OR risks outweigh
benefits; most patients would not receive the intervention
– Weak - risks and benefits are finely balanced; pros and cons would be considered in context of
evidence
– No recommendation - insufficient evidence to support any recommendation
⚬ quality of evidence
– High - further research very unlikely to change confidence in estimate of effect

– Moderate - further research likely to have important impact on confidence in estimate of effect and
may change estimate
– Low - further research very likely to have important impact on confidence in estimate of effect and
likely to change estimate
– Very low - any estimate of effect very uncertain
⚬ Reference - BAD 2018 guidelines for the management of Stevens-Johnson syndrome/toxic epidermal
necrolysis in children and young people (Br J Dermatol 2019 Jul;181(1):37 )
● American Society for Apheresis (ASFA) recommendation grading system
⚬ categories of indications for therapeutic apheresis
– Category I - disorders for which apheresis is accepted as first-line therapy, either as primary stand-
alone treatment or in conjunction with other modes of treatment
– Category II - disorders for which apheresis is accepted as second-line therapy, either as stand-alone
treatment or in conjunction with other modes of treatment
– Category III - optimum role of apheresis therapy is not established and decision-making should be
individualized
– Category IV - disorders in which published evidence demonstrates or suggests apheresis to be
ineffective or harmful; Institutional Review Board (IRB) approval is desirable if apheresis treatment is
undertaken in these circumstances
⚬ grades of recommendations
– Grade 1A - strong recommendation, high-quality evidence
● can apply to most patients in most circumstances without reservation

● supported by randomized controlled trials (RCTs) without important limitations or overwhelming
evidence from observational studies
– Grade 1B - strong recommendation, moderate-quality evidence
● can apply to most patients in most circumstances without reservation

● supported by RCTs with important limitations (inconsistent results, methodological flaws, indirect,
or imprecise) or exceptionally strong evidence from observational studies
– Grade 1C - strong recommendation, low- or very low-quality evidence
● recommendation may change when higher quality evidence becomes available

● supported by observational studies or case series
– Grade 2A - weak recommendation, high-quality evidence
● best action may differ depending on circumstances of patients' or societal values

● supported by RCTs without important limitations or overwhelming evidence from observational
studies
– Grade 2B - weak recommendation, moderate-quality evidence
● best action may differ depending on circumstances of patients' or societal values

● supported by RCTs with important limitations (inconsistent results, methodological flaws, indirect,
or imprecise) or exceptionally strong evidence from observational studies
– Grade 2C - weak recommendation, low- or very low-quality evidence
● very weak recommendation; other alternatives may be equally reasonable

● supported by observational studies or case series
⚬ Reference - ASFA guideline on use of therapeutic apheresis in clinical practice (J Clin Apher 2016
Jun;31(3):149 )
● American College of Rheumatology (ACR) recommendation grading system
⚬ Level A - supported by multiple randomized clinical trials or meta-analyses

⚬ Level B - derived from a single randomized trial or nonrandomized studies
⚬ Level C - consensus opinion of experts, case studies, or standard-of-care
⚬ Reference - ACR guidelines for management of gout part 1: systematic nonpharmacologic and
pharmacologic therapeutic approaches to hyperuricemia (Arthritis Care Res (Hoboken) 2012
Oct;64(10):1431 full-text )
Synthesized Recommendation Grading System for DynaMed Content
● The DynaMed Team systematically monitors clinical evidence to continuously provide a synthesis of the
most valid relevant evidence to support clinical decision-making (see 7-Step Evidence-Based Methodology
).
● Guideline recommendations summarized in the body of a DynaMed topic are provided with the
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guidelines agree and where guidelines differ from each other and from the current evidence.
● In DynaMed content, we synthesize the current evidence, current guidelines from leading authorities, and
clinical expertise to provide recommendations to support clinical decision-making in the Overview &
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synthesized recommendations as Strong or Weak.
⚬ Strong recommendations are used when, based on the available evidence, clinicians (without conflicts
of interest) consistently have a high degree of confidence that the desirable consequences (health
benefits, decreased costs and burdens) outweigh the undesirable consequences (harms, costs,
burdens).
⚬ Weak recommendations are used when, based on the available evidence, clinicians believe that
desirable and undesirable consequences are finely balanced, or appreciable uncertainty exists about
the magnitude of expected consequences (benefits and harms). Weak recommendations are used when
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How to cite
National Library of Medicine, or "Vancouver style" (International Committee of Medical Journal Editors):
● DynaMed [Internet]. Ipswich (MA): EBSCO Information Services. 1995 - . Record No. T114705, Stevens-
Johnson Syndrome/Toxic Epidermal Necrolysis; [updated 2018 Nov 30, cited place cited date here].
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Stevens-Johnson Syndrome - Toxic Epidermal Necrolysis

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17/2/22, 12:29 Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis

Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis

● The amount of body surface area involvement may define classification.

⚬ SJS is diffuse and involves < 10% of body surface area.

⚬ resuscitation, hydration, control of electrolyte imbalances, and adequate nutrition

● Staphylococcal Scalded Skin Syndrome (SSSS)

⚬ most commonly caused by systemic drug

● toxic epidermal necrolysis also called Lyell syndrome

● original 1993 consensus classification for acute bullous disorders

⚬ forms of epidermal necrolysis

– bullous erythema multiforme

● detachment < 10% of the body surface area

● detachment < 10% of the body surface area

– overlap Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN)

● detachment between 10% and 30% of the body surface area

– toxic epidermal necrolysis with spots

● detachment > 30% of the body surface area

● widespread purpuric macules or flat atypical targets

– toxic epidermal necrolysis without spots

● detachment > 10% of the body surface area

⚬ Reference - Arch Dermatol 1993 Jan;129(1):92

● SJS/TEN may be more likely to recur in children 2

● mortality from SJS/TEN higher in elderly than younger patients 2

CROSS-SECTIONAL STUDY: J Invest Dermatol 2016 Jul;136(7):1387 | Full Text

⚬ based on cross-sectional study

– Asian OR 3.27 (95% CI 3.02-3.54)

⚬ Reference - J Invest Dermatol 2016 Jul;136(7):1387 full-text

epidermal necrolysis (TEN) are rare conditions 1 , 3

occurrence of SJS, Stevens-Johnson syndrome/toxic epidermal necrolysis (overlap), or TEN 1 , 3

CROSS-SECTIONAL STUDY: J Invest Dermatol 2016 Jul;136(7):1387 | Full Text

⚬ based on cross-sectional study

⚬ Reference - J Invest Dermatol 2016 Jul;136(7):1387 full-text

CROSS-SECTIONAL STUDY: J Am Acad Dermatol 2017 May;76(5):811 | Full Text

⚬ based on cross-sectional study

⚬ estimated frequency per million children

– 4.3-5.8 for SJS

⚬ Reference - J Am Acad Dermatol 2017 May;76(5):811 full-text

Medical Conditions and Cross-reactivity

Genetic Risk Factors

● human leukocyte antigens (HLA)

⚬ patients with certain HLA may be at increased risk 2 , 5

⚬ HLA-B*5901 associated with methazolamide-induced SJS/TEN in Asian populations (Pharmacogenomics

– systemic lupus erythematosus (SLE)

⚬ Reference - J Invest Dermatol 2016 Jul;136(7);1387 full-text

● Drug-induced Liver Injury 5

Etiology and Pathogenesis

● > 200 drugs have been associated with SJS/TEN 1 , 2

⚬ anticancer drugs associated with SJS/TEN

– traditional chemotherapeutics including bleomycin, cladribine, lenalidomide, mithramycin,

– based on pooled analysis of 2 multicenter case-control studies

● antimicrobial sulfonamides in 13% vs. 0%

– Reference - Pediatrics 2009 Feb;123(2):e297

DIAGNOSTIC COHORT STUDY: Clin Pharmacol Ther 2010 Jul;88(1):60

– based on diagnostic cohort study with validation

● probability of drug presence in body on index day (scored 0 to -3)

⚬ SJS/TEN after use of same drug, scored +4

● presence of drug beyond the progression phase of disease (scored 0 or -2)

⚬ drug unknown or discontinued, scored 0

● drug notoriety based on EuroSCAR trial (scored 3 to -1)

⚬ calculate total intermediate score from criteria above

● other causes of SJS/TEN 1 , 2

History and Physical

lesions, bullae, erosions, and ulcers, with or without systemic symptoms 1