137

TABLE 19-1 Diseases Associated with Fever and Rash (Continued)

GROUP AFFECTED/
EPIDEMIOLOGIC
DISEASE ETIOLOGY DESCRIPTION FACTORS CLINICAL SYNDROME CHAPTER
Bacterial endocarditis Streptococcus, Subacute course (e.g., viridans streptococci): Abnormal heart New or changing heart 128
(Fig. A1-23) Staphylococcus, etc. Osler’s nodes (tender pink nodules on finger valve (e.g., viridans murmur
or toe pads); petechiae on skin and mucosa; streptococci),
splinter hemorrhages. Acute course (e.g., intravenous drug use
Staphylococcus aureus): Janeway lesions
(painless erythematous or hemorrhagic
macules, usually on palms and soles)

CHAPTER 19 Fever and Rash

COVID-19 (Fig. A1-57) SARS-CoV-2 Mild or asymptomatic COVID-19: Pernio Infection with SARS- Ranging from
(macules, papules, or plaques that are CoV-2; MIS-C in older asymptomatic to mild/
tender, erythematous/violaceous; acral, feet children/adolescents moderate with loss of
more common than hands); Moderate/severe taste/smell, pharyngitis,
COVID-19: vesicles, urticaria, maculopapular cough, fever, to severe
erythema; often pruritic; occur on trunk, with dyspnea, ARDS;
extremities; Severe COVID-19: Retiform complications include
purpura (net-like, purple patches/ thrombosis, especially
plaques often with necrosis); lesions with retiform purpura;
often asymptomatic; occur on extremities, lesions may be delayed
buttocks; Multisystem inflammatory compared to other
syndrome in children (MIS-C): findings COVID-19 symptoms;
similar to Kawasaki disease MIS-C occurs ~2-6
weeks following acute
(often asymptomatic)
infection
Confluent Desquamative Erythemas
Scarlet fever (second Group A Streptococcus Diffuse blanchable erythema beginning on Most common among Fever, pharyngitis, 148
disease) (pyrogenic exotoxins A, face and spreading to trunk and extremities; children 2–10 years headache
(Fig. A1-25) B, C) circumoral pallor; “sandpaper” texture to old; usually follows
skin; accentuation of linear erythema in skin group A streptococcal
folds (Pastia’s lines); enanthem of white pharyngitis
evolving into red “strawberry” tongue;
desquamation in second week
Kawasaki disease Idiopathic Rash similar to scarlet fever (scarlatiniform) Children <8 years old Cervical adenopathy, 58, 363
(Fig. A1-29) or EM; fissuring of lips, strawberry tongue; pharyngitis, coronary
conjunctivitis; edema of hands, feet; artery vasculitis
desquamation later in disease
Streptococcal toxic shock Group A Streptococcus When present, rash often scarlatiniform May occur in setting Multiorgan failure, 148
syndrome (associated with of severe group A hypotension; mortality
pyrogenic exotoxin A and/ streptococcal infections rate 30%
or B or certain M types) (e.g., necrotizing
fasciitis, bacteremia,
pneumonia)
Staphylococcal toxic S. aureus (toxic shock Diffuse erythema involving palms; Colonization with toxin- Fever >39°C (>102°F), 147
shock syndrome syndrome toxin 1, pronounced erythema of mucosal surfaces; producing S. aureus hypotension, multiorgan
enterotoxins B and conjunctivitis; desquamation 7–10 days into dysfunction
others) illness
Staphylococcal scalded- S. aureus, phage group II Diffuse tender erythema, often with bullae Colonization with toxin- Irritability; nasal or 147
skin syndrome and desquamation; Nikolsky’s sign producing S. aureus; conjunctival secretions
(Fig. 19-3, Fig. A1-28) occurs in children
<10 years old (termed
Ritter’s disease in
neonates) or adults with
renal dysfunction
Exfoliative erythroderma Underlying psoriasis, Diffuse erythema (often scaling) interspersed Usually occurs in adults
Fever, chills (i.e., 58, 60
syndrome eczema, drug eruption, with lesions of underlying condition over age 50; more difficulty with
(Fig. A1-27) mycosis fungoides common among men thermoregulation);
lymphadenopathy
DRESS (drug-induced Aromatic anticonvulsants; Maculopapular eruption (mimicking Individuals genetically Lymphadenopathy, 60
hypersensitivity syndrome other drugs, including exanthematous drug rash), sometimes unable to detoxify arene multiorgan failure
[DIHS]) sulfonamides, progressing to exfoliative erythroderma; oxides (anticonvulsant (especially hepatic),
(Fig. A1-48) minocycline profound edema, especially facial; pustules metabolites), patients eosinophilia, atypical
may occur with slow N-acetylating lymphocytes; mimics
capacity (sulfonamides) sepsis
Stevens-Johnson Drugs (80% of cases; Erythematous and purpuric macules, Uncommon among Dehydration, sepsis 60
syndrome (SJS), toxic often allopurinol, sometimes targetoid, or diffuse erythema children; more common sometimes resulting
epidermal necrolysis anticonvulsants, progressing to bullae, with sloughing and among patients with HIV from lack of normal skin
(TEN) antibiotics), infection, necrosis of entire epidermis; Nikolsky’s infection, systemic lupus integrity; mortality rates
(Fig. A1-26) idiopathic factors sign; involves mucosal surfaces; TEN (>30% erythematosus, certain up to 30%
epidermal necrosis) is maximal form; SJS HLA types, or slow
involves <10% of epidermis; SJS/TEN overlap acetylators
involves 10–30% of epidermis
(Continued)
 259
TABLE 36-1 Vesicular, Bullous, or Ulcerative Lesions of the Oral Mucosa (Continued)
CONDITION USUAL LOCATION CLINICAL FEATURES COURSE
Bacterial or Fungal Diseases (Continued)
Histoplasmosis Any area of the mouth, Nodular, verrucous, or granulomatous lesions; ulcers are Systemic antifungal therapy necessary
particularly tongue, indurated and painful; usual source hematogenous or
gingiva, or palate pulmonary, but may be primary
Candidiasisa
Dermatologic Diseases
Mucous membrane Typically produces Painful, grayish-white collapsed vesicles or bullae of full- Protracted course with remissions and

CHAPTER 36 Oral Manifestations of Disease

pemphigoid marked gingival thickness epithelium with peripheral erythematous zone; exacerbations; involvement of different sites
erythema and gingival lesions desquamate, leaving ulcerated area develops slowly; glucocorticoids may temporarily
ulceration; other reduce symptoms but do not control disease
areas of oral cavity,
esophagus, and vagina
may be affected
EM minor and EM major Primarily oral mucosa Intraoral ruptured bullae surrounded by inflammatory area; Onset very rapid; usually idiopathic, but may be
(Stevens-Johnson and skin of hands and lips may show hemorrhagic crusts; “iris” or “target” lesion associated with trigger such as drug reaction;
syndrome) feet on skin is pathognomonic; patient may have severe signs of condition may last 3–6 weeks; mortality rate for
toxicity untreated EM major is 5–15%
Pemphigus vulgaris Oral mucosa and skin; Usually (>70%) presents with oral lesions; fragile, ruptured With repeated occurrence of bullae, toxicity may
sites of mechanical bullae and ulcerated oral areas; mostly in older adults lead to cachexia, infection, and death within 2
trauma (soft/hard palate, years; often controllable with oral glucocorticoids
frenulum, lips, buccal
mucosa)
Lichen planus Oral mucosa and skin White striae in mouth; purplish nodules on skin at sites White striae alone usually asymptomatic; erosive
of friction; occasionally causes oral mucosal ulcers and lesions often difficult to treat, but may respond to
erosive gingivitis glucocorticoids
Other Conditions
Recurrent aphthous Usually on Single or clustered painful ulcers with surrounding Lesions heal in 1–2 weeks but may recur monthly
ulcers nonkeratinized oral erythematous border; lesions may be 1–2 mm in diameter in or several times a year; protective barrier with
mucosa (buccal and crops (herpetiform), 1–5 mm (minor), or 5–15 mm (major) benzocaine and topical glucocorticoids relieve
labial mucosa, floor symptoms; systemic glucocorticoids may be
of mouth, soft palate, needed in severe cases
lateral and ventral
tongue)
Behçet’s syndrome Oral mucosa, eyes, Multiple aphthous ulcers in mouth; inflammatory ocular Oral lesions often first manifestation; persist
genitalia, gut, and CNS changes, ulcerative lesions on genitalia; inflammatory bowel several weeks and heal without scarring
disease and CNS disease
Traumatic ulcers Anywhere on oral Localized, discrete ulcerated lesions with red border; Lesions usually heal in 7–10 days when irritant is
mucosa; dentures produced by accidental biting of mucosa, penetration by removed, unless secondarily infected
frequently responsible foreign object, or chronic irritation by dentures
for ulcers in vestibule
Squamous cell carcinoma Any area of mouth, most Red, white, or red and white ulcer with elevated or indurated Invades and destroys underlying tissues;
commonly on lower border; failure to heal; pain not prominent in early lesions frequently metastasizes to regional lymph nodes
lip, lateral borders of
tongue, and floor of
mouth
Acute myeloid leukemia Gingiva Gingival swelling and superficial ulceration followed Usually responds to systemic treatment of
(usually monocytic) by hyperplasia of gingiva with extensive necrosis and leukemia; occasionally requires local irradiation
hemorrhage; deep ulcers may occur elsewhere on mucosa,
complicated by secondary infection
Lymphoma Gingiva, tongue, palate, Elevated, ulcerated area that may proliferate rapidly, giving Fatal if untreated; may indicate underlying HIV
and tonsillar area appearance of traumatic inflammation infection
Chemical or thermal burns Any area in mouth White slough due to contact with corrosive agents (e.g., Lesion heals in several weeks if not secondarily
aspirin, hot cheese) applied locally; removal of slough infected
leaves raw, painful surface
See Table 36-3.
a

Abbreviations: CNS, central nervous system; EM, erythema multiforme; HSV, herpes simplex virus; VZV, varicella-zoster virus.

usually a late feature of severe disease. Bilateral preauricular pain, par- in the distribution of the ninth cranial nerve. Swallowing, sneezing,
ticularly in the morning, limits range of motion. coughing, or pressure on the tragus of the ear triggers pain that is felt
Migrainous neuralgia may be localized to the mouth. Episodes of in the base of the tongue, pharynx, and soft palate and may be referred
pain and remission without an identifiable cause and a lack of relief to the temporomandibular joint. Neuritis involving the maxillary and
with local anesthesia are important clues. Trigeminal neuralgia (tic mandibular divisions of the trigeminal nerve (e.g., maxillary sinusitis,
douloureux) can involve the entire branch or part of the mandibular neuroma, and leukemic infiltrate) is distinguished from ordinary
or maxillary branch of the fifth cranial nerve and can produce pain in toothache by the neuropathic quality of the pain. Occasionally, phan-
one or a few teeth. Pain may occur spontaneously or may be triggered tom pain follows tooth extraction. Pain and hyperalgesia behind the
by touching the lip or gingiva, brushing the teeth, or chewing. Glos- ear and on the side of the face in the day or so before facial weakness
sopharyngeal neuralgia produces similar acute neuropathic symptoms develops often constitute the earliest symptom of Bell’s palsy. Likewise,
 413

CHAPTER 60 Cutaneous Drug Reactions

FIGURE 60-7 Stevens-Johnson syndrome (SJS).

withdrawal of the suspected culprit drug is required. Given the severe

long-term complications of myocarditis, patients should undergo
cardiac evaluation in cases of severe DIHS or if heart involvement is
suspected due to hypotension or arrhythmia. Patients should be closely
monitored for resolution of organ dysfunction and for development of
late-onset autoimmune thyroiditis and diabetes (up to 6 months).
FIGURE 60-9 Toxic epidermal necrolysis, hand.
Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis
SJS and TEN are characterized by blisters and mucosal/epider-
mal detachment resulting from full-thickness epidermal necrosis in target lesions, typically with an acral distribution and limited skin
the absence of substantial dermal inflammation. The term Stevens- detachment. Mycoplasma and other respiratory infections in children
Johnson syndrome (SJS) describes cases in which the total body surface cause a clinically distinct presentation with prominent mucositis and
area of blistering and eventual detachment is <10% (Fig. 60-7). The limited cutaneous involvement. The term reactive infectious mucocu-
term Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) taneous eruption (RIME) has been proposed to help differentiate this
overlap is used to describe cases with 10–30% epidermal detachment clinical entity, which some believe may be the syndrome originally
(Fig. 60-8), and the term toxic epidermal necrolysis (TEN) is used to described by Stevens and Johnson.
describe cases with >30% detachment (Figs. 60-9 and 60-10). Patients with SJS/TEN initially present with fever >39°C (102.2°F);
Other blistering eruptions with concomitant mucositis may be sore throat; conjunctivitis; and acute onset of painful dusky, atypical,
confused with SJS/TEN. Erythema multiforme (EM) associated with target-like lesions (Fig. 60-11). Intestinal and upper respiratory tract
herpes simplex virus is characterized by painful mucosal erosions and involvement are associated with a poor prognosis, as are older age and
greater extent of epidermal detachment. At least 10% of those with

FIGURE 60-8 SJS-TEN overlap. FIGURE 60-10 Toxic epidermal necrolysis.

 414 part of the epidermis, unlike the full-thickness epidermal necrosis that
characterizes SJS. Before the pustules appear, AGEP may also mimic
DIHS due to the prominent fever and erythroderma.
The principal differential diagnosis for AGEP is acute pustular pso-
riasis, which has an identical clinical and histologic appearance. Many
patients with AGEP have a personal or family history of psoriasis. AGEP
classically begins within 24–48 hours of drug exposure, although it may
occur as much as 1–2 weeks later. β-Lactam antibiotics, calcium channel
blockers, macrolide antibiotics, and other inciting agents (including
radiocontrast and dialysates) have been reported. Patch testing with the
responsible drug often results in a localized pustular eruption.
PART 2

Overlap Hypersensitivity Syndromes An important concept in

the clinical approach to severe drug eruptions is the presence of “over-
lap syndromes,” most notably DIHS with TEN-like features, DIHS with
pustular eruption (AGEP-like), and AGEP with TEN-like features. In
Cardinal Manifestations and Presentation of Diseases

several case series of AGEP, 50% of cases had TEN-like or DRESS-like

features, and 20% of cases had mucosal involvement resembling SJS/
TEN. In one study, up to 20% of all severe drug eruptions had overlap
FIGURE 60-11 Target-like lesion in SJS. features, suggesting that AGEP, DIHS, and SJS/TEN represent a clinical
spectrum with some common pathophysiologic mechanisms. Desig-
nation of a single diagnosis based on cutaneous and extracutaneous
SJS and 30% of those with TEN die from the disease. Drugs that most involvement may not always be possible in cases of hypersensitivity;
commonly cause SJS/TEN are sulfonamides, allopurinol, antiepilep- in such instances, treatment should be geared toward addressing the
tics (e.g., lamotrigine, phenytoin, carbamazepine), oxicam NSAIDs, dominant clinical features. The timing of rash onset with respect to
β-lactam and other antibiotics, and nevirapine. Frozen-section skin drug administration, which is usually much more delayed in DIHS,
biopsy may aid in rapid diagnosis. and the presence of systemic manifestations such as hepatitis are help-
At this time, there is no consensus on the most effective treatment ful clues to that diagnosis.
for SJS/TEN. The best outcomes stem from early diagnosis, immediate
discontinuation of the suspected drug, and meticulous supportive ther- Vasculitis Cutaneous small-vessel vasculitis (CSVV) typically
apy in an intensive care or burn unit. Fluid management, atraumatic presents with purpuric papules and macules involving the lower
wound care, infection prevention and treatment, and ophthalmologic extremities and other dependent areas (Fig. 60-13) (Chap. 363). Pus-
and respiratory support are critical. Early administration of systemic tular and hemorrhagic vesicles as well as rounded ulcers also occur.
glucocorticoids, intravenous immunoglobulin, cyclosporine, or etaner- Importantly, vasculitis may involve other organs, including the kidneys,
cept may improve disease outcomes, but randomized studies to evalu-
ate potential therapies are lacking and difficult to perform.
Pustular Eruptions AGEP is a rare reaction pattern affecting 3–5
people per million per year. It is thought to be secondary to medication
exposure in >90% of cases (Fig. 60-12). Patients typically present with
diffuse erythema or erythroderma, as well as high spiking fevers and
leukocytosis with neutrophilia. One to two days later, innumerable
pinpoint pustules develop overlying the erythema. The pustules are
most pronounced in body fold areas; however, they may become gen-
eralized and, when coalescent, can lead to superficial erosion. In such
cases, differentiating the eruption from SJS in its initial stages may be
difficult, although in AGEP, any erosions tend to be more superficial,
and prominent mucosal involvement is lacking. Skin biopsy shows col-
lections of neutrophils and sparse necrotic keratinocytes in the upper

FIGURE 60-12 Acute generalized exanthematous pustulosis. FIGURE 60-13 Cutaneous small-vessel vasculitis (CSVV, leukocytoclastic vasculitis).
 416
TABLE 60-3 Clinical Features of Severe Cutaneous Drug Reactions
FREQUENT SIGNS AND MOST COMMON CULPRIT
DIAGNOSIS MUCOSAL LESIONS TYPICAL SKIN LESIONS SYMPTOMS DRUGS
Stevens-Johnson syndrome Erosions usually at two Small blisters form from dusky macules Most cases involve fever Sulfonamides, anticonvulsants,
(SJS) or more sites or atypical targets; rare areas of allopurinol, nonsteroidal anti-
confluence; detachment ≤10% body inflammatory drugs (NSAIDs)
surface area
Toxic epidermal necrolysis Erosions usually at two Individual lesions like those seen in Nearly all cases involve fever, Same as for SJS
(TEN)a or more sites SJS; confluent dusky erythema; large “acute skin failure,” leukopenia
sheets of necrotic epidermis; total
detachment of >30% body surface area
Drug-induced hypersensitivity Mucositis reported in as Diffuse, deep red morbilliform eruption Fever, lymphadenopathy, Anticonvulsants, sulfonamides,
PART 2

syndrome/drug rash with many as 30% with facial involvement; facial and acral hepatitis, nephritis, myocarditis, allopurinol, minocycline
eosinophilia and systemic swelling eosinophilia, atypical
symptoms (DIHS/DRESS) lymphocytosis
Acute generalized Oral erosions in perhaps Innumerable pinpoint pustules overlying High fever, leukocytosis β-Lactam antibiotics, calcium
exanthematous pustulosis 20% a diffuse erythematous eruption; may (neutrophilia), hypocalcemia channel blockers, macrolide
Cardinal Manifestations and Presentation of Diseases

(AGEP) develop superficial erosions antibiotics

Serum sickness or serum Absent Urticarial serpiginous or polycyclic Fever, arthralgias Antithymocyte globulin,
sickness–like reaction rash; purpuric eruption along the sides cephalosporins, monoclonal
of the feet and hands is characteristic antibodies
Anticoagulant-induced Infrequent Purpura and necrosis, especially of Pain in affected areas Warfarin, heparin
necrosis central, fatty areas
Angioedema Often involved Urticaria or swelling of the central face, Respiratory distress, Angiotensin-converting
other areas cardiovascular collapse enzyme (ACE) inhibitors,
NSAIDs, contrast dye
a
Overlap of SJS and TEN have features of both, and attachment of 10–30% of body surface area may occur.
Source: From JC Roujeau, RS Stern: Severe adverse cutaneous reactions to drugs. N Engl J Med 331:1272, 1994. Copyright © 1994 Massachusetts Medical Society.
Reprinted with permission from Massachusetts Medical Society.

is hypersensitivity to aromatic antiepileptics (barbiturates, phenytoin, agents. Negative skin tests do not totally rule out IgE-mediated reactiv-
carbamazepine) with up to 50% reaction to a second drug in patients ity; however, the risk of anaphylaxis in response to penicillin admin-
who reacted to one. For other drugs, in vitro and in vivo data have sug- istration in patients with negative skin tests is about 1%. In contrast,
gested that cross-reactivity exists only between compounds with very two-thirds of patients with a positive skin test experience an allergic
similar chemical structures. Sulfamethoxazole-specific lymphocytes response upon rechallenge. The skin tests themselves carry a small risk
may be activated by other antibacterial sulfonamides but not diuretics, of anaphylaxis.
antidiabetic drugs, or anti-COX2 NSAIDs with a sulfonamide group. For patients with delayed-type hypersensitivity, the clinical utility of
Though it has been previously reported that 10% of patients with peni- skin tests remains questionable. At least one of a combination of several
cillin allergies will also develop allergic reactions to cephalosporin class tests (prick, patch, and intradermal) is positive in 50–70% of patients
antibiotics, the cross-reactivity is likely much lower, as is the incidence with a reaction “definitely” attributed to a single medication. This low
of true penicillin allergy itself, and severe reactions are very rare. sensitivity corresponds to the observation that readministration of
Recent data suggest that although the risk of developing a drug drugs with negative skin testing results in eruptions in 17% of cases.
eruption to another drug is increased in persons with a prior reaction, Desensitization can be considered in those with a history of reaction
“cross-sensitivity” is probably not the explanation. As an example, to a medication that must be used again. Efficacy of such procedures
those with a history of an allergic-like reaction to penicillin are at has been demonstrated in cases of immediate reaction to penicillin and
greater risk of developing a reaction to antibacterial sulfonamides than positive skin tests, anaphylactic reactions to platinum chemotherapy,
to cephalosporins. and delayed reactions to sulfonamides in patients with AIDS. Desensi-
These data suggest that the list of drugs to avoid after a drug reac- tization is often successful in HIV-infected patients with morbilliform
tion should be limited to the causative one(s) and to a few very similar eruptions to sulfonamides but is not recommended in HIV-infected
medications. patients who developed erythroderma or a bullous reaction in response
Because of growing evidence that some severe cutaneous reactions to prior sulfonamide exposure. Various protocols are available, includ-
to drugs are associated with HLA genes, it is recommended that ing oral and parenteral approaches. Oral desensitization appears to
first-degree family members of patients with severe cutaneous reac- have a lower risk of serious anaphylactic reaction. Desensitization
tions also should avoid causative agents. This may be most relevant for carries the risk of anaphylaxis regardless of how it is performed and
sulfonamides and antiepileptic medications. should be performed in monitored clinical settings such as an intensive
care unit. After desensitization, many patients experience non-life-
■ ROLE OF TESTING FOR CAUSALITY AND DRUG threatening reactions during therapy with the culprit drug.
RECHALLENGE
The usefulness of laboratory tests, skin-prick, or patch testing to ■ REPORTING
determine causality is debated and may be of limited practical value. Any severe reaction to drugs should be reported to a regulatory agency
Many in vitro immunologic assays have been developed for research or to pharmaceutical companies. Because severe reactions are too rare
purposes; however, the predictive value of these tests has not been to be detected in premarketing clinical trials, spontaneous reports are
validated in large series of affected patients. In some cases, diagnos- of critical importance for early detection of unexpected life-threatening
tic rechallenge may be appropriate, even for drugs with high rates of events. To be useful, the report should contain enough details to permit
adverse reactions. ascertainment of severity and drug causality.
Skin-prick testing has clinical value in specific settings. In patients
with a history suggesting immediate IgE-mediated reactions to peni- Acknowledgments
cillin, skin-prick testing with penicillins or cephalosporins has proven We acknowledge the contribution of Drs. Jean-Claude Roujeau and
useful for identifying patients at risk of anaphylactic reactions to these Robert S. Stern to this chapter in previous editions.
STEVENS-JOHNSON SYNDROME & TOXIC EPIDERMAL NECROLYSIS
I. ETIOPATHOGENESIS
Epidermal necrolysis (SJS and TEN) is an acute life-threatening mucocutaneous
reaction characterized by blisters and mucosal/epidermal detachment resulting from
full-thickness epidermal necrosis in the absence of substantial dermal inflammation
Most commonly due to drugs (some due co infection or idiopathic)

A. Classification
CLASSIFICATION I EXTENT OF SKIN DETACHMENT
SJS • <IO% body surface area (less severe condition)

SJS/TEN Overlap • 10-30% body surface area

TEN • >30% body surface area

SJS: Stevens-Johnson Syndrome

TEN:ToxicEpidermalNecrolysis
'
B. Commonly Implicated Medications:
0Allopurinol
0Antibacterial sulfonamides (e.g., sulfamethoxazole, sulfadiazine, sulfapyridine,
sulfadoxine, sulfasalazine)
0Antiseizure medications (e.g., carbamazepine, lamotrigine, phenobarbital, phenytoin,
phenylbutazone)
0Nevirapine
0Oxicam NSA!Ds
0Thiacetazone

II. CLINICALFEATURES
• Begins 8 weeks (usually 4-30 days) after exposure to a drug for the 1st time
Prodrome • Fever, headache, rhinitis, cough, malaise, odynophagia, burning or
stinging of eyes, heralding mucous membrane involvement
• Appear first on the trunk, spreading to the neck, face and proximal upper
extremities with distal extremities relatively spared
• Stages:
Begin as morbilliform, target lesion-like, multiple erythematous dusky
0

irregular macules
Cutaneous ° Confluence of individual lesions leads to extensive and diffuse
lesions erythema
Necrotic epidermis detaches from the dermis giving rise to flaccid
0

blisters (sheets of necrotic epidermis resembling wet cigarette paper)

Large denuded areas of red, oozing dermis similar to a second-
0

degree thermal burn progress to a plateau phase (but life-threatening

complications may occur)
• Mucous membrane involvement in 90% & can precede or follow skin
Mucosa! eruption
lesions • May involve mucosa! surfaces: oral, ocular, urogenital, pharyngeal,
tracheal/bronchial, esophageal, and intestinal (rare)
• Nikolsky sign: epidermal dislodgement by lateral pressure on
erythematous zones
Signs
• Asboe-Hansen sign (bulla-spread sign): the extension of the blisters
laterally by slight pressure of the thumb

578
lll. DIAGNOSIS
Clues that this is SJS/TEN: rapid progression, severe pain, constitutional symptoms
Frozen-section skin biopsy may aid in rapid diagnosis: hallmark histologic finding is
keratinocyte necrosis, ranging from partial to full-thickness necrosis of the epidermis

SCORTEN Score for SJS/TEN• (r point for each factor)

FACTOR I INDICATOR FOR MORE SEVERE DISEASE
Age • ?:40 years old
Malignancy • Yes (cancer & hematologic malignancy)
BSA detached • ~10%

Tachycardia • ?:120bpm

Serum urea • >IO mmol/L

Serum glucose • >I4mmol/L

Serum
• <20 mmol/L
bicarbonate
*Patients with more severe disease (detachment >30% BSA)or SCORTEN Score ,!:2should be
referred to an ICU, burn unit, or specialized dermatology units
Source: Guegan S, et al. J Invest Dermatol;2006

IV. MANAGEMENT
• Early recognition and withdrawal of offending drug
• Fluid and electrolyte replacement, early nutritional support, cultures
(blood, skin, urine), optimal environmental temperature (28-30°C)
Supportive
• Daily eye exam and disruption of early synechiae by an ophthalmologist
• Antiseptic mouth rinse
• Admission in intensive care or burn unit

• Corticosteroids (still controversial): dexamethasone IV 1.5mg/kg/day for

Specific 3 days; however, long-term or late systemic glucocorticoid use has been
treatment associated with increased mortality
in the acute • Cyclosporine 3-4 mg/kg/day
phase • Use of intravenous immunoglobulin (!VIG) in SJS/TEN remains
controversial, and more recent data question whether it is beneficial

V. COMPLICATIONS
Most common: sepsis from superimposed bacterial infection (S. aureus, Pseudomonas,
Enterobacteriaceae)
Dehydration
Multiple organ system failure
Late complications of mucosa! membrane involvement

Source: Kang S, et al. Fitzpatrick'sDermatology,9th [Link]-HillEducation; 2019

I
579
OTHER COMMON INPATIENT CASES
CONDITION I DEFINITION I FEATURES I MANAGEMENT
• Fluid and electrolyte
• Severe, potentially • Erythematous replacement, warm
life-threatening patches that humid environment
Erythroderma/ condition increase in size (30-32°C), wet
Exfoliative characterized by and coalesce dressings on
dermatitis diffuse erythema into generalized weeping lesions,
and scaling erythema with a antihistamines and
involving ~90% BSA shiny appearance low-potency topical
corticosteroids

• Prodrome followed • Immediate

• Severe adverse by a diffuse withdrawal of
Drug-induced multi-organ morbilliform suspected culprit
hypersensitivity drug reaction eruption usually drug; systemic
syndrome (most common: involving the face, glucocorticoids (1.5-2
(formerly known allopurinol) 2-8 weeks after mg/kg/d prednisone
as DRESS) characterized by an starting the drug equivalent) tapered
extensive skin rash and persisting slowly over 8-12
after cessation weeks

• Pinpoint pustules
• Rare, acute eruption
overlying an area
characterized by
of erythema, • Withdrawal of the
the development
Acute generalized classically offending drug
of numerous
exanthematous beginning within (self-limiting disease
non-follicular
pustulosis (AGEP) 24-48 hours of with a favorable
sterile pustules on
drug exposure prognosis)
a background of
(may occur 1-2
edematous erythema
weeks later)
Source:Goldsmith
AL, et al. Fitzpatrick's
Dermatologyin GeneralMedicine,8th Ed1t1on.
2012
Davis,M. Erythrodermain [Link] Date.Mar2021
Jamesonet al. Harrison'sPrinciplesof InternalMedicine,20thEdition.2018

REFERENCES
1. Bolognia JL,JorizzoJJ,Schaffer JY,et al., editors. Dem1atology,3rd Edition. Elsevier;2012.
2. Davis, M. Erythrodenna in Adults. Uptodate. Available online lmps://[Link]/contents/erythrodenna-in-adults.
Accessed March 2021.
3. Depanment of Health, Philippines. National Leprosy Control Program Manual of Procedures, [Link] hnps:/[Link].
ph/leprosy-control-program Accessed October 2021.
4. Dofitas BL A Practical Guide to Leprosy Care: Philippine Leprosy Mission, Inc., 2018.
5. Feldman SR. Psoriasis:epidemiology, clinical manifestations, and diagnosis. [Link] hnps://[Link]/
contems/psoriasis-epidemiology-dinical-manifestations-and-diagnosis Accessed September 2021.
6. Fowler [Link] MJ, eds. Fisher's Comae! Denmuitis. 7th ed. Contact Dem1atitis Institute; 2019
7. Fransway AF, Reeder MJ. lnitant contact dennatitis in adults. Uptodate. Available online hups://[Link]/contems/
[Link] Sept 19,2021
[Link] H, Cinliffe W, Berson D, et al. Management of acne: a report from a Global AlUance 10 improve outcomes in acne. J Am
Acad Dcm1atol;2003~9
[Link] S, Basruji-GarinS, Poszepczynska-GuigneE, et [Link] of the SCORTEN during the first fivedays of hospitalization
to predict the prognosis of epidcnnal necrolysis. J Invest Dennatol; 2oo6;126:272
10. Kang S, Amagai M, Bruckner AL,et al, editors. Fitzpatrick's Dennatology, 9th Edition. McGraw-Hill Education; 2019.
11. Lawley LP, McCall CO, [Link])' TJ. Eczema, Psoriasis, Cuianeous Infections. Acne, and Other Common Skin Disorders. In:
Jameson JL. Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J, eds. Harrison's Principles of Internal Medicine. 20th ed.
McGraw Hill;2018
12. Michelleti RG, Rosenbach M, Winrroub Bu, Shinkai K. Curaneous Drug Reactions. In: Jameson JL. Fauci AS, Kasper DL, Hauser
SL Longo DL Loscalzo J,eds. Hanison's Principles oflmemal Medicine. 20th ed. McGraw Hill; 20!8
13, Ridley OS and Jopling WH. Classification ofleprosy according to immunity. Int J Lepr Other Mycobact Dis. Jul-Sept 1966;34(3):255
14. WolffK, Johnson RA, Saavedra AP and Roh EK Fitzpa1rick'sColor Adas and Synopsis of Clinical Dem1a1ology,6th Edition; 2013.
15. World Health Organization. Operational Manual, Global Leprosy Strategy [Link] online hups://[Link]/iris/
bitstream/handle/io665'250119/[Link] Accessed October 2021.
16. World Health Organization. Guidelines for the Diagnosis, Treatment, and Prevention of Leprosy:WHO, 2018
17. World Health [Link] Committee on [Link] [Link] Health Organisation Technical Report Series 1998;
18. YanceyKB,L,wley TJ. Approach 10the Patient with a Skin Disorder. In: Jameson JL. Fauci AS, Kasper DL, Hauser SL, Longo DL,
LoscalzoJ,eds. Hanison's Principles oflntemal Medicine. 2oth ed. McGraw Hill;2018
580
 Stevens-Johnson Syndrome 1302.e1

TABLE E1 Classification of Stevens-Johnson Syndrome, Toxic Epidermal

BASIC INFORMATION Necrolysis, and Stevens-Johnson Syndrome–Toxic Epidermal Necrolysis
Overlap
DEFINITION
Stevens-Johnson syndrome (SJS) is a rare, SJS SJS-Ten Ten
severe vesiculobullous form of erythema multi-
forme (EM) affecting the skin, mouth, eyes, and Lesional morphology Targetoid lesions, dusky Targetoid lesions, Targetoid lesions,
genitalia. SJS is defined as affecting <10% of red macules, bullae dusky red macules, dusky erythematous
body surface area (BSA). When it affects 10% to bullae macules and plaques;
30% of BSA, it is known as SJS-toxic epidermal detachment of epi-
necrolysis (TEN) overlap syndrome. TEN affects dermis
>30% of BSA. Table E1 provides a classification Localization of skin May be scattered and May be scattered and iso- -
of SJS and TEN. lesions isolated; may be lated; often ment with widespread
confluent, especially on confluent confluence
SYNONYMS
the trunk and face
SJS
Herpes iris <10% 10%-30% >30%
Febrile mucocutaneous syndrome Biopsy features More interface dermatitis Significant interface der-
matitis + necrolysis
ICD-10CM CODE necrolysis
L51.1 Stevens-Johnson syndrome Mucosal changes May be less than in SJS
Systemic involvement Often present Always present Always present
EPIDEMIOLOGY &
SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis.
DEMOGRAPHICS Hurwitz clinical pediatric dermatology, a textbook of skin disorders of childhood and adolescence, ed

young adults.

PHYSICAL FINDINGS & CLINICAL

PRESENTATION

within 4 wk of drug initiation and is gen-

erally preceded by vague, nonspecific
symptoms of low-grade fever and fatigue
(influenza-like symptoms) occurring 1 to 14
days before the skin lesions. Cough is often
present. Fever may be high during the active
stages. The acute phase of the disease lasts

Fig. E1) or
papules and bullae generally occur on the FIG. E1 Stevens-Johnson syndrome (SJS).
conjunctiva, mucous membranes of the Hurwitz clinical pediatric derma-
mouth ( ), nares, and genital regions. tology, a textbook of skin disorders of childhood and adolescence,
Lesions rapidly spread to their maximum

crusting (Fig. E3).

pressure on skin) can be present.

-
lae may be distributed on the trunk or be
widespread.

fluid intake and result in dehydration.

may interfere with breathing.

Box E1 summarizes features of SJS and TEN.
ETIOLOGY

infections (e.g., Mycoplasma pneumoniae)

and HSV infections have also been implicated.
HLA-B*1502 and FIG. E2 Stevens-Johnson syndrome.
HLA-B*5801, - Hurwitz clinical pediatric dermatology, a textbook of skin
firmed autoimmune diseases. disorders of childhood and adolescence
Stevens-Johnson Syndrome 1302.e2

ACUTE GENERAL Rx

acyclovir for HSV infection, azithromycin for

Mycoplasma infection)

wet Burow compresses

with lidocaine (Xylocaine Viscous)

ensure proper hydration

antibiotics
FIG. E3 Stevens-Johnson syndrome. Mucous membrane involvement with severe swelling and hemor-
Hurwitz clinical pediatric dermatology, a textbook of
and there is a clear risk of sepsis; they should
skin disorders of childhood and adolescence,
be used only in severe cases early in the

bid until new lesions no longer appear, then

BOX E1 Features of Stevens- BOX E2 Most Common rapidly tapered
Johnson Syndrome Pharmacologic Triggers
and Toxic Epidermal of Stevens-Johnson and plaques; however, should not be applied
Necrolysis Syndrome and Toxic to eroded areas
Epidermal Necrolysis
Constitutional
Fever Allopurinol hyposecretion
Dehydration Barbiturates
Mucocutaneous Carbamazepine
Stomatitis with hemorrhagic crusts Lamotrigine DISPOSITION
Oral and genital erosions NSAIDs
Dysphagia Penicillins is generally good in patients with limited dis-
Purulent conjunctivitis with photophobia Phenytoin ease; however, mortality rate may approach
Occasionally esophageal and pulmo- Sulfonamides 10% in patients with extensive involvement. A
nary mucosal sloughing
Dusky erythematous macules, targetoid NSAIDs, Nonsteroidal antiinflammatory drugs.
lesions, bullae, and skin sloughing From Paller AS, Mancini AJ: Hurwitz clinical pediatric that incorporates increased glucose level
dermatology, a textbook of skin disorders of child-
Visceral hood and adolescence, ed 5, 2016, Elsevier.
Lymphadenopathy
Hepatosplenomegaly with hepatitis age (>40 yr), immunosuppression (presence
Uncommonly: Pneumonitis, arthritis, of cancer), involvement >10% of BSA, and
myocarditis, and nephritis
Laboratory abnormalities WORKUP be used to calculate mortality risk.
Increased erythrocyte sedimentation -
rate (100%) sentation and characteristic appearance of
Leukocytosis (60%)
Eosinophilia (20%)
the lesions.
Anemia (15%) -
Elevated hepatic transaminase levels sic lesions are absent and diagnosis is uncertain. REFERRAL
(15%) Biopsy reveals epidermal necrolysis but cannot
Leukopenia (10%) distinguish between SJS, TEN, and EM. extensive burns. Hospital admission in a unit
Proteinuria, microscopic hematuria (5%) used for burn care is recommended in severe
LABORATORY TESTS cases.
From Paller AS, Mancini AJ: Hurwitz clinical pediatric
dermatology, a textbook of skin disorders of child- CBC with differential, cultures in cases of sus-
hood and adolescence, ed 5, 2016, Elsevier. pected infection catheterization.
IMAGING STUDIES an ophthalmologist.
DIAGNOSIS Chest x-rays may show patchy changes in
patients with pulmonary involvement. SUGGESTED READING
DIFFERENTIAL DIAGNOSIS Available at [Link]
TREATMENT
RELATED CONTENT
NONPHARMACOLOGIC THERAPY

Staphylococcus scalded-skin syndrome infection Fred F. Ferri, MD

SUGGESTED READING
A, Camilleri MJ
Mayo Clin Proc
 KEY REFERENCES
7. Tatnall FM, Schofield JK, Leigh IM: A double-blind, place-
bo-controlled trial of continuous acyclovir therapy in re-
6
current erythema multiforme. Br J Dermatol 132:267, 1995
Full reference list available at [Link] 13. Aurelian L, Ono F, Burnett J: Herpes simplex virus (HSV)-
associated erythema multiforme (HAEM): A viral disease
DVD contains references and additional content with an autoimmune component. Dermatol Online J 9:1,
2003
1. Bastuji-Garin S et al: A clinical classification of cases of 20. Wetter DA, Davis MD: Recurrent erythema multiforme:
toxic epidermal necrolysis, Stevens-Johnson syndrome Clinical characteristics, etiologic associations, and treat-
and erythema multiforme. Arch Dermatol 129:92, 1993 ment in a series of 48 patients at Mayo Clinic, 2000 to 2007.
2. Auquier-Dunant A et al: Correlations between clinical J Am Acad Dermatol 62:45, 2010
patterns and causes of erythema multiforme majus, Ste- 21. Riley M, Jenner R: Towards evidence based emergency
vens-Johnson Syndrome and toxic epidermal necrolysis. medicine: Best BETs from the Manchester Royal Infirma-
Arch Dermatol 138:1019, 2002 ry. Bet 2. Steroids in children with erythema multiforme.
5. Weston WL: Herpes-associated erythema multiforme. J Emerg Med J 25:594, 2008
Invest Dermatol 124:xv, 2005

Chapter 40
Chapter 40 :: Epidermal Necrolysis
(Stevens–Johnson Syndrome

::
and Toxic Epidermal Necrolysis)

Epidermal Necrolysis
:: L. Valeyrie-Allanore & Jean-Claude Roujeau
Toxic epidermal necrolysis (TEN) and Stevens–
EPIDERMAL NECROLYSIS Johnson syndrome (SJS) are acute life-threatening
AT A GLANCE mucocutaneous reactions characterized by extensive
necrosis and detachment of the epidermis. Stevens
Rare and life-threatening reaction, mainly and Johnson first reported two cases of disseminated
drug induced. cutaneous eruptions associated with an erosive sto-
matitis and severe ocular involvement.1 In 1956, Lyell
Widespread apoptosis of keratinocytes described patients with epidermal loss secondary to
provoked by the activation of a cell- necrosis and introduced the term toxic epidermal necrol-
mediated cytotoxic reaction and amplified ysis.2 Both SJS and TEN are characterized by skin and
by cytokines, mainly granulysin. mucous membrane involvement. Because of the simi-
larities in clinical and histopathologic findings, risk
Confluent purpuric and erythematous factors, drug causality, and mechanisms, these two
macules evolving to flaccid blisters and conditions are now considered severity variants of an
epidermal detachment predominating on the identical process that differs only in the final extent of
trunk and upper limbs and associated with body surface involved.3–5 Therefore, it is better to use
mucous membrane involvement. the designation epidermal necrolysis for both, as pro-
posed by Ruiz-Maldonado (acute disseminated epi-
Pathologic analysis shows full-thickness dermal necrosis)6 and Lyell (exanthematic necrolysis).7
necrosis of epidermis associated with mild
mononuclear cell infiltrate.
EPIDEMIOLOGY
A dozen “high-risk” drugs account for
one half of cases. Epidermal necrolysis (EN) is rare. The overall inci-
dence of SJS and TEN was estimated at 1 to 6 cases
Up to 20% of cases remain idiopathic.
per million person-years and 0.4 to 1.2 cases per mil-
lion person-years, respectively.8,9 EN can occur at any
age, with the risk increasing with age after the fourth
Early identification and withdrawal of
decade, and more frequently affects women, showing
suspect drugs are essential for good patient
a sex ratio of 0.6. Patients infected with human immu-
outcome.
nodeficiency virus and to a lesser degree patients with
collagen vascular disease and cancer are at increased
Treatment is mainly symptomatic. risk.10–12 The overall mortality associated with EN is
20% to 25%, varying from 5% to 12% for SJS to more
Sequelae are nearly constant, needing than 30% for TEN. Increasing age, significant comor-
systematic follow-up examinations. bidity, and greater extent of skin involvement correlate
with poor prognosis. In the United States, evaluation 439
6 TABLE 40-1
amides, aromatic anticonvulsants, allopurinol, oxicam
nonsteroidal anti-inflammatory drugs, lamotrigine,
SCORTEN: A Prognostic Scoring System for and nevirapine.26–27 The risk seems confined to the first
Patients with Epidermal Necrolysis 8 weeks of treatment. Slow dose escalation decreases
the rate of rash with lamotrigine and nevirapine,28,29 but
SCORTEN there is no evidence that it decreases the risk of EN.26
Prognostic Factors Points Oxcarbazepine, a 10-keto derivative of carbamazepine,
which was considered to carry a lower risk, seems to
Age >40 years 1
significantly cross-react with carbamazepine.30 Many
Heart rate >120 beats/minute 1
Cancer or hematologic malignancy 1 nonsteroidal anti-inflammatory drugs (primarily oxi-
Body surface area involved >10% 1 cam derivatives and diclofenac) were suspected to be
Serum urea level >10 mM 1 associated with EN.12,31,32 A significant but much lower
Serum bicarbonate level >20 mM 1 risk has also been reported for non-sulfonamide anti-
Serum glucose level >14 mM 1 biotics such as aminopenicillins, quinolones, cepha-
losporins, and tetracyclines.22Corticosteroids were
Section 6

Mortality Rate significantly associated with a high relative risk, but

SCORTEN (%) confounding was not excluded.22
0–1 3.2 The role of infectious agents in the development
2 12.1 of EN is much less prominent than for erythema
::

3 35.8 multiforme. However, cases of EN associated with

4 58.3 Mycoplasma pneumoniae infection, viral disease, and
Inflammatory Diseases Based on Abnormal Humoral Reactivity

5 90
immunization have been reported, particularly in
Data from Bastuji-Garin S et al: SCORTEN: A severity-of-illness score children.33,34 These rare observations underscore the
for toxic epidermal necrolysis. J Invest Dermatol 115:149, 2000. fact that medications are not the only cause of EN, but
there is still little evidence that infections can explain
of death certificates suggested a seven time higher risk more than a very small percentage of cases.
of dying from EN among blacks than whites.13 Cases of EN have been reported after bone mar-
A prognosis score (SCORTEN) has been constructed row transplantation. Some are an extreme form of
for EN,14 and its usefulness has been confirmed by sev- acute graft-versus-host disease (see Chapter 28); oth-
eral teams.15–18 (See Table 40-1.) ers could be drug induced. The relationship between
EN and graft-versus-host disease is difficult to assess
because clinical and histological skin features are
ETIOLOGY nearly indistinguishable.35 Lupus erythematosus
(systemic LE or subacute cutaneous LE) is associated
The pathophysiology of EN is still unclear; however, with an increased risk of EN.12,22 In such cases, drug
drugs are the most important etiologic factors. More causality is often doubtful and necrolysis might be
than 100 different drugs have been implicated,19–21 but an extreme phenotype of cutaneous lupus.36 Finally,
fewer than a dozen “high-risk” medications account radiotherapy in addition to treatment with antiepi-
for about one half of cases in Europe (Table 40-2), as leptic drugs, such as phenytoin, phenobarbital, or
evidenced by two multinational case–control stud- carbamazepine, can trigger EN with lesions localized
ies.12,22–25 These high-risk drugs are antibacterial sulfon- predominantly at sites of radiation treatment.37,38 In

TABLE 40-2
Medications and the Risk of Epidermal Necrolysis

High Risk Lower Risk Doubtful Risk No Evidence of Risk

Allopurinol Acetic acid NSAIDs (e.g., Paracetamol (acetaminophen) Aspirin
Sulfamethoxazole diclofenac) Pyrazolone analgesics Sulfonylurea
Sulfadiazine Aminopenicillins Corticosteroids Thiazide diuretics
Sulfapyridine Cephalosporins Other NSAIDs (except aspirin) Furosemide
Sulfadoxine Quinolones Sertraline Aldactone
Sulfasalazine Cyclins Calcium channel blockers
Carbamazepine Macrolides β Blockers
Lamotrigine Angiotensin-converting enzyme inhibitors
Phenobarbital Angiotensin II receptor antagonists
Phenytoin Statins
Phenylbutazone Hormones
Nevirapine Vitamins
Oxicam NSAIDs
Thiacetazone

440 NSAIDs = nonsteroidal anti-inflammatory drugs.

clinical practice, the causality of a medication can be
clearly established in approximately 60% of cases and
CD25+ T cells have been demonstrated to be poten-
tially important in the prevention of severe epidermal
6
suspected in 20%. Other causes (infection, GVH, LE) damage induced by reactive cytotoxic T lymphocytes
are rarely apparent, about 20% of cases as idiopathic.39 in a mouse model of EN.53 Similar regulatory cells may
play a role in drug eruptions in humans.54 Altered
regulation of the immune response to medications in
PATHOGENESIS patients with EN could result from comorbidities that
are frequent, for example, cancer, HIV infection, col-
Even if the precise sequence of molecular and cellu- lagen vascular disease; from comedications, for exam-
lar events is incompletely understood, several studies ple, corticosteroids; or from genetic background.
provided important clues to the pathogenesis of EN. Genetic susceptibility plays an important role in the
The immunologic pattern of early lesions suggests a development of EN to a few “high-risk” medications.
cell-mediated cytotoxic reaction against keratinocytes A strong association was observed in Han Chinese
leading to massive apoptosis.39–41 Immunopathologic from Taiwan between the human leukocyte antigen
studies have demonstrated the presence within early HLA-B*1502 and EN induced by carbamazepine, and

Chapter 40
lesions of cytotoxic cells including natural killer T between HLA-B*5801 and EN induced by allopuri-
cells (NKT) and drug-specific CD8+ T lymphocytes; nol.55,56 B*1502 association with carbamazepine-related
monocytes/macrophages and granulocytes are also cases was confirmed in several Asian countries,57,58
recruited.42–44 However, it is generally accepted that with the remarkable exceptions of Japan and Korea.59,60
specific and nonspecific cytotoxic cells are too few The association between carbamazepine-induced EN

::
within the lesions to explain the death of cells on the and HLA-B*1502 was not present in European patients

Epidermal Necrolysis
full thickness and large areas of the epidermis and who do not have Asian ancestry.61 On the other hand,
mucous membranes. Amplification by cytokines has HLA-B*5801 was confirmed to be associated with
been suspected for years, especially for factors acti- allopurinol-related EN in Japan59 and Europe,62 but the
vating “death receptors” on cell membranes, espe- strength of association was lower than in Taiwan.
cially antitumor necrosis factor (TNF) α and soluble
Fas ligand (Fas-L).42,45 In the past decade it had been
widely accepted that Fas-L was inducing the apopto- CLINICAL FINDINGS
sis of keratinocytes in EN,45,46 despite partial evidence
and discordant findings.47–49 An important recent Even in cases requiring immediate referral to special-
study has challenged this dogma by demonstrating ized wards, the dermatologist will have a specific role
the key role in EN of granulysin.50 Granulysin was in the management of patients with EN (Fig. 40-1).
present in the blister fluid of EN at concentrations
much higher than those of perforin, granzyme B, or
Decision tree for referral of a patient with EN
Fas-L. At such concentrations, only granulysin, and to
a much lesser degree perforin, were able to kill human
Diagnosis of epidermal necrosis
keratinocytes in vitro; Fas-L was not. Furthermore
injection of granulysin in the dermis of normal mice
resulted in clinical and histological lesions of EN.50
When combined, the above results strongly suggest Involved BSA < 10% Involved BSA > 10%
that the effector mechanisms of EN have been deci-
phered. Cytotoxic T-cells develop and are usually spe-
cifically directed against the native form of the drug Serum bicarbonate < 20 mM
Serum urea level > 10 mM
rather than against a reactive metabolite, contrarily Serum glucose level > 14 mM
Slow progression
to what has been postulated for 20 years. These cells No severity marker Respiratory rate > 20
kill keratinocytes directly and indirectly through the pO2 < 80 mm Hg
or rapid progression
recruitment of other cells that release soluble death
mediators, the principal being granulysin.50,51
These advances on understanding the final steps of Stable Progression Transfer to specialized center
the reaction point to inhibition of release and/or block-
ade of granulysin as major aims of therapeutic inter-
ventions. Usual medical wards
Little is known on what are the initial and inter-
mediate steps. We still do not understand why very
few individuals develop a violent immune response Systemic follow-up
to medications and why effector cells are especially High risk of serious sequelae
directed to the skin and other epithelia. Actually, most (skin, eyes, genitalia, mouth, psychic...)
drugs associated with a “high risk” for EN can also
induce a variety of milder and more frequent reactions. Figure 40-1 Decisional tree for referral of a patient with
Drug-specific CD8 cytotoxic T-lymphocytes were also EN. (Adapted from Ellis MW: A case report and a pro-
often found in skin reactions with more benign pheno- posed algorithm for the transfer of patients with Stevens-
type.52 Hence, it is tempting to speculate on an abnor- Johnson syndrome and toxic epidermal necrolysis to a
mal regulation of immune response. Regulatory CD4+ burn center. Mil Med 167:701, 2002) 441
6 HISTORY
junctivitis, and painful micturition. The oral cavity
and the vermilion border of the lips are almost invari-
ably affected and feature painful hemorrhagic ero-
EN clinically begins within 8 weeks (usually 4 to 30 sions coated by grayish white pseudomembranes and
days) after the onset of drug exposure for the first crusts of the lips (Fig. 40-4). Approximately 80% of
time. Only in very rare cases with prior reaction and patients have conjunctival lesions,64,65 mainly mani-
inadvertent rechallenge with the same drug does it fested by pain, photophobia, lacrimation, redness,
appear more rapidly, within a few hours. Nonspecific and discharge. Severe forms may lead to epithelial
symptoms such as fever, headache, rhinitis, cough, defect corneal ulceration, anterior uveitis, and puru-
or malaise may precede the mucocutaneous lesions lent conjunctivitis. Synechiae between eyelids and
by 1 to 3 days. Pain on swallowing and burning or conjunctiva often occur. There may be shedding of
stinging of the eyes progressively develop, heralding eyelashes (see Fig. 40-4B). Genital erosions are fre-
mucous membrane involvement. About one-third of quent, often overlooked in women, and may lead to
cases begin with nonspecific symptoms, one-third synechiae.66
with symptoms of mucous membrane involvement, Shedding of nails occurs in severe forms.
Section 6

and one-third with an exanthema. Whatever the ini-

tial symptoms are, their rapid progression, the addi-
tion of new signs, severe pain, and constitutional EXTRACUTANEOUS SYMPTOMS
symptoms should alert one to the onset of a severe
disease. EN is associated with high fever, pain, and weakness.
::

Visceral involvement is also possible, particularly

Inflammatory Diseases Based on Abnormal Humoral Reactivity

with pulmonary and digestive complications. Early

CUTANEOUS LESIONS pulmonary complications occur in approximately 25%
of patients and are essentially manifested by elevated
The eruption is initially symmetrically distributed respiratory rate and cough, which should prompt
on the face, the upper trunk, and the proximal part strict surveillance.67,68 Bronchial involvement in EN is
of limbs.63 The distal portions of the arms as well as not correlated with the extent of skin lesions or with
the legs are relatively spared, but the rash can rap- the offending agent. In most cases chest radiographs
idly extend to the rest of the body within a few days are normal on admission but can rapidly reveal inter-
and even within a few hours. The initial skin lesions stitial lesions that can progress to acute respiratory
are characterized by erythematous, dusky red, purpu- distress syndrome (ARDS). In all reported cases, when
ric macules, irregularly shaped, which progressively acute respiratory failure developed rapidly after the
coalesce. Atypical target lesions with dark centers are onset of skin involvement, it was associated with poor
often observed (Fig. 40-2A). Confluence of necrotic prognosis. In the case of respiratory abnormalities,
lesions leads to extensive and diffuse erythema. fiberoptic bronchoscopy may be useful to distinguish
Nikolsky’s sign, or dislodgement of the epidermis by a specific epithelial detachment in the bronchi from
lateral pressure, is positive on erythematous zones (Fig. an infectious pneumonitis, which has a much better
40-3 and eFig. 40-3.1 in online edition). At this stage, prognosis.
the lesions evolve to flaccid blisters, which spread with Gastrointestinal tract involvement is less commonly
pressure and break easily (see Fig. 40-2B). The necrotic observed, with epithelial necrosis of the esophagus,
epidermis is easily detached at pressure points or by small bowel, or colon manifesting as profuse diar-
frictional trauma, revealing large areas of exposed, red, rhea with malabsorption, melena, and even colonic
sometimes oozing dermis (see Figs. 40-2C and 40-2D). perforation.69,70 Renal involvement has been reported.
In other areas, epidermis may remain. Proteinuria, microalbuminuria, hematuria, and azote-
Patients are classified into one of three groups mia are not rare. Proximal tubule damage can result
according to the total area in which the epidermis is from necrosis of tubule cells by the same process that
detached or “detachable” (positive Nikolsky): (1) SJS, destroys epidermal cells.71 Glomerulonephritis is
less than 10% of body surface area (BSA); (2) SJS/TEN rare.72
overlap, between 10% and 30%; (3) TEN, more than
30% of BSA (eFig. 40-3.2 in online edition). Correct
evaluation of the extent of lesions is difficult, especially LABORATORY TESTS
in zones with spotty lesions. It is helpful to remember
that the surface of one hand (palm and fingers) repre-
sents a little less than 1% of the BSA.
LABORATORY VALUES
There is no laboratory test to support the diagnosis of
MUCOUS MEMBRANE INVOLVEMENT EN. Laboratory examinations are essential to evalua-
tion of severity and daily management as for all life-
Mucous membrane involvement (nearly always on threatening conditions in intensive care units.
at least two sites) is observed in approximately 90% Evaluation of respiratory rate and blood oxygen-
of cases and can precede or follow the skin eruption. ation are among the first steps to take in the emergency
It begins with erythema followed by painful erosions room. Any alteration should be checked through mea-
of the oral, ocular, and genital mucosa. This usually surement of arterial blood gas levels. Serum bicarbon-
442 leads to impaired alimentation, photophobia, con- ate levels below 20 mM indicate a poor prognosis.14
 6

Chapter 40
::
Epidermal Necrolysis
A B

C D

Figure 40-2 A. Early eruption. Erythematous dusky red macules (flat atypical target lesions) that progressively coalesce
and show epidermal detachment. B. Early presentation with vesicles and blisters, note the dusky color of blister roofs,
strongly suggesting necrosis of the epidermis. C. Advanced eruption. Blisters and epidermal detachment have led to large
confluent erosions. D. Full-blown epidermal necrolysis characterized by large erosive areas reminiscent of scalding.

They usually result from respiratory alkalosis related an unfavorable prognostic factor but is too rare to have
to the specific involvement of bronchi and more rarely a significant impact on SCORTEN. Transient periph-
from metabolic acidosis. eral CD4+ lymphopenia is nearly always seen and is
Massive transdermal fluid loss is responsible for associated with decreased T-cell function. Mild eleva-
electrolyte imbalances, hypoalbuminemia, and hypo- tion in levels of hepatic enzymes and amylase (most
proteinemia, and mild and transient renal insufficiency probably of salivary origin) are frequent but without
and prerenal azotemia are common. Raised blood urea impact on prognosis. A hypercatabolic state is respon-
nitrogen level is one marker of severity. Anemia is sible for inhibition of insulin secretion or insulin resis-
usual, and mild leukocytosis as well as thrombocyto- tance, which results in hyperglycemia and occasionally
penia may occur. Neutropenia is often considered to be overt diabetes. A blood glucose level above 14 mM is 443
6 full-thickness necrosis and subepidermal detachment
(Fig. 40-5). Apoptosis of epithelial cells may involve
sweat glands and hair follicles. A moderately dense
mononuclear cell infiltrate of the papillary dermis is
observed, mainly represented by lymphocytes, often
CD8+ and macrophages.73,74 Eosinophils seems to be
less common in patients with the most severe form of
EN. Results of direct immunofluorescence study are
negative. Histopathology of involved mucous mem-
branes, rarely performed, would show similar altera-
tions.75

DIFFERENTIAL DIAGNOSIS
Section 6

(Box 40-1)
Milder presentations of EN must be distinguished
from erythema multiforme minor (EMM) (see Chap-
ter 39). Early EN cases are often initially diagnosed as
::

varicella. The rapid progression of skin lesions and the

severity of mucous membrane involvement should
Inflammatory Diseases Based on Abnormal Humoral Reactivity

raise the probability of EN.

Figure 40-3 Early exanthematous phase with Nikolsky’s
sign. The absence of mucous membrane involvement or
its restriction to a single site must always raise the
suspicion of an alternative diagnosis: staphylococ-
one marker of severity.14 Other abnormalities in labora- cal scalded skin syndrome in infants; purpura fulmi-
tory values may occur, indicating involvement of other nans in children and young adults; acute generalized
organs and complications such as sepsis. exanthematous pustulosis, phototoxicity, or pressure
blisters in adults. Thermal burns or scalding are occa-
sionally an issue when a transient loss of conscious-
HISTOPATHOLOGY ness occurs.
Linear immunoglobulin (Ig) A bullous disease and
Skin biopsy for routine histologic and possibly immu- paraneoplastic pemphigus present with a less acute
nofluorescence studies should be strongly consid- progression. Pathologic findings and a positive result
ered, especially if there are alternative diagnoses to on direct immunofluorescence testing are important
consider. In the early stages, epidermal involvement for these diagnoses.
is characterized by sparse apoptotic keratinocytes In all aspects, including pathology, generalized bul-
in the suprabasal layers, which rapidly evolves to a lous fixed drug eruption (GBFDE) resembles EN. It

A B

Figure 40-4 A. Extensive erosions and necroses of the lower lip and oral mucosa. B. Massive erosions covered by crusts
444 on the lips. Note also shedding of eyelashes.
 6

Chapter 40
::
Epidermal Necrolysis
A B

Figure 40-5 Histologic appearance of toxic epidermal necrolysis. A. Eosinophilic necrosis of the epidermis in the peak
stage, with little inflammatory response in the dermis. Note cleavage in the junction zone. B. The completely necrotic
epidermis has detached from the dermis and folded like a sheet.

may have a similar drug-related mechanism. How-

ever, the distinction is worthwhile because GBFDE
has a reputation for much better prognosis, probably
BOX 40-1 DIFFERENTIAL DIAGNOSIS because of the mild involvement of mucous mem-
branes and the absence of visceral complications. Prior
OF EPIDERMAL NECROLYSIS (EN)
attacks, rapid onset after drug intake, and very large,
Most Likely well-demarcated blisters are the hallmarks of GBFDE.
Limited EN (Stevens–Johnson syndrome) Toxic destruction of epithelia, whether through con-
tact (fumigants) or ingestion (colchicine poisoning,
Erythema multiforme major
methotrexate overdose), may result in clinical features of
Varicella
EN, but with skin erosions often predominating in the
Widespread EN folds. In these rare cases, causality is generally obvious.
Acute generalized exanthematous pustulosis Overreporting of SJS is common. It usually arises
Generalized bullous fixed drug eruption from confusion between desquamation and detach-
ment of epidermis, and also between mucous mem-
Consider
branes and periorificial skin. Because of such confusion,
Paraneoplastic pemphigus patients with a desquamative rash and scaly lips are
Linear immunoglobulin A bullous disease not rarely diagnosed with and reported as having SJS.
Pressure blisters after coma
Phototoxic reaction
Graft-versus-host disease COMPLICATIONS AND SEQUELAE
Always Rule Out During the acute phase, the most common com-
Staphylococcal scalded skin syndrome plication of EN is sepsis. The epithelial loss pre-
Thermal burns disposes these patients to infections, which are the
Skin necrosis from disseminated intravascular main causes of mortality.4,63 Staphylococcus aureus
coagulation or purpura fulminans and Pseudomonas are the most frequent pathogens,
Chemical toxicity (e.g., colchicine intoxication, but about one-third of positive blood cultures con-
tain enterobacteriae not present on the skin, a find-
methotrexate overdose)
ing that suggests bacterial translocation from gut
lesions.76 Multisystem organ failure and pulmonary 445
6 complications are observed in more than 30% and
15% of cases, respectively.77
A very important advance in EN is the recent under-
standing that sequelae are more frequent and more
severe than previously thought.78 After the well-known
risks of the acute stage, EN behaves as a chronic dis-
ease. More medical attention should be directed to that
phase to better understand the frequency, mechanisms,
and evolution of sequelae. Adequate management and
prevention of sequelae are as important as saving the
life during the acute phase.
A large European cohort has found that 90% of patients
who survived EN suffered from sequelae at 1 year, with
a mean of three different problems per patient and an Figure 40-7 Abnormal regrowth of nails after SJS.
important negative impact on the quality of life for about
Section 6

half of them (RegiSCAR group, unpublished data).

Symptoms suggesting posttraumatic stress disorder one-third of patients who complain of dryness, altered
are not rare. Psychiatric consultation and/or psycho- taste, and late alterations of teeth.79
logical support are probably necessary in a majority Vulvar and vaginal complications of EN are reported
::

of cases. Late ophthalmic complications are reported by about 25% of patients.66 Dyspareunia is not rare and
in 20% to 75% of patients with EN, with a credible is related to vaginal dryness, itching, pain, and bleed-
Inflammatory Diseases Based on Abnormal Humoral Reactivity

figure of about 50% (Fig. 40-6).64,65,78 The relationship ing. Genital adhesions may lead to the requirement
between the initial severity of ocular involvement and for surgical treatment. Esophageal, intestinal, urethral,
the development of late complications seems now to and anal strictures may also develop in rare cases.
be well established. Late ophthalmic complications are Chronic lung disease can be observed after EN, often
mainly due to functional alteration of the conjunctival attributed to bronchiolitis obliterans, and occasionally
epithelium with dryness and abnormal lacrimal film. requires lung transplantation.68,80 Because these late
This leads to chronic inflammation, fibrosis, entropion, complications and sequelae may develop insidiously,
trichiasis, and symblepharon. Long-term irritation it is strongly suggested that all patients surviving EN
and deficiency of stem cells in the limbus may result have a clinical follow-up a few weeks after discharge
in metaplasia of corneal epithelium with painful ulcer- and 1 year later, including examination by an ophthal-
ations, scarring, and altered vision. Such severe eye mologist and by other organ specialist(s) as indicated
lesions occasionally develop in patients who had no by abnormal signs and symptoms.
patent ocular signs during the acute phase of EN.64
Hypopigmentation and/or hyperpigmentation are
most frequent; residual hypertrophic or atrophic scars PROGNOSIS AND CLINICAL COURSE
rarely occur. Nail changes, including change in pig-
mentation of the nail bed, ridging, dystrophic nails, The epidermal detachment progresses for 5 to 7 days.
and permanent anonychia, occur in more than 30% of Then, patients enter a plateau phase, which corresponds
cases (Fig. 40-7). Mouth sequelae are present in about to progressive reepithelialization. This can take a few
days to a few weeks, depending on the severity of the
disease and the prior general condition of the patient.
During this period, life-threatening complications such
as sepsis or systemic organ failure may occur. The
overall hospital mortality rate of EN is 22–25%, vary-
ing from 5% to 12% for SJS to more than 30% for TEN.
The prognosis is not affected by the type or dose of the
responsible drug or the presence of human immunode-
ficiency virus infection (see Table 40-1).12,14,63,77
Prospective follow-up has shown an additional
abnormally increased mortality in the 3-month period
following hospital discharge, which seems to result
from the negative impact of EN on prior severe chronic
conditions, for example, malignancies (RegiSCAR,
unpublished data).

TREATMENT
Figure 40-6 Late ocular complications of SJS. Note
opaque corneal epithelium, neovessels, and irritating eye- EN is a life-threatening disease that requires optimal
lashes on lower eyelids. (Photograph provided by Julie management: early recognition and withdrawal of the
Gueudry MD and Marc Muraine MD, PhD, Hôpital Charles offending drug(s) and supportive care in an appropri-
446 Nicolle, Rouen, France.) ate hospital setting.
 Prompt withdrawal of offending agent(s) is asso-
ciated with an increased rate of survival in patients
preserved amniotic membrane has been proposed as
capable to decrease the rate of severe eye sequelae.64
6
with EN induced by drugs with short elimination half- The mouth should be rinsed several times a day
lives.81 On the other hand, it is preferable to continue with antiseptic or antifungal solution.
every important and nonsuspected medication. That
will avoid reluctance on the part of the patient’s physi-
cians to prescribe them in the future. In case of doubt, all SPECIFIC TREATMENT IN ACUTE STAGE
nonlife-sustaining drugs should be stopped, and partic-
ularly those administered within the previous 8 weeks. Because of the importance of immunologic and cyto-
toxic mechanisms, a large number of immunosuppres-
sive and/or anti-inflammatory therapies have been
SYMPTOMATIC TREATMENT tried to halt the progression of the disease. None has
clearly proved its efficacy. The low prevalence of the dis-
Only patients with limited skin involvement, a ease makes randomized clinical trials hard to perform.
SCORTEN score of 0 or 1, and a disease that is not

Chapter 40
rapidly progressing can be treated in nonspecialized CORTICOSTEROIDS. The use of systemic corti-
wards. Others should be transferred to intensive care costeroids is still controversial. Some studies found
units or burn centers.82 There is no “specific” treatment that such therapy could prevent the extension of the
of demonstrated efficacy and supportive measures are disease when administered during the early phase,
the most important.5 Supportive care consists of main- especially as intravenous pulses for a few days.86

::
taining hemodynamic equilibrium and preventing life- Other studies concluded that steroids did not stop the

Epidermal Necrolysis
threatening complications. The aims are basically the progression of the disease and were even associated
same as for extensive burns. with increased mortality and adverse effects, particu-
EN is associated with significant fluid loss from ero- larly sepsis. Thus, systemic corticosteroids cannot be
sions, which results in hypovolemia and electrolyte recommended as the mainstay treatment of EN,5 but
imbalance. Fluid replacement must be started as soon a large cohort study has suggested a possible benefit
as possible and adjusted daily. Volumes of infusions are that should be explored by a prospective study.87
usually less than for burns of similar extent, because
interstitial edema is absent. Peripheral venous lines are INTRAVENOUS IMMUNOGLOBULIN. The
preferred when possible, because the sites of insertion of proposal to use high-dose intravenous Ig was based
central lines are often involved in detachment of epider- on the hypothesis that Fas-mediated cell death can be
mis and prone to infection. The environmental tempera- abrogated by the anti-Fas activity present in commer-
ture should be raised to 28°C to 30°C (82.4°F to 86°F). The cial batches of normal human Ig .45 Benefits have been
use of an air-fluidized bed improves patient comfort. claimed by several studies and case reports,45,88–90 but
Early nutritional support is preferentially pro- refuted by several others.16,87,91,92 Thus, intravenous Ig
vided by nasogastric tube to promote healing and to cannot be considered the standard of care,5 especially
decrease the risk of bacterial translocation from the after recent findings that the Fas-L/Fas pathway was
gastrointestinal tract. To reduce the risk of infection, not, or only marginally, involved in the mechanisms of
aseptic and careful handing is required. Skin, blood, EN.50 If used, a minimal precaution is to avoid prepara-
and urine specimens should be cultured for bacteria tions that are potentially nephrotoxic.
and fungi at frequent intervals. Prophylactic antibiot-
ics are not indicated. Patients should receive antibiot- CYCLOSPORINE A. Cyclosporine is a powerful
ics when clinical infection is suspected. Prophylactic immunosuppressive agent associated with biologic
anticoagulation is provided during hospitalization. effects that may theoretically be useful in treatment of
We do not recommend extensive and aggressive EN: activation of T helper 2 cytokines, inhibition of CD8+
debridement of necrotic epidermis in EN because the cytotoxic mechanisms, and antiapoptotic effect through
superficial necrosis is not an obstacle to reepithelial- inhibition of Fas-L, nuclear factor-κB, and TNF-α. Sev-
ization, and might even accelerate the proliferation eral case reports and series suggested some efficacy of
of stem cells due to the inflammatory cytokines. This cyclosporine A in halting the progression of EN without
is the single noticeable divergence between authors worrisome side effects when administered early.93,94
of this chapter and the recommendations of US Burn
centers.5 A few recent series suggest that debride- PLASMAPHERESIS OR HEMODIALYSIS. The
ment is necessary neither in superficial burns81 nor in rationale for using plasmapheresis or hemodialysis is
EN. 84,85 There is no standard policy on wound dressings to prompt the removal of the offending medication, its
and the use of antiseptics. It is a matter of experience metabolites, or inflammatory mediators such as cyto-
for each center. Skillfulness on the part of specialized kines. A small series reported their efficacy and safety
nurses, careful manipulation, and an aggressive proto- in treating EN.95–98 However, considering the absence
col of prevention and treatment of pain are essential. of evidence and the risks associated with intravascular
Eyes should be examined daily by an ophthalmolo- catheters, these treatments cannot be recommended.
gist. Preservative-free emollients, antibiotic or anti-
septic eye drops, and vitamin A are often used every ANTITUMOR NECROSIS FACTOR AGENTS.
2 hours in the acute phase, and mechanical disruption Anti-TNF monoclonal antibodies have been success-
of early synechiae is indicated. Early graft of cryo- fully used to treat a few patients. Because a prior 447
6 randomized controlled trial of thalidomide, an anti-
TNF agent, had to be interrupted due to significantly
A list of the suspected medication(s) and molecules
of the same biochemical structure must be given to the
increased mortality,99 extreme caution is suggested in patient on a personal “allergy card.” It is also very use-
the use of anti-TNF agents to treat EN. ful to provide a list of drugs of common use that cannot
be suspected. Because of recent indications of genetic
susceptibilities to the development of EN, prescription
TREATMENT OF SEQUELAE of the offending agent to family members should also
be avoided.
Very promising treatments have now been developed
for the ocular sequelae of EN, including gas permeable
scleral lenses100,101 and grafting of autologous stem cells KEY REFERENCES
from contralateral limbus or mouth mucosa.102,103 With
the exception of ocular sequelae, the literature contains Full reference list available at [Link]
only case reports related to treating sequelae. Photo- DVD contains references and additional content
protection and cosmetic lasers may help resolve the
Section 6

pigmentation changes on the skin. 3. Bastuji-Garin S et al: Clinical classification of cases of

toxic epidermal necrolysis, Stevens-Johnson syndrome,
and erythema multiforme. Arch Dermatol 129:92, 1993
PREVENTION 5. Endorf FW et al: Toxic epidermal necrolysis clinical
guidelines. J Burn Care Res 29:706, 2008
::

22. Mockenhaupt M et al: Stevens-Johnson syndrome and toxic

Primary prevention is only feasible in populations where epidermal necrolysis: Assessment of medication risks with
Inflammatory Diseases Based on Abnormal Humoral Reactivity

a strong association has been established between a sim- emphasis on recently marketed drugs. The EuroSCAR-
ple genetic maker and the risk of EN. That is the case study. J Invest Dermatol 128:35, 2008
23. Auquier-Dunant A et al: Correlation between clinical
for HLAB*1502 and EN induced by carbamazepine. The patterns and causes of erythema multiforme major, Ste-
FDA has issued the recommendation to test patients vens Johnson and toxic epidermal necrolysis. Arch Der-
from “Asian ancestry” for HLAB*1502 before prescrib- matol 138:1019, 2002
ing carbamazepine. This recommendation should be 25. Halevy S et al: Allopurinol is the most common cause of
refined to exclude persons of Japanese or Korean origin. Stevens-Johnson syndrome and toxic epidermal necroly-
sis in Europe and Israel. J Am Acad Dermatol 58:25, 2008
In individuals of Han Chinese origin, alternative anti- 36. Ting W et al: Toxic epidermal necrolysis-like acute cuta-
epileptic drugs can be carefully prescribed, although neous lupus erythematosus and the spectrum of the
there may be an association of EN with phenytoin and acute syndrome of apoptotic pan-epidermolysis (ASAP):
HLAB*1502 as well.57 The present status of research on A case report, concept review and proposal for new clas-
the pharmacogenetics of EN (RegiSCAR unpublished sification of lupus erythematosus vesiculobullous skin
lesions. Lupus 13:941, 2004
data) makes unlikely the finding of other genetic mark- 44. Nassif A et al: Drug specific cytotoxic T-cells in the skin
ers useful for primary prevention. lesions of a patient with toxic epidermal necrolysis. J
Secondary prevention is important for patients who Invest Dermatol 118:728, 2002
experienced EN and are reluctant to take any medi- 50. Chung WH et al: Granulysin is a key mediator for dis-
cation. The most important issue is to evaluate drug seminated keratinocyte death in Stevens-Johnson syn-
drome and toxic epidermal necrolysis. Nat Med 14:1343,
causality. In vitro tests or patch tests to medications 2008
occasionally can be useful in the exploration of drug 54. Takahashi R et al: Defective regulatory T cells in patients
allergy. When used in EN patients, their sensitivity is with severe drug eruptions: Timing of the dysfunction
low.104,105 Careful inquiry into all exposures to medica- is associated with the pathological phenotype and out-
tions in the few weeks preceding the onset of the reac- come. J Immunol 182:8071, 2009
55. Chung WH et al: Medical genetics: A marker for Stevens
tion leads to the identification of a probable culprit Johnson syndrome. Nature 428:486, 2004
drug in approximately 70% of cases. The most useful 56. Hung SI et al: HLA-B*5801 allele as a genetic marker for
clinical criteria are duration of treatment before onset severe cutaneous adverse reactions caused by allopurinol.
(typically 4 to 30 days), absence of prior intake, and Proc Natl Acad Sci U S A 102:4134, 2005
use of a drug known for being associated with a high 62. Lonjou C et al: A European study of HLA-B in Stevens-
Johnson syndrome and toxic epidermal necrolysis
risk.39 related to five high-risk drugs. Pharmacogenet Genomics
The few published cases of recurrent SJS or TEN 18:99, 2008
were always due to inadvertent readministration of 64. Shay E et al: Amniotic membrane transplantation as a
the same or a very closely related medication. Epide- new therapy for the acute ocular manifestations of Ste-
miology and in vitro studies suggest that the list of vens-Johnson syndrome and toxic epidermal necrolysis.
Surv Ophthalmol 54:686, 2009
possible cross-reactive medications is rather narrow, 87. Schneck J et al: Effects of treatments on the mortality of
based on close chemical similarities. As an example, Stevens-Johnson syndrome and toxic epidermal necroly-
there is no evidence that patients who experienced SJS sis: A retrospective study on patients included in the
or TEN in reaction to an anti-infectious sulfonamide prospective EuroSCAR Study. J Am Acad Dermatol 58:33,
are at increased risk for reaction to sulfonamide- 2008
101. Tougeron-Brousseau B et al: Vision-related function after
related diuretics or antidiabetic medications. Only scleral lens fitting in ocular complications of Stevens-
anti-infectious sulfonamides should be contraindi- Johnson syndrome and toxic epidermal necrolysis. Am J
cated in this situation. Ophthalmol 148:852, 2009

448
Allergology International. 2006;55:9-16
REVIEW ARTICLE

Toxic Epidermal Necrolysis and

Stevens Johnson Syndrome: Our
Current Understanding
Lars E French1

ABSTRACT
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN, Lyell’s syndrome) are now considered
to be distinct clinical entities within a spectrum of adverse cutaneous drug reactions of increasing severity
based on their surface of skin detachment. Within this spectrum, SJS which can be considered as a minor form
of TEN is characterized by less than 10% body surface area of skin detachment, and an average reported mor-
tality of 1 5%, whereas TEN is characterized by more than 30% skin detachment, and an average reported
mortality 25 35%.
Both SJS and TEN are characterized morphologically by the rapid onset of keratinocyte cell death by apopto-
sis, a process that results in the separation of the epidermis from the dermis. Recent evidence is supportive of
a role for inflammatory cytokines and the death receptor Fas and its ligand FasL in the pathogenesis of kerati-
nocyte apoptosis during TEN. This Fas-mediated keratinocyte apoptosis that is the last step culminating in epi-
dermal detachment in TEN can be inhibited in vitro by antagonistic monoclonal antibodies to Fas, and by intra-
venous immunoglobulins (IVIG) which have been shown to contain natural anti-Fas antibodies.
Consequently, over the last few years, numerous case reports and 9 non-controlled clinical studies containing
10 or more patients have analyzed the therapeutic effect of IVIG in TEN. Taken together, although each study
has its potential biases, 7 of 9 such studies point towards a benefit of IVIG used at doses greater than 2 g!kg
on the mortality associated with TEN. These studies should serve as the basis for designing an appropriate
prospective trial or for conducting a metaanalysis in the near future, in order to determine the therapeutic effi-
cacy of IVIG in TEN.

KEY WORDS
apoptosis, Fas, intravenous immunoglobulin, Lyell’s syndrome, Severe adverse drug reaction

neous lesions. It became known as Stevens-Johnson

INTRODUCTION syndrome (SJS) and was recognized as a severe mu-
Stevens-Johnson syndrome (SJS) and toxic epidermal cocutaneous disease with a prolonged course and oc-
necrolysis (TEN) are severe adverse drug reactions casional fatalities, and is now known to ba an adverse
characterized by a low incidence but high mortality. drug reaction and clinically distinct from erythema
The incidence of SJS is approximately 6 cases per multiforme major which is in most cases para-
million persons per year, and that of TEN is approxi- infectious. 2-4 TEN, also called Lyell’s syndrome was
mately 2 cases per million persons per year.1 first described by the scottish dermatologist Alan
Historically, SJS was first described in 1922 by two Lyell in 1956. He reported four patients with an erup-
American physicians named Stevens and Johnson . tion ‘resembling scalding of the skin objectively and
They described an acute mucocutaneous syndrome subjectively’, which he called toxic epidermal necroly-
in two young boys characterized by severe purulent sis or TEN.5 ‘Toxic’ referred to toxemia-circulation of
conjunctivitis , severe stomatitis with extensive mu- a toxin-which was thought at the time to be responsi-
cosal necrosis, and ‘Erythema multiforme-like’ cuta- ble for the constitutional symptoms and epidermal

1Department of Dermatology, Geneva University Hospital and Email: [Link]@[Link]

Medical School, Geneva, Switzerland. Received 9 November 2005.
Correspondence: Lars [Link], M.D., Department of Dermatol- !2006 Japanese Society of Allergology
ogy, Geneva University Hospital, 24 rue Micheli−du − Crest CH −
1211 Gen ve 14, Switzerland.

Allergology International Vol 55, No1, 2006 http:!!

[Link]! 9
 French LE

Stevens Johnson Toxic Epidermal

Maculo-papular rash Necrolysis(TEN)
Syndrome

Epidermal
0% 1 10% 30%
detachment:
Average
0% 1 5% 25 35%
mortality:

!"#$%&!"#$!%&$'(
)*+!
,-!
./0$)
%$!
/)*1!
)$.'(
2
!"#$
!%$
&"'(
)*#&
"+$
#),)(
&-
.$(
*"+&
"+$
%!
"#$
%&'$
(')*
+)$
#,-./
"01,1./
,!$
!"#$%&
'%()(*
%"+,%
-./

[Link] coined the term ‘necrolysis’, by com- Garin et al. refer to as SJS-TEN overlap, 3 and severe
bining the key clinical feature ‘ epidermolysis’ with (>30% TBSA)in full-blown TEN (Fig. 1). Within this
the characteristic histopathological feature ‘necrosis’. spectrum, the severity or extent of epidermal detach-
He also described an attack on the mucous mem- ment is tightly correlated with the observed rate of
branes as part of the syndrome, and noted that there mortality, the latter ranging from 1 5% in SJS to 25
was very little inflammation in the dermis, a feature 35% in TEN according to the epidemiological studies
that was later referred to as ‘dermal silence’. 6 This puiblished in the litterature over the past decade.1,7,8
feature contrasted with the obvious inflammatory in- With the objective of being able to precisely predict
filtrate of other blistering disorders such as erythema patient mortality, Batuji-Garin et al. have recently pro-
multiforme , dermatitis herpetiformis , and bullous posed a scoring system for TEN named the
pemphigoid. Although the origin of the ‘ toxin’ was SCORTEN severity of illness score (Fig. 2). 9 Seven
not immediately obvious, it is now well established clinico-biologic parameters including known adverse
that an adverse reaction to certain drugs is the cause prognostic factors such as age greater than 40-years
of TEN and initial surface of epidermal detachment greater
than 10%, are given one point if positive and zero if
CLINICAL FEATURES OF STEVENS- negative. Computing the sum of the scores for each
JOHNSON SYNDROME AND TOXIC EPI- clinico-biologic parameter results in a “ SCORTEN ”
DERMAL NECROLYSIS ranging from 0 to 7, with a score of 0 or 1 predicting a
SJS and TEN are idiosyncratic in nature and thereby mortality of 3.2%, and a score of 5 or above predicting
have the potential to affect any individual taking a a mortality of greater than 90%. This scoring system
medication, the most frequently incriminated drugs that was developped with a french-based patient co-
being antibiotics , non-steroidal anti-inflammatory hort has recently been validated in a US-based patient
drugs and anti-convulsants . SJS and TEN are cur- cohort, 10 and is proving to be a valuable tool for pre-
rently considered to be part of a spectrum of clinically dicting patient outcome.
and pathogenically related drug-induced skin dis- Initial symptoms of both TEN and SJS can be fever,
eases with increasing severity (Fig. 1). In contrast to stinging eyes , and pain upon swallowing , any of
the common morbiliform drug rash that is not associ- which can precede cutaneous manifestations by 1 to 3
ated with epidermal detachment, both SJS and TEN days. Skin lesions tend to appear first on the trunk,
are characterized by epidermal detachment ranging spreading to the neck, face, and proximal upper ex-
from mild(1 10% of total body surface area (TBSA) in tremities. The distal portions of the arms as well the
SJS), to moderate (10 30% TBSA) in what Bastuji- legs are relatively spared, but the palms and soles can

10 ![Link]!
Allergology International Vol 55, No1, 2006 http:!
 Toxic Epidermal Necrolysis

!"# $#!%"& '#("()#!*+%& !"#$%&'( !"#$%&'#$(

!
"#!
$!#%&'(
)*+,-
!"#$%$! !
"#$%!
&'!
()*(
+(*$,-
!#.&/
0#1 !
"#$%&'( %)!
!*
+,
!"#! !"# !"#! !"
#$%! ! !! ! !"#
!"#$%&"&' ( !"#! !"
#$%! ! ! !"#
!
!"#$%#"& '(")
*! !"#$%&'( !"#! !"
#$%! ! ! !"#
!
!
"#$
#%&'( )*+
%,-'.+'-/#0-*1%&
' !"#! !"
#$%! ! ! !"#
$
!"#$%&'"(#! !"#
!"#$%& $#"'! !"#$$%& '( !"#! !"
#$%! ! !
! " !"
!"#$%& '($)*+"&
! !"#$$%& '
( !"#! !"
#$%! !
!"#$%&'($)*+! !"#$$%&'( !"#! !"
#$%! !

!"
#$%&!!"#$
%&'(!)*$
+,-
.-
+/,
$0+12
-.3$
0405
#6$
!"#
$%#
&'(
)*
(+,$
"-*
)".&$
(+$
/01!

be an early site of involvement. Erythema and ero- drugs and SJS, as only 50% of reported SJS cases are
sions of the buccal, ocular , and genital mucosa are claimed to be drug related. This is certainly an under-
present in more than 90% of patients. The epithelium estimation, however, and most likely is due, in part,
of the respiratory tract is involved in 25% of cases of to the confusion that previously existed concerning
TEN, and gastrointestinal lesions can also occur. The the diagnostic distinction between SJS and erythema
skin lesions are usually tender, and mucosal erosions multiforme.
are very painful. The morphology of the skin lesions More than 100 drugs have been identified to date
has been studied in detail. First , lesions appear as as being associated with SJS !TEN . The most fre-
erythematous, dusky-red, or purpuric macules of ir- quently implicated drugs consist primarily of antibiot-
regular size and shape, and have a tendency to coa- ics, NSAIDs, and anticonvulsants. Among the former,
lesce. At this stage, and in the presence of mucosal sulfonamides are the most strongly associated with
involvement and tenderness , the risk of rapid pro- SJS! TEN; other antibiotics include aminopenicillins,
gression to SJS or TEN should be strongly suspected. quinolones, cephalosporins, tetracyclines, and imida-
As the epidermal involvement progresses toward full- zole antifungals. For these drugs, the risk of develop-
thickness necrosis , the dusky-red macular lesions ing SJS! TEN is reported to be highest during the in-
take on a characteristic gray hue. This process can be itial week (s) of therapy. For the aromatic anticonvul-
very rapid (hours), or take several days. The necrotic sants, the risk is highest during the first 2 months of
epidermis then detaches from the underlying dermis, treatment. 14 Furthermore, drugs with long half-lives
and fluid fills the space between the dermis and the are more likely to cause drug reactions and a fatal
epidermis, giving rise to blisters. The blisters have outcome than those with short half-lives, even if they
special features: they break easily (flaccid) and can are chemically related.15
be extended sideways by slight pressure of the
thumb as more necrotic epidermis is displaced later- PATHOGENESIS
ally (Nikolsky sign). The skin resembles wet ciga- To date, the precise sequence of molecular and cellu-
rette paper as it is pulled away by trauma, often re- lar events that lead to the development of SJS! TEN is
vealing large areas of raw and bleeding dermis only partially understood. The proposed pathogene-
sis has to take into account the rarity of these dis-
EPIDEMIOLOGY eases and the involvement of specific types of drugs.
SJS and TEN are rare diseases with an annual inci- Circumstantial evidence suggests that SJS! TEN is
dence of 1.2 6 and 0.4 1.2 per million persons, re- associated with an impaired capacity to detoxify reac-
spectively. TEN affects women more frequently than tive intermediate drug metabolites. It is thought to be
men with a ratio of 1.5 : 1, and the incidence in- initiated by an immune response to an antigenic com-
creases with age.11 Patient groups particularly at risk plex formed by the reaction of such metabolites with
are those with slow acetylator genotypes , immuno- certain host tissues . 16-20 Genetic susceptibility may
compromised patients ( e . g . HIV infection , lym- also play a role, as evidenced by the increased inci-
phoma), and patients with brain tumors who are un- dence of HLA-B12 in individuals affected by TEN. 21
dergoing radiotherapy and concomitantly receiving In SJS and TEN due to allopurinol, a genetic predis-
antiepileptics.12,13 position in Han Chinese with the HLA-B*5801 allele
Use of therapeutic drugs is reported in over 95% of has recently been identified.22 Furthermore, a strong
patients with TEN . A strong association between association between HLA-B*1502, and Stevens-
drug ingestion and development of the cutaneous Johnson syndrome induced by carbamazepine was
eruption is observed in 80% of cases . Other rare also reported in the Han Chinese population.23
causes include infections and immunizations. The lit- Cytotoxic T cells expressing the skin-homing re-
erature reflects a less clear relationship between ceptor , cutaneous lymphocyte-associated antigen

Allergology International Vol 55, No1, 2006 http:!!

[Link]! 11
 French LE

(CLA), are seen early in the development of cutane- FasL Normal skin
ous lesions. 24-26 These are likely to be drug-specific intracellular Death receptor Specific Ligand
cytotoxic T cells. 27,28 Important cytokines such as in- (Fas) (FasL)
terleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-
alpha), interferon gamma, interleukin 18 (IL-18), and
No
Fas ligand (FasL) are also present in the lesional epi- Ligand-Receptor
dermis and or blister fluid of patients with TEN, and contact
their actions could explain some of the constitutional
symptoms of TEN as well as the frequently observed
discrepancy between the extent of epidermal damage
and the paucity of the inflammatory infiltrate . 29 No death
Lastly, the typical interval between the onset of drug signal
therapy and SJS! TEN is between 1 and 3 weeks, sug-
gesting a period of sensitization and providing further
support for the role of the immune system in the
pathogenesis of SJS! TEN. This period (‘memory’) is Toxic Epidermal Necrolysis
considerably shortened in patients who are unfortu- FasL (Fas) (FasL)
nately re-exposed to a drug that previously resulted extracellular
in SJS or TEN
Recently, it has been clearly shown that the tissue
damage described by pathologists as epidermal ne-
Ligand-Receptor
crolysis is due to massive keratinocyte cell death via
contact
apoptosis. 30 Keratinocyte apoptosis is clearly a hall-
mark of the early stages of SJS and TEN, and it is the
first clear morphological sign of tissue damage in this
[Link] more classic histologic image of exten- Death
sive epidermal ‘necrolysis’ is in fact an image of the signaling
aftermath of keratinocyte apoptosis, since the apop-
Specific inhibition
totic state of cells is known to be transient in nature
possible ? (IVIG)
Recent advances in our understanding of the mo-
lecular control of apoptosis have provided insights !"#$%&!"#$% &'() #*'(!+', #*)-./0* '!#1.1* .$)$
!" #!$%&!
into a possible triggering mechanism for the massive !"#$%&' ("')!*$+(,-!") .+$&/ $) "-) 0)
')&!"#$"% &%'"( )*"
keratinocyte apoptosis that characterizes TEN and !"#$%& !'()*%( %#+!& ,
(+*- $#& (!%. /!-$. 0!"#$%& "'%()" $*+
probably also SJS. Certain cytokines of the TNF fam- !"#$$%&'()'*( %
'+"),#--.-)"(-&,)-%$)+!"#$ %&'('#)$*!#+!#,$)"$
ily, by binding to their specific cell-surface receptors !"#$"%&$'()
**+( )
%*$ ,-$
.+( "')
%,/0' +$"!"!# "$%$&'
("##")' !*+,
(death receptors), have the ability to induce apopto-
!"
#$%&'()$!*(+!, -." $
/!) ,&"0 1(
1 2
$3/+4!" #$%&$'&()*+"#%$!,")&
sis.31 We and others have recently shown that kerati-
!"#$% &'()&##*+,%",-% *,.&)"/.*+,% 0*.1!"#$! #%!
%&'!('))!$
*+,
nocyte apoptosis in lesional skin of patients with TEN
!
"# $%&
'$"()*+&,-&.$/",)
*-# 0,
$& "1-1, -!" !
#$
is associated with highly increased expression of
keratinocyte membrane-bound FasL , together with
conserved levels of keratinocyte Fas expres-
sion. 29,32,33 Functional experiments , performed by Upon contact with Fas, cell surface FasL induces Fas
overlaying cryostat sections of lesional skin with Fas- multimerization and rapid signaling of keratinocyte
sensitive cells as targets, have further demonstrated cell death by apoptosis . As Fas and FasL are co-
that keratinocyte FasL is cytolytically active in TEN. expressed on a large number of keratinocytes in le-
This cytolytic activity can be blocked with monoclo- sional skin, keratinocyte apoptosis can be abundant,
nal antibodies that interfere with the interaction of resulting in the destruction of large areas of epider-
Fas and FasL, thus supporting the hypothesis that in- mis. This recent concept of the pathogenesis of TEN
creased keratinocyte FasL expression is responsible provides new potential avenues for therapeutic inter-
for the keratinocyte apoptosis that characterizes vention
TEN
The emerging model as shown in Figure 3 is that, TREATMENT
in normal skin, low levels of FasL are expressed by Optimal medical management of SJS and TEN re-
keratinocytes and localized intracellularly . 34 In le- quires early diagnosis, immediate discontinuation of
sional skin of TEN, high levels of FasL are expressed the causative drug(s), supportive care, and specific
by keratinocytes and localized at the cell surface. As a therapy. Attempts have been made to decrease mor-
result, cell surface interactions between keratinocyte tality in TEN patients essentially through improved
Fas and FasL on adjacent cells are then possible . supportive care. The low prevalence of TEN makes

12 ![Link]!
Allergology International Vol 55, No1, 2006 http:!
 Toxic Epidermal Necrolysis

!" #
$%& !" #$%& !"#$%& ' !"#$%&& !" #$%
!"#$
%& !"#$% &'() !"
#$%& '()
(* !"#
!"#$% !"#$ !"#$% !"#$%&" !"#$%&"
!"# $%& !
"#$
%&#%! !"#$%&'( )% !
"#$%
$&'( )$ !"
#$% &'()*
"
!"# $ !"# $% !"# $ !"#$% !"# $
!""# !""# !""# !""#
!""# !""# !""# !""# !""#
!"#$%& !"# $%&'( !"#$%&'( ! "#$%&! !"#$%& !"# $
%&' !"# $%&' !"#$% !"# $
%&'
!"#$%&
!"#$%"#& !"#$ %"#& !"#$ %"#& !"#$ %"#& !"#$ %"#& !"#$%"#& !"#$ %"#& !"#$ %"#& !"#$ %"#&
!"#$%&#' !" !" !" !" !" !" !" !" !"
!"# !" !" !" !" !" !" !" !" !"
!"#$% &'"(# !"#$ !" !" !" !" !"#$%
&'() !" !" !"
!"# $%&'&( !"#$
%# !"#$%# !"#$%# !"#$%# !"#$%# !"#$%&'% !"#$ %&
'% !! !"#$%# !"#$%#
!"#$%&'#$(
!!!
!! !!!
!! !"
#$%&'()!" #$%#&'( !"#$%!#&' !"
#$%&' !"
#$%&
!'( !
!!
!! !
!!
!!
!"#$%&
!"#$%&'
!"
#!!"#$! !"
#$! "
#$!! !"
!#! !!"# !!"!
"#!" !" !"#$% !"
!"#$% !!!
"#$%
&'( !!
!"#$ !"
!"#$
!"#$%&

!"
#$%&!"#$$%&
'!()
!*+
#,-
.*!
&./(&
+-
01!
+2.!
.)!
"#$
%&!
%'
(')%
*+%
,&-
"%$
./+%
01%
2/$
*"+$
!"#
$%&
#'()
#*
+,(*
)+-"

randomized clinical trials hard to perform however, days) starting on average 7.3 days after the onset of
and consequently most reported therapeutic ap- disease.42 Success was concluded based upon an 88%
proaches consist of individual cases or small uncon- survival rate, but also the rapid (mean of 2.3 d) cessa-
trolled series. In such studies, several treatments, in- tion of skin and mucosal detachment in 89.6% of pa-
cluding cyclosporine (ciclosporin; 3 4 mg!kg!day), tients. Mortality was associated with a lower dose of
cyclophosphamide (100 300 mg! day), plasmaphere- IVIG, longer time of onset to IVIG use, co-existing un-
sis, and N-acetylcysteine (2 g! 6hr) have shown prom- derlying chronic conditions, older age , and greater
ising results. 35-40 The use of systemic corticosteroids body surface area involved
remains controversial, and it may even increase mor- Two other studies published simultaneously by
[Link], a controlled study using thalidomide Trent et al. and Bachot et al., used SCORTEN to com-
was interrupted because of higher mortality in the pare the effect of IVIG on expected mortality and re-
thalidomide group (10 of 12 patients died) compared ported contradictory results.43,44 Trent et al. analyzed
with the placebo group (3 of 10 patients died). 41 It in a retrospective non controlled manner 16 patients
was suggested that the increased mortality may have with a mean TBSA of epidermal detachment of 43%,
been due to a paradoxical increase in TNF-alpha pro- and Bachot et al. studied in a prospective non con-
duction trolled manner 34 patients with a mean TBSA of epi-
In theory, and based on recent research, therapies dermal detachment of 19% . Whereas Trent et al.
that have the potential to selectively block keratino- found an 84.4% reduction in predicted mortality in pa-
cyte apoptosis have significant potential for treating tients treated with IVIG, the Bachot study reported
TEN. In 1998, we reported that commercial prepara- an increase in mortality ( 24% predicted vs. 32% ob-
tions of intravenous immunoglobulins (IVIG) contain served). However, it is of note that the latter study in-
antibodies against Fas that are able to block the bind- cluded several SJS patients at admission , two of
ing of FasL to Fas.32 Furthermore intravenous immu- which were considered as TEN by day 3, thus possi-
noglobulins , by blocking Fas , potently inhibit cell bly leading to a lower than predicted SCORTEN .
death mediated by recombinant FasL in vitro. In the Also , 32 of 34 patients in the Bachot study were
same report, we suggested based on the results of a treated with IVIG originating from the same batch,
pilot trial, that IVIG used in high doses (0.75 g!kg! and we have reported that large batch to batch vari-
day for 4 consecutive days ) to treat patients with ability in anti-Fas activity can be observed in IVIG ,
TEN, consistently and rapidly blocked the progres- with rare batches even completely lacking activ-
sion of skin detachment and disease in 10 out of 10 ity.42 Finally, differences in doses of IVIG used in the
patients.32 Since then, 8 other reports of studies with two studies (2 g! kg in the Bachot study vs. 4 g! kg in
10 or more patients treated with intravenous immuno- the Trent study) may have contributed to the differ-
globulin ( IVIG ) for TEN have been published . 42-49 ent outcomes.
While none of these studies are controlled, and the The study by Campione et al. describes 10 patients
results illustrate that controversy as to the efficacy of suffering from TEN with a mean TBSA of 44% that
IVIG still exists, interesting information can be ex- were treated with 400 mg!kg of IVIG per day on 5
tracted from their analysis (Fig. 4). consecutive days (2 g! kg total dose), starting on av-
The largest of the studies summarized in Figure 4 erage 3 days after disease onset. 45 According to the
was a multicenter study of 48 patients with TEN calculated SCORTEN for this patient cohort at admis-
treated with IVIG at a mean total dose of 2.7 g !kg sion, the predicted mortality rate was 35%, and the ob-
(doses ranging from 0.65 5.8 g! kg divided over 1 5 served mortality after intravenous immunoglobulin

Allergology International Vol 55, No1, 2006 http:!!

[Link]! 13
 French LE

therapy was of 10%. The authors also report that in 9 pore.49 The total dose of IVIG administered was 2 g!
of their patients, clinical improvement could already kg body weight, with the exception of 2 patients who
be observed after the first infusion of IVIG. received a total dose of 1.5 g!kg body weight. The
Shortt et al. report the results of a retrospective mean age of patients was 49.9+!−18.8 years (range,
non-controlled analysis of 32 patients with TEN evalu- 19 to 70 years), but the mean surface of epidermal de-
ated to have a mean TBSA of 65%, 16 of which re- tachment is unfortunately not reported. Eleven of 12
cieved IVIG at a total dose of 2.8 g! kg and 16 others patients ( 92% ) survived , and in these patients the
standard care only.46 A mortality of 25% was observed mean time to objective response was 3.6+! −1.9 days,
in the IVIG-treated group against 38% in the standard suggesting that high-dose IVIG may be a safe and ef-
care group. Although the authors correctly state that fective therapy for Asian patients with TEN
the observed difference in mortality is not significant Taken together, although all studies published to
p= 0.364), significance may have been achieved had date are non-controlled, 7 of the 9 studies summa-
the study groups been larger rized in Figure 4 point towards a benefit of high dose
The retrospective non controlled study by Brown et IVIG upon the mortality associated with TEN . It
al. concerned 45 TEN patients with a mean TBSA epi- should be noted that in the two studies that showed
dermal detachment of 45%, 21 of which recieved stan- no benefit on mortality, the total dose of IVIG used
dard care including surgical debridement in a burn was of 2 g!kg or less, whereas in 5 of the 7 studies
unit, and the remaining 24 recieved similar standard showing a benefit of IVIG on mortality, the total dose
care along with IVIG at a significantly lower than of IVIG used was greater than 2 g! kg
usual total dose of 1.6 g! kg.47 In this study, mortality Use of IVIG for the treatment of SJS has also been
was 42% in the IVIG group versus 29% in the standard reported, but conclusions are more difficult to draw
care [Link] in the IVIG treated group was as the mortality associated with this condition is usu-
also higher than that predicted by SCORTEN (38%). ally low (1 5%). A total of three studies exist to date,
These results are somewhat surprising, and several two of which concern pediatric patients . In adults ,
features of this study are quite unusual . First , the Prins et al . have reported a series of 12 patients
standard care protocol is different from that used in treated with a mean dose of 0.6 g!kg!d for an aver-
most centers with experience in the management of age of 4 days. 50 An objective response to IVIG infu-
TEN, in that wound debridement, a practice that is no sion was observed within a mean of 2 days in 100% of
longer recommended, is performed on all patients at treated patients with an overall survival rate of 100%
admission. Second, the mortality rate of 42% observed and total skin healing in an average of 8.3 days. In pe-
in the IVIG treated group of patients is higher than diatric patients, a first study by Morici et al. in which
that reported in epidemiological studies of TEN, and 7 children received IVIG (2 g!kg total dose) and 5
that historically observed with standard care in most supportive care only, the authors report a significant
experienced centers. This suggests that some individ- reduction in the duration of fever for the IVIG-treated
ual or combined aspect of the management protocol (8 days) versus supportive care (14 days) group. A
for patients in the IVIG group of this study may differ second study by Metry et al., retrospectively analyzed
from that of the other studies assessing the effect of 7 children treated with IVIG (2g!kg total dose) and
IVIG in TEN. The association of IVIG treatment and reported the absence of new blisters within 24 48 h
debridement is certainly one difference between this of the initiation of IVIG, good outcome in all patients
and other [Link], the total dose of IVIG used is and the absence of side effects . High-dose IVIG
the lowest of all studies described herein as only 1.6 seems therefore effective in blocking the progression
g! kg total dose of IVIG was administered, and lastly, of SJS and reducing the time to complete skin heal-
the onset of IVIG treatment was quite late (average of ing
7 days after onset of disease) In conclusion, studies of the pathogenesis of TEN
Al-Mutairi et al. report 12 consecutive patients with suggest that destruction of the epidermis, in the con-
TEN treated in Kuwait with a dose of 0.5 1.0 g! kg! d text of the ongoing drug-related hypersensitivity reac-
of IVIG for 4 5 days along with standard care proto- tion, is due to massive Fas-mediated keratinocyte cell
col . 48 The average age of their patients was 27.16 death by apoptosis. IVIG inhibits Fas-FasL interaction
years (7 50 years), including 4 children, and the aver- and cell death in vitro, and thus provides a rationale
age total body surface area involvement was 57.5%. for use in humans. Since that discovery, 9 large non-
All patients studied responded well to IVIG treat- controlled clinical studies have been published, and
ment. There was no mortality, and the progression of lower than expected mortality has been reported in 7
disease was arrested in a mean of 2.83 days ( 1 5 of these. Although each study has its potential biases,
days) and the 9 studies are not strictly comparable , it ap-
Tan et al. have reported retrospective data from 8 pears from comparative analysis that IVIG at total
patients with TEN and 4 patients with Stevens- doses of more than 2 g! kg are a safe and potentially
Johnson syndrome-toxic epidermal necrolysis ( SJS- useful treatment for TEN. Hopefully the cumulative
TEN) overlap treated with high-dose IVIG in Singa- results obtained in a non controlled manner to date

14 ![Link]!
Allergology International Vol 55, No1, 2006 http:!
 Toxic Epidermal Necrolysis

will serve as the basis for designing a prospective long HF. Predisposition to phenytoin hepatotoxicity as-
controlled trial in the near future. Such an approach sessed in vitro. N. Engl. J. Med. 1981;305:722-727.
appears the only way to definitively define the thera- 17. Shear NH, Spielberg SP, Grant DM, Tang BK, Kalow W.
Differences in metabolism of sulfonamides predisposing
peutic potential of IVIG in TEN
to idiosyncratic toxicity. Ann. Intern. Med. 1986;105:179-
184.
REFERENCES 18. Wolkenstein P, Charue D, Laurent P, Revuz J, Roujeau
1. Roujeau JC, Stern RS. Severe adverse cutaneous reactions JC, Bagot M. Metabolic predisposition to cutaneous ad-
to drugs. N. Engl. J. Med. 1994;331:1272-1285. verse drug reactions. Role in toxic epidermal necrolysis
2. Assier H, Bastuji-Garin S, Revuz J, Roujeau J-C. Erythema caused by sulfonamides and anticonvulsants. Arch . Der-
multiforme with mucous membrane involvement and matol. 1995;131:544-551.
Stevens-Johnson syndrome are clinically different disor- 19. Wolkenstein P, Carriere V, Charue D et al. A slow acetyla-
ders with distinct causes. Arch. Derm. 1995;131:539-543. tor genotype is a risk factor for sulphonamide-induced
3. Bastuji-Garin S, Rzany B, Stern RS, Shear NH, Naldi L, toxic epidermal necrolysis and Stevens-Johnson syn-
Roujeau J-C. Clinical classification of cases of toxic epider- drome. Pharmacogenetics 1995;5:255-258.
mal necrolysis, Stevens-Johnson syndrome, and erythema 20. Dietrich A, Kawakubo Y, Rzany B, Mockenhaupt M, Si-
multiforme. Arch. Dermatol. 1993;129:92-96. mon JC, Schopf E. Low N-acetylating capacity in patients
4. Auquier-Dunant A, Mockenhaupt M, Naldi L, Correia O, with Stevens-Johnson syndrome and toxic epidermal ne-
Schroder W, Roujeau JC. Correlations between clinical crolysis. Exp. Dermatol. 1995;4:313-316.
patterns and causes of erythema multiforme majus , 21. Roujeau JC, Huynh TN, Bracq C, Guillaume JC, Revuz J,
Stevens-Johnson syndrome, and toxic epidermal necroly- Touraine R. Genetic susceptibility to toxic epidermal ne-
sis : results of an international prospective study. Arch . crolysis. Arch. Dermatol. 1987;123:1171-1173.
Dermatol. 2002;138:1019-1024. 22. Hung SI, Chung WH, Liou LB et al. HLA-B*5801 allele as
5. Lyell A. Toxic epidermal necrolysis : an eruption resem- a genetic marker for severe cutaneous adverse reactions
bling scalding of the skin. Br. J. Dermatol. 1956;68:355- caused by allopurinol. Proc. Natl. Acad. Sci. U. S. A. 2005;
361. 102:4134-4139.
6. Achten G, Ledoux-Corbusier M. Lyell’s toxic epidermal 23. Chung WH, Hung SI, Hong HS et al. Medical genetics: a
necrolysis : histologic aspects. Arch . Belg . Dermatol . marker for Stevens-Johnson syndrome. Nature 2004;428:
Syphiligr. 1970;26:97-114. 486.
7. Roujeau J-C, Guillaume J-C, Fabre JP, Penso D, Flechet 24. Merot Y, Gravallese E, Guillen FJ, Murphy GF. Lympho-
ML, Girre JP. Toxic epidermal necrolysis ( Lyell syn- cyte subsets and Langerhans’ cells in toxic epidermal ne-
drome) . Incidence and drug etiology in France , 1981- crolysis. Report of a case. Arch. Dermatol. 1986;122:455-
1985. Arch. Dermatol. 1990;126:37-42. 458.
8. Revuz J, Penso D, Roujeau JC et al. Toxic epidermal ne- 25. Villada G, Roujeau JC, Clerici T, Bourgault I, Revuz J. Im-
crolysis. Clinical findings and prognosis factors in 87 pa- munopathology of toxic epidermal necrolysis . Keratino-
tients. Arch. Dermatol. 1987;123:1160-1165. cytes, HLA-DR expression, Langerhans cells, and mono-
9. Bastuji-Garin S, Fouchard N, Bertocchi M, Roujeau JC, nuclear cells: an immunopathologic study of five cases.
Revuz J, Wolkenstein P. SCORTEN : a severity-of-illness Arch. Dermatol. 1992;128:50-53.
score for toxic epidermal necrolysis. J. Invest. Dermatol. 26. Correia O, Delgado L, Ramos JP, Resende C, Torrinha JA.
2000;115:149-153. Cutaneous T-cell recruitment in toxic epidermal necroly-
10. Trent JT, Kirsner RS, Romanelli P, Kerdel FA. Use of sis. Further evidence of CD8+ lymphocyte involvement.
SCORTEN to accurately predict mortality in patients with Arch. Dermatol. 1993;129:466-468.
toxic epidermal necrolysis in the United States. Arch. Der- 27. Nassif A, Bensussan A, Boumsell L et al. Toxic epidermal
matol. 2004;140:890-892. necrolysis : effector cells are drug-specific cytotoxic T
11. Roujeau JC, Chosidow O, Saiag P, Guillaume JC. Toxic cells. J. Allergy Clin. Immunol. 2004;114:1209-1215.
epidermal necrolysis(Lyell syndrome). J. Am. Acad. Der- 28. Nassif A, Bensussan A, Dorothee G et al. Drug specific
matol. 1990;23:1039-1058. cytotoxic T-cells in the skin lesions of a patient with toxic
12. Rzany B, Mockenhaupt M, Stocker U, Hamouda O, epidermal necrolysis. J. Invest. Dermatol . 2002;118:728-
Schopf E. Incidence of Stevens-Johnson syndrome and 733.
toxic epidermal necrolysis in patients with the acquired 29. Nassif A, Moslehi H, Le Gouvello S et al. Evaluation of the
immunodeficiency syndrome in Germany. Arch. Derma- potential role of cytokines in toxic epidermal necrolysis. J.
tol. 1993;129:1059. Invest. Dermatol. 2004;123:850-855.
13. Duncan KO, Tigelaar RE, Bolognia JL. Stevens-Johnson 30. Paul C, Wolkenstein P, Adle H et al. Apoptosis as a
syndrome limited to multiple sites of radiation therapy in mechanism of keratinocyte death in toxic epidermal ne-
a patient receiving phenobarbital. J. Am. Acad. Dermatol. crolysis. Br. J. Dermatol. 1996;134:710-714.
1999;40:493-496. 31. Wehrli P, Viard I, Bullani R, Tschopp J, French LE. Death
14. Roujeau JC, Kelly JP, Naldi L et al. Medication use and receptors in cutaneous biology and disease. J. Invest. Der-
the risk of Stevens-Johnson syndrome or toxic epidermal matol. 2000;115:141-148.
necrolysis. N. Engl. J. Med. 1995;333:1600-1607. 32. Viard I, Wehrli P, Bullani R et al. Inhibition of toxic epi-
15. Garcia-Doval I, LeCleach L, Bocquet H, Otero XL, Rou- dermal necrolysis by blockade of CD95 with human intra-
jeau JC. Toxic epidermal necrolysis and Stevens-Johnson venous immunoglobulin. Science 1998;282:490-493.
syndrome: does early withdrawal of causative drugs de- 33. Ito K, Hara H, Okada T, Shimojima H, Suzuki H. Toxic
crease the risk of death Arch . Dermatol . 2000;136: epidermal necrolysis treated with low-dose intravenous
323-327. immunoglobulin: immunohistochemical study of Fas and
16. Spielberg SP, Gordon GB, Blake DA, Goldstein DA, Her- Fas-ligand expression. Clin. Exp. Dermatol. 2004;29:679-

Allergology International Vol 55, No1, 2006 http:!!

[Link]! 15
 French LE

680. intravenous immunoglobulin for the treatment of toxic

34. Viard-Leveugle I, Bullani RR, Meda P et al. Intracellular epidermal necrolysis using SCORTEN: The University of
localization of keratinocyte Fas ligand explains lack of cy- Miami Experience. Arch. Dermatol. 2003;139:39-43.
tolytic activity under physiological conditions. J . Biol . 44. Bachot N, Revuz J, Roujeau JC. Intravenous immuno-
Chem. 2003;278:16183-16188. globulin treatment for Stevens-Johnson syndrome and
35. Heng MC, Allen SG. Efficacy of cyclophosphamide in toxic epidermal necrolysis: a prospective noncomparative
toxic epidermal necrolysis: clinical and pathophysiologic study showing no benefit on mortality or progression.
aspects. J. Am. Acad. Dermatol. 1991;25:778-786. Arch. Dermatol. 2003;139:33-36.
36. Hewitt J, Ormerod AD. Toxic epidermal necrolysis 45. Campione E, Marulli GC, Carrozzo AM, Chimenti MS,
treated with cyclosporin. Clin . Exp . Dermatol . 1992;17: Costanzo A, Bianchi L. High-dose intravenous immuno-
264-265. globulin for severe drug reactions: efficacy in toxic epi-
37. Arevalo JM, Lorente JA, Gonzalez-Herrada C, Jimenez- dermal necrolysis. Acta [Link]. 2003;83:430-432.
Reyes J. Treatment of toxic epidermal necrolysis with cy- 46. Shortt R, Gomez M, Mittman N, Cartotto R. Intravenous
closporin A. J. Trauma. 2000;48:473-478. immunoglobulin does not improve outcome in toxic epi-
38. Trautmann A, Klein CE, Kampgen E, Brocker EB. Severe dermal necrolysis. J . Burn . Care Rehabil . 2004;25:246-
bullous drug reactions treated successfully with cyclo- 255.
phosphamide [ letter ]. Br . J . Dermatol . 1998;139:1127- 47. Brown KM, Silver GM, Halerz M, Walaszek P, Sandroni
1128. A, Gamelli RL. Toxic epidermal necrolysis : does im-
39. Kamanbroo D, Schmitz-Landgraf W, Czarnetski BM. Plas- munoglobulin make a difference J. Burn. Care Rehabil.
mapheresis in severe drug-induced toxic epidermal ne- 2004;25:81-88.
crolysis. Arch. Dermatol. 1985;121:1548-1549. 48. Al-Mutairi N, Arun J, Osama NE et al. Prospective , non-
40. Redondo P, Defelipe I, Delapena A, Aramendia JM, Vana- comparative open study from Kuwait of the role of intra-
clocha V. Drug-induced hypersensitivity syndrome and venous immunoglobulin in the treatment of toxic epider-
toxic epidermal necrolysis-treatment with N-acetylcyst- mal necrolysis. Int. J. Dermatol. 2004;43:847-851.
eine. Br. J. Dermatol. 1997;136:645-646. 49. Tan AW, Thong BY, Yip LW, Chng HH, Ng SK. High-
41. Wolkenstein P, Latarjet J, Roujeau J-C et al. Randomised dose intravenous immunoglobulins in the treatment of
comparison of thalidomide versus placebo in toxic epider- toxic epidermal necrolysis: an Asian series. J. Dermatol.
mal necrolysis. Lancet 1998;352:1586-1589. 2005;32:1-6.
42. Prins C, Kerdel FA, Padilla RS et al. Treatment of toxic 50. Prins C, Vittorio C, Padilla RS et al. Effect of high-dose in-
epidermal necrolysis with high-dose intravenous immuno- travenous immunoglobulin therapy in Stevens-Johnson
globulins : multicenter retrospective analysis of 48 con- syndrome: a retrospective, multicenter study. Dermatol-
secutive cases. Arch. Dermatol. 2003;139:26-32. ogy 2003;207:96-99.
43. Trent JT, Kirsner RS, Romanelli P, Kerdel FA. Analysis of

16 ![Link]!
Allergology International Vol 55, No1, 2006 http:!
 F1000Research 2020, 9(F1000 Faculty Rev):612 Last updated: 31 MAR 2022

REVIEW

Recent advances in managing and understanding Stevens-

Johnson syndrome and toxic epidermal necrolysis [version 1;
peer review: 2 approved]
Akito Hasegawa , Riichiro Abe
Division of Dermatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

v1 First published: 16 Jun 2020, 9(F1000 Faculty Rev):612 Open Peer Review
[Link]
Latest published: 16 Jun 2020, 9(F1000 Faculty Rev):612
[Link] Approval Status

1 2
Abstract
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) version 1
are life-threatening diseases characterized by detachment of the 16 Jun 2020

epidermis and mucous membrane. SJS/TEN are considered to be on

the same spectrum of diseases with different severities. They are Faculty Reviews are review articles written by the
classified by the percentage of skin detachment area. SJS/TEN can also prestigious Members of Faculty Opinions. The
cause several complications in the liver, kidneys, and respiratory tract.
articles are commissioned and peer reviewed
The pathogenesis of SJS/TEN is still unclear. Although it is difficult to
diagnose early stage SJS/TEN, biomarkers for diagnosis or severity before publication to ensure that the final,
prediction have not been well established. Furthermore, optimal published version is comprehensive and
therapeutic options for SJS/TEN are still controversial.
accessible. The reviewers who approved the final
Several drugs, such as carbamazepine and allopurinol, are reported to
have a strong relationship with a specific human leukocyte antigen version are listed with their names and
(HLA) type. This relationship differs between different ethnicities. affiliations.
Recently, the usefulness of HLA screening before administering
specific drugs to decrease the incidence of SJS/TEN has been
investigated. 1. Marc Vocanson, Université de Lyon, Lyon,
Skin detachment in SJS/TEN skin lesions is caused by extensive France
epidermal cell death, which has been considered to be apoptosis via CIRI-INSERM U1111, Lyon, France
the Fas-FasL pathway or perforin/granzyme pathway. We reported
that necroptosis, i.e. programmed necrosis, also contributes to 2. Julia Spoendlin, University of Basel, Basel,
epidermal cell death. Annexin A1, released from monocytes, and its
Switzerland
interaction with the formyl peptide receptor 1 induce necroptosis.
Several diagnostic or prognostic biomarkers for SJS/TEN have been Any comments on the article can be found at the
reported, such as CCL-27, IL-15, galectin-7, and RIP3.
end of the article.
Supportive care is recommended for the treatment of SJS/TEN.
However, optimal therapeutic options such as systemic
corticosteroids, intravenous immunoglobulin, cyclosporine, and TNF-α
antagonists are still controversial. Recently, the beneficial effects of
cyclosporine and TNF-α antagonists have been explored. In this
review, we discuss recent advances in the pathophysiology and
management of SJS/TEN.

Page 1 of 12
 F1000Research 2020, 9(F1000 Faculty Rev):612 Last updated: 31 MAR 2022

Keywords
Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema
multiforme, drug reaction, necroptosis

Corresponding authors: Akito Hasegawa (hakito@[Link]), Riichiro Abe (aberi@[Link])

Author roles: Hasegawa A: Conceptualization, Data Curation, Writing – Original Draft Preparation, Writing – Review & Editing; Abe R:
Data Curation, Supervision, Writing – Original Draft Preparation, Writing – Review & Editing
Competing interests: No competing interests were disclosed.
Grant information: The author(s) declared that no grants were involved in supporting this work.
Copyright: © 2020 Hasegawa A and Abe R. This is an open access article distributed under the terms of the Creative Commons
Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.
How to cite this article: Hasegawa A and Abe R. Recent advances in managing and understanding Stevens-Johnson syndrome and
toxic epidermal necrolysis [version 1; peer review: 2 approved] F1000Research 2020, 9(F1000 Faculty Rev):612
[Link]
First published: 16 Jun 2020, 9(F1000 Faculty Rev):612 [Link]

Page 2 of 12
 F1000Research 2020, 9(F1000 Faculty Rev):612 Last updated: 31 MAR 2022

Introduction Table 1. Classification of SJS/TEN.

Stevens-Johnson syndrome (SJS) and toxic epidermal necroly-
sis (TEN) are severe and life-threatening mucocutaneous reac- Diagnosis Skin detachment area (%)
tions characterized by blisters and skin detachment. Drugs and
SJS <10
infection, such as by Mycoplasma or the herpes simplex virus,
are the main causes1. SJS/TEN overlap 10–30
TEN >30
SJS/TEN are considered to be on the same spectrum of dis-
SJS, Stevens-Johnson syndrome; TEN, toxic epidermal
eases with different severities. They are classified by the necrolysis
percentage of skin detachment area (Table 1)2. Although a
study in the USA indicated that the incidence rate is 1.58 to
2.26 cases/million people, the overall incidence of SJS/TEN Table 2. Risk factors for SCORTEN.
remains unclear. Contrary to its low incidence rate, the mortal-
ity rate is high (SJS: 4.8%, TEN: 14.8%)3. Furthermore, even Age over 40 years
after recovery, sequelae such as blindness remain in some cases1.
Thus, patients with SJS/TEN should be accurately diagnosed, Heart rate >120 beats per minute
and appropriate treatment should commence as soon as possible. Presence of cancer or hematologic malignancy
Therefore, a biomarker for early diagnosis and severity predic- Epidermal detachment area involving body surface area >10%
tion is necessary. Further issues include the lack of evidence
Blood urea nitrogen >28 mg/dL (10 mmol/L)
regarding the adequate management of SJS/TEN.
Blood glucose >252 mg/dL (14 mmol/L)
In this review, we describe recent advances in the research and Bicarbonate <20 mEq/L
management of SJS/TEN.
SCORTEN, Score of Toxic Epidermal Necrosis

Clinical features
The cutaneous symptoms for SJS/TEN are a painful ery- Table 3. Mortality rate in SCORTEN.
thematous rash, bullae, and erosion appearing on the face and
trunk and spreading to the extremities. The early skin lesions Number of risk factors Mortality rate (%)
appear as round lesions with only two nonpalpable zones with an
indistinct border and are called “atypical targets”. Skin lesions 0–1 3.2
typically test positive for the Nikolsky sign, which manifests 2 12.1
with skin erosion upon gentle pressure4. Malaise, fever, and 3 35.3
upper respiratory tract symptoms often precede the onset of the
4 58.3
skin rash by a few days. Almost all patients with SJS/TEN
develop mucosal involvement of the eyes, mouth, and genitalia5. 5 90
The involvement of the eyes often relates to sequelae such as SCORTEN, Score of Toxic Epidermal Necrosis
dry eyes, visual acuity, conjunctivitis, corneal erosions, and
trichiasis. In severe cases, ocular sequelae can reach as far as
blindness.
Table 4. Medications associated with high risk of
SJS/TEN.
The severity-of-illness score for TEN (SCORTEN) is widely
used to predict mortality for SJS/TEN6. SCORTEN should be Nevirapine
assessed within the first 24 hours after admission and again on
day 3. SCORTEN is based on seven independent risk factors Lamotrigine
(Table 2). The more risk factors that are present, the higher Carbamazepine
the mortality rate (Table 3). Phenytoin
Cotrimoxazole and other anti-infective sulfonamides
SJS/TEN are mainly drug-induced diseases. The most frequently
causative drugs include antibiotics, allopurinol, non-steroidal Sulfasalazine
anti-inflammatory drugs, and antiepileptic drugs (Table 4)7. Allopurinol
Oxicam/NSAIDs
Genetic factors
There is increasing evidence of a genetic contribution to NSAID, non-steroidal anti-inflammatory drug; SJS, Stevens-
Johnson syndrome; TEN, toxic epidermal necrolysis
the incidence of cutaneous adverse reactions. In 2004, Chung
et al. reported on a strong relationship between human leuko-
cyte antigen (HLA)-B*15:02 and carbamazepine (CBZ)-induced immune response. In this study, 44 patients with CBZ-induced
SJS/TEN in a Han Chinese population8. HLA alleles are divided SJS/TEN were included, and all patients had the HLA-
into class I and class II, and they are specialized to present B*15:02 allele (100%). Following this, similar studies reported
antigenic peptides to T cells, resulting in the activation of the the relationship between CBZ-induced SJS/TEN and the

Page 3 of 12
 F1000Research 2020, 9(F1000 Faculty Rev):612 Last updated: 31 MAR 2022

HLA-B*15:02 allele in Asian populations including those in Cost-effectiveness analysis of HLA-B*58:01 screening in Taiwan
China, Thailand, Malaysia, and India9–20. suggested a cost-saving effect in preventing allopurinol-
induced SJS/TEN46. In a US study, it was suggested that testing
The relationship between SJS/TEN and HLA-B*15:02 has also for HLA-B*5801 prior to allopurinol initiation is cost effective
been demonstrated in aromatic antiepileptic drugs other than for Asians and African Americans but not for Caucasians or
CBZ. Although the incidence was lower than that seen with Hispanics47.
CBZ, HLA-*15:02 showed a strong association with phenytoin-,
lamotrigine-, and oxcarbazepine-induced SJS/TEN11,21–25. Con- Abacavir, a nucleoside reverse transcriptase inhibitor used
versely, there was no association between CBZ-induced SJS/ to treat HIV infection, is reported to induce SJS/TEN in patients
TEN and HLA-B*15:02 in Japanese, Korean, and European carrying HLA-B*57:0148–52. In 2008, HLA-B*57:01 screen-
populations26–32. ing was added to clinical care guidelines to reduce the risk of
hypersensitivity reaction from abacavir53. The frequency of
Ozeki et al. discovered that HLA-A*31:01 is also associated HLA-B*57:01 screening then increased steadily, and the inci-
with CBZ-induced SJS/TEN33. HLA-A*31:01 revealed a rela- dence of abacavir-induced SJS/TEN was decreased54. However,
tionship with CBZ-induced SJS/TEN not only in Japanese but many patients have not undergone HLA-B*57:01 screening. The
also in Korean and European populations14,32,34,35. Although the expansion of HLA*B-57:01 screening is expected to reduce the
majority of CBZ-induced SJS/TEN is associated with HLA- incidence of abacavir-induced SJS/TEN.
B*15:02 in Asian populations, the association with HLA-A*31:01
is shown in multiethnic populations. Thus, the HLA association Cytochrome P (CYP) is also an important genetic factor.
in SJS/TEN is different among different ethnicities. CYPs are involved in drug metabolism. CYP450 genes have 57
variants, and each variant shows functional differences. Patients
In 2008, the US Food and Drug Administration released whose drug metabolism is slow because of CYP450 variants
a recommendation to perform HLA-B*15:02 genotyping have a high risk of developing adverse drug reactions55. Chung
before administering CBZ36. In Taiwan, it is reported that HLA- et al. discovered specific genetic factors associated with pheny-
B*15:02 screening is strongly associated with a decrease in the toin-induced SJS/TEN56. In this study, 16 significant single
incidence of CBZ-induced SJS/TEN37. nucleotide polymorphisms in CYP2C9 were identified. Patients
with phenytoin-induced SJS/TEN who had CYP2C9*3 showed
As well as antiepileptic drugs, several other drugs, such as a delayed clearance of phenytoin, resulting in increased disease
allopurinol and abacavir, have been reported to have HLA asso- severity.
ciations. Allopurinol is an anti-hyperuricemia drug which is a
major cause of SJS/TEN. The relationship between HLA- Pathogenesis and diagnostic biomarkers
B*58:01 and allopurinol-induced SJS/TEN has been reported in Immunopathogenesis
many ethnicities, including in Taiwanese, Japanese, Korean, SJS/TEN is traditionally thought to be a T-cell-mediated
Thai, and European individuals26,28,30,38–45. Therefore, these data disorder. T cells are activated by binding of drugs to T cell recep-
suggested that HLA-B*58:01 genotyping may be useful to tors (TCRs) from antigen-presenting cells (APCs). There are cur-
prevent allopurinol-induced SJS/TEN. rently three hypotheses on T cell activation57–59 (Figure 1): (1) the

Figure 1. Models of T cell activation in Stevens-Johnson syndrome/toxic epidermal necrolysis. (A) Hapten/pro-hapten model: drugs or
drug metabolites form a complex with carrier proteins and are presented as haptenated peptides in the peptide-binding groove of the HLA
molecules. (B) p-i concept: drugs directly bind to HLA and TCR non-covalently. (C) Altered peptide model: drugs bind to the peptide-binding
groove of HLA, resulting in the alteration of the HLA-binding peptide repertoire. APC, antigen-presenting cell; HLA, human leukocyte antigen;
TCR, T cell receptor.
Page 4 of 12
 F1000Research 2020, 9(F1000 Faculty Rev):612 Last updated: 31 MAR 2022

hapten/pro-hapten model, (2) the pharmacological interaction in the serum of TEN patients. sFasL also has the potential to
(p-i) concept, and (3) the altered peptide model. The majority mediate apoptosis83.
of drugs and their metabolites are pro-haptens and do not act
as haptens themselves. They acquire the immunogenicity by We showed that FasL serum levels increased in patients
covalently binding to carrier proteins (hapten antigen). Hapten with TEN84,85. This study revealed that sFasL was produced
antigens form a complex with HLA in APCs and are recognized by peripheral blood mononuclear cells (PBMCs) when the
by TCRs. This stimulation triggers the drug-specific T cell acti- causative drugs were added. sFasL released from PBMCs binds
vation. In this model, antigenic drugs are covalently bound to to Fas expressed on keratinocytes to cause apoptosis. This study
peptides presented by HLA molecules to TCRs60–63. However, suggested that elevated levels of serum sFasL may be a useful
some drugs can non-covalently bind directly to HLA and/or diagnostic marker for SJS/TEN. However, a correlation between
TCRs. This type of binding is termed the p-i concept. CBZ, lamo- sFasL levels and disease severity has not been established84,86.
trigine, sulfamethoxazole, and celecoxib are known to fit this
model64–68. In general, HLA polymorphisms are dependent on Nassif et al. emphasized the importance of the perforin/
the antigen-binding cleft. It has been reported that unmodified granzyme pathway87,88. Upon recognition of a target cell, the
abacavir binds to the antigen-binding cleft lying in the cytotoxic CD8+ T cell releases perforin and granzyme B80. This
bottom of HLA-B*57:01 and changes the shape and chemis- study revealed that mononuclear cells in the blister fluid of TEN
try of the antigen-binding cleft, altering the repertoire of endog- patients have cytotoxic effects in the presence of a causative
enous peptides that can bind HLA-B*57:01 (altered peptide)69,70. drug. This cytotoxicity is blocked by the perforin/granzyme
The TCR profile is also associated with the development of pathway inhibitor. These findings suggest that the perforin/
SJS/TEN. Ko et al. identified the VB-11-ISGSY clonotype granzyme pathway causes epidermal damage in the skin lesions
in 84% of patients with CBZ-associated SJS/TEN71,72. This of SJS/TEN87,88.
clonotype was not present in CBZ-tolerant patients. The
clonotype specificity is also reported in oxypurinol-induced In 2008, Chung et al. demonstrated the cytotoxic effect of
SJS/TEN73. Recently, Pan et al. investigated the TCR reper- granulysin in SJS/TEN89. Granulysin is a pro-apoptotic pro-
toire through next-generation sequencing and identified a public tein which permits cell-mediated cytotoxicity without direct
TCR from the cytotoxic T cells of patients with CBZ-induced cell-to-cell contact. In SJS/TEN blisters, high levels of granu-
SJS/TEN. This public TCR can bind with CBZ and mediate lysin are detected. Granulysin is released from blister cells in
an immune response74. skin lesions of SJS/TEN including cytotoxic CD8+ T cell and
NK cells. The severity of the cutaneous lesions correlated with
In the early stages of the disease, cytotoxic CD8+ T cells serum granulysin levels. We also reported granulysin as an
mainly infiltrate blister fluid and the epidermis, and CD4+ T early diagnostic marker90. However, serum granulysin levels
cells mostly infiltrate the dermis75,76. Monocytes are present are also elevated in patients with drug-induced hypersensitivity
in the epidermis of TEN patients. In the later stages, lym- syndrome/drug reactions with eosinophilia and systemic symp-
phocytes are decreased and an increased number of monocytes is toms, which are other types of severe cutaneous adverse drug
observed. Tohyama et al. reported that monocytes play an reaction characterized by a viral infection91. Therefore, it is
important role in epidermal damage, probably by enhancing the difficult to use granulysin as an SJS/TEN-specific biomarker.
cytotoxicity of CD8+ T cells77. In the serum and blister fluid of
SJS/TEN patients, increased levels of soluble IL-2 receptors In 2014, we reported that necroptosis induced by annexin
were observed78. Soluble IL-2 receptors are a marker for acti- A1–formyl peptide receptor 1 (FPR1) interaction contributes to
vated T cells, indicating the importance of activated cytotoxic keratinocyte death in SJS/TEN92. Necroptosis is a type of pro-
CD8+ T cells in the pathogenesis of SJS/TEN. grammed cell death which reveals morphological necrosis.
Necroptotic cells release damage-associated molecular patterns
Keratinocyte death (DAMPs), including a range of pro-inflammatory cytokines,
The epidermal damage in the skin lesions of SJS/TEN patients resulting in inflammation, unlike apoptosis. Apoptotic cells are
is considered to be of apoptotic origin79. Apoptosis is induced by quickly phagocytosed by macrophages and degraded within
cytotoxic CD8+ T cells through the Fas-Fas ligand (FasL) phagolysosomes. No inflammatory reaction occurs with the
pathway or the perforin/granzyme pathway80. process of apoptosis or with the removal of apoptotic cells93.
In general, necroptosis occurs through the stimulation of
Cytotoxic CD8+ T cells and natural killer (NK) cells produce TNF- under conditions in which apoptosis is blocked. In
FasL, which binds Fas on target cells. Recognition of FasL causes TNF- stimulation, receptor interacting kinase 1 (RIP1) and
activation of the caspase cascade and the resulting cells receptor interacting kinase 3 (RIP3) are phosphorylated and form
undergo apoptosis80. Under normal conditions, Fas is present a “necrosome” complex. Furthermore, the mixed lineage kinase
on the surface of keratinocytes and FasL is expressed intracellu- domain-like (MLKL) pseudokinase is recruited to the necro-
larly. FasL is transported to the cell surface when the cell needs some and phosphorylated by RIP3. The phosphorylated MLKL
to self-destruct81. Viard et al. demonstrated that the cell sur- (pMLKL) is localized to the plasma membrane and induces cell
face of keratinocytes of TEN patients has FasL on it but not the death93. Supernatant from PBMCs, which are exposed to the
keratinocytes of patients with maculopapular drug reactions82. causative drug in SJS/TEN patients, induces the death of SJS/
In addition, high levels of soluble FasL (sFasL) were found TEN keratinocytes. This cytotoxicity is blocked by necrostatin-1,

Page 5 of 12
 F1000Research 2020, 9(F1000 Faculty Rev):612 Last updated: 31 MAR 2022

a specific inhibitor of RIP1. In SJS/TEN skin lesions, keratino- hypothesized that CCL-27 is produced by keratinocytes in the
cytes express abundant FPR1 and monocytes secrete annexin skin lesions found in SJS/TEN and released into the circulation.
A1. The interaction of annexin A1 and FPR1 induces necro-
some formation (Figure 2). Inhibition of necroptosis com- Su et al. reported that interleukin-15 (IL-15) is associated with
pletely prevents SJS/TEN-like responses in a mouse model of mortality and severity in SJS/TEN by measuring 28 serological
SJS/TEN92,94. Therefore, these results suggest that necroptosis factors using multiplex immunoassay or ELISA99. They also
plays an important role in the pathogenesis of SJS/TEN. revealed that IL-15 contributes to TEN severity by enhancing
NK- and T-cell-mediated responses. IL-15 is known to induce the
Diagnostic biomarkers production of TNF- and downstream cytokines/chemokines100.
Although SJS/TEN is a severe disease, clinical manifesta- The elevation of many cytokines/chemokines in SJS/TEN might
tions of early stage SJS/TEN are occasionally undistinguishable be a secondary effect derived from IL-15.
from those of maculopapular exanthema and erythema
multiforme. However, useful biomarkers for the diagnosis or the We identified galectin-7 as a diagnostic biomarker using
prediction of severity have not been well established. Recently, proteomics analysis101. We hypothesized that certain soluble
some researchers discovered useful diagnostic or prognos- factors could be secreted only by drug-specific lymphocytes in
tic biomarkers for SJS/TEN. These biomarkers are now in the SJS/TEN patients and not in those with a non-severe cutane-
research phase and have not been used in the clinic yet. ous adverse drug reaction. Hence, these soluble factors could
be biomarkers for SJS/TEN. PBMCs from patients with
Wang et al. revealed an increased concentration of CCL-27 SJS/TEN were cultured with the causative drugs and super-
in the serum of SJS/TEN patients, which correlated with disease natant was collected. The elevated proteins in the supernatant
activity95,96. CCL-27 is reported to be associated with cutane- underwent proteomic analysis102. Hama, Nishimura, and col-
ous inflammatory diseases by regulating the trafficking of T cells leagues concluded that this method allowed for the identification
to the skin97. Tapia et al. found CCL-27 was highly expressed of new SJS/TEN-specific biomarkers that are not known to
in the skin lesions of SJS/TEN patients98. Wang et al. be associated with the pathogenesis of this condition.

Very recently, we focused on the mechanisms of epidermal

necroptosis and identified serum RIP3 as a key mediator of
necroptosis and as a diagnostic and severity marker103. It is
reported that the expression of RIP3 increased in cells
undergoing necroptosis104. We revealed that the expression of
RIP3 increased in necroptotic keratinocytes as well, and the
levels of serum RIP3 were high in the acute phase of patients
with SJS/TEN. We also indicated that serum RIP3 levels may
correlate with disease activity.

Management
In SJS/TEN patients, the epidermal and mucosal membranes
are predominantly affected. However, SJS/TEN can also cause
complications in several organs, such as the liver, kidneys,
and respiratory tract. Thus, multidisciplinary assessment and
early management in a specialized hospital environment are
key for improving mortality.

Immediate discontinuation of suspected causative drugs is

crucial in the initial management of SJS/TEN. In addition,
supportive care including fluid replacement105, nutritional
assessment106, pain relief107, and supplemental oxygen is nec-
essary. Since infection from skin detachment is a common
complication in SJS/TEN patients and it is associated with the
impairment of re-epithelialization and may lead to sepsis, daily
skin care should be performed. Antibiotic treatment should
be given when cutaneous infection is clinically suspected108.

Figure 2. Necroptosis pathway in Stevens-Johnson syndrome/ The optimal therapeutic strategy in SJS/TEN is still
toxic epidermal necrolysis. Drug-stimulated monocytes secrete controversial109. Although there have been some reports of ben-
annexin A1. Annexin A1 binds to FPR1, RIP1 and RIP3 form the
efits with the use of systemic corticosteroids, intravenous immu-
necrosome, and MLKL is phosphorylated by RIP3. Phosphorylated
MLKL translocates to the plasma membrane and induces cell noglobulins (IVIGs), cyclosporine, TNF- antagonists (infliximab
death. FPR1, formyl peptide receptor 1; MLKL, mixed lineage kinase and etanercept), and plasmapheresis (PP)110,111, evidence for
domain-like; RIP1, receptor interacting kinase 1. systemic treatment is still insufficient. UK guidelines for the
Page 6 of 12
 F1000Research 2020, 9(F1000 Faculty Rev):612 Last updated: 31 MAR 2022

management of SJS/TEN, published in 2016, concluded T-lymphocyte-mediated cytotoxicity and inhibits FasL, nuclear
that withdrawal of the culprit drug and multidisciplinary sup- factor-kB, and TNF- 130. Some case reports and meta-analyses
portive care are prioritized over systemic treatment because of have shown that cyclosporine treatment improved mortality
the lack of evidence to demonstrate the benefits of the latter112. in SJS/TEN patients131–138. Gilbert and Scherrer reported that
However, in Japanese guidelines for SJS/TEN, published in 2016, cyclosporine appears to have not only a mortality benefit in the
systemic treatment is prioritized over supportive care alone. treatment of SJS/TEN but also few side effects139. These data
This guideline recommended early initiation of systemic cor- support a potential role for cyclosporine in the treatment of
ticosteroid therapy as a first-line treatment. A combination of SJS/TEN. However, the number of reported patients is small.
IVIG or PP therapy is added to systemic corticosteroid therapy Further studies are required to validate the efficacy of
if the clinical symptoms are severe or the disease is refractory cyclosporine.
to systemic corticosteroid alone.
Plasmapheresis
The efficacy of systemic therapy may depend on the disease Several case series have shown that PP is effective for the
phase. For example, in the acute phase, immunosuppressive treatment of SJS/TEN140–145. The purpose of PP is to remove
treatments are considered to be suitable since a strong inflam- pathogenic factors such as a drug, drug metabolites, and disease-
mation-like “cytokine storm” occurs in the patient. However, induced cytokines/chemokines from the patient’s blood. PP
at the peak period during which wide skin detachment sessions are carried out every other day or daily. PP is a safe
develops, strong immunosuppressive treatment may avoid treatment and can be performed with few adverse side effects.
re-epithelization and increase the risk of infection. Previous stud- Although one observational study has concluded PP treatment
ies have not considered this point and included all phase results, to be ineffective, the overall survival in this study was 87.5%146.
leading to discrepant results. We introduce each treatment below. Narita et al. reported that PP was effective in TEN patients who
were refractory to supportive therapy or systemic corticosteroid
Systemic corticosteroids
therapy and revealed that cytokine serum levels decreased after
Previous studies revealed that treatment with corticosteroids
PP147.
in SJS/TEN patients increased the risk of infection and overall
complications, including higher mortality113–115. Analyses and
systematic reviews have not revealed a survival advantage of A study suggested a beneficial effect of combined PP and IVIG
systemic corticosteroids116–118. therapy148. However, another study reported negative results for
the combined therapy while treatment with PP alone revealed
However, recent studies suggested a beneficial role for cor- a good result149. Randomized studies are needed to further define
ticosteroid treatment. A European multicenter retrospective its usefulness.
study and recent meta-analysis of observational studies showed
the beneficial effects of corticosteroids110,119. An observational Tumor necrosis factor inhibitors
study reported that the short-term use of high-dose corticosteroids Owing to the skin lesions and blister fluid in SJS/TEN
in the early stages of SJS/TEN reduced mortality without containing high levels of TNF- 150,151, TNF- inhibitors such
increasing the risk of infection120. Since cutaneous infection is as etanercept and infliximab have been used and, in some cases,
the most important point in the use of corticosteroids for beneficial effects have been suggested152–159. However, only
SJS/TEN patients, short-term use of corticosteroids, improvement a small number of cases have reported the use of TNF- inhibi-
of infection control, and wound management are necessary to tors for SJS/TEN. Additional studies are required to confirm
decrease the mortality rate. the efficacy of these drugs in the treatment of SJS/TEN.

IVIG
IVIG has been widely used for patients with SJS/TEN. Future directions
However, the mechanisms of IVIG treatment remain unknown. Rapid withdrawal of the culprit drug and intensive supportive
While some case reports concluded that IVIG did not confer a care are the basis of treatment for SJS/TEN. The use of systemic
beneficial effect in decreasing mortality121–123, there are some corticosteroids and IVIG is still controversial. However, recently,
reports which revealed that IVIG had some beneficial effects for there has been an increasing number of studies suggesting
patients with SJS/TEN124–128. In the largest retrospective study the efficacy of cyclosporine or TNF- inhibitors. Accumulating
in this field, the European Study of Severe Cutaneous Adverse evidence of these treatments is desirable. In addition, the patho-
Reactions (EuroSCAR), IVIG did not improve mortality com- genesis of SJS/TEN has been elucidated. It is hoped that this
pared with supportive care alone119. However, recent meta-analyses research will lead to the discovery of new therapeutic targets.
have shown that high-dose IVIG (<2 g/kg) has a beneficial effect
in decreasing the mortality of SJS/TEN129. Thus, the use of Conclusions
IVIG for SJS/TEN patients is still controversial. Randomized This review summarizes recent advances in the pathophysi-
controlled trials are required. ology, diagnosis, and treatment of SJS/TEN. SJS/TEN is a
severe disease which has a high mortality rate. However, its
Cyclosporine diagnostic method and treatment algorithm have not been well
Cyclosporine, a calcineurin inhibitor, has been reported to established. Further studies to elucidate the pathogenesis of
have a therapeutic benefit in SJS/TEN. Cyclosporine affects SJS/TEN are needed.

Page 7 of 12
 F1000Research 2020, 9(F1000 Faculty Rev):612 Last updated: 31 MAR 2022

References Faculty Opinions Recommended

1. Lerch M, Mainetti C, Terziroli Beretta-Piccoli B, et al.: Current Perspectives on of Malaysian epilepsy patients. Asian Pac J Allergy Immunol. 2011; 29(3): 290–3.
Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis. Clin Rev Allergy PubMed Abstract
Immunol. 2018; 54(1): 147–76. 21. Hung SI, Chung WH, Liu ZS, et al.: Common risk allele in aromatic antiepileptic-
PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation drug induced Stevens-Johnson syndrome and toxic epidermal necrolysis in
2. Bastuji-Garin S, Rzany B, Stern RS, et al.: Clinical Classification of Cases of Han Chinese. Pharmacogenomics. 2010; 11(3): 349–56.
Toxic Epidermal Necrolysis, Stevens-Johnson Syndrome, and Erythema PubMed Abstract | Publisher Full Text
Multiforme. Arch Dermatol. 1993; 129(1): 92–6. 22. Chen CB, Hsiao YH, Wu T, et al.: Risk and association of HLA with
PubMed Abstract | Publisher Full Text oxcarbazepine-induced cutaneous adverse reactions in Asians. Neurology.
3. Hsu DY, Brieva J, Silverberg NB, et al.: Morbidity and Mortality of Stevens- 2017; 88(1): 78–86.
Johnson Syndrome and Toxic Epidermal Necrolysis in United States Adults. PubMed Abstract | Publisher Full Text
J Invest Dermatol. 2016; 136(7): 1387–97. 23. Chang CC, Ng CC, Too CL, et al.: Association of HLA-B*15:13 and HLA-B*15:02
PubMed Abstract | Publisher Full Text with phenytoin-induced severe cutaneous adverse reactions in a Malay
4. Griffiths C, Barker J, Bleiker T, et al.: Rook’s Textbook of Dermatology. 9th ed. population. Pharmacogenomics J. 2017; 17(2): 170–3.
Wiley. 2016. PubMed Abstract | Publisher Full Text
Publisher Full Text 24. Shi YW, Min FL, Zhou D, et al.: HLA-A*24:02 as a common risk factor for
5. Revuz J, Penso D, Roujeau JC, et al.: Toxic epidermal necrolysis. Clinical antiepileptic drug–induced cutaneous adverse reactions. Neurology. 2017;
findings and prognosis factors in 87 patients. Arch Dermatol. 1987; 123(9): 88(23): 2183–91.
1160–5. PubMed Abstract | Publisher Full Text | Free Full Text
PubMed Abstract | Publisher Full Text 25. Cheung YK, Cheng SH, Chan EJM, et al.: HLA-B alleles associated with severe
6. Bastuji-Garin S, Fouchard N, Bertocchi M, et al.: SCORTEN: A severity-of-illness cutaneous reactions to antiepileptic drugs in Han Chinese. Epilepsia. 2013;
score for toxic epidermal necrolysis. J Invest Dermatol. 2000; 115(2): 149–53. 54(7): 1307–14.
PubMed Abstract | Publisher Full Text PubMed Abstract | Publisher Full Text

7. Mockenhaupt M, Viboud C, Dunant A, et al.: Stevens-Johnson Syndrome and 26. Kaniwa N, Saito Y, Aihara M, et al.: HLA-B locus in Japanese patients with
Toxic Epidermal Necrolysis: Assessment of Medication Risks with Emphasis anti-epileptics and allopurinol-related Stevens-Johnson syndrome and toxic
on Recently Marketed Drugs. The EuroSCAR-Study. J Invest Dermatol. 2008; epidermal necrolysis. Pharmacogenomics. 2008; 9(11): 1617–22.
128(1): 35–44. PubMed Abstract | Publisher Full Text
PubMed Abstract | Publisher Full Text 27. Kaniwa N, Saito Y, Aihara M, et al.: HLA-B*1511 is a risk factor for
8. Chung WH, Hung SI, Hong HS, et al.: Medical genetics: A marker for Stevens- carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal
Johnson syndrome. Nature. 2004; 428(6982): 486. necrolysis in Japanese patients. Epilepsia. 2010; 51(12): 2461–5.
PubMed Abstract | Publisher Full Text PubMed Abstract | Publisher Full Text

9. Hung SI, Chung WH, Jee SH, et al.: Genetic susceptibility to carbamazepine- 28. Park HJ, Kim YJ, Kim DH, et al.: HLA Allele Frequencies in 5802 Koreans: Varied
induced cutaneous adverse drug reactions. Pharmacogenet Genomics. 2006; Allele Types Associated with SJS/TEN According to Culprit Drugs. Yonsei Med
16(4): 297–306. J. 2016; 57(1): 118–26.
PubMed Abstract | Publisher Full Text PubMed Abstract | Publisher Full Text | Free Full Text

10. Man CBL, Kwan P, Baum L, et al.: Association between HLA-B*1502 Allele and 29. Alfirevic A, Jorgensen AL, Williamson PR, et al.: HLA-B locus in Caucasian
Antiepileptic Drug-Induced Cutaneous Reactions in Han Chinese. Epilepsia. patients with carbamazepine hypersensitivity. Pharmacogenomics. 2006; 7(6):
2007; 48(5): 1015–8. 813–8.
PubMed Abstract | Publisher Full Text PubMed Abstract | Publisher Full Text

11. Locharernkul C, Loplumlert J, Limotai C, et al.: Carbamazepine and phenytoin 30. Lonjou C, Borot N, Sekula P, et al.: A European study of HLA-B in Stevens-
induced Stevens-Johnson syndrome is associated with HLA-B*1502 allele in Johnson syndrome and toxic epidermal necrolysis related to five high-risk
Thai population. Epilepsia. 2008; 49(12): 2087–91. drugs. Pharmacogenet Genomics. 2008; 18(2): 99–107.
PubMed Abstract | Publisher Full Text PubMed Abstract | Publisher Full Text

12. Mehta T, Prajapati L, Mittal B, et al.: Association of HLA-B*1502 allele and 31. Ramírez E, Bellón T, Tong HY, et al.: Significant HLA class I type associations
carbamazepine-induced Stevens-Johnson syndrome among Indians. Indian J with aromatic antiepileptic drug (AED)-induced SJS/TEN are different from
Dermatol Venereol Leprol. 2009; 75(6): 579–82. those found for the same AED-induced DRESS in the Spanish population.
PubMed Abstract | Publisher Full Text Pharmacol Res. 2017; 115: 168–178.
PubMed Abstract | Publisher Full Text
13. Ou GJ, Wang J, Ji X, et al.: A study of HLA-B*15: 02 in 9 different Chinese
32. Kim SH, Lee KW, Song WJ, et al.: Carbamazepine-induced severe cutaneous
ethnics: Implications for carbamazepine related SJS/TEN. HLA. 2017; 89(4):
adverse reactions and HLA genotypes in Koreans. Epilepsy Res. 2011; 97(1–2):
225–9.
190–7.
PubMed Abstract | Publisher Full Text
PubMed Abstract | Publisher Full Text
14. Khor AHP, Lim KS, Tan CT, et al.: HLA-A*31: 01 and HLA-B*15: 02 association
33. Ozeki T, Mushiroda T, Yowang A, et al.: Genome-wide association study
with Stevens-Johnson syndrome and toxic epidermal necrolysis to
identifies HLA-A*3101 allele as a genetic risk factor for carbamazepine-
carbamazepine in a multiethnic Malaysian population. Pharmacogenet
induced cutaneous adverse drug reactions in Japanese population. Hum Mol
Genomics. 2017; 27(7): 275–8.
Genet. 2011; 20(5): 1034–41.
PubMed Abstract | Publisher Full Text
PubMed Abstract | Publisher Full Text
15. Zhang Y, Wang J, Zhao LM, et al.: Strong association between HLA-B*1502
and carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal 34. McCormack M, Alfirevic A, Bourgeois S, et al.: HLA-A*3101 and
necrolysis in mainland Han Chinese patients. Eur J Clin Pharmacol. 2011; 67(9): Carbamazepine-Induced Hypersensitivity Reactions in Europeans. N Engl J
885–7. Med. 2011; 364(12): 1134–43.
PubMed Abstract | Publisher Full Text PubMed Abstract | Publisher Full Text | Free Full Text |
Faculty Opinions Recommendation
16. Wu XT, Hu FY, An DM, et al.: Association between carbamazepine-induced
cutaneous adverse drug reactions and the HLA-B*1502 allele among patients 35. Amstutz U, Shear NH, Rieder MJ, et al.: Recommendations for HLA-B*15: 02 and
in central China. Epilepsy Behav. 2010; 19(3): 405–8. HLA-A*31: 01 genetic testing to reduce the risk of carbamazepine-induced
PubMed Abstract | Publisher Full Text hypersensitivity reactions. Epilepsia. 2014; 55(4): 496–506.
PubMed Abstract | Publisher Full Text
17. Wang Q, Zhou JQ, Zhou LM, et al.: Association between HLA-B*1502 allele and
36. Ferrell PB, McLeod HL: Carbamazepine, HLA-B*1502 and risk of
carbamazepine-induced severe cutaneous adverse reactions in Han people of
Stevens-Johnson syndrome and toxic epidermal necrolysis: US FDA
southern China mainland. Seizure. 2011; 20(6): 446–8.
recommendations. Pharmacogenomics. 2008; 9(10): 1543–6.
PubMed Abstract | Publisher Full Text
PubMed Abstract | Publisher Full Text | Free Full Text
18. Tassaneeyakul W, Tiamkao S, Jantararoungtong T, et al.: Association between
HLA-B*1502 and carbamazepine-induced severe cutaneous adverse drug 37. Chen P, Lin JJ, Lu CS, et al.: Carbamazepine-induced toxic effects and
reactions in a Thai population. Epilepsia. 2010; 51(5): 926–30. HLA-B*1502 screening in Taiwan. N Engl J Med. 2011; 364(12): 1126–33.
PubMed Abstract | Publisher Full Text PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation
19. Chang CC, Too CL, Murad S, et al.: Association of HLA-B*1502 allele with 38. Hung SI, Chung WH, Liou LB, et al.: HLA-B*5801 allele as a genetic marker
carbamazepine-induced toxic epidermal necrolysis and Stevens-Johnson for severe cutaneous adverse reactions caused by allopurinol. Proc Natl Acad
syndrome in the multi-ethnic Malaysian population. Int J Dermatol. 2011; 50(2): Sci U S A. 2005; 102(11): 4134–9.
221–4. PubMed Abstract | Publisher Full Text | Free Full Text |
PubMed Abstract | Publisher Full Text Faculty Opinions Recommendation
20. Then SM, Rani ZZM, Raymond AA, et al.: Frequency of the HLA-B*1502 allele 39. Tassaneeyakul W, Jantararoungtong T, Chen P, et al.: Strong association
contributing to carbamazepine-induced hypersensitivity reactions in a cohort between HLA-B*5801 and allopurinol-induced Stevens-Johnson syndrome

Page 8 of 12
 F1000Research 2020, 9(F1000 Faculty Rev):612 Last updated: 31 MAR 2022

and toxic epidermal necrolysis in a Thai population. Pharmacogenet Genomics. Implications for hapten formation. Chem Res Toxicol. 2009; 22(5): 937–48.
2009; 19(9): 704–9. PubMed Abstract | Publisher Full Text
PubMed Abstract | Publisher Full Text 61. Weltzien HU, Padovan E: Molecular Features of Penicillin Allergy. J Invest
40. Niihara H, Kaneko S, Ito T, et al.: HLA-B*58: 01 strongly associates with Dermatol. 1998; 110(3): 203–6.
allopurinol-induced adverse drug reactions in a Japanese sample population. PubMed Abstract | Publisher Full Text
J Dermatol Sci. 2013; 71(12): 150–2. 62. Naisbitt DJ, Hough SJ, Gill HJ, et al.: Cellular disposition of sulphamethoxazole
PubMed Abstract | Publisher Full Text and its metabolites: Implications for hypersensitivity. Br J Pharmacol. 1999;
41. Cheng L, Xiong Y, Qin CZ, et al.: HLA-B*58: 01 is strongly associated with 126(6): 1393–407.
allopurinol-induced severe cutaneous adverse reactions in Han Chinese PubMed Abstract | Publisher Full Text | Free Full Text
patients: a multicentre retrospective case-control clinical study. Br J Dermatol. 63. Friedmann PS, Lee MS, Friedmann AC, et al.: Mechanisms in cutaneous drug
2015; 173(2): 555–8. hypersensitivity reactions. Clin Exp Allergy. 2003; 33(7): 861–72.
PubMed Abstract | Publisher Full Text PubMed Abstract | Publisher Full Text
42. Sukasem C, Jantararoungtong T, Kuntawong P, et al.: HLA-B*58: 01 for 64. Pichler WJ: Pharmacological interaction of drugs with antigen-specific immune
Allopurinol-Induced Cutaneous Adverse Drug Reactions: Implication for receptors: The p-i concept. Curr Opin Allergy Clin Immunol. 2002; 2(4): 301–5.
Clinical Interpretation in Thailand. Front Pharmacol. 2016; 7: 186. PubMed Abstract | Publisher Full Text
PubMed Abstract | Publisher Full Text | Free Full Text
65. Pichler WJ: Delayed Drug Hypersensitivity Reactions. Ann Intern Med. 2003;
43. Gonçalo M, Coutinho I, Teixeira V, et al.: HLA-B*58: 01 is a risk factor for 139: 683.
allopurinol-induced DRESS and Stevens-Johnson syndrome/toxic epidermal Publisher Full Text
necrolysis in a Portuguese population. Br J Dermatol. 2013; 169(3): 660–5.
PubMed Abstract | Publisher Full Text 66. Yun J, Marcaida MJ, Eriksson KK, et al.: Oxypurinol Directly and Immediately
Activates the Drug-Specific T Cells via the Preferential Use of HLA-B*58: 01.
44. Yu KH, Yu CY, Fang YF: Diagnostic utility of HLA-B*5801 screening in severe
J Immunol. 2014; 192(7): 2984–93.
allopurinol hypersensitivity syndrome: An updated systematic review and
PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation
meta-analysis. Int J Rheum Dis. 2017; 20(9): 1057–71.
PubMed Abstract | Publisher Full Text 67. Pichler WJ, Beeler A, Keller M, et al.: Pharmacological Interaction of Drugs with
Immune Receptors: The p-i Concept. Allergol Int. 2006; 55(1): 17–25.
45. Wu R, Cheng YJ, Zhu LL, et al.: Impact of HLA-B*58: 01 allele and
PubMed Abstract | Publisher Full Text
allopurinol-induced cutaneous adverse drug reactions: evidence from 21
pharmacogenetic studies. Oncotarget. 2016; 7(49): 81870–9. 68. Yang CWO, Hung SI, Juo CG, et al.: HLA-B*1502-bound peptides: Implications
PubMed Abstract | Publisher Full Text | Free Full Text for the pathogenesis of carbamazepine-induced Stevens-Johnson syndrome.
J Allergy Clin Immunol. 2007; 120(4): 870–7.
46. Ke CH, Chung WH, Wen YH, et al.: Cost-effectiveness Analysis for Genotyping
PubMed Abstract | Publisher Full Text
Before Allopurinol Treatment to Prevent Severe Cutaneous Adverse Drug
Reactions. J Rheumatol. 2017; 44(6): 835–43. 69. Illing PT, Vivian JP, Dudek NL, et al.: Immune self-reactivity triggered by
PubMed Abstract | Publisher Full Text drug-modified HLA-peptide repertoire. Nature. 2012; 486(7404): 554–8.
47. Jutkowitz E, Dubreuil M, Lu N, et al.: The Cost-Effectiveness of HLA-B*5801 PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation
Screening to Guide Initial Urate-Lowering Therapy for Gout in the United 70. Ostrov DA, Grant BJ, Pompeu YA, et al.: Drug hypersensitivity caused by
States. Semin Arthritis Rheum. 2017; 46(5): 594–600. alteration of the MHC-presented self-peptide repertoire. Proc Natl Acad Sci U S
PubMed Abstract | Publisher Full Text | Free Full Text A. 2012; 109(25): 9959–64.
48. Mallal S, Nolan D, Witt C, et al.: Association Between Presence of HLA-B*5701, PubMed Abstract | Publisher Full Text | Free Full Text |
HLA-DR7, and HLA-DQ3 and Hypersensitivity to HIV-1 Reverse-Transcriptase Faculty Opinions Recommendation
Inhibitor Abacavir. Lancet. 2002; 359: 727–32.
PubMed Abstract | Publisher Full Text 71. Ko TM, Chung WH, Wei CY, et al.: Shared and restricted T-cell receptor use
is crucial for carbamazepine-induced Stevens-Johnson syndrome. J Allergy
49. Hetherington S, Hughes AR, Mosteller M, et al.: Genetic Variations in HLA-B Clin Immunol. 2011; 128(6): 1266–1276.e11.
Region and Hypersensitivity Reactions to Abacavir. Lancet. 2002; 359(9312): PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation
1121–2.
PubMed Abstract | Publisher Full Text 72. Wei CY, Chung WH, Huang HW, et al.: Direct interaction between HLA-B and
carbamazepine activates T cells in patients with Stevens-Johnson syndrome.
50. Martin AM, Nolan D, Gaudieri S, et al.: Predisposition to Abacavir J Allergy Clin Immunol. 2012; 129(6): 1562-9.e5.
Hypersensitivity Conferred by HLA-B*5701 and a Haplotypic Hsp70-Hom PubMed Abstract | Publisher Full Text
Variant. Proc Natl Acad Sci U S A. 2004; 101(12): 4180–5.
PubMed Abstract | Publisher Full Text | Free Full Text 73. Chung WH, Pan RY, Chu MT, et al.: Oxypurinol-Specific T Cells Possess
Preferential TCR Clonotypes and Express Granulysin in Allopurinol-Induced
51. Hughes AR, Mosteller M, Bansal AT, et al.: Association of genetic variations Severe Cutaneous Adverse Reactions. J Invest Dermatol. 2015; 135(9): 2237–48.
in HLA-B region with hypersensitivity to abacavir in some, but not all, PubMed Abstract | Publisher Full Text
populations. Pharmacogenomics. 2004; 5(2): 203–11.
PubMed Abstract | Publisher Full Text 74. Pan RY, Chu MT, Wang CW, et al.: Identification of drug-specific public TCR
driving severe cutaneous adverse reactions. Nat Commun. 2019; 10(1): 3569.
52. Saag M, Balu R, Phillips E, et al.: High Sensitivity of Human Leukocyte Antigen–
PubMed Abstract | Publisher Full Text | Free Full Text |
B*5701 as a Marker for Immunologically Confirmed Abacavir Hypersensitivity
Faculty Opinions Recommendation
in White and Black Patients. Clin Infect Dis.. 2008; 46(7): 1111–8.
PubMed Abstract | Publisher Full Text 75. Correia O, Delgado L, Ramos JP, et al.: Cutaneous T-cell recruitment in toxic
epidermal necrolysis. Further evidence of CD8+ lymphocyte involvement. Arch
53. Mallal S, Phillips E, Carosi G, et al.: HLA-B*5701 screening for Dermatol. 1993; 129(4): 466–8.
hypersensitivity to abacavir. N Engl J Med. 2008; 358(6): 568–79. PubMed Abstract
PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation
76. Le Cleach L, Delaire S, Boumsell L, et al.: Blister fluid T lymphocytes during
54. Mounzer K, Hsu R, Fusco JS, et al.: HLA-B*57: 01 screening and toxic epidermal necrolysis are functional cytotoxic cells which express human
hypersensitivity reaction to abacavir between 1999 and 2016 in the OPERA® natural killer (NK) inhibitory receptors. Clin Exp Immunol. 2000; 119(1): 225–30.
observational database: a cohort study. AIDS Res Ther. 2019; 16(1): 1. PubMed Abstract | Publisher Full Text | Free Full Text
PubMed Abstract | Publisher Full Text | Free Full Text | 77. Tohyama M, Watanabe H, Murakami S, et al.: Possible involvement of CD14+
Faculty Opinions Recommendation CD16+ monocyte lineage cells in the epidermal damage of Stevens-Johnson
55. Wilkinson GR: Drug metabolism and variability among patients in drug syndrome and toxic epidermal necrolysis. Br J Dermatol. 2012; 166(2): 322–30.
response. N Engl J Med. 2005; 352(21): 2211–21. PubMed Abstract | Publisher Full Text
PubMed Abstract | Publisher Full Text
78. Correia O, Delgado L, Roujeau JC, et al.: Soluble interleukin 2 receptor and
56. Chung WH, Chang WC, Lee YS, et al.: Genetic variants associated with interleukin 1alpha in toxic epidermal necrolysis: A comparative analysis of
phenytoin-related severe cutaneous adverse reactions. JAMA. 2014; 312(5): serum and blister fluid samples. Arch Dermatol. 2002; 138(1): 29–32.
525–34. PubMed Abstract | Publisher Full Text
PubMed Abstract | Publisher Full Text
79. Paul C, Wolkenstein P, Adle H, et al.: Apoptosis as a mechanism of keratinocyte
57. Pichler WJ: Modes of presentation of chemical neoantigens to the immune death in toxic epidermal necrolysis. Br J Dermatol. 1996; 134(4): 710–4.
system. Toxicology. 2002; 181-182: 49–54. PubMed Abstract | Publisher Full Text
PubMed Abstract | Publisher Full Text
80. Elmore S: Apoptosis: A Review of Programmed Cell Death. Toxicol Pathol. 2007;
58. Adam J, Pichler WJ, Yerly D: Delayed drug hypersensitivity: Models of T-cell 35(4): 495–516.
stimulation. Br J Clin Pharmacol. 2011; 71(5): 701–7. PubMed Abstract | Publisher Full Text | Free Full Text
PubMed Abstract | Publisher Full Text | Free Full Text
81. Viard-Leveugle I, Bullani RR, Meda P, et al.: Intracellular localization of
59. Abe R:: Immunological response in Stevens-Johnson syndrome and toxic keratinocyte Fas ligand explains lack of cytolytic activity under physiological
epidermal necrolysis. J Dermatol. 2015; 42(1): 42–8. conditions. J Biol Chem. 2003; 278(18): 16183–8.
PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation PubMed Abstract | Publisher Full Text
60. Callan HE, Jenkins RE, Maggs JL, et al.: Multiple adduction reactions of 82. Viard I, Wehrli P, Bullani R, et al.: Inhibition of Toxic Epidermal Necrolysis by
nitroso sulfamethoxazole with cysteinyl residues of peptides and proteins: Blockade of CD95 with Human Intravenous Immunoglobulin. Science. 1998;

Page 9 of 12
 F1000Research 2020, 9(F1000 Faculty Rev):612 Last updated: 31 MAR 2022

282(5388): 490–3. 104. Qing DY, Conegliano D, Shashaty MGS, et al.: Red blood cells induce
PubMed Abstract | Publisher Full Text necroptosis of lung endothelial cells and increase susceptibility to lung
83. Tanaka M, Suda T, Haze K, et al.: Fas ligand in human serum. Nat Med. 1996; inflammation. Am J Respir Crit Care Med. 2014; 190(11): 1243–54.
2(3): 317–22. PubMed Abstract | Publisher Full Text | Free Full Text
PubMed Abstract | Publisher Full Text 105. Shiga S, Cartotto R: What Are the Fluid Requirements in Toxic Epidermal
84. Abe R: Toxic epidermal necrolysis and Stevens-Johnson syndrome: Soluble Necrolysis? J Burn Care Res. 2010; 31(1): 100–4.
Fas ligand involvement in the pathomechanisms of these diseases. J Dermatol PubMed Abstract | Publisher Full Text
Sci. 2008; 52(3): 151–9. 106. Coss-Bu JA, Jefferson LS, Levy ML, et al.: Nutrition requirements in patients
PubMed Abstract | Publisher Full Text with toxic epidermal necrolysis. Nutr Clin Pract. 1997; 12(2): 81–4.
85. Abe R, Shimizu T, Shibaki A, et al.: Toxic Epidermal Necrolysis and Stevens- PubMed Abstract | Publisher Full Text
Johnson Syndrome Are Induced by Soluble Fas Ligand. Am J Pathol. 2003; 107. Valeyrie-Allanore L, Ingen-Housz-Oro S, Chosidow O, et al.: French referral center
162(5): 1515–20. management of Stevens–Johnson syndrome/toxic epidermal necrolysis.
PubMed Abstract | Publisher Full Text | Free Full Text Dermatologica Sinica. 2013; 31(4): 191–5.
Publisher Full Text
86. Stur K, Karlhofer FM, Stingl G:: Soluble FAS ligand: A discriminating feature
between drug-induced skin eruptions and viral exanthemas. J Invest Dermatol. 108. de Prost N, Ingen-Housz-Oro S, Duong Ta, et al.: Bacteremia in Stevens-Johnson
2007; 127(4): 802–7. syndrome and toxic epidermal necrolysis: Epidemiology, risk factors, and
PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation predictive value of skin cultures. Medicine (Baltimore). 2010; 89(1): 28–36.
PubMed Abstract | Publisher Full Text
87. Nassif A, Bensussan A, Bachot N, et al.: Drug Specific Cytotoxic T-Cells in the
Skin Lesions of a Patient with Toxic Epidermal Necrolysis. J Invest Dermatol. 109. White KD, Abe R, Ardern-Jones M, et al.: SJS/TEN 2017: Building
2002; 118(4): 728–33. Multidisciplinary Networks to Drive Science and Translation. J Allergy Clin
PubMed Abstract | Publisher Full Text Immunol Pract. 2018; 6(1): 38–69.
PubMed Abstract | Publisher Full Text | Free Full Text
88. Nassif A, Bensussan A, Boumsell L, et al.: Toxic epidermal necrolysis: Effector
cells are drug-specific cytotoxic T cells. J Allergy Clin Immunol. 2004; 114(5): 110. Zimmermann S, Sekula P, Venhoff M, et al.: Systemic Immunomodulating
1209–15. Therapies for Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: A
PubMed Abstract | Publisher Full Text Systematic Review and Meta-analysis. JAMA Dermatol. 2017; 153(6): 514–22.
PubMed Abstract | Publisher Full Text | Free Full Text |
89. Chung WH, Hung SI, Yang JY, et al.: Granulysin is a key mediator for
Faculty Opinions Recommendation
disseminated keratinocyte death in Stevens-Johnson syndrome and toxic
epidermal necrolysis. Nat Med. 2008; 14(12): 1343–50. 111. Schneider JA, Cohen PR: Stevens-Johnson Syndrome and Toxic Epidermal
PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation Necrolysis: A Concise Review with a Comprehensive Summary of Therapeutic
Interventions Emphasizing Supportive Measures. Adv Ther. 2017; 34(6):
90. Abe R, Yoshioka N, Murata J, et al.: Granulysin as a marker for early diagnosis
1235–44.
of the Stevens-Johnson syndrome. Ann Intern Med. 2009; 151(7): 514–5.
PubMed Abstract | Publisher Full Text | Free Full Text
PubMed Abstract | Publisher Full Text
112. Creamer D, Walsh SA, Dziewulski P, et al.: U.K. guidelines for the management
91. Saito N, Abe R, Yoshioka N, et al.: Prolonged elevation of serum granulysin in
of Stevens-Johnson syndrome/toxic epidermal necrolysis in adults 2016. Br J
drug-induced hypersensitivity syndrome. Br J Dermatol. 2012; 167(2): 452–3.
Dermatol. 2016; 174(6): 1194–227.
PubMed Abstract | Publisher Full Text
PubMed Abstract | Publisher Full Text
92. Saito N, Qiao H, Yanagi T, et al.: An annexin A1-FPR1 interaction 113. Ginsburg CM: Stevens-Johnson syndrome in children. Pediatr Infect Dis J. 1982;
contributes to necroptosis of keratinocytes in severe cutaneous adverse drug 1: 155–8.
reactions. Sci Transl Med. 2014; 6(245): 245ra95–245ra95. Publisher Full Text
PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation
114. Halebian PH, Corder VJ, Madden MR, et al.: Improved Burn Center Survival of
93. Linkermann A, Green DR: Necroptosis. N Engl J Med. 2014; 370(5): 455–65. Patients with Toxic Epidermal Necrolysis Managed without Corticosteroids.
PubMed Abstract | Publisher Full Text | Free Full Text Ann Surg. 1986; 204(5): 503–12.
94. Saito N, Yoshioka N, Abe R, et al.: Stevens-Johnson syndrome/toxic PubMed Abstract | Publisher Full Text | Free Full Text
epidermal necrolysis mouse model generated by using PBMCs and the skin of 115. Kelemen JJ 3rd, Cioffi WG, McManus WF, et al.: Burn center care for patients
patients. J Allergy Clin Immunol. 2013; 131(2): 434–41.e1-9. with toxic epidermal necrolysis. J Am Coll Surg. 1995; 180(3): 273–8.
PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation PubMed Abstract
95. Wang F, He D, Tang X, et al.: Chemokine expression in diverse nonimmediate 116. Finkelstein Y, Soon GS, Acuna P, et al.: Recurrence and Outcomes of Stevens-
drug hypersensitivity reactions: Focus on thymus activation-regulated Johnson Syndrome and Toxic Epidermal Necrolysis in Children. Pediatrics.
chemokine, cutaneous T-cell-attracting chemokine, and interleukin-10. Ann 2011; 128(4): 723–8.
Allergy Asthma Immunol. 2014; 113(2): 204–8. PubMed Abstract | Publisher Full Text
PubMed Abstract | Publisher Full Text 117. Sekula P, Dunant A, Mockenhaupt M, et al.: Comprehensive Survival Analysis
96. Wang F, Ye Y, Luo ZY, et al.: Diverse expression of TNF-α and CCL27 in of a Cohort of Patients with Stevens-Johnson Syndrome and Toxic Epidermal
serum and blister of Stevens-Johnson syndrome/toxic epidermal necrolysis. Necrolysis. J Invest Dermatol. 2013; 133(5): 1197–204.
Clin Transl Allergy. 2018; 8: 12. PubMed Abstract | Publisher Full Text
PubMed Abstract | Publisher Full Text | Free Full Text | 118. Roujeau JC, Bastuji-Garin S: Systematic review of treatments for Stevens-
Faculty Opinions Recommendation Johnson syndrome and toxic epidermal necrolysis using the SCORTEN score
97. McCully ML, Moser B: The Human Cutaneous Chemokine System. Front as a tool for evaluating mortality. Ther Adv Drug Saf. 2011; 2(3): 87–94.
Immunol. 2011; 2: 33. PubMed Abstract | Publisher Full Text | Free Full Text
PubMed Abstract | Publisher Full Text | Free Full Text 119. Schneck J, Fagot JP, Sekula P, et al.: Effects of treatments on the mortality of
98. Tapia B, Padial A, Sánchez-Sabaté E, et al.: Involvement of CCL27-CCR10 Stevens-Johnson syndrome and toxic epidermal necrolysis: A retrospective
interactions in drug-induced cutaneous reactions. J Allergy Clin Immunol. 2004; study on patients included in the prospective EuroSCAR Study. J Am Acad
114(2): 335–40. Dermatol. 2008; 58(1): 33–40.
PubMed Abstract | Publisher Full Text PubMed Abstract | Publisher Full Text
120. Kardaun SH, Jonkman MF: Dexamethasone Pulse Therapy for Stevens-Johnson
99. Su SC, Mockenhaupt M, Wolkenstein P, et al.: Interleukin-15 Is Associated
Syndrome/Toxic Epidermal Necrolysis. Acta Derm Venereol. 2007; 87(2): 144–8.
with Severity and Mortality in Stevens-Johnson Syndrome/Toxic Epidermal
PubMed Abstract | Publisher Full Text
Necrolysis. J Invest Dermatol. 2017; 137(5): 1065–73.
PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 121. Lee HY, Lim YL, Thirumoorthy T, et al.: The role of intravenous immunoglobulin
100. McInnes IB, Leung BP, Sturrock RD, et al.: Interleukin-15 mediates T cell- in toxic epidermal necrolysis: A retrospective analysis of 64 patients managed
dependent regulation of tumor necrosis factor-alpha production in rheumatoid in a specialized centre. Br J Dermatol. 2013; 169(6): 1304–9.
arthritis. Nat Med. 1997; 3(2): 189–95. PubMed Abstract | Publisher Full Text
PubMed Abstract | Publisher Full Text 122. Bachot N, Revuz J, Roujeau JC: Intravenous immunoglobulin treatment for
101. Hama N, Nishimura K, Hasegawa A, et al.: Galectin-7 as a potential biomarker Stevens-Johnson syndrome and toxic epidermal necrolysis: A prospective
of Stevens-Johnson syndrome/toxic epidermal necrolysis: Identification by noncomparative study showing no benefit on mortality or progression. Arch
targeted proteomics using causative drug-exposed peripheral blood cells. J Dermatol. 2003; 139(1): 33–6.
Allergy Clin Immunol Pract. 2019; 7(8): 2894–2897.e7. PubMed Abstract | Publisher Full Text
PubMed Abstract | Publisher Full Text 123. Brown KM, Silver GM, Halerz M, et al.: Toxic epidermal necrolysis: Does
102. Vidova V, Spacil Z: A review on mass spectrometry-based quantitative immunoglobulin make a difference? J Burn Care Rehabil. 2004; 25(1): 81–8.
proteomics: Targeted and data independent acquisition. Anal Chim Acta. 2017; PubMed Abstract | Publisher Full Text
964: 7–23. 124. Huang YC, Li YC, Chen TJ: The efficacy of intravenous immunoglobulin for
PubMed Abstract | Publisher Full Text the treatment of toxic epidermal necrolysis: A systematic review and meta-
103. Hasegawa A, Shinkuma S, Hayashi R, et al.: RIP3 as a diagnostic and severity analysis. Br J Dermatol. 2012; 167(2): 424–32.
marker for Stevens-Johnson syndrome and toxic epidermal necrolysis. J PubMed Abstract | Publisher Full Text
Allergy Clin Immunol Pract. 2020; 8(5): 1768–1771.e7. 125. Metry DW, Jung P, Levy ML: Use of intravenous immunoglobulin in children
PubMed Abstract | Publisher Full Text with stevens-johnson syndrome and toxic epidermal necrolysis: Seven cases

Page 10 of 12
 F1000Research 2020, 9(F1000 Faculty Rev):612 Last updated: 31 MAR 2022

and review of the literature. Pediatrics. 2003; 112(6 Pt 1): 1430–6. 142. Chaidemenos GC, Chrysomallis F, Sombolos K, et al.: Plasmapheresis in toxic
PubMed Abstract | Publisher Full Text epidermal necrolysis. Int J Dermatol. 1997; 36(3): 218–21.
126. Prins C, Vittorio C, Padilla RS, et al.: Effect of High-Dose Intravenous PubMed Abstract | Publisher Full Text
Immunoglobulin Therapy in Stevens-Johnson Syndrome: A Retrospective, 143. Egan CA, Grant WJ, Morris SE, et al.: Plasmapheresis as an adjunct treatment in
Multicenter Study. Dermatology. 2003; 207(1): 96–9. toxic epidermal necrolysis. J Am Acad Dermatol. 1999; 40(3): 458–61.
PubMed Abstract | Publisher Full Text PubMed Abstract | Publisher Full Text
127. Faye O, Roujeau JC: Treatment of epidermal necrolysis with high-dose 144. Bamichas G, Natse T, Christidou F, et al.: Plasma exchange in patients with toxic
intravenous immunoglobulins (IV Ig): Clinical experience to date. Drugs. 2005; epidermal necrolysis. Ther Apher. 2002; 6(3): 225–8.
65(15): 2085–90. PubMed Abstract | Publisher Full Text
PubMed Abstract | Publisher Full Text
145. Yamada H, Takamori K, Yaguchi H, et al.: A Study of the Efficacy of
128. Morici MV, Galen WK, Shetty AK, et al.: Intravenous immunoglobulin therapy for Plasmapheresis for the Treatment of Drug Induced Toxic Epidermal Necrolysis.
children with Stevens-Johnson syndrome. J Rheumatol. 2000; 27(10): 2494–7. Ther Apher. 1998; 2(2): 153–6.
PubMed Abstract PubMed Abstract | Publisher Full Text
129. Barron SJ, Del Vecchio MT, Aronoff SC:: Intravenous immunoglobulin in the 146. Furubacke A, Berlin G, Anderson C, et al.: Lack of significant treatment effect
treatment of Stevens-Johnson syndrome and toxic epidermal necrolysis: A of plasma exchange in the treatment of drug-induced toxic epidermal
meta-analysis with meta-regression of observational studies. Int J Dermatol. necrolysis? Intensive Care Med. 1999; 25(11): 1307–10.
2015; 54(1): 108–15. PubMed Abstract | Publisher Full Text
PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation
147. Narita YM, Hirahara K, Mizukawa Y, et al.: Efficacy of plasmapheresis for
130. Chung WH, Wang CW, Dao RL:: Severe cutaneous adverse drug reactions. the treatment of severe toxic epidermal necrolysis: Is cytokine expression
J Dermatol. 2016; 43(7): 758–66. analysis useful in predicting its therapeutic efficacy? J Dermatol. 2011; 38(3):
PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 236–45.
131. Valeyrie-Allanore L, Wolkenstein P, Brochard L, et al.: Open trial of ciclosporin PubMed Abstract | Publisher Full Text
treatment for Stevens-Johnson syndrome and toxic epidermal necrolysis. Br J 148. Lissia M, Figus A, Rubino C: Intravenous immunoglobulins and plasmapheresis
Dermatol. 2010; 163(4): 847–53. combined treatment in patients with severe toxic epidermal necrolysis:
PubMed Abstract | Publisher Full Text Preliminary report. Br J Plast Surg. 2005; 58(4): 504–10.
132. Kirchhof MG, Miliszewski MA, Sikora S, et al.: Retrospective review of Stevens- PubMed Abstract | Publisher Full Text
Johnson syndrome/toxic epidermal necrolysis treatment comparing
intravenous immunoglobulin with cyclosporine. J Am Acad Dermatol. 2014; 149. Han F, Zhang J, Guo Q, et al.: Successful treatment of toxic epidermal
71(5): 941–7. necrolysis using plasmapheresis: A prospective observational study. J Crit
PubMed Abstract | Publisher Full Text Care. 2017; 42: 65–8.
PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation
133. Kumar P, Das NK: Cyclosporine in toxic epidermal necrolysis: A brief review
of the emerging therapeutic modality. Dermatol Online J. 2016; 22(10): 13030/ 150. Paquet P, Nikkels A, Arrese JE, et al.: Macrophages and Tumor Necrosis Factor
qt3m82s074. Alpha in Toxic Epidermal Necrolysis. Arch Dermatol. 1994; 130(5): 605–8.
PubMed Abstract PubMed Abstract | Publisher Full Text
134. Lee HY, Fook-Chong S, Koh HY, et al.: Cyclosporine treatment for Stevens- 151. Nassif A, Moslehi H, Le Gouvello S, et al.: Evaluation of the potential role of
Johnson syndrome/toxic epidermal necrolysis: Retrospective analysis of a cytokines in toxic epidermal necrolysis. J Invest Dermatol. 2004; 123(5):
cohort treated in a specialized referral center. J Am Acad Dermatol. 2017; 76(1) 850–5.
106–113. PubMed Abstract | Publisher Full Text
PubMed Abstract | Publisher Full Text
152. Wojtkiewicz A, Wysocki M, Fortuna J, et al.: Beneficial and rapid effect of
135. Ng QX, de Deyn MLZQ, Venkatanarayanan N, et al.: A meta-analysis of infliximab on the course of toxic epidermal necrolysis. Acta Derm Venereol.
cyclosporine treatment for Stevens-Johnson syndrome/toxic epidermal 2008; 88(4): 420–1.
necrolysis. J Inflamm Res. 2018; 11: 135–142. PubMed Abstract
PubMed Abstract | Publisher Full Text | Free Full Text | 153. Patmanidis K, Sidiras A, Dolianitis K, et al.: Combination of infliximab and high-
Faculty Opinions Recommendation dose intravenous immunoglobulin for toxic epidermal necrolysis: Successful
136. González-Herrada C, Rodríguez-Martín S, Cachafeiro L, et al.: Cyclosporine Use treatment of an elderly patient. Case Rep Dermatol Med. 2012; 2012: 915314.
in Epidermal Necrolysis Is Associated with an Important Mortality Reduction: PubMed Abstract | Publisher Full Text | Free Full Text
Evidence from Three Different Approaches. J Invest Dermatol. 2017; 137(10):
154. Zárate-Correa LC, Carrillo-Gómez DC, Ramírez-Escobar AF, et al.: Toxic
2092–100.
epidermal necrolysis successfully treated with infliximab. J Investig Allergol
PubMed Abstract | Publisher Full Text
Clin Immunol. 2013; 23(1): 61–3.
137. Roujeau J-C, Mockenhaupt M, Guillaume J-C, et al.: New Evidence Supporting PubMed Abstract
Cyclosporine Efficacy in Epidermal Necrolysis. J Invest Dermatol. 2017;
137(10): 2047–9. 155. Scott-Lang V, Tidman M, McKay D: Toxic Epidermal Necrolysis in a Child
PubMed Abstract | Publisher Full Text Successfully Treated with Infliximab. Pediatr Dermatol. 2014; 31(4): 532–4.
PubMed Abstract | Publisher Full Text
138. Shah R, Chen ST, Kroshinsky D:: Use of Cyclosporine for the treatment of
Steven Johnson Syndrome/ Toxic Epidermal Necrolysis. J Am Acad Dermatol. 156. Pham CH, Gillenwater TJ, Nagengast E, et al.: Combination therapy:
2019; S0190–9622(19)30001-5. Etanercept and intravenous immunoglobulin for the acute treatment of
PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation Stevens-Johnson syndrome/toxic epidermal necrolysis. Burns. 2019; 45(7):
1634–1638.
139. Gilbert M, Scherrer LA:: Efficacy and safety of cyclosporine in Stevens- PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation
Johnson syndrome and toxic epidermal necrolysis. Dermatol Ther. 2019; 32(1):
e12758. 157. Paradisi A, Abeni D, Bergamo F, et al.: Etanercept therapy for toxic epidermal
PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation necrolysis. J Am Acad Dermatol. 2014; 71(2): 278–83.
PubMed Abstract | Publisher Full Text
140. Kamanabroo D, Schmitz-Landgraf W, Czarnetzki BM: Plasmapheresis in Severe
Drug-Induced Toxic Epidermal Necrolysis. Arch Dermatol. 1985; 121(12): 158. Hunger RE, Hunziker T, Buettiker U, et al.: Rapid resolution of toxic epidermal
1548–1549. necrolysis with anti-TNF-alpha treatment. J Allergy Clin Immunol. 2005; 116(4):
PubMed Abstract | Publisher Full Text 923–4.
141. Sakellariou G, Koukoudis P, Karpouzas J, et al.: Plasma Exchange (Pe) Treatment PubMed Abstract | Publisher Full Text
in Drug-Induced Toxic Epidermal Necrolysis (Ten). Int J Artif Organs. 1991; 159. Gubinelli E, Canzona F, Tonanzi T, et al.: Toxic epidermal necrolysis
14(10): 634–8. successfully treated with etanercept. J Dermatol. 2009; 36(3): 150–3.
PubMed Abstract | Publisher Full Text PubMed Abstract | Publisher Full Text

Page 11 of 12
 F1000Research 2020, 9(F1000 Faculty Rev):612 Last updated: 31 MAR 2022

Open Peer Review

Current Peer Review Status:

Editorial Note on the Review Process

Faculty Reviews are review articles written by the prestigious Members of Faculty Opinions. The articles
are commissioned and peer reviewed before publication to ensure that the final, published version is
comprehensive and accessible. The reviewers who approved the final version are listed with their names
and affiliations.

The reviewers who approved this article are:

Version 1
1. Julia Spoendlin
Basel Pharmacoepidemiology Unit, Department of Pharmaceutical Sciences, University of Basel, Basel,
Switzerland
Competing Interests: No competing interests were disclosed.
2. Marc Vocanson
1 CIRI, International Center for Infectiology Research, Université de Lyon, Lyon, France
2 CIRI-INSERM U1111, Lyon, France
Competing Interests: No competing interests were disclosed.

The benefits of publishing with F1000Research:

• Your article is published within days, with no editorial bias

• You can publish traditional articles, null/negative results, case reports, data notes and more

• The peer review process is transparent and collaborative

• Your article is indexed in PubMed after passing peer review

• Dedicated customer support at every stage

For pre-submission enquiries, contact research@[Link]

Page 12 of 12
 TYPE Review
PUBLISHED 11 October 2023
DOI 10.3389/fmed.2023.1213889

Updates in SJS/TEN:
OPEN ACCESS collaboration, innovation, and
community
EDITED BY
Je-Ho Mun,
Seoul National University, Republic of Korea

REVIEWED BY
David Andrew Fulcher, Madeline E. Marks 1†, Ramya Krishna Botta 1†, Riichiro Abe 2,
Australian National University, Australia Thomas M. Beachkofsky 3, Isabelle Boothman 4,
Omer Iqbal,
Loyola University Chicago, United States Bruce C. Carleton 5, Wen-Hung Chung 6, Ricardo R. Cibotti 7,
*CORRESPONDENCE Roni P. Dodiuk-Gad 8,9,10, Christian Grimstein 11, Akito Hasegawa 2,
Elizabeth J. Phillips
[Link]@[Link] Jay H. Hoofnagle 12, Shuen-Iu Hung 13, Benjamin Kaffenberger 14,
These authors have contributed equally to this
† Daniela Kroshinsky 15, Rannakoe J. Lehloenya 16,
work and share first authorship
Michelle Martin-Pozo 1, Robert G. Micheletti 17,
RECEIVED 28 April 2023
ACCEPTED 31 July 2023 Maja Mockenhaupt 18, Keisuke Nagao 7, Suman Pakala 1,
PUBLISHED 11 October 2023
Amy Palubinsky 1, Helena B. Pasieka 3,19,20, Jonathan Peter 21,
CITATION
Marks ME, Botta RK, Abe R, Beachkofsky TM,
Munir Pirmohamed 22, Melissa Reyes 23, Hajirah N. Saeed 24,
Boothman I, Carleton BC, Chung W-H, Jeffery Shupp 25, Chonlaphat Sukasem 26, Jhih Yu Syu 27,
Cibotti RR, Dodiuk-Gad RP, Grimstein C,
Hasegawa A, Hoofnagle JH, Hung S-I, Mayumi Ueta 28, Li Zhou 29, Wan-Chun Chang 5, Patrice Becker 30,
Kaffenberger B, Kroshinsky D, Lehloenya RJ,
Martin-Pozo M, Micheletti RG, Mockenhaupt M,
Teresa Bellon 31, Kemberlee Bonnet 32, Gianpiero Cavalleri 4,
Nagao K, Pakala S, Palubinsky A, Pasieka HB, James Chodosh 33, Anna K. Dewan 34, Arturo Dominguez 35,
Peter J, Pirmohamed M, Reyes M, Saeed HN,
Shupp J, Sukasem C, Syu JY, Ueta M, Zhou L, Xinzhong Dong 36, Elena Ezhkova 37, Esther Fuchs 38,
Chang W-C, Becker P, Bellon T, Bonnet K,
Cavalleri G, Chodosh J, Dewan AK,
Jennifer Goldman 39, Sonia Himed 40, Simon Mallal 41,
Dominguez A, Dong X, Ezhkova E, Fuchs E, Alina Markova 42, Kerry McCawley 43, Allison E. Norton 44,
Goldman J, Himed S, Mallal S, Markova A,
McCawley K, Norton AE, Ostrov D, Phan M, David Ostrov 45, Michael Phan 46, Arthur Sanford 47,
Sanford A, Schlundt D, Schneider D, Shear N,
Shinkai K, Tkaczyk E, Trubiano JA, Volpi S,
David Schlundt 32, Daniel Schneider 48, Neil Shear 8,
Bouchard CS, Divito SJ and Phillips EJ (2023) Kanade Shinkai 49, Eric Tkaczyk 50, Jason A. Trubiano 51,
Updates in SJS/TEN: collaboration, innovation,
and community. Simona Volpi 52, Charles S. Bouchard 53, Sherrie J. Divito 15 and
Front. Med. 10:1213889.
doi: 10.3389/fmed.2023.1213889
Elizabeth J. Phillips 1*
COPYRIGHT
1
Center for Drug Interactions and Immunology, Division of Infectious Disease, Department of Medicine,
© 2023 Marks, Botta, Abe, Beachkofsky, Vanderbilt University Medical Center, Nashville, TN, United States, 2 Division of Dermatology, Niigata
Boothman, Carleton, Chung, Cibotti, University Graduate School of Medical and Dental Sciences, Niigata, Japan, 3 Departments of
Dodiuk-Gad, Grimstein, Hasegawa, Hoofnagle, Dermatology and Medicine, Uniformed Services University, Bethesda, MD, United States, 4 The SFI
Hung, Kaffenberger, Kroshinsky, Lehloenya, Centre for Research Training in Genomics Data Science, Dublin, Ireland, 5 Division of Translational
Martin-Pozo, Micheletti, Mockenhaupt, Nagao, Therapeutics, Department of Pediatrics, Faculty of Medicine, University of British Columbia and the
Pakala, Palubinsky, Pasieka, Peter, Pirmohamed, British Columbia Children’s Hospital Research Institute, Vancouver, BC, Canada, 6 Department of
Reyes, Saeed, Shupp, Sukasem, Syu, Ueta, Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital,
Zhou, Chang, Becker, Bellon, Bonnet, Cavalleri, Taoyuan, Taiwan, 7 National Institute of Arthritis and Musculoskeletal and Skin (NIAMS), National
Chodosh, Dewan, Dominguez, Dong, Ezhkova, Institutes of Health (NIH), Bethesda, MD, United States, 8 Department of Dermatology, Emek Medical
Fuchs, Goldman, Himed, Mallal, Markova, Center, Afula, Israel, 9Division of Dermatology, Department of Medicine, University of Toronto, Toronto, ON,
McCawley, Norton, Ostrov, Phan, Sanford, Canada, 10 Department of Dermatology, Bruce Rappaport Faculty of Medicine, Technion Institute of
Schlundt, Schneider, Shear, Shinkai, Tkaczyk, Technology, Haifa, Israel, 11 Office of Clinical Pharmacology, Office of Translational Sciences, Center for
Trubiano, Volpi, Bouchard, Divito and Phillips. Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, United States,
This is an open-access article distributed under
12
Liver Disease Research Branch, Division of Digestive Diseases and Nutrition of NIDDK, National
the terms of the Creative Commons Attribution Institutes of Health (NIH), Bethesda, MD, United States, 13 Cancer Vaccine and Immune Cell Therapy
License (CC BY). The use, distribution or Core Laboratory, Department of Medical Research, Chang Gung Memorial Hospital, Taoyuan, Taiwan,
reproduction in other forums is permitted,
14
Department of Dermatology, Ohio State University Wexner Medical Center, Columbus, OH, United
provided the original author(s) and the States, 15 Department of Dermatology, Brigham and Women’s Hospital, Harvard Medical School, Boston,
copyright owner(s) are credited and that the MA, United States, 16 Division of Dermatology, Department of Medicine, University of Cape Town, Cape
original publication in this journal is cited, in Town, South Africa, 17 Department of Dermatology, Perelman School of Medicine, University of
accordance with accepted academic practice. Pennsylvania, Philadelphia, PA, United States, 18 Dokumentationszentrum schwerer Hautreaktionen
No use, distribution or reproduction is (dZh), Department of Dermatology, Medical Center and Medical Faculty, University of Freiburg, Freiburg,
permitted which does not comply with these Germany, 19 The Burn Center, MedStar Washington Hospital Center, Washington, D.C., DC, United
terms. States, 20 Department of Dermatology, MedStar Health/Georgetown University, Washington, D.C., DC,

Frontiers in Medicine 01 [Link]

Marks et al. 10.3389/fmed.2023.1213889

United States, 21 Division of Allergy and Clinical Immunology, Department of Medicine, University of
Cape Town, Cape Town, South Africa, 22 Department of Pharmacology and Therapeutics, University of
Liverpool, Liverpool, United Kingdom, 23 Center for Drug Evaluation and Research, United States Food
and Drug Administration, Silver Spring, MD, United States, 24 Massachusetts Eye and Ear, Harvard Medical
School, Boston, MA, United States, 25 Department of Surgery, Plastic and Reconstructive Surgery,
Biochemistry, and Molecular and Cellular Biology, MedStar Washington Hospital Center, Georgetown
University School of Medicine, Washington, D.C., DC, United States, 26 Department of Pathology, Faculty
of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand, 27 Department of Cell Biology
and Anatomy, College of Medicine, National Cheng Kung University, Tainan, Taiwan, 28 Department of
Frontier Medical Science and Technology for Ophthalmology, Kyoto Prefectural University of Medicine,
Kyoto, Japan, 29 Division of General Internal Medicine and Primary Care, Brigham and Women’s Hospital,
Harvard Medical School, Boston, MA, United States, 30 Division of Allergy, Immunology, and
Transplantation, National Institute of Allergy and Infectious Disease, Bethesda, MD, United States, 31 Drug
Hypersensitivity Laboratory, La Paz Health Research Institute (IdiPAZ), Madrid, Spain, 32 Department of
Psychology, Vanderbilt University, Nashville, TN, United States, 33 University of New Mexico School of
Medicine, Albuquerque, NM, United States, 34 Department of Dermatology, Vanderbilt University Medical
Center, Nashville, TN, United States, 35 Department of Dermatology and Internal Medicine, UT
Southwestern Medical Center, Dallas, TX, United States, 36 Department of Neuroscience, Johns Hopkins
University School of Medicine, Baltimore, MD, United States, 37 Department of Cell, Developmental, and
Regenerative Biology and Dermatology, Black Family Stem Cell Institute, Mount Sinai School of
Medicine, New York, NY, United States, 38 Department of Obstetrics and Gynecology, University of
Washington, Seattle, WA, United States, 39 Division of Pediatric Infectious Diseases and Clinical
Pharmacology, Children’s Mercy, Kansas City, MO, United States, 40 College of Medicine, University of
Cincinnati, Cincinnati, OH, United States, 41 Division of Infectious Diseases, Department of Medicine,
Vanderbilt University Medical Center, Nashville, TN, United States, 42 Department of Dermatology,
Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY, United States,
43
Stevens-Johnson Syndrome Foundation, Westminster, CO, United States, 44 Division of Pediatric
Allergy, Immunology, and Pulmonary Medicine, Department of Pediatrics, Vanderbilt University Medical
Center, Nashville, TN, United States, 45 Department of Pathology, Immunology and Laboratory Medicine,
University of Florida, Gainesville, FL, United States, 46 Division of Pharmacovigilance-I, Center for Drug
Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, United States, 47 Division
of Trauma, Surgical Critical Care, and Burns, Loyola University Medical Center, Chicago, IL, United
States, 48 Department of Psychiatry and Surgery, MedStar Washington Hospital Center, Georgetown
University School of Medicine, Washington, D.C., DC, United States, 49 Department of Dermatology,
University of California, San Francisco, San Francisco, CA, United States, 50 Department of Veterans
Affairs, Vanderbilt Dermatology Translational Research Clinic ([Link]), Nashville, TN, United States,
51
Department of Infectious Diseases and Medicine, Austin Health, University of Melbourne, Melbourne,
VIC, Australia, 52 National Human Genome Research Institute (NHGRI), National Institutes of Health
(NIH), Bethesda, MD, United States, 53 Department of Opthalmology, Loyola University Medical Center,
Chicago, IL, United States

Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) is a

predominantly drug-induced disease, with a mortality rate of 15–20%, that
engages the expertise of multiple disciplines: dermatology, allergy, immunology,
clinical pharmacology, burn surgery, ophthalmology, urogynecology, and
psychiatry. SJS/TEN has an incidence of 1–5/million persons per year in the
United States, with even higher rates globally. One of the challenges of SJS/TEN
has been developing the research infrastructure and coordination to answer
questions capable of transforming clinical care and leading to improved patient
outcomes. SJS/TEN 2021, the third research meeting of its kind, was held as
a virtual meeting on August 28–29, 2021. The meeting brought together 428
international scientists, in addition to a community of 140 SJS/TEN survivors and
family members. The goal of the meeting was to brainstorm strategies to support
the continued growth of an international SJS/TEN research network, bridging
science and the community. The community workshop section of the meeting
focused on eight primary themes: mental health, eye care, SJS/TEN in children,
non-drug induced SJS/TEN, long-term health complications, new advances in
mechanisms and basic science, managing long-term scarring, considerations for
skin of color, and COVID-19 vaccines. The meeting featured several important
updates and identified areas of unmet research and clinical need that will
be highlighted in this white paper.

KEYWORDS

Stevens-Johnson Syndrome, Toxic Epidermal Necrolysis, severe adverse cutaneous drug

reactions, HLA genotyping, pharmacogenomics, body surface area, electronic medical
record, SCORTEN

Frontiers in Medicine 02 [Link]

Marks et al. 10.3389/fmed.2023.1213889

1. Introduction distribution of standardized care plans for SJS/TEN would also

be beneficial for mending this gap. Delphi-based consensus exercises
Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis have both supported a consensus on the best supportive care practice
(TEN) are life-threatening, immunologically-mediated, severe, (11) for SJS/TEN. A survey of SJS survivors attending SJS/TEN 2021
cutaneous adverse drug reactions (IM-ADRs) (1). They are thought identified several barriers to receiving the post-discharge information
to be clinically and mechanistically one illness defined across a and care they need (12).
spectrum of severity and classified according to the extent of body SJS/TEN patients have also stressed the need for a standardized
surface area (BSA) detached: SJS (<10% BSA detached), SJS/TEN care protocol for improving patient outcomes (Table 1). SJS/TEN
(10–30% BSA detached), and TEN (>30% BSA detached) (2). SJS/ patients and survivors are concerned with the provision of
TEN has an overall mortality of 15–20% but can be more than 50% in standardized guidelines, a multidisciplinary team, and universal
the elderly and immunocompromised (2). The incidence rate for SJS/ protocols for eye care during the acute stage of SJS/TEN. Patients
TEN is 1–5 cases per million persons annually in the developed world would benefit from a standardized evidence-based protocol for early
(3). These rates are likely even higher in the developing world, where transfer to specialized facilities, that include both dermatologic and
many infectious diseases are endemic, and corresponding treatments intensive care, for diagnosis and treatment (6). Additionally, the
include drugs that are commonly associated with SJS/TEN. Although development of take-home care guidelines, and the distribution of
SJS/TEN can have an underlying infectious etiology, it is more educational materials to medical teams, patients, and caregivers would
commonly related to small-molecule drug therapies in more than 80% help improve post-discharge outcomes (12).
of adults (4). Drug therapies with the highest risks include aromatic Decreasing the time to diagnosis and immediate cessation of
antiepileptic drugs, sulfonamide antibiotics, and allopurinol (1). A the most likely implicated drug(s) is critical (6). Additionally,
causality assessment tool, known as the algorithm of drug causality for documenting all potentially implicated drugs in the EHR is imperative
EN (ALDEN), defines drugs with a score of 4 or higher as being at to ensure future drug safety. Optimization of specialized protocols,
higher risk of being associated with SJS/TEN (5). Over the last two such as eye care, is necessary to reduce long-term ocular complications
decades, research has revealed that drug-induced SJS/TEN is an HLA like blindness. Early engagement of a multidisciplinary team
class I-restricted CD8+ T-cell mediated disease (6). Yet, most drugs comprised of dermatology, ophthalmology, gynecology, urology,
still lack known HLA risk alleles and other genetic associations. For pulmonology, gastroenterology, psychology and/or psychiatry, and
some drugs, an HLA risk allele defined in one population will not pharmacy is also essential to the creation of an effective rehabilitation
actually be the main HLA risk association generalizable across all plan. Such a plan should be decided directly upon admission to
populations. If a known risk HLA allele is present, however, the risk preserve a patient’s quality of life.
of developing SJS/TEN is thought to be equal across different races Another key issue for SJS/TEN is the lack of appropriate follow-up
and ethnicities. More research is needed to gain a more comprehensive post-discharge. Patients need guidance on proper follow-up care from
understanding of the genetic risk factors associated with SJS/ knowledgeable professionals to ensure physical, mental, and emotional
TEN. Stereotyping and race-based testing for HLA risk is discouraged (6, 7). recovery. Follow-ups with specialists and discharge materials, like a
Several conferences have furthered goals of increased mentoring list of low versus high-risk drugs, are vital. Another priority voiced by
and networking in the field of SJS/TEN. In 2021, a two-day virtual SJS/TEN survivors and their families were referrals, by providers, to
meeting titled “SJS/TEN 2021: Collaboration, Innovation, and community and psychosocial support groups. These groups, whether
Community” brought together scientists and community members face-to-face or online, would help to facilitate continued engagement
(Figure 1) to promote awareness, review recent progress, and set and education following discharge from acute care (12).
priorities for improving patient outcomes (4, 6, 8). At this meeting,
we were saddened to acknowledge the loss of a great leader in SJS/
TEN: Professor Jean-Claude Roujeau (9) (Supplementary Figure). 2. Preventive efforts
This international meeting was built on the success of previous
conferences in 2017 (8) and 2019 (4) highlighting the cutting-edge 2.1. Advances in SJS/TEN
research on the prediction, prevention, early diagnosis, and pharmacogenomics
treatment of SJS/TEN. In this paper we review the current state of
knowledge in the field, along with the future priorities for patients, Clinical implementation and assessment for pharmacogenetic risk
providers, and researchers. markers before initiating drugs suspected of causing severe cutaneous
Improving outcomes and raising awareness for SJS/TEN requires adverse reactions (SCARs) has added significantly to prevention and
community engagement and is extremely important for moving the diagnosis. Several medical centers worldwide have implemented
field forward. Awareness among physicians and broad healthcare clinical pharmacogenetic services with an aim to prevent SCARs,
constituencies is essential to facilitating early identification, diagnosis, including SJS/TEN, and have reported on this experience (13–18). The
and accurate documentation of high-risk medications in the electronic preliminary results of large-scale prospective pharmacogenetic
health records (EHR) for SJS/TEN. Patients perceive that most screenings conducted in Southeast Asia have substantially reduced
providers are not appropriately trained in the recognition, early rates of SCARs (19). HLA-B*15:02 genotyping prior to carbamazepine
diagnosis, triage, or treatment of SJS/TEN. Part of the challenge is administration was found to be a cost-effective means to preventing
the lack of high-level evidence to support specific therapeutic carbamazepine-induced SJS/TEN. This has been shown in several, but
interventions. However, across critical care, the implementation of not all, Asian countries (20), like Southeast and South Asian countries
supportive care has made the most difference in patient outcomes, where the population has a higher HLA-B*15:02 allele frequency
which stands true today (10). Additionally, the development and (5–20%), and a strong association between HLA-B*15:02 and SJS/

Frontiers in Medicine 03 [Link]

Marks et al. 10.3389/fmed.2023.1213889

FIGURE 1
Pie chart representing the percentage of participants per research/healthcare categories.

TEN (21). The cost of HLA-B*15:02 screening is paid by national TEN has been the integration of pharmacogenetics into electronic
health insurance (Figure 2) in Hong Kong, Taiwan, Singapore health records (EHR) in Southeast Asian countries such as Thailand
(Chinese and Malay ethnicity), Thailand, and China (20). Caveats and Taiwan. The EHR-linked clinical decision support system (CDSS)
have been raised to the fact that the B75 serotype of HLA (which improves the value of evidence-based pharmacogenetic screening
includes not only HLA-B*15:02 but HLA-B*15:21, HLA-B*15:08, through automated pop-up alerts that warn the prescriber if a high-
HLA-B*15:11, HLA-B*15:30 and HLA-B*15:3) has been associated risk allele is present (Figure 3). Diagnostic considerations and optimal
with carbamazepine SJS/TEN, however, the cost-effective single allele treatment strategies are further offered so that clinicians are guided to
assays have been largely set-up to detect only HLA-B*15:02. Reports choose lower-risk medications based on a patient’s genetic profile,
of carbamazepine SJS/TEN in patients carrying these other B75 HLA without being overwhelmed by large amounts of clinical and genetic
serotypes have been a primary reason in Southeast Asian countries for information (28). This approach has significantly reduced the
HLA-B*15:02 not detecting all patients at risk of developing incidence of specific drug-induced SJS/TEN in Taiwan and Thailand
carbamazepine SJS/TEN (22–25). Not all HLA alleles are associated (20, 28).
with multiple clinical phenotypes of SCAR. For instance, HLA-B*58:01 The training curriculum for certification of proficiency in
is associated with both allopurinol SJS/TEN and drug reaction with pharmacogenetics and precision medicine has gradually received
eosinophilia and systemic symptoms/drug-induced hypersensitivity greater attention and is now being incorporated into many medical
syndrome (DRESS/DIHS), however, HLA-B*15:02 is only associated schools and relevant postgraduate training programs. This curriculum
with carbamazepine SJS/TEN. Therefore, even in Southeast Asia if an has helped healthcare providers and trainees understand the
individual was negative for HLA-B*15:02 and other B75 HLA importance of the clinical implementation of pharmacogenetics for the
serotypes, they would still be at risk for carbamazepine DRESS/DIHS prediction and prevention of SJS/TEN (29). The pharmacogenetics
(Table 2) (26, 27) which has been associated with HLA-A*31:01. course contains fundamental principles to provide knowledge on
A model for precision medicine for the prediction and prevention pharmacology (e.g., drug metabolism and pharmacokinetics) and
of severe cutaneous adverse drug reactions (SCARs) including SJS/ human genetics/genomics (e.g., pathogenesis and polymorphism

Frontiers in Medicine 04 [Link]

Marks et al. 10.3389/fmed.2023.1213889

TABLE 1 SJS survivorship and patient perspectives.

Themes Community perspective Physician perspective

Mental health -Follow up care -Understand the psychological impact, and related long term health complications
-Bridge between hospital care and follow-up care -Conduct qualitative and quantitative research to implicate in clinical care
-Increase healthcare provider education for SJS/TEN PTSD -Understand how the disease condition affects the individual (psychologically,
-Address mental health and changes immediately after SJS/TEN interpersonally, vocationally, and overall quality of life)
-Assist through the recovery process -Provide realistic expectations about challenges during hospitalization and after
-Implement mandatory mental wellness checks before discharge from the hospital discharge
and beyond -Provide a multidisciplinary support team (social work, psychiatry, psychology)
-Address survivor’s guilt -Provide proper discharge document with a list of medications
-Improve mental health/grief counseling for loved ones who lost an SJS/TEN -Ensure post-discharge follow-ups and counseling with survivors
patients
-Provide grief counseling for your “lost life” and changed life
-Discuss financial burden
-Address low self-esteem

Long-term health -Improve education for healthcare professionals on residual side effects -Understand the various long-term health-related complications and their effects
complications -Recognize SJS/TEN side effects -Understand complications vary based on the severity of cases
-Improve treatment for all side effects (more than only eye care, esophageal care, -Recognize that treatment options will change according to the case presentation
skin care, live care, reproductive care, oral care, dental care) -Increase collaborative research projects to study cases post SJS/TEN
-Increase access to healthcare professionals who specialize with SJS/TEN patients -Prioritize long-term follow-up of cases
(both in-person and telehealth appointments) -Provide advice on referral centers
-Increase/improve physician response time -Standardize health checkups to identify complications
-Ease transfer of patient records -Increase collaborative and coordinative work among clinicians
-Develop and utilize an SJS/TEN identification checklist -Provide proper documentation for future referrals
-Implement the use of educational materials by doctors (flyers, brochures, posters)

Eye care -Treatment during the acute stage -Understanding treatment during acute stage is critical
-Treatment post SJS/TEN -Provide proper examination and care by specialists
-Prompt treatment and diagnosis -Recognize treatment options should not be limited to topical steroids. Surgical
-Education on eye care treatment procedures need to be considered when appropriate
-Contact an eye care specialist -Plan on decreasing the risk of infection and vision loss
-Aftercare and follow-up appointments -Increase knowledge of advanced surgical and sutureless procedures

Long-term scarring -Awareness of how scarring impacts SJS/TEN survivors (skin, eyes, organs) -Research best practices to identify, early diagnose and treat SJS/TEN
-How scarring changes over time (thickening) -Implement standard treatment protocols
-Improved education for healthcare professionals -Confirm diagnosis through histology
-Eliminate the use of “Rare” to classify SJS/TEN -Determine specific signs that occur in the presence of certain medications
-Educate patients post SJS/TEN about scarring -Have evidence-based studies to determine the casual drugs and treatment options
-Prioritize early diagnosis
-Provide second opinions from healthcare providers who have treated SJS/TEN
-Implement mandatory certification on SJS/TEN and retraining
-Provide examples of SJS/TEN scaring (at all stages from early identification)

Children with no -Bring awareness that over-the-counter products are medications -Awareness and documentation of the causal factors
identifiable drug cause -Create awareness about infections causing SJS/TEN and avoid accusing medications -Knowledge of the possibility of life-threatening GI tract involvement when treating
used to treat the first symptoms of SJS/TEN cases of SJS/TEN
-Provide for mental health concerns -Consider the usage of steroids and enteric feeding
-Look at genetic factors (HLA-b1502)
-Create screenings

Special considerations in -Identify SJS/TEN in the acute stage -Educate on dyspigmentation, skin changes, and different types of scarring
skin of color -Acknowledge the difference between the appearance of SJS/TEN in the skin of color -Understand disease effect on all types of skin cells
-Awareness of hyperpigmentation -Change of practice: start counseling at the bedside
-Lack of visible blisters at the acute stage -Improve interactions with patients, survivors, and families
-Consider low visibility (lack of redness) of SJS/TEN presentation -Improve pharmacist education on common drug allergies
-Improve time to diagnosis -Improve response to queries or concerns of survivors
-Improve education for healthcare providers of SJS/TEN in the skin of color -Provide detailed discharge instructions with frequent concerns (what products to
-Implement a specific checklist for skin of color (purple-looking skin vs. red-looking use on skin, etc.)
skin) for identification

Scientific advances in -Genetic testing -Strengthen experimental models

SJS/TEN -More research studies and increased patient/survivor participation -Predict possible risks and validate signals
-Gaining the patient perspective -Capture cases, specimens, interoperable repositories
-Spread knowledge/awareness of new SJS/TEN treatments -Promote consistency and quality in research methods
-Get more funding for SJS/TEN research -Use pharmacogenomics for drug safety
-Bring more awareness of SJS/TEN -Integrate distributed databases/biobanks could enable biomarker discovery/
-Eliminate the use of the word RARE validation, test monitoring/utility
-Increase box warnings -Implement multicenter investigations to further understand management and
-Increase funding to assist patients with SJS/TEN who are not financially stable treatment

(Continued)

Frontiers in Medicine 05 [Link]

Marks et al. 10.3389/fmed.2023.1213889

TABLE 1 (Continued)

Themes Community perspective Physician perspective

Safety of COVID-19 -Ensure that patients/survivors understand that COVID-19 vaccines are safe, -Answer vaccine-related queries-Educate on different responses to the vaccine
vaccines including risks of COVID-19 vs. risk of vaccine -Ensure patients it is safe to get the COVID-19 vaccine
-Develop education on potential complications of COVID-19 as an SJS/TEN -Address the misconceptions, hesitancy, and fear of getting the vaccine
survivor

FIGURE 2
HLA risk alleles associated with SCAR in different ethnic populations.

TABLE 2 HLA class I risk alleles are shared amongst some but not all drugs & phenotypes.

Drug HLA risk allele MDE DRESS/DIHS SJS/TEN DILI HSS

Allopurinol HLA-B*58:01

Carbamazepine HLA-B*15:02/B75
serotype

Carbamazepine HLA-A*31:01

Dapsone HLA-B*13:01

TMP-SMX/Sulfapyridine HLA-B*13:01

Vancomycin HLA-A*32:01

Abacavir HLA-B*57:01

Flucloxacillin HLA-B*57:01
HLA-B*57:03
MDE, maculopapular drug eruption; DRESS/DIHS, drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome; SJS/TEN, stevens-johnson syndrome/
toxic epidermal necrolysis; DILI, drug-induced liver injury; HSS, hypersensitivity syndrome.

Frontiers in Medicine 06 [Link]

Marks et al. 10.3389/fmed.2023.1213889

FIGURE 3
Pharmacogenomics test clinical workflow to alert physicians for drug prescriptions.

analysis). A practical approach is taken whereupon clinical decision- low-pass whole-genome sequencing) have the potential to make
making strategies are built upon robust scientific evidence, clinical significant contributions to the field by uncovering increased genetic
practice guidelines, and recommendations. Learning through case information, particularly for rare variants. More reliable evidence
studies helps prescribers to become familiar with pharmacogenetic test generated from real-world data, especially for under-served
interpretation and have confidence in incorporating the results into populations like First Nations, LatinX, and other diverse populations
each patient’s healthcare management plan (30). globally, remains an urgent need to advance the science of SJS/TEN
There are a growing number of clinical recommendations for research with regards to all ancestries.
pharmacogenetic tests used in clinical practice (31). Compared with To improve public health and drug safety, regulators update drug
a single test for a particular variant, the utilization of multiple-variant labeling and mandate boxed warnings to guide prescribers on the use
panels are considered beneficial since multiple risk variants can of SJS/TEN suspect drugs. The U.S. Food and Drug Administration
be screened for simultaneously. A pharmacogenetic panel containing (FDA) has been proactive in incorporating pharmacogenetic risk
multiple genetic variants that are significantly associated with an factors in labeling. As of December 2020, 453 drug-biomarker pairs,
increased risk for developing SJS/TEN, or other SCAR, has been including 311 drugs and 133 biomarkers, have been documented by
proposed and separately developed by research groups in Taiwan, the FDA, while 252 pairs are considered clinically actionable in
Thailand, the UK, and Canada (19, 20, 30, 32). In a prospective SCAR. In the past, the recommendation for pharmacogenetic testing
observational study conducted in Southeast Asians (e.g., Taiwanese, has varied based on the likelihood that SCAR, related to a specific
Chinese, Thai, and Malaysian), the sensitivity and specificity of a drug, will occur in a specific population, and is largely based on the
multiple-variant panel for specific antiepileptic drugs (e.g., frequency of the HLA risk allele. As highlighted above to avoid
carbamazepine, oxcarbazepine, and phenytoin) was 75 and 90%, structural racism and pharmacogenetic screening approaches that
respectively (20). Although the less than 100% negative predictive would disadvantage specific populations, a targeted approach based
value (NPV) means this would not be the perfect screening test, the on provider stereotyped patient race is inaccurate. In addition, there
results from the panel contribute to drug causality assessment. The has been widespread population admixture and the implications of a
panel is also helpful for identifying drugs with increased risk of SCARs specific risk allele when present is the same regardless of the
to which the patient has not yet been exposed and making shared population (6). Other regulatory actions that have been taken by the
medical and therapeutic decisions with the patient. Therefore, the Taiwanese FDA include collaboration with advisory committees, drug
development of such multiple-variant pharmacogenetic panels is a reporting centers that collect necessary safety data, and consultant
dynamic and ongoing process, allowing for cost-efficient additions of experts who provide suggestions. A search for drugs which have a
newly discovered variants as the evidence base grows. warning for SJS/TEN in the label can be done using the FDA
Given the low incidence of SJS/TEN, several international label tool1.
collaborations are underway to increase statistical power for identifying
genetic variants and novel, but clinically relevant, pharmacogenetic
associations across diverse ancestries. The latest scientific methods and 1 [Link]
technologies (e.g., GWAS meta-analysis, polygenic risk scoring, fdalabel-full-text-search-drug-product-labeling

Frontiers in Medicine 07 [Link]

Marks et al. 10.3389/fmed.2023.1213889

3. Updates in diagnosis, assessment,

and causality
3.1. General principles

The mainstay of SJS/TEN management is early clinical diagnosis

and triage into a critical care setting with a high standard of supportive
care, as discussed above. Histopathology aids in the clinical diagnosis
and direct immunofluorescence helps identify autoimmune bullous
disorders which can be confused with SJS/TEN particularly early in
disease. All new drugs, and particularly those initiated within 4 days
to 6 weeks, are suspect and should be discontinued (33). Early
recognition is key. Although biological markers, such as granulysin,
appear quite sensitive and specific for early identification of SJS/TEN,
they lack widespread validation (34–36). An HLA risk allele, in
addition to being a pre-prescription strategy that prevents SJS/TEN to
specific drugs, may also add to the causality assessment that a specific
drug is the culprit. Skin and patch testing generally have low sensitivity
FIGURE 4
but high specificity for SJS/TEN with the exception of aromatic
Example photograph of Vanderbilt Drug Safety patient (with
anticonvulsants which have a sensitivity of >50%. However, there is a permission) to guide standardized SJS/TEN scoring by illustrating the
range of sensitivity across different drugs from 0% (allopurinol) to categorization of different appearances of skin into different
terminology. Photo by Madeline Marks and Austin Cronin, VDTRC.
>50% (aromatic anticonvulsants) (37, 38). Ex vivo and in vitro testing
org.
has had lower sensitivity than other severe cutaneous adverse drug
reactions and needs more widespread validation and optimization (34,
39, 40). Rechallenge is contraindicated for all suspected culprit drugs
and potentially cross-reactive drugs. The exception to this is the the seven SCORTEN prognostic factors are completely objective,
treatment of tuberculosis in low and middle-income countries where drawing from irrefutable patient demography or quantitative
progress has been made using combinations of ex vivo testing and physiologic or laboratory measurements. Coupled with these is a
sequential additive challenges with methylprednisolone rescue (41, single subjective measure known as body surface area (BSA) of
42). Integrated approaches combining HLA typing, in vivo and ex epidermal detachment, which was found to have a remarkable
vivo/in vitro testing have been advocated as having higher positive and mortality association upon crossing a threshold of 10% BSA on the
negative predictive values than any one test alone (27, 42, 43). first day of hospitalization.
All clinical methods to estimate BSA have been shown to suffer
major errors and inter-observer variations. For example, dermatology
3.2. Photography and artificial intelligence providers applying the rule of 9 s overestimated psoriatic plaque area
to improve SJS/TEN assessment by more than a factor of two in 49/80 patient assessments (50).
Similarly, a meta-analysis of 26 studies in the burn literature found an
The SJS/TEN-specific severity-of-illness score (SCORTEN) has average BSA estimation error of 70% across nearly 3,000 patients and
been the mainstay of measurements to define mortality risk of SJS/ concluded that neither the rule of 9 s nor palmar surface area are
TEN in both clinical practice and research (44). The ABCD-10 (age, reliable estimates (51). Errors were significantly greater when under
bicarbonate, cancer, dialysis, 10% BSA) is another cross-sectional 20% BSA was affected. Notably, the rule of 9 s and more accurate
severity scoring system that incorporated end-stage renal disease Lund-Browder charts are both derived from paper-mâché molds from
and was shown to perform slightly inferior to SCORTEN by only 12 individuals (52). Very recently, our understanding of the
underestimating mortality (45, 46). Another study proposed adding human skin surface has been substantially advanced by high-
inflammatory markers to the SCORTEN to improve predictive resolution surface anthropometry laser body scans of 3,047 adults
accuracy. The only marker that was shown to improve predictive in the Civilian American and European Surface Anthropometry
accuracy was the red cell width over hemoglobin ratio (47). More Resource (53), which proved that there is an enormous variability
recently the CRISTEN (clinical risk score for TEN) was developed as between individuals as to how much each body region contributes to
a clinical risk score that does not require laboratory values and this the total BSA. Thus, regardless of evaluation by a dermatologist or in
initial study was validated across 416 patients multinationally (48). the burn unit, knowing the true BSA of an individual SJS/TEN patient
However, it must be realized that all of these scoring systems are cross- is challenging. This represents a major barrier to the successful
sectional tools weighed toward patient co-morbidities that measure application of decades of clinical experience in SJS/TEN.
severity at one point in time and are not useful for longitudinal Collection and analysis of SJS/TEN patient photos could serve
assessments that measure changes in disease severity over time or the an important role in addressing the gap presented by clinical BSA
specific course of the disease. Due to the difficulties of undertaking estimation variation. The development of standardized SJS/
randomized controlled trials in an uncommon and unpredictable TEN-specific scoresheets with accompanying training and photos,
disease, studies typically draw their primary outcome from a including preferred terminology for different skin appearances (e.g.,
comparison of survival on therapy to the SCORTEN-predicted Figure 4), could be a major step forward in comparing the outcomes
survival – the standardized mortality ratio for the therapy (49). Six of of individual patients and the results of different studies. For

Frontiers in Medicine 08 [Link]

Marks et al. 10.3389/fmed.2023.1213889

FIGURE 5
Infographic to illustrate the challenges of photographing in burn ICU.

example, clinicians vary widely in whether they perform a Nikolsky 1. Collating large numbers of standardized SJS/TEN patient
sign or refer to dusky areas of erythema as detached skin. photographs, ideally together with clinical variables and
Photography-based adjudication that follows patient bedside BSA patient outcomes
assessments, whether by the rater or another trained adjudicator, 2. Annotating the images with markings of different types of
could further improve data quality. However, standardizing critically affected skin
ill patient photography presents several challenges illustrated in 3. Connecting these data sets to experts, for example, through
Figure 5 and Table 3 and so may not be practical for all research global challenges like the melanoma challenge driven by the
groups. In this case, we recommend that future publications of SJS/ International Skin Imaging Collaboration (58)
TEN studies specify the primary data collection sheet used as well
as detailed methods on how BSA was estimated. For example, the Numerous FDA approvals for medical AI use and even specific
Lund-Browder method is more reliable than the rule of 9 s but may guidelines for AI dermatology development (59) and validation lend
take more time (54). Ideally, the study would retain marked avatars promise that the combination of photography and AI will eventually lead
and note the corresponding rater’s (or raters’) experience and to substantial advances in SJS/TEN research and patient care. In the near
specific training in BSA estimation. term, higher-quality skin surface assessment and standardized reporting
Provided that high-quality photographs are collected, several of skin assessment in studies can improve personalized management,
computer, web-based, and smartphone options for image analysis prognostic models, and understanding of SJS/TEN. Aside from the
have been shown to add significant accuracy to BSA assessment limitations stated above, there has been little consensus amongst
(55), enabling completely untrained individuals to outperform dermatologists on SJS/TEN terminology, morphological terms and
experienced providers (56). The application of these technologies progression and consensus on the most affected sites. A recent study
could revolutionize the way SJS/TEN studies are conducted by conducted a Delphi consensus exercise to establish a baseline consensus
removing time and space constraints in the burn ICU, permitting for the development of a standardized SJS/TEN instrument with
centralized and standardized quality assurance, and adjudication by consistent terminology (60).
off-site experts. A limitation remains the amount of time necessary
for a human user to mark borders and otherwise manipulate the
photographs in these software interfaces, which can exceed the 4. Other considerations for clinical
amount of time to do clinical scoring. One approach is leveraging diagnosis and management
crowdsourcing of multiple non-expert raters to achieve expert-level
accuracy (57), but this would raise issues of patient privacy and 4.1. SJS mimickers and differential
data security. diagnosis
In the future, the application of artificial intelligence (AI) image
analysis to standardized photographs could offer practical, rapid, and The early features of SJS/TEN are subtle and non-specific with
standardized solutions to the critical gap in SJS/TEN BSA assessments. a prodrome of low-grade fever, malaise, anorexia, and mucosal
While there is currently a paucity of literature on this direct discomfort. It can then progress to include features such as skin pain,
application, the SJS/TEN research community can take the following and development of bullae, even before the characteristic sloughing of
steps to advance: the skin occurs (61). There are many illnesses including infections,

Frontiers in Medicine 09 [Link]

Marks et al. 10.3389/fmed.2023.1213889

TABLE 3 Challenges in photographing SJS/TEN patients.

Category Challenge Explanation Solution

Room conditions Lighting inconsistency: Lighting inconsistencies increase the chance of • Document the light sources in the room
Variation in light tone and/or intensity, time of shadowing, glare, and distorted skin tone in during the photo session.
day, or weather. images. • Consistently utilize the same device between
sessions.
• Capture both flash and non-flash photos.
• Use portable light devices.

Rushed environment: A rushed environment negatively impacts • Establish a relationship with the care team.
A high-stress intensive care environment caused attention to detail and photography session • Communicate with the care team.
by time constraints, simultaneous performance quality. • Get familiar with the hospital and the unit.
of procedures, photographer inexperience, or • Regularly conduct timed practice sessions
patient discomfort. with a volunteer.

Distractions/obstructions: Objects may obstruct part of the skin, visually • Move items out of frame.
Objects, unrelated to the photography, which distract the viewer, and impact the consistency • Move items off patients’ skin, if able.
distract from or obstruct the patient’s skin. of daily images. • Drape distracting items.

Communication Scheduling: Missed dressing changes or baths prevent a • Communicate daily with the patient’s care
A missed opportunity to capture uncovered complete photograph of the entire skin surface team.
patient’s skin (e.g., dressing change, bath) due to across all body sites from being collected daily. • Ideally, multiple trained photographers
miscommunication between the patient’s care should be available.
team and photographer or unavailability of the • Photographers should have flexible schedules
photographer. to allow time for sessions when needed.

Patients Patient wellbeing: Patient wellbeing determines if they are willing • Communicate with the patient and their
The physical or emotional comfort and to fully participate in repeated photography caretaker.
discomfort of the patient. sessions. • Ask permission to photograph at each
session.
• Explain that the photography session can
be stopped at any time.
• Limit the number of people in the room.

PHI Protecting PHI & privacy: Protecting privacy and PHI helps to establish • Cover hospital bands with gauze or tape.
Photographs may contain sensitive and/or trust between the patient and photographer. • Flag photos considered sensitive.
identifying information. • Flag photos containing PHI.
• De-identify photos.

Data Data management: Standardized data management protocol ensures • Develop a protocol for naming and storing
management The organization of photos by establishing optimal organization, prevents data loss, and photos.
standard operating procedures for naming and makes locating files easier. • Ensure that filenames are consistent with the
storing files. naming convention.
• Keep at least two copies of each photo (have a
back-up).

Technical Technical difficulties: Technical difficulties can prevent data from • Use newer-model devices.
difficulties Technological malfunctions due to a loss of being collected properly and affect its overall • Fully charge the device before each session.
power, Wi-Fi, or issues capturing images. quality. • Bring a backup photography device.
• Confirm all photos are submitted before
exiting the photo capture app.

autoimmune diseases, and other types of drug reactions that may epidermis concentrated in intertriginous areas; such as: inguinal folds,
mimic SJS/TEN (Table 4). Since treatments, prognosis, short and long- axillae, inframammary folds, and folds of the neck. Additionally, peri-
term complications, and outcomes vary, prompt and accurate oral radial fissures, as well as erythema of the eyes and ears is classic.
diagnosis is important to guide early intervention and management. The skin is red and tender before it sloughs. A very superficial layer of
Staphylococcal scalded skin syndrome (SSSS) is a condition with the skin is what sloughs off, revealing a moist, pink, and slightly matte
cutaneous involvement that can mimic SJS/TEN. It is a blistering skin surface at the base, underneath compared to the deep red and shiny
condition caused by a toxin from staphylococcus seen either in healthy exposed dermis that is seen at the base of desquamations in SJS/TEN
children with a bacterial focus or in adults with renal insufficiency. (61, 62). The skin usually heals completely within 5–7 days after
SSSS (62) usually presents with tissue-paper thin wrinkling of the starting treatment with antibiotics and supportive care.

Frontiers in Medicine 10 [Link]

Marks et al. 10.3389/fmed.2023.1213889

TABLE 4 Most common clinical mimickers of Stevens-Johnson Syndrome & Toxic Epidermal Necrolysis.

Diagnosis Context Main clinical difference Causes

Abrupt eruption of prominent mucositis Minimal to absent cutaneous eruption, mostly Mycoplasma pneumoniae and several other
RIME triggered by infectious etiologies children and young adults infections

Development of typical and atypical targetoid Typical, papular 3-zoned targetoid lesions in Herpes simplex virus most commonly,
macules with central deeper purple or dusky conjunction with atypical raised targets having occasionally other infections, idiopathic,
coloration. only 2 zones, whereas SJS/TEN tends to be flat or radiation
EMM flaccid bullous.

Smoldering onset of bullae and lichenoid 2 morphologies to eruption: there is both a B-cell Non-Hodgkin lymphoma, chronic lymphocytic
dermatitis with mucositis, often mistaken for mediated bullous morphology and a T-cell leukemia. Rarely, Castleman’s disease,
“chronic SJS/TEN” mediated lichenoid component thymomas, sarcomas, and Waldenström’s
PNP macroglobulinemia.

Usually newborns, young children, adults with Split is very superficial with a periocular, Staphylococcal exotoxin (epidermolysin)
renal failure perioral, and intertriginous predilcition. Base of targeting desmoglein 1
blisters have intact epidermis rather than beefy
red dermal appearance. Often intense peri-oral
SSSS involvement but spares mucous membranes.

Explosive eruption of a brightly erythematous Primary morphology is innumerable, tiny, non- Medications
with moist slough follicularly based pustules on a brightly
erythematous base which coalesce to form “lakes
of pus.” Time to onset is shorter than SJS/TEN
(<4 d), and split is superficial. Absence of
AGEP mucosal involvement, generally.

Morbilliform exanthem that goes on to become Predicliction for dorsal hands and feet, palms Transplantation of bone marrow, sometimes with
blistering, usually within the first 3 months (but and soles, forearms, upper trunk, ears and multivisceral or small bowel
can occur later) after transplantation. postauricular areas. GI and hepatic signs/
aGVHD4 symptoms may be concurrent.
RIME, Reactive infectious mucocutaneous eruption; EMM, Erythema multiforme major; PNP, Paraneoplastic pemphigus; SSSS, Staphylococcus scalded skin syndrome; AGEP, acute
generalized exanthematous pustulosis; aGVHD4, Acute Graft vs. Host Disease, grade IV.

Autoimmune and other immune-mediated disorders comprise an children, whose predominant cause is infection with Mycoplasma
array of diseases that can mimic SJS/TEN. Lupus erythematosus can pneumonia (64, 65).
have many similarities to SJS/TEN. Important differences are Acute graft vs. host disease (GVHD) is a major complication
photodistribution, and subacute presentation (weeks). Additionally, associated with bone marrow transplants. It is a multi-organ disorder
patients with lupus may have positive antinuclear and reflex-ENA that is most commonly due to foreign blood stem cells being
antibodies, elevated anti-dsDNA levels, lymphopenia, and other transferred to a new host which in turn stimulates an immune
cytopenia’s and low complement levels which are not typically seen in reaction. The reaction can be seen following bone marrow transplants,
patients with SJS/TEN (63). Hemophagocytic lymphohistiocytosis non-irradiated blood transfusions, maternal-fetal transmission, and
(HLH) is a very rare condition caused by natural killer cells and T solid organ transplants. In its most severe form (Stage IV), acute skin
lymphocytes. It differs from SJS/TEN in that it forms a reticuloform disease can consist of generalized involvement with blister formation
rash and is smoldering, with various stages of resolve although and skin sloughing resembling SJS/TEN (66).
occasionally a positive Nikolsky sign can be seen. Bullous pemphigoid Several other severe cutaneous adverse drug reactions can present
(BP) is a disease that involves the basement membrane. Unlike SJS/ with clinical features mimicking SJS/TEN. These include linear IgA bullous
TEN, patients with BP will complain of pruritus instead of pain, and dermatosis, drug-induced hypersensitivity syndrome/drug reaction with
their lesions will show a positive Asboe-Hansen sign and a negative eosinophilia and systemic symptoms (DiHS/DRESS) which can present
Nikolsky sign. Additionally, BP is more often seen in elderly patients with a wide range of skin morphologies, acute generalized exanthematous
without a drug ingestion history. Direct immunofluorescence (DIF) pustulosis (AGEP), generalized bullous fixed drug eruption (GBFDE),
studies of skin reveal linear deposition of IgG and C3 at the bullous lichenoid, and multiforme-like drug eruption caused by various
basal membrane. medications, and more recently, by the immune checkpoint inhibitors and
Reactive conditions such as erythema multiforme majus (EMM) most commonly PD-1 and PDL-1 inhibitors used in lung cancer. Tumors
are self-limited but occasionally recurrent and may be confused with have evolved to have several mechanisms to cloak themselves from the
SJS/TEN. It is hallmarked by typical and/or atypical raised target human immune system. Immune checkpoint inhibitors are used to
lesions predominantly on the extremities (acral) in adults and on the unharness T and NK cell responses to improve the host tumor response.
face and trunk in children. High fever and several swollen, painful, While this class of medication has been helpful in patient care, it can trigger
and erosive mucous membranes may lead to a severe condition in reactions similar to SJS/TEN.

Frontiers in Medicine 11 [Link]

Marks et al. 10.3389/fmed.2023.1213889

One last unusual severe cutaneous adverse drug reaction and/or perivascular dermatitis with a predominately lymphocytic
presentation is a delay in the development of a second mucosal site. It infiltrate. Treatment is usually limited to the use of topical steroids and
has been reported that greater than 85% of patients will present with oral antihistamines. Lichenoid reactions have an unclear incidence but
involvement of two mucosal sites (1, 64). However, we are now are more commonly reported with PD-1/PD-L1 inhibitors compared
becoming aware of a delay in the presentation of the second site in a with CTLA-4 inhibitors (78). They are best treated with topical steroids,
subset of patients, which may provide initial confusion in the diagnosis. phototherapy, acitretin, hydroxychloroquine, or apremilast. Vitiligo-like
depigmentation does not need therapy, but patients should be educated
on the risk of photosensitivity in affected areas. Development of bullous
4.2. SJS/TEN and drug-induced liver injury dermatoses is rare, but also likely underreported and underdiagnosed
(79, 80). These patients present with a median latency of 6–8 months
Significant literature exists that describes the co-existence of drug- after PD1/PD-L1 treatment initiation (79, 80). IgG and C3 linear
induced liver injury (DILI) and SJS/TEN. DILI is the most common deposits are typically demonstrated on immunofluorescence (80).
cause of acute liver failure in the Western world and is associated with Considerations for therapy include systemic corticosteroids, dupilumab,
SCARs in 5% of cases. Although DILI most commonly occurs in the omalizumab, intravenous immunoglobulin (IVIG), or rituximab. Lastly,
setting of DRESS/DIHS, a study looking at 1718 cases of validated SJS/TEN-like reactions can begin as morbilliform eruptions that evolve
DILI, found that 14 patients were diagnosed with concurrent SJS/TEN into a lichenoid reaction with mucositis of oral, ocular, and genital
attributed to 9 different agents (67). The injury pattern in these cases regions (81, 82). It has recently been suggested that two types of SJS-like
was diverse. Seven presented with hepatocellular injury, while the other eruptions can occur following ICI. Bullous lichenoid reactions, which
seven presented with cholestatic/mixed injury. Most patients presented progress slowly and often occur in the presence of a small molecule drug
with a rash and fever but were not jaundiced at the clinical onset but associated with SCAR, and where rechallenge with ICI may not
became jaundiced with disease progression. Two patients were be contraindicated and reactions appear more like TEN (83, 84). The
classified with mild liver injury, five with moderate injury, and seven name progressive immunotherapy-related mucocutaneous eruption
with severe injury. Compared with DILI cases, those with concurrent (PIRME) has been suggested to refer to these lower acuity reactions
SJS/TEN were more often younger, more likely to be Black, had a which may appear SJS-like but progress more slowly, may have a small
shorter latency period from drug exposure to hepatic dysfunction, and molecule culprit drug, and where the pathology suggests a lichenoid
ultimately developed a more severe liver injury. While genetic bullous reaction (84). Patients then develop full-thickness epidermal
predisposition is suspected, HLA subtyping has not yet demonstrated necrosis. These patients are best managed in a burn ICU and systemic
any clear clinical patterns associated with SJS/TEN co-occurring with immunomodulating therapy should be considered.
DILI. The experience with DILI in the setting of DRESS/DIHS suggests Although complications of immune checkpoint inhibitor therapy
that the same HLA associations may be relevant (68, 69). Physicians are generally treated with immunosuppression, recent data has
diagnosing SJS/TEN should be aware of the possibility of drug-induced demonstrated a significant difference in the overall survival and time to
liver injury. treatment failure with either low or high-dose corticosteroids in patients
(85), which sets a precautionary tone. Biomarkers such as IL-6, IgE, and
elafin have been correlated with the severity of adverse events, as well as
4.3. Cutaneous toxicities and management predicted six-month survival (86, 87). A future goal is for a combination
of immune checkpoint inhibitor toxicity of biomarkers and known pathophysiology of the eruption to guide the
and SJS/TEN most judicious and targeted treatment options (87). In addition to
corticosteroids, which have been the mainstay of treatment for ICI
Immune checkpoint inhibitors (ICIs) such as PD-1, PD-L1, and immune-related adverse events (iRAEs), more targeted therapies, such
CTLA-4 inhibitors often lead to non-specific immune activation, of as etanercept and tocilizumab, are currently being studied and have
which the skin is the most common target (70–72). Most patients treated demonstrated clinical benefit in treating cutaneous immune-related
with a PD-1 inhibitor will experience at least two or more adverse events adverse events (88, 89). True severe cutaneous adverse events related to
(70); fortunately, patients with a cutaneous reaction also demonstrated immunotherapy likely have a distinct immunopathogenesis when
improved survival rates (73). Common cutaneous adverse events can compared with SJS/TEN related to a small molecule. In addition, ICI
be classified into psoriasiform, morbilliform, lichenoid eruptions, and may unmask or increase the risk of a SCAR related to a small molecule,
vitiligo-like depigmentation (74). Less common adverse events SCARs such as those described above with lichenoid bullous reactions.
or blistering dermatoses (74) with the occurrence of an adverse event, Currently, rechallenge is still not recommended with severe cutaneous
the severity of the reaction is categorized utilizing the Common adverse events related to ICI that mimic and progress rapidly and are
Terminology Criteria for Adverse Events (CTCAE) to communicate the similar to SJS/TEN as case reports of fatalities have occurred even with
severity of the rash, including total body surface area involved, as well as ICI monotherapy rechallenge (90). However, case reports are emerging
the safety of reinitiating immunotherapy. that may distinguish at least a subgroup of ICI SCAR that appear to
The subtypes of cutaneous adverse events are associated with the tolerate rechallenge with a different ICI (e.g., distinct PD-1 inhibitor) or
type of immune checkpoint inhibitor. Psoriasiform eruptions generally even the same drug in some instances (84, 91).
occur with PD1/PD-L1 inhibitors and can be associated with
inflammatory joint disease and uveitis. Flares of pre-existing psoriasis
are commonly reported, and treatment should resemble a similar 4.4. Updates on mechanisms
therapeutic ladder to classical psoriasis. Morbilliform reactions are the
most common adverse event described with CTLA-4 inhibition (75–77). Current innovation in studying gene-protein and T-cell receptor
Histopathology typically demonstrates spongiosis, interface dermatitis, expression at the site of tissue damage in SJS/TEN such as blister fluid

Frontiers in Medicine 12 [Link]

Marks et al. 10.3389/fmed.2023.1213889

and sloughed skin has provided insights into the disease as a important role in the immunopathogenesis of SJS/TEN (99).
CD8-dependent class I HLA-restricted condition with upregulation of Therefore, inhibition of necroptosis could be an effective therapeutic
markers of cytotoxicity and proliferation. The expression of cytolytic target. Several compounds, including a new FPR1 antagonist now in
peptides such as granulysin and granzyme B by CD8+ T cells, NK T development, have been shown to inhibit TEN patient serum-
cells, and NK cells has become the hallmark of SJS/TEN. Examples of mediated cytotoxicity and keratinocyte death.
how the tissue signatures can be utilized to provide the rationale for Differential gene expression of matrix metalloproteinases (MMPs)
successful targeted therapy were exemplified by Kim et al. (92) in the and TIMP1 may also predict chronic eye disease in SJS/TEN. In one
case of a patient with a refractory DiHS/DRESS. Capabilities and the study, MMP9 was a prognostic predictor of poor best-corrected visual
ability to deconvolute and analyze complex datasets are equally acuity (BCVA) post-cultivated oral mucosal epithelial transplantation
important (93, 94). (COMET) (100). Another study suggested that epidermal MMP9
expression was significantly higher in SJS/TEN skin than in healthy
control skin and non-bullous skin reactions. Serum from SJS/TEN
4.5. Cell death pathways and novel patients also induced MMP9 expression in healthy skin explants
therapeutics which were reduced by etanercept. Furthermore, etanercept reduced
TNF-α induced MMP9 expression in cell lines providing additional
SJS/TEN is characterized by the death of keratinocytes. Previously, support for the potential role of etanercept as an SJS/TEN therapeutic
this epidermal damage in the skin lesions of SJS/TEN patients had agent (101).
been considered to be due to apoptosis. Apoptosis is induced by Other unexplored areas include the potential for innate triggers
cytotoxic CD8+ T cells through the Fas–Fas ligand (FasL) pathway or for SJS/TEN such as MRGPRX2, a mast cell-specific receptor crucial
the perforin/granzyme pathway. The cell surface of keratinocytes of for pseudo-allergic drug reactions, and the application of novel areas
TEN patients has revealed a high expression of FasL. In addition, high of research such as the field of epigenomics.
levels of soluble FasL (sFasL) have been found in the serum of SJS/ Study of particular antigenic epitopes that generate an immune
TEN patients. Fas–FasL interactions mediated apoptosis in the response to specific drugs is of significant interest. This approach has
skin lesion of SJS/TEN patients, and in addition, granulysin also been championed by Kula et al. (102) who described the Tscan ®
demonstrated a cytotoxic effect in SJS/TEN (31). Granulysin, which is ®
methodology of epitope discovery. Tscan uses a library screening
found in high levels in SJS/TEN blisters, is released from blister cells strategy to validate epitopes of interest. For instance, T cells from an
in skin lesions of SJS/TEN, including cytotoxic CD8+ T cells, NK T SJS/TEN patient could target cells engineered to carry the human
cells, and NK cells. Very recently it has been reported that the peptidome or virus-specific libraries in addition to the suspected HLA
exosomal miRNA, miR-375-3p, was markedly upregulated in risk allele. Granzyme B-producing cells are sorted and processed by
the plasma of SJS/TEN patients, where it induced mitochondria- deep sequencing to identify epitopes in conjunction with activated T
dependent apoptosis via downregulation of the X-linked inhibitor of cells (102).
apoptosis protein (XIAP) (95). In 2014, Saito et al. (96) reported that
necroptosis induced by annexin A1 – formyl peptide receptor 1
(FPR1) interaction contributes to keratinocyte death in SJS/TEN. In 5. Updates in acute care
electron microscopic analysis, both necrotic cells and apoptotic cells
were observed in the skin lesions of patients. Necroptotic (a type of 5.1. Updates in supportive care
programmed cell death that reveals morphological necrosis) cells management (Table 5)
release damage-associated molecular patterns (DAMPs), including a
range of pro-inflammatory cytokines, resulting in inflammation,
unlike apoptosis (97). The induction of necroptosis in the skin and gut 5.1.1. Burn and critical care management
provokes a strong inflammatory response, which might be triggered Acute SJS/TEN is characterized initially by flat, atypical targets or
by the emission of DAMPs (98). In general, necroptosis occurs purpuric macules predominantly on the trunk and by mucosal erosions
through the stimulation of TNF-α under conditions in which in at least two mucosal sites, often including the ocular surface. Transfer
apoptosis is blocked (97). In TNF-α stimulation, receptor-interacting and consultation for patients with SJS/TEN should happen early before
kinase 1 (RIP1) and receptor-interacting kinase 3 (RIP3) are advanced critical care is needed. Once progression to multi-organ
phosphorylated and form a “necrosome” complex. Furthermore, the failure occurs, the transfer of patients may be futile and often leads to a
mixed lineage kinase domain-like (MLKL) pseudo kinase is recruited transition to comfort care once they arrive at the tertiary or quaternary
to the necrosome and phosphorylated by RIP3. The phosphorylated hospital with a burn center. These delayed transfers can utilize already
MLKL (pMLKL) is localized to the plasma membrane and induces cell scarce resources, distract from the acute management of burn patients,
death (97). Kinoshita et al. (99) discovered neutrophils associated with and challenge future collaboration with referring hospitals.
the mechanism of necroptosis in SJS/TEN. CD8+ T cells produced The consensus on how to manage states of shock after burn injury
lipocalin-2, which triggered the formation of neutrophil extracellular continues to be debated (103). Nonetheless, hospitals with burn
traps (NETs) in early lesioned skin. Neutrophils undergoing NETosis programs have extensive expertise in managing non-hemorrhagic
released LL-37, and LL-37 induced the expression of FPR1 on hypovolemia. Additionally, some centers have reported that, like burn
keratinocytes through P2X7R stimulation. FPR1 expression caused injury, SJS/TEN may be associated with multifactorial shock. This may
necroptosis of keratinocytes that caused the further release of LL-37 include vasodilatory, cardiogenic, and distributive shock phenotypes,
and induced FPR1 expression on surrounding keratinocytes, which and may occur through a perturbed inflammatory stimulation which
likely amplified the necroptotic response. Necroptosis plays an warrants further investigation. There remains variation by practice on

Frontiers in Medicine 13 [Link]

Marks et al. 10.3389/fmed.2023.1213889

TABLE 5 Key points discussed during “updates for clinicians.”

Specialized units
1. Consideration should be made to transfer patients with suspected SJS/TEN to hospitals with dermatology inpatient wards or burn centers early in their presentation. The
decision should be based on the extent of skin detachment and the need for intensive care.
2. Acute and critical care needs for patients with SJS/TEN can be similar to those of patients suffering a thermal injury.
3. Psychosocial, rehabilitation, and after care needs for patients with SJS/TEN might be better addressed at hospitals with established programs for patients recovering from
thermal injury.
Eye care
1. Early ocular involvement is highly variable and can result in chronic complications leading to severe ocular surface disease including corneal blindness.
2. Patients who receive acute ophthalmic care based on an evidence-based treatment that involves the use of amniotic membrane may be more likely to retain >20/40 vision
than those who do not.
3. Customized scleral lenses provide a protective barrier, support the ocular surface, and can prevent corneal complications, improving visual acuity and comfort.
Genitourinary issues
1. Gynecology was only consulted in half of the cases of possible vulvovaginal involvement.
2. There appeared to be an assumption that there was no need for vulvovaginal care in patients presumably not sexually active.
3. Obtaining consent in a sensitive matter is important in very young/older patients as to explain long-term sequelae.
Unusual presentations
1. Recognition of SJS/TEN mimickers is critical as management and prognosis can be very different for each category. These include infectious, autoimmune, reactive, and
other drug response etiologies.
2. Autoimmune conditions and reactive conditions can produce cutaneous mimics of SJS/TEN but differences exist in presentation, chronicity, laboratory studies and
histopathology.
3. While greater than 85% of patients will present with involvement of two mucosal sites some patients have a delayed second mucosal site involvement. Often times this 2nd
site includes ocular mucosa.

how bullae (or blisters) are managed (104, 105). Some centers remove conjunctival hyperemia to near-total sloughing of the ocular surface,
blisters, while others drain. Most dermatologists prefer to drain bullae including the tarsal conjunctiva and eyelid margins. Chronic
that result from SJS/TEN, and therefore collaboration is required complications can result in severe ocular surface disease including
between teams to reach a consensus on wound management. Similarly, corneal blindness.
there is some variability in the selection of topical dressing, which For survivors, ocular complications are among the most common
should be a subject of future studies. An international team has just and debilitating. In a recent survey conducted at 11 academic health
published a Delphi-based consensus paper and wound management centers in the US which evaluated 121 adults diagnosed with SJS/
was one item examined (11). Regardless of bullae management and TEN by inpatient consultive dermatologists, 60% of SJS/TEN patients
dressing choice, wounds should be cleaned and examined for stigmata reported long-term eye problems (112). In another study evaluating
of infection. If infection concerns arise, topical or/and systemic 105 eyes of 66 patients, the ocular surface worsened during a
antimicrobials should be initiated to prevent wound-related infection, follow-up of over 5 years, and more than 50% of eyes with partial
and subsequent systemic sepsis. There have been studies examining the conjunctivalization progressed toward total conjunctivalization. The
effects of grafting the wounds in SJS/TEN after mild wound bed severity of tarsal conjunctival or lid-margin scarring affected the
preparation; however, these practices have not become standard in most worsening of the ocular surface (113).
burn centers (106–108). Re-epithelialization of large areas of skin, All of this points to the critical importance of acute phase
either primarily or assisted with grafting, requires significant energy management. There is a window of opportunity in the first 7 days to
expenditure. Although not studied formally, most burn centers will alter visual outcomes. Intervention with the amniotic membrane (AM)
provide hyperalimentation for patients with SJS/TEN using similar is the most critical decision to be made to mitigate eyelid margin
formulae that they would use for patients with burns (109). Burn disease and prevent the long-term sequelae associated with eyelid
centers work closely with dieticians and most have them embedded microtrauma to the ocular surface (114, 115). Traditionally,
within their teams. Protein calorie malnutrition must be prevented, and AM transplantation (AMT) involved the use of bolsters and sutures to
assessment of nutritional status should be performed either by indirect secure AM across the eyelid margin and a symblepharon ring to secure
calorimetry or adjuncts such as urinary excretion of nitrogen if normal it onto the ocular surface. Recent advances in AMT techniques include
kidney function is maintained. Hypermetabolic states persist after using cyanoacrylate glue instead of sutures to secure the AM to the
wound closure and need to be monitored similarly to those receiving eyelids and allow for a painless and rapid procedure that does not
care for burns. Pharmacotherapies such as propranolol and oxandrolone require the use of sedation or general anesthesia. This may be of critical
are currently under study for patients with burns (110, 111), and further importance in acutely ill patients such as those with SJS/TEN (116).
work in this area will be needed depending on the results. According to a recent study, patients who receive acute ophthalmic
care based on an evidence-based treatment that involves the use of
AM were more likely to retain >20/40 vision than those who did not
5.2. Eye care in SJS/TEN (92% vs.33%). Vision-threatening complications in the chronic phase
were also significantly higher in the latter group (67% vs. 17%) (117).
Early ocular involvement is highly variable and not proportionately However, AMT is not a panacea and long-term complications do still
related to the extent of body surface area detached. It ranges from occur, particularly eyelid-related complications and dry eye (118).

Frontiers in Medicine 14 [Link]

Marks et al. 10.3389/fmed.2023.1213889

Systemic treatments for SJS/TEN have long shown equivocal when sedation was applied to minimize pain and adverse symptoms
outcomes in ocular disease. More recently, corticosteroid pulse associated with vulvovaginal exams.
therapy (CPT), systemic cyclosporine, and etanercept have been In a subsequent long-term follow-up study involving the same 55
explored. In a retrospective case series study by Mieno et al. (119), 36 patients, nine patients were found to be deceased, and one patient had
patients who received CPT within 4 days of disease onset were an unknown mailing address. Among the remaining 45 patients who
compared against 49 patients who did not receive such therapy. The were sent follow-up questionnaires, only five patients responded.
percentage of patients with a best corrected visual acuity of 20/200 or Although responses were scarce, many noted persistent complaints of
greater in the worst eye was significantly different between the two vaginal dryness (126).
groups, with 52.8% reaching ≥20/200 in those who received CPT vs. The overall goal emphasized by this study is the need to standardize
14.3% in those who did not. Severe ocular complications were also the clinical management of women experiencing vulvovaginal sloughing
significantly less in the group that received CPT. It is important to and men with a urogenital disease during the acute phase. It also
note that this study was not randomized, so more research may highlights the importance of improving follow-up care in the gynecology
be needed to further validate these findings. Another study evaluated and urology clinics, or alternatively, implementing a multidisciplinary
the effects of acute systemic cyclosporine in a small cohort of patients follow-up plan for affected patients.
and found no association between the use of systemic cyclosporine During the acute phase of SJS/TEN, it is strongly encouraged to
therapy and chronic ocular complications (120). Etanercept, however, consult with gynecology or urology and remain cognizant of potential
has been shown, along with concurrent use of AMT, to have a long-term sequelae such as scarring, strictures, and vaginal dryness.
beneficial effect in reducing chronic ocular sequela in a small cohort, A follow-up plan involving collaboration between different specialties
though the effects of etanercept vs. AMT may be difficult to separate involving gynecologists and urologists is imperative.
(121). The question of whether specific acute therapies may be better
than others for preventing chronic eye sequelae in SJS/TEN is still an
open one. 5.4. Considerations for rehabilitation
A pivotal point in the care of chronic ocular disease in SJS/TEN therapy, hyperproliferative healing, and
was the introduction of customized scleral lenses known as prosthetic aftercare reintegration
®
replacement of the ocular surface ecosystem (PROSE ). These provide
both a protective barrier and support for the ocular surface and can Physical and occupational therapy is a keystone of burn care and
prevent corneal complications, thus improving visual acuity and benefits patients with SJS/TEN. Hospitals with burn programs have a
®
comfort. PROSE is often thought of as an intervention that applies higher density of therapists comfortable with managing patients in
only to adults but recently, Wang et al. have shown that pediatric intensive care units with open wounds. Therapists are also poised to
®
patients with SJS/TEN can also benefit from PROSE treatment (122). manage anti-deformity positioning and scar prevention. Although not
Treatment was feasible in over two-thirds of pediatric patients with always discussed, patients with SJS/TEN may develop hypertrophic
chronic ocular surface disease from SJS/TEN and resulted in scars that can be remarkably similar to those seen after burn injury
significant improvements in vision. Other variations of scleral lenses (127). Burn therapists are specialists in scar management and employ
have recently been explored, including a limbal-supported contact adjuncts such as splints and compression garments. Acute stress and
lens that led to improved vision compared to spectacles and reduced later post-traumatic stress disorders may develop and burn programs
ocular pain in patients with ocular sequelae from SJS/TEN (123). are poised to screen and treat these early. Community, school, and
Significant advances in our understanding of ocular disease in work reintegration are also areas where burn programs have unique
SJS/TEN have fostered progress in management and outcomes. expertise and can provide additional resources to patients with
Though it remains a blinding disease, future advancements will SJS/TEN.
continue to improve vision and visual function in patients with SJS/
TEN (124).
5.5. Long-term physical and mental health
complications of SJS/TEN
5.3. Genitourinary disease in SJS/TEN
Long-term health complications following SJS/TEN are prevalent
Although there is consensus on the need that standardized and underrecognized. SJS survivors have articulated in a recent survey
supportive measures should be instituted to prevent long-term their concerns for inadequacy of post-discharge physical and mental
genitourinary and reproductive complications in men and women, health care (12). Due to incomplete follow-up of SJS/TEN populations,
knowledge of what happens in real clinical practice is lacking. Strictures many complications may not have been initially recognized as being
in the urogenital tract may be more common in women (125). A associated with SJS/TEN. Recognized complications can include but
review of 55 female SJS/TEN survivors sheds light on this issue (126). are not limited to the eye, skin, mucous membrane, ear, internal organ
The key findings from this retrospective review included that stricture, reproductive, and mental health concerns. One study found
gynecology was consulted in <50% of cases and this was unimpacted that 88.2% of participants felt that their SJS/TEN diagnosis impacted
by the severity of SJS/TEN disease. Furthermore, consultation and care their physical health. In that same study, 70.2% of participants felt that
were particularly neglected in girls and young women presumed to their physicians did not sufficiently address these complications (12).
be sexually inactive, with no reporting of sexual activity and pregnancy. The acute stage of SJS/TEN is characterized by mucosal membrane
There was also underutilization of the operating room (OR) and times involvement (21). Such involvement may include erosion of the ocular

Frontiers in Medicine 15 [Link]

Marks et al. 10.3389/fmed.2023.1213889

mucous membranes. The most feared long-term effects in SJS/TEN plate damage. Hyper-or hypopigmentation, fibrosis, and hypertrophic
are chronic ocular complications. Approximately 50% of SJS survivors scars are more prevalent in people of color. Survivors with hypertrophic
report long-term ocular complications (128). Ocular damage can scars may experience sealed pores, leading to overheating in hot weather
include limbal stem cell deficiency and numerous side effects. and the inability to sweat. Additionally, survivors may experience hair
Survivors with limbal stem cell deficiency often have epithelial defects, follicle destruction causing loss of hair, and many survivors experience
corneal scarring, lid entropion, vascularization, dry eye syndrome, damage to their nail beds and plates resulting in slow-growing, fragile,
photophobia, corneal abrasions, and erosions due to the corneal or missing nails.
epithelium losing the ability to repair itself. Often corneal abrasions SJS/TEN can affect the regenerative capacity of the mucosal surfaces.
and erosions lead to visual impairment, including blindness. In severe cases, it manifests as scarring/fibrosis. Skin areas exposed to
According to Gregory (114), “Interventions during the acute stage are pressure and friction may show delayed healing and sometimes even
crucial, as the long-term sequelae can be difficult, if not impossible, to failure to re-epithelialize. Deeper tissue involvement causes significant
repair.” Additionally, 77% of SJS/TEN patients present with ocular damage to progenitor and stem cell populations in affected tissues and
involvement during the acute stage (129). Standard treatment for SJS/ can impact the surrounding cellular, immunological, and cytokine
TEN patients can include but is not limited to topical medications, microenvironment (130). Hair follicle destruction has also been
pulse corticosteroid therapy, systemic cyclosporine, symblepharon associated with secondary dermal microcalcifications, scarring, and
®
rings, amniotic membrane transplantation, PROKERA ring, scleral sebaceous hyperplasia (131).
® ®
contact lenses, PROSE contact lenses, SynergEYES contact lenses, Many survivors also experience oral health complications,
and limbal supported contact lenses. including dental growth abnormalities, low saliva volume (dry
It is suggested that daily rinsing of the eyes with sterile saline helps mouth), altered tongue, pain, burning sensation, numbness, and loss
combat inflammatory disease. When used in combination with of taste and smell. Dental growth abnormalities, such as stunted root
prophylactic topical antibiotics that are bactericidal, rinsing may also development, enamel damage, and loss of tooth buds have been
decrease the risk of infection. According to Mieno et al. (119), if given observed in children, resulting in missing permanent teeth. SJS/TEN
within 4 days of symptom onset, pulse corticosteroid therapy led to survivors may experience altered tongue, which appears smooth due
significantly better vision and fewer corneal and conjunctival to filiform and/or fungiform papillae damage. This damage can result
complications. Gregory (114) suggests that systemic cyclosporine may in pain, burning sensation, numbness, and loss of taste. Closely related
decrease ocular surface inflammation. to loss of taste, there may be sinus damage from mucous membrane
Symblepharon may still occur with the treatments above, which involvement, resulting in disordered smell perception.
indicates the implementation of a symblepharon ring to prevent Ear damage can occur which includes scarring and loss of cilia.
adhesion of the conjunctiva with the eyelid. In addition, amniotic This can result in complete occlusion of the external auditory canal.
membrane transplantation may be used for anti-inflammatory and Loss of cilia can also lead to abnormal ear wax drainage and loss
anti-scarring purposes and to promote epithelial healing. Increasing of hearing.
evidence supports a combination of the two previously mentioned Urogenital complications most commonly include internal
®
treatments, called the PROKERA ring, which prevents symblepharon, strictures. Female SJS/TEN survivors may experience vulvar, vaginal,
and decreases inflammation and scarring risk while promoting and cervical adhesions and scarring, as well as vaginal and cervical
epithelial healing. stenosis (narrowing) due to damage to mucous membranes which can
Increasing evidence for treatment of chronic eye complications subsequently complicate childbirth.
includes, but is not limited to topical medications, scleral contact Female survivors may also suffer from menstrual disturbances
® ®
lenses, PROSE contact lenses, SynergEYES contact lenses, and caused by obstruction of the outflow of menstrual blood manifesting
limbal supported contact lenses. SJS/TEN survivors frequently as: cyclical abdominal pain, hematocolpos (blood accumulated in the
suffer from dry eye syndrome and therefore require constant use of vagina), and hematometra (blood accumulated in the uterine cavity).
artificial eye drops throughout the day and eye ointment during the Both male and female survivors may experience urethral adhesions
night. In addition, some survivors opt to use blood serum tears and scarring, urethral stenosis, hypogastric mass, recurrent painful
during the day as they provide healing properties for healthy cell urination, urinary tract infection, and sexual dysfunction.
growth and may afford patients additional relief and comfort. Other internal organs can be involved largely from mechanical
Scleral contact lenses are gas-permeable contact lenses designed to fractures (strictures) and other organ damage including to the
cover the eye’s cornea and help with dry eye syndrome. PROSE ® esophagus, colon, liver, renal, gastrointestinal, and respiratory systems.
contacts provide durable improvements in vision. SynergEYES ® Esophageal strictures commonly manifest as difficulty swallowing.
contact lenses consist of a stable, rigid center with high oxygen Survivors may also have colon complications such as colitis. Ileal
permeability that delivers clear vision and the comfort of a soft lens. strictures can be associated with chronic diarrhea, intestinal ulcers,
Limbal-supported contact lenses are a type of scleral lens that can intussusception (intestinal inversion), ileal pseudodiverticula, and
improve vision and reduce ocular pain. Itoi et al. (123) suggest that bleeding. Respiratory complications most commonly include asthma,
wearing limbal-supported lenses improved vision and reduced chronic bronchitis, bronchiolitis obliterations, chronic obstructive
ocular pain compared to spectacles. pulmonary disease (COPD), interstitial lung disease, pulmonary air
Outside of ocular complications, complications vary in severity as leak syndrome, and laryngeal obstruction.
SJS/TEN cases and treatment courses differ among individuals. Acute and chronic mental health issues are an important, and
According to one study, 80% of patients reported skin sequelae from SJS/ often overlooked complication of SJS/TEN that can be prevalent
TEN (128). Skin damage can manifest as hyper-or hypopigmentation, decades later and be a key factor impairing return to work and regular
fibrosis, scarring, sealed pores, hair follicle destruction, and nail bed and daily activities. Psychiatric damage among survivors can manifest as

Frontiers in Medicine 16 [Link]

Marks et al. 10.3389/fmed.2023.1213889

TABLE 6 Future directions to move SJS/TEN forward.

Unmet needs/gaps Implementation/focus points

Prevention, prediction, and regulation:

-Lack of knowledge on all casual factors -Conduct studies across diverse population groups (age, race, gender, ethnicity)
-Generalized genetic test findings -Low and cost-effective testing
-Limited information on casual drugs and targets -Networks and collaborations to study on multiple drugs, and risk factors
-Genetic tests with low positive predictive value -Studies to include genetic and other risk factor identifications
-Need of evidence-based pre-prescription genetic tests -Advancement in pharmacovigilance for immediate updates and alerts on new
-Lack of real time information on SJS/TEN cases with any new casual drug adverse drug effects

Early diagnosis and treatment:

-Unidentifiable/unreported cases -Clinical awareness and decision-making support

-Inadequate transfer specialized centers -Telehealth triage services
-Lack of knowledge on biological markers that aid in early diagnosis -Studies to provide genetic markers and point of care markers for early diagnosis and
-Identify culprit drugs with testing methods (in vivo/ex vivo/ in vitro) prognosis
-Photographic data to assess risk and prognosis -Validate drugs causes across different cohorts
-Introduce artificial intelligence algorithms into clinical care

Clinical care and follow-up:

-Need for evidence-based studies to provide best supportive care -Provide evidence-based study results for best clinical practices
-Short term treatment plans -Introduce collaborative networks (domestic and international) in clinical trial
-Long term clinical/health complications studies
-Coordinated clinical care and support services -Follow-up and long-term care for survivors and families
-Coordination among clinical specialties

Understanding mechanisms and providing care:

-Mechanistic studies to identify cellular and molecular signals that act as a biological -Cohort studies on prospectively collected samples for long-term storage with
marker and novel targets for treatment collaborative effort from international networks

anxiety and fear of new medicines, survivor guilt, flashbacks, insomnia, includes a critical review of patient-centered clinical and research
depression, and post-traumatic stress disorder. Survivors often feel priorities and unmet evidence-based research needs.
frustrated due to a lack of providers versed in the disease and a lack of Strengths and opportunities prevail, and in this paper, we have tried
appropriate explanations of how to access specialty care and what to to summarize the updated literature on SJS/TEN while highlighting
expect. They are particularly fearful of trying new medications and knowledge gaps and research opportunities. Although there have been
products such as vaccines due to the concern of recurrence. many recent advances in SJS/TEN research that will improve SJS/TEN
outcomes and care, ongoing global research collaboration is urgently
needed to address the challenges of studying diverse SJS/TEN
6. Moving the field forward/future populations to include adequate representation of age, gender, race, and
directions ethnicity. Several national and international projects have had small
sample sizes that were not ancestrally diverse enough to identify risk
SJS/TEN remains a life-threatening and a largely drug-induced alleles, generalized-based risk factors, or effective treatment strategies.
disease in adults with high morbidity and mortality. Research into These international collaboration networks grown over time will be a
prevention, earlier diagnosis, and treatment of SJS/TEN is impacted powerful vehicle to address unmet needs like developing affordable
by its overall rarity which challenges the ability to study large and pharmacogenomic assays, piloting preemptive testing, and incorporating
diverse populations. The continued development of international genotypic information that supports the decision-making directly into
networks to synergize efforts from researchers with expertise in the medical record which will aid in drug prescription and dispensing
different genres of research will be key to the overall success, systems (Table 6) (6). These networks can also facilitate genome-wide
advancement, and translation. Engagement with the community of association research studies of other implicated drugs/agents for which
SJS/TEN survivors and affected families remains key in this process. robust genomic risk factors are yet to be identified as well as multiomic
Particularly relevant is the fragmentation of healthcare and lack of and mechanistic studies to facilitate the development of earlier
information on long-term health outcomes for survivors of SJS/ diagnostic and prognostic markers and new targeted therapeutic agents.
TEN. Notable recent advances in SJS/TEN have included insights
into earlier diagnosis, mechanisms, risk identification, clinical
implications, and pharmaco-surveillance, making risk prediction Author’s note
and prevention possible for some causative factors. As some of the
main barriers remain unaddressed, and to truly understand the This paper was written using the priority framework of content
disease, this research effort requires the collaboration of experts, presented at the virtual meeting: SJS/TEN 2021: Collaboration, Innovation
multidisciplinary leadership/approach, and coordination that and Community ([Link]

Frontiers in Medicine 17 [Link]

Marks et al. 10.3389/fmed.2023.1213889

Author contributions Conflict of interest

MEM and RKB are the co-first-authors of this manuscript. CB, KM was employed by Stevens-Johnson Syndrome Foundation.
SD, and EJP are the last authors, with EJP as the corresponding author EJP reports grants from National Institutes of Health (R01HG010863,
of this manuscript. RKB and MM contributed to the R01AI152183, U01AI154659) and from the National Health and
Supplementary Figure. SP, MEM, RKB and EJP contributed to Medical Research Council of Australia. She receives Royalties and
Figure 1. W-HC and MEM contributed to Figure 2. W-CC and CS consulting fees from UpToDate and has received consulting fees from
contributed to Figure 3. ET and MEM contributed to Figure 4. MEM Janssen, Verve, Biocryst, Regeneron, AstraZeneca and Novavax.
contributed to Figure 5. RKB, MEM, HBP, and KM contributed to The remaining authors declare that the research was conducted in
Table 1. SH, BK, MM, and RKB contributed to Table 2. MEM and ET the absence of any commercial or financial relationships that could
contributed to Table 3. HBP contributed to Table 4. JS, TMB, HNS, be construed as a potential conflict of interest.
AS, JC, EF, HBP, and MM contributed to Table 5. RKB contributed to The reviewer OI declared a shared affiliation with the author AS
Table 6. All authors listed have made a substantial, direct, and to the handling editor at the time of review.
intellectual contribution to the work and approved it for publication.

Publisher’s note
Funding
All claims expressed in this article are solely those of the authors
This work was partially supported by Vanderbilt University and do not necessarily represent those of their affiliated organizations,
Medical Center Department of Medicine, the University of Ottawa or those of the publisher, the editors and the reviewers. Any product
Department of Medicine, and the Canadian Dermatology that may be evaluated in this article, or claim that may be made by its
Foundation. EP reports grants from National Institutes of Health manufacturer, is not guaranteed or endorsed by the publisher.
(R01HG010863, R01AI152183, and U01AI154659) and from the
National Health and Medical Research Council of Australia. The
funder was not involved in the study design, collection, analysis, Author disclaimer
interpretation of data, the writing of this article, or the decision to
submit it for publication. TB, MR, and HBP the opinions and assertions expressed herein
are those of the authors and do not reflect the official policy or position
of the U.S. Food and Drug Administration, Uniformed Services,
Acknowledgments University of the Health Sciences, or the Department of Defense. This
work was prepared by a military or civilian employee of the US
The authors would like to thank the patients and their medical Government as part of the individual’s official duties. Therefore, is in
care teams whose efforts and cooperation greatly contributed to the the public domain and does not possess copyright protection (public
value of this work. We would like to thank all attendees, including domain information may be freely distributed and copied; however,
Stephen Elledge for their presence at the virtual meeting. The as a courtesy it is requested that the Uniformed Services University
contents of this paper are solely the responsibility of the authors and and the author be given an appropriate acknowledgement).
do not necessarily represent the views of the National Institutes of
Health. The opinions and assertions expressed herein are those of
the authors and do not reflect the official policy or position of the Supplementary material
U.S. Food and Drug Administration. Eric Tkaczyk was supported
by Career Development Award Number IK2 CX001785 from the The Supplementary material for this article can be found online
United States Department of Veterans Affairs Clinical Science at: [Link]
R&D Service. full#supplementary-material

References
1. Peter JG, Lehloenya R, Dlamini S, Risma K, White KD, Konvinse KC, et al. Severe based nested case-control study. Am J Clin Dermatol. (2022) 23:257–66. doi: 10.1007/
delayed cutaneous and systemic reactions to drugs: a global perspective on the science s40257-021-00661-0
and art of current practice. J Allergy Clin Immunol Pract. (2017) 5:547–63. doi: 10.1016/j.
jaip.2017.01.025 6. Phillips EJ, Bouchard CS, Divito SJ. Stevens-Johnson syndrome and toxic epidermal
necrolysis-coordinating research priorities to move the field forward. JAMA Dermatol.
2. Dobry AS, Himed S, Waters M, Kaffenberger BH. Scoring assessments in Stevens- (2022) 158:607–8. doi: 10.1001/jamadermatol.2022.0484
Johnson syndrome and toxic epidermal necrolysis. Front Med (Lausanne). (2022)
9:883121. doi: 10.3389/fmed.2022.883121 7. Goodman CW, Brett AS. Race and pharmacogenomics-personalized medicine or
misguided practice? JAMA. (2021) 325:625–6. doi: 10.1001/jama.2020.25473
3. Frantz R, Huang S, Are A, Motaparthi K. Stevens-Johnson syndrome and toxic
epidermal necrolysis: A review of diagnosis and management. Medicina. (2021) 57:895. 8. White KD, Abe R, Ardern-Jones M, Beachkofsky T, Bouchard C, Carleton B, et al.
doi: 10.3390/medicina57090895 SJS/TEN 2017: building multidisciplinary networks to drive science and translation. J
Allergy Clin Immunol Pract. (2018) 6:38–69. doi: 10.1016/[Link].2017.11.023
4. Chang WC, Abe R, Anderson P, Anderson W, Ardern-Jones MR, Beachkofsky TM,
et al. SJS/TEN 2019: from science to translation. J Dermatol Sci. (2020) 98:2–12. doi: 9. Stern RS. Professor Jean-Claude Roujeau (1944-2021). Br J Dermatol. (2021)
10.1016/[Link].2020.02.003 185:470–1. doi: 10.1111/bjd.20076
5. Gronich N, Maman D, Stein N, Saliba W. Culprit medications and risk factors 10. Micheletti RG, Chiesa-Fuxench Z, Noe MH, Stephen S, Aleshin M, Agarwal A,
associated with Stevens-Johnson syndrome and toxic epidermal necrolysis: population- et al. Stevens-Johnson syndrome/toxic epidermal necrolysis: a multicenter retrospective

Frontiers in Medicine 18 [Link]

Marks et al. 10.3389/fmed.2023.1213889

study of 377 adult patients from the United States. J Invest Dermatol. (2018) 138:2315–21. 33. Yoo HW, Kim HY, Shin K, Kim SH. Clinical characteristics of drug-induced
doi: 10.1016/[Link].2018.04.027 Stevens-Johnson syndrome and toxic epidermal necrolysis: a single-center study. Asia
Pac Allergy. (2022) 12:e17. doi: 10.5415/apallergy.2022.12.e17
11. Bruggen MC, Le ST, Walsh S, Toussi A, de Prost N, Ranki A, et al. Supportive care
in the acute phase of Stevens-Johnson syndrome and toxic epidermal necrolysis: an 34. Porebski G. In vitro assays in severe cutaneous adverse drug reactions: are they
international, multidisciplinary Delphi-based consensus. Br J Dermatol. (2021) still research tools or diagnostic tests already? Int J Mol Sci. (2017) 18:1737. doi: 10.3390/
185:616–26. doi: 10.1111/bjd.19893 ijms18081737
12. Coromilas AJ, Divito SJ, Phillips EJ, Micheletti RG. Physical and mental health 35. Sadek M, Iqbal O, Siddiqui F, Till S, Mazariegos M, Campbell E, et al. The role of
impact of Stevens-Johnson syndrome/toxic epidermal necrolysis and post–hospital IL-13, IL-15 and granulysin in the pathogenesis of Stevens-Johnson syndrome/toxic
discharge care: identifying practice gaps. JAAD Int. (2023) 11:88–9. doi: 10.1016/j. epidermal necrolysis. Clin Appl Thromb Hemost. (2021) 27:1076029620950831. doi:
jdin.2023.01.012 10.1177/1076029620950831
13. Bousman CA, Bengesser SA, Aitchison KJ, Amare AT, Aschauer H, Baune BT, et al. 36. Schwartz RA, McDonough PH, Lee BW. Toxic epidermal necrolysis: Part II.
Review and consensus on pharmacogenomic testing in psychiatry. Pharmacopsychiatry. Prognosis, sequelae, diagnosis, differential diagnosis, prevention, and treatment. J
(2021) 54:5–17. doi: 10.1055/a-1288-1061 Am Acad Dermatol. (2013) 69:187.e1–187.e16; Quiz 203-4. doi: 10.1016/j.
14. Chang CJ, Chen CB, Hung SI, Ji C, Chung WH. Pharmacogenetic testing for jaad.2013.05.002
prevention of severe cutaneous adverse drug reactions. Front Pharmacol. (2020) 11:969. 37. Barbaud A, Romano A. Skin testing approaches for immediate and delayed
doi: 10.3389/fphar.2020.00969 hypersensitivity reactions. Immunol Allergy Clin N Am. (2022) 42:307–22. doi: 10.1016/j.
15. Liu H, Wang Z, Bao F, Wang C, Sun L, Zhang H, et al. Evaluation of prospective iac.2022.01.003
HLA-B*13: 01 screening to prevent dapsone hypersensitivity syndrome in patients with 38. Phillips EJ, Bigliardi P, Bircher AJ, Broyles A, Chang YS, Chung WH, et al.
leprosy. JAMA Dermatol. (2019) 155:666–72. doi: 10.1001/jamadermatol.2018.5360 Controversies in drug allergy: testing for delayed reactions. J Allergy Clin Immunol.
16. Sung C, Tan L, Limenta M, Ganesan G, Toh D, Chan CL. Usage pattern of (2019) 143:66–73. doi: 10.1016/[Link].2018.10.030
carbamazepine and associated severe cutaneous adverse reactions in Singapore following 39. Copaescu A, Gibson A, Li Y, Trubiano JA, Phillips EJ. An updated review of the
implementation of HLA-B*15:02 genotyping as standard-of-care. Front Pharmacol. diagnostic methods in delayed drug hypersensitivity. Front Pharmacol. (2020) 11:573573.
(2020) 11:527. doi: 10.3389/fphar.2020.00527 doi: 10.3389/fphar.2020.573573
17. Tang MM, Fok JS, Thong BY, Yun J, Li PH, Kang HR, et al. Diagnostic procedures 40. Copaescu AM, Ben-Shoshan M, Trubiano JA. Tools to improve the diagnosis and
& practices in drug allergy/hypersensitivity: a survey of 13 Asian countries. Asia Pac management of T-cell mediated adverse drug reactions. Front Med. (2022) 9:923991.
Allergy. (2020) 10:e36. doi: 10.5415/apallergy.2020.10.e36 doi: 10.3389/fmed.2022.923991
18. Thong BY, Lucas M, Kang HR, Chang YS, Li PH, Tang MM, et al. Drug 41. Lehloenya RJ, Isaacs T, Nyika T, Dhana A, Knight L, Veenstra S, et al. Early high-
hypersensitivity reactions in Asia: regional issues and challenges. Asia Pac Allergy. dose intravenous corticosteroids rapidly arrest Stevens Johnson syndrome and drug
(2020) 10:e8. doi: 10.5415/apallergy.2020.10.e8 reaction with eosinophilia and systemic symptoms recurrence on drug re-exposure. J
19. Su SC, Chen CB, Chang WC, Wang CW, Fan WL, Lu LY, et al. HLA alleles and Allergy Clin Immunol. (2021) 9:582–584.e1. doi: 10.1016/[Link].2020.08.012
CYP2C9*3 as predictors of phenytoin hypersensitivity in east Asians. Clin Pharmacol 42. Lehloenya RJ, Peter JG, Copascu A, Trubiano JA, Phillips EJ. Delabeling delayed
Ther. (2019) 105:476–85. doi: 10.1002/cpt.1190 drug hypersensitivity: how far can you safely go? J Allergy Clin Immunol Pract. (2020)
20. Yang SC, Chen CB, Lin MY, Zhang ZY, Jia XY, Huang M, et al. Genetics of severe 8:2878–2895.e6. doi: 10.1016/[Link].2020.07.005
cutaneous adverse reactions. Front Med. (2021) 8:652091. doi: 10.3389/fmed.2021.759559 43. Copaescu AM, Trubiano JA. In vitro/ex vivo assays for severe cutaneous drug
21. Tempark T, John S, Rerknimitr P, Satapornpong P, Sukasem C. Drug-induced reactions. J Allergy Clin Immunol. (2023) 152:39–41. doi: 10.1016/[Link].2023.03.024
severe cutaneous adverse reactions: insights into clinical presentation, 44. Bastuji-Garin S, Fouchard N, Bertocchi M, Roujeau JC, Revuz J, Wolkenstein P.
immunopathogenesis, diagnostic methods, treatment, and pharmacogenomics. Front SCORTEN: a severity-of-illness score for toxic epidermal necrolysis. J Invest Dermatol.
Pharmacol. (2022) 13:832048. doi: 10.3389/fphar.2022.832048 (2000) 115:149–53. doi: 10.1046/j.1523-1747.2000.00061.x
22. Capule F, Tragulpiankit P, Mahasirimongkol S, Jittikoon J, Wichukchinda N, 45. Koh HK, Fook-Chong S, Lee HY. Assessment and comparison of performance of
Theresa Alentajan-Aleta L, et al. Association of carbamazepine-induced Stevens- ABCD-10 and SCORTEN in prognostication of epidermal necrolysis. JAMA Dermatol.
Johnson syndrome/toxic epidermal necrolysis with the HLA-B75 serotype or (2020) 156:1294–9. doi: 10.1001/jamadermatol.2020.3654
HLA-B*15:21 allele in Filipino patients. Pharmacogenomics J. (2020) 20:533–41. doi:
10.1038/s41397-019-0143-8 46. Suo H, Jiang B, Sun X, Dong J, Alamgir M, Guan X, et al. Comparing the accuracy
of ABCD-10 and SCORTEN in predicting the in-hospital mortality of Stevens-Johnson
23. Pan RY, Chu MT, Wang CW, Lee YS, Lemonnier F, Michels AW, et al. Identification syndrome/toxic epidermal necrolysis: a multi-institutional study from Central China.
of drug-specific public TCR driving severe cutaneous adverse reactions. Nat Commun. Dermatology. (2022) 238:736–44. doi: 10.1159/000520494
(2019) 10:3569. doi: 10.1038/s41467-019-11396-2
47. Koh HK, Fook-Chong SMC, Lee HY. Improvement of mortality prognostication
24. Phillips EJ, Sukasem C, Whirl-Carrillo M, Muller DJ, Dunnenberger HM, in patients with epidermal necrolysis: the role of novel inflammatory markers and
Chantratita W, et al. Clinical pharmacogenetics implementation consortium guideline proposed revision of SCORTEN (Re-SCORTEN). JAMA Dermatol. (2022) 158:160–6.
for HLA genotype and use of carbamazepine and oxcarbazepine: 2017 update. Clin doi: 10.1001/jamadermatol.2021.5119
Pharmacol Ther. (2018) 103:574–81. doi: 10.1002/cpt.1004
48. Hama N, Sunaga Y, Ochiai H, Kokaze A, Watanabe H, Kurosawa M, et al.
25. Wong CSM, Yap DYH, Ip P, Wong WHS, Chua GT, Yeung CK, et al. HLA-B*15:11 Development and validation of a novel score to predict mortality in Stevens-Johnson
status and carbamazepine-induced severe cutaneous adverse drug reactions in syndrome and toxic epidermal necrolysis: CRISTEN. J Allergy Clin Immunol Pract.
HLA-B*15:02 negative Chinese. Int J Dermatol. (2022) 61:184–90. doi: 10.1111/ijd.15792 (2023). doi: 10.1016/[Link].2023.07.001
26. Deshpande P, Hertzman RJ, Palubinsky AM, Giles JB, Karnes JH, Gibson A, et al. 49. Ng QX, De Deyn M, Venkatanarayanan N, Ho CYX, Yeo WS. A meta-analysis of
Immunopharmacogenomics: mechanisms of HLA-associated drug reactions. Clin cyclosporine treatment for Stevens-Johnson syndrome/toxic epidermal necrolysis. J
Pharmacol Ther. (2021) 110:607–15. doi: 10.1002/cpt.2343 Inflamm Res. (2018) 11:135–42. doi: 10.2147/JIR.S160964
27. Gibson A, Deshpande P, Campbell CN, Krantz MS, Mukherjee E, Mockenhaupt 50. Ramsay B, Lawrence CM. Measurement of involved surface area in patients with
M, et al. Updates on the immunopathology and genomics of severe cutaneous adverse psoriasis. Br J Dermatol. (1991) 124:565–70. doi: 10.1111/j.1365-2133.1991.tb04952.x
drug reactions. J Allergy Clin Immunol. (2023) 151:289–300.e4. doi: 10.1016/j.
jaci.2022.12.005 51. Pham C, Collier Z, Gillenwater J. Changing the way we think about burn size
estimation. J Burn Care Res. (2019) 40:1–11. doi: 10.1093/jbcr/iry050
28. Jantararoungtong T, Tempark T, Koomdee N, Medhasi S, Sukasem C. Genotyping
HLA alleles to predict the development of severe cutaneous adverse drug reactions 52. DuBOIS D, Dubois EF. Fifth paper the measurement of the surface area of man.
(SCARs): state-of-the-art. Expert Opin Drug Metab Toxicol. (2021) 17:1049–64. doi: Arch Intern Med. (1915) XV (5_2):868–81.
10.1080/17425255.2021.1946514 53. Choi J, Patil A, Vendrow E, Touponse G, Aboukhater L, Forrester JD, et al.
29. Guy JW, Patel I, Oestreich JH. Clinical application and educational training for Practical computer vision application to compute total body surface area burn:
pharmacogenomics. Pharmacy. (2020) 8:163. doi: 10.3390/pharmacy8030163 reappraising a fundamental burn injury formula in the modern era. JAMA Surg. (2022)
157:129–35. doi: 10.1001/jamasurg.2021.5848
30. Sukasem C, Jantararoungtong T, Koomdee N. Pharmacogenomics research
and its clinical implementation in Thailand: lessons learned from the resource- 54. Wachtel TL, Berry CC, Wachtel EE, Frank HA. The inter-rater reliability of
limited settings. Drug Metab Pharmacokinet. (2021) 39:100399. doi: 10.1016/j. estimating the size of burns from various burn area chart drawings. Burns. (2000)
dmpk.2021.100399 26:156–70. doi: 10.1016/S0305-4179(99)00047-9
31. Relling MV, Klein TE, Gammal RS, Whirl-Carrillo M, Hoffman JM, Caudle KE. 55. Chong HP, Quinn L, Jeeves A, Cooksey R, Lodge M, Carney B, et al. A comparison
The clinical pharmacogenetics implementation consortium: 10 years later. Clin study of methods for estimation of a burn surface area: Lund and Browder, e-burn and
Pharmacol Ther. (2020) 107:171–5. doi: 10.1002/cpt.1651 Mersey burns. Burns. (2020) 46:483–9. doi: 10.1016/[Link].2019.08.014
32. Plumpton CO, Pirmohamed M, Hughes DA. Cost-effectiveness of panel tests for 56. Tocco-Tussardi I, Presman B, Huss F. Want correct percentage of TBSA burned?
multiple pharmacogenes associated with adverse drug reactions: an evaluation Let a layman do the assessment. J Burn Care Res. (2018) 39:295–301. doi: 10.1097/
framework. Clin Pharmacol Ther. (2019) 105:1429–38. doi: 10.1002/cpt.1312 BCR.0000000000000613

Frontiers in Medicine 19 [Link]

Marks et al. 10.3389/fmed.2023.1213889

57. Tkaczyk ER, Coco JR, Wang J, Chen F, Ye C, Jagasia MH, et al. Crowdsourcing to 79. Tsiogka A, Bauer JW, Patsatsi A. Bullous pemphigoid associated with anti-
delineate skin affected by chronic graft-vs-host disease. Skin Res Technol. (2019) programmed cell death protein 1 and anti-programmed cell death ligand 1 therapy: a
25:572–7. doi: 10.1111/srt.12688 review of the literature. Acta Derm Venereol. (2021) 101:adv 00377. doi:
10.2340/00015555-3740
58. Codella NCF, Gutman D, Celebi ME, Helba B, Marchetti MA, Dusza SW, et al. Skin
lesion analysis toward melanoma detection: A challenge at the 2017 international 80. Siegel J, Totonchy M, Damsky W, Berk-Krauss J, Castiglione F Jr, Sznol M, et al.
symposium on biomedical imaging (ISBI), hosted by the international skin imaging Bullous disorders associated with anti-PD-1 and anti-PD-L1 therapy: a retrospective
collaboration (ISIC). Proceedings of the 2018 IEEE 15th International Symposium on analysis evaluating the clinical and histopathologic features, frequency, and impact on
Biomedical Imaging (ISBI 2018). Washington, DC, USA: IEEE. (2018): 168–172. cancer therapy. J Am Acad Dermatol. (2018) 79:1081–8. doi: 10.1016/[Link].2018.07.008
59. Daneshjou R, Barata C, Betz-Stablein B, Celebi ME, Codella N, Combalia M, et al. 81. Goldinger SM, Stieger P, Meier B, Micaletto S, Contassot E, French LE, et al.
Checklist for evaluation of image-based artificial intelligence reports in dermatology: Cytotoxic cutaneous adverse drug reactions during anti-PD-1 therapy. Clin Cancer Res.
CLEAR Derm consensus guidelines from the international skin imaging collaboration (2016) 22:4023–9. doi: 10.1158/[Link]-15-2872
artificial intelligence working group. JAMA Dermatol. (2022) 158:90–6. doi: 10.1001/
82. Kwon CW, Murthy RK, Kudchadkar R, Stoff BK. Pembrolizumab-induced lichen
jamadermatol.2021.4915 planus pemphigoides in a patient with metastatic Merkel cell carcinoma. JAAD Case
60. Waters M, Dobry A, Le ST, Shinkai K, Beachkofsky TM, Davis MDP, et al. Rep. (2020) 6:1045–7. doi: 10.1016/[Link].2020.03.007
Development of a skin-directed scoring system for Stevens-Johnson syndrome and 83. Kuo AM, Markova A. High grade dermatologic adverse events associated with
epidermal necrolysis: a delphi consensus exercise. JAMA Dermatol. (2023) 159:772–7. immune checkpoint blockade for cancer. Front Med. (2022) 9:898790. doi: 10.3389/
doi: 10.1001/jamadermatol.2023.1347 fmed.2022.898790
61. Charlton OA, Harris V, Phan K, Mewton E, Jackson C, Cooper A. Toxic epidermal 84. Shi CR, Shaughnessy M, Sehgal K, Clark JR, Reynolds KL, Toyohara J, et al.
necrolysis and Steven-Johnson syndrome: a comprehensive review. Adv Wound Care. Successful rechallenge with pembrolizumab after case of progressive immunotherapy-
(2020) 9:426–39. doi: 10.1089/wound.2019.0977 related mucocutaneous eruption (PIRME), a Stevens-Johnson syndrome-like reaction.
62. Brazel M, Desai A, Are A, Motaparthi K. Staphylococcal scalded skin syndrome Int J Dermatol. (2023). doi: 10.1111/ijd.16572
and bullous impetigo. Medicina. (2021) 57:1157. doi: 10.3390/medicina57111157 85. Faje AT, Lawrence D, Flaherty K, Freedman C, Fadden R, Rubin K, et al. High-dose
63. Tankunakorn J, Sawatwarakul S, Vachiramon V, Chanprapaph K. Stevens-Johnson glucocorticoids for the treatment of ipilimumab-induced hypophysitis is associated with
syndrome and toxic epidermal necrolysis-like lupus erythematosus. J Clin Rheumatol. reduced survival in patients with melanoma. Cancer. (2018) 124:3706–14. doi: 10.1002/
(2019) 25:224–31. doi: 10.1097/RHU.0000000000000830 cncr.31629
64. Klimas N, Quintanilla-Dieck J, Vandergriff T. Stevens–Johnson syndrome and 86. Mori S, Hickey A, Dusza SW, Lacouture ME, Markova A. Markers of systemic
toxic epidermal necrolysis. Cutaneous Drug Eruptions. (2015):259–69. doi: involvement and death in hospitalized cancer patients with severe cutaneous
10.1007/978-1-4471-6729-7_24 adverse reactions. J Am Acad Dermatol. (2019) 80:608–16. doi: 10.1016/j.
jaad.2018.10.039
65. Newkirk RE, Fomin DA, Braden MM. Erythema multiforme versus Stevens-
Johnson syndrome/toxic epidermal necrolysis: subtle difference in presentation, major 87. Phillips GS, Wu J, Hellmann MD, Postow MA, Rizvi NA, Freites-Martinez A, et al.
difference in management. Mil Med. (2020) 185:e1847–50. doi: 10.1093/milmed/usaa029 Treatment outcomes of immune-related cutaneous adverse events. J Clin Oncol. (2019)
37:2746–58. doi: 10.1200/JCO.18.02141
66. Hung YT, Chen YW, Huang Y, Lin YJ, Chen CB, Chung WH. Acute graft-versus-
host disease presenting as Stevens-Johnson syndrome and toxic epidermal necrolysis: a 88. Campochiaro C, Farina N, Tomelleri A, Ferrara R, Lazzari C, De Luca G, et al.
retrospective cohort study. J Am Acad Dermatol. (2022) 88:792–801. doi: 10.1016/j. Tocilizumab for the treatment of immune-related adverse events: a systematic literature
jaad.2022.10.035 review and a multicentre case series. Eur J Intern Med. (2021) 93:87–94. doi: 10.1016/j.
ejim.2021.07.016
67. Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, et al. Features
and outcomes of 899 patients with drug-induced liver injury: the DILIN prospective 89. Hibler BP, Markova A. Treatment of severe cutaneous adverse reaction with
study. Gastroenterology. (2015) 148:1340–1352.e7. doi: 10.1053/[Link].2015.03.006 tocilizumab. Br J Dermatol. (2020) 183:785–7. doi: 10.1111/bjd.19129
68. Fontana RJ, Li Y-J, Phillips E, Saeed N, Barnhart H, Kleiner D, et al. Allopurinol 90. Pollack MH, Betof A, Dearden H, Rapazzo K, Valentine I, Brohl AS, et al. Safety
hepatotoxicity is associated with human leukocyte antigen class I alleles. Liver Int. (2021) of resuming anti-PD-1 in patients with immune-related adverse events (ir AEs) during
41:1884–93. doi: 10.1111/liv.14903 combined anti-CTLA-4 and anti-PD1 in metastatic melanoma. Ann Oncol. (2018)
29:250–5. doi: 10.1093/annonc/mdx642
69. Nicoletti P, Barrett S, McEvoy L, Daly AK, Aithal G, Lucena MI, et al. Shared
genetic risk factors across carbamazepine-induced hypersensitivity reactions. Clin 91. Ingen-Housz-Oro S, Milpied B, Bensaid B, Elshot Y, Bruggen MC, Starace M, et al.
Pharm Ther. (2019) 106:1028–36. doi: 10.1002/cpt.1493 Drug reactions with eosinophilia and systemic symptoms induced by immune
checkpoint inhibitors: an international cohort of 13 cases. Melanoma Res. (2023)
70. Hasan Ali O, Berner F, Bomze D, Fassler M, Diem S, Cozzio A, et al. Human
33:155–8. doi: 10.1097/CMR.0000000000000877
leukocyte antigen variation is associated with adverse events of checkpoint inhibitors.
Eur J Cancer. (2019) 107:8–14. doi: 10.1016/[Link].2018.11.009 92. Kim D, Kobayashi T, Voisin B, Jo JH, Sakamoto K, Jin SP, et al. Targeted therapy
guided by single-cell transcriptomic analysis in drug-induced hypersensitivity
71. Sznol M, Ferrucci PF, Hogg D, Atkins MB, Wolter P, Guidoboni M, et al. Pooled
syndrome: a case report. Nat Med. (2020) 26:236–43. doi: 10.1038/s41591-019-0733-7
analysis safety profile of nivolumab and ipilimumab combination therapy in patients
with advanced melanoma. J Clin Oncol. (2017) 35:3815–22. doi: 10.1200/ 93. Deshpande P, Li Y, Thorne M, Palubinsky AM, Phillips EJ, Gibson A. Practical
JCO.2016.72.1167 implementation of genetics: new concepts in immunogenomics to predict, prevent, and
diagnose drug hypersensitivity. J Allergy Clin Immunol Pract. (2022) 10:1689–700. doi:
72. Santini FC, Rizvi H, Plodkowski AJ, Ni A, Lacouture ME, Gambarin-Gelwan M,
10.1016/[Link].2022.04.027
et al. Safety and efficacy of re-treating with immunotherapy after immune-related
adverse events in patients with NSCLC. Cancer Immunol Res. (2018) 6:1093–9. doi: 94. Hertzman RJ, Deshpande P, Leary S, Li Y, Ram R, Chopra A, et al. Visual genomics
10.1158/[Link]-17-0755 analysis studio as a tool to analyze multiomic data. Front Genet. (2021) 12:642012. doi:
10.3389/fgene.2021.642012
73. Freeman-Keller M, Kim Y, Cronin H, Richards A, Gibney G, Weber JS. Nivolumab
in resected and unresectable metastatic melanoma: characteristics of immune-related 95. Zhang C, Zhu Z, Gao J, Yang L, Dang E, Fang H, et al. Plasma exosomal mi
adverse events and association with outcomes. Clin Cancer Res. (2016) 22:886–94. doi: R-375-3p regulates mitochondria-dependent keratinocyte apoptosis by targeting XIAP
10.1158/[Link]-15-1136 in severe drug-induced skin reactions. Sci Transl Med. (2020) 12:eaaw6142. doi: 10.1126/
scitranslmed.aaw6142
74. Geisler AN, Phillips GS, Barrios DM, Wu J, Leung DYM, Moy AP, et al. Immune
checkpoint inhibitor-related dermatologic adverse events. J Am Acad Dermatol. (2020) 96. Saito N, Qiao H, Yanagi T, Shinkuma S, Nishimura K, Suto A, et al. An annexin
83:1255–68. doi: 10.1016/[Link].2020.03.132 A1-FPR1 interaction contributes to necroptosis of keratinocytes in severe cutaneous
adverse drug reactions. Sci Transl Med. (2014) 6:245ra95. doi: 10.1126/
75. Belum VR, Benhuri B, Postow MA, Hellmann MD, Lesokhin AM, Segal NH, et al.
scitranslmed.3008227
Characterisation and management of dermatologic adverse events to agents targeting
the PD-1 receptor. Eur J Cancer. (2016) 60:12–25. doi: 10.1016/[Link].2016.02.010 97. Shi FL, Yuan LS, Wong TS, Li Q, Li YP, Xu R, et al. Dimethyl fumarate inhibits
necroptosis and alleviates systemic inflammatory response syndrome by blocking the
76. Powles T, O'Donnell PH, Massard C, Arkenau HT, Friedlander TW, Hoimes CJ,
RIPK1-RIPK3-MLKL axis. Pharmacol Res. (2023) 189:106697. doi: 10.1016/j.
et al. Efficacy and safety of durvalumab in locally advanced or metastatic urothelial
phrs.2023.106697
carcinoma: updated results from a phase 1/2 open-label study. JAMA Oncol. (2017)
3:e172411. doi: 10.1001/jamaoncol.2017.2411 98. Kaczmarek A, Vandenabeele P, Krysko DV. Necroptosis: the release of damage-
associated molecular patterns and its physiological relevance. Immunity. (2013)
77. Minkis K, Garden BC, Wu S, Pulitzer MP, Lacouture ME. The risk of rash
38:209–23. doi: 10.1016/[Link].2013.02.003
associated with ipilimumab in patients with cancer: a systematic review of the literature
and meta-analysis. J Am Acad Dermatol. (2013) 69:e121–8. doi: 10.1016/j. 99. Kinoshita M, Ogawa Y, Hama N, Ujiie I, Hasegawa A, Nakajima S, et al.
jaad.2012.12.963 Neutrophils initiate and exacerbate Stevens-Johnson syndrome and toxic epidermal
necrolysis. Sci Transl Med. (2021) 13:eaax2398. doi: 10.1126/scitranslmed.aax2398
78. Joseph RW, Millis SZ, Carballido EM, Bryant D, Gatalica Z, Reddy S, et al. PD-1
and PD-L1 expression in renal cell carcinoma with sarcomatoid differentiation. Cancer 100. Venugopal R, Sharma N, Sen S, Mohanty S, Kashyap S, Agarwal T, et al.
Immunol Res. (2015) 3:1303–7. doi: 10.1158/[Link]-15-0150 Prognostic significance of matrix metalloproteinase 9 in COMET operated chronic

Frontiers in Medicine 20 [Link]

Marks et al. 10.3389/fmed.2023.1213889

ocular Stevens-Johnson syndrome. Br J Ophthalmol. (2023) 107:187–94. doi: 10.1136/ 116. Shanbhag SS, Chodosh J, Saeed HN. Sutureless amniotic membrane
bjophthalmol-2021-319302 transplantation with cyanoacrylate glue for acute Stevens-Johnson syndrome/toxic
epidermal necrolysis. Ocul Surf. (2019) 17:560–4. doi: 10.1016/[Link].2019.03.001
101. Olsson-Brown A, Yip V, Ogiji ED, Jolly C, Ressel L, Sharma A, et al. TNF-alpha–
mediated keratinocyte expression and release of matrix metalloproteinase 9: putative 117. Shanbhag SS, Hall L, Chodosh J, Saeed HN. Long-term outcomes of amniotic
mechanism of pathogenesis in Stevens–Johnson syndrome/toxic epidermal necrolysis. membrane treatment in acute Stevens-Johnson syndrome/toxic epidermal necrolysis.
J Invest Dermatol. (2022) 143:1023–1030.e7. doi: 10.1016/[Link].2022.11.024 Ocul Surf. (2020) 18:517–22. doi: 10.1016/[Link].2020.03.004
102. Kula T, Dezfulian MH, Wang CI, Abdelfattah NS, Hartman ZC, Wucherpfennig 118. Shanbhag SS, Rashad R, Chodosh J, Saeed HN. Long-term effect of a treatment
KW, et al. T-scan: a genome-wide method for the systematic discovery of T cell epitopes. protocol for acute ocular involvement in Stevens-Johnson syndrome/toxic epidermal
Cells. (2019) 178:1016–1028.e13. doi: 10.1016/[Link].2019.07.009 necrolysis. Am J Ophthalmol. (2019) 208:331–41. doi: 10.1016/[Link].2019.07.006
103. Burmeister DM, Smith SL, Muthumalaiappan K, Hill DM, Moffatt LT, Carlson 119. Mieno H, Ueta M, Kinoshita F, Teramukai S, Kinoshita S, Sotozono C.
DL, et al. An assessment of research priorities to dampen the pendulum swing of burn Corticosteroid pulse therapy for Stevens-Johnson syndrome and toxic epidermal
resuscitation. J Burn Care Res. (2021) 42:113–25. doi: 10.1093/jbcr/iraa214 necrolysis patients with acute ocular involvement. Am J Ophthalmol. (2021) 231:194–9.
doi: 10.1016/[Link].2021.06.015
104. Ro HS, Shin JY, Sabbagh MD, Roh SG, Chang SC, Lee NH. Effectiveness of
aspiration or deroofing for blister management in patients with burns: a prospective 120. Hall LN, Shanbhag SS, Rashad R, Chodosh J, Saeed HN. The effects of systemic
randomized controlled trial. Medicine. (2018) 97:e0563. doi: 10.1097/ cyclosporine in acute Stevens-Johnson syndrome/toxic epidermal necrolysis on ocular
MD.0000000000010563 disease. Ocul Surf. (2021) 19:128–32. doi: 10.1016/[Link].2020.05.003
105. Swain AH, Azadian BS, Wakeley CJ, Shakespeare PG. Management of blisters in 121. Ma DH, Tsai TY, Pan LY, Chen SY, Hsiao CH, Yeh LK, et al. Clinical aspects of
minor burns. Br Med J. (1987) 295:181. Stevens-Johnson syndrome/toxic epidermal necrolysis with severe ocular complications
in Taiwan. Front Med. (2021) 8:661891. doi: 10.3389/fmed.2021.800685
106. Bradley T, Brown RE, Kucan JO, Smoot EC 3rd, Hussmann J. Toxic epidermal
necrolysis: a review and report of the successful use of biobrane for early wound 122. Wang Y, Rao R, Jacobs DS, Saeed HN. Prosthetic replacement of the ocular surface
coverage. Ann Plast Surg. (1995) 35:124–32. doi: 10.1097/00000637-199508000-00002 ecosystem treatment for ocular surface disease in pediatric patients with Stevens-Johnson
syndrome. Am J Ophthalmol. (2019) 201:1–8. doi: 10.1016/[Link].2019.01.006
107. Marvin JA, Heimbach DM, Engrav LH, Harnar TJ. Improved treatment of the
Stevens-Johnson syndrome. Arch Surg. (1984) 119:601–5. doi: 10.1001/ 123. Itoi M, Ueta M, Ogino K, Sumi E, Imai K, Teramukai S, et al. Clinical trial to
archsurg.1984.01390170097019 evaluate the therapeutic benefits of limbal-supported contact lens wear for ocular
sequelae due to Stevens-Johnson syndrome/toxic epidermal necrolysis. Cont Lens
108. Young JB, Gondek SP, Troche M, Summitt JB, Rae L, Thayer WP, et al. The use of Anterior Eye. (2020) 43:535–42. doi: 10.1016/[Link].2020.05.007
porcine xenografts in patients with toxic epidermal necrolysis. Burns. (2016) 42:1728–33.
doi: 10.1016/[Link].2016.06.003 124. Toth G, Lukacs A, Schirra F, Sandor GL, Killik P, Maneschg OA, et al. Ophthalmic
aspects of Stevens-Johnson syndrome and toxic epidermal necrolysis: a narrative review.
109. Graves C, Faraklas I, Maniatis K, Panter E, La Force J, Aleem R, et al. Nutrition Ophthalmol Ther. (2023) 12:1795–811. doi: 10.1007/s40123-023-00725-w
in toxic epidermal necrolysis: a multicenter review. Nutr Clin Pract. (2016) 31:836–40.
doi: 10.1177/0884533616642746 125. Gulanikar A, Abrol A, Sagar S. Study of genital manifestations of Stevens Johnson
syndrome/toxic epidermal necrolysis. Indian J Sex Transm Dis AIDS. (2022) 43:39–42.
110. Knuth CM, Auger C, Jeschke MG. Burn-induced hypermetabolism and skeletal doi: 10.4103/ijstd.IJSTD_61_19
muscle dysfunction. Am J Physiol Cell Physiol. (2021) 321:C58–71. doi: 10.1152/
ajpcell.00106.2021 126. Den Adel MA, Hendrickson SE, Fuchs E. Stevens Johnson syndrome: past,
present, and future directions gynecologic manifestations and management in SJS/TEN.
111. Gus EI, Shahrokhi S, Jeschke MG. Anabolic and anticatabolic agents used in burn
Front Med. (2022) 9:874445. doi: 10.3389/fmed.2022.874445
care: what is known and what is yet to be learned. Burns. (2020) 46:19–32. doi: 10.1016/j.
burns.2018.03.009 127. Olteanu C, Shear NH, Chew HF, Hashimoto R, Alhusayen R, Whyte-Croasdaile S,
et al. Severe physical complications among survivors of Stevens-Johnson syndrome and
112. Hoffman M, Chansky PB, Bashyam AR, Boettler MA, Challa N, Dominguez A,
toxic epidermal necrolysis. Drug Saf. (2018) 41:277–84. doi: 10.1007/s40264-017-0608-0
et al. Long-term physical and psychological outcomes of Stevens-Johnson syndrome/
toxic epidermal necrolysis. JAMA Dermatol. (2021) 157:712–5. doi: 10.1001/ 128. Oplatek A, Brown K, Sen S, Halerz M, Supple K, Gamelli RL. Long-term follow-
jamadermatol.2021.1136 up of patients treated for toxic epidermal necrolysis. J Burn Care Res. (2006) 27:26–33.
doi: 10.1097/[Link].0000194268.01514.f8
113. Yoshikawa Y, Ueta M, Fukuoka H, Inatomi T, Yokota I, Teramukai S, et al.
Long-term progression of ocular surface disease in Stevens-Johnson syndrome 129. Sotozono C, Ueta M, Yokoi N. Severe dry eye with combined mechanisms is
and toxic epidermal necrolysis. Cornea. (2020) 39:745–53. doi: 10.1097/ involved in the ocular sequelae of SJS/TEN at the chronic stage. Invest Ophthalmol Vis
ICO.0000000000002263 Sci. (2018) 59:DES80–6. doi: 10.1167/iovs.18-24019
114. Gregory DG. Treatment of acute Stevens-Johnson syndrome and toxic epidermal 130. Lehloenya RJ, Esmail F, Christians SJ, Motsepe D, Todd G. Toxic epidermal
necrolysis using amniotic membrane: a review of 10 consecutive cases. Ophthalmology. necrolysis with failure of re-epithelialization. Could umbilical cord mesenchymal stem
(2011) 118:908–14. doi: 10.1016/[Link].2011.01.046 cell transplantation have a role? J Eur Acad Dermatol Venereol. (2013) 27:923–5. doi:
10.1111/j.1468-3083.2012.04667.x
115. Hsu M, Jayaram A, Verner R, Lin A, Bouchard C. Indications and outcomes of
amniotic membrane transplantation in the management of acute Stevens-Johnson 131. Habre M, Ortonne N, Colin A, Meningaud JP, Chosidow O, Wolkenstein P, et al.
syndrome and toxic epidermal necrolysis: a case-control study. Cornea. (2012) Facial scars following toxic epidermal necrolysis: role of adnexal involvement?
31:1394–402. doi: 10.1097/ICO.0b013e31823d02a8 Dermatology. (2016) 232:220–3. doi: 10.1159/000443164

Frontiers in Medicine 21 [Link]