Download Stevens-Johnson syndrome and toxic epidermal necrolysis: Clinical

Stevens-Johnson syndrome and toxic
epidermal necrolysis: Clinical
manifestations, pathogenesis, and
diagnosis
Author
Milton H Nirken, MD
Whitney A High, MD
Section Editor
N Franklin Adkinson, Jr,
MD
Moise L Levy, MD
Deputy Editor
Anna M Feldweg, MD
Last literature review for version 17.1: January 1, 2009 | This topic last updated:
February 12, 2009
INTRODUCTION AND TERMINOLOGY — Stevens-Johnson syndrome (SJS) and
toxic epidermal necrolysis (TEN) are severe idiosyncratic reactions, most commonly
triggered by medications, which are characterized by fever and mucocutaneous lesions
leading to necrosis and sloughing of the epidermis. SJS and TEN are distinguished
chiefly by severity and percentage of body surface involved. In this review, the term
"SJS/TEN" is used to refer collectively to SJS, TEN, and SJS/TEN overlap syndrome.
The clinical manifestations, pathogenesis, evaluation, and diagnosis of SJS/TEN will be
presented in this topic review. The treatment, prognosis, and long-term complications are
discussed separately. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis:
Management, prognosis, and long-term sequelae").
Stevens-Johnson syndrome — SJS is the less severe condition, in which skin sloughing is
limited to less than 10 percent of the body surface [1]. It is characterized by a prodrome
of malaise and fever, followed by the rapid onset of erythematous or purpuric macules
and plaques [1,2]. The skin lesions progress to epidermal necrosis and sloughing (show
picture 1A-1B). Mucosal membranes are affected in 92 to 100 percent of patients, usually
at two or more distinct sites (ocular, oral, and genital) [3].
Toxic epidermal necrolysis — Toxic epidermal necrolysis (TEN), or Lyell's syndrome,
involves sloughing of greater than 30 percent of the body surface area [1]. TEN also
begins with a prodrome of fever and malaise, although temperatures are typically higher
than those seen with SJS, often exceeding 39 degrees Celsius. Mucous membranes are
involved in nearly all cases [4]. The skin lesions are widely distributed erythematous
macules and patches, although about 50 percent of cases begin with diffuse erythema
[1,5,6]. In the early stages, skin pain may be prominent and out of proportion to clinical
findings [7]. The skin lesions progress to full-thickness epidermal necrosis leads. The
ultimate appearance of the skin has been likened to that of extensive thermal injury (show
picture 2A-2B) [5].
SJS/TEN overlap syndrome — SJS/TEN overlap syndrome describes patients with
involvement of greater than 10 percent, but less than 30 percent of body surface area [1].
There is a lack of consensus regarding whether SJS and TEN represent different
severities of the same condition or separate disorders, primarily because the pathogenesis
of these disorders is not well-understood. Likewise, there are differing opinions about the
degree to which SJS overlaps with severe erythema multiforme (EM), a condition with
similar presentation. The most widely employed criteria, which are presented herein,
propose a continuum between TEN and SJS, and distinguish SJS from severe EM (show
table 1) [1,3,8]. The nosologic controversies surrounding these disorders are discussed
below. (See "Nosologic controversies" below).
EPIDEMIOLOGY — Various estimates of the incidence of SJS, SJS/TEN overlap, and
TEN are reported in the literature, and the imprecise distinctions among these disorders
has impeded more definite figures. SJS is the more common disorder, outnumbering TEN
by as much as three cases to one [9]. Estimates of incidence for all three disorders range
from two to seven cases per million people per year [10-14].
SJS and TEN can occur in patients of any age. The mean age of patients with SJS has
varied from 25 to 47 years, depending upon the series [14-16]. Patients affected by TEN
tend to be slightly older, with a mean reported age between 46 and 63 years [13,14].
Women account for over 60 percent of cases [14].
ETIOLOGIES — Medications are the leading trigger of SJS and TEN in both adults and
children, although in children, infections are responsible for a relatively higher
percentage of cases of SJS.
In adults — In adults, medications cause 30 to 50 percent of cases of SJS and up to 80
percent of cases of TEN [1,7,8,17,18]. Infections are the next most common trigger of
adult SJS (up to 15 percent). In contrast, it is unusual for infections to trigger TEN in
adults [4,19,20]. Rare causes of SJS and TEN include vaccinations, systemic diseases,
chemical exposure, herbal medicines, and foods [8,21-23].
Medications — The following groups of agents are most commonly implicated (show
table 2) [14,24-26]:




Anti-gout agents (especially allopurinol)
Antibiotics (sulfonamides >> penicillins > cephalosporins)
Antipsychotics and anti-epileptics (including carbamazepine, dilantin,
lamotrigine, and phenobarbital)
Analgesics and non-steroidal anti-inflammatory agents (especially piroxicam)
A case control study published in the 1990s quantified the relative risk of SJS/TEN
corresponding with common medications (show table 3) [27]. A 2007 multinational study
from Europe and Israel indicated that allopurinol was the most common cause of SJS and
TEN in these areas [28]. Newer drugs that have been associated with SJS and TEN
include nevirapine, lamotrigine, sertraline, pantoprazole, and tramadol [26].
In children — Medications are the leading cause of SJS and TEN in children, as in adults.
However, infections, particularly Mycoplasma pneumonia, are associated with a greater
proportion of pediatric cases of SJS [29].
The medications most often implicated in pediatric SJS/TEN are sulfonamide
antimicrobials, phenobarbital, carbamazepine, lamotrigine, valproic acid, and
acetaminophen/paracetamol [30]. The combination of azithromycin and ibuprofen has
also been associated [31].
HISTORY AND CLINICAL PRESENTATION — Drug exposure commonly precedes
the onset of symptoms by one to three weeks (average 14 days) in medication-related
cases [32]. Reexposure may result in onset of symptoms in as little as 48 hours [33].
Signs and symptoms
Prodrome — SJS and TEN typically have a prodrome of fever and influenza-like
symptoms one to three days before the development of mucocutaneous lesions [34].
Fever is usually higher with TEN, and often exceeds 39 degrees Celsius [32]. Skin
tenderness, photophobia, and conjunctival itching or burning may be early symptoms in
both conditions.
The following signs and symptoms, when present early in the course of a drug reaction or
illness, should alert clinicians to the possibility of SJS/TEN [34]:








Confluent erythema (erythroderma)
Facial edema or central facial involvement
Skin pain
Palpable purpura
Skin necrosis
Blisters and/or epidermal detachment
Mucous membrane erosions and crusting
Swelling of tongue
Skin — The skin lesions typically begin as ill-defined erythematous macules with
purpuric centers, although about 50 percent of cases of TEN begin with diffuse erythema
[1,5,6]. In SJS, the lesions are often quite targetoid, while in TEN, the targets may be
more atypical and less well-demarcated. A burning sensation or other paresthesias may
be noted. In the early stages, skin pain can be prominent and out of proportion to clinical
findings, particularly in TEN [7,32]. Lesions are symmetrically distributed, and start
upon the face and thorax before spreading to other areas [7]. The scalp is typically
spared, and palms and soles are less often involved [35,36].
Vesicles and bullae then form, which spread laterally with pressure. The skin begins to
slough within days. Sloughing progresses rapidly for two to three days and then usually
stabilizes [37]. Fulminant cases of TEN have been described, in which nearly 100 percent
of the epidermis sloughed over a matter of hours [35,36].
Mucosa — Mucous membranes are involved in more than 90 percent of cases of
SJS/TEN [3]. Typically, at least two mucus membranes are affected, although this may
not always include the oral mucosa [34,38]. Painful crusts and erosions may occur upon
any mucosal surface [32,34].

Ophthalmologic - Conjunctival lesions have been reported in 85 percent of
patients [32,39]. Excessive tearing sometimes occurs from obstruction of the tear
punctae [34]. Ocular involvement may range from simple hyperemia and
congestion of vessels to scarring with the development of synechiae between the
eyelids and conjunctiva [7,39].

Urogenital - Urethritis may result in dysuria or even urinary retention [8].

Pulmonary - Pulmonary complications of TEN may include dyspnea, hypoxia,
bronchial hypersecretion, tracheobronchitis, pulmonary edema, bacterial
pneumonitis, and bronchiolitis obliterans [40,41].
Laboratory abnormalities — Hematologic abnormalities, particularly anemia and
lymphopenia, are common in TEN [7]. Eosinophilia is unusual, despite the strong
association of TEN with drug ingestion. Neutropenia is noted in about one-third of
patients, and is correlated with a poor prognosis [7,42]. Glucocorticoids can cause
demarginalization and mobilization of neutrophils into the circulation, and this must be
considered in patients who received these agents prior to testing, as this may obscure
neutropenia. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis:
Management, prognosis, and long-term sequelae", section on Prognosis).
Mild elevations in serum aminotransferase levels (two to three times normal) are present
in about one-half of patients with TEN, while overt hepatitis occurs in approximately 10
percent [32].
Time course — The time course of SJS/TEN, from prodrome to hospital discharge in the
absence of significant complications, is typically two to four weeks.
Reepithelialization — Reepithelialization may begin after several days, and typically
requires two to three weeks; corresponding to the usual duration of hospitalization [43].
Skin that remained attached during the acute process may peel gradually and nails may be
shed.
RISK FACTORS — Risk factors for SJS and TEN include HIV infection, genetic
factors, concomitant viral infections, underlying immunologic diseases, and possibly
physical factors.
HIV infection — Patients with HIV infection have been reported to be at three times
increased risk for SJS/TEN. The reasons for this susceptibility are not fully understood,
although exposure to multiple medications (including sulfonamide antibiotics), "slow
acetylation" status, immune dysregulation, and the presence of concomitant infections
may contribute [44-46].
A 40-fold increased risk for SJS/TEN due to trimethoprim-sulfamethoxazole specifically
has been reported in HIV-infected patients, as compared to the risk among the general
population taking this same medication [47]. Toxic hydroxylamine metabolites and
depleted systemic glutathione reserves have been implicated in this toxicity [48].
Genetic factors — Genetic factors associated with an increased risk of SJS/TEN include
the following:

Certain HLA-types (show table 4) [49-53]: Patients with HLA-B* 1502 are at
sufficiently increased risk for SJS/TEN due to carbamazepine and other aromatic
anticonvulsants (eg, phenytoin, phenobarbital) that the United States Food and
Drug Administration has suggested screening patients of Asian and South Asian
ancestry (in whom the prevalence of this allele is significant) if use of
carbamazepine is under consideration [54].

Lower N-acetylation capacity ("slow acetylators"), which may be congenital or
acquired (eg, with HIV infection): Patients with this condition may have
prolonged exposure to immunogenic or toxic drug metabolites [44].

Polymorphisms in the IL4 receptor gene, which are biologically linked to Th2
cytokine-driven inflammatory mediators [55].
Other factors

Malignancy may increase the risk of SJS and TEN, although data are conflicting
as to whether malignancy truly increases the risk, or is simply associated with
increased exposure to causative medications [7,56,57].

Higher doses and more rapid introduction of medications may increase the risk of
SJS or TEN. As examples, allopurinol doses below 200 mg/dL were associated
with a lower risk of SJS/TEN than higher doses [28]. Similarly, lamotrigine was
associated with high rates of severe skin reactions when it was initially introduced
[58]. Recommendations were subsequently made for gradual titration when
beginning therapy, and more recent studies suggest much lower rates of SJS/TEN
[59].

Coincidental viral infections or other coingestants [60]

Patients with systemic lupus erythematosus appear to experience higher rates of
SJS and TEN [61]

Physical stimuli, such as ultraviolet light or radiation therapy, may be co-factors
in some cases [56,62,63]
PATHOGENESIS — The pathologic mechanisms that induce skin damage in SJS/TEN
are incompletely understood. The shortened interval between a recurrent exposure and
the onset of symptoms is consistent with an immunologic process [32].
A promising line of investigation has implicated granulysin, a cytolytic protein produced
and secreted by cytotoxic T lymphocytes and natural killer (NK cells) [64]. Cells from
five patients with SJS or TEN were analyzed with gene expression profiling. Granulysin
was identified as the most highly expressed cytotoxic molecule. Both fluid and cells from
SJS/TEN patients' blisters demonstration cytotoxicity when incubated with keratinocytes,
and depletion of granulysin reduced the effect. Control fluid/cells from patients with
burns showed no such activity. The levels of granulysin in individual patient's blister
fluid correlated with the severity of disease. In addition, injection of granulysin from
patients' blisters into mouse skin caused dose-dependent blistering and necrosis.
A role for reactive drug metabolites has been supported by the finding that many patients
with SJS and TEN demonstrate altered metabolic capabilities, such as slow N-acetylation
[44,45,65]. This may result in prolonged exposure to toxic and/or immunogenic
metabolites in these individuals. (See "Genetic factors" above).
Other hypothesized mechanisms for SJS/TEN have involved mixed drug-induced and
immunologically-mediated phenomenon. Keratinocytes normally express the death
receptor, CD95 (fas). When fas interacts with its ligand (fas ligand), the affected cell
undergoes apoptosis, a highly-controlled process that eliminates unwanted cells without
creating an inflammatory reaction. Mass triggering of apoptosis among keratinocytes
may explain the pauci-inflammatory nature of the epidermal necrosis observed in
SJS/TEN. Serum levels of soluble fas ligand were reported to be elevated in 5 of 7
patients with early drug reactions who subsequently developed SJS/TEN, even before
skin detachment or mucosal lesions appeared [66]. In contrast, soluble fas ligand levels
were normal in a group of 32 control patients with less severe drug reactions. (See
"Histology" below).
Perforin, TNF-a, and granzyme B, which are involved in distinct non-apoptotic cell death
pathways, are also found in the high concentrations in the peripheral mononuclear cells
and blister fluid of SJS/TEN patients [67]. However, elevations in these mediators are not
specific to SJS/TEN.
NOSOLOGIC CONTROVERSIES — The categorization, or nosology, of SJS, TEN, and
severe EM, is an area of ongoing controversy that will only be resolved once the
pathophysiology of these disorders has been revealed. An understanding of the
controversy requires a brief historical review.
Erythema multiforme, the least severe of the disorders, was described by von Hebra in
1866 as acral (peripheral), targetoid, edematous papules and/or plaques without mucosal
involvement (show picture 3) [68]. It is associated with infections, particularly herpes
simplex virus [69].
Stevens-Johnson syndrome was subsequently described as a pediatric affliction by
Stevens and Johnson in 1922 [2]. These authors reported on two cases consisting of a
"generalized eruption with continued fever, inflamed buccal mucosa, and severe purulent
conjunctivitis." The cases were distinguished from EM (von Hebra) by the "character of
the lesions...the prolonged high fever and the terminal heavy crusting."
Two categories of EM were later suggested: erythema multiforme minor (von Hebra),
and a severe form, erythema multiforme major (EM major), which encompassed SJS
[70]. Subsequently, SJS came to be used synonymously with EM major, a view which is
still held by many dermatologists [6,71].
However, this categorization did not address cases with predominantly acral, targetoid
eruptions, characteristic of EM minor (von Hebra), but with mucosal involvement more
characteristic of EM major. To encompass this variant, it was proposed that EM major
and SJS be considered distinct conditions with the term EM being restricted to acral,
targetoid lesions, either with or without mucosal involvement, and the term SJS applied
to mucous membrane involvement and widespread vesicles arising upon erythematous
skin, without classic targetoid lesions [1,17]. Distinguishing the two conditions is also
consistent with observations about etiology, as there is a strong association between
herpes virus infections and EM, while SJS is more often associated with exogenous
agents (eg, drugs) [18]. While differing slightly in definitional characteristics of the
diseases, studies of the expression of IL-13 and other cytokines lends further support to
the notion that SJS and TEN are diseases akin to one another, but distinct from classic
erythema multiforme [72,73].
TEN was first described in 1948, with a small series appearing a decade later [5]. TEN
was distinguished by an acute, diffuse, erythematous rash followed by widespread fullthickness epidermal sloughing, and was initially believed to be distinct from SJS.
It was later proposed that SJS and TEN were varying degrees of the same process,
differing only in the extent of involvement [35,74]. However, this unifying concept has
not been universally accepted. Some have cited subtle histologic differences between SJS
and TEN [9]. In addition, one report demonstrated that serum from TEN patients was
directly cytotoxic to cultured keratinocytes, while serum from SJS patients was toxic only
in the presence of lymphocytes [75]. This observation supported the original hypothesis
that the conditions were different, with a toxic metabolite triggering TEN and an
immunologic cellular response mediating SJS [5].
Summary — Severe EM (EM major) and SJS are viewed by many experts as separate
entities, based on etiologic and clinical distinctions. In contrast, the concept that SJS and
TEN exist along a continuum of a single disease process appears well-supported by the
majority of evidence and is accepted by most, although not all.
EVALUATION AND DIAGNOSIS — SJS, TEN, and SJS/TEN overlap are clinical
diagnoses supported by compatible histologic findings. There are no universally-accepted
diagnostic criteria, and histology findings are neither specific nor diagnostic. Despite
these limitations, the diagnosis of SJS or TEN would be appropriate in a patient with:




A suggestive history of antecedent drug exposure or illness
A prodrome of acute-onset febrile illness and malaise
Erythematous macules, targetoid lesions, or diffuse erythema progressing to
vesicles and bullae
Necrosis and sloughing of the epidermis (of varying degrees)
Histology — Skin biopsy is useful in excluding or including many of the conditions in
the differential diagnosis. An appropriate sample may be obtained using a large (>4 mm)
punch biopsy or by deep shave biopsy ("saucerization") technique.
The earliest histologic finding in SJS is a perivascular mononuclear inflammatory
infiltrate comprised primarily of T-lymphocytes [76,77]. This infiltrate is not diagnostic,
and it may be seen in a wide variety of conditions, including a simple drug-induced
exanthem. A sparse infiltrate of lymphocytes develops at the dermoepidermal junction,
with lymphocytes clustered around dying basal keratinocytes ("satellitosis") [9]. As the
lesions progress, frank subepidermal vesiculation develops, with full thickness epidermal
necrosis.

Fully developed SJS is distinguished by full thickness epidermal detachment with
splitting above the basement membrane, minimal inflammatory infiltrate, and
normal immunofluorescence.

The histopathology of TEN is similar. In addition, abnormalities of the underlying
sweat ducts have been described in TEN, including lymphocytic infiltration, basal
cell hyperplasia, and necrosis [78].
Cultures — Appropriate cultures should be performed on blood, wounds, and mucosal
lesions to evaluate for the presence of staphylococcal species, in particular. In children,
serologies for Mycoplasma pneumoniae infection should also be obtained. (See
"Mycoplasma pneumoniae infection in children", section on Diagnosis).
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of SJS/TEN includes:

Erythema multiforme (See "Nosologic controversies" above)






Erythroderma and other erythematous drug eruptions
Acute generalized exanthematous pustulosis (AGEP) and other pustular drug
eruptions
Phototoxic eruptions
Toxic shock syndrome (TSS)
Staphylococcal scalded skin syndrome (SSSS) (in children)
Paraneoplastic pemphigus

Erythroderma and erythematous drug eruptions - Erythematous drug reactions are
commonplace. The generalized and symmetric maculopapular erythema of a drug
eruption can mimic early SJS/TEN. However, erythematous drug eruptions lack
mucosal involvement as well as the ill-defined but prominent skin pain of TEN.
Treatment of erythematous drug reactions includes withdrawal of possible
causative agents and supportive measures (eg, antihistamines for pruritus). (See
"Drug eruptions").

Pustular drug eruptions - Pustular drug reactions, including acute generalized
exanthematous pustulosis (AGEP), may also be severe and mimic early SJS/TEN
[79]. AGEP is an eruption consisting of non-follicularly centered pustules that
often begin on the neck and intertriginous areas. Most commonly, AGEP is
caused by beta-lactam antibiotics, occurring within a few days of ingestion. The
lesions are not associated with pain, and mucosal involvement is rare. The
pustules of AGEP may coalesce and slough, but this occurs during resolution of
the disorder, and is not present during the evolving phase of the disease.
Treatment of pustular drug reactions includes withdrawal and supportive
measures.

Phototoxic eruptions - Phototoxic eruptions are caused by direct interaction of a
chemical with sunlight to yield a byproduct toxic to the skin. The most common
phototoxic reactions to be confused with SJS/TEN are those that are due to oral
ingestants. As an example, fluoroquinolones may yield a phototoxic reaction,
which can lead to widespread epidermal sloughing. Important clues to the
presence of a phototoxic eruption include recent sun exposure, known phototoxic
qualities of certain medications, and locations of the lesions on sun-exposed areas.
When sloughing is marked, the patient with a severe phototoxic reaction is
managed in a burn unit, much like a patient with SJS/TEN. (See "Drug
eruptions").

Toxic shock syndrome - Toxic shock syndrome (TSS) is classically caused by
Staphylococcus aureus, although a similar disorder can be caused by toxinelaborating strains of Group A streptococci. Compared to SJS/TEN, TSS presents
with more prominent involvement of multiple organ systems.
TSS is caused by elaboration of specific bacterial toxin(s) from staphylococci or
streptococci that act as superantigens, non-specifically activating large numbers of T
lymphocytes [80]. These disorders are described briefly here and presented in detail
elsewhere. (See "Staphylococcal toxic shock syndrome" and see "Epidemiology, clinical
manifestations, and diagnosis of streptococcal toxic shock syndrome").
TSS develops acutely in healthy individuals, particularly young women, typically (but
not always) within days of menstruation or a surgical procedure.
Cutaneous manifestations may include a diffuse, red, macular rash resembling sunburn
that may involve the palms and soles. This eruption may be subtle or fleeting (show
picture 4). Petechiae, vesicles, and bullae may develop in severe cases. Desquamation
occurs one to two weeks after the onset of illness and chiefly affects the palms and soles
(show picture 5). Mucosal involvement in TSS includes hyperemia of the vaginal and
oropharyngeal mucosa and conjunctival-scleral suffusion and hemorrhage (show picture
6) [81].
Systemic signs and symptoms include fever, non-pitting edema of the face and hands,
diarrhea and vomiting, myalgias, hypotension, mental status changes, and multi-organ
failure. Early laboratory findings include elevations of creatinine phosphokinase, elevated
transaminases, and elevated creatinine. The diagnosis of TSS is based upon clinical
presentation, utilizing the CDC case definition (show table 5).

Staphylococcal scalded skin syndrome - Staphylococcal scalded skin syndrome
(SSSS), also known as Ritter disease, is caused by epidermolytic toxins produced
by certain strains of Staphylococci [82]. This toxin is distributed systemically and
results in dissolution of keratinocyte attachments in only the upper layer of the
epidermis (stratum granulosum). SSSS usually affects newborns and children
[83]. Adults are less commonly affected because improved renal function allows
for clearance of the toxins from the body, although adults with renal failure are
more susceptible [84]. (See "Vesiculobullous and pustular lesions in the
newborn").
SSSS presents with fever, irritability, and a generalized, erythematous, micromacular to
maculopapular rash (show picture 7 and show picture 8) [82-84]. The exfoliative phase is
heralded by perioral exudation and crusting with large radial fissures, likened to an
"unhappy clown," appearing around the mouth. However, mucosal membranes are not
involved. There is usually no history of drug exposure.
SSSS is distinguished clinically from SJS/TEN chiefly by its epidemiology and sparing
of mucous membranes. The diagnosis is supported by histologic examination, which
reveals sloughing of only the upper layers of the epidermis. Frozen section examination
of sloughing epidermis can often distinguish SSSS from TEN as histology in TEN will
reveal a subepidermal split with full thickness epidermal necrosis, while only partial
thickness epidermal sloughing and minimal keratinocyte necrosis will be noted in SSSS
[85,86].
Treatment of SSSS involves eradication using intravenous antibiotics [82]. (See
"Treatment of invasive methicillin-resistant Staphylococcus aureus infection in
children").

Paraneoplastic pemphigus — Paraneoplastic pemphigus (PNP) is a rare disorder
that can represent the initial presentation of a malignancy or occur in a patient
with a known neoplastic process, such as non-Hodgkin lymphoma in adults or
Castleman's disease in children. Patients may develop severe mucocutaneous
disease with ocular and oral blisters and skin lesions that resemble erythema
multiforme, bullous pemphigoid, or lichen planus. (See "Pemphigus", section on
Paraneoplastic pemphigus).
SUMMARY AND RECOMMENDATIONS

SJS, TEN, and SJS/TEN overlap syndrome represent disorders of uncertain
etiology that are characterized by desquamative lesions of the skin and mucous
membranes. Cases with less than 10 percent epidermal involvement are classified
as SJS; those with 30 percent or more involvement are classified as TEN; cases
with between 10 and 30 percent involvement are considered overlap SJS/TEN.
(See "Introduction and terminology" above).

TEN is almost invariably drug-induced, while SJS is associated with infections, as
well as drug administration. (See "Etiologies" above).

SJS and TEN begin with a prodrome of fever and influenza-like symptoms one to
three days before the development of mucocutaneous and skin lesions.
Characteristic vesicular and bullous skin lesions then appear and progress over
several days, followed by sloughing. There may be multiorgan involvement. In
the absence of complications, the disorder generally resolves sufficiently that the
patient can be discharged from the hospital in two to four weeks. (See "History
and clinical presentation" above).

Risk factors for SJS and TEN include HIV infection, genetic factors, concomitant
viral infections, underlying immunologic diseases, and possibly physical factors.
(See "Risk factors" above).

The diagnosis of SJS or TEN is clinical. Histologic findings on skin biopsy are
supportive, but not independently diagnostic. (See "Evaluation and diagnosis"
above).

The differential diagnosis includes erythema multiforme, other types of severe
medication reactions, severe reactions to bacterial toxins (eg, toxic shock
syndrome, staphylococcal scalded skin syndrome), and Kawasaki disease. (See
"Differential diagnosis" above).
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GRAPHICS
Stevens Johnson syndrome I
Stevens-Johnson syndrome-I
Reproduced with permission from: Fein, J, Hamann, K. Stevens-Johnson Syndrome. N
Engl J Med 2005; 352:1696. Copyright © 2005 Massachusetts Medical Society.
Stevens-Johnson Syndrome-II
Generalized eruption of lesions that initially had a target-like appearance but then became
confluent, brightly erythematous, and bullous. The patient had extensive mucous
membrane involvement and tracheobronchitis. Reproduced with permission from:
Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis. In: Color Atlas and
Synopsis of Clinical Dermatology: Common and Serious Diseases, 3rd edition,
Fitzpatrick, TB, Johnson, RA, Wolff, K, et al (Eds), McGraw-Hill, New York 1997.
Copyright © 1997 McGraw-Hill.
Toxic epidermal necrolysis I
Toxic epidermal necrolysis
Usually caused by drugs, toxic epidermal necrolysis begins with widespread erythema;
confluent vesicular and necrotic areas of the arm and trunk then lead to peeling away of
the skin. Underlying erythema is visible after peeling. Courtesy of Lee T Nesbitt, Jr. (The
Skin and Infection: A Color Atlas and Text, Sanders, CV, Nesbitt, LT Jr (Eds), Williams
& Wilkins, Baltimore, 1995.
Toxic epidermal necrolysis caused by a sulfonamide antibiotic
Generalized, macular eruption with some target-like lesions which rapidly developed
epidermal necrosis, bulla formation, and denuded, eroded areas. Reproduced with
permission from: Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis. In: Color
Atlas and Synopsis of Clinical Dermatology: Common and Serious Diseases, 3rd edition,
Fitzpatrick, TB, Johnson, RA, Wolff, K, et al (Eds), McGraw-Hill, New York 1997.
Copyright © 1997 McGraw-Hill.
Proposed classification of cases in the spectrum of severe bullous erythema multiforme
Bullous erythema multiforme
Detachment less than 10 percent of BSA plus
Typical targets or
Raised atypical targets
Stevens-Johnson syndrome
Detachment less than 10 percent of BSA plus
Widespread macules or
Flat atypical targets
Overlap Stevens-Johnson syndrome-Toxic epidermal necrolysis
Detachment between 10 and 30 percent of BSA plus
Widespread macules or
Flat atypical targets
Toxic epidermal necrolysis
With spots or without blisters
Detachment of greater than 30 percent of BSA plus
Widespread macules or
Flat atypical targets
Without spots
Detachment greater than 10 percent of BSA with large epidermal sheets and
Without any macules or targets
Adapted from Bastuji-Garin, S, Rzany, B, Stern, R, et al. Arch Dermatol 1993:129:92.
Drugs associated with Stevens-Johnson syndrome and TEN
More Frequently
Less Frequently
Allopurinol
Cephalosporin
Amithiozone (anti-tubuculosis agent) Diclofenac
Amoxicillin
Ethambutol
Ampicillin
Fenbufen
Barbituates
Fluoroquinolone
Carbamazepine
Ibuprofen
Cotrimoxazole
Ketoprofen
Hydantoins
Naproxen
Lamotrigine
Pantoprazole
Nevirapine
Rifampin
Phenylbutazone
Sertraline
Piroxicam
Sulindac
Sulfadiazine
Tenoxicam
Sulfadoxine
Thiabendazole
Sulfasalazine
Tiaprofenic acid
Trimethoprim-sulfamethoxazole
Tramadol
Vancomycin
Drugs are listed in alphabetical order within each column. Adapted and modified from:
Roujeau, JC, Stern, RS, N Engl J Med 1994; 331:1272.
Odds ratio from a case-control study of SJS/TEN
Medication/medication class
Odds ratio
Trimethoprim sulfamethoxazole & other sulfonamide antibiotics 172
Chlormezanone
62
Aminopenicillins
6.7
Quinolones
10
Cephalosporins
14
Carbamazepine
90
Phenobarbital
45
Phenytoin
53
Valproic acid
25
Oxicam & NSAIDs
72
Allopurinol
52
Corticosteroids
54
The odds ratio for exposure to specific medications in patients hospitalized for SJS/TEN
compared to patients hospitalized for other reasons. Adapted from: Roujeau, JC, Kelly,
JP, Naldi, L, et al. Medication use and the risk of Stevens-Johnson syndrome or toxic
epidermal necrolysis. N Engl J Med 1995; 333:1600.
HLA types & associated risk
Drug type yielding increased risk of SJS/TEN HLA type
Sulfonamides
HLA-A29, HLA-B12, HLA-DR7
Oxicam (an NSAID)
HLA-A2, HLA-B12
Carbamazepine
HLA-B*1502
Allopurinol
HLA-B*5801
Methazolamide (with ocular involvement)
HLA-B59
Erythema multiforme
Characteristic target lesions of the palm in erythema multiforme begin with a central
vesicle. Courtesy of Lee T Nesbitt, Jr. (The Skin and Infection: A Color Atlas and Text,
Sanders, CV, Nesbitt, LT Jr (Eds), Williams &Wilkins, Baltimore 1995.
Rash in staphylococcal TSS
Erythematous maculopapular eruption on the abdomen in a patient with staphylococcal
toxic shock syndrome (TSS). The erythroderm of TSS can be subtle and resemble a
sunburn. Courtesy of Charles V Sanders. The Skin and Infection: A Color Atlas and Text,
Sanders, CV, Nesbitt, LT Jr (Eds), Williams &Wilkins, Baltimore, 1995.
Toxic shock syndrome: desquamation
The epidermis is desquamating on the wrist and volar hand in a female with menstrual
TSS; 7 days previously, the skin was diffusely erythematous. Reproduced with
permission from: Toxic Shock Syndrome. In: Color Atlas and Synopsis of Clinical
Dermatology: Common and Serious Diseases, 3rd edition, Fitzpatrick, TB, Johnson, RA,
Wolff, K, et al (Eds), McGraw-Hill, New York 1997. Copyright ©1997 McGraw-Hill.
Conjunctivae in staphylococcal TSS
Conjunctival suffusion in a patient with staphylococcal toxic shock syndrome (TSS).
Courtesy of Charles V Sanders. The Skin and Infection: A Color Atlas and Text, Sanders,
CV, Nesbitt, LT Jr (Eds), Williams & Wilkins, Baltimore, 1995.
Case definition of toxic shock syndrome from the CDC*
Fever
T >38.9°C (102.0°F)
Hypotension
Systolic blood pressure 90 mmHg for adults or less than fifth percentile by age for
children <16 years of age; orthostatic drop in diastolic blood pressure 15 mmHg
Orthostatic syncope or dizziness
Rash
Diffuse macular erythroderma
Desquamation
1 to 2 weeks after onset of illness, particularly involving palms and soles
Multisystem involvement (3 or more of the following organ systems)
GI: Vomiting or diarrhea at onset of illness
Muscular: Severe myalgia or CPK elevation >2 times the normal upper limit
Mucous membranes: Vaginal, oropharyngeal, or conjunctival hyperemia
Renal: BUN or serum creatinine >2 times the normal upper limit, or pyuria (>5
WBC/hpf)
Hepatic: Bilirubin or transaminases >2 times the normal upper limit
Hematologic: Platelets <100,000/ L
Central nervous system: Disorientation or alterations in consciousness without focal
neurologic signs in the absence of fever and hypotension
Negative results on the following tests, if obtained
Blood, throat, or cerebrospinal fluid cultures for another pathogen (blood cultures may be
positive for Staphylococcus aureus)
Serologic tests for Rocky Mountain spotted fever, leptospirosis, or measles
CPK, creatine phosphokinase; BUN, blood urea nitrogen.*Criteria for a probable case
include a patient with fever >38.9°C, hypotension, diffuse erythroderm, desquamation
(unless the patient dies before desquammation can occur), and involvement of at least
three organ systems. A probable case, is a patient who is missing one of the
characteristics of the confirmed case definition.Data from CDC: Case definitions for
public health surveillance MMWR Morb Mortal Wkly Rep 1990; 39(RR-13):1. CDC:
Case definitions for infectious conditions under public health surveillance. MMWR Morb
Mortal Wkly Rep 1997; 46(RR-10):39.
Staphylococcal scalded-skin syndrome-I
The skin of this infant is diffusely erythematous; gentle pressure to the skin of the arm
has sheared off the epidermis revealing a moist red base. Reproduced with permission
from: Gram-Positive Infections. In: Color Atlas and Synopsis of Clinical Dermatology:
Common and Serious Diseases, 3rd edition, Fitzpatrick, TB, Johnson, RA, Wolff, K, et al
(Eds), McGraw-Hill, New York 1997. Copyright ©1997 McGraw-Hill.
Staphylococcal scalded-skin syndrome-II
In this infant, painful, tender, diffuse erythema was followed by generalized epidermal
sloughing. S. aureus had colonized the nares with perioral impetigo, the site of exotoxin
production. Reproduced with permission from: Toxic Shock Syndrome. In: Color Atlas
and Synopsis of Clinical Dermatology: Common and Serious Diseases, 3rd edition,
Fitzpatrick, TB, Johnson, RA, Wolff, K, et al (Eds), McGraw-Hill, New York 1997.
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