US Pharm. 2013;38(7):69-79.
ABSTRACT: Stevens-Johnson syndrome (SJS) is a
rare, life-threatening mucocutaneous reaction that is often
drug-induced. SJS and toxic epidermal necrolysis (TEN) are considered to
be the same condition on two ends of a spectrum, differing only by the
extent of epidermal detachment. Despite reports of more than 100 drugs
being taken in patients who develop SJS/TEN, a few classes such as
antibiotics and anticonvulsants are thought to carry the highest risk.
Genetic susceptibility due to polymorphisms of the human leukocyte
antigen (HLA) gene may influence the development of SJS/TEN. There is
conflicting evidence on the benefit of treatment of SJS/TEN with
immunomodulating therapies. Although SJS is rare, pharmacists need to be
prepared to identify and manage the acute and long-term effects of this
Cutaneous (skin) reactions account for a large portion of
drug-induced adverse effects. These reactions can range from a mild
penicillin-induced rash to life-threatening conditions involving both
the skin and mucous membranes, progressing to further organ involvement.
One example of a life-threatening mucocutaneous condition is
Stevens-Johnson syndrome (SJS). With the broad spectrum of potential
severity, it is important for clinicians to be able to recognize the
differences between cutaneous reactions, identify potential causative
agents, and initiate therapy if indicated. The early recognition of
severe cutaneous reactions is especially important to reduce fatal
SJS is a mucocutaneous immunologic reaction that is often
drug-induced and can result in long-term sequelae and mortality. The
incidence of SJS is estimated at 1 to 6 cases per million person-years.1
SJS itself was first described in 1922 with the publication of a case
report involving two young boys. The authors described the presence of
extensive cutaneous eruptions with severe mucosal and ocular
involvement, and stated that the condition was “unlike anything
previously observed.”2 Other than case reports, most current knowledge of SJS comes from studies conducted in other countries, especially in Europe.
In 1956, a dermatologist named Alan Lyell described a mucocutaneous condition similar to but more severe than SJS, toxic epidermal necrolysis (TEN) or Lyell’s syndrome.3
Both SJS and TEN are characterized by epidermal detachment and erosive
mucosal lesions. After years of debate, SJS and TEN are now considered
to be the same condition but differ in severity and cutaneous
involvement.4 The percentage of epidermal detachment is the
primary differentiating factor between SJS and TEN, with SJS presenting
with <10% epidermal detachment and TEN presenting with >30%.5
Both SJS and TEN are debatably included in the same
spectrum as erythema multiforme (EM). This mucocutaneous condition has
similarities in clinical presentation to SJS/TEN but has some distinct
differences. TABLE 1 outlines some of the differences in the categorization of EM, SJS, and TEN.5,6
Disputes regarding the categorization of these conditions into the same
spectrum revolve around the marked differences between SJS/TEN and EM
in the common etiology and rate of recurrence. The most common cause of
EM is the herpes simplex virus (HSV) infection, which contrasts with the
medication-induced reaction in SJS/TEN.4,6 Due to the viral
etiology in EM, recurrence can occur in 30% of patients; for SJS/TEN,
recurrence is rare unless a patient is reexposed to the causative
The appearance of the cutaneous lesions is another
differentiating feature distinguishing EM from SJS/TEN. EM lesions have a
target appearance with concentric rings of color and a dark center,
while SJS/TEN lesions are irregularly shaped with a dark center that
progressively coalesces.4-6 SJS/TEN patients normally present
with flat macules (spots), which are absent in EM. Mortality is rarely
seen in EM, while mortality in patients with SJS is about 10%.4-6
The typical clinical course of SJS begins within 8 weeks
(usually 4 to 30 days) following the first exposure to the causative
agent. Only in very rare cases where an inadvertent rechallenge occurs
do symptoms appear within hours. Patients who develop SJS/TEN can have
varying levels of cutaneous, extracutaneous, and mucous membrane
manifestations (TABLE 2).4,7-9 About one-third of
patients will present with nonspecific symptoms (e.g., fever, headache,
sore throat, cough, malaise) and/or burning of the eyes followed by the
appearance of mucocutaneous lesions of the eyes, mouth, genitals, and
urinary tract in 1 to 3 days.4 Another third of patients will present with mucous membrane lesions (FIGURE 1),
while the remainder of patients present with a diffuse rash. Following
the appearance of the diffuse rash, the lesions convert to flaccid
blisters, which spread with pressure and break easily, leading to
extensive epidermal detachment. The detachment of the epidermis can be
effortless, normally as a result of frictional trauma and on pressure
points. A positive Nikolsky’s sign, which is the dislodgment of the
epidermis with lateral pressure, may be present in these patients.4,7
Almost all patients with mucosal involvement develop
painful hemorrhagic erosions coated by grayish white pseudo-membranes
and crusts in the oral cavity and on the border of the lips.4
Involvement of the gastrointestinal (GI) tract can also affect the
esophagus, small bowel, and colon, which may impact enteral nutrition
and the absorption of oral medications.8 Ocular involvement
is frequent, reported in up to 80% of patients, and can involve severe
conjunctivitis and blepharitis along with visual disturbances and
photophobia.4 Eyes can appear swollen, erythematous, and crusted as a result of ocular discharge.4, 9
Involvement of the respiratory tract epithelium may occur leading to
hypoxemia, hypocapnia, and acid-base disturbances potentially requiring
the need for mechanical ventilation.9 Patients who develop
respiratory epithelium involvement have a higher risk of mortality.
About 20% of TEN patients will develop epithelium involvement of the
trachea and bronchi.9
Septicemia is another serious complication and is the most
common cause of death in SJS/TEN. Normally, the epithelium provides a
natural barrier to the systemic invasion of bacteria, but this barrier
is compromised as large areas of the epidermis become detached.
Extensive detachment can result in the collection of intravascular fluid
in nontraditional body areas such as the peritoneal or pleural
cavities, also known as third spacing of intravascular fluid and protein loss; this may lead to hypotension and possible organ dysfunction.8,9
The effects of SJS continue beyond the healing of the
cutaneous lesions to include long-term complications such as vision
loss, severe dry eye syndrome, GI/gynecological strictures, and nail
disfigurement.4,7-9 Even though the cutaneous lesions rarely
scar the skin, patients can exhibit hyper- and hypo-pigmentation of the
affected areas.9 Low severity or lack of acute ocular symptoms is not predictive of the presence or absence of subsequent ocular sequelae.7
Survivors of this condition may display symptoms of posttraumatic
stress disorder (PTSD) and have a fear of syndrome reoccurrence with
exposure to a variety of medications.
Pathophysiology and Genetics
The specific pathophysiology of SJS and TEN is not well
defined at this time. There are several theories as to the key
immunologic players in their development, along with continued debate
over whether it’s the parent drug or a metabolite that results in immune
cell activation. The rare and seemingly random occurrence of SJS/TEN
cannot be explained by medication exposure alone. Research into genetic
susceptibilities has begun to elucidate the potential reasons why some
individuals develop such a severe mucocutaneous reaction while others
remain unaffected. Studies have shown that the presence of specific
human leukocyte antigen (HLA) genotypes, which is a human version of the
major histocompatibility complex (MHC), are associated with an
increased risk of SJS/TEN when individuals are exposed to specific
Recent studies have identified a relationship between
HLA-B*1502 and the development of SJS/TEN in people given carbamazepine
who were of Southeast Asian descent (e.g., Han Chinese, Malaysian).11
The presence of HLA-B*1502 in the Han Chinese confers a 7.7% predictive
value that a patient could develop carbamazepine-induced SJS/TEN,
whereas the absence of this allele has a negative predictive value of
100%.11 This same increase in susceptibility was not demonstrated in European populations.11
Interestingly, the majority of patients in the European study who were
positive for HLA-B*1502 and developed carbamazepine-induced SJS/TEN were
of Southeast Asian descent.11,12 This ethnic selectivity may
be explained by the fact that Europeans have a low prevalence of this
particular HLA allele, 0.1%, compared to individuals with Southeast
Asian ancestry (4.8%-12.8%), making the numbers needed to detect a
statistically significant difference difficult to obtain.11 As a result, genetic testing for HLA-B*1502 is only recommended in patients of Southeast Asian descent.
HLA-B*5801 is another allele that has demonstrated a
predictive relationship with a specific medication, allopurinol, and the
development of SJS/TEN. In one study, all 51 patients who developed
allopurinol-induced SJS/TEN were positive for HLA-B*5801 compared to
only 15% (20/135) of allopurinol-tolerant patients.13 In
Taiwan, the allopurinol labeling was recently updated to recommend
genetic screening of patients prior to initiation of therapy.14
Currently, there is no FDA recommendation to test for HLA-B*5801 prior
to therapy. Different from HLA-B*1502, this allele is equally
distributed among ethnic groups, making genetic testing less practical.13
The development of the cutaneous lesions and epidermal
necrosis are thought to occur as a result of massive apoptosis of
keratinocytes. This is suspected to be a cell-mediated cytotoxic
reaction. Studies have confirmed the presence of various cytotoxic
cells, including natural killer T cells (NK) and drug-specific CD8+ T
lymphocytes, within early cutaneous lesions.10 These
cytotoxic cells are thought to lead to the amplification and release of
cytokines, such as granulysin, perforin, and granzyme B, which likely
play a separate role in apoptosis (FIGURE 2).4,10
Original theories proposed the interaction between Fas and
Fas ligand (FasL), a member of the tumor necrosis factor (TNF) family
found on the surface of activated T cells, as the main differentiating
factor that leads to the extensive apoptosis of keratinocytes, cells of
the epidermis, and the epidermal detachment not seen in other
drug-mediated hypersensitivity reactions.8,10 The binding of
FasL to Fas is known to induce activation of caspases, which are
proteases that mediate apoptotic cell death, necrosis, and inflammation.4,10
This theory was challenged when recent studies identified elevated
concentrations of granulysin in the blister fluid of patients with
SJS/TEN.15 Unlike granulysin, the concentrations of granzyme
B, perforin, and soluble Fas ligand (sFasL) in the blister fluid were
insufficient to produce distinct cytotoxicity.15
Interestingly enough, the concentration levels of granulysin identified
in the blisters directly correlated with the clinical severity of the
symptoms; SJS lesions contained lower concentrations of granulysin
compared to TEN lesions, which could explain the differences of clinical
severity in these pathologically identical conditions.15
This relationship was further explored when granulysin was injected into
mice and the clinical features of SJS/TEN, blistering and considerable
epidermal and dermal necrosis, soon developed.15 Granulysin
has a direct apoptotic effect on keratinocytes and is now thought to be a
key mediator in the apoptosis of keratinocytes.7,10
Up to 60% of cases of SJS can demonstrate causality to a medication exposure, but other factors including infection (e.g., Mycoplasma pneumonia) have been implicated in the development of this mucocutaneous condition, and up to 20% of cases remain idiopathic.4
More than 100 medications have been identified as potential causative
agents of SJS/TEN. Even though some drugs have been implicated in case
reports, not all of these agents have demonstrated a strong association
with the development of SJS (TABLE 3).4,16,17 In two large European case-control studies, fewer than a dozen medications accounted for half of the analyzed SJS/TEN cases.16,17
Some of the most notorious medications associated with the development
of SJS/TEN include sulfonamide antibiotics, antiepileptics
(carbamazepine, phenytoin, lamotrigine, phenobarbital), allopurinol,
nevirapine, and certain oxicam nonsteroidal anti-inflammatory drugs
(NSAIDs; e.g., meloxicam, piroxicam).16 One important
distinction to note is that aspirin, unlike other NSAIDs, has not been
associated with the development of SJS/TEN.
The presence of certain conditions, such as HIV, collagen vascular disease, and cancer can increase the risk of developing SJS.4 This is thought to be due to abnormalities of the immune system as a result of these conditions.
Current evidence is limited as to how significant the risk
of cross-reaction is between structurally similar medications.
Avoidance of these agents may not be a viable option in certain medical
conditions. Seizure disorders can be particularly challenging due to
structural similarities of several of the commonly used antiepileptics.
Treatment with levetiracetam may be a viable option because of a lack of
structural similarity with the high-risk anticonvulsants and with no
strong association to the development of SJS/TEN. In a study by
Locharernkul et al, some patients who developed either carbamazepine- or
phenytoin-induced SJS were noted to have been exposed, and demonstrated
tolerance, to other antiepileptics (phenytoin, phenobarbital, valproic
acid, carbamazepine, and/or lamotrigine).18 Nine out of 10
patients with phenytoin- or carbamazepine-induced SJS/TEN in this study
were at one point treated with valproic acid without incidence. These
observational findings suggest that the risk of cross-reactivity may not
be as significant as once thought, but more research is needed to
confirm these findings.
Treatment and Management
The pharmacist can be an asset in the acute- and long-term
management of SJS. Outpatient pharmacists are encouraged to emphasize
the importance of reporting new rash symptoms in patients who are
recently started on medications more commonly associated with SJS.
In the acute setting, prompt identification and removal of
the highly suspected agent is vital. It is important to gather a
detailed medication history in order to identify the most likely
causative agent. The knee-jerk reaction to discontinue all of the
patient’s medications is not appropriate and can complicate the clinical
course if chronic conditions are not adequately treated. Each
medication’s duration of therapy is important in implicating or
excluding drugs most likely to be involved; the history should focus on
those medications that were initiated within the last 8 weeks.4
If a causative agent is identified, rechallenge with that medication is
not recommended, and if unintentionally done may cause a rapid
recurrence of symptoms. Patients should be evaluated for future anxiety
and potential PTSD symptoms when they are initiated on new medications.
Prompt initiation of appropriate treatment can potentially
reduce the morbidity and mortality associated with SJS. Supportive
care, similar to that provided to burn victims, is a vital component in
the acute management of patients with SJS. Patients will commonly have
fluid and electrolyte abnormalities that require careful monitoring; a
recommended equation for fluid replacement is 0.7 mL/kg per percentage
of body surface area (BSA) affected.9 Fluid requirements for
SJS patients are normally 66% to 75% of those required in burn patients
with the same extent of BSA involved. To prevent hypoperfusion of the
kidneys, urine output should be maintained at 50 to 80 mL/h.7
Nonstick dressings can be placed on denuded areas of the body, with or
without a saturated anti-infective, such as 0.5% silver nitrate.19
Topical anti-infectives with a sulfa moiety (e.g., silver sulfadiazine)
should be avoided, especially if the causative agent is a sulfa
Mouth care with disinfecting mouthwashes (chlorhexidine)
and mild ointments (white petroleum) is essential in managing the
mucosal lesions of the oral cavity and lips.9,19 Every
patient, whether acute ocular involvement is apparent or not, should
have his or her eyes evaluated, preferably by an ophthalmologist.9
Treatment can include prophylactic ophthalmic antibiotics (e.g.,
bacitracin or a fluoroquinolone), preservative-free emollients,
antiseptic eye drops, and/or vitamin A. Recent evidence suggests that
the use of ophthalmic topical steroids (fluorometholone ointment 0.1%
every 1-2 hours for about 1-2 weeks) and amniotic membranes may help to
preserve visual acuity and protect against scarring.20
Routine use of oral or parenteral prophylactic antibiotics is not
recommended, although patients should frequently be monitored for the
signs and symptoms of an infection and sepsis. Wound debridement is not
always necessary because, unlike in burn victims, the epidermis can
reepithelialize if it is maintained in place.7 Removal of the
activated immune cells though plasmapheresis and hemodialysis has
demonstrated mixed results in studies and is currently not considered
the standard of care.7,21,22
Intravenous immunoglobulin (IVIG) and corticosteroids are
two therapies thought to improve clinical outcomes when used in addition
to supportive care. The evidence to support the use of either IVIG or
corticosteroids is conflicting and complicated by a wide variation in
dosing and duration of therapy (TABLE 4).7-9,19,21-23 Whether to provide patients with high-dose pulse therapy or low-dose extended therapy is still being investigated.21
Cyclosporine is another immunomodulating therapy that has been investigated with varying results.9,23
There is currently no consensus as to what is the best medication
regimen to reduce the clinical severity, complications, and occurrence
of sequelae. If immunomodulating therapy is to be utilized, it should be
initiated as soon as the diagnosis of SJS/TEN is determined. Currently,
there are no prospective, randomized, placebo-controlled trials
available to confirm whether either therapy reduces mortality or
long-term sequelae. When data for 281 patients from the EuroSCAR study
were retrospectively evaluated, no difference was found in mortality
between IVIG and/or corticosteroids when compared to supportive care
SJS is a life-threatening mucocutaneous reaction that is
commonly medication induced. Symptoms can be cutaneous, extracutaneous,
or involve the mucous membrane and lead to further body system
involvement if not addressed. Once the acute manifestations of the
condition have healed, patients can experience long-term sequelae and
psychological issues. Early identification and discontinuation of the
causative agent are important. Currently there is no consensus on the
use of various immunomodulating therapies for acute treatment of SJS.
Future studies will hopefully address the ambiguous data that are
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