Toxic Epidermal Necrolysis

and Steven–Johnson Syndrome:

A Comprehensive Review

Olivia A. Charlton,1,2 Victoria Harris,3 Kevin Phan,4

Erin Mewton,1 Chris Jackson,2,5 and Alan Cooper1,2
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1
Department of Dermatology, Royal North Shore Hospital, Sydney, Australia.
2
Northern Clinical School, University of Sydney, Sydney, Australia.
3
Department of Dermatology, Prince of Wales Hospital, Sydney, Australia.
4
Department of Dermatology, Liverpool Hospital, Sydney, Australia.
5
Kolling Institute of Medical Research, Sydney, Australia.

Significance: Toxic epidermal necrolysis (TEN) and Steven–Johnson syn-

drome (SJS) are potentially fatal acute mucocutaneous vesiculobullous disor-
ders. Evidence to date suggests that outcomes for patients with both TEN and
SJS are largely dependent on stopping the causative agent, followed by sup-
portive care and appropriate wound management in a specialized burns unit.
These are life-threatening conditions characterized by widespread full-
thickness cutaneous and mucosal necrosis. This article outlines the approach
Olivia A. Charlton, BAS, MBBS, MPH
to holistic management of such patients, in a specialized unit, highlighting
various practical aspects of wound care to prevent complications such as in- Submitted for publication March 4, 2019.
Accepted in revised form September 21, 2019.
fection, mucosal and adhesions, and ocular scaring.
*Correspondence: Lotus Dermatology, Level 5
Recent Advances: There is improved understanding of pain and morbidity Hunter Mall Chambers, 175 Scott St., Newcastle,
with regard to the type and frequency of dressing changes. More modern NSW 2300, Australia
(e-mail: oacharlton@gmail.com).
dressings, such as nanocrystalline, are currently favored as they may be kept
in situ for longer periods. The most recent evidence on systemic agents, such
as corticosteroids and cyclosporine, and novel treatments, are also discussed.
Critical Issues: Following cessation of the culprit trigger, management in a
specialized burns unit is the most important management step. It is now
understood that a multidisciplinary team is essential in the care of these pa-
tients. Following admission of such patients, dermatology, ear, nose, and
throat surgery, ophthalmology, urology, colorectal surgery, and gynecology
should all be consulted to prevent disease sequelae.
Future Directions: Looking forward, research is aimed at achieving prospective
data on the efficacy of systemic immunomodulating agents and dressing types.
Tertiary centers with burns units should develop policies for such patients to
ensure that the relevant teams are consulted promptly to avoid mucocutane-
ous complications.

Keywords: toxic epidermal necrolysis, Steve–Johnson syndrome, drug reaction

SCOPE AND SIGNIFICANCE tiated by certain drugs and their me-

Toxic epidermal necrolysis (TEN)
and Steven–Johnson syndrome (SJS)
are rare and life-threatening mucocu-
taneous conditions caused by immune
system activation most commonly ini-
tabolites. They are characterized by
widespread keratinocyte death re-
sulting in full-thickness denudation of
the skin and mucosa, which leaves the
patient highly susceptible to sepsis

ADVANCES IN WOUND CARE, VOLUME 00, NUMBER 00

Copyright ª 2019 by Mary Ann Liebert, Inc. DOI: 10.1089/wound.2019.0977
j 1
 2 CHARLTON ET AL.
with a mortality rate of 30%.1 Here we summarize
the evidence on management of the SJS/TEN wound
and various oral treatments.
TRANSLATIONAL RELEVANCE
This review highlights various approaches de-
rived from interdisciplinary collaboration between
clinicians and researchers. Understanding the
TEN/SJS wound and potential complications has
allowed the proposition of novel dressings and
systemic treatments, which are discussed.
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CLINICAL RELEVANCE
There remains controversy around the nursing
and medical treatment of these patients, including
the role of corticosteroids, intravenous immuno-
globulin (IVIG), and other experimental treatments.
Based on the current speculation about the patho-
genesis of TEN/SJS, numerous treatments have
been proposed for their anti-inflammatory and im-
munomodulatory effects. Here we discuss the details
of practical approaches to nursing care in a special-
ized unit and the role of various systemic agents.
BACKGROUND
TEN and SJS are considered a disease contin-
uum, distinguished largely by their severity, as
determined by the percentage of body surface area
(BSA) affected by erosive blistering. Here we use
the term TEN/SJS to refer to TEN, SJS, and TEN/
SJS overlap. The more severe presentation TEN is
always initiated by drugs, but the milder presen-
tation SJS can often by caused by infectious agents.
The mainstay of treatment of TEN/SJS is early
identification and cessation of the culprit trigger
and subsequent supportive care in a specialized
burns intensive care unit (ICU) or a similar high-
dependency unit. The exact mechanism of the dis-
ease is still not fully understood and there is little
convincing evidence for the efficacy of systemic
treatment. In addition, the rarity of the disease has
meant randomized control trials are difficult to
conduct. Recently, immunotherapy for melanoma
and lymphoma patients has been implicated in
cases of TEN.2,3
EPIDEMIOLOGY
TEN/SJS are rare, with reports ranging from
two to seven cases per million people per year.4–10
SJS, the less severe form, is three times more
common than TEN. Both are more common in wo-
men than men, and people of all ages are affected.11
Patients with a malignancy, particularly hemato-
logic cancers,12 and human immunodeficiency vi-
rus (HIV) are also at increased risk of SJS/TEN.8
The mortality rate for TEN is 50% and 10% for SJS,
with a combined rate of 30%. Increased age (more
than 70) and comorbidities are associated with
greater mortality.8
Genome-wide studies have identified popula-
tions at increased risk of TEN/SJS, for example,
the HLA-B 15:02 allele confers increased risk in the
Han Chinese population in the context of carba-
mazepine use.13 Furthermore the HLA-B 58:01
allele has been linked with allopurinol-induced
TEN/SJS in European and Asian populations.14
PATHOGENESIS
Medications are the most common trigger for
TEN/SJS and will usually trigger disease within 8
weeks in both adults and children; however, the
typical exposure period is 4 days to 4 weeks. A his-
tory of tolerated use of a medication makes it less
likely as a trigger. Common medication triggers in-
clude nonsteroidal anti-inflammatories, allopurinol,
anticonvulsants such as lamotrigine, phenytoin, and
carbamazepine, antibacterial sulfonamides, and the
antiretroviral nevirapine.15 Other less strongly as-
sociated medications include antibiotics such as
doxycycline, ciprofloxacin, and amoxicillin, and
there is a suspected association with other agents
such as pantoprazole, glucocorticoids, and terbina-
fine to name a few.15 Targeted immunotherapy and
more conventional cancer medications have also
been implicated in TEN/SJS cases, such as vemur-
afenib, ipilimumab, pembrolizumab, nivoliumab,16
thalidomide, and tamoxifen.17
Mycoplasma pneumoniae infection is the second-
most common trigger of SJS, more so in the pedi-
atric population. However, in more than a third of
cases, a trigger is not found.18 Other triggers have
been reported such as herbal medicine,19,20 vacci-
nations,21,22 systemic diseases, and contrast agents,
however, whether such cases were in fact caused by
these agents is not clear.
The pathogenesis of TEN/SJS is incompletely
understood. It is considered a T cell-mediated, type
IV hypersensitivity response.23 It is postulated
that the reaction is initiated by an immune re-
sponse, in which an antigenic drug/host tissue
complex is made. Following this, there are various
theories about events leading to stimulation of
T cells, such as the hapten/prohapten theory, al-
tered peptide theory, drug immune receptor theory,
and an altered T cell receptor repertoire theory.20
Studies assessing the immunophenotype of
blister fluid reinforce it as a cell-mediated cytotoxic
 TOXIC EPIDERMAL NECROLYSIS AND STEVEN–JOHNSON SYNDROME
reaction against keratinocytes, resulting in wide-
spread apoptosis.24 Epidermal necrosis is under-
stood as the result of a cumulative effect of risks,
T cell clonotypes, HLA alleles, drug structure, and
drug metabolism.20 The proposed mechanisms can
be classified as intrinsic and extrinsic. Intrinsic
refers to the production of toxic metabolites by
keratinocytes, which then produce reactive oxygen
species and ultimately lead to the production of
TNF (tumor necrosis factor) alpha, causing further
damage. The extrinsic pathway includes cytotoxic
lymphocytes, monocytes, granulysin, perforin,
granzyme, and Fas/Fas ligand interactions.20
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In the hapten/prohapten theory, it is the me-
tabolite not the drug that is antigenic. The drug is
metabolized to form a hapten, which then stimu-
lates the immune system. Carrier proteins then
bind neoantigens, which are presented via antigen-
presenting cells, to T cells.20 In the altered peptide
model, the causative drug binds to a specific HLA,
which then forms a complex, before the binding of
other peptides. Thus, the display to T cell receptors
is altered and a different T cell may be triggered.25
In the pharmacological interaction theory, the
drug itself binds T cell receptors, resulting in the
activation of specific T cells. Ko et al. highlighted
that drugs triggering TEN/SJS have the capacity to
directly kill keratinocytes by binding the T cell
receptor and MHC class I, ultimately resulting in
massive clonal expansion of cytotoxic T cells, and
indirectly through dispersement of toxic soluble
mediators such as granulysin, a cytolytic protein.26
The final theory postulated relates to an altered
T cell receptor repertoire, where the drug binds a
TCR and thus alters its structure.27
More recently, IL-15 is thought to play a central
role, expressed by both immune and nonimmune
cells, it activates NK cells, CD8+ cells, dendritic
cells, and macrophages. IL-15 signals through the
Figure 1. Widespread epidermal detachment with exposed dermis, affecting >30% of the total body surface area, consistent with a diagnosis of TEN. (a)
Upper limb. (b) Torso. TEN, toxic epidermal necrolysis.
3
JAK-STAT pathway and then has downstream ef-
fects on the PI3K/AKT/mTOR pathway responsible
for the IL-15-mediated effect on NK and CD8+
cells.28 It has been demonstrated that cytotoxic T
cells target the drug rather than its metabolites,
are drug specific, and HLA class I restricted.29,30
Mediators of nonapoptotic cell death pathways
involving Fas-ligand, TNF-alpha, granzyme B, and
perforin have been documented in high concen-
trations in blister fluid and mononuclear cells.31,32
CLINICAL FEATURES
The clinical manifestations of TEN/SJS include
a prodrome of fever and malaise for several days,
followed by a rapidly progressing symmetric mac-
ular exanthem with mucosal involvement. Lesions
are initially ill-defined erythematous macules,
with purpuric centers that coalesce. Atypical le-
sions may appear targetoid. The skin is painful and
out of proportion with the clinical appearance. The
characteristic features then evolve within days;
blistering and detachment of the epidermis with
light pressure (known as the Nikolsky sign).33 The
widespread shedding results in exposed and in-
flamed dermis that is very painful for the patient.
The lesional skin is similar to a large wound as
there has been loss of the epidermis with subse-
quent exposed dermis, with considerable fluid loss
and risk of infection (Fig. 1).
Defining disease as SJS or TEN can be difficult
in areas with spotty lesions. In SJS, <10% of BSA is
affected by skin detachment, 10–30% is an overlap
area between SJS and TEN, and >30% is defined as
TEN (Figs. 2 and 3).34
The severity of illness score for toxic epidermal
necrolysis (SCORTEN), first proposed in 2000,30 is
used in the determination of severity, as deter-
mined partially by the degree of skin detachment.
 4 CHARLTON ET AL.

Figure 2. TEN affecting mucosal sites. (a) Penis, (b) mouth, and (c) eyes.
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Others factors such as age (>40), malignancy,
tachycardia (>120 bpm), serum glucose (> 14 mM),
serum bicarbonate (<20 mM), and serum urea
(>10 mM) also contribute to the final score repre-
sentative of the severity of illness. The SCORTEN
is highly predictive of mortality.1 Other severity of
illness scores exist, such as the modified APACHE
(Acute Physiology and Chronic Health Evaluation)
II and ICNARC (Intensive Care National Audit &
Research Center) score. However, an ICU-based
study in the United Kingdom compared its appli-
cation in 145 patients and found no statistically
significant difference in the outcome when com-
paring scoring systems, and that the SCORTEN
was much easier to apply.35
Two modified SCORTEN systems were devel-
oped by Sorrell et al. for application in a pediatric
population; however, these were not shown to be
superior to the original adult score.36 A recent
Brazilian study also found the SCORTEN to be
valid in patients with acquired immunodeficiency
syndrome (AIDS).37

Figure 3. (a) Wound care for the torso in TEN/SJS. (b) Area-specific wound care in TEN/SJS. SJS, Steven–Johnson syndrome.
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j
Figure 3. (Continued).

5
 6 CHARLTON ET AL.
The final diagnosis is made by corresponding
these clinical features with histopathological find-
ings, namely widespread epidermal necrosis, sub-
epidermal blisters, apoptotic keratinocytes, and
usually sparse dermal inflammatory infiltrate.38
Unlike autoimmune blistering disorders, direct
immunofluorescence will not show immunoglobu-
lin deposition.
There are considerable long-term sequelae from
the initial insult of TEN/SJS. For patients who
survive the acute stages of the disease, there is
long recovery with multiple possible complica-
tions from the resultant mucosal scarring and
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adhesions.
Oral and genital (Fig. 2a, b) mucosa is involved
in 90% of cases with complications from the shed-
ding of all epidermal surfaces, including oral mu-
cosa, larynx, cornea, urethra, vagina, labia, and
scrotal skin, resulting in sequelae such as acute
respiratory distress, gastrointestinal disturbance,
and genitourinary denudation and dysfunction.39
Ocular involvement and subsequent scarring are
common, leading to chronic ocular discomfort and
potential loss of vision (Fig. 2c).
Consideration of the genitourinary tract is im-
portant as adhesions can cause significant func-
tional complications. Genitourinary involvement
occurs in approximately one-third of TEN/SJS pa-
tients. Basal keratinocytes are present in the ker-
atinized stratified squamous epithelium of the
external genitalia and both the stratified squa-
mous and pseudostratified columnar epithelium of
the urethra, and hence are at risk of being involved.
Women must be monitored for vulvar ulceration,
synechiae of the vulva and vagina, and vaginal
stenosis. There should be prompt involvement of a
gynecology team at the point of admission. In rare
cases, significant obstruction develops, resulting in
hydrocolpos.29 Vaginal dilators and potent topical
corticosteroids have a role in preventing stenosis in
some patients, to minimize the chances of requiring
surgical intervention. Vaginal and urethral adhe-
sions may require regular manual lysis, and close
gynecological monitoring in female patients is im-
portant from the early stages of the disease.40
Genital disease is painful, results in scarring, and
may affect normal sexual activity. Men must be
monitored for erosive balanitis and phimosis.41 The
role of catheterization is unclear.42 It is unknown
whether this might prevent or potentiate stric-
tures, and facilitate infection.43 However, in many
patients with extensive disease who are intubated
and receiving potent analgesia, catheterization is
necessary to monitor fluid balance and treat uri-
nary retention.31
Early oral and upper airway involvement is
typically characterized by dysphagia, excessive
salivation, and painful oral ulceration and crusting
at the vermillion border.44 The epithelial involve-
ment can extend down to the larynx, with inflam-
mation and edema compromising airway patency.
Bronchial epithelial sloughing may also occur, af-
fecting the lower respiratory tract with edema,
infection, and atelectasis.45,46 Williams et al. re-
cently developed criteria for intubation, in a ret-
rospective study of 40 patients with SJS and TEN.
On the basis of their findings, they have suggested
that there must be oral involvement plus one of the
following: (1) initial total body surface area (TBSA)
>70%, (2) progression of TBSA sloughed while in
hospital, >15% from days 1 to 3, (3) underlying
neurologic diagnosis inhibiting protection of air-
way, or (4) visualization of airway involvement
with direct laryngoscopy.47
Ocular complications occur in approximately
half of patients with TEN/SJS (Fig. 2c).48 In the
more acute stages, severe ocular complications in-
clude epithelial defects of the ocular surface (con-
junctiva and cornea), and conjunctivitis with
pseudomembrane.49 In rare cases, patients may
first present for medical attention with ocular er-
ythema as the initial sign of SJS/TEN.50 Under
blue illumination with fluorescein staining, large
areas of confluent corneal and conjunctival epi-
thelial loss will be seen.38 Opportunistic infection is
frequently observed with methicillin-resistant
Staphylococcus aureus (MRSA) and methicillin-
resistant Staphylococcus epidermidis (MRSE).35
Long-term complications include vision loss,51
permanent dry eye, trichiasis, and conjunctival
invasion into the cornea.52
MANAGEMENT
The multisystem involvement and high mor-
bidity and mortality of TEN/SJS necessitate high-
dependency, multidisciplinary care of these pa-
tients in a specialized burns unit or ICU. The most
important aspect of the management of TEN/SJS
remains; early diagnosis, identification and with-
drawal of culprit medication, supportive care, and
specialist wound and multidisciplinary care.
Supportive care
The components of supportive care of TEN/SJS
patients are similar to that of a severe burns pa-
tient. They include nutritional support due to the
high catabolic state of these often septic patients,
fluid and electrolyte monitoring and replacement
due to multiorgan involvement and high fluid loss,
thermoregulation, and adequate analgesia. The
 TOXIC EPIDERMAL NECROLYSIS AND STEVEN–JOHNSON SYNDROME
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Figure 4. TEN affecting the face, eyes, lips, oral mucosa, and respiratory
tract, necessitating intubation.
involvement of respiratory mucosa may require
intubation and sedation for analgesia (Fig. 4).
Multisystem involvement also necessitates early
multidisciplinary involvement from gynecology,
urology, colorectal, ear, nose, and throat (ENT)
surgeons, and ophthalmology to help prevent se-
quelae of the disease. These patients are often
managed in an induced coma for up to 4 weeks to
manage the severe pain of this condition.
Prompt identification and management of sec-
ondary infection in this cohort are imperative.
Sepsis and pneumonia are the most common com-
plications in TEN/SJS.53 A recent Japanese study
compared the sensitivity of procalcitonin (PCT)
and C-reactive protein (CRP) in detecting systemic
infection.54 They demonstrated that PCT levels
were significantly higher in patients with systemic
bacterial infections, than in patients with only su-
perficial cutaneous infection or no infection. The
PCT and SCORETEN were also positively corre-
lated. This was the first study to highlight PCT as a
superior diagnostic tool and further prospective
multicenter studies are required.
TEN/SJS: the wound
Specialized wound care in a burns unit setting is
preferable for these patients. These patients re-
quire early isolation and barrier precautions to
prevent infection. Dressings also prevent further
mechanical trauma. Although TEN/SJS patients
are managed in a similar way to burns patients, the
7
wound is fundamentally different, with only in-
volvement of the epidermis. Thus, TEN/SJS do not
cause scarring. The type of dressings used varies
greatly among different centers. Some centers use
the detached epidermal sheets as a type of biolog-
ical dressing.55 However, once there is extensive
necrosis, the risk of infection may necessitate the
debridement of necrotic tissue. The overall goals
are avoidance of infection, avoidance of further
trauma, management of exudate, and prevention
of maceration (Fig. 3).
Care of the wound involves expressing fluid from
blisters, cleaning with an antibacterial solution, and
application of a dressing. Areas of intact skin re-
quire a thick layer of emollient containing cortico-
steroid. Absorbent pads are then applied to areas
that are weeping, and the area is wrapped. Eyes
must be regularly cleansed and reviewed by an
ophthalmology service. Lubricating eye drops are to
be applied every 1–2 h and white soft paraffin ap-
plied to the eyelids. Corticosteroid eye drops and
possibly antibiotic eye drops may also be used.
Careful attention to the urogenital region is re-
quired. In men, the foreskin must be regularly re-
tracted and cleansed. Manual severing of adhesions
may be necessary. Similarly in women, the vulva
and vagina must be regularly examined and manual
lysis of synechia may be required. A dilator may be
considered to prevent vaginal stenosis (Fig. 3).
In the context of early surgical debridement, it is
important to consider that while the wound in
TEN/SJS is treated similarly to a burn, they have
different pathomechanisms, that is, the epidermal
process is more dynamic in TEN/SJS. This is im-
portant as the time to maximum detachment in
TEN/SJS is approximately 7–10 days, and thus, at
the outset it is difficult to determine the TBSA to be
involved. Thus, early debridement may involve
unnecessary removal of epidermis. This is espe-
cially relevant in the use of more modern tech-
niques discussed below such as xenografts, as
operative debridement is often required to promote
adherence of the biologic membranes.56
Currently, nanocrystalline gauze materials con-
taining silver are increasingly replacing petrolatum-
impregnated gauze for the coverage of denuded skin,
although controlled trials have not been per-
formed.57 A single multisite study has also recom-
mend the use of silicone silver foam dressings with
silver sulfate in burns patients,58 which may be ap-
plicable in TEN/SJS, demonstrated successfully by
McCarthy and Donovan.59 The benefit of the foam
dressings being decreased frequency of dressing
changes, and thus associated pain and skin trauma.
There is some caution with using silver dressings
 8 CHARLTON ET AL.
over extensive exposed due to the theoretical risk of
absorption. However, there is a lack of evidence that
proposed absorption causes any clinical problems.60
The advantage of nanocrystalline dressings is they
can be left in situ for up to 7 days, and this decreases
the pain from handling the patient. Biosynthetic
skin substitutes have also been investigated as al-
ternative dressings, including ‘‘Biobrane’’ that has
been found to reduce pain, eliminate need for further
dressings allowing early physiotherapy.61
Castillo et al.62 conducted a literature review in
2018 to compare the efficacy of different dressing
types in TEN/SJS. They included 22 studies that
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examined the time to re-epithelialization. They
noted that these studies included simple older style
dressings such as ointment with bandages and
more modern biosynthetic and silver impregnated
dressings. While no significant difference was
found in healing time, more modern dressings
could be left in place for longer and thus facilitated
improved patient comfort. This reinforces the
benefits of the abovementioned use of nanocrys-
talline dressings. While further studies are re-
quired to establish what chemical properties of
dressings, if any, will facilitate reduced healing
time, it is evident that dressings that can be left in
situ for longer are preferable.
SYSTEMIC THERAPY
Currently, there is insufficient evidence to sup-
port active medical therapy for TEN/SJS beyond
that of supportive care. The comparison of clinical
studies is difficult due to lack of uniform reporting
and measurement standards at different centers.
Also, the rarity of the disease has meant that large-
scale studies are difficult to perform.
Despite this, there are numerous immunosup-
pressive and immunomodulating treatments that
have been proposed, including corticosteroids,
IVIG, cyclosporine, and TNF antagonists. The use
of these agents is based on the evidence that vari-
ous cytotoxic proteins and cytokines such as solu-
ble Fas ligand, perforin/granzyme, tumor necrosis
factor-alpha, TNF-related apoptosis inducing li-
gand, and most importantly granulysin are medi-
ators for the widespread keratinocyte apoptosis in
TEN/SJS.63
Immunosuppression (corticosteroids,
cyclosporine)
The role of systemic corticosteroids in the
treatment of TEN/SJS has long been debated as to
whether it is beneficial or detrimental. Advocates
of corticosteroids state high doses early in the dis-
ease are useful to inhibit inflammation and have
been shown to decrease some of the biomarkers
(IFN-IL-6) of inflammation in TEN/SJS.64 The
counter argument is that patients on high-dose
steroids are at greater risk of complications such as
prolonged wound healing leading to increased risk
of infection, occult early signs of sepsis, severe
gastrointestinal bleeding, and increased mortali-
ty.65 There are also theoretical concerns that cor-
ticosteroids may have some proapoptotic effects,
based on the findings that corticosteroids may
downregulate NF-jB activity in the presence of an
abundance of TNF and consequently promote
apoptosis.66
A large retrospective European study of 281
German and French patients named EuroSCAR
found a trend for beneficial effect of corticosteroid
over the group of patients treated with supportive
care alone.67 However, the subsequent RegiSCAR
study that involved 442 patients with TEN and SJS
did find a significant improved survival rate in the
patients treated with corticosteroids versus sup-
portive care alone.12 There were limitations to this
study in that patients were treated in different
ways and some already immunomodulated at the
start of the reaction. Also, there was a noted lack of
detailed information about the course of the reac-
tion, and therefore, the investigators had several
limitations on the validity of their findings.38 This
highlights the need for international multicenter
standardized diagnostic criteria and reporting
standards in TEN to allow for rigorous interna-
tional studies.
The questionable attributes of oral corticoste-
roids in the treatment of TEN have been affirmed
in a number of studies. A large retrospective review
of 366 patients for ocular sequelae found that there
was no significant change in ocular outcomes in
response to corticosteroids.68 In addition, a case/
control study that compared 92 TEN patients who
were already on high doses of corticosteroid for pre-
existing conditions at the onset of TEN versus 321
randomly selected TEN patients and found that the
prophylactic exposure did not affect the severity or
mortality of the disease.10 Therefore, given that
there is not a clear benefit to the use of corticoste-
roids and there is a theoretical risk, the use of
corticosteroids in TEN cannot be recommended.69
Cyclosporine
Cyclosporine is relatively less studied compared
with corticosteroids in TEN/SJS. However, there
are several case series and reports of its efficacy in
slowing disease progression. Cyclosporine has an
established suppressive action on activated T
lymphocytes.70 Cytotoxic T cell-derived granulysin
 TOXIC EPIDERMAL NECROLYSIS AND STEVEN–JOHNSON SYNDROME
Table 1. Summary of Studies Investigating Cyclosporine
in Toxic Epidermal Necrolysis
SCORTEN-
No. of Dose No. of
Study Year patients (mg/kg) deaths
Arevelo et al.99 2000 11 3 0
Reese et al.100 2011 4 0
Valeyrie-Allanore 2010 29 3 0
et al.71
Singh et al.101 2013 11 3 0
Kirchhoff et al.102 2014 16 5–7 1 2.4
Lee et al.103 2017 44 3 3
ND, not done; SCORTEN, severity of illness score for toxic epidermal
necrolysis.
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has been recognized as the key mediator in the
disseminated keratinocyte apoptosis seen in TEN/
SJS. Therefore, there is a plausible theoretical
benefit to its early administration in the disease
process. There have been a number of small case
series and individual case reports that have had
favorable outcomes for patients treated with cy-
closporine (Table 1). Of particular note was the
recent study by Lee, through which 24 patients
received cyclosporine (3 mg/kg per day); there were
only 3 deaths, despite SCORTEN-predicted rate of
7.2, versus the comparison group of 20 patients
treated supportively, where 6 deaths occurred in
line with SCORTEN-predicted 5.9.46 Lee et al.46
chose the dose of 3 mg/kg based on a regimen pub-
lished by a French referral center for toxic bullous
disorders. Valeyrie-Allanore et al. had shown this
dose to reduce both mortality and rate of progres-
sion of detachment.71 The favorable outcome in the
cyclosporine-treated group warrants further ran-
domized studies to validate these findings. The
2017 JAMA systematic review found that there
was some evidence for both corticosteroids and cy-
closporine; however, these findings need further
substantiation.72
Immunomodulating: IVIG
There was a promising in vitro study that
showed IVIG could effectively block the interaction
of the Fas receptor with Fas ligand, a reported
pathway of keratinocyte death.73 There was sub-
sequent interest in clinical studies for IVIG in the
treatment of TEN to prevent disease progression.
However, the subsequent clinical trials examining
the efficacy of IVIG have not convincingly proved
its efficacy.
A large study that included 48 patients with
SJS/TEN and TEN suggested some benefit from
IVIG at a dose of 3 g/kg over 3 days.74 Another
single-center study showed outcomes for patients
with SJS/TEN and TEN treated at a lower dose of
9
IVIG (0.4–1 g/kg dose). This Miami-based study
that involved 16 consecutively treated patients had
significantly decreased mortality using the
expected Reported SCORTEN-predicted mortality tool.75
mortality benefit
Despite these positive studies and a sound the-
ND Yes oretical basis for the efficacy of IVIG, a more recent
ND Yes systematic review and meta-analysis concluded
2.75 Yes
that the current evidence overall does not support a
ND Yes clinical benefit.76 The lack of evidence for the effi-
Yes cacy of IVIG has been affirmed in two subsequent
7.2 Yes studies. A study including 23 patients with TEN
treated with IVIG versus supportive care alone
showed no improved survival.77 More recently, a
larger retrospective analysis of 64 patients (in-
cluding SJS/TEN and TEN) treated at a single
center showed no improved survival from treat-
ment with IVIG regardless of whether it was high
(>3 g/kg) or low dose (<3 g/kg). The uncertainty
around the use of IVIG was highlighted in recent
U.K. guidelines for management of TEN that sta-
ted there were strong advocates for and against the
use of IVIG.78 This highlights the need for more
rigorous trials in this area.
Antitumor necrosis factor
agents—thalidomide, infliximab
The only known randomized control trial for
TEN that studied thalidomide versus placebo
found 10 deaths out of a cohort of 12 treated pa-
tients, versus 3 out of 10 deaths in the placebo
group, resulting in early termination of the
study.79 The proposed mechanism for the delete-
rious effect of thalidomide was the paradoxical
increase of TNF-alpha production observed in
plasma concentrations of the treated patient in this
study. Despite this cautionary trial, there has been
a subsequent report of infliximab (another TNF
antagonist) as a single dose (5 mg/kg) administered
on day 4 of rash to a 50-year-old woman with rap-
idly progressing TEN (affecting >35% BSA), who
had rapid cessation of spread of rash following
treatment.80 There is also a case series of 10 pa-
tients with SJS/TEN treated with a single dose of
etanercept (50 mg subcutaneous injection) with all
patients surviving despite an SCORTEN-predicted
mortality of 50%.81 Etanercept was also recently
shown to be effective in a child, an 11-year-old fe-
male, with SJS that had progressed despite methyl-
prednisolone and cyclosporine.82 While TNF-alpha
antagonists have been shown to be effective at halt-
ing the progression of TEN/SJS, they are potent im-
munosuppressants and the risk of infection must be
considered in each patient. Further studies are
required to characterize the place of TNF-alpha
inhibition in TEN/SJS.83
 10 CHARLTON ET AL.
Granulocyte colony-stimulating factor
The use of granulocyte colony-stimulating factor
(G-CSF) has come about in an effort to boost bior-
egeneration and promote the re-epithelialization
healing stage of TEN. It has been proposed that by
accelerating healing, the complications of infection
and sepsis-related death are avoided. The acceler-
ation of wound healing with G-CSF has been seen
in other conditions such as chronic leg ulcers.84
However, the mechanism of action remains un-
known. It was proposed as a useful adjunct in two
cases of severe TEN with concurrent neutropenia
that showed rapid re-epithelialization following
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administration of G-CSF.85 There has also been a
successful pediatric case report of a 7-year-old girl
with TEN (affecting up to 70% BSA epidermal loss),
complicated by neutropenia, who had normaliza-
tion of white cell count after 48 h of rG-CSF (Neu-
pogen), 500,000 units/kg per day by intravenous
infusion on 4 successive days and complete recov-
ery with no reported sequelae.86 There have been
very few subsequent reports of the efficacy of G-
CSF to validate these case reports.
EMERGING AND EXPERIMENTAL
TREATMENTS
There are a number of experimental treatments
that have been reported for the topical treatment of
TEN/SJS, including different wound dressing me-
diums and topical therapies. One example of this is
the use of porcine xenografts, shown in a retro-
spective study to have significantly improved in-
travenous fluid requirements, pain and analgesia
requirements in 8 patients treated versus those in
the control group; however, the mortality rate was
identical in both groups (12.5%).87 A 2018 system-
atic review assessed the role of biological skin
substitutes in TEN and SJS, looking at 29 cases of
xenograft use, in which the average TBSA in-
volvement was 73.87%.88 Their review highlighted
that only 2 of the 29 subjects died (10%), compared
with the reported mortality figures of 50% in pa-
tients with such extensive disease. Further studies
are, however, required to validate these findings.
Another new topical therapy that has been tested
for the prevention of the long-term ocular complica-
tions of TEN/SJS is the use of cultivated oral mucosal
epithelial transplantation (COMET). One case series
reported the successful treatment of three patients
with SJS who underwent COMET and, despite all
patients experiencing the perioperative complication
of methicillin-resistant staphylococcal aureus infec-
tion, they all had complete re-epithelialization and
avoidance of vision loss.89
A second novel topical treatment for the ocular
complications of TEN/SJS is the use of amniotic
membrane in conjunction with topical corticoste-
roids. An ophthalmic case series found that covering
the entire ocular surface (as opposed to partial cov-
erage) with amniotic membrane coupled with ap-
plication of topical corticosteroids was associated
with preservation of visual acuity and the entire
ocular surface in six patients. These ocular case
series have promising results for the use of novel
dressings in TEN and highlight the need for further
studies in this area. Porcine amnion has also been
use successfully on the torso and face in TEN.90
Activated protein C contributes to maintaining
and promoting skin barrier integrity. It increases
proliferation and migration of keratinocytes, junc-
tion proteins, and anti-inflammatory mediators,
while decreasing apoptosis and inflammatory me-
diators, thereby enhancing the physical and im-
munological barrier.91 In animal models, it has
been shown to induce re-epithelialization in full-
thickness biopsies. It has also been used topically
in humans in pressure sores,92 diabetic ulcers,93
and pyoderma gangrenosum-associated ulcers.94
Given its success in other areas, it has been pos-
tulated that activated protein C may have a future
role in the management of patients with TEN/SJS.
There has been a single case report of extracor-
poreal therapy, in the form of hemodialysis, which
has been used effectively to halt progression of
TEN.95 In this case, bullae formation was seen to
cease shortly after the initiation of therapy. It is
unclear whether this was the product of expedited
drug clearance, or possibly removal of uremic toxins
contributing to cellular dysfunction. This same
group reported success in a patient with linear im-
munoglobulin A bullous dermatosis and acute gen-
eralized exanthematous pustulosis. These findings
are preliminary and isolated, however, it has been
suggested that hemodialysis may have a role in
patients in which the triggering agent is not clear.
Other targets being investigated in preclinical
wound and burn studies may also be later consid-
ered for application in TEN/SJS. Morasso and col-
leagues have examined the rapid healing of oral
mucosa and the central role of SOX 2 in increased
cell migration.96 Studies analyzing angiogenesis
and the role of pigment epithelium-derived growth
factor by Michalczyk et al. address the concept of
wound resolution and healing.97 Yang et al. have
demonstrated the effect of IL-27 on epidermal
proliferation, specifically skin wound closure, and
antiviral host defense.98 Such preliminary findings
may eventuate in clinical applications with impli-
cations for future therapeutic use in TEN/SJS.
 TOXIC EPIDERMAL NECROLYSIS AND STEVEN–JOHNSON SYNDROME
CONCLUSION
TEN and SJS are severe and life-
threatening conditions. Early diagnosis,
elimination of the culprit medication, and
supportive care in a specialized facility are
the cornerstones of management for these
patients. There is minimal supporting evi-
dence for the use of systemic treatment for
TEN/SJS. This is due, in part, to the rarity
of the disease and the lack of randomized
control trials.
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ACKNOWLEDGMENTS
AND FUNDING SOURCES
There are no sources of funding to
declare.
AUTHOR DISCLOSURE
AND GHOSTWRITING
C.J. and A.C. have shares in a company with
an interest in a variant of activated protein C
to treat diabetic wounds. No other competing
financial interests exist.
None of the other authors has any disclosures.
The content of this article was expressly written by
the authors listed. No ghostwriters were used to
write this article.
ABOUT THE AUTHORS
Olivia A. Charlton, BAS, MBBS, MPH, is a
Dermatology Registrar at Lotus Dermatology in
Newcastle. Victoria Harris, MBBS, M Phil, LLB
(Hons), is a Dermatology Registrar at the Prince of
Wales Hospital. Kevin Phan, MD, BSc (Adv), MSc,
MPhil, is a Dermatology Resident at Liverpool Hos-
pital, Sydney. Erin Mewton, BN, Postgraduate
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TAKE-HOME MESSAGES
 TEN/SJS are potentially fatal acute mucocutaneous vesiculobullous
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 Early elimination of the culprit medication is essential.
 In SJS <10% of TBSA is affected by skin detachment, 10–30% is an
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randomized controlled trials are required to validate findings from
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Certification in Tissue Viability, is the Derma-
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ABBREVIATIONS
AND ACRONYMS
BSA ¼ body surface area
COMET ¼ cultivated oral mucosal
epithelial transplantation
ENT ¼ ear, nose, and throat
G-CSF ¼ granulocyte colony-stimulating
factor
ICU ¼ intensive care unit
IVIG ¼ intravenous immunoglobulin
PCT ¼ procalcitonin
SCORTEN ¼ severity of illness score for
toxic epidermal necrolysis
SJS ¼ Steven–Johnson syndrome
TBSA ¼ total body surface area
TEN ¼ toxic epidermal necrolysis
TNF ¼ tumor necrosis factor