DERMATOLOGICA SINICA 31 (2013) 175e180

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Dermatologica Sinica
journal homepage: http://www.derm-sinica.com

REVIEW ARTICLE

Update on pathobiology in Stevens-Johnson syndrome and toxic

epidermal necrolysis
Shih-Chi Su 1, Wen-Hung Chung 1, 2, *
1
2

Drug Hypersensitivity Clinical and Research Center, Department of Dermatology, Chang Gung Memorial Hospital, Taipei, Keelung, Taiwan
School of Medicine, Chang Gung University, Taoyuan, Taipei and Linkou Branches, Taiwan

a r t i c l e i n f o

a b s t r a c t

Article history:
Received: Aug 22, 2013
Revised: Sep 24, 2013
Accepted: Sep 24, 2013

Stevens-Johnson syndrome (SJS) and toxic epidermal necrosis (TEN) are rare but life-threatening severe
cutaneous adverse reactions (SCARs), which are mainly induced by a variety of drugs. Once considered to
be unpredictable, signicant progress has been achieved in understanding the pathological mechanisms
underlying such reactions. Recent studies suggested that SJS/TEN is a specic immune reaction where
human leukocyte antigen (HLA) alleles specic for certain drugs in dened populations are involved in
the activation of cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. Upon the activation, various
cytotoxic and immunological signals, including but not limited to Fas/Fas ligand, perforin/granzyme B,
and granulysin are launched to mediate the disseminated keratinocyte death in SJS/TEN. This review
provides an update on the pathobiology of SJS/TEN in both the genomic and immunologic perspectives.
The knowledge gained from these cutting-edge studies will form the basis for better prevention and
management of SJS/TEN.
Copyright 2013, Taiwanese Dermatological Association.
Published by Elsevier Taiwan LLC. All rights reserved.

Keywords:
drug hypersensitivity
human leukocyte antigens
Stevens-Johnson syndrome
toxic epidermal necrolysis

Introduction
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis
(TEN) are considered a spectrum of rare but potentially fatal cutaneous diseases, differing only in their extent of skin detachment
[with the degree of epidermal detachment less than 10% of body
surface area (BSA) being classied as SJS, greater than 30% as TEN,
and 10e30% as SJS/TEN overlap] (Figure 1).1 Histopathology typically shows widespread keratinocyte apoptosis and full-thickness
epidermal necrosis and detachment with a sparse dermal monocytic (predominantly T cell) inltrate.2 Without immediate medical
intervention, uncontrolled separation of the epidermis can lead to
large denuded areas that cause extreme pain, massive loss of uid
and protein, bleeding, evaporative heat loss with subsequent hypothermia, and infection.3
Although microbial infections have occasionally been reported
as the causes of SJS/TEN, this devastating disease is mainly triggered by drug exposure.1,4e6 To date, more than 100 drugs have
been associated with SJS and TEN,1 among which aromatic anticonvulsants, sulfonamide antibiotics, allopurinol, oxicam nonsteroidal anti-inammatory drugs, and nevirapine exhibit a high
* Corresponding author. Drug Hypersensitivity Clinical and Research Center,
Department of Dermatology, Chang Gung Memorial Hospital, No. 5, Fusing St.,
Gueishan Township, Taoyuan County 333, Taiwan.
E-mail address: chung1@cgmh.org.tw (W.-H. Chung).

relative risk.7e10 In this article, we primarily review the current

advances in exploring the genetic predisposing factor and pathogenic mechanism of drug-induced SJS/TEN.
Epidemiology
The incidence of SJS/TEN is estimated at one to six cases per million
inhabitants per year in Europe and the US,9e13 yet the mortality rate
is 10% for patients with SJS, approximately 30% for patients with
SJS/TEN overlap, and almost 50% for patients with TEN.14,15 The
condition is more common in adults than in children, and females
are affected more frequently than males.13,16 In addition, people
over 60 years old seem to be more likely to develop TEN.17,18 This
disease occurs sporadically and as a singular event, but the incidence and prevalence can arise in specic populations while
exposed to particular drugs. Pharmacogenomic studies have
demonstrated that ethnicity and HLA types may predispose patients to SJS/TEN caused by certain drugs, which will be discussed
later in this article. Although SJS/TEN has been mainly attributed to
drug exposure, approximately 5% of SJS/TEN cases were reported to
be associated with HIV infection in Europe.19 Furthermore, other
agents such as Mycoplasma pneumonia, Herpes simplex virus, and
some neoplastic and autoimmune diseases may have an impact on
the incidence of SJS/TEN.5,6,20e24 However, there are still cases of
SJS/TEN without any identiable cause.

1027-8117/$ e see front matter Copyright 2013, Taiwanese Dermatological Association. Published by Elsevier Taiwan LLC. All rights reserved.
http://dx.doi.org/10.1016/j.dsi.2013.09.002

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S.-C. Su, W.-H. Chung / Dermatologica Sinica 31 (2013) 175e180

Figure 1 Histological analysis of a toxic epidermal necrosis (TEN) skin section with
prominent keratinocyte death and separation at the dermoepidermal junction (black
arrows).

Proposed models of drug hypersensitivity

As discussed previously, the majority of SJS/TEN cases were caused
by a variety of drugs. It is now recognized that drug-induced SJS and
TEN are severe hypersensitivity reactions that involve major histocompatibility class (MHC) I-restricted drug presentation and an
expansion of cytotoxic T lymphocytes (CTLs), ultimately leading to
extensive keratinocyte death in skin lesions (Figure 2). Because
drugs are usually too small to trigger an immunogenic response,
several mechanistic models have been proposed to explain how
small molecular synthetic compounds are recognized by T cells in
an MHC-dependent fashion. These include the hapten/prohapten
model, the pei model, and the altered repertoire model.
The hapten/prohapten concept proposes that the drug or its
metabolite (hapten/prohapten) reacts with a self-protein through
covalent binding to produce a haptenated, de novo product. This
product then undergoes antigen processing to generate a novel

MHC ligand that is loaded onto the MHC and trafcked to the cell
surface, where it activates antigen-specic T lymphocytes.25,26 In
some cases where drug hypersensitivity takes place rapidly, the
immunogenic complexes produced by drug presentation are unlikely to depend on antigen processing or cellular metabolism. A
second concept, the pei or pharmacological interaction with immune receptors model, therefore, is proposed, according to which
a noncovalent, labile interaction of the drug with the MHC receptor at the cell surface is involved in MHC-dependent T cell
stimulation by various drugs.27 Neither cellular metabolism nor
antigen processing is required in such an interaction. Recently, we
identied shared and restricted T cell receptor (TCR) usage in
carbamazepine (CBZ)-induced SJS/TEN patients28 and also
demonstrated that the endogenous peptide-loaded HLA-B*1502
molecule presented CBZ to CTLs without the involvement of
intracellular drug metabolism or antigen processing.29 These
ndings favor a role of the pei model in the pathogenesis of CBZinduced SJS/TEN.
Another concept, the altered repertoire model, has recently
been proposed. In this model, it is postulated that drugs or drug
metabolites can bind noncovalently within the pocket of the peptide binding groove of certain MHC molecules with exquisite
specicity, allowing a new repertoire of endogenous self-peptides
to be bound and presented. Various studies of abacavir-mediated
drug hypersensitivity have documented that the binding of abacavir to the antigen-binding cleft of HLA-B*5701 sterically hindered
the binding of the original repertoire of peptides, thereby
prompting the binding of a new repertoire of peptides bearing
immunogenic neoepitopes.30e32 In addition, a similar process is
also observed in the interaction of CBZ with HLA-B*1502 in SJS/TEN
cases.30 However, this model is insufcient to explain the clinical
observation that there are approximately 7% of tolerant CBZ users
who carry the predisposing allele, HLA-B*1502, while the drug
essentially alters the peptide repertoire in every carrier of the risk
allele as proposed. Moreover, about 8% of Han Chinese are carriers
of HLA-B*1502, but the prevalence of CBZ-induced SJS/TEN in this
population is much lower (< 0.1% of new users). This suggests that
additional determinants are implicated in the development of CBZmediated SJS/TEN.

Figure 2 The proposed model of keratinocyte apoptosis in Stevens-Johnson syndrome (SJS)/toxic epidermal necrosis (TEN). As illustrated, the immune response is triggered by the
human leukocyte antigen (HLA; e.g. HLA-B*1502)-dependent presentation of an antigen (an interaction of an endogenous self-peptide with a causative drug/metabolite) to specic
T cell receptors (TCRs) on the CD8 cytotoxic T cells. Upon this recognition, cytotoxic T cells produce cytokines/chemokines as well as various cytotoxic proteins to induce extensive
keratinocyte apoptosis.

S.-C. Su, W.-H. Chung / Dermatologica Sinica 31 (2013) 175e180

generating genetic databases that allow prescriptions to be tailored

to an individuals genetic risk.

Genetic susceptibility to SJS/TEN

Current pharmacogenomic studies have advanced our knowledge
on the genetic predispositions to adverse drug reactions. The correlation of HLA alleles with drug-induced SJS/TEN was rst reported in cases of sulfonamide- and oxicam-related TEN.33 The
physiological role of HLA is to present an antigen to the TCR and
subsequently initiate specic T cell-mediated immune responses,
which ts perfectly with the pathogenic mechanism of this condition. It is now recognized that genetic associations of HLA alleles
with drug hypersensitivity are drug- and ethnicity-specic. We
have previously shown that there is a strong association of CBZinduced SJS/TEN with the HLA-B*1502 allele among Han Chinese
in Taiwan.34 This association was also found in a similar ethnic
group of Hong Kong Han Chinese with severe adverse reactions to
antiepileptic drugs.35 Another study further veried the susceptibility of individuals with HLA-B*1502 to CBZ in a Thai population.36
The US Food and Drug Administration, thus, has recommended
genetic test for all patients requiring CBZ whose ancestries have
high allele frequency of HLA-B*1502. However, the genetic correlation between HLA-B*1502 and CBZ-induced SJS was relatively
weak in Indians37 and also in Korean, Japanese, and European
groups.38e40 This discrepancy may be related to different frequencies of this allele among distinct populations.
In addition to the ethnical specicity, the genetic susceptibility
to drug-induced SJS/TEN highly depends on the nature of the
offending medications. HLA-B*5801, rather than HLA-B*1502, was
found to be strongly linked to allopurinol-mediated SJS/TEN.41
Unlike the cases in CBZ-induced SJS/TEN, the association of HLAB*5801 with allopurinol-mediated SJS/TEN was not only observed
in other southeast Asians,42 but also in Japanese, Korean patients,40,43 and patients of European origin.44
Moreover, regardless of the ethnical differences in genetic
backgrounds and HLA allele frequencies, as well as inconsistent
clinical classication of the enrolled cases and sample sizes, other
HLAedrug associations that contribute to the pathogenesis of SJS/
TEN have been reported; HLA-A*3101 and HLA-B*1511 with
CBZ,45e48 HLA-B*1502 with phenytoin,36,49 HLA-B*38 with sulfamethoxazole or lamotrigine,44 HLA-B*73 with oxicam,44 and HLAB*5901 with methazolamide.50 A summary of genetic relationships
between various HLA allotypes and drug-induced SJS/TEN is shown
in Table 140e43,34e37,45e49,67e69 and Figure 3. The knowledge gained
from such pharmacogenomic studies are highly benecial for
lowering the incidence of drug-induced SJS/TEN and ultimately

Table 1 Genetic associations of HLA alleles with SJS/TEN.

Drug

HLA allele

Ethnic population

Refs

Allopurinol

B*5801

40e44

Carbamazepine

B*1502
B*1511
B*5901
A*3101

Han Chinese, Thai, Japanese,

European
Han Chinese, Thai, Indian
Japanese
Japanese
Han Chinese, Japanese,
European
Han Chinese
European

Korean, Japanese
European
Han Chinese
Han Chinese, Thai
European

50

Lamotrigine

Methazolamide
Oxicam
Oxcarbazepine
Phenytoin
Sulfamethoxazole

B*1502, B*38
B*5801, A*6801
Cw*0718
DQB1*0609
DRB1*1301
B*5901, CW*0102
B*73, A*2, B*12
B*1502
B*1502
B*38

177

34e37
47
69
46,48,70

44,49,71

44,71
49
36,49
44

HLA human leukocyte antigen; SJS/TEN Stevens-Johnson syndrome/toxic

epidermal necrolysis.

Cytotoxic and immunological mediators of drug

hypersensitivity in SJS/TEN
With the identication of specic HLA alleles as the predisposing
factor to the disease, it becomes clear that the pathogenesis of
drug-mediated SJS/TEN involves MHC-restricted activation of CTL
response. This CTL response requires several downstream signals or
mediators to trigger extensive keratinocyte death. FaseFas ligand
(FasL) interaction is the rst reported mechanism that modulates
keratinocyte apoptosis in TEN.51 In this landmark study, the pathophysiological presence of both Fas and FasL in the epidermis of
patients with TEN was unveiled. More specically, an elevation of
soluble FasL (sFasL) and epidermal FasL expression were observed
in the sera and skin biopsy specimens from patients with TEN,
respectively, implying that sFasL detected in the sera resulted from
cleavage of a membrane-bound FasL on the epidermal cells of TEN
patients. In addition, apoptosis was abrogated while TEN skin
sections were pretreated with a FasL-blocking antibody. The authors concluded that TEN keratinocytes express lytically active FasL,
whose ligation with Fas on adjacent keratinocytes leads to
apoptosis. A follow-up study further showed that FasL expression
was restricted to the basal and suprabasal layers of normal human
epidermis. Despite demonstrating the coexpression of both Fas and
FasL in the lower dermis, keratinocyte FasL, however, was primarily
cytoplasmic in vivo and unable to cause apoptosis.52 This proposed
mechanism was also challenged by others. It is documented that
keratinocytes failed to overexpress Fas.53,54 Moreover, elevated
levels of sFasL in SJS and TEN were detected by the other group, but
they found no membrane-bound FasL expression on keratinocytes
in TEN patients or in healthy controls.55 Noteworthily, sFasL levels
increased signicantly when peripheral blood mononuclear cells
(PBMCs) from TEN patients were cultured with the offending drug,
suggesting an alternative source of serum sFasL in SJS/TEN.
Although the involvement of FaseFasL interactions in mediating
keratinocyte death in SJS/TEN was pointed out in numerous studies,
several questions in terms of the origin of sFasL, the coexistence of
Fas and FasL in the same areas of epidermis, and a dened role for
FasL in TEN apoptosis still remain unanswered.
Another hypothetical mechanism involves perforin and granzyme B, two cytolytic proteins that are released by activated cytotoxic T cells and natural killer (NK) cells. It is believed that perforin
creates pores within the cell membranes, through which granzyme
B can enter the cell and induce apoptosis by turning on the caspase
cascade.56 However, new evidence indicates that perforin and
granzyme B are enclosed in a vesicle and delivered into the cell
through the mannose 6-phosphate receptor to cause apoptosis by
various pathways.57 Increasing levels of perforin, granzyme B, tumor
necrosis factor-alpha (TNF-alpha), and FasL have been observed to
be correlated with disease severity of drug hypersensitivity from
mild maculopapular rashes to severe TEN.58 In addition, the cytotoxic effect of TEN blister lymphocytes toward keratinocytes has
been shown to be attenuated by the inhibition of perforin/granzyme
B expression, but not by the anti-Fas monoclonal antibody.59
Our recent study of granulysin, which is a multifunctional,
cytolytic protein, further provides a revealing insight into the
pathogenic mechanism underlying widespread keratinocyte death
in SJS/TEN. We have demonstrated that the level of 15-kDa granulysin was predominant over that of perforin, granzyme B, and
sFasL in the SJS/TEN blister uids. Depletion of granulysin reduced
the cytotoxicity of SJS/TEN blister uids to keratinocytes, and a
further injection of granulysin into mouse skin resulted in blistering and epidermal necrosis mimicking SJS/TEN.60 Moreover, an

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S.-C. Su, W.-H. Chung / Dermatologica Sinica 31 (2013) 175e180

Figure 3 Geographic distribution of drugehuman leukocyte antigen (HLA) association in Stevens-Johnson syndrome (SJS)/toxic epidermal necrosis (TEN). This illustration depicts
the ethnic specicity in the association of HLA with drug-induced SJS/TEN. ALL allopurinol; CBZ carbamazepine; LMT lamotrigine; MTZ methazolamide; NVP nevirapine;
OXC oxcarbazepine; PHT phenytoin; SMX sulfamethoxazole.

increase in the serum levels of granulysin during the early stage of

SJS/TEN but not in patients with drug-induced maculopapular
eruption was also observed by another group.61 In addition to the
cytotoxic effect, granulysin has been shown to serve as a chemoattractant for T lymphocytes, NK cells, monocytes, and other inammatory cells,62 which may, in part, account for the inltration
of CTLs and NK cells observed in skin lesions of TEN patients.63 It is
expected to have a specic antigranulysin therapy for SJS/TEN in
the near future.64 However, the search for an available effective
therapeutic agent based on the pathomechanism of SJS/TEN is urgent before embarking on the long road to developing a new specic anti-granulysin drug.
Other than those mentioned above, various cytokines/chemokines that are responsible for trafcking, proliferation, and activation of T cells and other immune cells have been found to be
elevated in the skin lesions, blister uids, blister cells, PBMCs, or
plasma of SJS/TEN patients. These include interferon-gamma (IFNgamma), TNF-alpha, interleukin-2 (IL-2), IL-5, IL-6, IL-10, IL-12, IL13, IL-15, IL-18, CeC chemokine receptor type 3 (CCR3), CeXeC
chemokine receptor 3 (CXCR3), CXCR4, and CCR10.54,58,65e68
Conclusion
Despite the rareness, SJS and TEN have a substantial impact on
public health because of high mortality. The condition frequently
results in lasting disability of patients and hinders the physicians
from prescribing the medications that are commonly administered
in clinical practice. Fortunately, recent studies have made a significant stride in our understanding of the pathobiology of SJS and TEN
during the last decade. Major breakthroughs, such as the discovery
of genetic markers, the clarication of HLAedrugeTCR interactions,
and the identication of granulysin as the key mediator in

epidermal necrolysis, offer us a solid foundation for disease prevention and early diagnosis, as well as providing the potential
therapeutic target for the treatment of SJS/TEN. The translation of
HLA-B*1502 and CBZ-induced SJS/TEN from discovery to a
guideline-based test used routinely in Taiwan is a notable example
(Table 2). Although the incidence has improved with the successful

Table 2 Roadmap of contemporary CBZeSJS research and its clinical applications.

Highlights of landmark events in CBZ-related drug hypersensitivity
1998e2004
CBZ, an aromatic anticonvulsant, was recognized as the major cause of SJS, as
listed in the records of the Taiwan Drug Relief Foundation.
2004
A strong association of CBZ-induced SJS with HLA-B*1502 in Han Chinese was
rst uncovered in Taiwan.
2006
The correlation of CBZ-induced SJS with HLA-B*1502 was not existent in
Caucasian patients, indicating an ethnical specicity of HLA-B*1502 allele.
2007e2008
The association of CBZ-induced SJS with HLA-B*1502 was found among many
populations in Southeast Asia.
2007
The US Food and Drug Administration published an alert to healthcare
professionals on the use of CBZ in Asians. (The incidence rate of CBZ-induced
SJS is 5.9/10,000 in Taiwan and 0.2/10,000 in the US).
2007
The Taiwan and US Food and Drug Administration relabeled the drug
information of CBZ and recommended a genetic screening of HLA-B*1502 in
certain Asian groups before the use of CBZ.
2010
The screening of HLA-B*1502 was approved as a guideline-based test for
patients before the rst administration of CBZ and covered by the Bureau of
National Health Insurance in Taiwan.
CBZ carbamazepine; HLA human leukocyte antigen; SJS Stevens-Johnson
syndrome.

S.-C. Su, W.-H. Chung / Dermatologica Sinica 31 (2013) 175e180

application of uncovering genetic markers, treatment for SJS/TEN

remains ineffective and only supportive. Further studies on therapeutic aspects are needed to develop more options for disease
management and to achieve a better outcome.
Acknowledgments
This work was supported by grants from the National Science
Council, Taiwan [NSC 101-2321-B-182-008, 101-2628-B-182001-MY3, 98-2314-B-182A-027-MY3], and grants from Chang
Gung Memorial Hospital (CMRPG-290051w3, OMRPG2C0011,
OMRPG2C0021).
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