Journal Reading

UPDATE ON PATHOBIOLOGY IN STEVENS-JOHNSON

SYNDROME AND TOXIC EPIDERMAL NECROLYSIS

Penyaji:

By:
Siti Aminah Multazamiyah, S.Ked
Npm. 19360073

Preceptor :
dr. Resati Nando Panonsih, M.Sc.,Sp.KK.,FINSDV

CLINICAL SCIENCE OF DERMATOVENEREOLOGY

PERTAMINA BINTANG AMIN HOSPITAL
MEDICAL FACULTY OF MALAHAYATI UNIVERSITY
BANDAR LAMPUNG ON 2019
 VALIDITY SHEET

A journal was presented with the title:

UPDATE ON PATHOBIOLOGY IN STEVENS-JOHNSON
SYNDROME AND TOXIC EPIDERMAL NECROLYSIS

Bandar Lampung,

Presenters, Preceptor,

Siti Aminah Multazamiyah, S.Ked dr. Resati Nando P., M.Sc.,Sp.KK.,FINSDV

 DERMATOLOGICA SINICA 31 (2013) 175e180

Contents lists available at ScienceDirect

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
Drug Hypersensitivity Clinical and Research Center, Department of Dermatology, Chang Gung Memorial Hospital, Taipei, Keelung, Taiwan
2
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: Stevens-Johnson syndrome (SJS) and toxic epidermal necrosis (TEN) are rare but life-threatening severe
Received: Aug 22, 2013 cutaneous adverse reactions (SCARs), which are mainly induced by a variety of drugs. Once considered to
Revised: Sep 24, 2013 be unpredictable, significant progress has been achieved in understanding the pathological mechanisms
Accepted: Sep 24, 2013
underlying such reactions. Recent studies suggested that SJS/TEN is a specific immune reaction where
human leukocyte antigen (HLA) alleles specific for certain drugs in defined populations are involved in
Keywords:
the activation of cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. Upon the activation, various
drug hypersensitivity
cytotoxic and immunological signals, including but not limited to Fas/Fas ligand, perforin/granzyme B,
human leukocyte antigens
Stevens-Johnson syndrome
and granulysin are launched to mediate the disseminated keratinocyte death in SJS/TEN. This review
toxic epidermal necrolysis 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 Ó 2013, Taiwanese Dermatological Association.
Published by Elsevier Taiwan LLC. All rights reserved.

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

advances in exploring the genetic predisposing factor and patho-
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis genic mechanism of drug-induced SJS/TEN.
(TEN) are considered a spectrum of rare but potentially fatal cuta-
neous diseases, differing only in their extent of skin detachment
Epidemiology
[with the degree of epidermal detachment less than 10% of body
surface area (BSA) being classified as SJS, greater than 30% as TEN,
The incidence of SJS/TEN is estimated at one to six cases per million
and 10e30% as SJS/TEN overlap] (Figure 1).1 Histopathology typi-
inhabitants per year in Europe and the US,9e13 yet the mortality rate
cally shows widespread keratinocyte apoptosis and full-thickness
is 10% for patients with SJS, approximately 30% for patients with
epidermal necrosis and detachment with a sparse dermal mono-
SJS/TEN overlap, and almost 50% for patients with TEN.14,15 The
cytic (predominantly T cell) infiltrate.2 Without immediate medical
condition is more common in adults than in children, and females
intervention, uncontrolled separation of the epidermis can lead to
are affected more frequently than males.13,16 In addition, people
large denuded areas that cause extreme pain, massive loss of fluid
over 60 years old seem to be more likely to develop TEN.17,18 This
and protein, bleeding, evaporative heat loss with subsequent hy-
disease occurs sporadically and as a singular event, but the inci-
pothermia, and infection.3
dence and prevalence can arise in specific populations while
Although microbial infections have occasionally been reported
exposed to particular drugs. Pharmacogenomic studies have
as the causes of SJS/TEN, this devastating disease is mainly trig-
demonstrated that ethnicity and HLA types may predispose pa-
gered by drug exposure.1,4e6 To date, more than 100 drugs have
tients to SJS/TEN caused by certain drugs, which will be discussed
been associated with SJS and TEN,1 among which aromatic anti-
later in this article. Although SJS/TEN has been mainly attributed to
convulsants, sulfonamide antibiotics, allopurinol, oxicam nonste-
drug exposure, approximately 5% of SJS/TEN cases were reported to
roidal anti-inflammatory drugs, and nevirapine exhibit a high
be associated with HIV infection in Europe.19 Furthermore, other
agents such as Mycoplasma pneumonia, Herpes simplex virus, and
* Corresponding author. Drug Hypersensitivity Clinical and Research Center,
Department of Dermatology, Chang Gung Memorial Hospital, No. 5, Fusing St.,
some neoplastic and autoimmune diseases may have an impact on
Gueishan Township, Taoyuan County 333, Taiwan. the incidence of SJS/TEN.5,6,20e24 However, there are still cases of
E-mail address: chung1@cgmh.org.tw (W.-H. Chung). SJS/TEN without any identifiable cause.

1027-8117/$ e see front matter Copyright Ó 2013, Taiwanese Dermatological Association. Published by Elsevier Taiwan LLC. All rights reserved.
http://dx.doi.org/10.1016/j.dsi.2013.09.002
176 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 his-
tocompatibility 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
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 specific
T cell receptors (TCRs) on the CD8þ cytotoxic T cells. Upon this recognition, cytotoxic T cells produce cytokines/chemokines as well as various cytotoxic proteins to induce extensive
keratinocyte apoptosis.
MHC ligand that is loaded onto the MHC and trafficked to the cell
surface, where it activates antigen-specific T lymphocytes.25,26 In
some cases where drug hypersensitivity takes place rapidly, the
immunogenic complexes produced by drug presentation are un-
likely to depend on antigen processing or cellular metabolism. A
second concept, the pei or pharmacological interaction with im-
mune receptors model, therefore, is proposed, according to which
a noncovalent, labile interaction of the drug with the MHC re-
ceptor 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
identified 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
findings favor a role of the pei model in the pathogenesis of CBZ-
induced 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 pep-
tide binding groove of certain MHC molecules with exquisite
specificity, 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 aba-
cavir 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 insufficient 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 CBZ-
mediated SJS/TEN.
 S.-C. Su, W.-H. Chung / Dermatologica Sinica 31 (2013) 175e180
Genetic susceptibility to SJS/TEN
Current pharmacogenomic studies have advanced our knowledge
on the genetic predispositions to adverse drug reactions. The cor-
relation of HLA alleles with drug-induced SJS/TEN was first re-
ported 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 specific T cell-mediated immune responses,
which fits perfectly with the pathogenic mechanism of this con-
dition. It is now recognized that genetic associations of HLA alleles
with drug hypersensitivity are drug- and ethnicity-specific. We
have previously shown that there is a strong association of CBZ-
induced 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 verified the suscepti-
bility 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 corre-
lation 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 fre-
quencies of this allele among distinct populations.
In addition to the ethnical specificity, 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 HLA-
B*5801 with allopurinol-mediated SJS/TEN was not only observed
in other southeast Asians,42 but also in Japanese, Korean pa-
tients,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 classification 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 sulfa-
methoxazole or lamotrigine,44 HLA-B*73 with oxicam,44 and HLA-
B*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 beneficial 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
Allopurinol B*5801 Han Chinese, Thai, Japanese,
European
Carbamazepine B*1502 Han Chinese, Thai, Indian
B*1511 Japanese
B*5901 Japanese
A*3101 Han Chinese, Japanese,
European
Lamotrigine B*1502, B*38 Han Chinese
B*5801, A*6801 European
Cw*0718
DQB1*0609
DRB1*1301
Methazolamide B*5901, CW*0102 Korean, Japanese
Oxicam B*73, A*2, B*12 European
Oxcarbazepine B*1502 Han Chinese
Phenytoin B*1502 Han Chinese, Thai
Sulfamethoxazole B*38 European
HLA ¼ human leukocyte antigen; SJS/TEN ¼ Stevens-Johnson syndrome/toxic
epidermal necrolysis.
177
generating genetic databases that allow prescriptions to be tailored
to an individual’s genetic risk.
Cytotoxic and immunological mediators of drug
hypersensitivity in SJS/TEN
With the identification of specific 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 first reported mechanism that modulates
keratinocyte apoptosis in TEN.51 In this landmark study, the path-
ophysiological presence of both Fas and FasL in the epidermis of
patients with TEN was unveiled. More specifically, 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 au-
thors 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 significantly 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 defined role for
FasL in TEN apoptosis still remain unanswered.
Another hypothetical mechanism involves perforin and gran-
zyme B, two cytolytic proteins that are released by activated cyto-
toxic 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
Refs
through the mannose 6-phosphate receptor to cause apoptosis by
40e44
various pathways.57 Increasing levels of perforin, granzyme B, tumor
34e37 necrosis factor-alpha (TNF-alpha), and FasL have been observed to
47 be correlated with disease severity of drug hypersensitivity from
69 mild maculopapular rashes to severe TEN.58 In addition, the cyto-
46,48,70
toxic effect of TEN blister lymphocytes toward keratinocytes has
been shown to be attenuated by the inhibition of perforin/granzyme
44,49,71
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
50
44,71 in SJS/TEN. We have demonstrated that the level of 15-kDa gran-
49 ulysin was predominant over that of perforin, granzyme B, and
36,49 sFasL in the SJS/TEN blister fluids. Depletion of granulysin reduced
44
the cytotoxicity of SJS/TEN blister fluids to keratinocytes, and a
further injection of granulysin into mouse skin resulted in blis-
tering and epidermal necrosis mimicking SJS/TEN.60 Moreover, an
178 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 specificity in the association of HLA with drug-induced SJS/TEN. ALL ¼ allopurinol; CBZ ¼ carbamazepine; LMT ¼ lamotrigine; MTZ ¼ methazolamide; NVP ¼ nevirapine;
OXC ¼ oxcarbazepine; PHT ¼ phenytoin; SMX ¼ 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 chemo-
attractant for T lymphocytes, NK cells, monocytes, and other in-
flammatory cells,62 which may, in part, account for the infiltration
of CTLs and NK cells observed in skin lesions of TEN patients.63 It is
expected to have a specific 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 ur-
gent before embarking on the long road to developing a new spe-
cific anti-granulysin drug.
Other than those mentioned above, various cytokines/chemo-
kines that are responsible for trafficking, proliferation, and activa-
tion of T cells and other immune cells have been found to be
elevated in the skin lesions, blister fluids, blister cells, PBMCs, or
plasma of SJS/TEN patients. These include interferon-gamma (IFN-
gamma), TNF-alpha, interleukin-2 (IL-2), IL-5, IL-6, IL-10, IL-12, IL-
13, 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 signif-
icant 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 clarification of HLAedrugeTCR interactions,
and the identification of granulysin as the key mediator in
epidermal necrolysis, offer us a solid foundation for disease pre-
vention 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
first uncovered in Taiwan.
2006
The correlation of CBZ-induced SJS with HLA-B*1502 was not existent in
Caucasian patients, indicating an ethnical specificity 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 first administration of CBZ and covered by the Bureau of
National Health Insurance in Taiwan.
CBZ ¼ carbamazepine; HLA ¼ human leukocyte antigen; SJS ¼ 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 thera-
peutic 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-182-
001-MY3, 98-2314-B-182A-027-MY3], and grants from Chang
Gung Memorial Hospital (CMRPG-290051w3, OMRPG2C0011,
OMRPG2C0021).
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UPDATE ON PATHOBIOLOGY IN STEVENS-JOHNSON
SYNDROME AND TOXIC EPIDERMAL NECROLYSIS
Shih-Chi Su, Wen-Hung Chung, Taiwan
By:
Siti Aminah Multazamiyah, S.Ked
Npm. 19360073

Preceptor :
dr. Resati Nando Panonsih, M.Sc.,Sp.KK.,FINSDV

CLINICAL SCIENCE OF DERMATOVENEREOLOGY

PERTAMINA BINTANG AMIN HOSPITAL
MEDICAL FACULTY OF MALAHAYATI UNIVERSITY
BANDAR LAMPUNG ON 2019
 ABSTRACT
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, significant progress has
been achieved in understanding the pathological mechanisms
underlying such reactions. Recent studies suggested that SJS/TEN
is a specific immune reaction where human leukocyte antigen
(HLA) alleles specific for certain drugs in defined populations are
involved in the activation of cytotoxic T lymphocytes (CTLs) and
natural killer (NK) cells. The knowledge gained from these
cutting-edge studies will form the basis for better prevention
and management of SJS/TEN.
 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 classified as SJS, greater
than 30% as TEN, and 10-30% as SJS/TEN overlap] (Figure 1).
Figure 1
Histological analysis of a toxic epidermal necrosis (TEN)
skin section with prominent keratinocyte death and
separation at the dermoepidermal junction (black arrows).
 Histopathology typically shows widespread keratinocyte
apoptosis and full-thickness epidermal necrosis and detachment
with a sparse dermal monocytic (predominantly T cell) infiltrate.
Without immediate medical intervention, uncontrolled
separation of the epidermis can lead to large denuded areas that
cause extreme pain, massive loss of fluid and protein, bleeding,
evaporative heat loss with subsequent hypothermia, and
infection.
 Although microbial infections have occasionally been
reported as the causes of SJS/TEN, this devastating disease is
mainly triggered by drug exposure.
To date, more than 100 drugs have been associated with SJS
and TEN, among which:
• aromatic anticonvulsants
• sulfonamide antibiotics
• Allopurinol
• oxicam nonsteroidal anti-inflammatory drugs
• Nevirapine
exhibit a high relative risk.
 EPIDEMIOLOGY
The incidence of SJS/TEN is estimated at 1-6 cases per
million inhabitants per year in Europe and the US, 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. The condition is more common in adults than in children,
and females are affected more frequently than males. In addition,
people over 60 years old seem to be more likely to develop TEN.
 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.
Furthermore, other agents such as:
• Mycoplasma pneumonia
• Herpes simplex virus
• some neoplastic
• autoimmune diseases
may have an impact on the incidence of SJS/TEN.
However, there are still cases of SJS/TEN without any
identifiable cause.
 PROPOSED MODELS OF DRUG
HYPERSENSITIVITY
As discussed previously, the majority of SJS/TEN cases were
caused by a variety of drugs. It is nowrecognized 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).
Figure 2
As illustrated, the immune response is triggered by the human leukocyte (an interaction of
an endogenous self-peptide with a causative drug/metabolite) to specific T cell receptors
(TCRs) on the CD8þ cytotoxic T cells.
Upon this recognition, cytotoxic T cells produce cytokines/chemokines as well as various
cytotoxic proteins to induce extensive keratinocyte apoptosis.
 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
trafficked to the cell surface, where it activates antigen-specific T
lymphocytes.
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.
 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 first reported in cases of sulfonamide- and oxicam-
related TEN.
It is now recognized that genetic associations of HLA alleles
with drug hypersensitivity are drug- and ethnicity-specific. In
addition to the ethnical specificity, the genetic susceptibility to
drug-induced SJS/TEN highly depends on the nature of the
offending medications.
 Other HLA-drug associations that contribute to the
pathogenesis of SJS/TEN have been reported;
• HLA-A*3101 and HLA-B*1511 with CBZ
• HLA-B*1502 with phenytoin
• HLA-B*38 with sulfamethoxazole or lamotrigine
• HLA-B*73 with oxicam
• HLA-B*5901 with methazolamide.
The knowledge gained from such pharmacogenomic studies
are highly beneficial for lowering the incidence of drug-induced
SJS/TEN and ultimately generating genetic databases that allow
prescriptions to be tailored to an individual’s genetic risk.
 CYTOTOXIC AND IMMUNOLOGICAL MEDIATORS OF
DRUG HYPERSENSITIVITY IN SJS/TEN
With the identification of specific 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.
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.
 In addition to the cytotoxic effect, granulysin has been
shown to serve as a chemoattractant for T lymphocytes, NK cells,
monocytes, and other inflammatory cells, which may, in part,
account for the infiltration of CTLs and NK cells observed in skin
lesions of TEN patients.
Other than those mentioned above, various
cytokines/chemokines that are responsible for trafficking,
proliferation, and activation of T cells and other immune cells
have been found to be elevated in the skin lesions, blister fluids,
blister cells, PBMCs, or plasma of SJS/TEN patients.
 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 clarification of HLA-drug-TCR interactions, and the
identification 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.
Although the incidence has improved with the successful
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.