INVITED ARTICLE

Epidemiology of StevenseJohnson syndrome and toxic epidermal

necrolysis in Southeast Asia
q
Haur Yueh Lee
1,
*
, Wijaya Martanto
2
, Thamotharampillai Thirumoorthy
1
1
Department of Dermatology, Singapore General Hospital, Singapore
2
Duke-NUS Graduate Medical School, Singapore
a r t i c l e i n f o
Article history:
Received: Aug 7, 2013
Revised: Sep 24, 2013
Accepted: Sep 25, 2013
Keywords:
epidemiology
southeast Asia
StevenseJohnson syndrome (SJS)
toxic epidermal necrolysis (TEN)
Introduction
StevenseJohnson syndrome (SJS) and toxic epidermal necrolysis
(TEN) are severe life-threatening reactions characterized by
epidermal detachment and mucositis. These reactions are pre-
dominantly drug-related. Although a wide spectrum of medica-
tions have been reported to be causal in these reactions, the
international caseecontrol SCAR (severe cutaneous adverse re-
actions)
1
and EuroSCAR
2
studies have shown that in Europe, the
majority of reactions can be attributed to a group of high-risk drugs
such as allopurinol, carbamazepine, phenytoin, lamotrigine, oxicam
nonsteroidal anti-inammatory drugs, sulfonamide antibiotics, and
nevirapine.
In parallel, several epidemiological studies (both retrospective
and prospective) have been conducted in Europe looking at the
incidence of SJS/TEN. Initial hospital-based retrospective studies
have estimated the incidence of TEN in France and Germany to be
1.2 and 0.9 cases/million/year, respectively.
3,4
Newer prospective
population-based studies based on the German registry have
estimated the incidence of SJS/TENwithin Germany to be within 1e
2 cases/million/year.
5
It is now known that there is a strong genetic association be-
tween human leukocyte antigens and drug-induced SJS/TEN. These
genetic associations are not only drug and phenotypic specic, but
are also ethnic specic as well. The aim of this review is to sum-
marize existing epidemiological data on SJS/TEN within Southeast
(SE) Asia.
Geography of SE Asia
SE Asia is a diverse region made up of 10 member countries (Brunei,
Cambodia, Indonesia, Laos, Malaysia, Myanmar, Philippines,
Thailand, Singapore, and Vietnam). It covers a land area of 4.5
million km
2
and has a population of approximately 600 million
people of diverse ethnicities.
6
Many of the data on SJS/TEN in this
region have been derived from publications originating from
Malaysia, Philippines, Singapore, and Thailand and these will be
summarized in this review.
Epidemiology of SJS/TEN in SE Asia
The incidence of SJS/TEN in SE Asia is largely undetermined. No
prospectively epidemiological studies have been published. A
retrospective hospital-based study has estimated the incidence of
TEN in Singapore to be at least 1.4 cases/million.
7
When considered
as a whole, the prevalence of cutaneous adverse drug reactions
(CADR) in hospitalized patients varies from1.3 CADRs to 4.2 CADRs/
1000 hospitalized patients in Singapore with severe cutaneous
adverse reactions (SCAR) constituting 5e14% of these reactions.
8,9
In Malaysia, the incidence of CADR is 0.86% among new patients
assessed in a tertiary hospital and SJS/TEN account for 30% of these
reactions.
9
Drug causality
In SE Asia, based on published retrospective case series reported
from 1984 to 2013
10e19
(overlapping publications have been
excluded), the major culprit drugs implicated include carbamaze-
pine (CBZ; 17%), allopurinol (15%), sulfonamide antibiotics (12%),
q
Description: This review provides a concise account of the epidemiology of
StevenseJohnson syndrome and toxic epidermal necrolysis in Southeast Asia.
* Corresponding author. Dermatology Unit, Singapore General Hospital, Outram
Road, Singapore 169608. Tel.: 65 63214933.
E-mail address: Lee.haur.yueh@sgh.com.sg (H.Y. Lee).
Contents lists available at ScienceDirect
Dermatologica Sinica
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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.2013.09.007
DERMATOLOGICA SINICA 31 (2013) 217e220
phenytoin (PHT; 9%), nonsteroidal anti-inammatory drugs (8%),
lamotrigine (2%), phenobarbital (1%), and b-lactam antibiotics
(13%). The distribution of reported cases and causal drugs are
summarized inTable 1 and Figure 1. High-risk drugs, as identied in
the European studies, were also major culprits in SE Asia being the
implicated drug in 64% of cases.
1,2
Variations in SE Asia drug causality
CBZ and PHT induced SCAR
The proportion of CBZ and PHT-induced SJS/TEN in SE Asia is
signicantly higher, accounting for 26% of all cases (Figure 1), as
opposed to 12% in European populations.
20
Although variations in
clinical practice, prescribing patterns, and incidence of disease may
play a role, it is believed that pharmacogenetic variations between
different ethnicities is a major factor.
Complementary medications
The use of traditional/complementary medications such as tradi-
tional Chinese medications and jamuda form of Indonesian/Malay
herbal preparationdis widespread within the region and is
culturally acceptable and perceived to be safe due to its herbal
origin. However, such medications are poorly regulated and the
constituents of these medications are not always known. Comple-
mentary medications have been associated with 4% of cases in
Singapore and 5% of reported cases from Malaysia (Dr M.M. Tang,
Kuala Lumpur, Malaysia, personal communication) and reports of
these medications being adulterated by phenylbutazone have been
reported.
21,22
Occupational trigger
Occupational exposure to trichloroethylene has occasionally been
reported as a trigger of SJS/TEN and DRESS in SE Asia and Asia, with
cases being reported in Singapore, Thailand, Philippines, Japan,
Taiwan, and China.
23e25
Trichloroethylene is an organic solvent that
is used widely as a degreasing solvent in developing countries.
Typically, patients present with the cutaneous eruptions from 2
weeks to 2 months after occupational exposure. In the evaluation of
some of these cases, environmental levels, urinary trichloroethy-
lene concentrations, as well as airborne exposure concentrations
were found to be higher than the standard threshold limits.
Idiopathic cases
It is being increasingly recognized that a signicant proportion of
SJS/TEN are not drug related. From 15% to 25% of cases of SJS/TEN
had no prior drug history or occurred in circumstances in which the
drug causality was deemed to be unlikely.
2e20
In Singapore, about
10% of SJS/TEN cases were not drug related. In a series of 106 pa-
tients, there were three cases attributed to infections with myco-
plasma, three cases were associated with systemic lupus
erythematosus, and ve cases had no drug trigger.
19
Similar pro-
portions of non-drug-induced cases were also reported in the
Philippines (3/31).
14
Pharmacogenetic epidemiology of SJS/TEN
Genetic susceptibility for SJS/TEN has been proposed. It has been
claried that such genetic risks are specic for the type of reaction
as well as for the drug and ethnicity. The pharmacogenetic risks of
SJS/TEN are best demonstrated in the models of HLA-B*1502 and
HLA-B*5801 for CBZ and allopurinol respectively.
26,27
Table 1 Reported cases of StevenseJohnson syndrome and toxic epidermal nec-
rolysis, and their associated causal drug.
Associated drug Singapore
N 159
Malaysia
N 162
Philippines
N 28
Thailand
N 60
Total
N 409
Carbamazepine 29 (29) 34 (21) 4 (14) 4 (7) 71(17)
Allopurinol 23 (14) 33 (20) 6 (21) 1 (7) 63 (15)
Infective sulfonamide 11(7) 28 (17) 2 (7) 9 (15) 50 (12)
Phenytoin 14 (9) 13 (8) 5 (18) 4 (7) 36 (9)
NSAIDs 14 (9) 10 (7) 3 (11) 4 (7) 31(8)
Lamotrigine 2 (1) 7 (4) 0 (0) 0 (0) 9 (2)
Phenobarbital 2 (1) 0 (0) 3 (11) 1 (2) 6(1)
Penicillins 19 (12) 14 (9) 1(4) 19 (32) 53(13)
Other antibiotics 16 (10) 3 (2) 2 (7) 12 (20) 33(8)
Others 17 (11) 16 (10) 1 (4) 6 (10) 40(10)
Traditional 12 (8) 4 (2) 1 (4) 0 (0) 17(4)
Data are presented as n (%).
NSAIDs nonsteroidal anti-inammatory drugs.
Figure 1 Distribution of StevenseJohnson syndrome, toxic epidermal necrolysis, and associated causal drugs (according to published case series). NSAIDS nonsteroidal anti-
inammatory drugs.
H.Y. Lee et al. / Dermatologica Sinica 31 (2013) 217e220 218
CBZ
Since the initial study by Chung et al,
26
which showed the strong
association between HLA-B*1502 and SJS/TEN in Han Chinese in
Taiwan, these results have been replicated in other Asian countries
including those within SE Asia such as Thailand,
28,29
Malaysia,
30
and Singapore (submitted for publication). In the original and
follow-up studies on Han Chinese in Taiwan, the odds ratio were
2504 [95% condence interval (CI) 126e49,522] and 1357 (95% CI
193e8838), respectively.
26,31
In the other SE Asian populations,
odds ratio were 16.2 (95% CI 4.6e62.0) for Malays in Malaysia and
54.76 for Thais in Thailand (95% CI 14.6e205.1). The association in
Caucasian populations is more tenuous. Lonjou et al
32
evaluated 12
patients with CBZ-induced SJS/TEN; only four patients carried the
HLA-B*1502 allele and all had Asian ancestry. In Asian populations,
the allele frequency of HLA-B*1502 is much higher compared to
Caucasian populations (Table 2). This variation in allelic frequency
may, in part, explain the variation in incidence of carbamazepine
induced SJS/TEN in SE Asia and Taiwan compared to other
populations.
Allopurinol
The link between HLA-B*5801 and allopurinol SCAR was rst re-
ported by Hung et al,
27
who demonstrated the presence of the allele
in 100% (51/51) of patients who developed allopurinol SCAR but
only in 15% (20/135) of controls. Similar ndings have been seen in
Thai populations where 100% (27/27) of patients with allopurinol
SCAR carried the HLA-B*5801 allele whereas only 13% (7/54) of the
controls carried the allele.
33
A meta-analysis of nine studies that
analyzed associations studies of HLA-B*5801 and SCAR (four
studies using case-matched controls and ve studies were popu-
lation controls) showed an odds ratio of 96.6 (95% CI 24.5e381) in
matched controls or 79.3 (95% CI 41.5e151.4) in population con-
trols. Subgroup analysis did not show signicant differences be-
tween Asian and non-Asian populations. Although there are ethnic
variations in the frequency of HLA-B*5801, it is signicantly less
compared to that of HLA-B*1502. The allele frequencies are sum-
marized in Table 3.
Prevention of SJS/TEN within SE Asia
Prescription habits/indications
Primary prevention of SJS/TENinvolves limiting exposure to a high-
risk drug through correct prescription indications and the use of
safer alternatives. The top three common classes of drugs in SE Asia
[CBZ and PHT (26%), allopurinol (15%), sulfonamide antibiotics
(12%)] are prone to such practice lapses. In SE Asia, allopurinol is
often prescribed for asymptomatic hyperuricemia and nonspecic
joint pains.
34,35
Similarly, phenytoin is often used as perioperative
seizure prophylaxis although evidence for its efcacy is lacking
36
and co-trimoxazole is used for the treatment of acne and follicu-
litis although safer and effective alternatives are available.
Screening prior to initiation of high-risk drugs
Screening and personalized drug therapy is the goal of phar-
amacogenetics research. However, prior to when such tests are
widely adopted, considerations such as the strength of pharmaco-
genetic association, the usefulness in therapeutic decision-making
(i.e., the presence of alternatives), the medical need, and cost-
effectiveness needs to be addressed. The usefulness of HLA
screening in preventing morbidity has been validated in the case of
HLA-B*1502 and CBZ SJS/TEN in Taiwan.
37
Since then, screening
prior to initiation of CBZ has also been found to be cost-effective in
Thailand, Malaysia, and Singapore
28e30,38
where the prevalence of
the HLA-B*1502 is high. With these initiatives in place, it is ex-
pected that the incidence of CBZ-induced SJS/TENin this regionwill
be lower in the future.
Conclusion
Prospective epidemiological studies are required to document the
incidence and drug causality of SJS/TEN in Asian populations. The
list of high-risk drugs appears similar in Asia and Europe. Although
variations in the incidence of SJS/TEN due to specic drugs may be
inuenced by both prescription practices and the incidence of the
underlying medical condition treated, it is likely that ethnic phar-
macogenetic differences play a major role. The use of screening
prior to initiation is a promising step to further reduce the mortality
and morbidity of such reactions.
Acknowledgments
The authors would like to acknowledge and thank Drs Choon Siew
Eng, Tang Min Moon, and Francisca Roa for providing information
on the local epidemiology of SJS/TEN from their countries.
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