DERMATOLOGICA SINICA 31 (2013) 217e220

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Dermatologica Sinica
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INVITED ARTICLE

Epidemiology of StevenseJohnson syndrome and toxic epidermal

necrolysis in Southeast Asiaq
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: estimated the incidence of SJS/TEN within Germany to be within 1e

Received: Aug 7, 2013 2 cases/million/year.5
Revised: Sep 24, 2013 It is now known that there is a strong genetic association be-
Accepted: Sep 25, 2013 tween human leukocyte antigens and drug-induced SJS/TEN. These
genetic associations are not only drug and phenotypic specic, but
Keywords:
are also ethnic specic as well. The aim of this review is to sum-
epidemiology
southeast Asia marize existing epidemiological data on SJS/TEN within Southeast
StevenseJohnson syndrome (SJS) (SE) Asia.
toxic epidermal necrolysis (TEN)

Geography of SE Asia

SE Asia is a diverse region made up of 10 member countries (Brunei,

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 EuroSCAR2 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
Cambodia, Indonesia, Laos, Malaysia, Myanmar, Philippines,
Thailand, Singapore, and Vietnam). It covers a land area of 4.5
million km2 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 from 1.3 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

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).
In SE Asia, based on published retrospective case series reported
from 1984 to 201310e19 (overlapping publications have been
excluded), the major culprit drugs implicated include carbamaze-
pine (CBZ; 17%), allopurinol (15%), sulfonamide antibiotics (12%),

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
218 H.Y. Lee et al. / Dermatologica Sinica 31 (2013) 217e220

Table 1 Reported cases of StevenseJohnson syndrome and toxic epidermal nec- origin. However, such medications are poorly regulated and the
rolysis, and their associated causal drug. constituents of these medications are not always known. Comple-
Associated drug Singapore Malaysia Philippines Thailand Total mentary medications have been associated with 4% of cases in
N 159 N 162 N 28 N 60 N 409 Singapore and 5% of reported cases from Malaysia (Dr M.M. Tang,
Carbamazepine 29 (29) 34 (21) 4 (14) 4 (7) 71(17) Kuala Lumpur, Malaysia, personal communication) and reports of
Allopurinol 23 (14) 33 (20) 6 (21) 1 (7) 63 (15) these medications being adulterated by phenylbutazone have been
Infective sulfonamide 11(7) 28 (17) 2 (7) 9 (15) 50 (12) reported.21,22
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) Occupational trigger
Phenobarbital 2 (1) 0 (0) 3 (11) 1 (2) 6(1)
Penicillins 19 (12) 14 (9) 1(4) 19 (32) 53(13)
Occupational exposure to trichloroethylene has occasionally been
Other antibiotics 16 (10) 3 (2) 2 (7) 12 (20) 33(8)
Others 17 (11) 16 (10) 1 (4) 6 (10) 40(10)
reported as a trigger of SJS/TEN and DRESS in SE Asia and Asia, with
Traditional 12 (8) 4 (2) 1 (4) 0 (0) 17(4) cases being reported in Singapore, Thailand, Philippines, Japan,
Taiwan, and China.23e25 Trichloroethylene is an organic solvent that
Data are presented as n (%).
NSAIDs nonsteroidal anti-inammatory drugs. 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
phenytoin (PHT; 9%), nonsteroidal anti-inammatory drugs (8%), some of these cases, environmental levels, urinary trichloroethy-
lamotrigine (2%), phenobarbital (1%), and b-lactam antibiotics lene concentrations, as well as airborne exposure concentrations
(13%). The distribution of reported cases and causal drugs are were found to be higher than the standard threshold limits.
summarized in Table 1 and Figure 1. High-risk drugs, as identied in
the European studies, were also major culprits in SE Asia being the Idiopathic cases
implicated drug in 64% of cases.1,2
It is being increasingly recognized that a signicant proportion of
Variations in SE Asia drug causality 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
CBZ and PHT induced SCAR 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-
The proportion of CBZ and PHT-induced SJS/TEN in SE Asia is tients, there were three cases attributed to infections with myco-
signicantly higher, accounting for 26% of all cases (Figure 1), as plasma, three cases were associated with systemic lupus
opposed to 12% in European populations.20 Although variations in erythematosus, and ve cases had no drug trigger.19 Similar pro-
clinical practice, prescribing patterns, and incidence of disease may portions of non-drug-induced cases were also reported in the
play a role, it is believed that pharmacogenetic variations between Philippines (3/31).14
different ethnicities is a major factor.
Pharmacogenetic epidemiology of SJS/TEN
Complementary medications
Genetic susceptibility for SJS/TEN has been proposed. It has been
The use of traditional/complementary medications such as tradi- claried that such genetic risks are specic for the type of reaction
tional Chinese medications and jamuda form of Indonesian/Malay as well as for the drug and ethnicity. The pharmacogenetic risks of
herbal preparationdis widespread within the region and is SJS/TEN are best demonstrated in the models of HLA-B*1502 and
culturally acceptable and perceived to be safe due to its herbal HLA-B*5801 for CBZ and allopurinol respectively.26,27

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 219

Table 2 Association of HLA-B*1502 and carbamazepine (CBZ) StevenseJohnson Table 3 Association of HLA-B*5801 and allopurinol StevenseJohnson syndrome
syndrome (SJS) and toxic epidermal necrolysis (TEN).a (SJS) and toxic epidermal necrolysis (TEN).a

Country Percentage HLA-B*1502 Incidence of HLA-B*1502 Country Percentage of SJS/ HLA-B*5801 Incidence of HLA-B*5801
of SJS/TEN population allele in CBZ induced SJS/TEN TEN cases population in allopurinol SJS/TEN
cases attributed frequency (%) attributed allele
to CBZ (%) to allopurinol (%) frequency (%)

Europe4,20,32,39,40 4e8 <0.1 (Germany, 0/13 (Caucasians), Europe20,32,40 14e17 1e6 19/31
Ireland, Italy) 4/4 (Asians in Europe) Taiwan27 17 Han Chinese: 11 21/21
26,31,41
Taiwan 25e33 Han Chinese: 8.6 41/41 (Han Chinese) Malaysia42 19e21 Malaysian NA
Malaysia30,42 24 Malaysian 12/16 (Malays) Malays: 6e14
Malays: 8.3 Philippines14 19 NA NA
Philippines14 13 Filipinos: 22 NA Singapore13,15,19 7e15 Chinese: 6e11
Singapore13,15,19,43 14e36 Singapore NA Malay: 3e5 NA
Chinese: 11.6 Thailand16,33 2 Thais: 6e8 27/27
Thailand16,28,29,44 7 Thais: 8.5 37/42 (Thai) a
Allele frequencies derived from references and www.allelefrequency.net.
a
Allele frequencies derived from references and www.allelefrequency.net.

(12%)] are prone to such practice lapses. In SE Asia, allopurinol is

CBZ often prescribed for asymptomatic hyperuricemia and nonspecic
joint pains.34,35 Similarly, phenytoin is often used as perioperative
Since the initial study by Chung et al,26 which showed the strong seizure prophylaxis although evidence for its efcacy is lacking36
association between HLA-B*1502 and SJS/TEN in Han Chinese in and co-trimoxazole is used for the treatment of acne and follicu-
Taiwan, these results have been replicated in other Asian countries litis although safer and effective alternatives are available.
including those within SE Asia such as Thailand,28,29 Malaysia,30
and Singapore (submitted for publication). In the original and
Screening prior to initiation of high-risk drugs
follow-up studies on Han Chinese in Taiwan, the odds ratio were
2504 [95% condence interval (CI) 126e49,522] and 1357 (95% CI
Screening and personalized drug therapy is the goal of phar-
193e8838), respectively.26,31 In the other SE Asian populations,
amacogenetics research. However, prior to when such tests are
odds ratio were 16.2 (95% CI 4.6e62.0) for Malays in Malaysia and
widely adopted, considerations such as the strength of pharmaco-
54.76 for Thais in Thailand (95% CI 14.6e205.1). The association in
genetic association, the usefulness in therapeutic decision-making
Caucasian populations is more tenuous. Lonjou et al32 evaluated 12
(i.e., the presence of alternatives), the medical need, and cost-
patients with CBZ-induced SJS/TEN; only four patients carried the
effectiveness needs to be addressed. The usefulness of HLA
HLA-B*1502 allele and all had Asian ancestry. In Asian populations,
screening in preventing morbidity has been validated in the case of
the allele frequency of HLA-B*1502 is much higher compared to
HLA-B*1502 and CBZ SJS/TEN in Taiwan.37 Since then, screening
Caucasian populations (Table 2). This variation in allelic frequency
prior to initiation of CBZ has also been found to be cost-effective in
may, in part, explain the variation in incidence of carbamazepine
Thailand, Malaysia, and Singapore28e30,38 where the prevalence of
induced SJS/TEN in SE Asia and Taiwan compared to other
the HLA-B*1502 is high. With these initiatives in place, it is ex-
populations.
pected that the incidence of CBZ-induced SJS/TEN in this region will
be lower in the future.
Allopurinol
Conclusion
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
Prospective epidemiological studies are required to document the
in 100% (51/51) of patients who developed allopurinol SCAR but
incidence and drug causality of SJS/TEN in Asian populations. The
only in 15% (20/135) of controls. Similar ndings have been seen in
list of high-risk drugs appears similar in Asia and Europe. Although
Thai populations where 100% (27/27) of patients with allopurinol
variations in the incidence of SJS/TEN due to specic drugs may be
SCAR carried the HLA-B*5801 allele whereas only 13% (7/54) of the
inuenced by both prescription practices and the incidence of the
controls carried the allele.33 A meta-analysis of nine studies that
underlying medical condition treated, it is likely that ethnic phar-
analyzed associations studies of HLA-B*5801 and SCAR (four
macogenetic differences play a major role. The use of screening
studies using case-matched controls and ve studies were popu-
prior to initiation is a promising step to further reduce the mortality
lation controls) showed an odds ratio of 96.6 (95% CI 24.5e381) in
and morbidity of such reactions.
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 Acknowledgments
variations in the frequency of HLA-B*5801, it is signicantly less
compared to that of HLA-B*1502. The allele frequencies are sum- The authors would like to acknowledge and thank Drs Choon Siew
marized in Table 3. Eng, Tang Min Moon, and Francisca Roa for providing information
on the local epidemiology of SJS/TEN from their countries.

Prevention of SJS/TEN within SE Asia

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