ro

p

Keywords:

d toxic epidermal necrolysisreactions characterized by

international caseecontrol SCAR (severe cutaneous adverse re-

1.2 and 0.9 cases/million/year, respectively. Newer prospectivepopulation-based studies based on the German registry have

The incidence of SJS/TEN in SE Asia is largely undetermined. Noeen published. Ad the incidence ofWhen consideredse drug reactionsDRs to 4.2 CADRs/severe cutaneousthese reactions.8,9

ong new patients

reactions.

Drug causality

In SE Asia, based on published retrospective case series reportedfrom 1984 to 201310e19 (overlapping publications have beenexcluded), 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 ofStevenseJohnson syndrome and toxic epidermal necrolysis in Southeast Asia.* Corresponding author. Dermatology Unit, Singapore General Hospital, Outram

Road, Singapore 169608. Tel.: 65 63214933.

Contents lists availab

Dermatolog

journal homepage: http: /

DERMATOLOGICA SINICA 31 (2013) 217e220E-mail address: Lee.haur.yueh@sgh.com.sg (H.Y. Lee).have estimated the incidence of TEN in France and Germany to be3,4

assessed in a tertiary hospital and SJS/TEN account for 30% of these9actions)1 and EuroSCAR2 studies have shown that in Europe, themajority of reactions can be attributed to a group of high-risk drugssuch as allopurinol, carbamazepine, phenytoin, lamotrigine, oxicamnonsteroidal anti-inammatory drugs, sulfonamide antibiotics, andnevirapine.

In parallel, several epidemiological studies (both retrospectiveand prospective) have been conducted in Europe looking at theincidence of SJS/TEN. Initial hospital-based retrospective studies

prospectively epidemiological studies have bretrospective hospital-based study has estimateTEN in Singapore to be at least 1.4 cases/million.7

as a whole, the prevalence of cutaneous adver(CADR) in hospitalized patients varies from 1.3 CA1000 hospitalized patients in Singapore withadverse reactions (SCAR) constituting 5e14% ofIn Malaysia, the incidence of CADR is 0.86% amtions have been reported to be causal in these reactions, theepidermal detachment and mucosidominantly drug-related. Althoughtis. These reactions are pre-a wide spectrum of medica- Epidemiology of SJS/TEN in SE Asiatoxic epidermal necrolysis (TEN)

Introduction

StevenseJohnson syndrome (SJS) an(TEN) are severe life-threateningepidemiologysoutheast AsiaStevenseJohnson syndrome (SJS)INVITED ARTICLE

Epidemiology of StevenseJohnson syndnecrolysis in Southeast Asiaq

Haur Yueh Lee 1,*, Wijaya Martanto 2, Thamotharam1Department of Dermatology, Singapore General Hospital, Singapore2Duke-NUS Graduate Medical School, Singapore

a r t i c l e i n f o

Article history:Received: Aug 7, 2013Revised: Sep 24, 2013Accepted: Sep 25, 20131027-8117/$ e see front matter Copyright 2013, Taiwanese Dermatological Associatiohttp://dx.doi.org/10.1016/j.dsi.2013.09.007me and toxic epidermal

illai Thirumoorthy 1

estimated the incidence of SJS/TENwithin Germany to bewithin 1e2 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. Thesegenetic associations are not only drug and phenotypic specic, butare 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 regionmade up of 10member countries (Brunei,Cambodia, Indonesia, Laos, Malaysia, Myanmar, Philippines,Thailand, Singapore, and Vietnam). It covers a land area of 4.5million km2 and has a population of approximately 600 millionpeople of diverse ethnicities.6 Many of the data on SJS/TEN in thisregion have been derived from publications originating fromMalaysia, Philippines, Singapore, and Thailand and these will besummarized in this review.

le at ScienceDirect

ica Sinica

/www.derm-sinica.comn. Published by Elsevier Taiwan LLC. All rights reserved.

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 aresummarized in Table 1 and Figure 1. High-risk drugs, as identied in

origin. However, such medications are poorly regulated and theconstituents of these medications are not always known. Comple-mentary medications have been associated with 4% of cases inSingapore and 5% of reported cases from Malaysia (Dr M.M. Tang,Kuala Lumpur, Malaysia, personal communication) and reports ofthese medications being adulterated by phenylbutazone have beenreported.21,22

Occupational trigger

Occupational exposure to trichloroethylene has occasionally beenreported as a trigger of SJS/TEN and DRESS in SE Asia and Asia, withcases being reported in Singapore, Thailand, Philippines, Japan,Taiwan, and China.23e25 Trichloroethylene is an organic solvent thatis used widely as a degreasing solvent in developing countries.Typically, patients present with the cutaneous eruptions from 2weeks to 2months after occupational exposure. In the evaluation ofsome of these cases, environmental levels, urinary trichloroethy-lene concentrations, as well as airborne exposure concentrationswere found to be higher than the standard threshold limits.

Table 1 Reported cases of StevenseJohnson syndrome and toxic epidermal nec-rolysis, and their associated causal drug.

Associated drug SingaporeN 159

MalaysiaN 162

PhilippinesN 28

ThailandN 60

TotalN 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.

H.Y. Lee et al. / Dermatologica Sinica 31 (2013) 217e220218the European studies, were also major culprits in SE Asia being theimplicated 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 issignicantly higher, accounting for 26% of all cases (Figure 1), asopposed to 12% in European populations.20 Although variations inclinical practice, prescribing patterns, and incidence of disease mayplay a role, it is believed that pharmacogenetic variations betweendifferent ethnicities is a major factor.

Complementary medications

The use of traditional/complementary medications such as tradi-tional Chinese medications and jamuda form of Indonesian/Malayherbal preparationdis widespread within the region and isculturally acceptable and perceived to be safe due to its herbalFigure 1 Distribution of StevenseJohnson syndrome, toxic epidermal necrolysis, and assoinammatory drugs.Idiopathic cases

It is being increasingly recognized that a signicant proportion ofSJS/TEN are not drug related. From 15% to 25% of cases of SJS/TENhad no prior drug history or occurred in circumstances inwhich thedrug causality was deemed to be unlikely.2e20 In Singapore, about10% 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 lupuserythematosus, and ve cases had no drug trigger.19 Similar pro-portions of non-drug-induced cases were also reported in thePhilippines (3/31).14

Pharmacogenetic epidemiology of SJS/TEN

Genetic susceptibility for SJS/TEN has been proposed. It has beenclaried that such genetic risks are specic for the type of reactionas well as for the drug and ethnicity. The pharmacogenetic risks ofSJS/TEN are best demonstrated in the models of HLA-B*1502 andHLA-B*5801 for CBZ and allopurinol respectively.26,27ciated causal drugs (according to published case series). NSAIDS nonsteroidal anti-

gicaCBZ

Since the initial study by Chung et al,26 which showed the strongassociation between HLA-B*1502 and SJS/TEN in Han Chinese inTaiwan, these results have been replicated in other Asian countriesincluding those within SE Asia such as Thailand,28,29 Malaysia,30

and Singapore (submitted for publication). In the original andfollow-up studies on Han Chinese in Taiwan, the odds ratio were2504 [95% condence interval (CI) 126e49,522] and 1357 (95% CI193e8838), respectively.26,31 In the other SE Asian populations,odds ratio were 16.2 (95% CI 4.6e62.0) for Malays in Malaysia and54.76 for Thais in Thailand (95% CI 14.6e205.1). The association inCaucasian populations is more tenuous. Lonjou et al32 evaluated 12patients with CBZ-induced SJS/TEN; only four patients carried theHLA-B*1502 allele and all had Asian ancestry. In Asian populations,the allele frequency of HLA-B*1502 is much higher compared toCaucasian populations (Table 2). This variation in allelic frequencymay, in part, explain the variation in incidence of carbamazepineinduced SJS/TEN in SE Asia and Taiwan compared to otherpopulations.

Allopurinol

The link between HLA-B*5801 and allopurinol SCAR was rst re-ported byHung et al,27 who demonstrated the presence of the allelein 100% (51/51) of patients who developed allopurinol SCAR butonly in 15% (20/135) of controls. Similar ndings have been seen inThai populations where 100% (27/27) of patients with allopurinolSCAR carried the HLA-B*5801 allele whereas only 13% (7/54) of thecontrols carried the allele.33 A meta-analysis of nine studies thatanalyzed associations studies of HLA-B*5801 and SCAR (four

Table 2 Association of HLA-B*1502 and carbamazepine (CBZ) StevenseJohnsonsyndrome (SJS) and toxic epidermal necrolysis (TEN).a

Country Percentageof SJS/TENcases attributedto CBZ (%)

HLA-B*1502population allelefrequency (%)

Incidence of HLA-B*1502in CBZ induced SJS/TEN

Europe4,20,32,39,40 4e8

3. Roujeau JC, Guillaume JC, Fabre JP, et al. Toxic epidermal necrolysis (Lyellssyndrome): incidence and drug etiology in France, 1981e1985. Arch Dermatol1990;126:37e42.

4. Schopf E, Sthmer A, Rzany B, et al. Toxic epidermal necrolysis and Stevenssyndrome: an epidemiologic study from West Germany. Arch Dermatol1991;127:839e42.

5. Mockenhaupt M. Epidemiology of cutaneous adverse drug reactions. ChemImmunol Allergy 2012;97:1e17.

6. ASEAN Statistics Leaet: Selected key indicators 2012. Available at: http://www.ASEAN.org [accessed 01.07.13].

7. Chan HL. Toxic epidermal necrolysis in Singapore 1989 through 1993: inci-dence and antecedent drug exposure. Arch Dermatol 1995;131:1212e3.

8. Lee HY, Tay LK, Thirumoorthy T, Pang SM. Cutaneous adverse drug reactions inhospitalised patients. Singapore Med J 2010;51:767e74.

9. Thong BYH, Leong KP, Tang CY, Chng HH. Drug allergy in a general hospital:results of a novel prospective inpatient reporting system. Ann Allergy AsthmaImmunol 2003;90:342e7.

10. Choon SE, Lai NM. An epidemiological and clinical analysis of cutaneousadverse drug reactions seen in a tertiary hospital in Johor, Malaysia. Ind J DermVenereol Leprol 2012;6:734e9.

11. Chan HL. Observations on drug-induced toxic epidermal necrolysis inSingapore. J Am Acad Dermatol 1984;10:973e8.

12. Tan WC, Lo Kang SC, Ong CK, et al. Cutaneous adverse drug reactionsobserved in a dermatology clinic, Penang General Hospital. Malays J Derm2008;21:83e7.

13. Khoo AK, Foo CL. Toxic epidermal necrolysis in a burns centre: a 6eyear re-

24. Phoon WH, Chan MO, Rajan VS, Tan KJ, Thirumoorthy T, Goh CL. StevenseJohnson syndrome associated with occupational exposure to trichloroethylene.Contact Dermatitis 1984;10:270e6.

25. Goon AT, Lee LT, Tay YK, Yosipovitch G, Ng SK, Giam YC. A case of trichloro-ethylene hypersensitivity syndrome. Arch Dermatol 2001;137:274e6.

26. Chung WH, Hung SI, Hong HS, et al. Medical genetics: a marker for StevenseJohnson syndrome. Nature 2004;428:426.

27. Hung SI, Chung WH, Liou LB, et al. HLA-B*5801 allele as a genetic marker forsevere cutaneous adverse reactions caused by allopurinol. Proc Natl Acad SciUSA 2005;102:4134e9.

28. Locharernkul C, Loplumlert J, Limotai C, et al. Carbamazepine and phenytoininduced StevenseJohnson syndrome is associated with HLA-B*1502 allele inThai population. Epilepsia 2008;49:2087e91.

29. Tassaneeyakul W, Tiamkao S, Jantararoungtong T, et al. Association betweenHLA-B*1502 and carbamazepine-induced severe cutaneous adverse drug re-actions in a Thai population. Epilepsia 2010;51:926e30.

30. Chang CC, Too CL, Murad S, Hussein SH. Association of HLA-B*1502 allele withcarbamazepine induced toxic epidermal necrolysis and StevenseJohnsonsyndrome in the multi-ethnic Malaysian population. Int J Dermatol 2011;50:221e4.

31. Hung SI, Chung WH, Jee SH, et al. Genetic susceptibility to carbamazepine-induced cutaneous adverse drug reactions. Pharmacogenet Genomics 2006;16:297e306.

32. Lonjou C, Thomas L, Borot N, et al. A marker for StevenseJohnson syndrome...:ethnicity matters. Pharmacogenomics J 2006;6:265e8.

33. Tassaneeyakul W, Jantararoungtong T, Chen P, et al. Strong association be-

H.Y. Lee et al. / Dermatologica Sinica 31 (2013) 217e220220view. Burns 1996;22:275e8.14. Onishi EC, Roa F. StevenseJohnson syndrome and toxic epidermal necrolysis at

the Philippine General Hospital: A seven-year retrospective study. J PhilippDermatol Soc 2013;1:29e36.

15. Tan SK, Tay YK. Prole and pattern of StevenseJohnson syndrome and toxicepidermal necrolysis in a General Hospital in Singapore: Treatment outcomes.Acta Derm Venereol 2012;92:62e6.

16. Leenutaphong V, Sivayathorn A, Suthipinittharm P, Sunthonpalin P. StevenseJohnson syndrome and toxic epidermal necrolysis in Thailand. Int J Dermatol1993;32:428e31.

17. Ting HC, Adam BA. Toxic epidermal necrolysis in Malaysian adults: a retro-spective study. Singapore Med J 1985;26:456e9.

18. Kamaliah MD, Zainal D, Mokhtar N, Nazmi N. Erythema multiforme, StevenseJohnson syndrome and toxic epidermal necrolysis in northeast Malaysia. Int JDermatol 1998;37:520e3.

19. Lee HY, Thirumoorthy T, Pang SM. StevenseJohnson syndrome and toxicepidermal necrolysis in Singapore: epidemiology and drug causality. Presentedat European Academy of Allergy and Clinical Immunology & World AllergyOrganization Meeting, June 22e26, 2013, Milan, Italy.

20. Sassolas B, Haddad C, Mockenhaupt M, et al. ALDEN, an algorithm for assess-ment of drug causality in StevenseJohnson syndrome and toxic epidermalnecrolysis: comparison with case-control analysis. Clin Pharmacol Ther2010;88:60e8.

21. Giam YC, Tham SN, Tan T, Lim A. Drug eruptions from phenylbutazone in Jamu.Ann Acad Med Singapore 1986;15:118e21.

22. Lim YL, Thirumoorthy T. Serious cutaneous adverse reactions to traditionalChinese medicines. Singapore Med J 2005;46:714e7.

23. Kamijima M, Hisanaga N, Wang H, Nakajima T. Occupational trichloroethyleneexposure as a cause of idiosyncratic generalized skin disorders and accompa-nying hepatitis similar to drug hypersensitivities. Int Arch Occup Environ Health2008;80:357e70.tween HLA-B*5801 and allopurinol-induced StevenseJohnson syndrome andtoxic epidermal necrolysis in a Thai population. Pharmacogenet Genomics2009;19:704e9.

34. Lee HY, Ariyasinghe JT, Thirumoorthy T. Allopurinol hypersensitivity syn-drome: a preventable severe cutaneous adverse reaction? Singapore Med J2008;49:384e7.

35. Athisakul S, Wangkaew S, Louthrenoo W. Inappropriate prescription of allo-purinol in a teaching. J Med Assoc Thai 2007;90:889e94.

36. Wu AS, Trinh VT, Suki D, Graham S. A prospective randomized trial of peri-operative seizure prophylaxis in patients with intraparenchymal brain tumors.J Neurosurg 2013;118:873e83.

37. Chen P, Lin JJ, Ong CT, et al. Carbamazepine-induced toxic effects and HLA-B*1502 screening in Taiwan. N Engl J Med 2011;364:1126e33.

38. Dong D, Sung C, Finkelstein EA. Cost-effectiveness of HLA-B*1502 genotypingin adult patients with newly diagnosed epilepsy in Singapore. Neurology2012;79:1259e67.

39. Guillaume JC, Roujeau JC, Revuz J, et al. The culprit drugs in 87 cases of toxicepidermal necrolysis. Arch Dermatol 1987;123:1166e70.

40. Halevy S, Ghislain PD, Mockenhaupt M, et al. Allopurinol is the most commoncause of StevenseJohnson syndrome and toxic epidermal necrolysis in Europeand Israel. J Am Acad Dermatol 2008;58:25e32.

41. Lin MS, Dai YS, Pwu RF, Chen YH, Chang NC. Risk estimates for drugs suspectedof being associated with StevenseJohnson syndrome and toxic epidermalnecrolysis: a caseecontrol study. Intern Med J 2005;35:188e90.

42. Ding WY, Lee CK, Choon SE. Cutaneous adverse drug reactions seen in a tertiaryhospital in Johor, Malaysia. Int J Dermatol 2010;49:834e41.

43. Williams F, Meenagh A, Darke C, et al. Analysis of the distribution of HLA-Balleles in populations from ve continents. Hum Immunol 2001;62:645e50.

44. Pimtanothai N, Charoenwongse P, Mutirangura A, Hurley CK. Distribution ofHLA-B alleles in nasopharyngeal carcinoma patients and normal controls inThailand. Tissue Antigens 2002;59:223e5.

Epidemiology of StevensJohnson syndrome and toxic epidermal necrolysis in Southeast AsiaIntroductionGeography of SE AsiaEpidemiology of SJS/TEN in SE AsiaDrug causalityVariations in SE Asia drug causalityCBZ and PHT induced SCARComplementary medicationsOccupational triggerIdiopathic cases

Pharmacogenetic epidemiology of SJS/TENCBZAllopurinol

Prevention of SJS/TEN within SE AsiaPrescription habits/indicationsScreening prior to initiation of high-risk drugs

ConclusionAcknowledgmentsReferences