Drug-induced hypersensitivity syndrome in Japan in the past 10 years based on data from the relief system of the Pharmaceuticals and Medical Devices Agency

Drug induced hypersensitivity syndrome in Japan in the past 10 years based on data from the relief system of the Pharmaceuticals and Medical Devices Agency lable at ScienceDirect Allergology Internati[.]

Letter to the Editor

Drug-induced hypersensitivity syndrome in Japan in the past 10 years

based on data from the relief system of the Pharmaceuticals and

Medical Devices Agency

Dear Editor,

Drug-induced hypersensitivity syndrome (DIHS) is

character-ized by a limited number of causal drugs, delayed onset, worsening

of clinical symptoms after discontinuation of the causal drugs,

sequential reactivations of several herpesviruses, and development

of several organ system failures long after clinical resolution.1,2The

causal drugs of DIHS include carmabazepine, phenytoin,

phenobar-bital, zonisamide, mexiletine, diaphenylsulfone (dapson),

salazo-sulfapyridine and allopurinol.2,3 The data of DIHS have been

collected to date mostly by referring to published article or meeting

abstracts Japan has a relief system for sufferers from adverse drug

reactions (ADRs) managed by the Pharmaceuticals and Medical

De-vices Agency (PMDA) which provides relief benefits for patients

with severe ADRs in the appropriate use of the drugs concerned.4

In recent years the proportion of DIHS among cutaneous ADRs

has significantly increased probably because this type of ADR has

become well known.5We analyzed the open data on DIHS patients

from the relief system of the PMDA during a 10-year period (http://

www.pmda.go.jp/relief-services/index.html) and elucidated the

recent trend of this ADR The c2-test was used to analyze the

data, and p< 0.05 was considered statistically significant

Table 1shows a summary of DIHS cases in the past 10 years The

total number of these cases during the period was 835 of which 51

had died (mortality rate: 6.1%).Figure 1a depicts the number of DIHS

cases fromfiscal year (FY) 2006e2015, disclosing that the number

tended to increase year by year There were 299 in thefirst 5 years

(FY 2006e2010), whereas these increased to 536 in the latter 5 years

(FY 2011e2015,Table 1).Figure 1b shows the mortality rates of DIHS

cases from FY 2006 to 2015, revealing they varied from 0.0% to 14.6%

depending on the year The average mortality rates in thefirst 5

years (6.0%) and the latter 5 years (6.2%) were almost the same

(Table 1) Of note, the mortality rates in the most recent two years

were very low, with 2.8% and 0.0% in FS 2014 and 2015, respectively

Of the total of 835 patients, 438 (52.5%) were males and 397 (47.5%)

were females The most frequent ages were 60e69 years (20.6%),

fol-lowed by 40e49 (19.3%), 30e39 (16.0%), 50e59 (14.7%), 70e79

(11.9%) and 20e29 (9.1%) The total number of causal drugs was

959 including overlapping drugs in the same patient The most

frequent type of causal drug was anticonvulsants (61.8%), followed

by antihyperuricemics (10.0%), bowel disease treating agents

(8.8%), antibiotics (4.9%), antiarrhythmic drugs (4.8%), antipsychotic

drugs (3.5%) and antileprosy drugs (2.4%) The percentage of antibi-otics was significantly higher in the latter 5 years than in the first 5 years (6.3% vs 2.5%, p< 0.05), and that of antipsychotic drugs was significantly lower (1.8% vs 6.5%, p < 0.001) With regard to individ-ual drugs, the most frequent causal drug was carbamazepine (35.1%,

an anticonvulsant), followed by allopurinol (10.0%, an antihyperuri-cemic), lamotrigine (9.3%, an anticonvulsant), salazosulfapyridine (8.4%, a bowel disease treating agent), mexiletine hydrochloride (4.8%, an antiarrhythmic drug), zonisamide (4.7%, an anticonvul-sant), phenobarbital (4.5%, an anticonvulanticonvul-sant), phenytoin (4.4%, an anticonvulsant), sodium valproate (3.3%, an anticonvulsant), diaphe-nylsulfone (2.4%, an antileprosy drug), chlorpromazine eprometha-zineephenobarbital (2.1%, an antipsychotic drug) and sulfametho-xazoleetrimethoprim (2.0%, an antibiotic) The percentage of lamo-trigine was significantly higher in the latter 5 years than in the first years (14.2% vs 0.8%, p< 1  10 10), and those of the following three drugs were lower: zonisamide (2.6% vs 8.2%, p< 1  10 4), pheno-barbital (3.3% vs 6.5%, p< 1  10 4) and chlorpromazine eprome-thazineephenobarbital (1.2% vs 3.7%, p < 0.05)

Fiscal years

Fiscal years

(a)

(b) 0 20 40 60 80 100 120 140 160

2006 2007 2008 2009 2010 2011 2012 2013 2014 2015

0 2 4 6 8 10 12 14 16

2006 2007 2008 2009 2010 2011 2012 2013 2014 2015

44 46 56

76 77 82

111 95

140

108

6.8 10.9

7.1

2.6 5.2

14.6

6.3 10.5

2.8

0.0

Fig 1 (a) Number of DIHS cases from fiscal year (FY) 2006e2015 (b) Mortality rates of DIHS cases from FY 2006e2015.

Peer review under responsibility of Japanese Society of Allergology.

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Allergology International xxx (2016) 1e3

http://dx.doi.org/10.1016/j.alit.2016.09.003

1323-8930/Copyright © 2016, Japanese Society of Allergology Production and hosting by Elsevier B.V This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/ licenses/by-nc-nd/4.0/ ).

DIHS is one of the severest forms of cutaneous ADRs and the

mor-tality rate is reported to be about 10%e20%.6The average mortality

rate in this study was 6.1% which was slightly lower than those in

the previous reports Of note, the mortality rates in FT2014 and

2015 were 2.8% and 0.0%, respectively, suggesting DIHS cases are

be-ing successfully treated nowadays in Japan, although there is no

apparent difference of treatment for DIHS between the recent two

years and other years The decrease of the mortality rate is seemingly

associated with accumulation of atypical or indefinite cases of DIHS

The mainstay of therapy is systemic corticosteroids and marked

dete-rioration is often observed with too rapid tapering of corticosteroids.7

Shiohara et al recommend that all DIHS patients be hospitalized even

if the initial presentation is mild.7Adults are more affected than

chil-dren with no gender predilection,6 which was confirmed in this

study It is necessary to recognize the recent trend of frequent causal

drugs in DIHS, and this study demonstrated that about 60% of the

cases were caused by anticonvulsants The most frequent causal

drug was carbamazepine which accounted for about one third of

the cases Lamotrigine is one of the newer anticonvulsant and

cutaneous ADR including DIHS caused by this drug has increased in the four most recent years.8 Criado et al reported that DIHS is commonly seen with the use of drugs such as anticonvulsants (phenytoin, carbamazepine, phenobarbital, mexiletine, lamotrigine, valproate, zonisamide), sulfonamides and sulfones (diaphenylsul-fone, salazosulfapyridine, sulfamethoxazoleetrimethoprim) and allo-purinol.6The top 12 causal drugs in this study were all included in Criado's report Mexiletine is used for patients with arrhythmia and diabetic neuropathy in Japan, but is known to show anticonvulsant activity.9Diaphenylsulfone is classified as an antileprosy drug, but

it is usually used for skin diseases such as erythema elevatum diuti-num, linear IgA bullous dermatosis and prurigo pigmentosa in Japan Although minocycline-induced DIHS has been reported frequently in other countries, it is not common in Japan,2and there were only 4 cases (0.4%) in this study It is true that PMDA data include the reports

by non-dermatologists However, all cases with cutaneous ADRs were scrutinized by three dermatologists including us who belong to the Judgment Committee of this relief system and inappropriate conclu-sions were revised It may be better to re-analyze these data after

Table 1

Summary of DIHS in Japan in the past 10 years.

Gender

Ages

DIHS, drug-induced hypersensitivity syndrome.

P values were evaluated when comparing between FY 2006e2010 and FY 2011e2015.

Letter to the Editor / Allergology International xxx (2016) 1e3 2

being grouped into typical and atypical DIHS, however it is

impos-sible because the open data of the PMDA does not contain the

infor-mation about typical and atypical one Further detailed

epidemiological studies of DIHS are necessary

Conflict of interest

The authors have no conflict of interest to declare.

Yuri Kinoshitaa, Hidehisa Saekia , *, Akihiko Asahinab,

Toyoko Ochiaic, Masafumi Iijimad

a Department of Dermatology, Nippon Medical School, Tokyo, Japan

b Department of Dermatology, The Jikei University School of Medicine, Tokyo, Japan

c Department of Dermatology, Nihon University Hospital, Tokyo, Japan

d Department of Dermatology, Showa University School of Medicine, Tokyo, Japan

* Corresponding author Department of Dermatology, Nippon Medical School,

1-1-5, Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan.

E-mail address: h-saeki@nms.ac.jp (H Saeki).

References

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infec-tion Clin Rev Allergy Immunol 2007;33:124e33

2 Tohyama M, Hashimoto K New aspects of drug-induced hypersensitivity syn-drome J Dermatol 2011;38:222e8

3 Shiohara T, Iijima M, Ikezawa Z, Hashimoto K The diagnosis of a DRESS syn-drome has been sufficiently established on the basis of typical clinical features and viral reactivations Br J Dermatol 2007;156:1083e4

4 Nanko H [Adverse drug reactions (ADR) and severe drug eruptions in Japan] [Jpn J Dermatol] 2005;115:1155e62 (in Japanese)

5 Saeki H, Ochiai T, Iijima M Comparison of severe drug eruptions in Japan be-tween 2005e2009 and 2010e2014 based on data from the relief system of the Pharmaceuticals and Medical Devices Agency J Dermatol 2016 http:// dx.doi.org/10.1111/1346-8138.13472

6 Criado PR, Criado RF, Avancini JM, Santi CG Drug reaction with eosinophilia and systemic symptoms (DRESS)/drug-induced hypersensitivity syndrome (DIHS): a review of current concepts An Bras Dermatol 2012;87:435e49

7 Shiohara T, Inaoka M, Kano Y Drug-induced hypersensitivity syndrome (DIHS): a reaction induced by a complex interplay among herpesviruses and anti-drug im-mune responses Allergol Int 2006;55:1e8

8 Saeki H, Yamada K, Morikawa N, Asahina A, Ochiai T, Iijima M Severe drug erup-tions due to lamotrigine in Japan based on data from the relief system of the Pharmaceuticals and Medical Devices Agency Allegol Int 2016 http:// dx.doi.org/10.1016/j.alit.2016.07.006

9 Borowicz KK, Banach M Antiarrhythmic drugs and epilepsy Pharmacol Rep 2014;66:545e51

Received 25 July 2016 Received in revised form 13 September 2016

Accepted 29 September 2016 Available online xxx