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[.]
Allergology International xxx (2016) 1e3 Contents lists available at ScienceDirect Allergology International journal homepage: http://www.elsevier.com/locate/alit 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 Peer review under responsibility of Japanese Society of Allergology (a) 160 140 140 DIHS cases Drug-induced hypersensitivity syndrome (DIHS) is characterized 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.1,2 The causal drugs of DIHS include carmabazepine, phenytoin, phenobarbital, zonisamide, mexiletine, diaphenylsulfone (dapson), salazosulfapyridine 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 Devices 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.5 We 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 shows 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 from fiscal year (FY) 2006e2015, disclosing that the number tended to increase year by year There were 299 in the first years (FY 2006e2010), whereas these increased to 536 in the latter 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 the first years (6.0%) and the latter 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%), followed 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 antibiotics was significantly higher in the latter years than in the first 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 individual drugs, the most frequent causal drug was carbamazepine (35.1%, an anticonvulsant), followed by allopurinol (10.0%, an antihyperuricemic), lamotrigine (9.3%, an anticonvulsant), salazosulfapyridine (8.4%, a bowel disease treating agent), mexiletine hydrochloride (4.8%, an antiarrhythmic drug), zonisamide (4.7%, an anticonvulsant), phenobarbital (4.5%, an anticonvulsant), phenytoin (4.4%, an anticonvulsant), sodium valproate (3.3%, an anticonvulsant), diaphenylsulfone (2.4%, an antileprosy drug), chlorpromazineepromethazineephenobarbital (2.1%, an antipsychotic drug) and sulfamethoxazoleetrimethoprim (2.0%, an antibiotic) The percentage of lamotrigine was significantly higher in the latter years than in the first years (14.2% vs 0.8%, p < 10 10), and those of the following three drugs were lower: zonisamide (2.6% vs 8.2%, p < 10 4), phenobarbital (3.3% vs 6.5%, p < 10 4) and chlorpromazineepromethazineephenobarbital (1.2% vs 3.7%, p < 0.05) 120 111 108 95 100 76 80 60 44 46 77 82 56 40 20 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 (b) 16 Fiscal years 14.6 14 Mortality rates (%) Dear Editor, 12 10.9 10.5 10 6.8 7.1 6.3 5.2 2.6 2.8 0.0 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 Fiscal years Fig (a) Number of DIHS cases from fiscal year (FY) 2006e2015 (b) Mortality rates of DIHS cases from FY 2006e2015 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/) Please cite this article in press as: Kinoshita Y, et al., 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, Allergology International (2016), http://dx.doi.org/10.1016/ j.alit.2016.09.003 Letter to the Editor / Allergology International xxx (2016) 1e3 DIHS is one of the severest forms of cutaneous ADRs and the mortality rate is reported to be about 10%e20%.6 The 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 being 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 deterioration 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.7 Adults are more affected than children 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 (diaphenylsulfone, salazosulfapyridine, sulfamethoxazoleetrimethoprim) and allopurinol.6 The 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.9 Diaphenylsulfone is classified as an antileprosy drug, but it is usually used for skin diseases such as erythema elevatum diutinum, 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,2 and there were only 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 conclusions were revised It may be better to re-analyze these data after Table Summary of DIHS in Japan in the past 10 years DIHS cases Of which: dead cases Gender Male Female Ages 0e9 10e19 20e29 30e39 40e49 50e59 60e69 70e79 80e Causal drugs (Drug types) Anticonvulsants Antihyperuricemics Bowel disease treating agents Antibiotics Antiarrhythmic drugs Antipsychotic drugs Antileprosy drugs Others Causal drugs (Anticonvulsants) Carbamazepine Lamotrigine Zonisamide Phenobarbital Phenytoin Sodium valproate Others Causal drugs (Antihyperuricemics) Allopurinol Causal drugs (Bowel disease treating agents) Salazosulfapyridine Others Causal drugs (Antibiotics) SulfamethoxazoleeTrimethoprim Others Causal drugs (Antiarrhythmic drugs) Mexiletine hydrochloride Causal drugs (Antipsychotic drugs) ChlorpromazineePromethazineePhenobarbital Others Causal drugs (Antileprosy drugs) Diaphenylsulfone FY 2006e2010 FY 2011e2015 Total 299 18 (6.0%) 536 33 (6.2%) 835 51 (6.1%) 167 (55.9%) 132 (44.1%) 271 (50.6%) 265 (49.4%) 438 (52.5%) 397 (47.5%) (1.3%) (3.0%) 28 (9.4%) 52 (17.4%) 64 (21.4%) 39 (13.0%) 61 (20.4%) 30 (10.0%) 12 (4.0%) 355 213 (60.0%) 36 (10.1%) 37 (10.4%) (2.5%) 21 (5.9%) 23 (6.5%) (1.4%) 11 (3.1%) 213 (60.0%) 125 (35.2%) (0.8%) 29 (8.2%) 23 (6.5%) 16 (4.5%) 17 (4.8%) (0.0%) 36 (10.1%) 36 (10.1%) 37 (10.4%) 35 (9.9%) (0.6%) (2.5%) (0.8%) (1.7%) 21 (5.9%) 21 (5.9%) 23 (6.5%) 13 (3.7%) 10 (2.8%) (1.4%) (1.4%) (0.4%) 20 (3.7%) 48 (9.0%) 82 (15.3%) 97 (18.1%) 84 (15.7%) 111 (20.7%) 69 (12.9%) 23 (4.3%) 604 380 (62.9%) 60 (9.9%) 47 (7.8%) 38 (6.3%) 25 (4.1%) 11 (1.8%) 18 (3.0%) 25 (4.1%) 380 (62.9%) 212 (35.1%) 86 (14.2%) 16 (2.6%) 20 (3.3%) 26 (4.3%) 15 (2.5%) (1.3%) 60 (9.9%) 60 (9.9%) 47 (7.8%) 46 (7.6%) (0.2%) 38 (6.3%) 16 (2.6%) 22 (3.6%) 25 (4.1%) 25 (4.1%) 11 (1.8%) (1.2%) (0.7%) 18 (3.0%) 18 (3.0%) (0.7%) 29 (3.5%) 76 (9.1%) 134 (16.0%) 161 (19.3%) 123 (14.7%) 172 (20.6%) 99 (11.9%) 35 (4.2%) 959 593 (61.8%) 96 (10.0%) 84 (8.8%) 47 (4.9%) 46 (4.8%) 34 (3.5%) 23 (2.4%) 36 (3.6%) 593 (61.8%) 337 (35.1%) 1st 89 (9.3%) 3rd 45 (4.7%) 6th 43 (4.5%) 7th 42 (4.4%) 8th 32 (3.3%) 9th (0.8%) 96 (10.0%) 96 (10.0%) 2nd 84 (8.8%) 81 (8.4%) 4th (0.3%) 47 (4.9%) 19 (2.0%) 12th 28 (2.9%) 46 (4.8%) 46 (4.8%) 5th 34 (3.5%) 20 (2.1%) 11th 14 (1.5%) 23 (2.4%) 23 (2.4%) 10th p Value p < 0.05 p < 0.001 p < 10 p < 10 p < 10 10 4 p < 0.05 DIHS, drug-induced hypersensitivity syndrome P values were evaluated when comparing between FY 2006e2010 and FY 2011e2015 Please cite this article in press as: Kinoshita Y, et al., 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, Allergology International (2016), http://dx.doi.org/10.1016/ j.alit.2016.09.003 Letter to the Editor / Allergology International xxx (2016) 1e3 being grouped into typical and atypical DIHS, however it is impossible because the open data of the PMDA does not contain the information 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 Kinoshita a, Hidehisa Saeki a,*, Akihiko Asahina b, Toyoko Ochiai c, Masafumi Iijima d a Department of Dermatology, Nippon Medical School, Tokyo, Japan 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 b * Corresponding author Department of Dermatology, Nippon Medical School, 1-15, Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan E-mail address: h-saeki@nms.ac.jp (H Saeki) References Shiohara T, Kano Y A complex interaction between drug allergy and viral infection Clin Rev Allergy Immunol 2007;33:124e33 Tohyama M, Hashimoto K New aspects of drug-induced hypersensitivity syndrome J Dermatol 2011;38:222e8 Shiohara T, Iijima M, Ikezawa Z, Hashimoto K The diagnosis of a DRESS syndrome has been sufficiently established on the basis of typical clinical features and viral reactivations Br J Dermatol 2007;156:1083e4 Nanko H [Adverse drug reactions (ADR) and severe drug eruptions in Japan] [Jpn J Dermatol] 2005;115:1155e62 (in Japanese) Saeki H, Ochiai T, Iijima M Comparison of severe drug eruptions in Japan between 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 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 Shiohara T, Inaoka M, Kano Y Drug-induced hypersensitivity syndrome (DIHS): a reaction induced by a complex interplay among herpesviruses and anti-drug immune responses Allergol Int 2006;55:1e8 Saeki H, Yamada K, Morikawa N, Asahina A, Ochiai T, Iijima M Severe drug eruptions 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 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 Please cite this article in press as: Kinoshita Y, et al., 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, Allergology International (2016), http://dx.doi.org/10.1016/ j.alit.2016.09.003 ... article in press as: Kinoshita Y, et al., 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, ... Available online xxx Please cite this article in press as: Kinoshita Y, et al., Drug-induced hypersensitivity syndrome in Japan in the past 10 years based on data from the relief system of the Pharmaceuticals. .. Morikawa N, Asahina A, Ochiai T, Iijima M Severe drug eruptions due to lamotrigine in Japan based on data from the relief system of the Pharmaceuticals and Medical Devices Agency Allegol Int 2016 http://