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Keywords:

  • Carbamazepine;
  • Stevens-Johnson syndrome;
  • HLA class I;
  • HLA-B*5901;
  • Cutaneous adverse drug reactions

Summary

  1. Top of page
  2. Summary
  3. Background
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Carbamazepine (CBZ) is frequently used for treating epilepsy, but this drug causes cutaneous adverse drug reactions (cADRs) that may range from mild to severe. It is reported recently that the human leukocyte antigen HLA-B*1502 is associated with Stevens-Johnson syndrome (SJS) induced by CBZ in Han Chinese. We examined HLA class I in 15 Japanese patients who fulfilled the diagnostic criteria for CBZ-induced cADRs (mild in 10 and severe = SJS in 5). HLA-B*1518, HLA-B*5901 and HLA-C*0704 alleles showed higher relative risks (above 10.0) for severe cADRs. The haplotype (HLA-A*2402-B*5901-C*0102) had high relative risk (16.09) for severe cADRs. In patients with severe cADRs, frequencies of HLA-A*1101, HLA-A*3303, HLA-B*1501, HLA-B*4403, HLA-B*5101, HLA-B*5201, HLA-C*0702, and HLA-C*1202 alleles are relatively lower than in the Japanese population. These data may suggest that HLA-B*5901 is one of the candidate markers for CBZ-induced SJS in Japanese.


Background

  1. Top of page
  2. Summary
  3. Background
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Skin rash is a well-known complication of antiepileptic drug (AED) treatment. The risk of cutaneous adverse drug reactions (cADRs) of AED treatment is reported to be higher compared to drugs other than AEDs (Roujeau et al., 1995). In particular, carbamazepine (CBZ), which is commonly used to treat partial epilepsy, frequently causes a wide spectrum of cADRs including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug-induced hypersensitivity syndrome (DIHS), macropapular eruption, and mild skin rash. CBZ induces cADRs in 2.9% of Japanese patients (http://www.info.pmda.go.jp/). Recently, a strong association has been reported between a genetic marker, the human leukocyte antigen HLA-B*1502 and SJS induced by CBZ in Han Chinese (Chung et al., 2004; Hung et al., 2006). However, HLA-B*1502 is rare in the Japanese population and is not found in patients with SJS induced by CBZ (Kashiwagi et al., 2008). The genetic markers for SJS seem to be heterogeneous in each race (Ueta et al., 2008). In the present study, we try to identify the HLA class I genetic markers in the Japanese population that may predict patients at high risk of cADRs induced by CBZ.

Patients and Methods

  1. Top of page
  2. Summary
  3. Background
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Patients

We classified cADRs into two categories: group A (10 patients) with mild cADRs such as exanthema and rash with or without fever, and group B (five patients) with severe cADRs such as SJS, TEN, and DIHS. The diagnosis of each cADR was based on the clinical criteria provided by Pharmaceuticals and Medical Devices Agency (PMDA) (http://www.info.pmda.go.jp/juutoku/juutoku_index.html). TEN and SJS are both defined as mucocutaneous disorders characterized by extensive erythema, blisters, epidermal detachment, erosions, enanthema, and high fever. However, SJS is defined as skin detachment of 10% or less of the body surface area, whereas TEN is defined as skin detachment of more than 10%, excluding staphylococcal scalded skin syndrome (Roujeau et al., 1995). DIHS is characterized by multiorgan involvement such as hepatitis and nephritis accompanied by systemic manifestations, including fever, eosinophilia, and lymphadenopathy, in addition to skin rashes. The five patients with severe cADR were diagnosed as SJS by the above-mentioned clinical criteria, patients B-2 and B-4 were reported in a previous report (Kashiwagi et al., 2008), and patient B-5 was included in a previous paper (Kaniwa et al., 2008). The characteristics of the patients are shown in Table 1. We conducted HLA genotyping after obtaining informed consent from each patient by the methods approved by the ethical committee of our hospital.

Table 1.   Clinical characteristics of patients in groups A and B
Type and Pt numberAgeSexEpilepsyAssociated diseaseDose of CBZ (mg)Latency to cADRs (days)Concurrent AEDsHistory of cADRs
  1. M, male; F, female; PE, localization-related epilepsy; RS, Rasmussen syndrome; AVM, arteriovenous malformation; SLE, systemic lupus erythematosus; cADRs, cutaneous adverse drug reaction; Concurrent AEDs, concurrently used AEDs on cADRs; CLB, clobazam; ZNS, zonisamide; PB, phenobarbital; CBZ, carbamazepine; PHT, phenytoin; ABPC, aminobenzylpenicillin.

A-112MPEBrain tumor?11
A-27FPEHyperthyroidism?30CLB, ZNS
A-311MRS?4 
A-41FPETuberous sclerosis6012 
A-58MPESequelae of encephalitis10035VPAPB
A-67FPEMental retardation15017VPA+ZNSCBZ, PHT
A-76FPESequelae of encephalitis by influenza vaccine1109 
A-89MPEAutism18012VPA 
A-914FPEMental retardation20030 
A-107FPE10014VPAZNS, PHT
B-160FPE1001CBZ, PHT
B-233MPEOperated AVM4007 
B-338FPESLE??PHT
B-424FPESequelae of Influenza encephalitis?7 
B-552FPESLE10011ZNSABPC

HLA genotype

High-resolution typing of HLA class I loci was performed by the sequence-based method using the SeCore sequencing kits (Invitrogen Corp., Brown Deer, WI, U.S.A.) and the ABI 3730 DNA sequencer (Applied Biosystems, Foster City, CA, U.S.A.). Using the kits for HLA-A, -B, and -Cw, exons 2–4 of each gene were amplified and sequenced to identify the genetic polymorphisms. HLA-A, -B, and -Cw alleles were estimated using the ASSIGN SBT software version 3.2.7b (Conexio Genomics, Freemantle, Western Australia, Australia).

Statistical analysis

The HLA-A and -B allele frequencies obtained from 493 Japanese healthy subjects were used as the frequencies for Japanese general population (Table 2). The HLA-C allele frequencies obtained from 114 Japanese healthy subjects were used as the frequencies for Japanese general population (Table 2). Relative risks were calculated according to the reference (Marsh et al., 2000). Relative risk in this study is defined as hK/Hk, where h is the allele frequency in patients with the antigen, k is the allele frequency in the patients without the antigen, H is the allele frequency in healthy controls with the antigen, and K is the allele frequency in controls without the antigen.

Table 2.   HLA-A, -B, and -C alleles in patients with cADRs
HLA alleleJapanese population allele frequencya (%)Group A (mild cADR)Group B (severe cADR)
Allele frequencyRelative riskAllele frequencyRelative risk
  1. HLA, human leucocyte antigen.

  2. aHLA*A & B, Tanaka et al. Clinical Transplants 1996; 139–144; HLA*C, Tokunaga et al. Immunogenetics 1997, 46: 199–205.

A*020110.90/200.002/102.03
A*020610.41/200.461/100.96
A*02073.42/203.110/100.00
A*11018.12/201.260/100.00
A*240235.610/201.805/101.80
A*26019.80/200.001/101.03
A*26032.12/205.370/100.00
A*31017.72/201.331/101.33
A*33037.91/200.610/100.00
B*13020.10/200.000/100.00
B*15017.22/201.450/100.00
B*15180.90/200.001/1013.58
B*35018.62/201.191/101.19
B*40015.11/200.990/100.00
B*40028.21/200.601/101.26
B*40065.31/200.950/100.00
B*44036.90/200.000/100.00
B*46013.83/204.402/106.24
B*48012.71/201.941/104.10
B*51017.93/202.050/100.00
B*520113.73/201.100/100.00
B*54016.52/201.601/101.60
B*55023.21/201.571/103.31
B*59011.70/200.002/1015.16
B*67011.00/200.000/100.00
C*010217.05/181.874/103.23
C*0103r1/18 0/10 
C*03037.81/180.712/103.00
C*030411.33/181.601/100.89
C*04016.51/180.920/100.00
C*06021.70/180.000/100.00
C*070211.31/180.470/100.00
C*07040.90/180.001/1012.89
C*080110.92/181.001/100.89
C*120210.42/181.090/100.00
C*14025.72/181.960/100.00
C*15021.70/180.001/106.39

Results

  1. Top of page
  2. Summary
  3. Background
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

HLA-A

Ten patients in group A and five patients in group B were analyzed (Table 2). In group A, relative risk was the highest for HLA-A*2603 allele (5.37), and zero for HLA-A*0201 and HLA-A*2601 alleles. In group B, the highest relative risk was 2.03, and zero risk was observed for HLA-A*1101 and HLA-A*3303 alleles among alleles with relatively high frequencies in the Japanese population.

HLA-B

Ten patients in group A and five patients in group B were analyzed. In group A, relative risk was highest for HLA-B*4601 allele (4.40), and zero in HLA-B*4403 allele among alleles with relatively high frequencies in the Japanese population. In group B, relative risks were high for HLA-B*1518 (13.58) and HLA-B*5901 alleles (15.16), and zero in HLA-B*1501, HLA-B*4403, HLA-B*5101, and HLA-B*5201 alleles among alleles with relatively high frequencies in the Japanese population.

HLA-C

Nine patients in group A and five patients in group B were analyzed. In group A, relative risks that can be calculated were lower than 2.0. Although C*0103 was detected in one patient only in group A, the relative risk could not be calculated because of rare frequency in the Japanese population. In group B, relative risks were high for HLA-C*0704 allele (12.89) and HLA-C*1502 allele (6.39), and zero for HLA-C*0702 and HLA-C*1202 alleles among alleles with relatively high frequencies in the Japanese population.

HLA A-B-C haplotype

Relative risks of the A-B-C haplotype were calculated depending on data of the Japanese population. The haplotype HLA-A*2402-B*5901-C*0102 and the haplotype HLA-A*0201-B*1518-C*0704 were found in two and one patient of group B, respectively. The relative risks of the former haplotype and the latter haplotype for severe cADRs are 16.09 and 28.94, respectively.

Discussion

  1. Top of page
  2. Summary
  3. Background
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

We have experienced many patients manifesting cADR at various levels of severity induced by AEDs. A total of 21,655 patients with epilepsy visited our epilepsy center up until 2006, and 166 patients (0.767%) experienced cADRs. Among them, 139 patients experienced cADRs causally related to AEDs, with 118 patients (0.545%) having mild cADRs (group A) and 21 patients (0.097%) having severe cADRs (group B) (Takahashi, 2007). Various attempts have been made to identify individuals at high risk of developing severe cADRs with intolerable sequelae. In the Han Chinese (Chung et al., 2004; Hung et al., 2005) and the Thai population (Locharernkul et al., 2008), a strong association between HLA-B*1502 and CBZ-induced SJS has been found. Our previous studies found that HLA-B*1502 is a rare allele in Japanese, and that no Japanese patients with CBZ-induced SJS have HLA-B*1502 (Kaniwa et al., 2008; Kashiwagi et al., 2008). Following these studies, we found that HLA-B*1518, HLA-B*5901, and HLA-C*0704 alleles showed higher relative risks above 10.0 in the extended group of patients with severe cADRs (group B). Although HLA-B*1518 and HLA-C*0704 alleles were found in only one patient, HLA-B*5901 was found in two patients in group B (B-2 and B-5). The haplotype HLA-A*2402-B*5901-C*0102 has a prevalence of 1.530% in the Japanese population. The relative risk of this haplotype for severe cADRs is 16.09. These data may suggest that HLA-B*5901 is a candidate marker of CBZ-induced SJS. The relative risk of HLA-B*5901 for CBZ-induced SJS (15.16) is higher than that for pemphigus vulgaris (DR4, relative risk = 14), acute anterior uveitis (B27, 10), and systemic lupus erythematosus (DR3, 6), but lower than that for ankylosing spondylitis (B27, 87) and Goodpasture syndrome (DR2, 16) (Marsh et al., 2000). HLA-B*5901 has been reported to be weakly associated with SJS/TEN with ocular complications in a Japanese study (Ueta et al., 2008), although this study included patients with SJS/TEN independent of offending drugs. Further studies will reveal the significance of HLA-B*5901 in SJS/TEN induced by CBZ.

HLA-B*5801 is reported to be strongly associated with severe cADRs caused by allopurinol in Han Chinese (Hung et al., 2005). HLA-B*5701 is reported to be strongly associated with a hypersensitivity reaction caused by abacavir in U.S. white and black patients (Saag et al., 2008). Because the amino acid sequence of HLA-B*5901 shares 93.9% homology with that of HLA-B*5701, and 95.0% homology with that of HLA-B*5801, the homology of amino acid residues among these HLA subtypes seems to be high. Therefore, HLA-B*5901 may be causally related to severe cADRs induced by CBZ. Further investigations with a larger number of patients with CBZ-induced SJS are required to confirm the involvement of HLA-B*5901 in CBZ-induced SJS in the Japanese population. We expect that this report would encourage HLA examinations in Japanese patients, leading to the development of prevention methods for CBZ-induced SJS.

Our data suggest that possible HLA class I markers for mild cADRs induced by CBZ are completely different from those for SJS. In the Thai population also, HLA-B*1502 had a strong association only with CBZ-induced SJS, but not with CBZ-induced maculopapular eruptions (Locharernkul et al., 2008). Therefore, differentiation between severe cADRs and mild cADRs in each patient is very important to confirm the true markers for CBZ-induced SJS. In patients with severe cADRs, frequencies of HLA-A*1101, HLA-A*3303, HLA-B*1501, HLA-B*4403, HLA-B*5101, HLA-B*5201, HLA-C*0702, and HLA-C*1202 alleles are relatively lower than in the Japanese population. Whether these HLA class I markers are inhibitory for SJS may be answered in the future through precise immunologic studies.

Acknowledgments

  1. Top of page
  2. Summary
  3. Background
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

This study was funded in part by Health and Labour Sciences Research Grants for Research on Human Genome Tailor made (H18-002), and on Psychiatry and Neurological Diseases and Mental Health (H20-021); Research Grants (19A-6) for Nervous and Mental Disorders from the Ministry of Health, Labor and Welfare; and grants-in-aid for Scientific Research I No. 16590859, 17591133, and 19591234.

Disclosure: We have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. None of the authors has any conflicts of interest to disclose.

References

  1. Top of page
  2. Summary
  3. Background
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References
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