Epilepsy is a chronic, recurrent, and transient brain dysfunction syndrome caused by recurrent seizures due to abnormal firing of brain neurons, and it is one of the most common neurological disorders. The incidence of epilepsy is associated with age; the highest prevalence is generally thought to be under 1 year of age, followed by a gradual reduction after1–10 years. In China, the male to female ratio of epilepsy is between 1.15:1 and1.7:1, and no significant differences associated with race have been found.
The main treatment for epilepsy is medication, with antiepileptic drugs (AEDs) as the principal method. After systemic long-term treatment, most epilepsy patients can be cured by medication. Because new AEDs have come into the market, adverse effects have been significantly reduced, and thus, AEDs treatments have become more acceptable to most epilepsy patients. Among the AEDs, aromatic antiepileptic drugs (AAEDs) are the most commonly used. This class of drugs was named for their similar chemical structures and their possession of benzene rings. Currently, commonly used AAEDs in the clinicinclude carbamazepine (CBZ), oxcarbazepine (OXC), phenobarbital (PB), lamotrigine (LTG), and phenytoin (PHT), mainly used in treatments foridiopathic generalized epilepsy with good efficacy. However, adverse reactions such as rash, fever, and organ damagecan occur. The most common reaction is cutaneous adverse drug reactions (CADRs), which includes mild maculopapular eruptions (MPE);drug hypersensitivity syndrome (HSS),as well as life-threatening reactions such as severe cutaneous reactions (SCRs)(Stevens-Johnson syndrome[SJS] and toxic epidermal necrolysis [TEN]), the mortality rate of which is as high as 40%, resulting in serious socio-economic and family burdens.
In individuals taking AEDs, the overall MPE incidence rate is 2.8%; incidence rates of rash caused by PHT, LG, and CBZ are higher at 5.9%, 4.7%, and 3.7%, respectively. In comparison, the incidence rates of SCRs(including HHS, SJS, and TEN) caused by the above drugs are lower. A population survey in Germany indicated that in patients who had just began AEDs treatment, the incidence rate of CBZ-SJS/TEN was 1.4/10,000, whereas the incidence rates of LTG-SJS/TEN, PB-SJS/TEN, and PHT-SJS/TEN were 2.5/10,000, 8.1/10,000, and 8.3/10,000, respectively. SJS and TEN are considered forms of the same disease at different stages, manifesting as blister-like rashes with skin peeling, and affecting the skin, mucous membranes, organs, visceral trunk, and limbs. SJS is characterized by total area of skin detachment of less than 10%, whereas TEN is defined by an area of detachment greater than 40%, and rates in between are considered SJS/TEN overlap. TEN is more severe, with mortality as high as 40%. Although the incidence rates of SJS and TEN are low, mortality rates nevertheless reach 10–50%. Thus, avoiding SJS/TEN is one of the major challenges during AEDs treatment. Recent studies have indicated that SCRs such as SJS and TEN induced by AAEDs are associated with the
2. Current cADRs prevalence in various countries and regions
In-depth genetics studies on AEDs-induced adverse reactions suggest that incidence rates of AEDs-induced SJS and TEN vary among ethnic groups and that the associations with relevant loci are different. In Europe, CBZ is the most common drug causing cADRs, with an incidence rate of 8.2%, followed by PB at 5.3%, and PHT at 5.0%. The prevalence rates of cADRs induced by CBZ are different depending on the country and/or region, at 5.88% in Australia, 6.60% in Japan, 27.70% in Singapore, 35.70% in Malaysia, 19.00% in India, and 26.00% in Taiwan. The prevalence rates of cADRs induced by PHT are also largely variable among different countries and regions, at 5.00% in Europe, 5.88% in Australia, 14.20% in Malaysia, 19.00% in India, and 4.30% in Taiwan. A similar phenomenon has also been observed in the prevalence of cADRs induced by other drugs in different countries and regions. CBZ is the main SJS/TEN-inducing drug in Southeast Asian countries and regions. The incidence rate of CBZ-SJS/TEN in Taiwan is approximately 59/10,000 each year, 41/10, 000 in Malaysia, and 55/10,000 in the Philippines, while it is relatively low in the United States and Europe, at 2/10,000 in the U.S.A., 9/10,000 in the United Kingdom, and 5/10,000 in France.
3. Association between AEDs-induced cutaneous adverse reactions and HLA alleles
Detailed studies in human genomics and pharmacogenomics have demonstrated a relationship between drug-induced cADRs and human leucocyte antigen (HLA) genes. HLA genes are located on human chromosome 6p21.3, and are a group of closely linked multiple alleles that include more than 100 loci and a total of 554 alleles, spanning 3,600 k band representing 1/3,000 of the entire human genome. It is a major gene system that regulates human-specific immune responses and individual differences in disease susceptibility, with apparent specificity in different ethnicities or populations of the same ethnicity.HLA genes can be divided into three classes: HLA class I, class II, and class III, on the basis of the structural expression, tissue distribution, and functions of the encoded proteins. HLA-I genes include A, B, and C loci; HLA-II genes consist of DR, DQ, and DP subregions; and HLA-III genes reside between HLA-I and HLA-II genes, and are mainly related to the complement system. Disease-related studies have generally been focused on HLA-I and HLA-II genes.
3.1. Correlation between cADRs incidence and the
HLA-B*1502 allele in different countries and regions
Recent studies have shown that the incidence of CBZ-SJS/TEN is strongly associated with
A study by Hung
3.1.1. Relationship between the
HLA-B*1502 allele and SJS/TEN due to other AEDs
Due to the structural similarity and clinical cross-reactivity of AAEDs, several subsequent studies have been conducted regarding the correlation between other AAEDs and the
3.1.2. Mechanism of the association between
HLA-B*1502-positive patients and AAEDs-SJS/TEN
Currently, the mechanism of severe cutaneous adverse reactions (SCAR) induced by AAEDs is unclear. Most scientists believe that provocation of the media results in severe symptoms within 2–3 days. In addition, a large number of infiltrating inflammatory cells are found in patient lesions, and increased dosage of CBZ significantly shortened the time for inflammatory cells to appear, which aggravated the symptoms. Therefore, the mechanistic origin likely lies in activation of the immune system. Cytotoxic T lymphocytes cause skin lesions in SJS/TEN patients with a common indicator of keratinocyte apoptosis induced by cytotoxic T-cells, and T-cells in the blister fluid of patients are mainlyCD8+ T-cells, implicating CD8+ T-cell-mediated cytotoxicity. Drugs such as CBZ and its metabolites are small chemicals, insufficient to induce immune responses, and thus the hapten hypothesis was proposed; that a specific drug or its metabolite covalently interacts with a protein or a polypeptide as a hapten, and is processed by cells and presented to the MHC molecules, resulting in HLA-specific T-cell activation. Another hypothesis is the p-i concept(direct pharmacological interaction between drug and immune receptor), i.e., the drug can be directly and non-covalently associated withT-cell receptors that match MHC molecules. Both hypotheses indicate that skin adverse reactions are triggered through interactions with specific MHC molecules, T-cell receptors, and drug-modified antigens. In 2007, Yang
3.1.3. Correlation of cADRs occurrence and other HLA loci
Scientists in Taiwan have also found that
In summary, cADRs incidence resulting from AEDs varies among different regions, and the associations with related gene loci are not consistent.
Supported by grants from the State Key Development Program for Basic Research of China (No.2003CB515509 and 2009CB522401) and from National Natural Scientific Foundation of China(No.81070450 and 30470751) to Dr. X.-Y.Z.
Ling ZY, Sun Y, Jiang JF. New development about safe questions of carbamazepine in epileptic. China Mod Med, 2010, 17(13): 13-14.
Beswick TC, Cohen JB. Dose-related levetiracetam-induced reticulated drug eruption. J Drugs Dermatol, 2010, 9(4): 409-410.
Ouyan H, Liu GG. A review over adverse drug reaction of anti-epileptic drugs. J Pediatr Pharm, 2005, 11(4): 57-59.
Lonjou C, Borot N, Sekula P, et al. A European study of HLA-B in Stevens-Johnson syndrome and toxic epidermal necrolysis related to five high-risk drugs. Pharmacogenet Genomics, 2008, 18(2) :99-107.
Gao MM, Shi YW, Yu MJ, et al. Association between cutaneous adverse reactions to antiepileptic drugs and HLA-B* 1502 allele. Chin J Neuromed, 2009, 8(5): 493-496.
Horton R, Wilming L, Rand V, et al. Gene map of the extended human MHC. Nat Rev Genet. 2004, 5(12): 889-899.
Chung WH, Hung SI, Hong HS, et al. Medical genetics: a marker for Stevens-Johnson syndrome. Nature. 2004, 428(6982):486.
Hung SI, Chung WH, Jee SH, et al. Genetic susceptibility to carbamazepine-induced cutaneous adverse drug reactions. Pharmacogenet Genomics. 2006, 16(4): 297-306.
Man CB, Kwan P, Baum L, et al. Association between HLA-B*1502 allele and antiepileptic drug-induced cutaneous reactions in Han Chinese. Epilepsia. 2007, 48(5):1015-8.
Wang GQ, Zhou YQ, Zhou LM, et al. Association between HLA-B*1502 Allele and carbamazepine-induced cutaneous adverse reactions in han people f China mainland. J Sun Yat sen Univ Med Sci, 2010, 31(6):828-832.
Mehta TY, Prajapati LM, Mittal B, et al. Association of HLA-B*1502 allele and carbamazepine-induced Stevens-Johnson syndrome among Indians.Indian J Dermatol Venereol Leprol. 2009, 75(6): 579-582.
Ding WY, Lee CK, Choon SE. Cutaneous adverse drug reactions seen in a tertiary hospital in Johor, Malaysia. Int J Dermatol. 2010, 49(7):834-841.
Locharernkul C, Loplumlert J Limotai C, et al. Carbamazepine and phenytoin induced Stevens-Johnson syndrome is associated with HLA-B*1502 allele in Thai population. Epilepsia. 2008, 49(12):2087-2091.
Lonjou C, Thomas L, Borot N, et al. A marker for Stevens-Johnson syndrome ...: ethnicity matters. Pharmacogenomics J. 2006, 6(4):265-268.
Kaniwa N, Saito Y, Aihara M, et al. HLA-B locus in Japanese patients with anti-epileptics and allopurinol-related Stevens-Johnson syndrome andtoxic epidermal necrolysis. Pharmacogenomics. 2008, 9(11) :1617-1622.
Kaniwa N, Hasegawa R. Exploratory studies on genetic biomarkers related to serious drug adverse reactions. Kokuritsu Iyakuhin Shokuhin Eisei Kenkyusho Hokoku. 2009, (127):1-14.
Ikeda H, Takahashi Y, Yamazaki E, et al. HLA class I markers in Japanese patients with carbama- zepine-induced cutaneous adverse reactions. Epilepsia. 2010, 51(2):297-300.
Hung SI, Chung WH, Liu ZS, et al. Common risk allele in aromatic antiepileptic-drug induced Stevens-Johnson syndrome and toxic epidermal necrolysis in Han Chinese. Pharmacogenomics, 2010, 11(3): 349-356.
Kazeem GR, Cox C, Aponte J, et al. High-resolution HLA genotyping and severe cutaneous adverse reactions in lamotrigine treated patients. Pharmacogenet Genomics, 2009, 19(9): 661-665.
Lin LC, Lai PC, Yang SF, et al. Oxcarbazepine-induced Stevens-Johnson syndrome: a case report. Kaohsiung J Med Sci, 2009, 25(2): 82-86.
Kuwbara S. Guillain-Barré syndrome: epidemiology, pathophysiology and management. Drugs, 2004, 64(6):597-610.
Nassif A, Bensussan A, Borothee G, et al. Drugs pecific cytotoxic T-cells in the skin lesions of a patient with toxic epidermal necrolysis. J Invest Dermatol, 2002, 118(4): 728-733.
Nassif A, Bensussan A, Boumsell L, et al. Toxic epidermal necrolysis: effector cells are drug-specific cytotoxic T cells. J Allergy Clin Immunol. 2004, 114(5):1209-1215.
Pichler WJ. Pharmacological interactionof drugs with antigen specific immunereceptors: the pi concept. Curr Opin Allergy Clin Immunol, 2002, 2(4): 301-305.
Wu Y, Sanderson JP, Farrell J, et al. Activation of T cells by carbamazepine and carbamazepine metabolites. J Allergy Clin Immunol. 2006, 118(1): 233-241.
Wu Y, Farrell J, Pirmohamed M, et al. Generation and characterization of antigen-specific CD4+, CD8+,and CD4+CD8+ T-cell clones from patients with carbamazepine hypersensitivity. J Allergy Clin Immunol. 2007, 119(4):973-981.
Yang CW,Hung SI,Juo CG, et al. HLA-B*1502-bound peptides:implications for the pathogenesis of carbamazepine-induced Stevens-Johnsonsyndrome. J Allergy Clin Immunol. 2007, 120(4):870-877.
Chung WH, Hung SI, Chen YT. Genetic predisposition of life-threatening antiepileptic-induced skin reactions. Expert Opin Drug Saf, 2010, 9( 1) :15-21.
Toledano R, Gil-Nagel A. Adverse effects of antiepileptic drugs. Semin Neurol, 2008, 28(3):317-327.
Arif H, Buchsbaum R, Weintraub D, et al. Comparison and predictors of rash associated with 15 antiepileptic drugs. Neurology, 2007, 68(20): 1701-1709.
Mockenhaupt M, Messenheimer J, Tennis P, et al. Risk of Stevens-Johnson syndrome and toxic epidermal necrolysis in new users of antiepileptics. Neurology, 2005, 64(7): 1134-1138.
Mockenhaupt M, Viboud C, Dunant A, et al. Stevens-Johnson syndrome and toxic epidermal necrolysis assessment of medication risks with emphasis on recently marketed drugs. The EuroSCAR-study. J Invest Dermatol, 2008 128(1): 35-44.
Tassaneeyakul W, Tiamkao S, Jantararoungtong T, et al. Association between HLA-B*1502 and carbamazepine-induced severe cutaneous adverse drug reactions in a Thai population. Epilepsia, 2010, 51(5): 926-930.
Chang CC, Too CL, Murad S, et al. Association of HLA-B*1502 allele with carbamazepine-induced toxic epidermal necrolysis and Stevens-Johnson syndrome in the multi-ethnic Malaysian population. Int J Dermatol, 2011, 50(2): 221-224.
Shi YW, Min FL, Liu XR, et al. Hla-B alleles and lamotrigine-induced cutaneous adverse drug reactions in the Han Chinese population. Basic Clin Pharmacol Toxicol, 2011, 109, 1: 42-46.
Min FL, Shi YW, Liu XR, et al. HLA-B*1502 genotyping in two Chinese patients with phenytoin-induced Stevens-Johnson syndrome. Epilepsy Behav, 2011, 20(2): 390-391.
Alfirevic A, Jorgensen AL, Williamson PR, et al. HLA-B locus in Caucasian patients with carbamazepine hypersensitivity. Pharmacogenomics, 2006, 7(6): 813-818.
Ozeki T, Mushiroda T, Yowang A, et al. Genome-wide association study identifies HLA-A*3101 allele as a genetic risk factor for carbamazepine-induced cutaneous adverse drug reactions in Japanese population. Hum Mol Genet, 2011, 20(5): 1034-1041.
Liao WP, Shi YW, Min FL. HLA-B*1502 screening and toxic effects of carbamazepine. N Engl J Med, 2011, 365(7): 672-673.
Shi YW, Min FL, Qin B, et al. Association between HLA and Stevens-Johnson syndrome induced by Carbamazepine in Southern Han Chinese genetic markers besides B*1502. Basic Clin Pharmacol Toxicol. 2012, 111(1):58-64. 7843.
Hung SI, Chung WH, Jee SH, et al. Genetic susceptibility to carbamazepine-induced cutaneous adverse drug reactions. Pharmacogenet Genomics, 2006, 16(4): 297-306.
An DM, Wu XT, Hu FY, et al. Association study of lamotrigine-induced cutaneous adverse reactions and HLA-B*1502 in a Han Chinese population. Epilepsy Res, 2010, 92(2-3): 226-230.
Hu FY, Wu XT, An DM, et al. Pilot association study of oxcarbazepine-induced mild cutaneous adverse reactions with HLA-B*1502 allele in Chinese Han population. Seizure, 2011, 20(2): 160-162.
Chen P, Lin JJ, Lu CS, et al. Carbamazepine-induced toxic effects and HLA-B 1502 screening in Taiwan. N Engl J Med, 2011, 364(12): 1126-1133.