|Year : 2011 | Volume
| Issue : 2 | Page : 137-144
|Cutaneous drug hypersensitivity : Immunological and genetic perspective
Kisalay Ghosh1, Gautam Banerjee2, Asok Kumar Ghosal1, Jayoti Nandi3
1 Department of Dermatology, MGM Medical College and LSK Hospital, Kishanganj, Bihar, India
2 Department of Dermatology, IPGMER, Kolkata, India
3 Sri Aurobindo Seva Kendra, Kolkata, West Bengal, India
|Date of Web Publication||5-May-2011|
83 Dumdum Park, Kolkata - 700 055
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Drug hypersensitivity is an unpredictable, immunologically mediated adverse reaction, clustered in a genetically predisposed individual. The role of "hapten concept" in immune sensitization has recently been contested by the "pharmacological interaction" hypothesis. After completion of the "human genome project" and with the availability of high-resolution genotyping, genetic susceptibility to hypersensitivity for certain drugs has been proved beyond doubt though the trend is ethnicity and phenotype dependent. Application of this newly acquired knowledge may reduce or abolish the morbidity and mortality associated with cutaneous drug hypersensitivity.
Keywords: Cutaneous drug hypersensitivity, danger signal, ethnicity, hapten, linkage disequilibrium, major histocompatibility complex, pharmacogenomics, pharmacological interaction
|How to cite this article:|
Ghosh K, Banerjee G, Ghosal AK, Nandi J. Cutaneous drug hypersensitivity : Immunological and genetic perspective. Indian J Dermatol 2011;56:137-44
|How to cite this URL:|
Ghosh K, Banerjee G, Ghosal AK, Nandi J. Cutaneous drug hypersensitivity : Immunological and genetic perspective. Indian J Dermatol [serial online] 2011 [cited 2020 Nov 28];56:137-44. Available from: https://www.e-ijd.org/text.asp?2011/56/2/137/80402
| Introduction|| |
The morbidity and mortality associated with adverse reactions to different drugs remain a major threat to present-day therapeutics. Many drug reactions involve the skin either in an isolated manner or as a component of systemic involvement. Some of these cutaneous adverse drug reactions (CADR) like maculopapular rash (MPR) or urticaria are mild, while some others like drug hypersensitivity syndrome (DHS) and Stevens-Johnson syndrome More Details (SJS) are associated with poorer outcomes. Adverse drug reactions (ADRs) can sometimes be explained by the pharmacological property of the drug and are predictable. This is known as "type A" ADR.  However, neither certain drug reactions can be explained by the pharmacological nature of the drug nor their occurrence can be predicted. This is categorized as "type B" ADR.  The majority of these are caused by immunological response of the host against the parent drug or its active metabolite. The term "drug hypersensitivity reaction" (DHR) is restricted to these immune-mediated "type B" ADRs. Many of these DHRs show familial and ethnic clustering that can only be explained by genetic susceptibility. Recent research has provided some objective proof to this hypothesis. Thus, drug hypersensitivity is an immunologically mediated response restricted to a few genetically predisposed individuals. If the genetic basis can be used to identify the "at-risk population" or the immunogenic component of the drug can be neutralized, many CADR may be predicted and prevented. This constitutes the basis of "personalized medicine".
| Basic Immunology of Drug Hypersensitivity Reaction|| |
Like all hypersensitivity reactions, DHR can be classified according to Gell and Coomb's classification  into four different groups, and the fourth group has recently been classified further into four subgroups (IVa-IVd) , [Table 1]. 
|Table 1: Drug hypersensitivity-Gell and Coomb's modified classification |
Click here to view
Most CADR are caused by type IV or delayed type hypersensitivity reaction (DTHR). The offending drug or its metabolite either diffuse through stratum corneum or enter via systemic circulation and provoke sensitization (vide infra). This leads to stimulation of Langerhans cells (LC) with liberation of inflammatory signals culminating in maturation of LC and their migration to regional lymph node. Consequently, antigen presentation to T-cells takes place through major histocompatibility complex (MHC), which causes expansion of clonal T-cells. Presence of costimulatory signals potentiates this expansion. Recently, these T-cells have been found to have heterogeneous function (cytokine production, inflammatory cellular response and subsequent nature of CADR)  [vide [Table 1]].
| Drug Sensitization|| |
Though sensitization and activation of immune system is thought to occur in all drug hypersensitivities, there is much controversy about the process of sensitization. In 1935, Landsteiner introduced the "hapten concept" to explain the mechanism of sensitization.  This concept has so far been used to explain the initiation of sensitization in DHR. A hapten, by definition, is a protein with low molecular weight (<1000 Da) which binds covalently in vivo to some protein structure, be it soluble or cell bound. [Prohaptens are proteins which generate hapten after metabolism in vivo]. This hapten-carrier complex is then taken up and processed by antigen presenting cells (APC) and presented to T-cells through MHC. As a result, T-cell activation takes place and primary immunological response is generated.
In recent years, this "haptenation" theory has been challenged by a novel concept called pharmacological-interaction (P-I) theory. , According to this theory, the drug can bind directly to the T-cell receptor (TCR) via a non-covalent bond. Neither is there a need for the drug to bind to any carrier protein nor the drug needs to be metabolically broken down into "haptens". It has been postulated that for this concept to be significant, the T-cell should express a TCR that can bind the drug and induce stimulatory signal. The T-cells should also have a lower threshold for stimulation so that they are stimulated by minor signal generated by "drug binding to TCR". Lastly, the TCR should interact with MHC on APC to enhance the immune response. 
Hapten theory or pharmacological-interaction concept?
The proponents of the hapten theory have cited the example of sulfamethoxazole (SMX)-nitroso which is a metabolic derivative of SMX and acts as a hapten to initiate SMX hypersensitivity. This SMX-nitroso is deactivated in vivo by non-protein thiol (glutathione) or ascorbate and it has been shown that people with lower level of thiol and ascorbate (like those suffering from HIV/AIDS) generate more SMX-nitroso and develop SMX hypersensitivity more frequently than those in the normal population.  However, using the same SMX model, it was shown that addition of glutathione did not reduce, but rather increased the immune stimulation,  though SMX-nitroso generation stopped and this could only be explained by the "P-I concept". In the past few years, several studies had been undertaken to establish or refute these two concepts. The pros and cons of the two theories are presented in [Table 2].
The nickel model: Futile unifying effort or fact?
These two contradictory views could be unified using the nickel model. In this, the nickel ion is shown to act both as a "hapten" as well as a metal ion directly binding to TCR simultaneously.  But the concept that priming of T-cells with reactive metabolites (hapten theory) may result in secondary reactivity toward the parent drug (P-I concept) has recently been refuted. 
Danger hypothesis: Redefining hapten theory
There was one chink in the armor of "hapten theory"-if certain drug metabolites can act as a hapten, why does not a drug always lead to drug hypersensitivity? The quest for the answer has generated the "danger hypothesis".  According to this hypothesis, the primary signal initiated by the hapten-carrier complex must be strengthened by co-stimulatory signals (danger signals) lest the primary signal should wean off and "tolerance" develops instead of hypersensitivity.
Further substantiation of danger hypothesis
The actual genre of danger signals is presently indefinite, yet the probable candidates are high mobility group box 1 protein (HMGB1), heat shock proteins (HSPs), and S100 proteins.  These molecules act through toll-like receptors. Concurrent presence of physical, chemical or viral stress is known to induce cell death and release these danger signals,  explaining the increased occurrence of drug hypersensitivity in these conditions. Recent studies have shown that polymorphism of the genes involved in synthesis of these "danger signals" (HSP, , tumor necrosis factor or TNF , ), their "receptors" (toll-like receptor 3  ) or the "signaling pathway" (proapoptotic Fas-L  and IL-4 receptor/IL-13 signaling pathway  ) can influence the occurrence and severity of drug hypersensitivity.
| Genetic Basis of Drug Hypersensitivity Reaction|| |
The idiosyncratic behavior and familial clustering of the drug hypersensitivities have intrigued researchers to find out a genetic basis. In the earlier days, studies of genetic background in drug hypersensitivity meant twin studies (monozygotic and dizygotic) where both twins suffered from the same disease and got the same treatment. In practical sense, it meant an extremely large and economically unfeasible study. The elementary role of MHC in drug hypersensitivity allured initial researchers to concentrate on human leukocyte antigen (HLA), but the outcome of their studies was confusing. The reason may be small number of cases, inadequate case definition or insensitive serological typing. 
A shift of idea: Multigenic concept in drug hypersensitivity reaction
Drug hypersensitivity was previously believed to originate from a single gene defect. But now we know that an intricate interaction between many genes as well as environmental factors culminates in drug hypersensitivity. The different genes can be classified function-wise into four groups: a) bio-activation genes, b) bio-inactivation genes, c) genes controlling immune-responsiveness, and 4) genes controlling tissue injury and repair. 
Metabolic gene: A suspect in earlier studies
Many investigators concentrated on polymorphisms of genes responsible for the synthesis of drug metabolizing enzymes. It was postulated that carbamazepine 10-11 epoxide, a major metabolite of carbamazepine (CBZ) both in vitro and in vivo, leads to immune sensitization, and defective detoxification of this metabolite causes CBZ induced DHR. In vitro lymphocyte cytotoxic assay also pointed to a detoxification defect underlying the propensity of CBZ hypersensitivity. But no specific polymorphism in microsomal epoxide hydrolase gene (responsible for CBZ 10-11 epoxide detoxification) could be detected in two separate studies. , Earlier studies demonstrated that slow acetylator phenotype arising from acetylator gene polymorphism is associated with SMX hypersensitivity both in normal population  and in HIV infected patients,  but recently this claim has been refuted. , Similarly, in abacavir hypersensitivity, polymorphism of metabolically important genes has been found to be insignificant. 
Re-exploration of major histocompatibility complex and high-resolution genotyping: Old suspect, new method
After failure of the "metabolic gene hypothesis", most investigators again turned their focus on MHC. In contrast to earlier studies using serology for HLA-typing, nowadays, high-resolution genotyping is being used for this purpose. Knowledge of linkage disequilibrium pattern [34,35] has further helped researchers to reach definitive conclusions, particularly in relation to an anti-retroviral drug, abacavir; antiepileptic drugs (AEDs) like carbamazepine (CBZ), oxcarbamazepine (OXC), phenytoin (PHT), lamotrizine (LTG); and the anti-gout drug, allopurinol.
| Abacavir and Pharmacogenomics|| |
A curtain raiser in the field
Abacavir is a neucleoside reverse transcriptase inhibitor with good activity against HIV-1 virus. About 5% of patients develop hypersensitivity reaction to abacavir. Majority of the reactions appear in the initial 6 weeks of drug introduction and present as skin rash, fever, gastrointestinal and respiratory manifestations.  They start subsiding within 72 hours of drug withdrawal and recur with more severity within hours of drug reintroduction.  Familial clustering and lower risk in Afro-Americans  suggested genetic susceptibility in abacavir hypersensitivity. High-resolution genetic assessment has found a strong association of abacavir hypersensitivity with HLA-B*5701, HLA-DR7 and HLA-DQ3 haplotypes (odds ratio>100).  Further studies using recombinant haplotype mapping has placed the responsible locus in the ancestral haplotype 57.1. Haplotypic polymorphism in the TNF promoter region has also been associated with abacavir hypersensitivity , and this may control severity by influencing TNF synthesis. It was shown recently  that concurrent presence of HLA-B*5701 and haplotypic Hsp 70-Hom variant was more specifically associated with abacavir hypersensitivity (odds ratio 3893, P<0.00001). HLA-B*5701 association to abacavir hypersensitivity was later confirmed in White males. 
Does ethnicity really matter in abacavir hypersensitivity?
The strong association of HLA-B*5701 allele to abacavir hypersensitivity could not be demonstrated in Afro-Americans and this discrepancy was attributed to linkage disequilibrium.  A different genetic basis in non-White population might be another possibility. But this ethnic bias has lately been questioned. Saag et al. have found that in immunologically (by patch test) confirmed (but not in clinically suspected) abacavir hypersensitivity, HLA-B*5701 allele is a 100% sensitive marker in Afro-Americans.  Besides, screening for HLA-B*5701 has been shown to reduce the incidence of abacavir hypersensitivity among ethnically mixed population. 
Bridging the gap: Clinical application of pharmacogenomics in abacavir hypersensitivity
Depending on a West Australian HIV cohort, Mallal et al. proposed routine HLA-B*5701 genotyping before prescribing abacavir to Whites.  Further studies among predominantly White population confirmed that screening is effective in reducing abacavir hypersensitivity , and is cost-effective.  Genetic screening has recently been demonstrated to be cost-effective even in multiethnic French population. 
Quest for newer genotyping method: Cheap, easy and quick
The complex and time-consuming HLA typing method using sequence-based primer intrigued scientists to invent an alternative path. Recently, an HIV cohort in Switzerland demonstrated a strong association between HCP5 single-nucleotide polymorphism (SNP) and abacavir hypersensitivity. This SNP, known as rs2395029, is in linkage disequilibrium with HLA-B*5701 in European ancestry and was found in all 98 HLA-B*5701 positive individuals, but absent in 999 of 1005 HLA-B*5701 negative persons. This HCP5 genotyping may be useful in place of sequence-based HLA typing for screening abacavir hypersensitivity.  A prospective Spanish study  found this method easier, cheaper and quicker compared to the conventional sequence based method.
| Carbamazepine Hypersensitivity: Second Milestone in Pharmacogenomics|| |
CBZ, SJS/TEN and the Han Chinese
The strongest genetic predisposition for drug hypersensitivity has been documented with CBZ. It is an AED associated with different clinical manifestations of hypersensitivity reaction including maculopapular rash (MPR), drug hypersensitivity syndrome (DHS) and Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). The last adverse effect is noted with excess frequency among people from Southeast Asian lineage, particularly Han Chinese, than their European or Japanese counterparts. In a path-finding study among Han Chinese in Taiwan, HLA-B*1502 allele was found among 100% patients who developed SJS/TEN after taking CBZ. The same allele was present only in 3% of CBZ-tolerant patients and the odds ratio was greater than 2504.49 and corrected P-value (Pc ) was 3.13 Χ 10−21 . 
Ethnicity matters in carbamazepine hypersensitivity
The allelic predisposition to development of SJS/TEN after CBZ intake could not be demonstrated in patients of Japanese  or European origin.  But multiple studies in non-Chinese Southeast Asian population could replicate the initial result. ,, (Among these, the Indian study  was methodologically weak as it did not consider the CBZ-tolerant patients). The exact cause of this ethnic difference is not yet clear. Some have attributed this to low prevalence of HLA-B*1502 allele in non-Southeast Asian population. Another explanation comes from the multigenic concept of drug hypersensitivity which claims that other genes may be responsible in non-Southeast Asian population. A recent study demonstrated that HLA-B*5901 may be one of the alleles responsible for CBZ-induced SJS in Japanese.  But the most acceptable concept till date is "linkage disequilibrium" which claims that HLA-B*1502 is in strong linkage disequilibrium in Southeast Asian population but not in Japanese or European.
Genetic predisposition is phenotype specific
It should be remembered that the association of HLA-B*1502 allele is only valid for CBZ-induced SJS/TEN, but not for other CBZ hypersensitivities like MPR , or DHS.  They may be caused by different allelic association (MPR has been associated with SNP in the HLA-E region and HLA-A*3101 and DHS with SNP in the motilin gene)  or by different immune mechanism.
Black-box warning for carbamazepine use
USFDA has issued a black-box warning stating that persons of genetically high risk ancestry should be screened for HLA-B*1502 allele before initiating treatment with CBZ.  Similar warning has been issued by Health Canada. 
Newer method of detecting the allele
In USA and Canada, many commercial laboratories now perform high-resolution genetic testing with sequence specific primer (SSP) using patient's blood or buccal swab.  These methods are costly and time-consuming (take around 1 week). Recently, a new (loop-mediated isothermal amplification or LAMP) method for detecting HLA-B*1502 genotype has been shown to be accurate (100% concordant with SSP), yet inexpensive, rapid and simple.  They may be useful in future in the clinical practice.
Does HLA-B*1502 allele confer a drug effect or a class effect?
There was another unanswered question: "Is this genetic susceptibility restricted to the drug (CBZ) or the class (drugs with similar aromatic ring)?" In clinical practice, cross-reactivity is known to exist between CBZ and three structurally similar drugs, phenytoin (PHT), lamotrigine (LTG) and oxcarbazepine (OXC). A large Thai cohort, in 2008, showed PHT-induced SJS to be associated with HLA-B*1502 allele.  In a recently published study, Hung et al. showed that OXC, PHT and LTG share the common risk allele HLA-B*1502 while inducing SJS. They recommended that CBZ, OXC and PHT should be avoided in the HLA-B*1502 carrier and LTG should be used with caution. 
Does other gene contribute in CBZ hypersensitivity?
Like abacavir, HSP gene polymorphism was also found to be associated with severe CBZ hypersensitivity, but it was not clear whether the association was causal or related to linkage disequilibrium with another gene in MHC. 
| Allopurinol Hypersensitivity and Genetic Predisposition|| |
Again the Han Chinese
The anti-gout drug, allopurinol, also has shown strong genetic predisposition for developing hypersensitivity reaction. It is the commonest cause of SJS/TEN in Europe  and one of the most frequent causes of DHS in the world.  In a case-control association study among Han Chinese, Hung et al.  found that the HLA-B*5801 allele was present in all 51 (100%) patients with allopurinol-induced severe cutaneous adverse reaction (30 DHS and 21 SJS/TEN) but only in 20 of 135 (15%) allopurinol-tolerant patients [odds ratio 580.3 (95% confidence interval, 34.4-9780.9), corrected P value = 4.7 Χ 10 -24 ].
Ethnic bias: Probably present
In Japanese population, a strong association of HLA-B*5801 allele to allopurinol-induced SJS/TEN , and DHS  was also evident. The association was moderate [odds ratio = 80 (confidence interval = 34-157), P<10−6 ] in the people of European ancestry.  This weaker association is probably due to lower frequency of the allele in the European population. A study among Thai population which has a high frequency of HLA-B*5801 allele has shown a strong association [odds ratio of 348.3 (95% confidence interval = 19.2-6336.9, P = 1.6 Χ 10)].  Further study with large cohort is needed for a definitive conclusion.
Does phenotype matter?
The study among Han Chinese  showed, unlike CBZ hypersensitivity, the genetic predisposition, here, is related to both DHS and SJS/TEN. This was confirmed by one Japanese study.  But the other studies ,, did not look into allopurinol-induced DHS.
Is prior genotyping mandatory for allopurinol use?
Tassaneeyakul et al.  demonstrated strong association between genotyping for HLA-B*5801 allele and allopurinol-induced SJS/TEN (sensitivity 100%, specificity 87%, positive predictive value 1.52 and negative predictive value 100%) in Thai population. This proves the allele to be a valid genetic marker among these people. But Fernando and Broadfoot  recommended screening of all patients irrespective of ethnicity before allopurinol therapy, without much statistical strength. Till date, there is no recommendation for prior genetic screening. Moreover, genotyping for HLA-B*5801 allele is complex and available only in research laboratories.  These have impeded the implementation of routine genetic testing before starting allopurinol.
| Other Drug: Newer Allele|| |
Apart from the above, weaker association of rare alleles to SJS/TEN has been documented in European study.  These include HLA-B*38 for SMX or LTG and HLA-B*73 for oxicam. Recently, HLA-B*5901 allele has been claimed to be strongly associated with methazolamide-induced SJS/TEN in Korean patients.  It is too early to comment on the significance of these studies.
| The Future|| |
In the future, newer genetic association of drug hypersensitivity will be explored, focusing on their pathogenesis. However, to translate these research findings into clinical application, several points require stringent persuasion. First of all, different immunological hypotheses of drug hypersensitivity need to be verified, unified and rejected (if needed) by practical experiments. Secondly, the phenotypic diagnostic criteria of individual drug hypersensitivity involving the skin (MPR, SJS/TEN and DHS) must be clearly delineated and the genetic association of each of them separately explored. Thirdly, to add statistical strength to these studies, a large number of cases should be included. Considering the rarity of certain drug hypersensitivities, this may necessitate multicenter and even multinational study. Fourthly, genetic susceptibility to individual drugs should be re-evaluated in the light of ethnic backgrounds. The fifth point to be considered is the availability and cost-effectiveness of the screening test. Designing easier, quicker and cheaper tests is essential in this regard. Finally, experimental bias toward immune genes should be avoided. Genetic susceptibility may be conferred by "metabolic" genes and novel "nonimmune" genes  as well.
| Glossary|| |
Allele: Alternative forms of genes or other DNA sequences that occupy a specific locus on a particular chromosome.
Haplotype: A set of alleles on a single chromosome which are closely linked and inherited as a unit; commonly used in reference to linked genes of the major histocompatibility (HLA) complex.
Linkage disequilibrium: A situation in which some combinations of alleles or genetic markers occur more or less frequently in a population than would be expected from a random combination of alleles based on their frequencies in the loci.
Polymorphism: The occurrence of two or more clearly different phenotypes in the same population of a species, independent of sexual variations.
Single-nucleotide polymorphism: DNA sequence variation occurring when one base at specific base pair position differs between members of a species or paired chromosomes in an individual; for example, from Cytosine (C) → Thymine (T); Adenine (A) → Guanine (G). (AAGCCTA to AAGCTTA).
| Acknowledgment|| |
We are indebted to Professor (Dr.) Debabrata Bandyopadhyay, Head of the Department, Department of Dermatology, R. G. Kar Medical College and Hospital, for his invaluable guidance.
| References|| |
|1.||Rawlins MD, Thompson JW. Pathogenesis of adverse drug reactions. In: Davies DM, editor. Textbook of adverse drug reactions. Oxford: Oxford University Press; 1977. p. 10. |
|2.||Gell PG, Coombs RR, editors. Clinical Aspects of Immunology. 1 st ed. Oxford, England: Blackwell; 1963. |
|3.||Pichler WJ. Delayed drug hypersensitivity reactions. Ann Intern Med 2003;139:683-93. |
|4.||Lerch M, Pichler WJ. The immunological and clinical spectrum of delayed drug-induced exanthems. Curr Opin Allergy Clin Immunol 2004;4:411-9. |
|5.||Landsteiner K, Jacobs J. Studies on the sensitization of animals with simple chemical compounds. J Exp Med 1935;61:643-56. |
|6.||Posadas SJ, Pichler WJ. Delayed drug hypersnsitivity reactions: New concepts. Clin Exp Allergy 2007;37:989-99. |
|7.||Benno S, Pichler WJ. Mechanisms of drug-induced allergy. Mayo Clin Proc 2009;84:268-72. |
|8.||Naisbitt DJ, Vilar FJ, Stalford AC, Wilkins EG, Pirmohamed M, Park BK. Plasma cysteine deficiency and decreased reduction of nitrososulfamethoxazole with HIV infection. AIDS Res Hum Retroviruses 2000;16:1929-38. |
|9.||Burkhart C, von Greyerz S, Depta JP, Naisbitt DJ, Britschgi M, Park KB, et al. Influence of reduced glutathione on the proliferative response of sulfamethoxazole-specific and sulfamethoxazole-metabolite-specific human CD4+ T cells. Br J Pharmacol 2001;132:623-30. |
|10.||Schnyder B, Mauri-Hellweg D, Zanni M, Bettens F, Pichler WJ. Direct, MHC-dependent presentation of the drug sulfamethoxazole to human alphabeta T cell clones. J Clin Invest 1997;100:136-41. |
|11.||Depta JP, Altznauer F, Gamerdinger K, Burkhart C, Weltzien HU, Pichler WJ. Drug interaction with T-cell receptors: T-cell receptor density determines degree of cross-reactivity. J Allergy Clin Immunol 2004;113:519-27. |
|12.||Burkhart C, Britschgi M, Strasser I, Depta JP, von Greyerz S, Barnaba V, et al. Non-covalent presentation of sulfamethoxazole to human CD4+ T cells is independent of distinct human leucocyte antigen-bound peptides. Clin Exp Allergy 2002;32:1635-43. |
|13.||Von Greyerz S, Bultemann G, Schnyder K, Burkhart C, Lotti B, Hari Y, et al. Degeneracy and additional alloreactivity of drug-specific human alpha beta(+) T cell clones. Int Immunol 2001;13:877-85. |
|14.||Padovan E, Bauer T, Tongio MM, Kalbacher H, Weltzien HU. Penicilloyl peptides are recognized as T cell antigenic determinants in penicillin allergy. Eur J Immunol 1997;27:1303-7. |
|15.||Gerber BO, Pichler WJ. Noncovalent interactions of drugs with immune receptors may mediate drug-induced hypersensitivity reactions. AAPS Journal 2006. p. 8. |
|16.||Roujeau JC. Immune mechanisms in drug allergy. Allergol Int 2006;55:27-33. |
|17.||Matzinger P. Tolerance, danger, and the extended family. Ann Rev Immunol 1994;12:991-1045. |
|18.||Li J, Uetrecht JP. The danger hypothesis applied to idiosyncratic drug reactions. Hand Exp Pharmacol 2010;196:493-509. |
|19.||Naisbitt DJ, Pirmohamed M, Park BK. Immunopharmacology of hypersensitivity reactions to drugs. Curr Allergy Asthma Rep 2003;3:22-9. |
|20.||Alfirevic A, Mills T, Harrington P, Pinel T, Sherwood J, Jawaid A, et al. Serious carbamazepine-induced hypersensitivity reactions associated with the HSP70 gene cluster . Pharmacogenet Genomics 2006;16:287-96. |
|21.||Martin AM, Nolan D, Gaudieri S, Almeida CA, Nolan R, James I, et al. Predisposition to abacavir hypersensitivity conferred by HLA-BFNx015701 and a haplotypic Hsp70-Hom variant. Proc Natl Acad Sci USA 2004;101:4180-5. |
|22.||Hetherington S, Hughes AR, Mostelle M, Shortino D, Baker KL, Spreen W, et al. Genetic variations in HLA-B region and hypersensitivity reactions to abacavir. Lancet 2002;359:1121-2. |
|23.||Pirmohamed M, Lin K, Chadwick D, Park BK. A TNFá promoter region gene polymorphisms in carbamazepine-hypersensitive patients. Neurology 2001;56:890-6. |
|24.||Ueta M, Sotozono C, Inatomi T, Kojima K, Tashiro K, Hamuro J, et al. Toll-like receptor 3 gene polymorphisms in Japanese patients with Stevens-Johnson syndrome. Br J Ophthalmol 2007;91:962-5. |
|25.||Ueta M, Sotozono C, Inatomi T, Kojima K, Hamuro J, Kinoshita S. Association of Fas Ligand gene polymorphism with Stevens-Johnson syndrome. Br J Ophthalmol 2008;92:989-91. |
|26.||Ueta M, Sotozono C, Inatomi T, Kojima K, Hamuro J, Kinoshita S. Association of combined IL-13/IL-4R signaling pathway gene polymorphism with Stevens-Johnson syndrome accompanied by ocular surface complications. Invest Ophthalmol Vis Sci 2008;49:1809-13. |
|27.||Pirmohamed M. Genetic Factors in the predisposition to drug-induced hypersensitivity reactions. AAPS Journal 2006;8:E20-6. |
|28.||Gaedigk A, Spielberg SP, Grant DM. Characterization of the microsomal epoxide hydrolase gene in patients with anticonvulsant adverse drug reactions. Pharmacogenetics 1994;4:142-53. |
|29.||Green VJ, Pirmohamed M, Kitteringham NR, Gaedigk A, Grant DM, Boxer M, et al. Genetic-analysis of microsomal epoxide hydrolase in patients with carbamazepine hypersensitivity. Biochem Pharmacol 1995;50:1353-9. |
|30.||Rieder MJ, Shear NH, Kanee A, Tang BK, Spielberg SP. Prominence of slow acetylator phenotype among patients with sulfonamide hypersensitivity reactions. Clin Pharmacol Ther 1991;49:13-7. |
|31.||Carr A, Gross AS, Hoskins JM, Penny R, Cooper DA. Acetylation phenotype and cutaneous hypersensitivity to trimethoprim-sulphamethoxazole in HIV-infected patients. AIDS 1994;8:333-7. |
|32.||Pirmohamed M, Alfirevic A, Vilar J, Stalford A, Wilkins EG, Sim E, et al. Association analysis of drug metabolizing enzyme gene polymorphisms in HIV-positive patients with co-trimoxazole hypersensitivity. Pharmacogenetics 2000;10:705-13. |
|33.|| Wolkenstein P, Loriot MA, Aractingi S, Cabelguenne A, Beaune P, Chosidow O. Prospective evaluation of detoxification pathways as markers of cutaneous adverse reactions to sulphonamides in AIDS. Pharmacogenetics 2000;10:821-8. |
|34.||Tsunoda T, Lathrop GM, Sekine A, Yamada R, Takahashi A, Ohnishi Y, et al. Variation of gene-based SNPs and linkage disequilibrium patterns in the human genome. Hum Mol Genet 2004;13:1623-32. |
|35.||Walsh EC, Mather KA, Schaffner SF, Farwell L, Daly MJ, Patterson N, et al. An integrated haplotype map of the human major histocompatibility complex. Am J Hum Genet 2003;73:580-90. |
|36.||Hetherington S, McGuirk S, Powell G, Cutrell A, Naderer O, Spreen B, et al. Hypersensitivity reactions during therapy with the nucleoside reverse transcriptase inhibitor abacavir. Clin Ther 2001;23:1603-14. |
|37.||Escaut L, Liotier JY, Albengres E, Cheminot N, Vittecoq D. Abacavir rechallenge has to be avoided in case of hypersensitivity reaction AIDS 1999;13:1419-20. |
|38.||Symonds W, Cutrell A, Edwards M, Steel H, Spreen B, Powell G, et al. Risk factor analysis of hypersensitivity reactions to abacavir. Clin Ther 2002;24:565-73. |
|39.||Mallal S, Nolan D, Witt C, Masel G, Martin AM, Moore C, et al. Association between presence of HLA-BFNx015701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse transcriptase inhibitor abacavir. Lancet 2002;35930:727-32. |
|40.||Martin AM, Gaudieri S, Witt C, Sayer D, Castley A, Mamotte C, et al. 00 in HLA: Immunobiology of the Human MHC, Proc. of the 13th IHWS. In: Hanson JA, Dupont B, editors. Seattle: IHWG Press; 2004. |
|41.||Hughes AR, Mosteller M, Bansal AT, Davies K, Haneline SA, Lai EH, et al. Association of genetic variations in HLA-B region with hypersensitivity to abacavir in some, but not all, populations. Pharmacogenomics 2004;5:203-11. |
|42.||Saag M, Balu R, Phillips E, Brachman P, Martorell C, Burman W, et al. High sensitivity of human leukocyte antigen-bFNx015701 as a marker for immunologically confirmed abacavir hypersensitivity in white and black patients. Clin Infect Dis 2008;46:1111-8. |
|43.||Zucman D, Truchis P, Majerholc C, Stegman S, Caillat-Zucman S. Prospective screening for human leukocyte antigen-BFNx015701 avoids abacavir hypersensitivity reaction in the ethnically mixed French HIV population. J Acquir Immune Defic Syndr 2007;45:1-3. |
|44.||Rauch A, Nolan D, Martin A, McKinnon E, Almeida C, Mallal S. Prospective genetic screening decreases the incidence of abacavir hypersensitivity reactions in the Western Australian HIV cohort study. Clin Infect Dis 2006;43:99-102. |
|45.||Mallal S, Phillips E, Carosi G, Molina JM, Workman C, Tomazic J, et al. PREDICT-1 Study Team. HLA-BFNx015701 screening for hypersensitivity to abacavir . N Engl J Med 2008;358:568-79. |
|46.||Hughes DA, Vilar FJ, Ward CC, Alfirevic A, Park BK, Pirmohamed M. Cost-effectiveness analysis of HLA BFNx015701 genotyping in preventing abacavir hypersensitivity. Pharmacogenetics 2004;14:335-42. |
|47.||Colombo S, Rauch A, Rotger M, Fellay J, Martinez R, Fux C, et al. Swiss HIV Cohort Study The HCP5 single-nucleotide polymorphism: A simple screening tool for prediction of hypersensitivity reaction to abacavir . J Infect Dis 2008;198:864-7. |
|48.||Rodríguez-Nóvoa S, Cuenca L, Morello J, Córdoba M, Blanco F, Jiménez-Nácher I, et al. Use of the HCP5 single nucleotide polymorphism to predict hypersensitivity reactions to abacavir: correlation with HLA-BFNx015701. J Antimicrob Chemother 2010;65:1567-9. |
|49.||Chung WH, Hung SI, Hong HS, Hsih MS, Yang LC, Ho HC, et al. Medical genetics: A marker for Stevens- Johnson syndrome. Nature 2004;428:486. |
|50.||Kaniwa N, Saito Y, Aihara M, Matsunaga K, Tohkin M, Kurose K, et al. HLA-B locus in Japanese patients with antiepileptics and allopurinol-related Stevens-Johnson syndrome and toxic epidermal necrolysis. Pharmacogenomics 2008;9:1617-22. |
|51.||Alfirevic A, Jorgensen AL, Williamson PR, Chadwick DW, Park BK, Pirmohamed M. HLA-B locus in Caucasian patients with carbamazepine hypersensitivity. Pharmacogenomics 2006;7:813-8. |
|52.||Locharernkul C, Loplumlert J, Limotai C, Korkij W, Desudchit T, Tongkobpetch S, et al. Carbamazepine and phenytoin induced Stevens-Johnson syndrome is associated with HLA-BFNx011502 allele in Thai population . Epilepsia 2008;49:2087-91. |
|53.||Chang CC, Too CL, Murad S, Hussein S. Association of HLA-BFNx011502 with carbamazepine-induced toxic epidermal necrolysis and Stevens-Johnson syndrome in Malaysian population. Proceeding in 7 th Asian- Oceanian Epilepsy Congress, Xiamen: 2008 |
|54.||Mehta YT, Prajapati ML, Mittal B, Joshi GC, Sheth JJ, Patel BD, et al. Association of HLA-BFNx011502 allele and carbamazepine-induced Stevens-Johnson syndrome among Indians. Indian J Dermatol Venereol Leprol 2009;75:579-82. |
|55.||Ikeda H, Takahashi Y, Yamazaki E, Fujiwara T, Kaniwa N, Saito Y, et al. HLA class I markers in Japanese patients with carbamazepine-induced cutaneous adverse reactions. Epilepsia 2010;51:297-300. |
|56.||Hung SI, Chung WH, Jee SH, Chen WC, Chang YT, Lee WR, et al. Genetic susceptibility to carbamazepine-induced cutaneous adverse drug reactions. Pharmacogenet Genomics 2006;16:297-306. |
|57.||Black box warnings. Black Box Information Center; 2009. Available from: http://www.formularyproductions.com/blackbox/. [accessed on 2009 Sep 2]. |
|58.||New safety information for the anti-epileptic drug TEGRETOL (carbamazepine). Ottawa (ON): Health Canada; 2008. Available from: http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2008/tegretol_hpc-cps-eng.php. [accessed on 2009 Jun 3]. |
|59.||Fernando SL, Broadfoot AJ. Prevention of severe cutaneous adverse drug reaction: thE emerging value of pharmacogenic screening. Available from: http://www.cmaj.ca on. [cited on 2009 Nov 23]. |
|60.||Cheng SH, Kwan P, Keung NH, Ng Margaret HL. New testing approach in HLA genotyping helps overcome barriers in effective clinical practice. Clin Chem 2009;55:1568-72. |
|61.||Hung SI, Chung WH, Liu ZS, Chen CH, Hsih MS, Hui RC, et al. Common risk allele in aromatic antiepileptic-drug induced Stevens-Johnson syndrome and toxic epidermal necrolysis in Han Chinese. Pharmacogenomics 2010;11:349-56. |
|62.||Halevy S, Ghislain PD, Mockenhaupt M, Fagot JP, Bouwes Bavinck JN, Sidoroff A, et al. EuroSCAR Study Group. Allopurinol is the most common cause of Stevens-Johnson syndrome and toxic epidermal necrolysis in Europe and Israel. J Am Acad Dermatol 2008;58:25-32. |
|63.||Roujeau JC, Laurence A, Yvonee L, Maja M. Severe Cutaneous Adverse Reactions to Drugs (SCAR): Definitions, Diagnostic Criteria, Genetic Predisposition. Dermatol Sinica 2009;27:203-9. |
|64.||Hung SI, Chung WH, Liou LB, Chu CC, Lin M, Huang HP, et al. HLA-BFNx015801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol. Proc Natl Acad Sci U S A 2005;102:4134-9. |
|65.||Dainichi T, Uchi H, Moroi Y, Furue M. Stevens-Johnson syndrome, drug-induced hypersensitivity syndrome and toxic epidermal necrolysis caused by allopurinol in patients with a common HLA allele: What causes the diversity. Dermatology 2007;215:86-8. |
|66.||Lonjou C, Borot N, Sekula P, Ledger N, Thomas L, Halevy S, 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;18:99-107. |
|67.||Tassaneeyakul W, Jantararoungtong T, Chen P, Lin PY, Tiamkao S, Khunarkornsiri U, et al. Strong association between HLA-BFNx015801 and allopurinol-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in a Thai population. Pharmacogenet Genomics 2009;19:704-9. |
|68.||Kim SH, Kim M, Lee KW, Kim SH, Kang HR, Park HW, et al. HLA-B FNx015901 is strongly associated with methazolamide-induced Stevens-Johnson syndrome / toxic epidermal necrolysis. Pharmacogenomics 2010;11:879-84. |
|69.||Alfirevic A, Pirmohamed M. Drug-induced hypersensitivity reactions and pharmacogenomics: Past, present and future. Pharmacogenomics 2010;11:497-9. |
[Table 1], [Table 2]
|This article has been cited by|
||Antiepileptic drugs and adverse skin reactions: An update
| ||Barbara Blaszczyk,Wladyslaw Lason,Stanislaw Jerzy Czuczwar |
| ||Pharmacological Reports. 2014; |
|[Pubmed] | [DOI]|
||Genetic susceptibility to the cross-reactivity of aromatic antiepileptic drugs-induced cutaneous adverse reactions
| ||Wei Wang,Fa-Yun Hu,Xin-Tong Wu,Dong-Mei An,Bo Yan,Dong Zhou |
| ||Epilepsy Research. 2014; |
|[Pubmed] | [DOI]|