lamotrigineanticonvulsanthla-cw*07, hla-dqb*06:09, or hla-drb1*13:01sjs, ten, sjs/ten ? ?european oxicamanti-inflammatoryhla-b*73, hla-a*2, or hla-b*12sjs, ten, sjs/ten ? ?european various sulfa drugsantibiotichla-cw*4sjs, ten, sjs/ten ? ?han chinese various sulfa drugsantibiotichla-b*38sjs, ten, sjs/ten ? ?european methazolamidelowers intraocular pressurehla-b*59:01 or hla-cw*01:02sjs, ten, sjs/ten ? ?korean, japanese dapsoneantibiotic, anti-inflammatoryhla-b*13:01dress syndrome7.8%99.8%han chinese allopurinolanti-gout drughla-b*58:01dress syndrome, sjs, ten, sjs/ten3%100% in han chinesehan chinese, korean, thai, european nevirapineanti-retroviralhla-drb1*01:01 or hla-drb1*01:012dress syndrome18%96%australian, european, south african nevirapineanti-retroviralhla-cw*8 or hla-cw*8:-b*14dress syndrome18%96%italian, japanese nevirapineanti-retroviralhla-b*35, hla-b*35:01, or hla-b*35:05sjs, ten, sjs/ten ? ?asian nevirapineanti-retroviralhla-c*04:01sjs, ten, sjs/ten ? ?malawian abacaviranti-retroviralhla-b*57:01dress syndrome55%100%european, african t-cell receptors due to gene editing. the number of diverse t-cell receptors expressed is estimated to be as high as 10 trillion. this has made it difficult to identify specific t-cell receptor types that are uniquely associated with the development of scars. one study, however, identified the preferential presence of the tcr-v-b and complementarity-determining region 3 in t-cell receptors found on the t cells in the blisters of patients with allopurinol-induced scars. this finding is compatible with the notion that specific types of t-cell receptors are involved in the development of specific drug-induced scars. adme certain variations in adme (i.e. absorption, distribution, metabolism, and excretion of a drug) are associated with the development of scars. these variations influence the levels and duration of a drug or drug metabolite in tissues and thereby impact the drug's or drug metabolite's ability to evoke scars. a prominent example of an adme-based genetic predisposition to scars involves the cyp2cp*3 allele of the cyp2c9 gene. cyp2c9, a cytochrome p450 enzyme, metabolizes various substances including phenytoin. the cyp2cp*3 variant of cyp29c has reduced catalytic activity. individuals studied in japan or malaysia, and the han chinese in taiwan that express this variant have an increased chance of developing the dress syndrome, sjs, sjs/ten, or ten when taking phenytoin while africans in mozambique expressing this variant taking phenytoin have an increase risk of developing sjs, sjs/ten, or ten. these reactions appear due to increases in the drug's blood and tissue levels. in a second example of a genetically based adme defect causing scars, japanese individuals bearing slow acetylating variants of the n-acetyltransferase 2 gene, (nat2), viz., nat2*6a and nat2*7b, acetylate sulfasalazine more slowly than individuals homozygous for the wild type gene. individuals expressing the nat2*6a and nat2*7 variants have an increased risk for developing a particularly severe form of the dress syndrome-like reactions to this anti-inflammatory drug. none-genetic adme factors are also associated with increased risks of developing scars. for example, allopurinol is metabolized to oxipurinol, a product with a far slower renal excretion rate than its parent compound. renal impairment is associated with abnormally high blood levels of oxipurinol and an increased risk of developing the dress syndrome, particularly the more severe forms of this disorder. dysfunction of the kidney and liver are also suggested to promote scars responses to other drugs due to the accumulation of scars-inducing drugs or metabolites in blood and tissues. currently, it is suspected that the expression of particular hla proteins and t-cell receptors interact with adme factors to promote scars particularly in their more serious forms. virus reactivation during the progression of the dress syndrome certain viruses which previously infected an individual and then became latent are reactivated and proliferate. viruses known to do so include certain members of the herpesviridae family of herpes viruses viz., epstein–barr virus, human herpesvirus 6, human herpesvirus 7, and cytomegalovirus. individuals suffering the dress syndrome may exhibit sequential reactivation of these four virus, typically in the order just given. reactivation of these viruses is associated with sequential flare-ups in symptoms, a prolonged course, and increased disease severity which includes significant organ involvement and the development of certain autoimmune diseases viz., systemic lupus erythematosus, autoimmune thyroiditis, and type 1 diabetes mellitus. while these viral reactivations, particularly of human herpes virus 6, have been suggested to be an important factor in the pathogenesis of the dress syndrome, studies to date have not clearly determined if they are a cause or merely a consequence of t cell-mediated tissue injury. rare case reports have associated the sjs/ten spectrum of scars with reactivation of human herpesvirus 6; reactivation of cytomegalovirus has also been proposed to be associated with agep although a large study failed to observe the latter association. in all cases, the relationships of viral reactivation to the development and severity of any scars disorder is uncertain and requires further study. infections although more than 90% of agep are associated with the intake of a presumptively offending drug, reports have associated infection with parvovirus b19, mycoplasma, cytomegalovirus, coxsackie b4 virus, chlamydophila pneumoniae, e. coli, and echinococcus with the drug-independent development of this disorder. the pathophysiology for the development of these drug-independent cases of agep is unclear. viral infections have also been observed to be associated with the development of sjs, sjs/ten, and ten in the absence of a causative drug. autoimmune disorders individuals suffering autoimmune disorders such as systemic lupus erythematosus may have an increased incidence of developing scars. while the cause for this possible predilection has not been determined, the altered immune system and the excessive production of cytokines occurring in these disorders could be contributing factors. effectors of tissue injury the tissue injury in scars is initiated principally by cd8+ or cd4+ t cells. once drug-activated, these lymphocytes elicit immune responses to self tissues that can result in scars drug reactions by mechanisms which vary with the type of disorder that develops. salient elements mediating tissue injury for each type of disorder include: sjs, sjs/ten, and ten: these three scars are variants of a common epidermal necrolysis disorder that differ only in severity. key down-stream elements that promote tissue injury in this spectrum of disorders are natural killer cells; death-inducing ligands that kill cells (viz., fas ligand, trail, and tnfsf12); cellular receptors for these ligands (viz., fas receptor, death receptor 4, death receptor 5, and tnfrsf12a); cell-injuring proteins made by cd8+ and natural killer cells, (viz., granulysin, granzyme b, and perforin); and two cytokines that stimulate the proliferation and activation of natural killer and t cells (viz., interleukin 5 and annexin a1). dress syndrome: key elements promoting tissue injury in the dress syndrome are: th2 cells and eosinophils; and cytokiness which either activate eosinophils (viz.,. interleukin 5), promote adaptive and allergic immune responses (viz., interleukin 4), promote allergic responses and tissue fibrosis (viz., interleukin 13), promote innate, adaptive, and auto-immune responses (viz., interferon gamma); or cause cell death (viz., tumor necrosis factor alpha). agep: key elements promoting tissue injury in agep are: neutrophils; recruiters and activators of neutrophils (viz., interleukin 8 and interleukin 17); a promoter of innate immune and autoimmune responses (viz., interleukin 22); and a cytokine which promotes the function of neutrophils, other granulocyte types, and monocytes as well as the production of these cells from their stem cells (viz., gm-csf). future studies may find that drugs which neutralize one or more of these effectors to be useful for treating scars disorders. prevention screening individuals for the expression of certain variant alleles of hla genes before initiating treatment with particular scars-inducing drugs is recommended. these recommendations typically apply only to specific populations that have a significant chance of expressing the indicated variant since screening of populations with extremely low incidences of expressing the variant allele is considered cost-ineffective. individuals expressing the hla allele associated with sensitivity to an indicated drug should not be treated with the drug. these recommendations include: carbamazepine: the taiwan and usa food and drug administrations recommend screening for hla-b*15:02 in certain asian groups before carbamazepine treatment. this has been implemented in taiwan, hong kong, singapore, and many medical centers in thailand and mainland china. allopurinol: the american college of rheumatology guidelines for the management of gout recommend hla-b*58:01 screening before allopurinol treatment. this is provided in many medical centers in taiwan, hong kong, thailand, and mainland china. abacavir: the usa food and drug administration recommends screening for hla-b*57:01 in the treatment of hiv with abacovir in caucasian populations. this screening is widely implemented. it has also been suggested that all individuals found to express this hla serotype avoid treatment with abacovir. current trials are underway to evaluate the cost-effectiveness of genetic screening for hla-b*13:01 to prevent dapsone-induced scars in china and indonesia. similar trials are underway in taiwan to prevent phenytoin-induced scars in individuals expressing the cyp2c9*3 allele of cyp2c9 or a series of hla alleles.