severe cutaneous adverse reactions severe cutaneous adverse reactions severe cutaneous adverse reactions are a group of potentially lethal adverse drug reactions that involve the skin and mucous membranes of various body openings such as the eyes, ears, and inside the nose, mouth, and lips. in more severe cases, scars also involves serious damage to internal organs. scars includes five syndromes: drug reaction with eosinophilia and systemic symptoms (i.e. dress syndrome, also termed drug-induced hypersensitivity syndrome ); stevens–johnson syndrome (sjs); toxic epidermal necrolysis (ten), stevens-johnson/toxic epidermal necrolysis overlap syndrome (sjs/ten); and acute generalized exanthematous pustulosis (agep). the five disorders have similar pathophysiologies, i.e. disease-causing mechanisms, for which new strategies are in use or development to identify individuals predisposed to develop the scars-inducing effects of specific drugs and thereby avoid treatment with them. maculopapular rash (mpr) is a less-well defined and benign form of drug-induced adverse skin reactions; while not classified in the scars group, it shares with scars a similar pathophysiology and is caused by some of the same drugs which cause scars. severe cutaneous adverse reactionsother namesscarsspecialtydermatology adverse drug reactions are major therapeutic problems estimated to afflict up to 20% of inpatients and 25% of outpatients. about 90% of these adverse reactions take the form of benign morbilliform rash hypersensitivity drug reactions such as mpr. however, they also include more serious reactions: a) pseudo-allergic reactions in which a drug directly stimulates mast cells, basophils, and/or eosinophils to release pro-allergic mediators (e.g. histamine); b) type i, type ii, and type iii hypersensitivity reactions of the adaptive immune system mediated by ige, igg, and/or igm antibodies; and c) scars and mpr which are type iv hypersensitivity reactions of the innate immune system initiated by lymphocytes of the t cell type and mediated by various types of leukocytes and cytokines. type iv hypersensitivity reactions are off-target drug reactions, i.e. reactions in which a drug causes toxicity by impacting a biological target other than the one(s) for which it is intended. they are t cell-initiated delayed hypersensitivity reactions occurring selectively in individuals who may be predisposed to do so because of the genetically-based types of human leukocyte antigens (i.e. hla) or t-cell receptors they express; the efficiency with which they absorb, distribute to tissues, metabolize, and eliminate a drug or drug metabolite; or less well-defined idiosyncrasies. scars are here considered as a group focusing on the similarities and differences in their pathophysiologies, clinical presentations, instigating drugs, and recommendations for drug avoidance. further details on these syndromes can be found on their individual wikipedia pages. types sjs, ten, and sjs/ten main article: stevens–johnson syndrome main article: toxic epidermal necrolysis stevens–johnson syndrome, toxic epidermal necrolysis, and stevens–johnson syndrome/toxic epidermal necrolysis overlap syndrome are a spectrum of type iv, subtype ivc, delayed hypersensitivity reactions, i.e. reactions initiated by cd8+ t cells and natural killer t cells. they are characterized initially by fever and flu-like symptoms followed within days by skin as well as mucous membrane blisters and denudation. differentiation of the three disorders is based on the extent of disease with sjs involving <10%, sgs/ten involving 10% to 30%, and ten involving >30% of the total bodily skin area. this spectrum of disorders is complicated by inflammation in and damage to internal organs such as the liver and, less commonly, kidney and heart. more importantly, they are also complicated by sepsis due to the loss of skin and mucous membrane epithelial barriers. in one study, sjs, ten, and sjs/ten mortality rates were 4.8%, 19.4%, and 14.8%, respectively, with an important portion of the deaths due to bacterial sepsis, particularly in the acute, early stage of these disorders. the drugs most commonly triggering the sjs, ten, and sjs/ten spectrum of disorders are anti-infective sulfonamides, anticonvulsants (e.g. carbamazepine and lamotrigine), non-steroidal anti-inflammatory drugs, allopurinol, nevirapine, and chlormezanone. allopurinol appears in some studies to be the most common instigator of these disorders. any new biological or herbal remedy, it is suggested, should be considered a possible cause of these disorders under the proper clinical circumstances. dress syndrome main article: dress syndrome the dress syndrome is a type iv, subtype ivb, hypersensitivity drug reaction, i.e. a reaction dependent on cd4(+) cells and the cell- and tissue-injuring action of eosinophils. skin lesions inflict 73% to 100% of afflicted individuals; they are generally infiltrative macules and plaques. about 75% of cases exhibit facial edema. the syndrome is also associated with other maladies caused by high levels of blood eosinophils such as the various hypereosinophilia-related disorders: persistent asthma and allergic rhinitis and, more significantly, eosinophil-based and lymphocyte-based inflammation of the liver (>70% of cases), kidney (20% to 40% of cases), lung (~33% of cases), heart (4% to 27% of cases), and, uncommonly, the meninges, brain, gastrointestinal tract, and spleen. the disorder is lengthened and worsened in individuals that develop reactivation of latent viruses of the herpes viruses. the estimated mortality rate for the dress syndrome is about 10%. allopurinol and sulfasalazine account for almost 66% of dress syndrome cases with minocycline being the third most common cause of the disorder; strontium ranelate, leflunomide, dapsone, and nonsteroidal anti-inflammatory drugs (diclofenac, celecoxib, ibuprofen, and phenylbutazone) are less common causes of the disorder. agep main article: acute generalized exanthematous pustulosis agep is a rare type iv, subtype ivd, hypersensitivity reaction dependent on neutrophils and characterized by the rapid formation of skin pustules on an erythematous background. in one study of 28 patients, the disorder was complicated by involvement of the kidney (36% of cases), lung (27%), and liver (11%). it is the least severe of the scars disorders, typically shows a mild course, and is rarely associated with severe complications although superinfection of skin lesions may be life-threatening. pathophysiology individuals are predisposed to develop scars in response to a given drug based on the types of human leukocyte antigen (i.e. hla) proteins and t-cell receptors that they express; their ability to process an instigating drug or the drug's metabolite(s); and other less well-defined factors. these predispositions are a consequence of the hla allele and t-cell receptor variants that individuals express in their antigen presentation immune pathways; their adme, i.e. efficiency in absorbing, distributing to tissues, metabolizing, and/or eliminating a drug or drug metabolite; and other less well-defined factors. hla proteins drugs can cause scars by subverting the antigen presentation pathways which recognize and trigger immune responses to non-self epitopes (i.e. antigens) on foreign proteins. these proteins are taken up by antigen-presenting cells (apc) and degraded into small peptides. the peptides are inserted into a groove on hla proteins that are part of major histocompatibility complexes (i.e. mhc) and presented to t-cell receptors (tcr) on nearby cytotoxic t cells (i.e. cd8+ t cells) or t helper cells (i.e. cd4+ t cells). t-cell receptors are heterologous; only a small fraction of them can bind a particular epitope on presented peptides and this binding is restricted to non-self epitopes. upon binding a non-self epitope on a presented peptide, a t-cell receptor becomes active in stimulating its parent cell to mount one of two types of immune responses based on whether the apc presenting the peptide is professional or non-professional in type. non-professional apc include all nucleated cells; these cells load the processed peptides onto mhc class i (i.e. hla-a, hla-b, or hla-c) proteins and thereon present the peptides to cd8+ t cells. those cd8+ t cells whose t-cell receptors bind a non-self epitope on the peptides are stimulated to attack cells or pathogens expressing this epitope. professional apc are dendritic cells, macrophages, and b cells. they load processed peptides onto mhc class ii (i.e. hla-dm, hla-do, hla-dp, hla-dq, or hla-dr) proteins and thereon present the peptides to cd4+ t cells. those cd4+ t cells whose t-cell receptors bind a non-self epitope on presented peptides are stimulated to orchestrate various immune reactions that attack soluble proteins, pathogens, and host cells and tissues that express the non-self epitope. scars-inducing drugs can act through these pathways to cause cd8+ or cd4+ t cells to mount immune responses that are inappropriately directed against bodily tissues. four models propose the underlying mechanisms by which scars-inducing drugs may activate t cells to mount immune responses against self: hapten model: a drug (here termed a hapten) covalently binds to a host protein to create a non-self epitope; the protein is degraded in apc to drug-bound peptides which are loaded onto the groove in hla proteins and then presented to t cells. those t cells whose t-cell receptors bind the drug-related epitope on a presented peptide are thereby activated. pro-hapten model: this model is identical to the hapten model except that a drug's metabolite rather than the drug acts as the hapten that forms the non-self epitope. p-i model: a drug or its metabolite fits into the groove in hla proteins to become a non-self epitope which is presented to and activates t cells whose t-cell receptors bind the drug-related epitope; alternatively, the drug binds to t-cell receptors on and thereby directly activates the receptors' parent t cells. altered peptide repertoire model: a drug or its metabolite binds directly to a hla protein outside of its groove to alter the hla protein's structure; the altered hla protein thereby contains a non-self epitope which activates those t cells whose t-cell receptors bind the drug-created epitope. hla genes are highly polymorphic, i.e. have many different serotypes (i.e. alleles) while t-cell receptor genes receptors are edited. i.e. altered to encode proteins with different amino acid sequences. humans, it is estimated, express more than 10,000 different hla class i proteins, 3,000 different hla class ii proteins, and 100 trillion different t-cell receptors. an individual, however, expresses only a fraction of these polymorphic or edited gene products. since a scars-inducing drug interacts with only one or a few types of hla proteins or t-cell receptors, its ability to induce a scars disorder is limited to those individuals who express those hla proteins that make the appropriate hla/non-self peptide or the t cell that expresses the t-cell receptor that recognize the non-self epitope created by the drug. thus, only rare individuals are predisposed to develop a scars disorder in response to a particular drug on the bases of their expression of specific hla protein or t-cell receptor types. scars disorders are triggered by wide range of drugs with the most commonly reported offenders being carbamazepine, allopurinol, abacavir, phenytoin, and nevirapine. these drugs evoke scars by interacting with one or just a few hla proteins. the following table list drugs repeatedly implicated in eliciting scars; it also gives the drugs' therapeutic targets, hla serotypes through which they act, the types of scars disorders they trigger, the negative and positive predictive values for the drugs (where known), and the populations afflicted. positive predictive values give the true percentages of individuals with the indicated hla gene allele (identified as a serotype) that develop the cited drug-induced scars; negative predictive values give the percentage of individuals without the indicated serotype that fail to develop the cited drug-induced scars. for example, chinese, korean, japanese, and european individuals that express the hla-a31:01 allele have a 1% true chance of developing the dress syndrome while hla-a31:01 negative individuals in these specific populations have a 99.9% true chance of not developing the dress syndrome when treated with carbamazepine. in this particular example, the hla-a31:01 allele is virtually necessary but clearly not sufficient for developing the dress syndrome in response to carbamazepine. the table also shows that: positive predictive values lie between 0.59-55%, i.e. far below 100%; positive as well as negative predictive values vary with the population tested; a drug may cause more than one type of scars disorder or interact with more than one hla serotype to cause scars; and the level of susceptibility to a drug varies between populations. these findings indicate that other factors, generally regarded as due to unspecified population-related genetic differences, contribute decisively to developing scars. drugdrug actionhla gene and allelescars disorder triggeredpositive predictive valuenegative predictive valuepopulations afflicted carbamazepineanticonvulsanthla-a*31:01dress syndrome1%99.9%chinese, koreans, japanese, european carbamazepineanticonvulsanthla-a*31:01sjs, ten, sjs/ten0.89%99.98%european carbamazepineanticonvulsanthla-a*31:01sjs, ten, sjs/ten0.59%99.97%chinese carbamazepineanticonvulsanthla-a*31:01sjs, ten, sjs/ten ? ?northern european, japanese, korean carbamazepineanticonvulsanthla-b*15:02sjs, ten, sjs/ten3%100%chinese, tai, malaysian, koreans, indian carbamazepineanticonvulsanthla-a*31:01mpe34/9%96.7%han chinese oxcarbazepineanticonvulsanthla-b*15:01sjs, ten, sjs/ten ? ?han chinese, taiwanese phenytoinanticonvulsanthla-b*13:01 or hla-b51:01dress syndrome, mpe ? ?han chinese phenytoinanticonvulsanthla-b*15:02, hla-cw*08:01, or hla-drb1*16:02dress syndrome ? ?han chinese lamotrigineanticonvulsanthla-b*15:02 or hla-b*38sjs, ten, sjs/ten ? ?han chinese lamotrigineanticonvulsanthla-b*38, hla-b*58:01, or hla:68:01sjs, ten, sjs/ten ? ?european