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.
[10] 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.
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.
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.
[3][13] 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.
[5] SCARs disorders are triggered by wide range of drugs[4] with the most commonly reported offenders being Carbamazepine, allopurinol, abacavir, phenytoin, and nevirapine.
[1][3] 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.
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.
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.
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.
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.
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.
[1][6] 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.
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.
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.
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.
Screening individuals for the expression of certain variant alleles of HLA genes before initiating treatment with particular SCARs-inducing drugs is recommended.
These recommendations include:[1][18] 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.