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<unk>  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. Drug Drug action HLA gene and allele SCARs disorder triggered Positive predictive value Negative predictive value Populations afflicted Carbamazepine anticonvulsant HLA-A*31:01 DRESS syndrome 1% 99.9% Chinese, Koreans, Japanese, European Carbamazepine anticonvulsant HLA-A*31:01 SJS, TEN, SJS/TEN 0.89% 99.98% European Carbamazepine anticonvulsant HLA-A*31:01 SJS, TEN, SJS/TEN 0.59% 99.97% Chinese Carbamazepine anticonvulsant HLA-A*31:01 SJS, TEN, SJS/TEN ? ? Northern European, Japanese, Korean Carbamazepine anticonvulsant HLA-B*15:02 SJS, TEN, SJS/TEN 3% 100% Chinese, Tai, Malaysian, Koreans, Indian Carbamazepine anticonvulsant HLA-A*31:01 MPE 34/9% 96.7% Han Chinese Oxcarbazepine anticonvulsant HLA-B*15:01 SJS, TEN, SJS/TEN ? ? Han Chinese, Taiwanese Phenytoin anticonvulsant HLA-B*13:01 or HLA-B51:01 DRESS syndrome, MPE ? ? Han Chinese Phenytoin anticonvulsant HLA-B*15:02, HLA-Cw*08:01, or HLA-DRB1*16:02 DRESS syndrome ? ? Han Chinese Lamotrigine anticonvulsant HLA-B*15:02 or HLA-B*38 SJS, TEN, SJS/TEN ? ? Han Chinese Lamotrigine anticonvulsant HLA-B*38, HLA-B*58:01, or HLA:68:01 SJS, TEN, SJS/TEN ? ? European Lamotrigine anticonvulsant HLA-Cw*07, HLA-DQB*06:09, or HLA-DRB1*13:01 SJS, TEN, SJS/TEN ? ? European Oxicam anti-inflammatory HLA-B*73, HLA-A*2, or HLA-B*12 SJS, TEN, SJS/TEN ? ? European various sulfa drugs antibiotic HLA-Cw*4 SJS, TEN, SJS/TEN ? ? Han Chinese various sulfa drugs antibiotic HLA-B*38 SJS, TEN, SJS/TEN ? ? European Methazolamide lowers intraocular pressure HLA-B*59:01 or HLA-CW*01:02 SJS, TEN, SJS/TEN ? ? Korean, Japanese Dapsone antibiotic, anti-inflammatory HLA-B*13:01 DRESS syndrome 7.8% 99.8% Han Chinese Allopurinol anti-gout drug HLA-B*58:01 DRESS syndrome, SJS, TEN, SJS/TEN 3% 100% in Han Chinese Han Chinese, Korean, Thai, European Nevirapine anti-retroviral HLA-DRB1*01:01 or HLA-DRB1*01:012 DRESS syndrome 18% 96% Australian, European, South African Nevirapine anti-retroviral HLA-Cw*8 or HLA-Cw*8:-B*14 DRESS syndrome 18% 96% Italian, Japanese Nevirapine anti-retroviral HLA-B*35, HLA-B*35:01, or HLA-B*35:05 SJS, TEN, SJS/TEN ? ? Asian Nevirapine anti-retroviral HLA-C*04:01 SJS, TEN, SJS/TEN ? ? Malawian Abacavir anti-retroviral HLA-B*57:01 DRESS syndrome 55% 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
Severe cutaneous adverse reactions
Chronic toxicity
Acute toxicity
Progressive disease
Autoimmune/inflammatory syndrome induced by adjuvants
Serious Hazards of Transfusion
Allergies in children
Limited symptom attack