Like other drug-induced SCARs disorders,<unk>  is a type IV hypersensitivity reaction in which a drug or its metabolite stimulates cytotoxic T cells (i.e. CD8+ T cells) or T helper cells (i.e. CD4+ T cells) to initiate autoimmune reactions that attack self tissues. SCARs are type IV, subtype IVb (DRESS syndrome), type IV, subtype IVc (SJS, SJS/TEN, TEN), or type IV, subtype IVd <unk>  hypersensitivity reactions.<unk>  therefore differs from the other SCARs disorders in that it involves the tissue-injuring action of inappropriately activated neutrophils and the excessive production of cytokines which stimulate production of, recruit to tissues, and/or activation of neutrophils (Interleukin 8, Interleukin 17, GM-CSF) and promote innate immune and autoimmune responses (Interleukin 22).<unk>  also differs from the other SCARs disorders in respect to the level of evidence supporting the underlying mechanism by which a drug or its metabolite stimulates CD8+ T or CD4+ T cells. Studies indicate that the mechanism by which a drug or its metabolites accomplishes this stimulation involves subverting the antigen presentation pathways of the innate immune system. A drug or metabolite covalently binds with a host protein to form a non-self, drug-related epitope. An antigen-presenting cell (APC) takes up these proteins; digests them into small peptides; places the peptides in a groove on the human leukocyte antigen (i.e. HLA) component of their major histocompatibility complex (i.e. MHC) (APC); and presents the MHC-associated peptides to the T-cell receptor on CD8+ T or CD4+ T cells. Those peptides expressing a drug-related, non-self epitope on their HLA-A, HLA-B, HLA-C, HLA-DM, HLA-DO, HLA-DP, HLA-DQ, or HLA-DR proteins may bind to a T-cell receptor to stimulate the receptor-bearing parent T cell to attack self tissues. Alternatively, a drug or metabolite may also stimulate T cells by inserting into the groove on a HLA protein to serve as a non-self epitope, bind outside of this groove to alter a HLA protein so that it forms a non-self epitope, or bypass the APC by binding directly to a T cell receptor. However, non-self epitopes must bind to specific HLA serotypes to stimulate T cells and the human population expresses some 13,000 different HLA serotypes while an individual expresses only a fraction of them. Since a SCARs-inducing drug or metabolite interacts with only one or a few HLA serotypes, their ability to induce SCARs is limited to those individuals who express HLA serotypes targeted by the drug or metabolite. Thus, only rare individuals are predisposed to develop SCARs in response to a particular drug on the bases of their expression of HLA serotypes. Studies have identified several HLA serotypes associated with development of DRESS syndrome, SJS, SJS/TEN, and TEN in response to various drugs which elici these disorders, developed tests to identify individuals who express these serotypes, and thereby determined that these individuals should avoid the offending drug. HLA serotypes associated with<unk>  and specific drugs have not been identified. A study conducted in 1995 identified of HLA-B51, HLA-DR11, and HLA-DQ3 of unknown serotypes to be associated with development of<unk>  but the results have not been confirmed, expanded to identify the serotypes involved, nor therefore useful in identifying individuals predisposed to develop<unk>  in response to any drug. Similarly, a specific T cell receptor variant has been associated with the development of DRESS syndrome, SJS, SJS/TEN, and TEN but not<unk> . Variations in ADME, i.e. an individuals efficiency in absorbing, distributing, metabolizing, and excreting a drug) has been found to occur in cases of the DRESS syndrome, SJS, SJS/TEN, and TEN. 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. In rare cases, the development of<unk>  has been reported to occur in individuals with loss of function mutations in their IL36RN gene. This gene codes for the interleukin 36 receptor antagonist (IL36RA). IL36RA blocks the pro-inflammatory actions of Interleukin-36 cytokines (viz., IL-36α, IL-36β and IL-36γ) on keratinocytes, synoviocytes, dendritic cells, macrophages, and T cells. It does so by binding to, but not stimulating, these cytokines' receptors, IL1RL2 and IL1RAP, thereby interfering with the interleukin-36 cytokines' binding to and stimulating IL1RL2 and IL1RAP. However, the IL36RN loss of function mutation has been reported in cases of<unk>  pustular psoriasis. The presence of this mutation in two seemingly unrelated disorders has led to suggestions that the classification of<unk>  as a SCARs or a form of psoriasis requires study.
Acute generalized exanthematous pustulosis
Streptococcal intertrigo
Impetigo herpetiformis
Acute cutaneous lupus erythematosus
Polymorphous light eruption
Keratolytic winter erythema
Shingles
Herpetic whitlow