Editing Stevens–Johnson syndrome (section)

==Pathophysiology==
SJS is a [[type IV hypersensitivity]] reaction in which a drug or its metabolite stimulates [[cytotoxic T cells]] (i.e. CD8<sup>+</sup> T cells) and [[T helper cells]] (i.e. CD4<sup>+</sup> T cells) to initiate [[autoimmune reaction]]s that attack self tissues. In particular, it is a type IV, subtype IVc, delayed hypersensitivity reaction dependent in part on the tissue-injuring actions of [[natural killer cells]].<ref name="pmid26553194"/> This contrasts with the other types of SCARs disorders, i.e., the [[DRESS syndrome]] which is a Type IV, Subtype IVb, hypersensitivity drug reaction dependent in part on the tissue-injuring actions of [[eosinophils]]<ref name="pmid26553194">{{cite journal | vauthors = Hoetzenecker W, Nägeli M, Mehra ET, Jensen AN, Saulite I, Schmid-Grendelmeier P, Guenova E, Cozzio A, French LE | title = Adverse cutaneous drug eruptions: current understanding | journal = Seminars in Immunopathology | volume = 38 | issue = 1 | pages = 75–86 | date = January 2016 | pmid = 26553194 | doi = 10.1007/s00281-015-0540-2 | s2cid = 333724 }}</ref><ref name="pmid22794701">{{cite journal | vauthors = Uzzaman A, Cho SH | title = Chapter 28: Classification of hypersensitivity reactions | journal = Allergy and Asthma Proceedings | volume = 33 Suppl 1 | issue = 3| pages = S96–9 | year = 2012 | pmid = 22794701 | doi = 10.2500/aap.2012.33.3561 | s2cid = 207394296 }}</ref> and [[acute generalized exanthematous pustulosis]] which is a [[type IV hypersensitivity|Type IV]], subtype IVd, hypersensitivity reaction dependent in part on the tissue-injuring actions of [[neutrophils]].<ref name="pmid26553194"/><ref name="pmid27472323">{{cite journal | vauthors = Feldmeyer L, Heidemeyer K, Yawalkar N | title = Acute Generalized Exanthematous Pustulosis: Pathogenesis, Genetic Background, Clinical Variants and Therapy | journal = International Journal of Molecular Sciences | volume = 17 | issue = 8 | pages = 1214| year = 2016 | pmid = 27472323 | pmc = 5000612 | doi = 10.3390/ijms17081214 | doi-access = free }}</ref>

Like other SCARs-inducing drugs, SJS-inducing drugs or their metabolites stimulate CD8<sup>+</sup> T cells or CD4<sup>+</sup> T cells to initiate autoimmune responses. Studies indicate that the mechanism by which a drug or its metabolites accomplishes this involves subverting the [[antigen presentation]] pathways of the [[innate immunity|innate immune]] system. The drug or metabolite covalently binds with a host protein to form a non-self, drug-related [[epitope]]. An [[Antigen-presenting cell|antigen presenting cell]] (APC) takes up these alter 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); and presents the MHC-associated peptides to [[T-cell receptor]]s on CD8<sup>+</sup> T cells or CD4<sup>+</sup> T cells. Those peptides expressing a drug-related, non-self epitope on one of their various HLA protein forms ([[HLA-A]], [[HLA-B]], [[HLA-C]], [[HLA-DM]], [[HLA-DO]], [[HLA-DP]], [[HLA-DQ]], or [[HLA-DR]]) can bind to a T-cell receptor and thereby stimulate the receptor-bearing parent T cell to initiate attacks on self tissues. Alternatively, a drug or its metabolite may stimulate these T cells by inserting into the groove on a HLA protein to serve as a non-self epitope or bind outside of this groove to alter a HLA protein so that it forms a non-self epitope. In all these cases, however, a non-self epitope must bind to a specific HLA [[Serotype#Human leukocyte antigen|serotype]] (i.e. variation) in order to stimulate T cells. Since the human population expresses some 13,000 different HLA serotypes while an individual expresses only a fraction of them and since a SJS-inducing drug or metabolite interacts with only one or a few HLA serotypes, a drug's ability to induce SCARs is limited to those individuals who express HLA serotypes targeted by the drug or its metabolite.<ref name="pmid28476287">{{cite journal | vauthors = Duong TA, Valeyrie-Allanore L, Wolkenstein P, Chosidow O | title = Severe cutaneous adverse reactions to drugs | journal = Lancet | volume = 390 | issue = 10106 | pages = 1996–2011 | year = 2017 | pmid = 28476287 | doi = 10.1016/S0140-6736(16)30378-6 | s2cid = 9506967 }}</ref><ref name="pmid29333670">{{cite journal | vauthors = Bachelez H | title = Pustular psoriasis and related pustular skin diseases | journal = The British Journal of Dermatology | volume = 178| issue = 3| pages = 614–618| date = January 2018 | pmid = 29333670 | doi = 10.1111/bjd.16232 | s2cid = 4436573 }}</ref> Accordingly, only rare individuals are predisposed to develop a SCARs in response to a particular drug on the bases of their expression of HLA serotypes:<ref name="pmid27960170">{{cite journal | vauthors = Pichler WJ, Hausmann O | title = Classification of Drug Hypersensitivity into Allergic, p-i, and Pseudo-Allergic Forms | journal = International Archives of Allergy and Immunology | volume = 171 | issue = 3–4 | pages = 166–179 | year = 2016 | pmid = 27960170 | doi = 10.1159/000453265 | doi-access = free }}</ref> Studies have identified several [[Severe cutaneous adverse reactions#HLA proteins|HLA serotypes]] associated with development of SJS, SJS/TEN, or TEN in response to certain drugs.<ref name="pmid26553194"/><ref name="pmid27362322">{{cite journal | vauthors = Wang CW, Dao RL, Chung WH | title = Immunopathogenesis and risk factors for allopurinol severe cutaneous adverse reactions | journal = Current Opinion in Allergy and Clinical Immunology | volume = 16 | issue = 4 | pages = 339–45 | year = 2016 | pmid = 27362322 | doi = 10.1097/ACI.0000000000000286 | s2cid = 9183824 }}</ref> In general, these associations are restricted to the cited populations.<ref name="pmid29333460">{{cite journal | vauthors = Fan WL, Shiao MS, Hui RC, Su SC, Wang CW, Chang YC, Chung WH | title = HLA Association with Drug-Induced Adverse Reactions | journal = Journal of Immunology Research | volume = 2017 | pages = 3186328 | date = 2017 | pmid = 29333460 | pmc = 5733150 | doi = 10.1155/2017/3186328 | doi-access = free }}</ref>

In some [[Ethnic groups in Asia|East Asian]] populations studied ([[Han Chinese]] and [[Thai people|Thai]]), [[carbamazepine]]- and [[phenytoin]]-induced SJS is strongly associated with HLA-B*1502 ([[HLA-B75]]), an [[HLA-B]] [[serotype]] of the broader serotype [[HLA-B15]].<ref name="pmid15057820">{{cite journal | author = Chung WH, Hung SI, Hong HS, Hsih MS, Yang LC, Ho HC, Wu JY, Chen YT | title = Medical genetics: A marker for Stevens–Johnson syndrome | journal = [[Nature (journal)|Nature]] | volume = 428 | issue = 6982 | page = 486 | year = 2004 | pmid = 15057820 | doi = 10.1038/428486a | department = Brief Communications | last2 = Hung | last3 = Hong | last4 = Hsih | last5 = Yang | last6 = Ho | last7 = Wu | last8 = Chen | bibcode = 2004Natur.428..486C | s2cid = 4423593 | doi-access = free }}</ref><ref name="pmid18637831">{{cite journal | author = Locharernkul C, Loplumlert J, Limotai C, Korkij W, Desudchit T, Tongkobpetch S, Kangwanshiratada O, Hirankarn N, Suphapeetiporn K, Shotelersuk V | title = Carbamazepine and phenytoin induced Stevens–Johnson syndrome is associated with HLA-B*1502 allele in Thai population | journal = [[Epilepsia (journal)|Epilepsia]] | volume = 49 | issue = 12 | pages = 2087–91 | year = 2008 | pmid = 18637831 | doi = 10.1111/j.1528-1167.2008.01719.x | last2 = Loplumlert | last3 = Limotai | last4 = Korkij | last5 = Desudchit | last6 = Tongkobpetch | last7 = Kangwanshiratada | last8 = Hirankarn | last9 = Suphapeetiporn | last10 = Shotelersuk | s2cid = 23063530| doi-access = free }}</ref><ref name="pmid17509004">{{cite journal | author = Man CB, Kwan P, Baum L, Yu E, Lau KM, Cheng AS, Ng MH | title = Association between HLA-B*1502 allele and antiepileptic drug-induced cutaneous reactions in Han Chinese | journal = [[Epilepsia (journal)|Epilepsia]] | volume = 48 | issue = 5 | pages = 1015–8 | year = 2007 | pmid = 17509004 | doi = 10.1111/j.1528-1167.2007.01022.x | last2 = Kwan | last3 = Baum | last4 = Yu | last5 = Lau | last6 = Cheng | last7 = Ng | s2cid = 34728720| doi-access = free }}</ref> A study in Europe suggested the [[Genetic marker|gene marker]] is only relevant for East Asians.<ref name="pmid16981842">{{cite journal | author = Alfirevic A, Jorgensen AL, Williamson PR, Chadwick DW, Park BK, Pirmohamed M | title = HLA-B locus in Caucasian patients with carbamazepine hypersensitivity | journal = Pharmacogenomics | volume = 7 | issue = 6 | pages = 813–8 | year = 2006 | pmid = 16981842 | doi = 10.2217/14622416.7.6.813 | last2 = Jorgensen | last3 = Williamson | last4 = Chadwick | last5 = Park | last6 = Pirmohamed }}</ref><ref name="pmid16415921">{{cite journal | author = Lonjou C, Thomas L, Borot N, Ledger N, de Toma C, LeLouet H, Graf E, Schumacher M, Hovnanian A, Mockenhaupt M, Roujeau JC | title = A marker for Stevens–Johnson syndrome ...: Ethnicity matters | journal = The Pharmacogenomics Journal | volume = 6 | issue = 4 | pages = 265–8 | year = 2006 | pmid = 16415921 | doi = 10.1038/sj.tpj.6500356 | last2 = Thomas | last3 = Borot | last4 = Ledger | last5 = De Toma | last6 = Lelouet | last7 = Graf | last8 = Schumacher | last9 = Hovnanian | last10 = Mockenhaupt | last11 = Roujeau | last12 = Regiscar| s2cid = 2654991 | doi-access =  }}</ref> This has clinical relevance as it is agreed upon that prior to starting a medication such as allopurinol in a patient of Chinese descent, HLA-B*58:01 testing should be considered.<ref name=":0" />

Based on the Asian findings, similar studies in Europe showed 61% of [[allopurinol]]-induced SJS/TEN patients carried the [[HLA-B58]] ([[phenotype]] frequency of the B*5801 allele in Europeans is typically 3%). One study concluded: "Even when HLA-B alleles behave as strong risk factors, as for allopurinol, they are neither sufficient nor necessary to explain the disease."<ref name="pmid18192896">{{cite journal | author = Lonjou C, Borot N, Sekula P, Ledger N, Thomas L, Halevy S, Naldi L, Bouwes-Bavinck JN, Sidoroff A, de Toma C, Schumacher M, Roujeau JC, Hovnanian A, Mockenhaupt M | title = A European study of HLA-B in Stevens–Johnson syndrome and toxic epidermal necrolysis related to five high-risk drugs | journal = Pharmacogenetics and Genomics | volume = 18 | issue = 2 | pages = 99–107 | year = 2008 | pmid = 18192896 | doi = 10.1097/FPC.0b013e3282f3ef9c | last2 = Borot | last3 = Sekula | last4 = Ledger | last5 = Thomas | last6 = Halevy | last7 = Naldi | last8 = Bouwes-Bavinck | last9 = Sidoroff | last10 = De Toma | last11 = Schumacher | last12 = Roujeau | last13 = Hovnanian | last14 = Mockenhaupt | last15 = Regiscar Study | s2cid = 35512622 }}</ref>

Other HLA associations with the development of SJS, SJS/TEN, or TEN and the intake of specific drugs as determined in certain populations are given in [[Severe cutaneous adverse reactions#HLA proteins|HLA associations with SCARs]].

=== T-cell receptors ===
In addition to acting through HLA proteins to bind with a T-cell receptor, a drug or its metabolite may bypass HLA proteins to bind directly to a T-cell receptor and thereby stimulate CD8<sup>+</sup> T or CD4<sup>+</sup> T cells to initiate autoimmune responses. In either case, this binding appears to develop only on certain T cell receptors. Since the genes for these receptors are highly [[Genome editing|edited]], i.e. altered to encode proteins with different amino acid sequences, and since the human population may express more than 100 trillion different (i.e. different amino acid sequences) T-cell receptors while an individual express only a fraction of these, a drug's or its metabolite's ability to induce the DRESS syndrome by interacting with a T cell receptor is limited to those individuals whose T cells express a T cell receptor(s) that can interact with the drug or its metabolite.<ref name="pmid28476287"/><ref name="pmid28345177">{{cite journal | vauthors = Garon SL, Pavlos RK, White KD, Brown NJ, Stone CA, Phillips EJ | title = Pharmacogenomics of off-target adverse drug reactions | journal = British Journal of Clinical Pharmacology | volume = 83 | issue = 9 | pages = 1896–1911 | date = September 2017 | pmid = 28345177 | pmc = 5555876 | doi = 10.1111/bcp.13294 }}</ref> Thus, only rare individuals are predisposed to develop SJS in response to a particular drug on the bases of their expression of specific T-cell receptor types.<ref name="pmid27960170"/> While the evidence supporting this T-cell receptor selectivity is limited, one study identified the preferential presence of the [[V(D)J recombination|TCR-V-b]] and [[complementarity-determining region 3]] in [[T-cell receptor#Structural characteristics of the TCR|T-cell receptors]] found on the T cells in the blisters of patients with allopurinol-induced DRESS syndrome. This finding is compatible with the notion that specific types of T cell receptors are involved in the development of specific drug-induced SCARs.<ref name="pmid27362322"/>

=== ADME === 
Variations in [[ADME]], i.e. an individual's efficiency in absorbing, tissue-distributing, metabolizing, or excreting a drug, have been found to occur in various [[severe cutaneous adverse reactions]] (SCARS) as well as other types of adverse drug reactions.<ref name="pmid27955861">{{cite journal | vauthors = Alfirevic A, Pirmohamed M | title = Genomics of Adverse Drug Reactions | journal = Trends in Pharmacological Sciences | volume = 38 | issue = 1 | pages = 100–109 | date = January 2017 | pmid = 27955861 | doi = 10.1016/j.tips.2016.11.003 }}</ref> These variations influence the levels and duration of a drug or its metabolite in tissues and thereby impact the drug's or metabolite's ability to evoke these reactions.<ref name="Adler2017"/> For example, [[CYP2C9]] is an important drug-metabolizing [[cytochrome P450]]; it metabolizes and thereby inactivates [[phenytoin]]. Taiwanese, Japanese, and Malaysian individuals expressing the [[CYP2C9*3]]<ref>{{cite web|url=https://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=1057910|title=Reference SNP (refSNP) Cluster Report: rs1057910 ** With drug-response allele **|last=snpdev|website=www.ncbi.nlm.nih.gov}}</ref> variant of CYP2C9, which has reduced metabolic activity compared to the [[wild type]] (i.e. CYP2c9*1) cytochrome, have increased blood levels of phenytoin and a high incidence of SJS (as well as SJS/TEN and TEN) when taking the drug.<ref name=Adler2017/><ref name="pmid25096692">{{cite journal | vauthors = Chung WH, Chang WC, Lee YS, Wu YY, Yang CH, Ho HC, Chen MJ, Lin JY, Hui RC, Ho JC, Wu WM, Chen TJ, Wu T, Wu YR, Hsih MS, Tu PH, Chang CN, Hsu CN, Wu TL, Choon SE, Hsu CK, Chen DY, Liu CS, Lin CY, Kaniwa N, Saito Y, Takahashi Y, Nakamura R, Azukizawa H, Shi Y, Wang TH, Chuang SS, Tsai SF, Chang CJ, Chang YS, Hung SI | title = Genetic variants associated with phenytoin-related severe cutaneous adverse reactions | journal = JAMA | volume = 312 | issue = 5 | pages = 525–34 | date = August 2014 | pmid = 25096692 | doi = 10.1001/jama.2014.7859 | doi-access = free }}</ref> In addition to abnormalities in drug-metabolizing enzymes, dysfunctions of the kidney, liver, or GI tract which increase a SCARs-inducing drug or metabolite levels are suggested to promote SCARs responses.<ref name="Adler2017" /><ref name=Ler2017/> These ADME abnormalities, it is also suggested, may interact with particular HLA proteins and T cell receptors to promote a SCARs disorder.<ref name=Adler2017/><ref name="pmid27154258">{{cite journal | vauthors = Chung WH, Wang CW, Dao RL | title = Severe cutaneous adverse drug reactions | journal = The Journal of Dermatology | volume = 43 | issue = 7 | pages = 758–66 | year = 2016 | pmid = 27154258 | doi = 10.1111/1346-8138.13430 | s2cid = 45524211 }}</ref>