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{{Stevens-Johnson syndrome}}
{{Stevens-Johnson syndrome}}


{{CMG}}; {{AE}}  
{{CMG}}; {{AE}} {{AHS}}
==Overview==
==Overview==
SJS, like [[toxic epidermal necrolysis]] and [[erythema multiforme]], are characterized by confluent epidermal [[necrosis]] with minimal associated inflammation. The acuity is apparent from the (normal) basket weave-like pattern of the [[stratum corneum]].
SJS, like [[toxic epidermal necrolysis]] and [[erythema multiforme]], are characterized by confluent epidermal [[necrosis]] with minimal associated inflammation. The acuity is apparent from the (normal) basket weave-like pattern of the [[stratum corneum]]. The exact pathogenesis of SJS/TEN is not completely understood. However, It is believed that SJS/TEN is immune-mediated and the result of an MHC Class-I restricted T-cell mediated cytotoxic reaction to drug antigens in [[Keratinocyte|keratinocytes]] leading to [[apoptosis]]<ref name="pmid8466217" />. Drug antigens bind to [[MHC-I]] and [[T cell Receptors (TCR)]] leading to the clonal proliferation of the drug-specific [[Cytotoxic T cell|cytotoxic T cells]]. On the activation of these T cells, various cytotoxic signals, including Fas/Fas ligand, [[perforin]]/[[granzyme B]], and [[granulysin]], are known to be responsible for mediating the damages in skin lesions and the subsequent worsening of the disease.  


==Pathophysiology==
==Pathophysiology==
===Physiology===
===Pathogenesis===
The normal physiology of [name of process] can be understood as follows:
*The exact pathogenesis of SJS/TEN is not completely understood


===Pathogenesis===
*However, It is believed that SJS/TEN is immune mediated and the result of a MHC Class-I restricted T-cell mediated cytotoxic reaction to drug antigens in keratinocytes leading to apoptosis<ref name="pmid8466217">{{cite journal| author=Correia O, Delgado L, Ramos JP, Resende C, Torrinha JA| title=Cutaneous T-cell recruitment in toxic epidermal necrolysis. Further evidence of CD8+ lymphocyte involvement. | journal=Arch Dermatol | year= 1993 | volume= 129 | issue= 4 | pages= 466-8 | pmid=8466217 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8466217  }}</ref>
*The exact pathogenesis of [disease name] is not completely understood.
*Drug antigens bind to MHC-I and T cell Receptors (TCR) leading to the clonal proliferation of the drug specific cytotoxic T cells
OR
*On the activation of these T cells, various cytotoxic signals, including Fas/Fas ligand , perforin/granzyme B , and granulysin, are known to be responsible for mediating the damages in skin lesions and the subsequent worsening of the disease as explained below.
*It is understood that [disease name] is the result of / is mediated by / is produced by / is caused by either [hypothesis 1], [hypothesis 2], or [hypothesis 3].
**[[T lymphocytes]] found in bisters were CD8+, HLA-DR+, CLA+ (cutaneous lymphocyte antigen), CD56+ and were shown to be strongly immunoreactive for granzyme B suggesting perforin/granzyme mediated cytotoxicity<ref name="pmid155364332">{{cite journal| author=Nassif A, Bensussan A, Boumsell L, Deniaud A, Moslehi H, Wolkenstein P et al.| title=Toxic epidermal necrolysis: effector cells are drug-specific cytotoxic T cells. | journal=J Allergy Clin Immunol | year= 2004 | volume= 114 | issue= 5 | pages= 1209-15 | pmid=15536433 | doi=10.1016/j.jaci.2004.07.047 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15536433  }}</ref>
*[Pathogen name] is usually transmitted via the [transmission route] route to the human host.
**There is also beleived to be some involvement of the soluble FasL (sFasL) in keratinocyte apoptosis in SJS and TEN. sFasL is secreted by [[peripheral bood mononuclear cells]] (PBMC's) and interacts with the Fas that is expressed on [[keratinocyte]] leading to apoptosis. Higher serum levels of [[sFasL]] may be seen in patients with suspicion of SJS/TEN<ref name="pmid12707034">{{cite journal| author=Abe R, Shimizu T, Shibaki A, Nakamura H, Watanabe H, Shimizu H| title=Toxic epidermal necrolysis and Stevens-Johnson syndrome are induced by soluble Fas ligand. | journal=Am J Pathol | year= 2003 | volume= 162 | issue= 5 | pages= 1515-20 | pmid=12707034 | doi=10.1016/S0002-9440(10)64284-8 | pmc=1851208 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12707034  }}</ref>
*Following transmission/ingestion, the [pathogen] uses the [entry site] to invade the [cell name] cell.
**Recent studies suggest that the Granulysin, which is a cytotoxic protein released from cytotoxic T cells or [[natural killer (NK) cells]], is a key mediator for disseminated keratinocyte apoptosis in SJS/TEN<ref name="pmid22541332">{{cite journal| author=Chung WH, Hung SI| title=Recent advances in the genetics and immunology of Stevens-Johnson syndrome and toxic epidermal necrosis. | journal=J Dermatol Sci | year= 2012 | volume= 66 | issue= 3 | pages= 190-6 | pmid=22541332 | doi=10.1016/j.jdermsci.2012.04.002 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22541332  }}</ref> and is identified by [[gene expression profiling]] as the highly cytotoxic molecule and confirmed by [[Polymerase chain reaction|PCR]] and [[immunohistochemistry]]. Granulysin concentrations in blister fluid were found to be 2x to 4x more than the Perforin/Granzyme B/sFasL thus making it the most important cytotoxic molecule in SJS/TEN pathogenesis<ref name="pmid19029983">{{cite journal| author=Chung WH, Hung SI, Yang JY, Su SC, Huang SP, Wei CY et al.| title=Granulysin is a key mediator for disseminated keratinocyte death in Stevens-Johnson syndrome and toxic epidermal necrolysis. | journal=Nat Med | year= 2008 | volume= 14 | issue= 12 | pages= 1343-50 | pmid=19029983 | doi=10.1038/nm.1884 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19029983  }}</ref>
*[Disease or malignancy name] arises from [cell name]s, which are [cell type] cells that are normally involved in [function of cells].
**Other cytokines that may be associated with trafficking, activation and proliferation of cytotoxic T cells and other immune cells include [[IFN-Y(gamma)]], [[TNF-aplha]], IL-2, IL-5, IL-6, IL-10, IL-13. IL-15 was one of the [[cytokines]] that was seen in the highest amount and also correlated with disease severity and mortality. Studies also suggest that IL-15 is important in mentaining long-lasting cytotoxic T lymphocyte responses as well as generating and mentaining Nk cells. It is also responsible for enhancing  MHC-I antigen  presentation thus has an important contribution in SJS/TEN pathogenesis<ref name="pmid28011147">{{cite journal| author=Su SC, Mockenhaupt M, Wolkenstein P, Dunant A, Le Gouvello S, Chen CB et al.| title=Interleukin-15 Is Associated with Severity and Mortality in Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis. | journal=J Invest Dermatol | year= 2017 | volume= 137 | issue= 5 | pages= 1065-1073 | pmid=28011147 | doi=10.1016/j.jid.2016.11.034 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28011147  }}</ref>
*The progression to [disease name] usually involves the [molecular pathway].
*The pathophysiology of [disease/malignancy] depends on the histological subtype.


==Genetics==
==Genetics==
[Disease name] is transmitted in [mode of genetic transmission] pattern.
*Some people have genetic predisposition which increases their risk of developing SJS in response to certain trigger medications. The most common genetic variation contributing to the predisposition is seen in the [[HLA-B]] gene. Examples include
 
**People with HLA-B 1502 gene have 10 percent risk of developing SJS on exposure to [[anti-Epileptic drugs|anti-epileptic drugs]] like [[Phenytoin]], [[Carbamazepine]], [[Phenobarbital]], [[Lamotrigine]]<ref name="pmid24871931">{{cite journal| author=Li X, Yu K, Mei S, Huo J, Wang J, Zhu Y et al.| title=HLA-B*1502 increases the risk of phenytoin or lamotrigine induced Stevens-Johnson Syndrome/toxic epidermal necrolysis: evidence from a meta-analysis of nine case-control studies. | journal=Drug Res (Stuttg) | year= 2015 | volume= 65 | issue= 2 | pages= 107-11 | pmid=24871931 | doi=10.1055/s-0034-1375684 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24871931  }}</ref>
OR
**People with HLA-B 5801 have high risk of developing SJS on exposure to [[Allupurinol]]<ref name="pmid21906289">{{cite journal| author=Somkrua R, Eickman EE, Saokaew S, Lohitnavy M, Chaiyakunapruk N| title=Association of HLA-B*5801 allele and allopurinol-induced Stevens Johnson syndrome and toxic epidermal necrolysis: a systematic review and meta-analysis. | journal=BMC Med Genet | year= 2011 | volume= 12 | issue=  | pages= 118 | pmid=21906289 | doi=10.1186/1471-2350-12-118 | pmc=3189112 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21906289  }}</ref>
 
**Certain studies have identified HLA-B 3101 as a genetic risk factor for carbamazepine induced skin reactions including SJS<ref name="pmid21428769">{{cite journal| author=McCormack M, Alfirevic A, Bourgeois S, Farrell JJ, Kasperavičiūtė D, Carrington M et al.| title=HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans. | journal=N Engl J Med | year= 2011 | volume= 364 | issue= 12 | pages= 1134-43 | pmid=21428769 | doi=10.1056/NEJMoa1013297 | pmc=3113609 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21428769  }}</ref>
Genes involved in the pathogenesis of [disease name] include:
**HLA-B 1511, HLA-B 2402 are also considered to increase SJS risk in certain populations
*[Gene1]
*[[Genetic Polymorphism|Genetic Polymorphism]] in CYP2C gene variants may lead to an increased risk of SJS/TEN on exposure to certain anti-seizure medications in some populations<ref name="pmid23551241">{{cite journal| author=Manuyakorn W, Siripool K, Kamchaisatian W, Pakakasama S, Visudtibhan A, Vilaiyuk S et al.| title=Phenobarbital-induced severe cutaneous adverse drug reactions are associated with CYP2C19*2 in Thai children. | journal=Pediatr Allergy Immunol | year= 2013 | volume= 24 | issue= 3 | pages= 299-303 | pmid=23551241 | doi=10.1111/pai.12058 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23551241  }}</ref>
*[Gene2]
*[Gene3]
 
OR
 
The development of [disease name] is the result of multiple genetic mutations such as:
 
*[Mutation 1]
*[Mutation 2]
*[Mutation 3]


==Associated Conditions==
==Associated Conditions==
Some conditions that are associated with an increased risk of SJS/TEN include [[Human Immunodeficiency Virus (HIV)|HIV]], immunodeficiency, active cancers (mostly hematological) and some genetic factors.


==Gross Pathology==
==Gross Pathology==
On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
* On gross examination in SJS/TEN, blisters/erosions/bullae and vesicles are seen along with Confluent redness and skin sloughing. Nikolsky Sign may be positive which is the detachment of superficial epidermis on gentle pressure or rubbing of skin


==Microscopic Pathology==
==Microscopic Pathology==
On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
On microscopic histopathological analysis,full-thickness extensive keratinocyte necrosis that develop into subepidermal bullae is seen in established SJS/TEN<ref name="pmid29226159">{{cite journal| author=Orime M| title=Immunohistopathological Findings of Severe Cutaneous Adverse Drug Reactions. | journal=J Immunol Res | year= 2017 | volume= 2017 | issue=  | pages= 6928363 | pmid=29226159 | doi=10.1155/2017/6928363 | pmc=5684554 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29226159  }}</ref>. Satellite cell necrosis may also be seen<ref name="pmid20536645">{{cite journal| author=Hosaka H, Ohtoshi S, Nakada T, Iijima M| title=Erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis: frozen-section diagnosis. | journal=J Dermatol | year= 2010 | volume= 37 | issue= 5 | pages= 407-12 | pmid=20536645 | doi=10.1111/j.1346-8138.2009.00746.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20536645  }}</ref>


==References==
==References==

Latest revision as of 15:34, 15 September 2018

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anila Hussain, MD [2]

Overview

SJS, like toxic epidermal necrolysis and erythema multiforme, are characterized by confluent epidermal necrosis with minimal associated inflammation. The acuity is apparent from the (normal) basket weave-like pattern of the stratum corneum. The exact pathogenesis of SJS/TEN is not completely understood. However, It is believed that SJS/TEN is immune-mediated and the result of an MHC Class-I restricted T-cell mediated cytotoxic reaction to drug antigens in keratinocytes leading to apoptosis[1]. Drug antigens bind to MHC-I and T cell Receptors (TCR) leading to the clonal proliferation of the drug-specific cytotoxic T cells. On the activation of these T cells, various cytotoxic signals, including Fas/Fas ligand, perforin/granzyme B, and granulysin, are known to be responsible for mediating the damages in skin lesions and the subsequent worsening of the disease.

Pathophysiology

Pathogenesis

  • The exact pathogenesis of SJS/TEN is not completely understood
  • However, It is believed that SJS/TEN is immune mediated and the result of a MHC Class-I restricted T-cell mediated cytotoxic reaction to drug antigens in keratinocytes leading to apoptosis[1]
  • Drug antigens bind to MHC-I and T cell Receptors (TCR) leading to the clonal proliferation of the drug specific cytotoxic T cells
  • On the activation of these T cells, various cytotoxic signals, including Fas/Fas ligand , perforin/granzyme B , and granulysin, are known to be responsible for mediating the damages in skin lesions and the subsequent worsening of the disease as explained below.
    • T lymphocytes found in bisters were CD8+, HLA-DR+, CLA+ (cutaneous lymphocyte antigen), CD56+ and were shown to be strongly immunoreactive for granzyme B suggesting perforin/granzyme mediated cytotoxicity[2]
    • There is also beleived to be some involvement of the soluble FasL (sFasL) in keratinocyte apoptosis in SJS and TEN. sFasL is secreted by peripheral bood mononuclear cells (PBMC's) and interacts with the Fas that is expressed on keratinocyte leading to apoptosis. Higher serum levels of sFasL may be seen in patients with suspicion of SJS/TEN[3]
    • Recent studies suggest that the Granulysin, which is a cytotoxic protein released from cytotoxic T cells or natural killer (NK) cells, is a key mediator for disseminated keratinocyte apoptosis in SJS/TEN[4] and is identified by gene expression profiling as the highly cytotoxic molecule and confirmed by PCR and immunohistochemistry. Granulysin concentrations in blister fluid were found to be 2x to 4x more than the Perforin/Granzyme B/sFasL thus making it the most important cytotoxic molecule in SJS/TEN pathogenesis[5]
    • Other cytokines that may be associated with trafficking, activation and proliferation of cytotoxic T cells and other immune cells include IFN-Y(gamma), TNF-aplha, IL-2, IL-5, IL-6, IL-10, IL-13. IL-15 was one of the cytokines that was seen in the highest amount and also correlated with disease severity and mortality. Studies also suggest that IL-15 is important in mentaining long-lasting cytotoxic T lymphocyte responses as well as generating and mentaining Nk cells. It is also responsible for enhancing MHC-I antigen presentation thus has an important contribution in SJS/TEN pathogenesis[6]

Genetics

  • Some people have genetic predisposition which increases their risk of developing SJS in response to certain trigger medications. The most common genetic variation contributing to the predisposition is seen in the HLA-B gene. Examples include
    • People with HLA-B 1502 gene have 10 percent risk of developing SJS on exposure to anti-epileptic drugs like Phenytoin, Carbamazepine, Phenobarbital, Lamotrigine[7]
    • People with HLA-B 5801 have high risk of developing SJS on exposure to Allupurinol[8]
    • Certain studies have identified HLA-B 3101 as a genetic risk factor for carbamazepine induced skin reactions including SJS[9]
    • HLA-B 1511, HLA-B 2402 are also considered to increase SJS risk in certain populations
  • Genetic Polymorphism in CYP2C gene variants may lead to an increased risk of SJS/TEN on exposure to certain anti-seizure medications in some populations[10]

Associated Conditions

Some conditions that are associated with an increased risk of SJS/TEN include HIV, immunodeficiency, active cancers (mostly hematological) and some genetic factors.

Gross Pathology

  • On gross examination in SJS/TEN, blisters/erosions/bullae and vesicles are seen along with Confluent redness and skin sloughing. Nikolsky Sign may be positive which is the detachment of superficial epidermis on gentle pressure or rubbing of skin

Microscopic Pathology

On microscopic histopathological analysis,full-thickness extensive keratinocyte necrosis that develop into subepidermal bullae is seen in established SJS/TEN[11]. Satellite cell necrosis may also be seen[12]

References

  1. ↑ 1.0 1.1 Correia O, Delgado L, Ramos JP, Resende C, Torrinha JA (1993). "Cutaneous T-cell recruitment in toxic epidermal necrolysis. Further evidence of CD8+ lymphocyte involvement". Arch Dermatol. 129 (4): 466–8. PMID 8466217.
  2. ↑ Nassif A, Bensussan A, Boumsell L, Deniaud A, Moslehi H, Wolkenstein P; et al. (2004). "Toxic epidermal necrolysis: effector cells are drug-specific cytotoxic T cells". J Allergy Clin Immunol. 114 (5): 1209–15. doi:10.1016/j.jaci.2004.07.047. PMID 15536433.
  3. ↑ Abe R, Shimizu T, Shibaki A, Nakamura H, Watanabe H, Shimizu H (2003). "Toxic epidermal necrolysis and Stevens-Johnson syndrome are induced by soluble Fas ligand". Am J Pathol. 162 (5): 1515–20. doi:10.1016/S0002-9440(10)64284-8. PMC 1851208. PMID 12707034.
  4. ↑ Chung WH, Hung SI (2012). "Recent advances in the genetics and immunology of Stevens-Johnson syndrome and toxic epidermal necrosis". J Dermatol Sci. 66 (3): 190–6. doi:10.1016/j.jdermsci.2012.04.002. PMID 22541332.
  5. ↑ Chung WH, Hung SI, Yang JY, Su SC, Huang SP, Wei CY; et al. (2008). "Granulysin is a key mediator for disseminated keratinocyte death in Stevens-Johnson syndrome and toxic epidermal necrolysis". Nat Med. 14 (12): 1343–50. doi:10.1038/nm.1884. PMID 19029983.
  6. ↑ Su SC, Mockenhaupt M, Wolkenstein P, Dunant A, Le Gouvello S, Chen CB; et al. (2017). "Interleukin-15 Is Associated with Severity and Mortality in Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis". J Invest Dermatol. 137 (5): 1065–1073. doi:10.1016/j.jid.2016.11.034. PMID 28011147.
  7. ↑ Li X, Yu K, Mei S, Huo J, Wang J, Zhu Y; et al. (2015). "HLA-B*1502 increases the risk of phenytoin or lamotrigine induced Stevens-Johnson Syndrome/toxic epidermal necrolysis: evidence from a meta-analysis of nine case-control studies". Drug Res (Stuttg). 65 (2): 107–11. doi:10.1055/s-0034-1375684. PMID 24871931.
  8. ↑ Somkrua R, Eickman EE, Saokaew S, Lohitnavy M, Chaiyakunapruk N (2011). "Association of HLA-B*5801 allele and allopurinol-induced Stevens Johnson syndrome and toxic epidermal necrolysis: a systematic review and meta-analysis". BMC Med Genet. 12: 118. doi:10.1186/1471-2350-12-118. PMC 3189112. PMID 21906289.
  9. ↑ McCormack M, Alfirevic A, Bourgeois S, Farrell JJ, Kasperavičiūtė D, Carrington M; et al. (2011). "HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans". N Engl J Med. 364 (12): 1134–43. doi:10.1056/NEJMoa1013297. PMC 3113609. PMID 21428769.
  10. ↑ Manuyakorn W, Siripool K, Kamchaisatian W, Pakakasama S, Visudtibhan A, Vilaiyuk S; et al. (2013). "Phenobarbital-induced severe cutaneous adverse drug reactions are associated with CYP2C19*2 in Thai children". Pediatr Allergy Immunol. 24 (3): 299–303. doi:10.1111/pai.12058. PMID 23551241.
  11. ↑ Orime M (2017). "Immunohistopathological Findings of Severe Cutaneous Adverse Drug Reactions". J Immunol Res. 2017: 6928363. doi:10.1155/2017/6928363. PMC 5684554. PMID 29226159.
  12. ↑ Hosaka H, Ohtoshi S, Nakada T, Iijima M (2010). "Erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis: frozen-section diagnosis". J Dermatol. 37 (5): 407–12. doi:10.1111/j.1346-8138.2009.00746.x. PMID 20536645.

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