Editing Erythema multiforme (section)

== Causes ==
Erythema multiforme typically arises as a [[type IV hypersensitivity]] reaction to certain infections or, rarely, certain medications. The most common trigger is an infection with any type of the [[herpes simplex virus]]. The second most common trigger, and the most common in children, is infection with ''[[Mycoplasma pneumoniae]]'', most commonly as an [[atypical pneumonia]]. When the body encounters these triggers, the immune system responds by activating various cells to fight off what it perceives as harmful invaders.<ref name=":0" /> Certain medications and other infections are also sometimes identified as causes of erythema multiforme, and while some experts doubt any true association with EM,<ref name=":0" /> others disagree, citing the lack of any HSV DNA found in cases of drug-associated EM.<ref name=":1">{{Cite journal |last=Lerch |first=Marianne |last2=Mainetti |first2=Carlo |last3=Terziroli Beretta-Piccoli |first3=Benedetta |last4=Harr |first4=Thomas |date=February 2018 |title=Current Perspectives on Erythema Multiforme |url=https://link.springer.com/10.1007/s12016-017-8667-7 |journal=Clinical Reviews in Allergy & Immunology |language=en |volume=54 |issue=1 |pages=177–184 |doi=10.1007/s12016-017-8667-7 |issn=1080-0549|url-access=subscription }}</ref><ref>{{Cite journal |last=Trayes |first=Kathryn P. |last2=Love |first2=Gillian |last3=Studdiford |first3=James S. |date=2019-07-15 |title=Erythema Multiforme: Recognition and Management |url=https://pubmed.ncbi.nlm.nih.gov/31305041 |journal=American Family Physician |volume=100 |issue=2 |pages=82–88 |issn=1532-0650 |pmid=31305041}}</ref>

The pathogenic immune response in EM involves both [[T helper cell|CD4+ helper T cells]] and [[Cytotoxic T cell|CD8+ cytotoxic T cells]], which orchestrate a [[type IV hypersensitivity]] reaction. Upon activation, these T cells release [[Inflammatory cytokine|proinflammatory cytokines]] such as [[Interferon gamma|IFN-γ]] and [[TNF-α]]. Despite the known association with IFN-γ, erythema multiforme is not considered a humorally-mediated autoimmune reaction.<ref name=":1" />

Rarely, some patients may suffer from a persistent and treatment-resistant form of erythema multiforme caused by the [[Epstein–Barr virus|Epstein-Barr virus]]. This pathology is distinct from the recurrent cases that sometimes arise from HSV-associated EM.<ref name=":1" />

[[Stevens–Johnson syndrome]] and [[toxic epidermal necrolysis]] used to be considered part of the erythema multiforme "spectrum," but EM is now recognized as a fundamentally different condition.<ref>{{cite web |last1=Wetter |first1=David |title=Erythema multiforme: Pathogenesis, clinical features, and diagnosis |url=https://www.uptodate.com/contents/erythema-multiforme-pathogenesis-clinical-features-and-diagnosis?search=Erythema%20multiforme&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1 |access-date=29 December 2018 |website=UpToDate.com}}</ref> In addition to the differing pathogenesis, SJS/TEN also differs in its clinical characteristics, and may be excluded based on clinical characteristics alone.<ref name=":2">{{Cite journal |last=Auquier-Dunant |first=Ariane |last2=Mockenhaupt |first2=Maja |last3=Naldi |first3=Luigi |last4=Correia |first4=Osvaldo |last5=Schröder |first5=Werner |last6=Roujeau |first6=Jean-Claude |date=2002-08-01 |title=Correlations Between Clinical Patterns and Causes of Erythema Multiforme Majus, Stevens-Johnson Syndrome, and Toxic Epidermal Necrolysis: Results of an International Prospective Study |url=http://archderm.jamanetwork.com/article.aspx?doi=10.1001/archderm.138.8.1019 |journal=Archives of Dermatology |language=en |volume=138 |issue=8 |doi=10.1001/archderm.138.8.1019 |issn=0003-987X|url-access=subscription }}</ref>

=== Herpes simplex virus ===
Herpes simplex virus (HSV) is by far the most frequent cause of erythema multiforme. HSV DNA is also detected in nearly half of patients with [[Idiopathic disease|idiopathic]] EM, suggesting that the true frequency is even higher than traditionally thought.<ref name=":1" /> Because of this frequency, more is understood about EM caused by HSV than any other type.<ref name=":0" />

100% of HSV-associated EM cases are found to have DNA for viral-type [[DNA polymerase]] (Pol) gene within keratinocytes. Despite this association, an active and infectious form of HSV has never been found in a patient suffering from EM, indicating that it is exclusively a post-viral hypersensitivity syndrome in these patients, rather than a symptom of the virus itself. The viral DNA polymerase protein is synthesized by [[Basal keratinocyte|basal keratinocytes]], which then present the protein or fragments of its DNA to immune cells via [[MHC class I|MHC I]]. The resulting immune reaction results in the creation of [[Cytotoxic T cell|CD8+ T-cells]] specific to HSV, which then induce a strong inflammatory response, recruiting other immune cells to places where infected keratinocytes are identified. Keratinocyte production of Pol protein only lasts for a few days, however, so most HSV-related cases of erythema multiforme do not become chronic or recurrent.<ref name=":0" /> However, recurrence is a known possibility with this type of EM, potentially justifying the use of preventative antiviral therapy.<ref name=":1" /><ref name=":2" />