Editing Erythema multiforme

{{Short description|Immune hypersensitivity reaction causing rash}}
{{Hatnote|Not to be confused with [[erythema migrans]], despite that both often involve target lesions (but from different causes).}}

{{Infobox medical condition (new)
| name = Erythema multiforme (EM)
| synonyms = 
| image = Erythema multiforme minor of the hand.jpg
| caption = Erythema multiforme minor of the hands (note the blanching centers of the lesion)
| pronounce = 
| field = [[Dermatology]], [[immunology]]
| symptoms = Rash, skin eruptions, fever, mucosal lesions
| complications = 
| onset = 
| duration = 
| types = 
| causes = [[Type IV hypersensitivity]]
| risks = [[Herpes simplex virus]] infection
| diagnosis = 
| differential = [[Stevens-Johnson syndrome]]/Toxic epidermal necrolysis
| prevention = 
| treatment = Corticosteroids, antivirals (HSV-associated cases only)
| medication = 
| prognosis = 
| frequency = 
| deaths = 
}}

'''Erythema multiforme''' ('''EM''') is an [[Immune-mediated inflammatory diseases|immune-mediated]] inflammatory [[cutaneous condition|skin condition]] associated with several viral infections, that appears with red patches evolving into [[target lesion]]s, typically on both hands. It is typically associated with infection by either [[herpes simplex virus]] or ''[[Mycoplasma pneumoniae]]''.<ref name=Weedon2017>{{cite book|last=Johnstone |first=Ronald B.|title=Weedon's Skin Pathology Essentials |url=https://books.google.com/books?id=NTE_DAAAQBAJ|year=2017|publisher=Elsevier |isbn=978-0-7020-6830-0|edition=2nd|page=41|chapter=3. Lichenoid reaction pattern}}</ref><ref name=Andrew2020>{{cite book |last1=James |first1=William D. |last2=Elston |first2=Dirk |last3=Treat |first3=James R. |last4=Rosenbach |first4=Misha A. |last5=Neuhaus |first5=Isaac |title=Andrews' Diseases of the Skin: Clinical Dermatology |date=2020 |publisher=Elsevier |isbn=978-0-323-54753-6 |pages=141–142 |edition=13th |chapter-url=https://books.google.com/books?id=UEaEDwAAQBAJ&dq=Erythema+Multiforme&pg=PA141 |language=en |chapter=7. Erythema and urticaria}}</ref><ref name=":0">{{Cite book |last=Roujeau |first=Jean-Claude |title=Fitzpatrick's Dermatology |last2=Mockenhaupt |first2=Maja |publisher=McGraw-Hill Education |year=2019 |edition=9th |chapter=Chapter 43: Erythema Multiforme}}</ref>

It is a [[type IV hypersensitivity]] reaction in which [[T cell|T-lymphocytes]] target skin [[Keratinocyte|keratinocytes]] due to the presence of specific proteins that resemble [[Antigen|antigens]] of HSV, ''Mycoplasma'', or other pathogens and foreign substances.<ref name=":0" /> It is an uncommon disorder, with peak incidence in the second and third decades of life. The disorder has various forms or presentations, which its name reflects (''multiforme'', "[[wikt:multiform#Adjective|multiform]]", from ''[[wikt:multi-#Prefix|multi-]]'' + ''[[wikt:forma#Latin|formis]]''). [[Target lesion]]s are a typical manifestation. Two standard types, one mild to moderate and one severe, are recognized ([[erythema multiforme minor]] and [[erythema multiforme major]]), as well as several rare and atypical types.<ref name=":0" />

== Signs and symptoms ==

The condition varies from a mild, self-limited rash ([[erythema multiforme minor|E. multiforme minor]])<ref>{{DorlandsDict|three/000036713|erythema multiforme}}</ref> to a severe, life-threatening form known as '''[[erythema multiforme major]]''' (or '''erythema multiforme majus''') that also involves mucous membranes.<ref>{{cite journal |vauthors= Leaute-Labreze C, Lamireau T, Chawki D, Maleville J, Taieb A
|date= October 2000 |title= Diagnosis, classification, and management of erythema multiforme and Stevens-Johnson syndrome
|journal=Archives of Disease in Childhood |volume=83 |issue=4 |pages=347–352 |doi=10.1136/adc.83.4.347 |pmid= 10999875
|pmc=1718505 }}</ref>
Consensus classification:<ref>{{EMedicine|article|1122915|Erythema Multiforme}}</ref>
* Erythema multiforme minor—typical targets or raised, edematous papules distributed [[wikt:acral|acrally]]
* Erythema multiforme major—typical targets or raised, edematous papules distributed acrally with involvement of one or more mucous membranes; epidermal detachment involves less than 10% of [[total body surface area]]

The mild form usually presents with mildly itchy (but itching can be very severe), pink-red blotches, symmetrically arranged and starting on the extremities. It often takes on the classical "target lesion" appearance,<ref name="pmid17168345">{{cite journal |vauthors=Lamoreux MR, Sternbach MR, Hsu WT |title=Erythema multiforme |journal=Am Fam Physician |volume=74 |issue=11 |pages=1883–8 |date=December 2006 |pmid=17168345 |url=http://www.aafp.org/afp/20061201/1883.html |access-date=2008-08-19 |archive-date=2021-08-28 |archive-url=https://web.archive.org/web/20210828075049/https://www.aafp.org/afp/2006/1201/p1883.html |url-status=dead }}</ref> with a pink-red ring around a pale center. Resolution within 7–10 days is the norm.

Individuals with persistent (chronic) erythema multiforme will often have a lesion form at an injury site, e.g. a minor scratch or abrasion, within a week.  Irritation or even pressure from clothing will cause the erythema sore to continue to expand along its margins for weeks or months, long after the original sore at the center heals.{{citation needed|date=June 2015}}

{{Gallery
|Image:Target_lesion_1.jpg|Target lesion
|File:Erythema Multiforme target lesions on the leg, Nell Brigham, 2011.jpg|Erythema Multiforme target lesions on the leg
|File:Erythema multiforme tongue.jpg|Erythema multiforme of tongue
|File:Riehl Zumbusch Tafel XXIX (2).jpg|Erythema multiforme of head and limbs
}}

== 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" />

== Treatment ==

Drug-induced erythema multiforme should be treated by immediately stopping the causative medication. Cases of idiopathic or infection-associated erythema multiforme may or may not be treated, depending on the underlying cause and the severity of the EM. Acute cases of erythema multiforme are often diagnosed clinically, based on symptom presentation, and treated with systemic [[Corticosteroid|steroid]] medications. Cases of EM known to be associated with HSV are frequently treated with antiviral medications such as [[acyclovir]].<ref name=":1" />

== See also ==
* [[Erythema multiforme major]]
* [[Erythema multiforme minor]]
* [[Toxic epidermal necrolysis]]
* [[Stevens–Johnson syndrome]]

== References ==
{{reflist}}

== External links ==
{{Medical resources
|  DiseasesDB = 4450
|  ICD10 = {{ICD10|L|51||l|50}}
|  ICD9 = {{ICD9|695.1}}
|  ICDO =
|  OMIM =
|  MedlinePlus = 000851
|  eMedicineSubj = derm
|  eMedicineTopic = 137
|  MeshID = D004892
}}
{{Diseases of the skin and appendages by morphology}}
{{Urticaria and erythema}}

[[Category:Erythemas]]
[[Category:Herpes simplex virus–associated diseases]]