Editing Pemphigus

{{Short description|Blistering autoimmune diseases}}
{{About|a skin blistering disease|another similar-looking blistering skin disease|Pemphigoid|the genus of true bugs|Pemphigus (bug)}}

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[[File:Permphigus.jpg|thumb|Pemphigus, from 1886 medical book]]
[[Image:Pemphigus immunofluorescence.jpg|thumb|200px|Microscopic image of direct [[immunofluorescence]] using an anti-[[Immunoglobulin G|IgG]] antibody. The tissue is skin from a patient with '''Pemphigus vulgaris'''. Note the intercellular IgG deposits in the [[Epidermis (skin)|epidermis]] and the early intraepidermal [[vesicle (dermatology)|vesicle]] caused by acantholysis.]]

'''Pemphigus''' ({{IPAc-en|ˈ|p|ɛ|m|f|ɪ|g|ə|s}} or {{IPAc-en|p|ɛ|m|ˈ|f|aɪ|g|ə|s}}) is a rare group of [[blister]]ing [[autoimmune disease]]s that affect the [[skin]] and [[mucous membrane]]s.<ref name="yeh">
{{cite journal|vauthors=Yeh SW, Ahmed B, Sami N, Ahmed AR | title = Blistering disorders: diagnosis and treatment| journal = [[Dermatologic Therapy]]| volume = 16| issue = 3| pages = 214–23| year = 2003| pmid = 14510878| doi = 10.1046/j.1529-8019.2003.01631.x| doi-access = free}}</ref> The name is derived from the Greek root ''pemphix'', meaning "blister".<ref>{{Cite web|url=https://www.merriam-webster.com/dictionary/pemphigus|title=Definition of PEMPHIGUS|website=www.merriam-webster.com|language=en|access-date=2017-03-11}}</ref>

In pemphigus, [[autoantibody|autoantibodies]] form against [[desmoglein]], which forms the "glue" that attaches adjacent [[Epidermis (skin)|epidermal]] cells via attachment points called [[desmosomes]]. When autoantibodies attack desmogleins, the cells become separated from each other and the epidermis becomes detached, a phenomenon called [[acantholysis]]. This causes [[blister]]s that slough off and turn into [[Ulcer (dermatology)|sores]]. In some cases, these blisters can cover a large area of the skin.<ref>[http://pemphigus.org/index.php?option=com_content&view=article&id=364&Itemid=100073/ International Pemphigus & Pemphigoid Foundation: What is Pemphigus?]</ref>

Originally, the cause of this disease was unknown, and "pemphigus" was used to refer to any blistering disease of the skin and mucosa.  In 1964, researchers found that the blood of patients with pemphigus contained antibodies to the layers of skin that separate to form the blisters.<ref>{{cite journal|last1=Beutner|first1= EH|last2= Jordon|first2 =RE|title= Demonstration of skin antibodies in sera of pemphigus vulgaris patients by indirect immunofluorescent staining|journal = Proceedings of the Society for Experimental Biology and Medicine|date=November 1964|volume = 117|issue= 2|pages = 505–510|pmid=14233481|doi=10.3181/00379727-117-29622|s2cid= 9443044}}</ref><ref>{{cite web |url=http://www.dermfnd.org/press01/beutner.html |title=Dermatology Foundation: BEUTNER, JORDAN SHARE 2000 DERMATOLOGY FOUNDATION DISCOVERY AWARD |access-date=2009-01-31 |archive-url=https://web.archive.org/web/20080518082952/http://www.dermfnd.org/press01/beutner.html |archive-date=2008-05-18 |url-status=dead }}</ref> In 1971, an article investigating the autoimmune nature of this disease was published.<ref>{{cite journal|doi=10.1111/1523-1747.ep12293273|authorlink1=Robert E. Jordon|authorlink4=Ernst H. Beutner|first1=Robert E.|last1=Jordon|first2 = W. Mitchell|last2 = Sams Jr.|first3= Gustavo|last3=Diaz|first4=Ernst H.|last4=Beutner|title=Negative Complement Immunofluorescence in Pemphigus|journal=Journal of Investigative Dermatology|year=1971|volume= 57|issue=6|pages=407–410|pmid=4108416|doi-access=free}}</ref><ref>{{cite journal|last=Serratos|first=BD|author2=Rashid, RM|title=Nail disease in pemphigus vulgaris|journal=Dermatology Online Journal|date=Jul 15, 2009|volume=15|issue=7|pages=2|doi=10.5070/D34X05D6VH |pmid=19903430|url=http://escholarship.org/uc/item/4x05d6vh|url-access=subscription}}</ref>

==Types==
The several types of pemphigus (pemphigus vulgaris, pemphigus foliaceus, intraepidermal neutrophilic IgA dermatosis, and paraneoplastic pemphigus) vary in severity. Skin lesions caused by pemphigus can lead to fatal infections, so treatment is extremely important.

*[[Pemphigus vulgaris]] (PV - [[ICD|ICD-10]] L10.0) is the most common form of the disorder and occurs when [[Antibody|antibodies]] attack [[desmoglein 3]]. Sores often originate in the mouth, making eating difficult and uncomfortable. Although PV may occur at any age, it is most common among people between 40 and 60. It is more frequent among [[Ashkenazi Jews]]. Rarely, it is associated with [[myasthenia gravis]].  [[Nail disease]] may be the only finding and has prognostic value in management.{{citation needed|date=November 2012}}<ref name=":0" />
* [[Pemphigus foliaceus]] (PF) is the least severe variety. [[Desmoglein 1]], the protein that is targeted by the autoantibodies, is enriched in the upper skin layers. PF is characterized by crusty sores that often begin on the [[scalp]], and may move to the chest, back, and face. Mouth sores do not occur. This form is also frequent among Ashkenazi Jews. It is not as painful as PV, and is often misdiagnosed as [[dermatitis]] or [[eczema]]<ref name=":0" /> PF is endemic in Brazil <ref name="pmid7805306">{{cite journal|vauthors=Sampaio SA et al | title=Brazilian pemphigus foliaceus, endemic pemphigus foliaceus, or fogo selvagem (wild fire)|journal= Dermatologic Clinics| volume=12|issue=4|pages=765–776|year=1994| doi=10.1016/S0733-8635(18)30140-2|pmid=7805306}}</ref> and Tunisia.<ref name="pmid25558949">{{cite journal|vauthors=Saleh MA | title=Pemphigus in the Arab world|journal= The Journal of Dermatology| volume=42|issue=1|pages=27–30|year=2015|pmid=25558949| doi=10.1111/1346-8138.12676| s2cid=5126848|doi-access=free}}</ref>
*[[Intraepidermal neutrophilic IgA dermatosis]] is characterized histologically by intraepidermal bullae with neutrophils, some [[eosinophils]], and acantholysis.<ref name=":0">{{cite journal | doi=10.7241/ourd.20134.158 | title=Autoimmune epidermal blistering diseases | year=2013 | last1=Abreu Velez | first1=Ana Maria | last2=Calle | first2=Juliana | last3=Howard | first3=Michael S. | journal=Our Dermatology Online | volume=4 | pages=631–646 | doi-access=free }}</ref>
* The least common and most severe type of pemphigus is [[paraneoplastic pemphigus]] (PNP). This disorder is a complication of [[cancer]], usually [[lymphoma]] or [[Castleman's disease]]. It may precede the diagnosis of the tumor. Painful sores appear on the mouth, lips, and the [[esophagus]]. In this variety of pemphigus, the disease process often involves the lungs, causing [[bronchiolitis obliterans]] (constrictive bronchiolitis). Though much less frequent, it is still found the most in the Ashkenazi Jewish population. Complete removal of and/or cure of the tumor may improve the skin disease, but lung damage is generally irreversible.
*Endemic pemphigus foliaceus includes fogo selvagem, the new variant of endemic pemphigus foliaceus in El Bagre, Colombia, and the Tunisian endemic pemphigus in North Africa.<ref>{{cite journal | doi=10.1067/s0190-9622(03)00851-x | title=A unique form of endemic pemphigus in northern Colombia | year=2003 | last1=Abrèu-Velez | first1=Ana María | last2=Hashimoto | first2=Takashi | last3=Bollag | first3=Wendy B. | last4=Tobón Arroyave | first4=Sergio | last5=Abrèu-Velez | first5=Clara Eugenia | last6=Londoño | first6=Martha Luz | last7=Montoya | first7=Fernando | last8=Beutner | first8=Ernst H. | journal=Journal of the American Academy of Dermatology | volume=49 | issue=4 | pages=599–608 | pmid=14512903 }}</ref>

[[Hailey-Hailey disease]], also called familial benign pemphigus, is an inherited skin disease, not an autoimmune disease, so it is not considered part of the pemphigus group of diseases.<ref>{{Cite web |url=http://www.haileyhailey.com/WhatIsHHD.htm |title=Hailey Hailey Disease Society |access-date=2008-03-04 |archive-url=https://web.archive.org/web/20121014124508/http://haileyhailey.com/WhatIsHHD.htm |archive-date=2012-10-14 |url-status=dead }}</ref>

==Diagnosis==
Pemphigus defines a group of autoimmune intraepithelial blistering diseases that are characterized by loss of normal cell-cell adhesion (acantholysis), and by the presence of pathogenic (predominantly IgG) autoantibodies reacting against epithelial adhesion molecules.<ref name=":0"/> Pemphigus is further divided in two major subtypes: pemphigus vulgaris (PV) and pemphigus foliaceus (PF). However, several other disorders such as IgA pemphigus, IgE pemphigus, pemphigus herpetiformis, drug-induced pemphigus, Senear Usher syndrome, and endemic pemphigus foliaceus exist, and are recognized by a [[dermatologist]] from the appearance and distribution of the skin lesions. It is also commonly diagnosed by specialists practicing [[otolaryngology- head and neck surgery]], periodontists, oral and maxillofacial surgeons, and [[ophthalmology|eye doctors]], as lesions can affect the eyes and mucous membranes of the oral cavity. Intraorally, it resembles the more common diseases [[lichen planus]] and [[mucous membrane pemphigoid]].<ref name="SappEversole1997">{{cite book|last1=Sapp|first1=J. Philip|last2=Eversole|first2=Lewis R.|last3=Wysocki|first3=George P.|title=Contemporary Oral and Maxillofacial Pathology|url=https://books.google.com/books?id=OvppAAAAMAAJ|year=1997|publisher=Mosby|isbn=978-0-8016-6918-7}}[http://www.sciencedirect.com/science/book/9780323017237 also here]</ref> Definitive diagnosis requires examination of a skin or mucous membrane [[biopsy]] by a [[dermatopathologist]] or oral pathologist. The skin biopsy is taken from the edge of a blister, prepared for [[histopathology]] and examined with a microscope. The pathologist looks for an intraepidermal [[Vesicle (dermatology)|vesicle]] caused by the breaking apart of epidermal cells (acantholysis). Thus, the superficial (upper) portion of the epidermis sloughs off, leaving the bottom layer of cells on the "floor" of the blister. This bottom layer of cells is said to have a "tombstone" appearance.

Definitive diagnosis also requires the demonstration of antidesmoglein autoantibodies by [[Immunofluorescence|direct immunofluorescence]] on the skin biopsy. These antibodies appear as [[IgG]] deposits along the desmosomes between epidermal cells, a pattern reminiscent of chicken wire. Antidesmoglein antibodies can also be detected in a blood sample using the [[ELISA]] technique.

=== Classification ===

Pemphigus is a group of autoimmune blistering diseases that may be classified into these types:<ref name="Fitz2">{{Fitzpatrick 6|59|559}}</ref>
:* [[Pemphigus vulgaris]]
:* [[Pemphigus vegetans]]
:*[[Pemphigus vegetans of Hallopeau]]
:*[[Pemphigus vegetans of Neumann]]
:* [[Pemphigus foliaceus]], of which there several forms:
:* [[Pemphigus erythematosus]] or [[Senear–Usher Syndrome]]
:* [[Endemic pemphigus foliaceus]] with its three variants, [[Fogo Selvagem]], the new variant endemic pemphigus Foliaeus and [[Tunisian endemic pemphigus foliaceus]]
:* [[Paraneoplastic pemphigus]]
:* [[IgA pemphigus]], of which there several forms:
:* [[Subcorneal pustular dermatosis]]
:* [[Intraepidermal neutrophilic IgA dermatosis]]
:*[[Drug induced pemphigus]]

==Treatment==
If not treated, pemphigus can be fatal, usually from overwhelming opportunistic [[infection]] of lesions. The most common treatment is the administration of oral steroids, especially [[prednisone]], often in high doses. The side effects of corticosteroids may require the use of so-called steroid-sparing or [[Adjuvant therapy|adjuvant]] drugs. One of the most dangerous side effects of high-dosage steroid treatments is [[Gastrointestinal perforation|intestinal perforations]],{{Citation needed|date=August 2020}} which may lead to sepsis. Steroids and other medications being taken to treat pemphigus may also mask the effects of the perforations. Patients on high dosages of oral steroids should closely monitor their [[gastrointestinal]] health. As lesions are usually terribly painful, pain medication<ref>{{cite journal|last=Rashid|first=RM|author2=Candido, KD|title=Pemphigus pain: a review on management|journal=The Clinical Journal of Pain|date=Oct 2008|volume=24|issue=8|pages=734–5|pmid=18806540|doi=10.1097/AJP.0b013e31817af6fc|s2cid=21201391}}</ref> likely complicates and exacerbates the gastrointestinal issues caused by steroids.

=== Treatment options ===

* Topical steroids, such as clobetasol
* Intralesional injection of steroids, such as [[dexamethasone]]
* Immunosuppressant drugs, such as CellCept ([[mycophenolic acid]]): In recent years, adjuvant drugs, especially biologics, have shown great promise.<ref>[http://www.bad.org.uk/public/leaflets/bad_patient_information_gateway_leaflets/pemphigus/treated/steroid.asp British Association of Dermtologists, Steroid sparing (or adjuvant) drugs] {{Webarchive|url=https://web.archive.org/web/20080918083600/http://www.bad.org.uk/public/leaflets/bad_patient_information_gateway_leaflets/pemphigus/treated/steroid.asp |date=2008-09-18 }}</ref>
* Serum- or plasma-pooled products, such as intravenous [[gamma globulin]] (IVIG) may be useful in severe cases, especially paraneoplastic pemphigus.  
* Biologics such as [[Rituximab]], an anti-[[CD20]] antibody, which was found to improve otherwise severe cases of recalcitrant pemphigus vulgaris.<ref name="pmid17065638">{{cite journal|vauthors=Ahmed AR, Spigelman Z, Cavacini LA, Posner MR |title=Treatment of pemphigus vulgaris with rituximab and intravenous immune globulin|journal= New England Journal of Medicine|volume=355|issue=17|pages=1772–9|year=2006|pmid=17065638|doi=10.1056/NEJMoa062930 |doi-access=free}}</ref><ref name="pmid17687130">{{cite journal |vauthors=Joly P, Mouquet H, Roujeau JC, etal |title=A single cycle of rituximab for the treatment of severe pemphigus|journal= New England Journal of Medicine|volume=357|issue=6|pages=545–52|year=2007|pmid=17687130|doi=10.1056/NEJMoa067752|doi-access=free}}</ref> Currently rituximab is considered a first-line treatment for some pemphigus patients according to Delphi consensus recommendations <ref name="pmid29438767">{{cite journal|vauthors=Murrell DF et al | title=Diagnosis and management of pemphigus: Recommendations of an international panel of experts|journal= Journal of the American Academy of Dermatology| volume=82|issue=3|pages=575–585|year=2020|pmid=29438767|doi=10.1016/j.jaad.2018.02.021| pmc=7313440}}</ref>    
           
All of these drugs may cause severe side effects, so patients should be closely monitored by doctors. Once the outbreaks are under control, dosage is often reduced, to lessen side effects.

A meta-analysis of the literature found insufficient evidence to determine the optimal treatment regimen for pemphigus vulgaris and pemphigus foliaceus, but it found that adding [[Cyclophosphamide|cyclophosphamid]] and [[azathioprine]] to a glucocorticoid regimen reduced the amount of glucocorticoid needed for treatment, and topical epidermal growth factor significantly reduced lesion healing time.<ref>{{Cite journal|last1=Martin|first1=Linda K|last2=Agero|first2=Anna Liza|last3=Werth|first3=Victoria|last4=Villanueva|first4=Elmer|last5=Segall|first5=Janet|last6=Murrell|first6=Dedee F|date=2009-01-21|title=Interventions for pemphigus vulgaris and pemphigus foliaceus|url=http://www.cochrane.org/CD006263/SKIN_interventions-for-pemphigus-vulgaris-and-pemphigus-foliaceus|journal=Cochrane Database of Systematic Reviews|issue=1|pages=CD006263|language=en|doi=10.1002/14651858.CD006263.pub2|pmid=19160272|s2cid=34912494 |issn=1465-1858|url-access=subscription}}</ref>

If skin lesions do become infected, [[antibiotic]]s may be prescribed. Tetracycline antibiotics have a mildly beneficial effect on the disease and are sometimes enough for pemphigus foliaceus. In addition, [[talcum powder]] is helpful to prevent oozing sores from adhering to bedsheets and clothes. Wound care and treatments are often akin to those used in burn units, including careful use of dressings that don't stick to the wounds, etc.

If paraneoplastic pemphigus is diagnosed with pulmonary disease, a powerful cocktail of immunosuppressant drugs is sometimes used in an attempt to halt the rapid progression of [[bronchiolitis obliterans]], including [[methylprednisolone]], [[ciclosporin]], [[azathioprine]], and [[thalidomide]]. [[Plasmapheresis]] may also be useful.

New research shows that the treatment options and clinical management of pemphigus are advancing, and new [[B cell|B-cell]][[Targeted therapy|-targeted-therapies]] are beginning to replace the broad-spectrum [[immunosuppression]] treatments.<ref>Lim, Y. L., Bohelay, G., Hanakawa, S., Musette, P., & Janela, B. (2022). Autoimmune pemphigus: latest advances and emerging therapies. Frontiers in Molecular Biosciences, 8. https://doi.org/10.3389/fmolb.2021.808536</ref> While promising, these new therapies may have significant side effects; hence, supporting research and extensive trials are needed to verify their effectiveness and safety.<ref>Lim, Y. L., Bohelay, G., Hanakawa, S., Musette, P., & Janela, B. (2022). Autoimmune pemphigus: latest advances and emerging therapies. Frontiers in Molecular Biosciences, 8. https://doi.org/10.3389/fmolb.2021.808536</ref>

==Animals affected==
[[Image:Canine pemphigus foliaceus 3.jpg|thumb|Pemphigus foliaceus skin eruption on the abdomen of a dog]]

Pemphigus foliaceus has been recognized in pet dogs, cats, and horses, and is the most common autoimmune skin disease diagnosed in veterinary medicine. PF in animals produces clusters of small vesicles that quickly evolve into pustules. Pustules may rupture, forming erosions or become crusted. Left untreated, PF in animals is life-threatening, leading to not only loss of condition, but also secondary infection.

PV is a very rare disorder described in pet dogs and cats. Paraneoplastic pemphigus has been identified in pet dogs.

== See also ==
* [[List of conditions caused by problems with junctional proteins]]
* [[List of cutaneous conditions]]
* [[List of immunofluorescence findings for autoimmune bullous conditions]]
* [[List of target antigens in pemphigus]]
* [[Pemphigoid]]
* [[Pemphigus herpetiformis]]

==References==
{{Reflist}}

== External links ==
{{Medical resources
| DiseasesDB =9764
| ICD10 = {{ICD10|L|10||l|10}}
| ICD9 = {{ICD9|694.4}}
| ICDO =
| OMIM = 169600
| OMIM_mult = Benign Chronic ~<br />{{nowrap|{{OMIM|169610||none}} ~ Vulgaris, Familial}}
| MedlinePlus = 000882
| eMedicineSubj = derm
| eMedicineTopic = 317
| eMedicine_mult =<br />{{eMedicine2|derm|318}} ~ foliaceus<br />{{eMedicine2|derm|314}} Drug-induced ~<br />{{eMedicine2|derm|543}} ~ herpetiformis<br />{{eMedicine2|derm|315}} ~ IgA<br />{{eMedicine2|derm|319}} ~ Vulgaris<br />{{eMedicine2|derm|535}}&nbsp;~Paraneoplastic<br />{{eMedicine2|derm|150}} Benign ~<br />&nbsp;&nbsp;([[Hailey Hailey Disease (Familial Benign Pemphigus)|Hailey-Hailey Disease]])
| MeshID = D010392
}}

*[https://rarediseases.org/rare-diseases/pemphigus/ National Organization of Rare Diseases: Pemphigus]

{{Vesiculobullous disease}}
{{Diseases of the skin and appendages by morphology}}
{{oral pathology}}
{{Authority control}}

[[Category:Chronic blistering cutaneous conditions]]
[[Category:Autoimmune diseases]]
[[Category:Ashkenazi Jews topics]]
[[Category:Oral mucosal pathology]]