Pemphigus Vulgaris
Diseases

Author: Martina Sanlorenzo
Date: 30/01/2009

Description

Martina Sanlorenzo Stefania Benetti

DEFINITION

Pemphigus is an autoimmune disease characterized by intraepidermal blisters and extensive erosions on apparently healthy skin and mucous membranes.The disease is characterized by the presence of autoantibodies directed against intercellular adhesion molecules desmoglein-1 and desmoglein-3 in the epidermis. They are Ca-dependent cadherins , involved in adhesion and cell signaling between epidermal cells.

Acantholysis result from either direct inhibition of function of the desmogleins by autoantibody binding or from autoantibody-induced cell signaling that results in down-regulation of cell-cell adhesion and formation of blisters. These autoantibodies are present in both serum and skin during active disease. Any area of stratified squamous epithelium may be affected, including mucosal surfaces.

EPIDEMIOLOGY

Pemphigus vulgaris is a rare (1/1000000) disease. It is found mainly in people of Ashkenazi Jewish descent and the age of onset if 60 years.

SYMPTOMS AND SIGNS

Mucous membranes typically are affected first in PV. Mucosal lesions may precede cutaneous lesions by months. Patients with mucosal lesions may present to dentists, oral surgeons, or gynecologists.

  • Mucous membranes
    • Intact bullae are rare in the mouth. More commonly, patients have ill-defined, irregularly shaped, gingival, buccal or palatine erosions, which are painful and slow to heal. The erosions extend peripherally with shedding of the epithelium.
    • The mucous membranes most often affected are those of the oral cavity, which is involved in almost all patients with PV and sometimes is the only area involved. Erosions may be seen on any part of the oral cavity. Erosions can be scattered and often extensive. Erosions may spread to involve the larynx with subsequent hoarseness. The patient often is unable to eat or drink adequately because the erosions are so uncomfortable.
    • Other mucosal surfaces may be involved, including the conjunctiva, esophagus, labia, vagina, cervix, penis, urethra, and anus.

  • Skin: The primary lesion of PV is a flaccid blister filled with clear fluid that arises on normal skin or on an erythematous base. The blisters are fragile; therefore, intact blisters may be sparse. The contents soon become turbid, or the blisters rupture producing painful erosions, which is the most common skin presentation. Erosions often are large because of their tendency to extend peripherally with the shedding of the epithelium.

  • Vegetating PV: Ordinary PV erosions may develop vegetation. Lesions in skin folds readily form vegetating granulations. In some patients, erosions tend to develop excessive granulation tissue and crusting, and these patients display more vegetating lesions. This type of lesion tends to occur more frequently in intertriginous areas and on the scalp or face. The vegetating type of response can be more resistant to therapy and can remain in one place for long periods of time.
  • Nails : Acute paronychia, subungual hematomas, and nail dystrophies have been reported with PV.
  • Nikolsky sign : In patients with active blistering, firm sliding pressure with a finger separates normal-appearing epidermis, producing an erosion. This sign is not specific for PV and is found in other active blistering diseases.
  • Asboe-Hansen sign: Lateral pressure on the edge of a blister may spread the blister into clinically unaffected skin.

DIAGNOSIS

Skin biopsy's usually show intraepidermal bulla, eosinophiul infiltrate and acantholysis, which refers to the separation of epidermal cells. Direct and indirect immunofluorescence, the presence of immunoglobulin G and complement C3 within the affected areas, and antibodies directed against desmoglein 3, a cellular adhesion molecule all aid in diagnosis. Prognosis is usually done by following antibody levels.

TREATMENT

Severe cases of pemphigus are treated similarly to severe burns. Treatment may require hospitalization, including care in a burn unit or intensive care unit. Treatment is aimed at reducing symptoms and preventing complications.

  • Treatment may involve:
    • Fluids, proteins, and electrolytes given through a vein (IV)
    • IV feedings if there are severe mouth ulcers
    • Anesthetic (numbing) mouth lozenges to reduce mouth ulcer pain
    • Antibiotics and antifungal medications to control or prevent infections

Body-wide (systemic) therapy is needed to control pemphigus and should be started as early as possible. Systemic treatment includes corticosteroids, medications containing gold, an anti-inflammatory drug called dapsone, and medications that suppress the immune system (such as azathioprine, methotrexate, cyclosporin, cyclophosphamide, or mycophenolate mofetil). However, side effects from systemic therapy are a major complication.
Some antibiotics are also effective, particularly minocycline and doxycycline.
The combination of rituximab and intravenous immune globulin is effective in patients with refractory pemphigus vulgaris.
Plasmapheresis is a process whereby antibody-containing plasma is removed from the blood and replaced with intravenous fluids or donated plasma. Plasmapheresis may be used in addition to the systemic medications to reduce the amount of antibodies in the bloodstream.
Localized treatment of ulcers and blisters may include soothing or drying lotions, wet dressings, or similar measures.

Rules
MeSH
Comments
2013-08-09T13:57:14 - Gianpiero Pescarmona

Pemphigus autoimmunity: hypotheses and realities., 2011

Hypothetical scheme of signaling events mediating keratinocyte damage in PV.

The desmosome and pemphigus.. 2008

Histology and autoantibody profile in pemphigus

Signaling Dependent and Independent Mechanisms in Pemphigus Vulgaris Blister Formation, 2012

The major forms of pemphigus include pemphigus vulgaris and pemphigus foliaceus.

non infectious factors

The extent of desmoglein 3 depletion in pemphigus vulgaris is dependent on Ca(2+)-induced differentiation: a role in suprabasal epidermal skin splitting? 2011

Because we did not detect reduced Dsg3 levels in keratinocytes cultured for longer periods under high-Ca(2+) conditions, we hypothesized that Dsg depletion depends on Ca(2+)-mediated keratinocyte differentiation.

infectious skin diseases

Autoimmune and infectious skin diseases that target desmogleins. 2010

Molecular cloning of cDNA encoding pemphigus antigens has indicated that IgG autoantibodies from patients recognize desmogleins, which are cadherin-type cell–cell adhesion molecules found in the adhering junctions, the desmosomes,

Desmoglein 3 molecular mimicry (Pemphigus Vulgaris)

Virus

>SWISSPROT_VIRUSES:RDRP_BPSP (P09675) RNA-directed RNA polymerase
beta chain (RNA replicase beta chain) [Enterobacteria
phage SP]
Length = 576

Score = 31.2 bits (69), Expect = 1.2, Method: Compositional matrix adjust.
Identities = 25/94 (26%), Positives = 44/94 (46%), Gaps = 18/94 (19%)

Query: 265 WFEIQTDPRTNEGILKVVKALDYEQLQSV--------------KLSIAVKNKAEFHQSVI 310
W+++ TD R++EGIL + + YE++ S+ ++ +V E QS +
Sbjct: 295 WYDLLTDLRSDEGILPDGRVVTYEKISSMGNGYTFELESLIFAAIARSVCELLEIDQSTV 354

Query: 311 SRYR---VQSTPVTIQVINVREGIAFRP-ASKTF 340
S Y + T +++V E + F P KTF
Sbjct: 355 SVYGDDIIIDTRAAAPLMDVFEYVGFTPNRKKTF 388

>SWISSPROT_VIRUSES:L_WWAVU (B2ZDY2) RNA-directed RNA polymerase L
(Protein L) (Large structural protein) (Replicase)
(Transcriptase) [Whitewater arroyo virus]
Length = 2219

Score = 29.3 bits (64), Expect = 4.4, Method: Compositional matrix adjust.
Identities = 29/113 (25%), Positives = 45/113 (39%), Gaps = 17/113 (15%)

Query: 177 REQASSYRLVVSGADKDG-EGLSTQCECNIKVKDVNDNFPMFRDSQYSARIEENILSSEL 235
RE+ Y+ + A DG T EC I + V D F + RDS + SE
Sbjct: 209 REEGLDYKTKLMEAIRDGIRPNLTASECRIGIAKVYDQFCLLRDSGQYQNVYCRTSRSEM 268

Query: 236 LRFQVTDLDEEYTDNWLAVYFFTS---GNEGNWFEIQTDPRTNEGILKVVKAL 285
+ WL + TS G+EG F + +L+V L
Sbjct: 269 IE-------------WLKDHKLTSLINGSEGTFFNNERCGFCQNHMLRVIAEL 308

>SWISSPROT_VIRUSES:MCP_IRV16 (O39164) Major capsid protein (MCP)
(P50) [Costelytra zealandica iridescent virus]
Length = 462

Score = 28.1 bits (61), Expect = 9.7, Method: Compositional matrix adjust.
Identities = 24/75 (32%), Positives = 34/75 (45%), Gaps = 4/75 (5%)

Query: 267 EIQTDPRTNEGIL-KVVKALDYEQLQSVK-LSIAVKNKAEFHQSVISRYRVQSTPVTIQV 324
++QT PR N L + D ++K L V+NK + S Y S VT Q
Sbjct: 274 QVQTAPRQNYTPLTNAMPTFDIRFSHAIKALFFSVRNKTS--SAEWSNYATSSPVVTGQL 331

Query: 325 INVREGIAFRPASKT 339
+N AF P S T
Sbjct: 332 VNYEPPGAFDPISNT 346

FUNGI

>SWISSPROT_FUNGI:DCL1_CRYPA (Q2VF19) Dicer-like protein 1
[Cryphonectria parasitica]
Length = 1548

Score = 32.3 bits (72), Expect = 1.1, Method: Compositional matrix adjust.
Identities = 24/98 (24%), Positives = 39/98 (39%), Gaps = 10/98 (10%)

Query: 111 IFMGEIEENSASNSLVMILNA--TDADEPNHLNSKIAFKIV--------SQEPAGTPMFL 160
F+G E S + +LN T +E L +K KI + P F
Sbjct: 788 LFLGPVEQEMTSDLVCQVLNCPITPTEEDLQLLTKFTLKIFVDIFNKKYAANAQALPYFF 847

Query: 161 LSRNTGEVRTLTNSLDREQASSYRLVVSGADKDGEGLS 198
N V N D A + L AD+D E +
Sbjct: 848 APTNKDHVFLFSNLQDPRNAVDWPLLRHVADRDAEAYT 885

>SWISSPROT_FUNGI:PKSL1_ASPPA (Q12053) Aflatoxin biosynthesis
polyketide synthase (PKS) [Aspergillus parasiticus]
Length = 2109

Score = 32.0 bits (71), Expect = 1.6, Method: Compositional matrix adjust.
Identities = 17/53 (32%), Positives = 28/53 (52%), Gaps = 4/53 (7%)

Query: 353 DYILGTYQAIDEDTNKAASNVKYVMGRNDGGYLM----IDSKTAEIKFVKNMN 401
DY+L Y ++E N+AAS V + G ++G + +D T F N N
Sbjct: 1504 DYMLLDYLVLNEAENEAASGVDFSLGSSEGTFAAHPAHVDAITQVAGFAMNAN 1556

>SWISSPROT_FUNGI:HFA1_YEAS7 (A6ZMR9) Acetyl-CoA carboxylase,
mitochondrial precursor (ACC) [Saccharomyces cerevisiae]
Length = 2273

Score = 30.0 bits (66), Expect = 6.2, Method: Compositional matrix adjust.
Identities = 23/68 (33%), Positives = 33/68 (48%), Gaps = 7/68 (10%)

Query: 310 ISRYRVQSTPVTIQVINVREGIA-FRPASKTFTVQKGISSKKLVDYILGTYQAIDEDTNK 368
S Y+++S P I + EGI F P K F V+K I+S D Q E+ K
Sbjct: 1351 MSNYKIRSLPTYDSSIRIFEGISKFTPLDKRFFVRKIINSSMYND------QKTTEENLK 1404

Query: 369 AASNVKYV 376
A N + V
Sbjct: 1405 AEINAQVV 1412

>SWISSPROT_FUNGI:AUS1_YEAST (Q08409) ATP-dependent permease AUS1
[Saccharomyces cerevisiae]
Length = 1394

Score = 29.6 bits (65), Expect = 7.9, Method: Compositional matrix adjust.
Identities = 15/50 (30%), Positives = 28/50 (56%)

Query: 334 RPASKTFTVQKGISSKKLVDYILGTYQAIDEDTNKAASNVKYVMGRNDGG 383
P ++T QK I S K ++Y +GT + I + +S + +MG + G
Sbjct: 738 QPITETVETQKHIISWKNINYTVGTKKLINNASGFISSGLTALMGESGAG 787


Antibodies to Saccharomyces cerevisiae in patients with Crohn's disease and their possible pathogenic importance. 1992
Raised IgA, but not IgG, yeast antibody levels were found in two patients with Crohn's disease who were intolerant to yeast, but these values were similar to those in other patients without yeast intolerance.

no significant similarities with bacteria

Desmoglein 1 molecular mimicry (Pemphigus Foliaceus)

Virus

>SWISSPROT_VIRUSES:VP87_NPVOP (P17930) Capsid protein p87 [Orgyia
pseudotsugata multicapsid polyhedrosis virus]
Length = 624

Score = 31.2 bits (69), Expect = 2.5, Method: Compositional matrix adjust.
Identities = 30/121 (24%), Positives = 42/121 (34%), Gaps = 12/121 (9%)

Query: 786 PQETEPVVSGHPPISPHFGTTTVISESTYPSGPGVLHPKPILDPLGYGNVTVTESYTTSD 845
PQ P+ PP P + T P P T +Y TS
Sbjct: 264 PQTPAPLQDQMPPQTPAYATPAQQPSQPTPAQTPAQQPS-----------QPTPAYVTS- 311

Query: 846 TLKPSVHVHDNRPASNVVVTERVVGPISGADLHGMLEMPDLRDGSNVIVTERVIAPSSSL 905
P+ P SN RV + DL + +PD D S+VI +R + L
Sbjct: 312 AQTPAQQPSQPTPVSNYSWERRVASMFANTDLPQNVPLPDSYDTSSVIGQKRRKRRAPPL 371

Query: 906 P 906
P
Sbjct: 372 P 372

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