Pemphigus
Encyclopedia
Pemphigus is a rare group of blister
ing autoimmune disease
s that affect the skin
and mucous membrane
s.
In pemphigus, autoantibodies
form against desmoglein
. Desmoglein forms the "glue" that attaches adjacent epidermal cells via attachment points called desmosomes. When autoantibodies attack desmogleins, the cells become separated from each other and the epidermis becomes "unglued", a phenomenon called acantholysis
. This causes blister
s that slough off and turn into sores. In some cases, these blisters can cover a significant area of the skin.
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, a historic paper that changed the understanding of pemphigus was published. In 1971, an article investigating the autoimmune nature of this disease was published.
Note that Hailey-Hailey disease, also called familial benign pemphigus, is an inherited (genetic) skin disease, not an autoimmune disease. It is therefore not considered part of the Pemphigus group of diseases.
and mucous membrane pemphigoid. 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 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 anti-desmoglein autoantibodies by direct immunofluorescence
on the skin biopsy. These antibodies appear as IgG deposits along the desmosomes between epidermal cells, a pattern reminiscent of chicken wire. Anti-desmoglein antibodies can also be detected in a blood sample using the ELISA
technique. A high titre of cANCA is claimed to be an important feature of the disease on several WWW pages, but is not mentioned in current Dermatology textbooks nor do the terms "Pemphigus" and "cANCA" produce any hits on a PUBMED search.
Half of pemphigus patients have oral lesions alone during the first year but develop skin lesions later.
of the sores. The most common treatment is the administration of oral steroids, especially prednisone
, and often in high doses. The side effects of cortico-steroids may require the use of so-called steroid-sparing or adjuvant drugs. The immuno-suppressant CellCept (Mycophenolic acid
) is among those being used.
Intravenous gamma globulin
(IVIG) may be useful in severe cases, especially paraneoplastic pemphigus. Mild cases sometimes respond to the application of topical steroids. Recently, Rituximab
, an anti-CD20
antibody, was found to improve otherwise untreatable severe cases of Pemphigus vulgaris.
All of these drugs may cause severe side effects, so the patient should be closely monitored by doctors. Once the outbreaks are under control, dosage is often reduced, to lessen side effects.
If paraneoplastic pemphigus is diagnosed with pulmonary disease, a powerful cocktail of immune suppressant 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.
If skin lesions do become infected, antibiotic
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.
Pain is a common part of the disease. Only one literature review on peer-reviewed articles reporting pemphigous pain management has been published in the professional medical literature.
This can be read at:
Pemphigus pain: a review on management.
Rashid RM, Candido KD.
Clin J Pain. 2008 Oct;24(8):734-5. Review.
Pemphigus vulgaris is a very rare disorder described in pet dogs and cats. Paraneoplastic pemphigus has been identified in pet dogs.
Blister
A blister is a small pocket of fluid within the upper layers of the skin, typically caused by forceful rubbing , burning, freezing, chemical exposure or infection. Most blisters are filled with a clear fluid called serum or plasma...
ing autoimmune disease
Autoimmune disease
Autoimmune diseases arise from an overactive immune response of the body against substances and tissues normally present in the body. In other words, the body actually attacks its own cells. The immune system mistakes some part of the body as a pathogen and attacks it. This may be restricted to...
s that affect the skin
Skin
-Dermis:The dermis is the layer of skin beneath the epidermis that consists of connective tissue and cushions the body from stress and strain. The dermis is tightly connected to the epidermis by a basement membrane. It also harbors many Mechanoreceptors that provide the sense of touch and heat...
and mucous membrane
Mucous membrane
The mucous membranes are linings of mostly endodermal origin, covered in epithelium, which are involved in absorption and secretion. They line cavities that are exposed to the external environment and internal organs...
s.
In pemphigus, autoantibodies
Autoantibody
An autoantibody is an antibody manufactured by the immune system that is directed against one or more of the individual's own proteins. It is derived from the Greek "auto" which means "self", "anti" which means "against" and "body"...
form against desmoglein
Desmoglein
The desmogleins are a family of cadherins consisting of proteins DSG1, DSG2, DSG3, and DSG4. They play a role in the formation of desmosomes that join cells to one another....
. Desmoglein forms the "glue" that attaches adjacent epidermal cells via attachment points called desmosomes. When autoantibodies attack desmogleins, the cells become separated from each other and the epidermis becomes "unglued", a phenomenon called acantholysis
Acantholysis
Acantholysis is the loss of intercellular connections, such as desmosomes, resulting in loss of cohesion between keratinocytes, seen in diseases such as pemphigus vulgaris. It is absent in bullous pemphigoid, making it useful for differential diagnosis....
. This causes blister
Blister
A blister is a small pocket of fluid within the upper layers of the skin, typically caused by forceful rubbing , burning, freezing, chemical exposure or infection. Most blisters are filled with a clear fluid called serum or plasma...
s that slough off and turn into sores. In some cases, these blisters can cover a significant area of the skin.
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, a historic paper that changed the understanding of pemphigus was published. In 1971, an article investigating the autoimmune nature of this disease was published.
Types
There are three types of pemphigus which vary in severity: pemphigus vulgaris, pemphigus foliaceus, and paraneoplastic pemphigus.- The most common form of the disorder is pemphigus vulgarisPemphigus vulgarisPemphigus vulgaris is a chronic blistering skin disease with skin lesions that are rarely pruritic, but which are often painful.-Pathophysiology:...
(PV - ICD-10ICDThe International Statistical Classification of Diseases and Related Health Problems is a medical classification that provides codes to classify diseases and a wide variety of signs, symptoms, abnormal findings, complaints, social circumstances, and external causes of injury or disease...
L10.0). It occurs when antibodiesAntibodyAn antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
attack Desmoglein 3Desmoglein 3Desmoglein-3 is a protein that in humans is encoded by the DSG3 gene.-Interactions:Desmoglein 3 has been shown to interact with PKP3.-Further reading:...
. Sores often originate in the mouthMouthThe mouth is the first portion of the alimentary canal that receives food andsaliva. The oral mucosa is the mucous membrane epithelium lining the inside of the mouth....
, making eating difficult and uncomfortable. Although pemphigus vulgaris may occur at any age, it is most common among people between the ages of 40 and 60. It is more frequent among Ashkenazi JewsAshkenazi JewsAshkenazi Jews, also known as Ashkenazic Jews or Ashkenazim , are the Jews descended from the medieval Jewish communities along the Rhine in Germany from Alsace in the south to the Rhineland in the north. Ashkenaz is the medieval Hebrew name for this region and thus for Germany...
. Rarely, it is associated with myasthenia gravisMyasthenia gravisMyasthenia gravis is an autoimmune neuromuscular disease leading to fluctuating muscle weakness and fatiguability...
. Nail diseaseNail diseaseNail diseases are distinct from diseases of the skin. Although nails are a skin appendage, they have their own signs and symptoms which may relate to other medical conditions. Nail conditions that show signs of infection or inflammation require medical assistance...
may be the only finding and has prognostic value in management. - Pemphigus foliaceusPemphigus foliaceusPemphigus foliaceus is an autoimmune blistering disease of the skin and mucous membranes with characteristic lesions that are scaly, crusted erosions, often on an erythematous base...
(PF) is the least severe of the three varieties. Desmoglein 1Desmoglein 1Desmoglein 1 is a protein that in humans is encoded by the DSG1 gene.-Interactions:Desmoglein 1 has been shown to interact with PKP3 and PKP2.-Further reading:...
, the protein that is destroyed by the autoantibody, is only found in the top dry layer of the skin. PF is characterized by crusty sores that often begin on the scalpScalpThe scalp is the anatomical area bordered by the face anteriorly and the neck to the sides and posteriorly.-Layers:It is usually described as having five layers, which can conveniently be remembered as a mnemonic:...
, and may move to the chest, back, and face. Mouth sores do not occur. It is not as painful as pemphigus vulgaris, and is often mis-diagnosed as dermatitisDermatitis-Etymology:Dermatitis derives from Greek derma "skin" + -itis "inflammation" and genetic disorder.-Terminology:There are several different types of dermatitis. The different kinds usually have in common an allergic reaction to specific allergens. The term may describe eczema, which is also called...
or eczemaEczemaEczema is a form of dermatitis, or inflammation of the epidermis . In England, an estimated 5.7 million or about one in every nine people have been diagnosed with the disease by a clinician at some point in their lives.The term eczema is broadly applied to a range of persistent skin conditions...
. - The least common and most severe type of pemphigus is paraneoplastic pemphigusParaneoplastic pemphigusParaneoplastic pemphigus is an autoimmune disorder that is almost invariably linked to an underlying lymphoproliferative disorder.-External links:*Wikipedia Pemphigus Page with PNP Information*...
(PNP). This disorder is a complication of cancerCancerCancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
, usually lymphomaLymphomaLymphoma is a cancer in the lymphatic cells of the immune system. Typically, lymphomas present as a solid tumor of lymphoid cells. Treatment might involve chemotherapy and in some cases radiotherapy and/or bone marrow transplantation, and can be curable depending on the histology, type, and stage...
and Castleman's diseaseCastleman's diseaseCastleman's disease is an uncommon lymphoproliferative disorder that can involve single lymph node stations or...
. It may precede the diagnosis of the tumor. Painful sores appear on the mouth, lips, and the esophagusEsophagusThe esophagus is an organ in vertebrates which consists of a muscular tube through which food passes from the pharynx to the stomach. During swallowing, food passes from the mouth through the pharynx into the esophagus and travels via peristalsis to the stomach...
. In this variety of pemphigus, the disease process often involves the lungs, causing bronchiolitis obliteransBronchiolitis obliteransBronchiolitis obliterans , also called obliterative bronchiolitis and constrictive bronchiolitis , is a rare and life-threatening form of non-reversible obstructive lung disease in which the bronchioles are compressed and narrowed by fibrosis and/or inflammation...
(constrictive bronchiolitis). Complete removal and/or cure of the tumor may improve the skin disease, but lung damage is generally irreversible .
Note that Hailey-Hailey disease, also called familial benign pemphigus, is an inherited (genetic) skin disease, not an autoimmune disease. It is therefore not considered part of the Pemphigus group of diseases.
Classification
Pemphigus is a group of autoimmune blistering diseases that may be classified into the following types:- Pemphigus vulgarisPemphigus vulgarisPemphigus vulgaris is a chronic blistering skin disease with skin lesions that are rarely pruritic, but which are often painful.-Pathophysiology:...
, of which there several forms:
-
-
- Pemphigus vegetansPemphigus vegetansPemphigus vegetans is a localized form of pemphigus vulgaris.in which there is a localized vegetating papillomatous response. The eroded areas do not heal like usual but form papillomatous growth and vegetation....
-
- Pemphigus vegetans of HallopeauPemphigus vegetans of HallopeauPemphigus vegetans of Hallopeau is a disease of localized pemphigus vulgaris.It is named for François Henri Hallopeau....
- Pemphigus vegetans of NeumannPemphigus vegetans of NeumannPemphigus vegetans of Neumann is a localized disease of pemphigus vulgaris slightly more extensive than pemphigus vegetans of Hallopeau....
- Pemphigus foliaceusPemphigus foliaceusPemphigus foliaceus is an autoimmune blistering disease of the skin and mucous membranes with characteristic lesions that are scaly, crusted erosions, often on an erythematous base...
, of which there several forms:
- Pemphigus foliaceus
- Pemphigus vegetans of Hallopeau
- Pemphigus erythematosusPemphigus erythematosusPemphigus erythematosus is simply a localized form of pemphigus foliaceus....
- Endemic pemphigusEndemic pemphigusEndemic pemphigus, also known as endemic pemphigus foliaceus and fogo selvagem , is a disease that is clinically, histologically, and immunopathologically the same as sporadic pemphigus foliaceus in any individual patient, but that is endemic in the rural areas of Brazil, especially along inland...
- Paraneoplastic pemphigusParaneoplastic pemphigusParaneoplastic pemphigus is an autoimmune disorder that is almost invariably linked to an underlying lymphoproliferative disorder.-External links:*Wikipedia Pemphigus Page with PNP Information*...
- IgA pemphigusIgA pemphigusIgA pemphigus is a subtype of pemphigus with two distinct forms, subcorneal pustular dermatosis and intraepidermal neutrophilic IgA dermatosis....
, of which there several forms:
- Paraneoplastic pemphigus
- Subcorneal pustular dermatosisSubcorneal pustular dermatosisSubcorneal pustular dermatosis is skin condition that is a rare, chronic, recurrent, pustular eruption characterized histopathologically by subcorneal pustules that contain abundant neutrophils....
- Intraepidermal neutrophilic IgA dermatosisIntraepidermal neutrophilic IgA dermatosisIntraepidermal neutrophilic IgA dermatosis is characterized histologically by intraepidermal bullae with neutrophils, some eosinophils, and acantholysis....
- Pemphigus vegetans
-
Diagnosis
Pemphigus is recognized by a dermatologist from the appearance and distribution of the skin lesions. It is also commonly diagnosed by periodontists, oral and maxillofacial surgeons (specialists qualified in both medicine and dentistry)and ophthalmologists (eye doctors) as lesions can affect the eyes and mucous membrane of the oral cavity. Intraorally it resembles the more common diseases lichen planusLichen planus
Lichen planus is a chronic mucocutaneous disease that affects the skin, tongue, and oral mucosa. The disease presents itself in the form of papules, lesions, or rashes. Lichen planus does not involve lichens, the fungus/algae symbionts that often grow on tree trunks; the name refers to the dry and...
and mucous membrane pemphigoid. Definitive diagnosis requires examination of a skin or mucous membrane biopsy
Biopsy
A biopsy is a medical test involving sampling of cells or tissues for examination. It is the medical removal of tissue from a living subject to determine the presence or extent of a disease. The tissue is generally examined under a microscope by a pathologist, and can also be analyzed chemically...
by a dermatopathologist or oral pathologist. The skin biopsy is taken from the edge of a blister, prepared for histopathology
Histopathology
Histopathology refers to the microscopic examination of tissue in order to study the manifestations of disease...
and examined with a microscope
Microscope
A microscope is an instrument used to see objects that are too small for the naked eye. The science of investigating small objects using such an instrument is called microscopy...
. The pathologist looks for an intraepidermal vesicle caused by the breaking apart of epidermal cells (acantholysis
Acantholysis
Acantholysis is the loss of intercellular connections, such as desmosomes, resulting in loss of cohesion between keratinocytes, seen in diseases such as pemphigus vulgaris. It is absent in bullous pemphigoid, making it useful for differential diagnosis....
). 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 anti-desmoglein autoantibodies by direct immunofluorescence
Immunofluorescence
Immunofluorescence is a technique used for light microscopy with a fluorescence microscope and is used primarily on biological samples. This technique uses the specificity of antibodies to their antigen to target fluorescent dyes to specific biomolecule targets within a cell, and therefore allows...
on the skin biopsy. These antibodies appear as IgG deposits along the desmosomes between epidermal cells, a pattern reminiscent of chicken wire. Anti-desmoglein antibodies can also be detected in a blood sample using the ELISA
ELISA
Enzyme-linked immunosorbent assay , is a popular format of a "wet-lab" type analytic biochemistry assay that uses one sub-type of heterogeneous, solid-phase enzyme immunoassay to detect the presence of a substance in a liquid sample."Wet lab" analytic biochemistry assays involves detection of an...
technique. A high titre of cANCA is claimed to be an important feature of the disease on several WWW pages, but is not mentioned in current Dermatology textbooks nor do the terms "Pemphigus" and "cANCA" produce any hits on a PUBMED search.
Half of pemphigus patients have oral lesions alone during the first year but develop skin lesions later.
Treatment
If not treated, pemphigus can be fatal from an overwhelming infectionInfection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
of the sores. The most common treatment is the administration of oral steroids, especially prednisone
Prednisone
Prednisone is a synthetic corticosteroid drug that is particularly effective as an immunosuppressant drug. It is used to treat certain inflammatory diseases and some types of cancer, but has significant adverse effects...
, and often in high doses. The side effects of cortico-steroids may require the use of so-called steroid-sparing or adjuvant drugs. The immuno-suppressant CellCept (Mycophenolic acid
Mycophenolic acid
Mycophenolic acid INN or mycophenolate is an immunosuppressant drug used to prevent rejection in organ transplantation. It inhibits an enzyme needed for the growth of T cells and B cells. It was initially marketed as the prodrug mycophenolate mofetil to improve oral bioavailability. More...
) is among those being used.
Intravenous gamma globulin
Gamma globulin
Gamma globulins are a class of globulins, identified by their position after serum protein electrophoresis. The most significant gamma globulins are immunoglobulins , more commonly known as antibodies, although some Igs are not gamma globulins, and some gamma globulins are not Igs.-Use as medical...
(IVIG) may be useful in severe cases, especially paraneoplastic pemphigus. Mild cases sometimes respond to the application of topical steroids. Recently, Rituximab
Rituximab
Rituximab, sold under the trade names Rituxan and MabThera, is a chimeric monoclonal antibody against the protein CD20, which is primarily found on the surface of B cells...
, an anti-CD20
CD20
B-lymphocyte antigen CD20 or CD20 is an activated-glycosylated phosphoprotein expressed on the surface of all B-cells beginning at the pro-B phase and progressively increasing in concentration until maturity....
antibody, was found to improve otherwise untreatable severe cases of Pemphigus vulgaris.
All of these drugs may cause severe side effects, so the patient should be closely monitored by doctors. Once the outbreaks are under control, dosage is often reduced, to lessen side effects.
If paraneoplastic pemphigus is diagnosed with pulmonary disease, a powerful cocktail of immune suppressant drugs is sometimes used in an attempt to halt the rapid progression of bronchiolitis obliterans
Bronchiolitis obliterans
Bronchiolitis obliterans , also called obliterative bronchiolitis and constrictive bronchiolitis , is a rare and life-threatening form of non-reversible obstructive lung disease in which the bronchioles are compressed and narrowed by fibrosis and/or inflammation...
, including methylprednisolone
Methylprednisolone
Methylprednisolone is a synthetic glucocorticoid or corticosteroid drug. It is marketed in the USA and Canada under the brand names Medrol and Solu-Medrol. It is also available as a generic drug....
, ciclosporin
Ciclosporin
Ciclosporin , cyclosporine , cyclosporin , or cyclosporin A is an immunosuppressant drug widely used in post-allogeneic organ transplant to reduce the activity of the immune system, and therefore the risk of organ rejection...
, azathioprine
Azathioprine
Azathioprine is a purine analogue immunosuppressive drug. It is used to prevent organ rejection following organ transplantation and to treat a vast array of autoimmune diseases, including rheumatoid arthritis, pemphigus, inflammatory bowel disease , multiple sclerosis, autoimmune hepatitis, atopic...
and thalidomide
Thalidomide
Thalidomide was introduced as a sedative drug in the late 1950s that was typically used to cure morning sickness. In 1961, it was withdrawn due to teratogenicity and neuropathy. There is now a growing clinical interest in thalidomide, and it is introduced as an immunomodulatory agent used...
. Plasmapheresis
Plasmapheresis
Plasmapheresis is the removal, treatment, and return of blood plasma from blood circulation. It is thus an extracorporeal therapy...
may also be useful.
If skin lesions do become infected, antibiotic
Antibiotic
An antibacterial is a compound or substance that kills or slows down the growth of bacteria.The term is often used synonymously with the term antibiotic; today, however, with increased knowledge of the causative agents of various infectious diseases, antibiotic has come to denote a broader range of...
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.
Pain is a common part of the disease. Only one literature review on peer-reviewed articles reporting pemphigous pain management has been published in the professional medical literature.
This can be read at:
Pemphigus pain: a review on management.
Rashid RM, Candido KD.
Clin J Pain. 2008 Oct;24(8):734-5. Review.
Pemphigus in domestic animals
Pemphigus foliaceus has been recognized in pet dogs, cats and horses and is the most common autoimmune skin disease diagnosed in veterinary medicine. Pemphigus foliaceus in animals produces clusters of small vesicles that quickly evolve into pustules. Pustules may rupture, forming erosions or become crusted. Left untreated, pemphigus foliaceus in animals is life-threatening leading to loss of condition and secondary infection.Pemphigus vulgaris is a very rare disorder described in pet dogs and cats. Paraneoplastic pemphigus has been identified in pet dogs.
External links
- International Pemphigus & Pemphigoid Foundation
- Pemphigus vulgaris, article from eMedicine.
- Pemphigus foliaceus, article from eMedicine.
- Paraneoplastic pemphigus, article from eMedicine.
- Paraneoplastic Pemphigus Survivor
- Pemphigus Vulgaris
- www.blisters.org.au
- http://tray.dermatology.uiowa.edu/PemVul01.htm