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NORD is very grateful to Jean-Claude Bystryn, MD, deceased, former Professor of Dermatology and Director of the Bullous Disease Clinic, Department of Dermatology, NYU School of Medicine, and to Victoria P. Werth, MD, Chairman, International Pemphigus and Pemphigoid Foundation (IPPF) Medical Advisory Board; Professor, Department of Dermatology, University of Pennsylvania; Chief of Dermatology, Philadelphia V.A. Medical Center, for assistance in the preparation of this report.
Pemphigus is a general term for a group of rare autoimmune blistering skin disorders. Autoimmune disorders occur when the body's own immune system mistakenly attacks healthy tissue. The symptoms and severity associated with the various forms of pemphigus vary. All forms of pemphigus are characterized by the development of blistering eruptions on the outer layer of the skin (epidermis). In pemphigus vulgaris, lesions also develop on the mucous membranes such as those lining the inside the mouth. Mucous membranes are the thin, moist coverings of many of the body's internal surfaces. If left untreated, pemphigus will usually be fatal. The exact cause of pemphigus is unknown.
The term pemphigus is a general term for a group of related autoimmune blistering skin diseases. The two main types of pemphigus are pemphigus vulgaris and pemphigus foliaceus. Each type has subtypes. Additional disorders are sometimes classified as pemphigus including paraneoplastic pemphigus and pemphigus IgA. Some physicians consider these disorders similar, yet distinct, autoimmune blistering disorders with different causes and clinical, immunological and microscopic tissue (histological) features. Pemphigoid is a general term for a different group of skin disorders. These other disorders are discussed in the related disorders section of this report.
There are several different types of pemphigus. The two main forms are pemphigus vulgaris and pemphigus foliaceus, which affect different layers of the outermost layer of the skin (epidermis) and have different symptoms. The epidermis serves as a protective barrier and consists of five different layers. Pemphigus vulgaris affects the deeper layers; pemphigus foliaceus affects the outermost layer.
The blisters that occur in pemphigus may be referred to as flaccid bullae because they are not firm and break open (rupture) easily. Individuals with pemphigus vulgaris generally feel ill. I; individuals with pemphigus foliaceus often only have crusted rather than blistering lesions because the lesions are too high in the epidermis to retain fluid. Both forms of pemphigus can be associated with itching.
Pemphigus can be controlled with treatment. If left untreated, serious life-threatening complications such as the loss of most of the epidermis can occur. Widespread involvement of the skin can also lead to severe infections of the skin, which can potentially spread to the bloodstream (sepsis) or imbalances of fluids or certain minerals (electrolytes) in the body. These imbalances can interfere with various essential chemical processes in the body. Prior to the introduction of effective therapy, most patients with pemphigus died within two years.
The most common form of pemphigus in the United States is pemphigus vulgaris. Affected individuals usually develop irregularly-shaped, painful erosions or lesions (ulcerations) of the mucous membranes lining the inside of the mouth (oral cavity). Blisters rarely form because they rupture almost immediately leaving multiple, superficial, ulcerated sores throughout the mouth. The mucous membranes lining the inside of the cheeks (buccal mucosa), the lips, the roof of the mouth (palate) and the tongue are most often affected. These lesions can join together so that large, raw sores affect the mouth. These lesions are slow to heal and may make it difficult to eat or drink.
Anywhere from a few weeks to months following the onset of mucous membrane involvement, blistering (bullous) lesions eventually develop on the skin. The scalp, face, neck and upper parts of the chest and back are most often the initial sites affected. The lesions of pemphigus vulgaris form in the deep layers of the epidermis and may be painful. The lesions may ooze clear fluid or bleed. As these lesions heal, they may become dry and crusty. Although they do not scar, they usually heal with treatment and rarely leave discolored or darkened patches of skin.
Additional areas of the skin that are frequently affected include the armpits and groin. Additional mucous membranes that are affected include the ones found in the nose (nasal mucosa), genitals, and lining the inside of the eyelids (conjunctiva). The throat and esophagus may also become affected. Involvement of the nasal mucosa may cause a stuffy nose and frequent discharge of bloody mucous. Involvement of the throat may cause hoarseness, difficulty swallowing and pain when swallowing.
A distinct finding called the Nikolsky sign is associated with pemphigus vulgaris. The Nikolsky sign refers to areas of normal looking skin in which the top part of the skin separates (peels off) from the underlying layer of skin when slight pressure is applied (e.g., slightly rubbed or pinched).
This form of pemphigus is characterized by multiple small, blisters or crusted lesions that quickly break apart to form itchy (pruritic), scaly, crusted lesions. Because the blisters form on the uppermost layer of the epidermis, they may break apart so quickly that only the ensuing crusted lesions are noticed. The lesions may also have a reddened (erythematous) base and can be painful or associated with a burning sensation. The scalp, face, chest and back are most often affected. Unlike pemphigus vulgaris, little to no involvement of the mucous membranes occurs.
Individuals with pemphigus foliaceus exhibit the Nikolsky sign, which describes areas of normal looking skin in which the top part of the skin separates (peels off) from the underlying layer of skin when slight pressure is applied (e.g., slightly rubbed or pinched).
In some cases, the lesions associated with pemphigus foliaceus may disappear on their own without treatment (spontaneous remission). In many cases, however, the lesions gradually increase in number over weeks and months. In severe cases, the lesions may spread, eventually coming together to resemble exfoliative erythroderma, a condition characterized by widespread red and scaly lesions that can cover large portions of the body.
In some cases, degenerative (atrophic) changes of the hair and nails may also occur.
Endemic pemphigus (fogo selvagum)
This form of pemphigus foliaceus occurs in a disproportionally large number of individuals (epidemically) in South America, especially rural areas of Brazil. It also occurs in other rural areas of the world. The symptoms of endemic pemphigus are identical to those described above for pemphigus foliaceus. This form of pemphigus often runs in families, which suggests that genetic or environmental factors play a significant role in the development of endemic pemphigus.
Pemphigus erythematosus (Senear-Usher syndrome)
This form of pemphigus is characterized by initial lesions that are reddened (erythematous) and crusty and, although the symptoms of pemphigus foliaceus are present, affected individuals also have symptoms normally associated with lupus. The lesions of this form of pemphigus are most likely to appear in areas of the body where oil-producing glands (seborrheic glands) are found such as the cheeks, scalp and upper chest and back. Affected individuals may also have antibodies usually found in individuals with lupus.
This form of pemphigus is considered a variant of pemphigus vulgaris. It is characterized by lesions that most frequently affect the skin fold areas (flexures) such as the armpits or groin. The lesions of pemphigus vegetans differ from pemphigus vulgaris because they often become overgrown, thickened and warty.
This general term refers to pemphigus (either pemphigus vulgaris or pemphigus foliaceus) that develops due to the use of certain drugs. Although drug-induced pemphigus is an uncommon occurrence, it is important to distinguish pemphigus that occurs secondary to drug use because symptoms often disappear once the drug is stopped. Penicillamine and a class of drugs known as angiotensin-converting enzyme (ACE) inhibitors (e.g., captopril) are most commonly associated with the development of pemphigus. ACE inhibitors are often used to treat high blood pressure or heart failure. Penicillamine is used to treat different conditions including rheumatoid arthritis.
Pemphigus is a group of autoimmune disorders. Autoimmune disorders occur when the body’s immune system mistakenly attacks healthy tissue.
The immune system normally produces specialized proteins called antibodies. Antibodies react against foreign materials (e.g., bacteria, virus, toxins) in the body bringing about their destruction. Specific antibodies are created in response to specific materials or substance. A substance that stimulates an antibody to be produced is called an antigen. When antibodies react against healthy tissue, they are known as autoantibodies. There are five main classes of antibodies - IgA, IgD, IgE, IgG, and IgM. Pemphigus is due to IgG antibodies.
In pemphigus, autoantibodies react to antigens found on the surface of certain skin cells (keratinocytes). Keratinocytes are the major cell of the epidermis and they stick (adhere) together to form the barrier that is the epidermis. Keratinocytes are able to stick together because specialized proteins called desmogleins act as glue to hold them together. The autoantibodies in pemphigus target the desmogleins causing keratinocytes to lose their ability to stick together, resulting in the separation of these skins cells from one another and the breakdown of the affected skin cell layer (acantholysis). This leads to the blistering that characterizes pemphigus. The autoantibodies in pemphigus specifically react to certain desmogleins. In pemphigus vulgaris, the autoantibodies react against desmoglein-3 and in half the cases to desmoglein-1; in pemphigus foliaceus, they react only against desmoglein-1.
The exact reason why the immune system malfunctions in individuals with pemphigus is unknown. Researchers believe that some individuals may have a genetic predisposition to developing pemphigus. A person who is genetically predisposed to a disorder carries a gene (or genes) for the disease, but it may not be expressed unless it is triggered or "activated" under certain circumstances, such as due to particular environmental factors (multifactorial inheritance).
A variety of factors have been speculated to trigger or worsen pemphigus. Such factors include exposure to ultraviolent light, trauma to the skin, and possibly certain foods. Stress may also aggravate pemphigus. Certain drugs are also known to play a role in the development or aggravation of pemphigus.
Pemphigus affects males and females in equal numbers. It usually occurs in middle-aged individuals, usually people in their 50s and 60s. In rare cases, pemphigus can affect children. The overall incidence and prevalence of pemphigus varies depending upon the specific population studied. Pemphigus is estimated to affect anywhere from 0.7-5 people per 1,000,000 per year in the general population. Pemphigus vulgaris is the most common form of pemphigus and is the most common form in Europe and the United States. Pemphigus foliaceus is more prevalent in Africa and certain rural areas in the world. Endemic pemphigus is a specific form of pemphigus foliaceus that occurs in individuals in certain rural regions of South America, especially within Brazil and Colombia. Pemphigus vulgaris occurs with greater frequency in individuals of Jewish and Mediterranean descent.
Symptoms of the following disorders can be similar to those of pemphigus. Comparisons may be useful for a differential diagnosis.
Hailey-Hailey disease, also known as familial benign pemphigus, is a rare genetic disorder that is characterized by blisters and lesions most often affecting the neck, armpits and genitals. The lesions may come and go and usually heal without scarring. Heat, sweating and friction often aggravate the disorder. As with pemphigus, the symptoms of Hailey-Hailey disease occur because of the failure of skin cells to stick together resulting in the breakdown of the affected skin layers. However, Hailey-Hailey disease occurs due to a mutation in a specific gene that creates a protein that is essential for the proper health of skin. Hailey-Hailey disease is not an autoimmune disorder and there are no autoantibodies. Hailey-Hailey disease is inherited as an autosomal dominant trait. Some cases may occur spontaneously with no family history (i.e., new mutation). The disorder usually becomes apparent in the third or fourth decade, but symptoms can develop at any age. (For more information on this disorder, choose "Hailey Hailey" as your search term in the Rare Disease Database.)
Paraneoplastic pemphigus is an extremely rare blistering disease that occurs in individuals who have cancer, especially blood (hematologic) cancers such as leukemia or lymphoma. Paraneoplastic pemphigus is characterized by painful lesions affecting the mucous membranes, especially those found in the mouth and the lips as well as with generalized skin lesions that resemble those seen in erythema multiforme. The mucous membrane lining the inside of the eyelids (conjunctiva) is also frequently affected and other mucosal sites such as the nose, throat, and genitals can be affected. Some individuals only experience lesions affecting the mouth. In other cases, the lesions can affect the linings of the gastrointestinal or respiratory tracts and potentially cause life-threatening complications. In paraneoplastic pemphigus, the mucosal lesions may be all that are present; in other cases individuals may also develop lesions affecting the skin. These lesions may vary from case to case and may appear as small, reddened bumps (erythematous macules), non-firm (flaccid) blisters, scaly plaques, pustules, or erosions.
Pemphigus IgA, also known as intraepidermal neutrophilic IgA dermatosis, is a rare chronic autoimmune skin disorder characterized by the development of fluid-filled blisters on the skin. The mucous membranes are usually not affected. IgA pemphigus resembles pemphigus foliaceus, however, the defective antibodies are classified as immunoglobulin A, unlike the more common forms of pemphigus which are caused by antibodies classified as immunoglobulin G. In most cases, the trunk and the upper arms or legs are affected. The scalp can be extensively affected in some people. Affected individuals may develop numerous small pus-filled bumps (pustules). The exact cause of pemphigus IgA is unknown.
Bullous pemphigoid (BP) is a chronic skin disease usually affecting the elderly that is characterized by firm, large blisters that develop on normal-appearing or reddened skin, usually around cuts or scars. Within weeks, blisters spread to skin of the flexor (muscles that contract or flex) areas, groin, armpit, and the abdomen and back. Mucous membranes seldom are affected and tend to heal quickly. The blisters have little tendency to spread, but heal quickly when they do. There is, however, severe irritation. Bullous pemphigoid is an autoimmune disorder. (For more information on this disorder, choose "Bullous Pemphigoid" as your search term in the Rare Disease Database.)
Mucous membrane pemphigoid (MMP) is a rare group of chronic autoimmune disorders characterized by blistering lesions that primarily affect the various mucous membranes of the body. The mucous membranes of the mouth and eyes are most often affected. The mucous membranes of the nose, throat, genitalia, and anus may also be affected. The symptoms of MMP vary among affected individuals depending upon the specific site(s) involved and the progression of the disease. Blistering lesions eventually heal, sometimes with scarring. Progressive scarring may potentially lead to serious complications affecting the eyes and throat. In some cases, blistering lesions also form on the skin, especially in the head and neck area. The exact cause of MMP is unknown. Mucous membrane pemphigoid has been known by many different names within the medical literature including benign mucous membrane pemphigoid, cicatricial (scarring) pemphigoid, and ocular cicatricial pemphigoid. In March of 2002, a consensus group of researchers determined that mucous membrane pemphigoid was the best designation for this group of disorders. The term "benign" mucous membrane pemphigoid was deemed inappropriate because of the potential for serious complications in some cases. The term "cicatricial" pemphigoid excluded affected individuals who do not develop scarring. Site-specific terms such as "ocular" cicatricial pemphigoid excluded individuals with multiple site involvement. (For more information on this disorder, choose "mucous membrane pemphigoid" as your search term in the Rare Disease Database.)
Several other blistering skin disorders may resemble pemphigus. These disorders include erythema multiforme, dermatitis herpetiformis, staphylococcal scalded skin syndrome, epidermolysis bullosa, linear IgA dermatosis, impetigo, and Grover's disease.
A diagnosis of pemphigus is suspected based upon identification of characteristic findings, a thorough clinical evaluation, and a detailed patient history. A diagnosis must be confirmed based upon a variety of specialized tests including blood tests for antibodies that cause the disease and a skin biopsy that shows the typical histological changes associated with the disease. Blood tests can reveal the characteristic antibodies that cause the symptoms of pemphigus. A skin biopsy is a small sample of affected tissue that is taken and examined under a microscope, which may reveal characteristic separation of skin cells. Physicians may also perform direct immunofluorescence on a skin biopsy sample. This is a test in which the sample is stained with special dyes that allow antibodies to seen under a special microscope. Determining the specific antibody present confirms a diagnosis of pemphigus and distinguishes the specific forms of pemphigus from one another.
If signs suggest the involvement of the throat or nasal cavity, an ear-nose-throat (ENT) specialist may need to assess these areas to determine whether pemphigus is affecting the mucous membranes in these areas.
The treatment of pemphigus is directed toward suppressing the skin and mucosal lesions of the disease and preventing complications potentially associated with pemphigus or its treatment. Although there is no cure for pemphigus, the disorder can usually be controlled. Most patients will eventually enter a complete remission in which they are off all therapy and there is no evidence of the disease. Generally, the less widespread the pemphigus is, the easier it is to control.
The development, severity and progression of pemphigus are not uniform and the response to particular therapies can vary among individuals. Consequently, physicians will take several different factors into account when planning an individual's treatment, which will be tailored to the individual's specific needs and situation.
Treatment of pemphigus is usually separated into phases: control, consolidation and maintenance. In the control phase, high-intensity therapy is used to bring the disorder under control by initiating the healing of current lesions, reducing or suppressing new lesion formation, and improving other symptoms such as relieving itching. In the consolidation phase, a consistent dose of medication is used until a significant portion of lesions have healed. In the maintenance phase, the dose of medication is gradually reduced until a minimal level is achieved that is successful in preventing the development of new lesions.
The mainstay of treatment for pemphigus is the use of high doses of corticosteroids such as prednisone, which are anti-inflammatory medications that also suppress the effects of the immune system. Steroids may be applied directly to the affected areas (topically) or may be taken by mouth or given by injection (systemic steroids). Topical therapy is generally given to reduce pain and prevent or treat infection. Most individuals will receive systemic steroids to bring about control of pemphigus. The dose of steroids used can be lessened (tapered) if control of the disorder is achieved.
Other medications that may be used in combination with corticosteroids to treat individuals with pemphigus include drugs that suppress the immune system (immunosuppressive drugs) such as azathioprine, cyclophosphamide, methotrexate, and mycophenolate mofetil; drugs that modify or regulate the immune system (immunomodulatory drugs) such as IVIg, Rituxan, dapsone; or antibiotics such as doxycycline. These medications may be used to allow physicians to lower the overall dose of steroids.
Some individuals respond to therapy quickly; others respond more slowly or do not respond at all. In severe cases or in cases where individuals fail to respond to other therapies, pulse steroids, plasmapheresis or intravenous immunoglobulin therapy (IVIG) may be used. Pulse steroid therapy refers to the administration of extremely high levels of steroids given for a short period of time. Plasmapheresis is a method for removing unwanted substances (e.g., autoantibodies) from the blood. Blood is removed from the patient and blood cells are separated from plasma. The patient's plasma is then replaced with other human plasma and the blood is transfused into the patient. For more information on IVIG therapy, see the investigational therapies section below.
Intravenous immunoglobulin (IVIG) therapy is being studied as a treatment for individuals with pemphigus. Initial research shows that this form of therapy may be an effective alternative for individuals who are unresponsive to conventional therapy, dependent upon corticosteroids, or experience adverse side effects to corticosteroids. Research has indicated that IVIG therapy can markedly decrease levels of the abnormal antibodies associated with pemphigus without decreasing the levels of normal, health antibodies. More research is necessary to determine the long-term safety and effectiveness of intravenous immunoglobulin therapy for individuals with pemphigus.
Researchers are studying rituximab for the treatment of individuals with pemphigus. This drug attacks the cells that produce the autoantibodies in pemphigus that damage the skin. Rituximab is classified as a monoclonal antibody or biologic therapy. More research is necessary to determine the long-term safety and effectiveness, as well as the timing, dose, and frequency of use of rituximab, for the treatment of individuals with pemphigus.
Scientists are studying a new approach to treatment of pemphigus that uses extracorporeal (outside the body) photopheresis. In this process, the blood is withdrawn, exposed to ultraviolet light, and then returned to an affected individual. More study is needed to determine the long-term safety and effectiveness of this procedure.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
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Report last updated: 2012/11/15 00:00:00 GMT+0