Information on the following diseases can be found in the Related Disorders section of this report:

• Bullous pemphigoid
• Darier disease (Darier-White disease, keratosis follicularis, DOC 22)
• Erythema hyperkeratosis (bullous type)
• Erythema multiforme
• Epidermolysis bullosa
• Epidermolysis bullosa acquista
• Dermatitis herpetiformis

Blisters in the outer layer of the skin are common to all types of pemphigus. Blisters develop due to the destruction of the "cement" that holds cells together (epidermal acantholysis) resulting in the separation of cells from one another. Soft (flaccid) blisters generally occur on the neck, scalp, mucous membranes, and/or underarm (axillary) and groin areas (inguinal). Most patients with pemphigus have deposits of IgG (an immune system antibody that defends against foreign substances) around the blistered areas (in the epidermal cells called keratinocytes). Antiepidermal antibodies directed against skin cells are typically present in the fluid of the blisters. The diagnosis of pemphigus requires microscopic examination of cells in the blisters as well as detection of the IgG antibodies that characterize this disease.

Pemphigus vulgaris is the most common form and may begin with isolated blisters on the scalp, and then in the mouth. These may persist for several months and may be followed by blistering of the esophagus, nose, rectum, and/or the membranes that line the inner surfaces of the eyelids (conjunctiva). The blisters are soft; they break easily and heal poorly. Pressure on the borders of blisters causes them to spread. Pressure on normal-looking skin can cause it to blister (Nikolsky sign) in people with pemphigus vulgaris. If left untreated, Pemphigus Vulgaris may cause life-threatening complications.

Pemphigus vegetans is a variation of pemphigus vulgaris. The blisters are fast-growing and have large (hypertrophic) lesions that are usually located in the groin (inguinal) and armpit (axillary) areas.

Pemphigus foliaceus is less severe and a less common form of the disorder. Soft blisters typically occur close to the surface of the skin. When they break, they ooze and become crusty, scaly, and susceptible to infection. Blisters may occur on the scalp, face, upper chest, and back; the mucous membranes are usually not affected. Small, horny plugs attached to the undersurface of the affected skin also may be seen.

Another type of pemphigus foliaceus occurs in South America, particularly Brazil and Colombia, and is called fogo selvagem.

When individuals have symptoms of both pemphigus foliaceus and systemic lupus erythematosus, they are said to have pemphigus erythematosus. Lupus, also known as SLE, is an inflammatory disease of connective tissue. (For more information on this disorder, choose "Lupus" as your search term in the Rare Disease Database.)

Pemphigus may also occur as a result of an adverse reaction to certain drugs such as d-penicillamine and rifampin; symptoms usually resemble those of pemphigus foliaceus rather than pemphigus vulgaris. Some research suggests that pemphigus herpetiformis is a subtle form of pemphigus with its own characteristic blisters. However, blisters that form during a relapse may resemble those of pmphigus foliaceus.

In benign familial pemphigus (Hailey-Hailey disease), recurrent blisters are seen primarily on the neck, groin, and armpits. Blisters may recur because of sweating, skin infections, and exposure to extreme heat and/or ultraviolet light.

Most forms of pemphigus are generally considered to be autoimmune-related. Autoimmune disorders are caused when the body's natural defenses (e.g., antibodies) against "foreign" or invading organisms begin to attack healthy tissue for unknown reasons.

Benign familial pemphigus (Hailey-Hailey disease) is not an autoimmune disorder. It is a genetic disorder inherited as an autosomal dominant trait. Genetic disorders are determined by two genes, one received from the father and one from the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.

The gene responsible is on the long arm (q) of chromosome 3 (3q21-q24). Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as "p" and a long arm identified by the letter "q". Chromosomes are further subdivided into bands that are numbered. For example, "chromosome 3q21" refers to band 21 on the long arm of chromosome 3.

Fogo selvagem (Brazilian Pemphigus Foliaceus) is an autoimmune blistering disorder that may be triggered by a substance transmitted through the bite of blackflies.

Pemphigus may also occur following x-ray exposure or adverse reaction to drugs such as d-penicillamine or rifampin.

Pemphigus affects males and females in equal numbers and is most common in middle-aged and elderly people. However, cases of children with pemphigus have been reported. This disorder has been found in all ethnic groups and races, but is more common in people of Jewish or Mediterranean ancestry. Pemphigus occurs once in 100,000 people in the United States. Fogo selvagem occurs in the central rural areas of Brazil that are heavily infested with a species of blackfly.

Symptoms of the following disorders can be similar to those of pemphigus. Comparisons may be useful for a differential diagnosis:

Bullous pemphigoid is a chronic mild skin disorder that generally affects elderly people. It is characterized by large firm fluid-filled blisters (bullous pemphoid) that heal quickly and typically disappear in several months or years. However they may recur later. Early symptoms include redness on the skin followed within weeks by the appearance of blisters. The mucous membranes are rarely affected by bullous pemphigoid. (For more information on this disorder, choose "bullous pemphigoid" as your search term in the Rare Disease Database.)

Darier disease (Darier-White disease or keratosis follicularis) is a progressive inherited skin disorder characterized by widespread firm elevated lesions on the skin and mucous membranes; abnormal changes of the finger and toe nails may also occur. Symptoms usually begin with a sensation of itching or burning on the skin, especially the scalp, forehead, face, neck, and back. Firm, elevated spots (papules) appear and typically become large and darkened; eventually these papules become scaly and crusty. As these spots enlarge, they may come together and form larger areas. The symptoms of Darier disease tend to become more severe during periods of emotional stress or with exposure to sunlight. (For more information on this disorder, choose "Darier" as your search term on the Rare Disease Database.)

Epidermolytic hyperkeratosis (bullous type) is a rare hereditary skin disorder characterized by the overgrowth of skin (hyperkeratosis) and an abnormal redness of the skin (erythroderma). The symptoms are present at birth and may range from mild to severe. The skin may appear "warty," blistered, and thick over most of the body, particularly in the skin creases over joints. The disorder can be detected before birth by amniocentesis (microscopic examination of the fluid that surrounds the developing fetus). (For more information on this disorder, choose "epidermolytic hyperkeratosis" as your search term in the Rare Disease Database.)

Erythema multiforme is an allergic inflammatory skin disorder characterized by lesions that develop on the skin and mucous membranes. The early symptoms may include red, elevated spots (erythematous macules or papules) that may have fluid filled centers and eventually grow into larger blisters. Affected areas generally include: hands, forearms, feet, and/or mucous membranes of the mouth, nose and/or genitals. The skin lesions and blisters caused by Erythema multiforme generally appear on both sides of the body and tend to heal in approximately 2 to 6 weeks. Erythema multiforme may also cause fever, joint pain, cough, and a sore throat. (For more information on this disorder, choose "erythema multiforme" as your search term in the Rare Disease Database.)

Epidermolysis bullosa refers to a group of rare hereditary skin diseases characterized by fragile skin; blisters and small fluid-filled lesions develop following minor trauma. In some forms of epidermolysis bullosa, the mucous membranes are involved. Healing may be impaired in some forms of this disorder resulting in multiple scars and/or damage to underlying muscle tissue. (For more information on these disorders, choose "Epidermolysis Bullosa" as your search term in the Rare Disease Database.)

Epidermolysis bullosa acquista is a rare autoimmune disorder of the skin that typically affects middle-aged and elderly people. Trauma may cause blisters on the skin of the elbows, knees, pelvis, buttocks, and scalp. Increased levels of IgG are usually found around the blisters; scars usually remain after healing. (For more information on this disorder, choose "epidermolysis bullosa" as your search term in the Rare Disease Database.)

Dermatitis herpetiformis is a rare chronic skin disorder that is characterized by groups of severely itching blisters and elevated lesions. This disorder is often associated with a sensitivity to foods that contain gluten (gluten-sensitive enteropathy). The onset of this disorder in generally slow in adults, but children may also be affected. Small, discrete blisters and itchy smooth lesions similar to hives may appear on the head, elbows, knees, lower back, and buttocks. Itching and burning may be almost intolerable, and the need to scratch may be overwhelming. (For more information on this disorder, choose "Dermatitis Herpetiformis" as your search term in the Rare Disease Database.)

Corticosteroids are the most widely used drugs for treating pemphigus. Frequently, topical corticosteroid ointments can relieve inflammation and itching, and oral (systemic) corticosteroids such as prednisone relieve inflammation and suppress the immune system.

Immunosuppressive drugs such as cyclosporine, cyclophosphamide, azathioprine, or methotrexate may be prescribed to treat severe cases of pemphigus. Cytotoxic drugs may also be used to suppress the immune system. Gold compounds such as auranofin may be given to relieve inflammation and to attempt to suppress the immune system (chrysotherapy). The drug, dapsone, may also be prescribed but should be used with extreme caution. To reduce immediate or long-term side effects, drug therapy may be stopped temporarily or changed.

Antibiotic drugs or creams may be given to manage infection and relieve inflammation. Silver sulfadiazine cream also may be used. Dusting the patient and their bed sheets with talcum powder may relieve the discomfort of raw skin.

Genetic counseling may be beneficial for patients and their families if they have the hereditary form of pemphigus. Other treatment is symptomatic and supportive.

In a recent study for patients with Pemphigus treatment with rituximab resulted in major clinical improvement and permitted a large decrease in the doses of corticosteroids.

The drug, known generically as rituximab, is made by the biotechnology companies Genentech Inc. and Biogen Idec Inc., and approved for non-Hodgkin's lymphoma and rheumatoid arthritis.

The drug is sold by Roche AG as MabThera outside the United States, Japan and Canada


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:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

Plasmapheresis may benefit some people with pemphigus. This procedure is a method for removing unwanted substances (toxins, metabolic substances and plasma parts) 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 retransfused into the patient. This therapy is still under investigation to analyze side effects and long-term effectiveness. More research is needed before plasmapheresis can be recommended for use in all but the most severe cases of Pemphigus.

Researchers are investigating a new method of plasmapheresis for individuals with pemphigus. An immunoglobin-free albumin solution is substituted for the plasma and blood that is usually transfused into an affected individual. This procedure may decrease the autoimmune response of the antibodies in the patient.

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.

Surgery is also being investigated to treat pemphigus when it is not responsive to standard therapy. Surgery involves removing the blistered skin and applying skin grafts.

Researchers at the National Institutes of Health (NIH) are conducting diagnostic procedures such as immunofluorescence testings and immumoprecipitation studies. More studies are needed to determine the long-term safety and effectiveness of these techniques for the treatment of pemphigus. For more information, contact:

NIH/National Cancer Institute
Attn: Kim Yancey M.D.
(301) 496-2681

Intravenous immunoglobulin 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 with who are unresponsive to conventional therapy, dependent upon corticosteroids, or experience adverse side effects to corticosteroids. More research is necessary to determine the long-term safety and effectiveness of intravenous immunoglobulin therapy for individuals with pemphigus.

Peptimmune, Inc. is in Stage I of a clinical trial to test the safety of a new treatment, PI-0824, for pemphigus vulgaris. The study is being done at four locations across the country. For more information, please contact:

Dr. M. Kari Conolly, MD
Christine Antolos
University of California, San Francisco
San Francisco, Ca 94107
(415) 502-6229

Dr. Grant Anhalt, MD
Anita Guidos, RN
Johns Hopkins School of Medicine
Baltimore, MD 21205
(410) 955-3422

Dr. Bruce Strober, MD, PhD
Lorrie Jondreau, RN
NYU School of Medicine
New York, NY 10016
(212) 263-5244

Dr. Neil Korman, MD, PhD
Zsa Zsa Porter
Case Western Reserve University
Cleveland, OH 44106
(216) 844-5899

Interested persons may reach Peptimmune, Inc., at:

Peptimmune, Inc
64 Sidney Street
Suite 380
Cambridge, MA 02139
(617) 715-8000
(617) 661-8855

Researchers are studying the administration of topical calcitriol for the treatment of benign familial pemphigus (Hailey-Hailey disease). Initial studies have demonstrated that calcitriol is beneficial for affected individuals. More research is necessary to determine the long-term safety and effectiveness of calcitriol in the treatment of benign familial pemphigus.

Researchers have conducted a pilot study to determine the effectiveness of cyclophosphamide pulses with oral prednisolone for the treatment of individuals with pemphigus. Initial results demonstrated improvement of the symptoms associated with pemphigus. More research is necessary to determine the long-term safety and effectiveness of this potential therapy.

TEXTBOOKS
Beers MH, Berkow R., eds. The Merck Manual, 17th ed. Whitehouse Station, NJ: Merck Research Laboratories; 1999:829-30.

Bennett JC, Plum F., eds. Cecil Textbook of Medicine. 20th ed. Philadelphia, PA: W.B. Saunders Co; 1996:2205-06.

Champion RH, et al., eds. Textbook of Dermatology. 5th ed. Cambridge, MA: Blackwell Scientific Publications; 1992:1636-45.

REVIEW ARTICLES
Korman NJ., New and emerging therapies in the treatment of blistering diseases. Dermatol Clin. 2000;18:127-37, ix-x.

Popovsky JL, et al., New and emerging therapies for diseases of the oral cavity. Dermatol Clin. 2000;18:113-125.

Cotell S, et al., Autoimmune blistering skin diseases. Am J Emerg Med. 2000;18:288-99.

JOURNAL ARTICLES
Rajpara SM, King CM. Hailey-Hailey disease responsive to topical calcitriol. Br J Dermatol. 2005;152:816-7.

Bhat R, et al., Cyclophosphamide pulses with oral prednisolone in the treatment of pemphigus: a pilot study. Dermatol Online J. 2005;11:4.

Akerman L, et al., Intravenous immunoglobulin for treatment of pemphigus. Clin Rev Allergy Immunol. 2005;29:289-94.

Bianchi L, et al., Treatment of Hailey-Hailey disease with topical calcitriol. J Am Acad Dermatol. 2004;51:475-6.

Sami N, et al., Corticosteroid-sparing effect of intravenous immunoglobulin therapy in patients with pemphigus vulgaris. Arch Dermatol. 2002;138:1158-62.

Palleschi GM, et al., Development of oesophageal involvement in a subject with pemphigus vulgaris: a case report and review of the literature. J Eur Acad Dermatol Venereol. 2002;16:405-8.

Bystryn JC, et al., Treatment of pemphigus with intravenous immunoglobulin. J Am Acad Dermatol. 2002;47:358-63.

Warren SJP, et al., The prevalence of antibodies against desmoglein 1 in endemic pemphigus foliaceus in Brazil. N Engl J Med. 2000;343:23-30.

Wu H., et al., Protection against pemphigus foliaceus by desmoglein 3 in neonates. N Engl J Med. 2000;343:31-35.

Fine JD., Management of acquired bullous skin diseases. N Engl J Med. 1995;333:1475-84.

INTERNET:

International Pemphigus and Pemphiod Foundation-Biologics

www.pemphigus.org/treating-the-disease-/treatments/biologics.html