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Last updated: 8/15/2023
Years published: 2008, 2012, 2015, 2019, 2023
NORD gratefully acknowledges Sandra Jerkovic Gulin, MD, MSc, PhD, Department Dermatology and Venereology, Ryhov County Hospital, Jรถnkรถping, Sweden, Adjunct Lecturer at Linkรถping University, Linkรถping, Sweden, and Peter Marinkovich, MD, Associate Professor, Director, Bullous Disease Clinic, Department of Dermatology, Stanford University School of Medicine, Center for Clinical Sciences Research, for assistance in the preparation of this report.
Autoimmune blistering diseases are a group of disorders in which the body mistakenly attacks healthy tissue, causing blistering lesions that primarily affect the skin and mucous and membranes. In autoimmune blistering diseases, antibodies erroneously attack proteins that are essential for the layers of skin to stick (adhere) together. The specific symptoms and severity of blistering diseases vary from one person to another, even among individuals with the same disorder. In some people, blistering lesions can cover a significant portion of the skin. Although there is no cure for autoimmune blistering diseases, they can often be controlled with treatment. In other cases, autoimmune blistering diseases if left untreated can eventually cause life-threatening complications. In recent years, new insight into the causes and development of these disorders has led to research into new therapies such as the development of drugs that target the specific antibodies which cause the symptoms of these diseases. NORD has individual reports on many of the specific disorders classified as autoimmune blistering diseases. For more information, choose the specific disease name as your search term in the Rare Disease Database.
The skin is the largest organ of the body. In addition to serving as a protective barrier, the skin is involved in many additional functions of the body such as regulating internal body temperature. Five distinct layers make up the skin; each layer is filled with specialized cells. The two main structural layers of the skin are the epidermis โ the outermost, protective layer of skin โ and the dermis โ an underlying layer that contains numerous specialized cells, tissues and structures. Specialized proteins and structures are required for the dermis and epidermis to stick together. When the epidermis separates from the dermis a blister (bulla) may form.
A blister can be either tiny or large and consists of a fluid-filled bubble that forms underneath the surface of damaged or dead skin. Most blisters develop in response to irritation or injury of the skin. In autoimmune blistering diseases, blisters form because the body creates antibodies that attack certain proteins required for the proper health and function of the skin. In many cases, blisters can rupture, becoming open sores or wounds.
In some autoimmune blistering diseases, blisters or lesions can also form on the mucous membranes, the thin, moist coverings of many of the bodyโs internal surfaces. Mucous membranes line the esophagus and anus, the inside of the mouth, the nasal passageways, the genitals and the throat. Associated symptoms depend on the location of blister formation, but can include gastrointestinal bleeding, difficulty swallowing or difficulty breathing.
There are several different categories of autoimmune blistering diseases including pemphigus, pemphigoid, IgA-mediated dermatoses and epidermolysis bullosa acquista. Pemphigus, pemphigoid and IgA-mediated dermatoses can be further broken down into additional subtypes.
Pemphigus
The term pemphigus is a general term for a group of related autoimmune blistering diseases. The two main types of pemphigus are pemphigus vulgaris and pemphigus foliaceus. Each type has additional subtypes.
Pemphigus vulgaris is the most common form of pemphigus. It is characterized by blisters that rupture easily and cause painful erosions. In most people, pemphigus vulgaris first develops in the mouth, followed by blistering of the skin. Any area may potentially be affected. The blisters are usually not itchy.
Pemphigus foliaceus is characterized by multiple small blisters that quickly break apart to form itchy (pruritic), scaly, crusted lesions that affect the uppermost layer of the skin. The scalp and face are usually affected first. Eventually, the chest and upper back may become involved. The lesions are usually not painful. The mucous membranes are usually not affected.
Additional disorders are sometimes classified as subtypes of pemphigus including paraneoplastic pemphigus and pemphigus IgA. Some physicians consider these disorders similar, yet distinct, autoimmune blistering diseases.
Paraneoplastic pemphigus is a rare 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. The mucous membrane lining the inside of the eyelids (conjunctiva) is also frequently affected. In other cases, the lesions can affect the linings of the gastrointestinal or respiratory tracts and potentially cause life-threatening complications. In some cases, lesions affecting the skin may develop. 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 characterized by the development of fluid-filled blisters on the skin. The mucous membranes are usually not affected. In most cases, the trunk and the upper arms or legs are affected. The scalp can be extensively affected in some people.
Pemphigoid
Pemphigoid is a general term for a group of related diseases characterized by blistering skin eruptions. The main forms of pemphigoid are bullous pemphigoid, mucous membrane pemphigoid, and pemphigoid gestationis.
Bullous pemphigoid is a chronic skin disease usually affecting the elderly that is characterized by firm, large blisters that develop on normal-appearing or reddened skin on the trunk or skin folds, sometimes around cuts or scars. Within weeks, blisters often spread to the groin, armpit, abdomen, and the skin where muscle contracts or flexes (flexor muscles). In some people, the lesions may become widespread covering a significant portion of the skin and blisters may form inside the mouth. In most people, the mucous membranes are not affected and, when they are, they tend to heal quickly. The lesions of bullous pemphigoid are often associated with intense itching.
Mucous membrane pemphigoid (MMP) is a rare group of chronic autoimmune diseases 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 people, blistering lesions also form on the skin, especially in the head and neck area. 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.
Pemphigoid gestationis occurs in women during pregnancy or shortly after birth (postpartum period). Affected individuals develop reddish bumps or hives usually around the navel (umbilicus) and the arms and legs. The rash may spread to affect other areas of the body and may be extremely itchy. Eventually, the skin lesions progress to form blisters. Pemphigoid gestationis usually resolves within three months without treatment (spontaneously).
IgA Mediated Bullous Dermatoses
IgA-mediated bullous dermatoses are disorders characterized by elevated levels within the body of a specialized protein known as immunoglobulin A (IgA). In these disorders, IgA has a particular tendency to accumulate in the skin. Dermatitis herpetiformis and linear IgA disease are IgA-mediated bullous dermatoses. When liner IgA disease affects children, it may be known as chronic bullous disease of childhood.
Dermatitis herpetiformis, also known as Duhring disease, is characterized by red clusters of extremely itchy (pruritic) blisters. The elbows, knees, scalp and buttocks are most often affected. The mucous membranes are rarely involved. The symptoms of dermatitis herpetiformis tend to come and go. Most cases of dermatitis herpetiformis are associated with celiac disease, a digestive disorder characterized by intolerance to dietary gluten, which is a protein found in wheat, rye and barley.
Linear IgA disease is characterized by blistering eruptions on the skin. The elbows, knees and buttocks are most often affected. New blisters may arise in areas where older blisters are โ a finding that creates a small group of blisters that may be described as a โcluster of jewelsโ. In some cases, itching (pruritis) may develop and may occur before the development of skin lesions. In approximately 50 percent of cases the mucous membranes are affected as well, especially the mucous membranes of the mouth and eyes. Eye involved can cause blurred vision, irritation, light sensitivity and corneal scarring.
Epidermolysis Bullosa Acquista
Epidermolysis bullosa acquista is a rare autoimmune disorder of the skin that typically affects middle-aged and elderly people. The skin of affected individuals is extremely fragile. Trauma to the skin can cause blisters to form. The elbows, knees, pelvis, buttocks and/or scalp are most often affected. Increased levels of a specialized protein known as immunoglobulin G are usually found around the blisters. After the blisters heal, scars and small white bumps or cysts (milia) may remain. The mucous membranes are rarely involved. A subset of patients with epidermolysis bullosa acquista has a widespread, inflammatory form of the disorder that develops rapidly and often involves the mucous membranes.
Autoimmune blistering diseases occur when the bodyโs 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. Antibodies can directly kill microorganisms or coat them, so they are more easily destroyed by white blood cells. Specific antibodies are created in response to specific materials or substances. A substance that stimulates an antibody to be produced is called an antigen. Antibodies are also known as immunoglobulins. There are four major classes of immunoglobulins known as IgM, IgG, IgA and IgE. When antibodies react against healthy tissue, they are known as autoantibodies.
In autoimmune blistering diseases, autoantibodies attack proteins that are essential to the proper function of the basement membrane zone, a network of proteins that acts as a โglueโ that holds the epidermis to the underlying tissues of the dermis. In autoimmune blistering disease, the connection (adhesion) of the epidermis and dermis is damaged because autoantibodies attack specific structures or proteins, causing the epidermis and dermis to separate and blisters to form.
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, and they serve as an anchor to the underlying skin layer (the dermis).
In pemphigoid, autoantibodies react against proteins found at the junction where the epidermis and dermis meet, known as the dermal-epidermal junction (DEJ). The DEJ is part of the basement membrane zone.
In linear IgA disease, autoantibodies react against structures found at the dermal-epidermal junction causing the epidermis and dermis to separate.
In dermatitis herpetiformis, it is believed that circulating IgA reacts against substances in the skin that ultimately results in damage to and the separation of the dermal-epidermal junction. However, in this disorder gluten sensitivity in combination with elevated levels of immunoglobulin A causes an immune system response, which may also contribute to the development of symptoms.
In epidermolysis bullosa acquista, autoantibodies react to collagen VII, a protein that is essential in anchoring the basement membrane to the dermis.
The exact, underlying reason why the immune system malfunctions in individuals with autoimmune blistering diseases is unknown. A variety of factors have been speculated to trigger or worsen autoimmune blistering diseases. Such factors include exposure to ultraviolent light, exposure to certain pesticides, hormones, several infectious agents and certain foods. Certain drugs are also known to play a role in the development or aggravation of these disorders. Stress may also aggravate some types of autoimmune blistering diseases.
Researchers believe that some individuals may have a genetic predisposition to developing certain autoimmune blistering diseases such as pemphigoid and dermatitis herpetiformis. 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 โactivatedโ under certain circumstances, such as due to particular environmental factors (multifactorial inheritance).
Autoimmune blistering diseases affect males and females in equal numbers. Most forms occur in middle-aged individuals, usually people in their 50s and 60s. However, autoimmune blistering diseases can affect individuals of any age including 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 (Israel has the highest incidence at 16 per 1,000,000 per year). The incidence of dermatitis herpetiformis has been estimated at 10 in 100,000. The exact incidence of epidermolysis bullosa acquista and the pemphigoid disorders is unknown.
A diagnosis of an autoimmune blistering disease is suspected based upon identification of characteristic findings, a thorough clinical evaluation and a detailed patient history. A diagnosis may be confirmed based upon a variety of specialized tests including blood tests or skin biopsy. Blood tests can reveal the characteristic antibodies associated with specific autoimmune blistering diseases. A skin biopsy is a small sample of affected tissue that is taken and examined under a microscope, which may reveal characteristic findings. Physicians also perform direct immunofluorescence (DIF) on a skin biopsy sample that presents a gold standard in the assessment of patients with bullous disorder. This is a test in which the sample is stained with special dyes that allow antibodies to be seen under a special microscope.
Determining the specific antibody present confirms a diagnosis of a specific autoimmune blistering disease.
Treatment
The treatment of autoimmune blistering diseases is directed toward the specific symptoms that are apparent in each individual and preventing complications potentially associated with these diseases. Although there is no cure for these disorders, they can be controlled medically. Generally, the less widespread an autoimmune blistering disease is, the easier it is to control.
The development, severity and progression of autoimmune blistering diseases are not uniform and the response to therapies can vary among individuals. Consequently, physicians will take several different factors into account when planning an individualโs treatment, which will be tailored to the individualโs specific needs and situation.
The mainstay of treatment for autoimmune blistering diseases is treatment with corticosteroids such as prednisone. Corticosteroid therapy is not effective in all cases and long-term treatment with high doses of corticosteroids can cause serious side effects.
Additional drugs have been used to treat individuals with autoimmune blistering diseases, either alone or in combination with corticosteroids. These drugs include drugs that suppress the immune system (immunosuppressive drugs) such as mycophenolate, azathioprine or cyclophosphamide, immunosuppressive biological therapies such as rituximab and intravenous immunoglobulin G (IVIG). Plasmapheresis also is a well-established form of treatment for severe cases of autoimmune blistering diseases.
Research is ongoing to learn more about the underlying causes of autoimmune diseases and why these diseases target some people, but not others. Research is also ongoing into the mechanisms that underlie the development of these diseases and into new therapies.
One particularly promising therapy currently being researched is medications that target the specific autoantibodies that underlie the various autoimmune blistering diseases. Although many of the autoantibodies have been identified many questions remain including why individuals develop these autoantibodies in the first place. The development of medications that can directly target the autoantibodies may allow physicians to gain control of these diseases.
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:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
TEXTBOOKS
James WD, Berger TG, Elston DM. Eds. Andrewโs Diseases of the Skin: Clinical Dermatology. 10th ed. Saunders. 2005:459-478.
Berkow R., ed. The Merck Manual-Home Edition.2nd ed. Whitehouse Station, NJ: Merck Research Laboratories; 2003:1216-1218.
JOURNAL ARTICLES
Jukic IL, Gulin SJ and Marinovik B. Blistering diseases in the mature patient. Clinics in Dermatology. 2018; 36, 2 MarchโApril:231-238.
Olasz EB, Yancey KB. Bullous pemphigoid and related subepidermal autoimmune blistering diseases. Curr Dir Autoimmmun. 2008;10:141-166.
Chaudhari P, Marinkovich MP. Whatโs new in blistering disorders? Curr Allergy Asthma Rep. 2007;7:255-263.
Mihai S, Sitaru C. Immunopathology and molecular diagnosis of autoimmune blistering diseases. J Cell Mol Med. 2007;11:462-481.
Tron F, Gilbert D, Mouquet H, et al. Genetic factors in pemphigus. J Autoimmun. 2005:24:319-328.
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