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Last updated: March 29, 2016
Years published: 1989, 1996, 2003, 2004, 2010, 2013, 2016
NORD gratefully acknowledges Carl M. Allen, DDS, MSD, Emeritus Professor, Division of Oral and Maxillofacial Pathology and Radiology, The Ohio State University College of Dentistry, for assistance in the preparation of this report.
Mucous membrane pemphigoid (MMP) is a group of rare 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.
MMP 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 โbenignโ mucous membrane pemphigoid was deemed inappropriate because of the potential for serious complications in some cases. The term โcicatricialโ pemphigoid excluded affected individuals who do not develop scarring. Site-specific terms such as โocularโ cicatricial pemphigoid excluded individuals with multiple site involvement.
MMP is characterized by the development of recurring blistering skin lesions affecting the mucous membranes of the body. These lesions may result in scarring of the affected area. Specific symptoms and severity vary from person to person depending upon the specific site(s) involved. It is important to note that affected individuals, in most cases, will not have all of the symptoms listed below.
The mucous membranes lining the mouth and eyes are most commonly affected. In some cases, the first sign of MMP is a red and blistered mouth. The gums (gingivae), roof of the mouth (palate), and the mucous membrane lining the inner cheek (buccal mucosa) may be affected. Involvement of the gums usually results in very red, tender gums that bleed easily and tend to slough off in shreds or sheets. Blistering lesions may spread to affect the tube that carries food from the mouth to the stomach (esophagus) as well as the voice box (larynx) potentially resulting in difficulty swallowing (dysphagia) and hoarseness. After these lesions heal, progressive scarring may occur, resulting in serious complications including narrowing (stenosis) of the esophagus and/or the larynx. In addition, the opening between the vocal cords (supraglottic region) may also narrow (supraglottic stenosis). In rare severe cases, such symptoms can ultimately result in life-threatening complications such as asphyxiation (breathing is cut off).
In many cases of MMP, the mucous membranes lining the eyes (conjunctiva) may be involved. Inflammation of conjunctiva (conjunctivitis) or erosions forming on the conjunctiva may be the initial signs of ocular involvement in MMP. Involvement of the eyes may not be obvious at first, however, and only a special examination by an eye doctor (ophthalmologist) can detect the earliest scarring that develops just beneath the conjunctiva. In most cases, one eye is involved first and the second eye becomes involved later, usually with two years. Ocular symptoms may include pain or grittiness of the eye, increased pressure within the eye (glaucoma), abnormal inward turning of the eyelid (entropion), and abnormal inward turning of the eyelashes (trichiasis) potentially causing irritation of the eyeball. Adhesions may form between the eyelids (symblepharon) or between the eyelid and the eye itself. In some cases, MMP may progress to cause clouding (opacity) of the corneas, loss of vision and, potentially, blindness.
In some cases, affected individuals may develop blistering lesions affecting only the eyes or the mouth, with no involvement of other mucosal sites. Scarring occurs with less frequency in cases of MMP that only involve the mucous membranes of the mouth (oral mucosa). Additional sites where lesions may form include mucous membranes of the nose, genitalia, and anus. Pain, bleeding and scarring may occur at these sites. Urinary and sexual dysfunction may result secondary to genital involvement.
In approximately 20-30 percent of cases, the skin may become involved. In these patients, the skin of the head and neck is usually affected. Skin lesions may be either fluid-filled blisters (bullous) or reddish (erythematous) plaques, which may bleed or itch. Eventually they scar upon healing. Scarring may result in areas of discoloration of the skin (known as hyperpigmentation when it is darkened patches and hypopigmentation when it is light patches). Involvement of the scalp may lead to patchy areas of hair loss (alopecia).
MMP usually has a long duration with frequent remissions and recurrence.
The exact cause of mucous membrane pemphigoid is unknown. MMP is an autoimmune disorder. Autoimmune disorders are caused when the bodyโs natural defenses (antibodies or immunoglobulins) against โforeignโ or invading organisms (antigens) begin to attack healthy tissue for unknown reasons. The term autoantibody is used to describe antibodies that are created to attack healthy tissue. The term autoantigen (โselfโ antigen) is used to describe the normal tissues and cells of the body that are targeted by the autoantibodies.
In patients who have MMP, autoantibodies are being produced that attack the basement membrane zone (BMZ) of the epithelium. The BMZ can be thought of as a sort of โglueโ that holds the outer layer of skin (epidermis or oral epithelium) onto the underlying tissues. Once this glue is attacked and destroyed by the autoantibodies, the skin is no longer tacked down, allowing it to lift off and produce blisters.
Researchers believe that in some cases affected individuals may have a genetic susceptibility to developing some forms of MMP. In these cases several factors may contribute to the development of the disorder including immunological, genetic, environmental, and/or other factors.
In a very small number of patients, MMP may be caused by the use of certain prescription drugs. Skin lesions associated with some cases of MMP may appear following trauma to the affected area. Some cases of MMP affecting the eyes may become apparent after eye (ocular) surgery such as cataract removal.
Mucous membrane pemphigoid is a rare group of autoimmune blistering disorders that affects females twice as often as males. The average age of onset of MMP is during the seventh decade (60 to 70 years of age). However, the disorder can occur at any age. The exact incidence of MMP is unknown. Because the disorder is difficult to identify, many researchers believe it is under-diagnosed.
A diagnosis of MMP is made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic findings and certain tests known as a biopsy and direct immunofluorescence. For a biopsy, a small sample of skin tissue is removed (biopsy) and microscopically examined. For direct immunofluorescence, a second biopsied skin sample is tested to detect the presence of the specific autoantibodies (e.g., IgA, IgG, and C3) that cause pemphigoid.
Treatment
The treatment of MMP is directed toward the specific symptoms that are apparent in each individual. Treatment depends upon the specific area(s) of the body affected, the severity of the disease, and its rate of progression. Treatment may require the combined efforts of a team of specialists. Dental specialists (oral pathologists), specialists who assess and treat skin problems (dermatologists), specialists who assess and treat eye problems (ophthalmologists), specialists who assess and treat ear and throat problems (otolaryngologists), and other healthcare professionals may need to systematically and comprehensively plan an affected individualโs treatment. If the patient has not seen an ophthalmologist, then an appointment should be made right away to have the eyes evaluated because treatment often depends on whether or not there is eye involvement. The earliest changes of scarring just underneath the lining of the eye (subepithelial fibrosis) are often asymptomatic and can only be detected by slit-lamp microscopic evaluation by an ophthalmologist. Such scarring interferes with the glands that produce the tears, and this results in dryness of the eye. Affected patients may need to use artificial tears frequently to reduce damage to the eye.
No large-scale, multi-center studies have been done regarding the treatment of MMP. The usual treatment for MMP is certain drugs, used either singly or in various combinations. Corticosteroid drugs are often prescribed for affected individuals. Topical corticosteroids such as fluocinonide can relieve inflammation and itching in mild cases such as those that affect oral cavity only or the oral cavity and the skin. Other, more potent, gel preparations such as betamethasone dipropionate or clobetasol may also be used. When pemphigoid affects the gums, keeping the teeth clean by tooth-brushing will help reduce the sores, especially when topical corticosteroids are used at the same time.
Some antibiotic drugs can affect the inflammatory process. One such drug is dapsone, a sulfa-type medication that may be used to treat mild cases of MMP. Special blood tests are needed before this drug is used, however. A combination of the antibiotic drug tetracycline and nicotinamide (vitamin B3) can also be helpful in some cases of MMP.
Individuals with widespread or severe MMP may be treated with systemic corticosteroids such as prednisone and/or immunosuppressive drugs such as mycophenolate mofetil, cyclophosphamide or azathioprine. Individuals with eye involvement, severe or rapidly progressing MMP may be treated with prednisone combined with cyclophosphamide, mycophenolate mofetil, or azathioprine. Patients who are taking the above mentioned drugs must be carefully monitored by a dermatologist or physician familiar with their use because of potentially significant side effects. If these drugs are not helping, or if the pemphigoid seems to be getting worse, then other treatments that can be tried include rituximab and IV-IG (intravenous immunoglobulin G). Rituximab is an antibody that destroys the cells that produce antibodies. IV-IG is produced by purifying and concentrating antibody molecules from hundreds of blood donors. Both rituximab and IV-IG can have very serious side effects, so they usually are not given unless the patient has pemphigoid that is not getting better with other treatments.
In rare cases, surgical procedures such as a tracheostomy may become necessary if scarring narrows the airway and breathing becomes difficult. A tracheostomy is a procedure in which a tube is inserted through a surgical opening in the windpipe (trachea) to assist breathing. A procedure to widen (dilate) a narrowed or obstructed esophagus may also be necessary if the esophagus is involved. Surgical removal (ablation) of ingrown eyelashes may be performed if the eyes are affected.
Other treatment is symptomatic and supportive.
Researchers are studying cornea epithelial stem-cell transplantation for the treatment of severe ocular-surface disorders including ocular MMP. Initial studies have demonstrated that transplantation of corneal epithelial stem cells can restore useful vision in some patients. More research is necessary to determine the long-term safety and effectiveness of this procedure as a treatment option for individuals with severe ocular symptoms of MMP.
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: [email protected]
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
Neville B, Damm DD, Allen CM, and Chi A, eds. Oral and Maxillofacial Pathology, 4th ed. St. Louis, MO: Elsevier Inc.: 2016.
Bolognia JL, Jorizzo JL, and Schaffer JV, eds. Dermatology, 3rd ed. Philadelphia, PA: Saunders Co.: 2012
JOURNAL ARTICLES
Taylor J, et al. World workshop on oral medicine VI: a systematic review of the treatment of mucous membrane pemphigoid. Oral Surg Oral Med Oral Pathol Oral Radiol 2015;120:161-171.
Murrell DF, et al. Definitions and outcome measures for mucous membrane pemphigoid: Recommendations of an international panel of experts. J Am Acad Dermatol 2015;72:168-174.
DiZenzo G, Carrozzo M, Chan LS. Urban legend series: mucous membrane pemphigoid. Oral Dis 2014;20:35-54.
Sobolewska B, Deuter C, Zierhut M. Current medical treatment of ocular mucous membrane pemphigoid. Ocul Surf 2013;11:259-266.
Xu H-H, et al. Mucous membrane pemphigoid. Dent Clin North Am 2013;57:611-630.
Schmidt E and Zillikens D: Pemphigoid diseases. Lancet 2013;381:320-332.
Chan LS: Ocular and oral mucous membrane pemphigoid (cicatricial pemphigoid). Clin Dermatol 2012;30:34-37.
Knudson RM, et al: The management of mucous membrane pemphigoid and pemphigus. Dermatol Ther 2010;23:268-280.
Saw VPJ and Dart JKG: Ocular mucous membrane pemphigoid. Ocular Surface 2008;6:128-142.
Scully C and Lo Muzio L: Oral mucosal diseases: Mucous membrane pemphigoid. Br J Oral Maxillofac Surg 2008;46:358-366.
Boedeker CC, et al. Cicatricial pemphigoid in the upper aerodigestive tract: diagnosis and management in severe laryngeal stenosis. Ann Otol Rhinol Laryngol. 2003;112:271-5.
Parisi E, et al. Modification to the approach of the diagnosis of mucous membrane pemphigoid: a case report and review of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2003;95:182-6.
Sami N, et al. Intravenous immunoglobulin therapy in patients with multiple mucosal involvement in mucous membrane pemphigoid. Clin Immunol. 2002;102:59-67.
Miserocchi E, et al. The effect of treatment and its related side effects in patients with severe ocular cicatricial pemphigoid. Ophthalmology. 2002;109:111-8.
Chan LS, et al. The first international consensus on mucous membrane pemphigoid: definition, diagnostic criteria, pathogenic factors, medical treatment, and prognostic indicators. Arch Dermatol. 2002;138:370-9.
Miziara ID, et al. Cicatricial pemphigoid: report of five cases. Ear Nose Throat J. 2002;81:442-8.
Kirtschig G, et al. Interventions for mucous membrane pemphigoid/cicatricial pemphigoid and epidermolysis bullosa acquista: a systematic review of the literature. Arch Dermatol. 2002;47:S193-5.
Kreyden OP, et al. Successful therapy with tetracycline and nicotinamide in cicatricial pemphigoid. Hautarzt. 2001;52:247-50.
Fleming TE, Korman NJ. Cicatricial pemphigoid. J Am Acad Dermatol. 2000;43:571-91.
Tsubota K, et al. Treatment of severe ocular-surface disorders with corneal epithelial stem-cell transplantation. N Engl J Med. 1999;340:1697-703.
Chan LS, et al. Laminin-6 and laminin-5 are recognized by autoantibodies in a subset of cicatricial pemphigoid. J Invest Dermatol. 1997;108:6486-53.
INTERNET
Frieman A. Cicatricial Pemphigoid. Medscape. Last Update: August 17, 2015. https://emedicine.medscape.com/article/1062534-overview Accessed March 29, 2016.
Foster CS and Hamam R. Cicatricial Pemphigoid. Medscape. Last Update: October 05, 2015. https://emedicine.medscape.com/article/1191261-overview Accessed March 29, 2016.
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