Mucous Membrane
(Cicatricial) Pemphigoid



Quick Summary
Introduction
References
Photos



Clinical Features
Histopathology
Treatment
Prognosis

Irregular, broken blisters of maxillary vestibule have prevented 
proper oral hygiene procedures.

 

 


 

Quick Review for Patients

 
Mucous membrane pemphigoid is an autoimmune or "self-allergy" disease in which a patientís own circulating antibodies become altered so that they attack the fibrous attachment of the skin and membrane epithelium to the underlying connective tissues. Women are more commonly affected than men and the disease is usually diagnosed between the ages of 40-60 years. The typical lesion is a small or large, clear-fluid blister which breaks fairly rapidly in the mouth to leave a flat white, somewhat tender ulcer with a thin red line around it. The gums are especially likely to be involved, resulting in sloughing during eating or tooth brushing ("desquamative gingivitis"). Usually patients with oral involvement will lack major skin involvement, but the eyelids and genital mucosa are quite susceptible to the blistering phenomenon. There is no cure for this pemphigus vulgaris look-alike disease, but lesions frequently respond well to topical or systemic corticosteroids. Death from this disease is extremely rare, but scar formation of the eyelids and eyeball surfaces may lead to blindness if the eyes are not closely monitored by an ophthalmologist.

 

 

 

Introduction

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Mucous membrane pemphigoid, also known as benign mucous membrane pemphigoid and cicatricial (scar-forming) pemphigoid, is one of a number of blister-producing autoimmune mucocutaneous diseases under the pemphigoid designation.  It is the variant most likely to occur in the mouth and other membranes of the body. While similar in its clinical presentation to pemphigus vulgaris, is is much less severe and the involved antibodies attack the attachment fibrils (Type VII collagen) of the basement membrane rather than the desmosomal attachments between epithelial cells, as occurs in pemphigus.  The antibodies react specifically against at least two hemidesmosome antigens, BPAG1 and BPAG2, collectively called the "bullous pemphigoid antigen," which bind the basal cell layer of the epithelium to the basement membrane. This results in separation of the epithelium from the underlying stroma at the level of the lamina lucida, the electron lucent zone found between the basal cell membrane and lamina densa.

 The effect may be quite localized, as circulating autoantibodies are not present in a large proportion of affected individuals, or are present only at low titers using indirect immunofluorescence techniques. The membranes of the mouth, eyes, larynx, pharynx and genital region may all be affected, but conjunctival mucosal involvement is likely the most severe problem because of the propensity for scar formation and eventual blindness.  Compared to pemphigus vulgaris, the disease runs a rather benign, protracted course, with at least a third of patients eventually developing skin involvement of the head and neck region, legs or genitalia. Additionally, half of all patients will develop bullae of other membranes of the upper aerodigestive tract, the anus or genitalia. There is an increased frequency of certain HLA tissue types, especially HLA-B12, HLA-DR4 and Dqw7, and some drug-induced cases have also been associated with different HLA types.


Clinical Features

This disease is characterized by bullous lesions of mucous membranes, especially oral and conjunctival membranes. Eye involvement results in scar formation or fibrous synechiae of palpebral and bulbar conjunctivae, with entropion and blindness occurring in almost a third of untreated cases (Figure 1). Disease onset is usually between 40 and 60 years of patient age, and oral lesions are the first manifestation of disease in two-thirds of cases. There is no racial or ethnic predilection, but the disease is much more common in women than in men (male:female ratio = 1:2).

Individual lesions develop slowly and are usually smaller and less frequent during the early months or years of the disease (Figures 2 & 3). Bullae may, however, become more than 3 cm. in diameter (Figure 4) and may remain intact long enough for the clinician to see them as clear or slightly bluish blisters. While there is seldom a surrounding inflammatory halo, the mucosa in the affected region may be quite diffusely erythematous and at least 10% of patients will have a positive Nikolsky test (creation of a blister by pressure or friction).  A ruptured blister leaves a shallow, mildly tender ulcer bed which heals in 7-10 days. Large or secondarily infected lesions may result in scar formation, but this phenomenon is much less severe than it is with conjunctival involvement.

Oral sites most often involved include the gingiva (90% of oral cases), palate and buccal mucosa. While individual blisters do not necessarily recur at the same exact site, new lesions do seem to remain contained within a limited anatomic region. When only the gingiva or alveolar mucosa are involved, the disease has a special tendency to remain localized, and this has led some authorities to prefer the more generic term, desquamative gingivitis. Desquamative gingivitis is, however, a term also used to describe gingival manifestations of pemphigus and bullous lichen planus.


Pathology and Differential Diagnosis

Oral bullae demonstrate separation of the epithelium from the basement membrane (Figure 5), often with small numbers of chronic and acute inflammatory cells, including eosinophils, in the extracellular serous fluid of the blister. Only rarely will chronic inflammatory cells be seen within the subepithelial stroma of a fresh, unruptured lesion. Most lesions, however, are ruptured at the time of biopsy, hence, the subepithelial separation may only be found at the edge of an otherwise nonspecific inflammatory ulceration. Direct immunofluorescence will demonstrate in almost all cases a continuous linear band of IgG and C3 immunoreactants along the basement membrane (Figure 6). More than half of all patients will also have circulating autoantibodies identifiable in the serum through indirect immunofluorescence.

Pemphigoid is distinguished from pemphigus by the vertical location of the blister: the latter produces acantholysis with cleavage of the spinous cell layer, while the former produces cleavage of the basement membrane region. Other entities can create subepithelial cleavage or blistering, including linear IgA disease, bullous lichen planus, epidermolysis bullosa (hereditary and acquired forms), bullosa hemorrhagica, erythema multiforme, bullous pemphigoid and dermatitis herpetiformis.

The ruptured blisters of adult onset linear IgA are very similar except that there is typically a neutrophilic infiltrate along the basement membrane and surrounding the blood vessels of the subepithelial stroma.  Neutrophilic microabscesses may be present within the connective tissue papillae and on direct immunofluorescence linear deposits of IgA are seen along the basement membrane. Eruptions identical in every way to linear IgA have occurred with the use of lithium, vancomycin, diclofenac, and glibenclamide.

Dermatitis herpetiformis has an histopathologic appearance similar to linear IgA disease, except that the basement membrane deposits of IgA have a more irregular or granular appearance. It also presents typically with small, viral-like vesicles rather than the larger bullae of pemphigoid or linear IgA.

Bullous lichen planus has a distinct band of chronic inflammatory /immunological cells immediately beneath the epithelium, which usually makes it easy to distinguish it from pemphigoid. A loss of rete ridges or the formation of saw-toothed ridges are also characteristically found, as is liquefactive (hydropic, ballooning) degeneration of the basal cells and a thickened surface layer of parakeratin. There are, however, occasional cases with lichenoid light microscopic changes and characteristic pemphigoid immunofluorescence.

Routine histopathology will often not distinguish between epidermolysis bullosa acquisita (EBA) and pemphigoid, and at least half of EBA patients have involvement of the oral mucosa. Immunofluorescence will, however, show IgG isoantibody deposition on the floor of the EBA bulla, while antibodies coat the roof of the blister in pemphigoid. In EBA, the blisters arise beneath the basal lamina, where the anchoring fibrils (Type VII collagen) are destroyed. EBA may, moreover, be associated with Crohnís disease and other inflammatory bowel diseases, rheumatoid arthritis, systemic lupus erythematosus, idiopathic pulmonary fibrosis, and chronic thyroiditis. Hereditary epidermolysis bullosa is more easily distinguished by its childhood onset and its classic acral distribution.

Erythema multiforme bullosa can present with subepithelial or intraepithelial cleavage, or both together, but it typically also has subepithelial edema and infiltration by mixed inflammatory cells, including eosinophils. Subepithelial vesiculation is seen in association with necrotic basal keratinocytes, while pemphigoid basal cells remain intact. Many cases cannot, however, be distinguished from pemphigoid using histopathologic and immunoreactive features, and the diagnosis is often based on the clinical presentation and exclusion of other vesiculobullous disorders. Erythema multiforme not only occurs at a younger age than pemphigoid, but it typically has a duration of limited to weeks or months while pemphigoid remains an incurable disease. 


Treatment and Prognosis

Oral pemphigoid can often be controlled by topical or systemic corticosteroids or other immunosuppressive agents, particularly cyclophosphamide, but there is no cure for this disease. Lesions occur intermittently and may affect different parts of the oral mucosa at different times. Seldom do blisters occur elsewhere in the upper aerodigestive tract, but patients with laryngeal or esophageal involvement will develop dysphagia or esophageal webs. Ocular involvement eventually becomes manifested in 50-85% of cases and skin involvement is eventually seen in up to 30% of cases. The patient should be followed carefully by an ophthalmologist whether or not conjunctival involvement is seen at the time of oral lesion diagnosis.


References (Chronologic Order)

Note: Click on underlined author's names for additional detail.

General references:

Neville BW, Damm DD, Allen CM, Bouquot JE. Oral and maxillofacial pathology. Philadelphia, W. B. Saunders; 1995.

Elder D, Elenitsas R, Jaworsky C, Johnson B Jr. Lever's Histopathology of the skin, 8th edition. Philadelphia; Lippincott-Raven, 1997.

Sapp JP, Eversole LR, Wysocki GP. Contemporary oral and maxillofacial pathology. Mosby; St. Louis, 1997.

Odell EW, Morgan PR. Biopsy pathology of the oral tissues. London; Chapman & hall Medical, 1998.

Specific references:

Laskaris G, Angelopoulos A. Cicatricial pemphigoid: direct and indirect immunofluorescent studies. Oral Surg Oral Med Oral Pathol 1981; 51:48-54.

Williams DM, et al. Benign mucous membrane (cicatricial) pemphigoid revisited: a clinical and  immunological reappraisal. Br Dent J 1984; 157:313-316.

Allen CM, Camisa C, Grimwood R. Lichen planus pemphigoides: report of a case with oral lesions. Oral Surg Oral Med Oral Pathol 1987; 63:184-188.

Hanson RD, Olsen KD, Rogers RS. Upper aerodigestive tract manifestations of cicatricial pemphigoid. Ann Otol Rhinol Laryngol 1988; 97:493-499.

Williams DM. Vesiculobullous mucocutaneous disease: benign mucous membrane and bullous pemphigoid. J Oral Pathol Med 1990; 19:16-23.

Boh EE, Millikan LE. Vesiculobullous disease with prominent immunologic features. JAMA 1992; 268:2893-2898.

Lamey P-J, Rees TD, Binnie WH, et al. Mucous membrane pemphigoid: treatment experience at two institutions. Oral Surg Oral Med Oral Pathol 1992; 74:50-53.

Stanley JR. Cell adhesion molecules as targets of autoantibodies in pemphigus and pemphigoid, bullous diseases due to defective epidermal cell adhesion. Adv Immunol 1993; 53:291-325.

Vincent SD, Lilly GE, Baker KA. Clinical, historic, and therapeutic features of cicatricial pemphigoid: a literature review and open therapeutic trial with corticosteroids. Oral Surg Oral Med Oral Pathol 1993; 76:453-459.

Cowan CG, Lamey PJ, Walsh M, Irwin ST, et al. Linear IgA disease (DAD): immunoglobulin deposition in oral and colonic lesions. J Oral Pathol Med 1995; 24:374-378.

Markopoulos AK, et al. Desquamative gingivitis: a clinical, histopathologic, and immunologic study. Quintessence Int 1996; 27:763-767.

Scully C, Porter SR. the clinical spectrum of desquamative gingivitis. Semin Cutan Med Surg 1997; 16:308-313.

Weinberg MA, et al. Mucocutaneous features of autoimmune blistering diseases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997; 84:517-534.

Bozkurt FY, Celenligil H, Sungur A, Ruacan S. Gingival involvement in mucous membrane pemphigoid. Quintessence Int 1998; 29:438-441.

Yih WY, Maier T, Kratochvil FJ, Zieper MB. Analysis of desquamative gingivitis using direct immunofluorescence in conjunction with histology. J Periodontol 1998; 69:678-785.


Pictures

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Figure 1:  Conjunctival involvement can be severe, resulting in loss of hair, of the lid itself, bulbar conjunctivitis and scar formation.  [return to text]

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Figure 2:   Whitish area of gingiva represents broken blister, with surrounding hemorrhage.  [return to text]

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Figure 3: Ulcer bed (left arrow) of old blister and freshly broken blister (lower arrow) on hard palate. [return to text] 

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Figure 4:  Ulcer bed of huge buccal mucosa bulla.  [return to text]

bmmp2.jpg (19694 bytes) Figure 5:  Subepithelial blister has intact overlying epithelium, without the liquefactive degenerative of bullous lichen planus.    [return to text]
bmmp3.jpg (8633 bytes) Figure 6:  Immunofluorescence shows apple green line along the basement membrane of the epithelium.   [return to text]
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