Author: Kim Gear, 2007.
Blisters arising in the mouth may be due to the autoimmune disease, pemphigus and bullous pemphigoid. These are characterised by autoantibodies directed against the adhesion molecules of the skin and mucous membranes.
Pemphigus is a term originally derived from the Greek term, pemphix, meaning bubble or blister.
It describes a group of blistering disorders characterised by antibodies directed against intercellular substance, which is found between epithelial cells (called keratinocytes in the skin). The antibodies cause the cells to separate from each other. Body fluid then fills the clefts to form blisters.
There are two main types of pemphigus than cause mucosal lesions:
Pemphigus vulgaris is the more common of the two, with an incidence of about 0.1 to 0.5 per 100,000 of the adult population. Pemphigus vulgaris is more common in patients of Ashkenazi Jewish descent and those of Mediterranean origin. Men and women are equally affected, with the mean age of onset being 50 to 60 years. However, it may also affect children and the elderly.
Pemphigus vulgaris involves mucosal surfaces in 50–70% of patients. Oral vesicles (small blisters) are rarely seen intact as they break down rapidly and become shallow irregular erosions (sores) that later ulcerate. Widespread erosions may be seen, particularly over the buccal mucosa (inner aspect of cheeks) or palate. The gums may also be affected. These lesions may be sore and result in difficulty eating. Other mucosal surfaces (ie, the nose, eyelids, genitals and anus) may also be affected.
Paraneoplastic pemphigus typically first affects the lips first but may result in widespread oral erosions or lichenoid lesions (these are lesions that resemble oral lichen planus), and it may be severe. The discomfort makes eating and drinking difficult. This type of pemphigus is due to antibodies produced by a benign or malignant tumour. The most common benign tumour associated with paraneoplastic pemphigus is thymoma, followed by Castleman tumour, a rare and complex type of lymphoma. The most common associated malignant tumour (cancer) is non-Hodgkin lymphoma, followed by chronic lymphocytic leukaemia.
The cause of pemphigus remains unknown. However, there is a genetic predisposition and it is considered to be an autoimmune disorder. In 1964, autoantibodies against keratinocyte surfaces were described in patients with pemphigus.
Pemphigus sometimes occurs in patients that suffer from other autoimmune diseases, particularly myasthenia gravis and thymoma.
The characteristic histological findings in a biopsy of pemphigus are a split within the epidermis above the basal layer, with epithelial cells floating separately instead of being joined together. The basal cells stand like a row of tombstones on the floor of the blister at the base of the mucosa and epidermis.
A special test called direct immunofluorescence performed on the biopsy helps to confirm the diagnosis and differentiate pemphigus from other blistering disorders. A positive test indicates the presence of antibodies binding to the epithelial cell surface.
The clefting arises because the antibodies bind to proteins called desmogleins, breaking up the plates that stick the keratinocytes together (these are called desmosomes). This results in the keratinocytes separating from each other (acantholysis).
The autoimmune antibodies can also be detected by a skin antibody blood test (indirect immunofluorescence). It is positive in 80-90% of patients with active pemphigus. Disease activity correlates with antibody titre (concentration) in most patients.
In the past, pemphigus has been associated with high mortality and morbidity. Conventional therapy consists of high-dose systemic corticosteroids, immunosuppressive agents and intravenous immunoglobulin. Rituximab (a biological agent) and epidermal growth factor have also been used effectively.
The advent of systemic corticosteroids reduced the mortality rate from 70–100% to about 30%. The most common causes of death in pemphigus nowadays are an adverse reaction to drugs and infections.
Pemphigoid is characterised clinically by the presence of large, tense blisters or bullae. These arise under the epidermis (subepidermal).
Three major forms exist:
These diseases have clinical, pathological and immunological similarities but the exact relationship to each other is not fully defined.
Direct immunofluorescence of a skin biopsy in reveals antibodies that attach to the skin below the epidermis and this results in blister formation below the epidermis. The autoantibodies in bullous pemphigoid and gestational pemphigoid are directed against hemidesmosomal antigens — hemidesmosomes are the structures that stick the basal cells to the underlying dermis. In cicatricial pemphigoid, they are directed against anchoring filaments below the epidermis.
Bullous pemphigoid is a chronic, autoimmune, subepidermal, blistering skin disease that may involve mucous membranes. It is by far the most common autoimmune blistering disease and mostly affects the elderly, although it may occur at any age including during childhood. Men and women of all races are equally affected.
The skin involvement of bullous pemphigoid may be extensive but oral involvement is usually minor with small blisters which break easily (but not as easily as those of pemphigus).
Treatment depends on the extent and severity of the skin and/or mucous membrane disease.
Most patients are managed with systemic steroids in varying doses.
Treatment may also include:
Gestational pemphigoid (pemphigoid gestationis) is similar to bullous pemphigoid except that is arises in pregnancy; it affects about 1 in 10,000 to 1 in 60,000 pregnancies. It is also known as herpes gestationis. Small oral blisters may occur, and these may break down to form ulcers.
It is treated with systemic steroids and usually resolves once the baby has been born; it may recur in another pregnancy.
Mucous membrane pemphigoid is a rare autoimmune blistering disease affecting about one person per million. It is also known as cicatricial pemphigoid. Most often patients are middle-aged to elderly. It causes severe blistering of the mouth and all mucous membranes, resulting in scarring. The eyes are particularly susceptible. There is little or no skin involvement.
Linear IgA bullous dermatosis is an uncommon blistering disorder affecting adults and children. On the skin, the blisters are often arranged in rings. Oral blisters develop into ulcers before healing.
Treatment with dapsone is usually effective.
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