In these rare disorders, bullae form the primary lesions and these result from cleavage at various levels at or near the epidermodermal junction. There is a significant mortality associated with the diseases and the treatments. Immunopathological findings are useful in the confirmation of the diagnosis, in monitoring disease activity, and for understanding the pathogenesis.
Pemphigus is a rare disease (incidence 0.5/100000) in which antibody, usually of the IgG class, reacts with an antigen (a glycoprotein) at the surface of the epidermal cell that forms part of the intercellular cement substance. The interaction causes proteases and plasmin to be released and the cells lose their adhesion and become rounded (acantholysis). Such cells may be seen when blister fluid obtained from skin lesions is spread on to a slide (Tzanck smear) and examined under the microscope.
The zone of separation within the epidermis may vary; in pemphigus vulgaris it appears just above the basal layer whilst in the superficial forms of pemphigus, clefts occur adjacent to the granular layer. Nikolsky’s sign consists of extension of the zone of separation by light pressure or rubbing the skin.
Patients are usually between the ages of 40 and 60 years and are often Jewish; 90% have HLA-DR4. It is also common in India. Antigen-antibody complexes have been shown, on immunofluorescence, to localize within the intercellular substance of the epidermis, adjacent to clefts. Animal and human keratinocytes lose adhesion when cultured in the presence of sera from patients with pemphigus vulgaris. The antigen is a 130 kDa glycoprotein of the desmosome complex.
There are several forms of pemphigus. In the most common form lesions may be confined to the mucosal surfaces in the early stages of the disease; 50% of cases start in the mouth with bright red, sore and denuded mucosa. In a few patients this may be the only site involved; more commonly, however, thin-walled blisters appear over normal-looking skin elsewhere on the body. Such lesions soon rupture to leave moist eroded areas and secondary bacterial infection is common. When large areas of the skin are denuded, fluid loss and catabolic changes may produce severe metabolic disturbance. These metabolic changes may be compounded in the early stages of systemic steroid treatment. Blisters may never be evident clinically in the more superficial patterns of pemphigus. A pemphigus-like eruption has been seen with drugs such as penicillamine, captopril and rifampicin.
The diagnosis is confirmed by the cytological examination of blister fluid and by direct immunofluorescent staining of a skin sample obtained from the edge of a fresh blister. Fluorescent anti-human IgG and anti-human C3 outline the intercellular substance between the epidermal cells and the edges of the cleft in the skin that forms the blister. Circulating IgG antibodies to intercellular areas ofkeratinocytes are present in 95%; the titres may reflect disease activity and act as a therapeutic marker.
Treatment includes general measures of controlling bacterial infection and fluid loss. Air beds are useful for nursing such patients. Prednisolone in doses of 60-100 mg daily or more may be needed to prevent new blisters forming, and drugs such as azathioprine or methotrexate may be required to enable the dose of steroid to be lowered at the earliest opportunity. Gold may be effective therapy in steroid-resistant patients.
Bullous pemphigoid Bullous pemphigoid occurs twice as frequently as pemphigus and most patients are more than 60 years old at the time of presentation. Direct immunofluorescence of skin demonstrates staining of IgG and C3 at the basement membrane zones. On electron microscopy blister formation is seen at the level of the lamina lucida (Fig. 20.7).Circulating antibodies can be detected in the sera in 70% of pat ients. Antigens are 230 kDa and 180 kDa proteins of the hemidesmosome complex.
The disease may begin with irritation and erythema of the skin occurring for weeks or months before blistering appears. Bullae then develop, often on an erythematous background but also on normal skin. These tense bullae, which are often secondarily infected, may be localized to one area of the skin or may be more widespread. The groin, axillae and flexural aspect of the limbs and lower abdomen are most commonly affected and correspond to areas of highest antigen expression. Involvement of mucosae IS rare.
The diagnosis may be confirmed by the immunofluorescent staining of the basement membrane with IgG. The majority of antigen is located in an intracellular position in the region of the hemidesmosome; a small proportion is in the lamina lucida of basement membrane.
Smaller doses of prednisolone than those required for pemphigus (40-50 mg daily) are needed to control this disease. Steroid-sparing or substitution may again be achieved with azathioprine or methotrexate and in some patients with dapsone 50-100 mg per day. Potent topical corticosteroids are a useful addition to treatment with localized disease. It is possible to stop all medication in many patients after 2-3 years of treatment.
This is the name given to a group of rare and largely genetically determined diseases that vary from localized disease on the soles of the feet in one form, to infants born with a loss of skin from large areas of their body surface at the other extreme. It is now possible to diagnose different forms of the disease in utero.
In epidermolysis bullosa simplex, blistering arises within the basal cells of the epidermis (see p. 993), while in junctional epidermolysis bullosa the area of cleavage is within the lamina lucida. In the dystrophic form of the disease, separation occurs beneath the lamina densa within the superficial dermis.
Epidermolysis bullosa simplex
This presents within the first year of life, when blisters appear over contact areas of the skin such as the palms and knees; the soles often become affected when walking commences. Scarring is unusual.
Epidermolysis bullosa dystrophica
There are two forms of this disease:
1 In the autosomal dominant form, bullae occur on the limbs in infancy.
2 In the recessive form, bullae occur at birth and large areas of the skin are denuded with subsequent scarring; contracture and fusion of the skin between the fingers and toes leads to syndactyly. Ulceration of mucosal surfaces, e.g. tongue, oesophagus and the anal margin may be seen.
Epidermolysis letalis (junctional epidermolysis bullosa)
Epidermolysis letalis presents at birth with both mucosaldisease and widespread erosions of the skin that often fails to heal. The child dies in infancy.
Epidermolysis bullosa acquisita (EBA)
EBA occurs in adult life with no family history of epidermolysis bullosa. It can clinically be confused with porphyria. Immunofluorescence of skin shows IgG deposition at the epidermodermal junction. The EBA antigen is the globular C-terrninus of type VII pro collagen. Patients often have HLA-DR2.
There is a tendency for non-lethal forms of the disease gradually to improve through childhood. Protection of the skin and the prompt care of newly eroded skin may lessen scarring. Attention to nutrition, anaemia, eyes and mucosal urfaces is essential but there is no good evidence that drugs ••i•l•l alter the extent of blistering.
Dermatitis herpetiformis produces an extremely itchy polymorphic rash that is symmetrically distributed over the extensor surfaces of the body. The unusual feature of this condition is that most patients also have a glutensensitive enteropathy, which is usually asymptomatic.
The dermal papillae are infiltrated with neutrophils, eosinophils and fibrin. Later subepidermal vesicles develop. The major diagnostic pointer is 19A deposits in the unaffected skin, which can be seen on immunofluorescence. These deposits are usually granular and subepidermal but occasionally linear deposits are seen. Linear deposits may also be seen in some other subepidermal blistering conditions, e.g. linear 19A disease. The smallbowel lesion is similar to that seen in coeliac disease (see p. 208) except that it is less severe and varying degrees of villous atrophy are seen. The small-bowel lesions occur in those with the granular 19A skin deposits.
The HLA markers and changes in humoral and cellular immunology are similar to those found in coeliac disease.
Dermatitis herpetiformis can occur at any age but is seen chiefly in the second, third and fourth decades. Erythematous plaques, excoriations, urticarial papules, crusts or vesicles appear on elbows, knees, shoulders, buttocks and scalp; the mucous membranes are occasionally affected. The lesions are extremely itchy and the vesicles have usually been burst by scratching, leaving encrusted lesions. The course of the disease is one of remissions and exacerbations. Patients can often predict an eruption 8- 12 hours before its onset because of localized itching. Gastrointestinal symptoms are rare, even with small intestinal esions, and steatorrhoea is seen in less than 5% of patients.
The diagnosis is made on the clinical and histological appearance of the skin (see above), and by the response to dapsone. A small-bowel biopsy is performed to confirm the gluten-sensitive enteropathy.
Dapsone 50-200 mg daily will usually control the rash within hours and on stopping the drug the symptoms promptly recur. Occasionally, higher doses of dapsone are required. Maintenance doses vary but patients can adjust their own medication to the minimal dose required to control the rash. Complications of dapsone therapy include haemolytic anaemia and methaemoglobinaemia. A gluten-free diet improves the intestinal lesions and also helps the skin lesions, leading to a reduction or cessation of dapsone.
Linear IgA disease
Linear deposition of 19A at the basement membrane zone delineates a rare disease with a prevalence of 1/250000. Lesions resemble those of bullous pemphigoid; ocular associations are seen and a minority of patients are dapsone resistant.
OTHER CONDITIONS that produce blistering include porphyria and drug eruptions.