Bullous disorders of immunological origin: In pemphigus and pemphigoid, the damage is done by autoantibodies directed at molecules that normally bind the skin . This type of mechanism has not yet been proven for dermatitis herpetiformis; but the characteristic deposition of immunoglobulin (Ig) A in the papillary dermis, and an association with a variety of autoimmune disorders, both suggest an immunological basis for the disease.
Pemphigus: Pemphigus is severe and potentially life-threatening. Types: 1.Pemphigus vulgaris, which accounts for three-quarters of all cases, and for most of the deaths. 2.Pemphigus vegetans, is a rare variant of pemphigus vulgaris
3.Superficial pemphigus, has two variants: a. generalized foliaceus type b. localized erythematosus type. 4.Drug induced pemphigus, like penicillamine, can trigger a pemphigus-like reaction, but autoantibodies are then seldom found. 5.paraneoplastic pemphigus, has been described in association with a thymoma or an underlying carcinoma; it is characterized by unusually severe mucosal lesions.
Cause All types of pemphigus are autoimmune diseases in which pathogenic IgG antibodies bind to antigens within the epidermis. The main antigens are desmoglein 3 (in pemphigus vulgaris) and desmoglein 1 (in superficial pemphigus). Both are cell-adhesion molecules found in desmosomes . The antigen–antibody reaction interferes with adhesion, causing the keratinocytes to fall apart.
Presentation -Pemphigus vulgaris is characterized by flaccid blisters of the skin and mouth and, after the blisters rupture, by widespread painful erosions. Most patients develop the mouth lesions first. Shearing stresses on normal skin can cause new erosions to form (a positive Nikolsky sign). -In the vegetans variant, heaped up cauliflower-like weeping areas are present in the groin and body folds. -The blisters in pemphigus foliaceus are so superficial, and rupture so easily, that the clinical picture is dominated more by weeping and crusting erosions than by blisters. -In the rarer pemphigus erythematosus, the facial lesions are often pink, dry and scaly.
Course The course of all forms of pemphigus is prolonged, even with treatment. The mortality rate of pemphigus vulgaris is still at least 15%. Superficial pemphigus is less severe. With modern treatments, most patients with pemphigus can live relatively normal lives, with occasional exacerbations.
Complications Complications are inevitable with the high doses of steroids and immunosuppressive drugs that are needed to control the condition. Indeed, side-effects of treatment are now the leading cause of death. Infections of all types are common. Severe oral ulcers make eating painful.
Investigations Biopsy shows that the vesicles are intraepidermal, with rounded keratinocytes floating freely within the blister cavity (acantholysis). Direct immunofluorescence of adjacent normal skin shows intercellular epidermal deposits of IgG and C3. The serum from a patient with pemphigus contains antibodies that bind to the desmogleins in the desmosomes of normal epidermis, so that indirect immunofluorescence can also be used to confirm the diagnosis.
Treatment Severe cases need very high doses of systemic steroids, such as prednisolone 80–120 mg/day, and the dose is dropped only when new blisters stop appearing. Immunosuppressive agents, such as azathioprine or cyclophosphamide and, mycophenylate mofetil, are often used as steroid-sparing agents. New and promising approaches include plasmapheresis and intravenous immunoglobulin as used in other autoimmune diseases. Treatment needs regular follow-up and is usually prolonged. In superficial pemphigus, smaller doses are usually needed, and the use of topical corticosteroids may help too.
Subepidermal immunobullous disorders: Pemphigoid: Pemphigoid is an autoimmune disease. Serum from about 70% of patients contains antibodies that bind in vitro to normal skin at the basement membrane zone. The IgG antibodies bind to two main antigens: most commonly to BP230 , and less often to BP180 . Complement is then activated an inflammatory cascade starts and mast cells degranulate, liberating a variety of inflammatory mediators.
Presentation Pemphigoid is a chronic, usually itchy, blistering disease, mainly affecting the elderly. The tense bullae can arise from normal skin but usually do so from urticarial plaques. The flexures are often affected; the mucous membranes usually are not. The Nikolsky test is negative. Course Pemphigoid is usually self-limiting and treatment can often be stopped after 1–2 years.
Complications Untreated, the disease causes much discomfort and loss of fluid from ruptured bullae. Systemic steroids and immunosuppressive agents carry their usual complications if used long-term. Investigations The histology is that of a subepidermal blister, often filled with eosinophils. Direct immunofluorescence shows a linear band of IgG and C3 along the basement membrane zone. Indirect immunofluorescence, using serum from the patient, identifies IgG antibodies that react with the basement membrane zone in some 70% of patients.
Treatment In the acute phase, prednisolone or prednisone at a dosage of 40–60 mg/day is usually needed to control the eruption. Immunosuppressive agents may also be required. The dosage is reduced as soon as possible, and patients end up on a low maintenance regimen of systemic steroids, taken on alternate days until treatment is stopped. For unknown reasons, tetracyclines and niacinamide help some patients.
Pemphigoid gestationis (herpes gestationis) This is pemphigoid occurring in pregnancy, or in the presence of a hydatidiform mole or a choriocarcinoma. As in pemphigoid, most patients have linear deposits of C3 along the basement membrane zone, although IgG is detected less often. The condition usually remits after the birth but may return in future pregnancies. Treatment is with systemic steroids. Oral contraceptives should be avoided.
Cicatricial pemphigoid Like pemphigoid itself, cicatricial pemphigoid is an autoimmune skin disease showing IgG and C3 deposition at the basement membrane zone. The antigens are often as in pemphigoid, but other antigens are sometimes targeted such as laminin 5 (in anchoring filaments). The condition differs from pemphigoid in that its blisters and ulcers occur mainly on mucous membranes such as the conjunctivae, the mouth and genital tract.
Bullae on the skin itself are uncommon. Lesions heal with scarring: around the eyes this may cause blindness, especially when the palpebral conjunctivae are affected. The condition tends to persist and treatment is relatively ineffective, although very potent local steroids, systemic steroids and immunosuppressive agents are usually tried. Good eye hygiene and the removal of ingrowing eyelashes are important.
Acquired epidermolysis bullosa This can also look like pemphigoid, but has two important extra features: 1.Many of the blisters are a response to trauma and arise on otherwise normal skin. 2.Milia are a feature of healing lesions. The target of the autoantibodies is type VII collagen in anchoring fibrils. The antigen lies on the dermal side of the lamina densa , in contrast to the pemphigoid antigens, which lie on the epidermal Side. The condition responds poorly to systemic corticosteroids or immunosuppressive agents.
Linear IgA bullous disease This is clinically similar to pemphigoid, but affects children as well as adults. Blisters arise on urticarial plaques, and are more often grouped, and on extensor surfaces, than is the case with pemphigoid. The so-called ‘string of pearls sign’, seen in some affected children, is the presence of blistering around the rim of polycyclic urticarial lesions. The conjunctivae may be involved. Linear IgA bullous disease is, as its name implies, associated with linear deposits of IgA and C3 at the basement membrane zone. IgG is sometimes also found. The disorder responds well to oral dapsone.
Dermatitis herpetiformis Dermatitis herpetiformis is a very itchy chronic subepidermal vesicular disease, in which the vesicles erupt in groups as in herpes simplex, hence the name ‘herpetiformis’.
Cause Gluten-sensitive enteropathy, demonstrable by small bowel biopsy, is always present. Absorption of gluten, or another dietary antigen, may form circulating immune complexes that lodge in the skin. A range of antibodies can be detected, notably directed against gliadin and endomysium component of smooth muscle. Granular deposits of IgA and C3 in the superficial dermis under the basement membrane zone induce inflammation, which then separates the epidermis from the dermis.
Presentation The extremely itchy, grouped vesicles and urticated papules develop particularly over the elbows and knees, buttocks and shoulders. They are often broken by scratching before they reach any size. A typical patient therefore shows only grouped excoriations, sometimes with eczema-like changes added by scratching.
Course The condition typically lasts for decades. Complications The complications of gluten-sensitive enteropathy include diarrhoea, abdominal pain, anaemia and, rarely, malabsorption. Small bowel lymphomas have been reported, and the use of a gluten-free diet may reduce this risk. There is a proven association with other autoimmune diseases, most commonly of the thyroid. Treatment , notably with dapsone.
Investigations If a vesicle can be biopsied before it is scratched away, the histology will be that of a subepidermal blister, with neutrophils packing the adjacent dermal papillae. Direct immunofluorescence of uninvolved skin shows granular deposits of IgA, and usually C3, in the dermal papillae and superficial dermis. Small bowel biopsy is no longer recommended as routine because the changes are often patchy.
Treatment Gluten-free diet, which should be supervised by a dietitian. The bowel changes revert quickly to normal but IgA deposits remain in the skin, and the skin disease can drag on for many months. Because of this, and because a gluten-free diet is hard to follow, some patients prefer to combine the diet with dapsone or sulphapyridine (sulfapyridine) at the start, although both can cause severe rashes, haemolytic anaemia (especially in those with glucose- 6-phosphate dehydrogenase deficiency), leucopenia thrombocytopenia, methaemoglobinaemia and peripheral neuropathy.
Congenital epidermolysis bullosa There are many types of epidermolysis bullosa. All are characterized by an inherited tendency to develop blisters after minimal trauma, although at different levels in the skin. The more severe types have a catastrophic impact on the lives of sufferers. Acquired epidermolysis bullosa is not inherited and was discussed earlier.
Simple epidermolysis bullosa Several subtypes are recognized, of which the most common are the Weber–Cockayne (mainly affecting the hands and feet) and the Dowling–Meara (featuring herpetiform blisters on the trunk) types. Most are inherited as autosomal dominant conditions and are caused by abnormalities in genes responsible for production of the paired keratins (K5 and K14) expressed in basal keratinocytes.
Blisters form within or just above the basal cell layers of the epidermis and so tend to heal without scarring. Nails and mucosae are not involved. The problems are made worse by sweating and ill-fitting shoes. Blistering can be minimized by avoiding trauma, wearing soft well-fitting shoes and using foot powder. Large blisters should be pricked with a sterile needle and dressed. Their roofs should not be removed. Local antibiotics may be needed.
Junctional epidermolysis bullosa The abnormalities in the basal lamina include loss of anchoring filaments and defective laminins . This rare and often lethal condition is evident at birth. The newborn child has large raw areas and flaccid blisters, which are slow to heal. The peri-oral and peri-anal skin is usually involved, as are the nails and oral mucous membrane. There is no effective systemic treatment.
Dystrophic epidermolysis bullosa There are many subtypes, all of which probably result from abnormalities of collagen VII , the major structural component of anchoring fibrils. 1. Autosomal dominant dystrophic epidermolysis bullosa In this type blisters appear in late infancy. They are most common on friction sites (e.g. the knees, elbows and fingers), healing with scarring and milia formation. The nails may be deformed or even lost. The mouth is not affected. The only treatment is to avoid trauma and to dress the blistered areas.
2. Autosomal recessive dystrophic epidermolysis bullosa In this tragic form of epidermolysis bullosa, blisters start in infancy. They are subepidermal and may be filled with blood. They heal with scarring, which can be so severe that the nails are lost and webs form between the digits. The hands and feet may become useless balls, having lost all fingers and toes. The teeth, mouth and upper part of the oesophagus are all affected; oesophageal strictures may form. Squamous cell carcinomas of the skin are a late complication. Treatment is unsatisfactory.