BOLLOUS DISEAESES

المرحلة الخامسة / مجموعة A

د.مازن حامد
DERMATOLOGY

BOLLOUS DISEAESES

Blisters are accumulations of fluid within or under the epidermis. They have many causes, and a correct clinical diagnosis must be based on a close study of the physical signs.The appearance of a blister is determined by the level at which it forms. Subepidermal blisters occur between the dermis and the epidermis. Their roofs are relatively thick and so they tend to be tense and intact.They may contain blood. Intraepidermal blisters appear within the prickle cell layer of the epidermis, and so have thin roofs and rupture easily to leave an oozing denuded surface: this tendency is even more marked with subcorneal blisters, which form just beneath the stratum corneum at the outermost edge of the viable epidermis, and therefore have even thinner roofs.Sometimes the morphology or distribution of a bullous eruption gives the diagnosis away, as in herpessimplex or zoster. Sometimes the history helps too, as in cold or thermal injury, or in an acute contact dermatitis.When the cause is not obvious, a biopsy should be taken to show the level in the skin at which the blister
has arisen.the three most important immunobullous disorders ,pemphigus,pemphigoid and dermatitis herpetiformis and the group of inherited bullous disorders known as epidermolysis bullosa. 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: is severe and potentially life-threatening.There are two main types. The most common is pemphigus vulgaris, which accounts for at least three-quarters of all cases, and for most of the deaths. Pemphigus vegetans is a rare variant of pemphigus vulgaris. The other important type of pemphigus,superficial pemphigus, also has two variants: the generalized foliaceus type and localized erythematosus type. A few drugs, led by penicillamine, can trigger a pemphigus-like reaction, but autoantibodies are then seldom found. Finally, a rare type of pemphigus (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 of the cadherin family 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, 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 pemphigus is prolonged, even with treatment, and 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
the side-effects of treatment (steroids and immunosuppressive) are the leading cause of death. Infections of all types are common. and severe oral ulcers make eating painful.

Differential diagnosis

pyoderma, impetigo, epidermolysis bullosa or ecthyma. Mouth ulcers can be mistaken for aphthae, Behçet’s disease or a herpes simplex.

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. The titre of these antibodies correlates loosely with clinical activity and may guide changes in the dosage of systemic steroids.

Treatment

patients should be treated in a specialized unit. Resistant and severe cases need very high doses of systemic steroids, such as prednisolone 80–320 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.plasmapheresis and intravenous immunoglobulin Treatment needs regular follow-up and is usually prolonged. In superficial pemphigus, smaller doses are usually needed, and also topical corticosteroids .

Other causes of subcorneal and intraepidermal blistering Bullous impetigo caused by Staphylococcus aureus.Scalded skin syndrome A toxin elaborated by some strains of S. aureus makes the skin painful and red; later it peels like a scald. The staphylococcus is usually hidden (e.g. conjunctiva,throat, wound, furuncle).Miliaria crystallina. Subcorneal pustular dermatosis the lesions are small groups of pustules rather than vesicles. However, the pustules pout out of the skin in a way that suggests they were once vesicles (like the vesico-pustules of chickenpox).The cause of this rare disease is unknown, but oral dapsone usually suppresses it. Severe acute eczema, especially of the contact allergic type, can be bullous. Plants such as poison ivy, poison oak or primula are common causes. The varied size of the vesicles, their close grouping, their asymmetry, their odd configurations (e.g. linear, square, rectilinear)and a history of contact with plants are helpful guides to the diagnosis.

Pompholyx :, highly itchy small eczematous vesicles occur along the sides of the fingers, and sometimes also on the palms and soles. Some call it ‘dyshidrotic eczema’, but the vesicles are not related to sweating or sweat ducts. The disorder is very common, but its cause is not known. Viral infections Some viruses create blisters in the skin by destroying epithelial cells. The vesicles of herpes simplex and zoster are the most common examples.Transient acantholytic dermatosis (Grover’s disease)
Itchy vesicles appear on the sun-damaged skin of the trunk, usually of middle-aged males. The cause is not known and the condition can be persistent despite its name.
Subepidermal immunobullous disorders These can be hard to separate on clinical grounds .

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 (within the cellular part of the hemidesmosome ), and less often to BP180 (a transmembrane molecule with one end within the hemidesmosome and the other bound to the lamina lucida). Complement is then activated and inflammatory cascade starts and mast cells degranulate, liberating a variety of inflammatory mediators.

Presentation

Pemphigoid is a chronic, usually itchy, blistering disease,of 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

loss of fluid from ruptured bullae. Systemic steroids and immunosuppressive agents carry their usual complications if used long-term .

Differential diagnosis

epidermolysis bullosa acquisita, bullous lupus erythematosus, dermatitis herpetiformis, pemphigoid gestationis, bullous erythema multiforme and linear IgA bullous disease. Immunofluorescence helps to differentiate.

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 antibodiesthat react with the basement membrane zone in some 70% of patients .

Treatment

In the acute phase, prednisolone at a dosage of 40–60 mg/day. Immuno-suppressive agents may 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. It is not caused by a herpes virus: the name herpes gestationis should be discarded now so that the disease is not confused with herpes genitalis.Treatment is with systemic steroids. Oral contraceptives should be avoided.

Cicatricial pemphigoid : also 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. 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.

Acquired epidermolysis bullosa

This can also look like pemphigoid, but has two important extra features: many of the blisters are a response to trauma and arise on otherwise normal skin; and 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 tothe pemphigoid antigens, which lie on the epidermal Side a difference that can be demonstrated when the basement membrane is split by incubating skin in a saline solution (the ‘salt-split’ technique). The condition responds poorly to systemic corticosteroids orimmunosuppressive agents.


Dermatitis herpetiformis:

Dermatitis herpetiformis is a very itchy chronic subepidermal vesicular disease, in which the vesicles erupt in groups as in herpes simplex and hence the name ‘herpetiformis’.

Cause:

Gluten-sensitive enteropathy, demonstrable by small bowel biopsy, is always present, but most patients do not suffer from diarrhoea, constipation or malnutrition as the enteropathy is mild, patchy and involves only the proximal small intestine. Absorption of gluten, or another dietary antigen, may form circulating immune complexes that lodge in the skin. Arange of antibodies can be detected, notably directed against reticulin, gliadin and endomysiuma a 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. These deposits clear slowly after the introduction of a gluten-free diet.

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 , can cause side-effects.

Differential diagnosis

The disorder masquerades as scabies, an excoriated eczema, insect bites or neurodermatitis.

Investigations

Biopsy of vesicle show 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
The disorder responds to a gluten-free diet, supervised by a dietitian. Adherence to this can be monitored using the titre of antiendomysial antibody, which should fall if gluten is strictly avoided.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 and enjoy,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. Regular blood checks are therefore necessary.

Other causes of subepidermal blisters Porphyria cutanea tarda ..Blisters in diabetes and renal disease Frusemide (furosemide) ..Bullous lupus erythematosus Bullous erythema multiforme..Stevens–Johnson syndrome .Toxic epidermal necrolysis (Lyell’s disease)

Toxic epidermal necrolysis (Lyell’s disease)

Presentation
The skin becomes red and intensely painful, and then begins to come off in sheets like a scald. This leaves an eroded painful glistening surface . Nikolsky’s sign is positive. The mucous membranes may be affected, including the mouth, eyes, and even the bronchial tree.

Course

The condition usually clears if the offending drug is stopped. New epidermis grows out from hair follicles so that skin grafts are not usually needed. The disorder may come back if the drug is taken again. Complications Toxic epidermal necrolysis is a skin emergency and can be fatal. Infection, and the loss of fluids and electrolytes,are life-threatening, and the painful denuded skin surfaces make life a misery. Corneal scarring may remain when the acute episode has settled.

Differential diagnosis

The epidermolysis of the staphylococcal scalded skin syndrome looks like toxic epidermal necrolysis clinically, but only the stratum corneum is lost. Whereas toxic epidermal necrolysis affects adults, the staphylococcal scalded skin syndrome is seen in infancy or early childhood. Histology differentiates the two.Pemphigus may also look similar, but starts more slowly and is more localized. Severe graft-vs.-host reactions can also cause this syndrome. Some believe that toxic epidermal necrolysis can evolve from Stevens–Johnson syndrome because some patients have the clinical features of both.

Investigations

Biopsy helps to confirm the diagnosis. The split is subepidermal in toxic epidermal necrolysis, and the entire epidermis may be necrotic. A frozen section provides a quick answer if there is difficulty in separating toxic epidermal necrolysis from the scalded skin syndrome .

Treatment

If toxic epidermal necrolysis is caused by a drug, this must be stopped; otherwise, treatment relies mainly on symptomatic management. Intensive nursing care and medical support are needed, including the use of central venous lines, intravenous fluids and electrolytes. Many patients are treated in units designed to deal with extensive thermal burns. Air suspension beds increase comfort. The weight of
opinion has turned against the use of systemic corticosteroids but, if they are given, it should be for short periods only, right at the start. Intravenous IgG seems more promising.


Epidermolysis bullosa
There are many types of epidermolysis bullosa: the five main ones 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.

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 . Linkage studies show that the genetic defects responsible for the most common types of simple epidermolysis bullosa lie on chromosomes 17 and 12.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 .

Dystrophic epidermolysis bullosa

many subtypes, all of which probably result from abnormalities of collagen VII, the major structural component of anchoring fibrils. 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 deformed or even lost. The mouth is not affected. The only treatment is to avoid trauma and to dress the blistered areas. Autosomal recessive dystrophic epidermolysis bullosa In this 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. Phenytoin, which reduces the raised dermal collagenase levels found in this variant, and systemic steroids are disappointing. It is especially important to minimize trauma, to prevent contractures and web formation between the digits, and to combat anaemia and secondary infection.Referral to centres with expertise.

With best wishes