Bullous diseases

• Vesicles and bullae are accumulations of fluid within or under the epidermis.

• Subepidermal blisters occur between the dermis and the epidermis. Their roofs are relatively thick and so they tend to be tense and intact.

• Intra-epidermal blisters appear within the prickle cell layer of the epidermis, and so have thin roofs and rupture easily to leave an oozing denuded surface.

• Subcorneal blisters, which form just beneath the stratum corneum at the outermost edge of the viable epidermis, and therefore have even thinner roofs.

Causes of bullae

Causes of bullae

Distinguishing features of the three main immunobullous diseases

The pemphigus family

• Pemphigus is severe and potentially life-threatening. Types1. Pemphigus vulgaris• is the most common, which accounts for at least three-

quarters of all cases, and for most of the deaths.2. Pemphigus vegetans3. Superficial pemphigus• also has two variants: the generalized foliaceus type and

localized erythematosus type. 4. Paraneoplastic pemphigus• arrises in association with a neoplasm such as thymoma,

Castleman’s tumour or lymphoma.

Cause

• Autoimmune diseases, (IgG) antibodies bind to antigens within the epidermis, mainly desmoglein3 (in pemphigus vulgaris) and desmoglein 1 (in superficial pemphigus), causing the keratinocytesto fall apart (acantholysis).

• Pemphigus vulgaris is particularly common in Ashkenazi Jews and people of Mediterranean or Indian origin.

Presentation

Pemphigus vulgaris• is characterized by flaccid blisters of the skin and

mouth which rupture easily to leave 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). Other types• In the vegetans variant, heaped-up cauliflower-like weeping areas are present in

the groin and body folds. • In pemphigus foliaceus blisters are so superficial, and rupture so easily, that the

clinical picture is dominated more by weeping and crusting erosions than by blisters.

Course

• Prolonged, even with treatment• the mortality rate of pemphigus vulgaris is still at

least 15%. • About one-third of patients with pemphigus

vulgaris will go into complete remission within 3 years.

• Superficial pemphigus is less severe. • With modern treatments, most patients with

pemphigus can live relatively normal lives, with occasional exacerbations.

Complications• Side effects of high doses of steroids and

immunosuppressive drugs and are now the leading cause of death.

• Infections of all types are common. • Severe oral ulcers make eating painful.

Differential diagnosis• Widespread erosions may suggest a pyoderma,

impetigo, epidermolysis bullosa or ecthyma. • Mouth ulcers can be mistaken for aphthae, Behçet’s

disease or a herpes simplex infection. • Scalp erosions suggest bacterial or fungal infections.

Investigations

• Biopsy shows that the vesicles are intra-epidermal, with rounded keratinocytes floating freely within the blister cavity (acantholysis).

• Direct immunofluorescence of adjacent normal skin shows intercellular epidermal deposits of IgGand C3

• Indirect immunofluorescence or assays (ELISA) can also be used to confirm the diagnosis.

Immunofluorescence (red)in bullous diseases

Treatment

Systemic steroids• Resistant and severe cases need very high doses of systemic

steroids, such as 80–180 mg/day prednisolone because prednisolone up-regulates the expression of desmoglein molecules on the surfaces of keratinocytes, in addition to their anti-inflammatory effect

• The dose is reduced only when new blisters stop appearing. Immunosuppressive agents• such as azathioprine, gold salts or cyclophosphamide and, recently,

mycophenylate mofetil, are often used as steroid-sparing agents. • Plasmapheresis and administration of intravenous immunoglobulin. Other• Rituximab• Dapsone

The pemphigoid family

• Pemphigoid is an autoimmune disease.

• The IgG antibodies bind to two main antigens: most commonly to BP230, and less often to BP180 at the basement membrane activating complement starting an inflammatory cascade causing the epidermis to separate from the dermis

• Antibodies titre does not correlate with clinical disease activity.

Presentation

• Chronic, usually itchy, blistering disease, mainly affecting the elderly.

• Usually no precipitating factors can be found, but rarely ultraviolet light or radiation therapy

• The skin often erupts with smooth, itching red plaques in which tense vesicles and bullae form

• Occasionally they arise from normal skin.• The flexures are often affected • mucous membranes usually are not. • The Nikolsky test is negative.• It is not fatal • factors carrying a high risk include old age, the need for

high steroid dosage and low serum albumin levels.

Course• Pemphigoid is usually self-limiting and treatment can

often be stopped after 1–2 years.

Complications• Discomfort and loss of fluid from ruptured bullae. • Systemic steroids and immunosuppressive agents carry

their usual complications if used long term

Differential diagnosis• other bullous diseases • Immunofluorescence helps to separate it from these

Investigations

• Direct immunofluorescence shows a linear band of IgG and C3 along the basement membrane zone.

• Indirect immunofluorescence identifies IgGantibodies that react with the basement membrane zone in some 70% of patients

• A subepidermal blister is often filled with eosinophils.

• Most patients have peripheral blood eosinophilia.

Treatment

• in the acute phase, prednisolone or prednisone at a dosage of 40–60 mg/day is usually needed to control the eruption

• 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.

• Immunosuppressive agents such as azathioprinemay also be required.

• 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

• 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

• Treatment is with systemic steroids. • Oral contraceptives should be avoided, because their

hormones may precipitate the disease.

Cicatricial pemphigoid

Like pemphigoid itself, but• other antigens at the dermal–epidermal junction are sometimes

targeted such as laminin 5 • its blisters and ulcers occur mainly on mucous membranes such as

the conjunctivae, the mouth and genital tract, but 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• Very potent local steroids, dapsone, systemic steroids and

immunosuppressive agents are usually tried. • Good eye hygiene and the removal of ingrowing eyelashes are

important.

Linear IgA bullous disease

• clinically similar to pemphigoid, but affects children as well as adults.

• Blisters arise on urticarial plaques, and 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 plaques.

• The conjunctivae may be involved. • 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

• 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 (sprue, adult celiac disease is

always present, but most patients do not suffer enteropathy as it mild, patchy and involves only the proximal small intestine.

• A range of antibodies can be detected in serum, notably directed against tissue transglutaminase, reticulin, gliadinand endomysium

• The IgA deposits in skin clear slowly after the introduction of a gluten-free diet.

• There is a strong association with certain human leucocyteantigen (HLA) types, particularly HLA-DR3 and HLA-DQw2.

Presentation

• The extremely itchy, grouped vesicles and urticatedpapules 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 a secondary eczematous dermatitis develops from fierce scratching. Thus, the name ‘dermatitis’ comes from scratching, and ‘herpetiformis’ comes from grouping of vesicles and crusts.

Course• Typically lasts for decades unless patients avoid gluten entirely.Complications• The complications of gluten-sensitive enteropathy include

diarrhoea, abdominal pain, anaemia and, rarely, malabsorption. • Small bowel lymphomas have been reported• proven association with other autoimmune diseases, most

commonly of the thyroid.Differential diagnosis• Scabies• an excoriated eczema• insect bites • neurodermatitis.

Investigations

• 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

• Serum antibody tests for anti-endomysial antibodies or tissue transglutaminase can help diagnose the enteropathy.

• Small bowel biopsy is no longer recommended as routine because the changes are often patchy and serum tests are more sensitive.

Treatment

• A gluten-free diet, Adherence can be monitored using the titre of antibodies to anti-endomysialantigens or to tissue transglutaminase, which fall if gluten is strictly avoided.

• Dapsone or sulfapyridine, 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.

Toxic epidermal necrolysis (Lyell’s disease)

Cause• usually a drug reaction, most commonly to sulphonamides,

lamotrigine, barbiturates, carbamazepine or allopurinol• graft-vs.-host disease • AIDsPresentation• The skin becomes red and intensely painful, and then

begins to come off in sheets like a scald leaving 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• It is a skin emergency and can be fatal. • Infection, and the loss of fluids and electrolytes, are life-

threatening• Corneal scarring may remain when the acute episode has

settled.

Differential diagnosis• Staphylococcal scalded skin syndrome but only the

stratum corneum is lost and is seen in infancy or early childhood.

• 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, in scalded skin syndrome where the split is subcorneal.

Treatment

• The drug must be stopped • treatment relies mainly on symptomatic management with

intensive nursing care and medical support including the use of central venous lines, intravenous fluids and electrolytes.

• Many patients are treated in units designed to deal with extensive thermal burns

• The weight of opinion has turned against the use of systemic corticosteroids.

• Intravenous IgG seems more promising and ciclosporintreatment has been associated with a decreased mortality rates.

• Plasmapheresis may remove triggering drugs, or inflammatory mediators.

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