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Bullous diseases
This document summarizes several bullous diseases: 1. It describes the locations and characteristics of vesicles and bullae. Vesicles can form within or under the epidermis or between the dermis and epidermis. 2. It then focuses on three main immunobullous diseases - pemphigus, pemphigoid, and linear IgA bullous disease. Pemphigus is caused by antibodies against desmoglein proteins and features flaccid blisters. Pemphigoid features tense blisters caused by antibodies against basement membrane proteins. Linear IgA bullous disease clinically resembles pemphigoid. 3. Dermatitis herpetiformis is described
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Bullous diseases
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- 2. • Vesicles andbullae 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.
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- 5. Distinguishing features ofthe three main immunobullous diseases
- 6. The pemphigus family •Pemphigus is severe and potentially life-threatening. Types 1. Pemphigus vulgaris • is the most common, which accounts for at least three- quarters of all cases, and for most of the deaths. 2. Pemphigus vegetans 3. 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.
- 7. Cause • Autoimmune diseases,(IgG) antibodies bind to antigens within the epidermis, mainly desmoglein 3 (in pemphigus vulgaris) and desmoglein 1 (in superficial pemphigus), causing the keratinocytes to fall apart (acantholysis). • Pemphigus vulgaris is particularly common in Ashkenazi Jews and people of Mediterranean or Indian origin.
- 8. Presentation Pemphigus vulgaris • ischaracterized 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.
- 12. Course • Prolonged, evenwith 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.
- 13. Complications • Side effectsof 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.
- 14. Investigations • Biopsy showsthat 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 IgG and C3 • Indirect immunofluorescence or assays (ELISA) can also be used to confirm the diagnosis.
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- 16. Treatment Systemic steroids • Resistantand 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
- 17. 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.
- 18. Presentation • Chronic, usuallyitchy, 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.
- 20. Course • Pemphigoid isusually 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
- 21. Investigations • Direct immunofluorescenceshows a linear band of IgG and C3 along the basement membrane zone. • Indirect immunofluorescence identifies IgG antibodies 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.
- 23. Treatment • in theacute 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 azathioprine may also be required. • For unknown reasons, tetracyclines and niacinamide help some patients.
- 24. 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.
- 25. Cicatricial pemphigoid Like pemphigoiditself, 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.
- 27. Linear IgA bullousdisease • 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.
- 28. Dermatitis herpetiformis • Avery 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, gliadin and endomysium • The IgA deposits in skin clear slowly after the introduction of a gluten-free diet. • There is a strong association with certain human leucocyte antigen (HLA) types, particularly HLA-DR3 and HLA-DQw2.
- 29. Presentation • The extremelyitchy, 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 a secondary eczematous dermatitis develops from fierce scratching. Thus, the name ‘dermatitis’ comes from scratching, and ‘herpetiformis’ comes from grouping of vesicles and crusts.
- 32. Course • Typically lastsfor 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.
- 33. Investigations • Histology willbe 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.
- 34. Treatment • A gluten-freediet, Adherence can be monitored using the titre of antibodies to anti-endomysial antigens 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.
- 35. Toxic epidermal necrolysis(Lyell’s disease) Cause • usually a drug reaction, most commonly to sulphonamides, lamotrigine, barbiturates, carbamazepine or allopurinol • graft-vs.-host disease • AIDs Presentation • 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.
- 37. Course • The conditionusually 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.
- 38. Differential diagnosis • Staphylococcalscalded 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.
- 39. Treatment • The drugmust 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 ciclosporin treatment has been associated with a decreased mortality rates. • Plasmapheresis may remove triggering drugs, or inflammatory mediators.
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