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Vesiculobullous disease 

Vesiculobullous disease
Chapter:
Vesiculobullous disease
Author(s):

Fenella Wojnarowska

DOI:
10.1093/med/9780199204854.003.2304

November 28, 2013: This chapter has been re-evaluated and remains up-to-date. No changes have been necessary.

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Essentials

The autoimmune blistering diseases have a dramatic clinical presentation, and are significant diseases with substantial morbidity and mortality.

The diseases can be split broadly pathologically into intraepidermal (pemphigus) and subepidermal (pemphigoid, dermatitis herpetiformis and others) groups, the former being characterized by pathogenic autoantibodies to desmosome components, and the latter by pathogenic antibodies to proteins of the basement membrane zone adhesion complex that link the epithelium/epidermis to the underlying mesenchyme/dermis (or genetic mutations of the same proteins). There are concomitant differences in clinical presentation, e.g. blistering lesions present in the subepidermal bullous diseases tend to be less easily ruptured than those observed in intraepidermal bullous diseases.

Treatment is often difficult, e.g. pemphigus vulgaris requires potent topical steroids and often systemic corticosteroids (e.g. prednisolone 45–60 mg/day), bullous pemphigoid requires topical steroids and often anti-inflammatory antibiotics or systemic corticosteroids, with both needing immunosuppressive or immunomodulatory treatments in difficult cases.

Introduction

The autoimmune vesiculobullous diseases are frequently caused by autoantibodies directed against the structural components of the skin (Tables 23.4.1 and 23.4.2, Figs. 23.4.1 and 23.4.2). The intraepidermal diseases are characterized by autoantibodies to desmosome components, the subepidermal blistering diseases by antibodies to proteins of the basement membrane zone adhesion complex that link the epithelium/epidermis to the underlying mesenchyme/dermis. Genetic counterparts for these diseases exist in which the same structural protein is mutated, also resulting in blistering (see Chapter 23.3). There is evidence for most of the autoimmune blistering diseases that the antibodies are pathogenic.

Table 23.4.1 Major vesiculobullous dermatoses

Dermatosis

Frequency

Target structure

Target antigen

Intraepidermal

Pemphigus vulgaris

Uncommon in western Europe

Desmosome

Desmoglein 1 and 3

Pemphigus foliaceus

Uncommon in western Europe

Desmosome

Desmoglein 1

Paraneoplastic pemphigus

Very rare

Desmosome

Plakins

Subepidermal

Bullous pemphigoid

Most common in Western Europe

Hemidesmosome

BP230 (BPAg1); BP180 (BPAg2)

Mucous membrane pemphigoid

Uncommon

Hemidesmosome anchoring filament

α‎6β‎4 integrins; BP180; laminin 5

Pemphigoid gestationis

1:50 000 pregnancies

Hemidesmosome

BP180

Linear IgA disease

Uncommon

Hemidesmosome

BP180 and its shed ectodomain

Epidermolysis bullosa acquisita

Rare

Anchoring fibril

Collagen VII

Dermatitis herpetiformis

Uncommon

Microfibrils

Unknown

Table 23.4.2 Clinical features of vesiculobullous dermatoses

Dermatosis

Clinical features

Immunofluorescence

First-line therapy

Intraepidermal

Pemphigus vulgaris

Oral and other mucosal erosions; superficial blisters and erosions

Intercellular IgG in epithelium and oral mucosa

Steroids

Pemphigus foliaceus

Superficial erosions

Intercellular IgG in epithelium

Steroids

Paraneoplastic pemphigus

Severe mucosal lesions; blistering of skin

Intercellular and basement membrane zone IgG in epithelium and rat bladder

Unresponsive

Subepidermal

Bullous pemphigoid

Tense blisters

Basement membrane zone IgG

Steroids

Mucous membrane pemphigoid

Mucosal blisters and erosions

Basement membrane zone IgG and IgA

Steroids; dapsone; cyclophosphamide

Pemphigoid gestationis

Tense blisters

Basement membrane zone IgG

Steroids

Linear IgA disease

Tense blisters; some mucosal lesions

Basement membrane zone IgA

Dapsone

Epidermolysis bullosa acquisita

Tense blisters; scarring

Basement membrane zone IgG

Steroids

Dermatitis herpetiformis

Uncommon

IgA granules in dermal papillae

Dapsone; gluten-free diet

Fig. 23.4.1 The desmosome and its target antigens.

Fig. 23.4.1
The desmosome and its target antigens.

Fig. 23.4.2 The basement membrane zone of the skin and mucosa.

Fig. 23.4.2
The basement membrane zone of the skin and mucosa.

Historical perspective

Blisters are referred to in early Greek and Arabic medical texts because of their striking clinical appearance. Differentiation of the diseases was difficult until the 1960s, when immunofluorescence enabled the detection of circulating and bound skin antibodies. This lead to the identification of their target antigens (Table 23.4.1), driven by interested clinician scientists who made the clinicopathological correlations that have illuminated the molecular biology of blistering diseases.

The individual diseases (Tables 23.4.1, 23.4.2, and 23.4.3) are described in detail below.

Table 23.4.3 Differential diagnosis of vesiculobullous dermatoses

Diagnosis

Frequency

Typical patient/circumstances

Intraepidermal

Impetigo

Common

Children >adults

Staphylococcal scalded skin syndrome

Rare

Child <10 years

Toxic epidermal necrolysis

Rare

Usually drug induced

Subepidermal

Viral infections

Herpes simplex

Common

Children >adults

Varicella–zoster virus

Common

  • Chickenpox: children >adults

  • Shingles: adults >children

Trauma

Common

Burns

Common

Insect bites

Common

Eczema

Common

Erythema multiforme

Common

  • Infections, e.g. herpes simplex

  • Drugs

Oedema blisters

Common

Oedematous legs

Drugs

Fixed drug eruption

Rare

e.g. paracetamol

Bullous reactions

Rare

e.g. furosemide, clindamycin

Pseudoporphyria cutanea tarda

Very rare

Drugs

Porphyria cutanea tarda

Rare

Liver damage, e.g. alcohol

Intraepidermal diseases: the pemphigus group

The intraepidermal diseases: pemphigus vulgaris, pemphigus foliaceus, and paraneoplastic pemphigus are characterized by autoantibodies to desmosome components, resulting in separation of the cells within the epithelium, so the blister roofs are thin and easily ruptured, forming erosions.

Pemphigus vulgaris

Aetiology, genetics, pathogenesis, and pathology

Pemphigus vulgaris is mediated by autoantibodies to desmoglein 3, the major adhesion molecule in the mucosa, neonatal epidermis, and basal layers of the epidermis (Fig. 23.4.1). These antibodies result in mucosal blistering, particularly prominent in the mouth, and in the skin of the neonate as a result of transplacental transmission of maternal antibodies. In addition, most patients also develop antibodies to desmoglein 1, which is the major adhesion molecule in the upper layers of the epidermis. The antibodies to desmoglein 1 and 3 result in the loss of cohesion in the epidermis, and splitting of the epidermis at the basal layer. Their pathogenicity has been demonstrated by transplacental transmission and animal models. Pemphigus vulgaris is associated with HLA class II antigens and with polymorphisms of desmoglein 3 in several racial groups.

The disease occurs worldwide, but is most common in the Middle East (Arabs, Iranians, Jews), Southeast Asia, and China. This susceptibility persists when these populations move to the West. It is rarer in northwestern Europe than in southern and eastern Europe.

Clinical features

The disease usually presents with mouth ulceration. The palate, gums, tongue, and buccal mucosa manifest painful erosions (Fig. 23.4.3). Eating is a problem and patients lose weight. The genitals may have similar erosions. The skin lesions are particularly common on the face, scalp, and upper torso, and are coin-sized thin-walled blisters that rapidly rupture to form erosions with a red base (Fig. 23.4.4), although in the healing phase they may become more scaly and heaped. In severe uncontrolled disease the patients lose fluid and may die from uncontrolled sepsis.

Fig. 23.4.3 Erosions on the palate in pemphigus vulgaris.

Fig. 23.4.3
Erosions on the palate in pemphigus vulgaris.

Fig. 23.4.4 Characteristic skin erosions in pemphigus vulgaris.

Fig. 23.4.4
Characteristic skin erosions in pemphigus vulgaris.

The diagnosis is made by the histological examination of an early blister or erosion, showing splitting of the epidermis above the basal layer with individual rounded cells (acantholysis). The gold standard is direct immunofluorescence testing (see Chapter 23.2) of perilesional skin or mucosa, and indirect immunofluorescence testing of serum on normal human skin or monkey oesophagus, demonstrating binding to the surface of the epidermal cells (Fig. 23.4.5), and in some centres, enzyme-linked immunosorbent assays (ELISA).

Fig. 23.4.5 Immunofluorescence demonstrating antibody binding in the epidermis in pemphigus.

Fig. 23.4.5
Immunofluorescence demonstrating antibody binding in the epidermis in pemphigus.

Treatment

Treatment is according to British Association of Dermatologists guidelines (see ‘Further reading’). Initial treatment is with potent topical steroids, and if necessary systemic steroids, e.g. prednisolone 45 to 60 mg per day. Adjuvant treatment with azathioprine, mycophenolate mofetil, cyclophosphamide, and tetracyclines is used, and in recalcitrant cases rituximab and intravenous immunoglobulins (IVIG). Remission occurs in 75% of patients, but may take 10 years or more.

Pemphigus foliaceus

Aetiology, genetics, pathogenesis, and pathology

Pemphigus foliaceus is mediated by autoantibodies to desmoglein 1, which is the major adhesion molecule in the upper layers of the epidermis (Fig. 23.4.1), but not in mucous membranes. The antibodies to desmoglein 1 result in loss of cohesion in the epidermis, and superficial splitting. Their pathogenicity has been demonstrated in animal models. In staphylococcal scalded skin syndrome (Chapters 7.6.4 and 23.10), a bacterial protease digests desmoglein 1, explaining the clinical similarity. Pemphigus foliaceus associations with HLA class II antigens have been found.

The disease is common in North Africa, the Middle East, Southeast Asia, and China. There is an endemic form in Brazil, which has a characteristic distribution along rivers in rural areas, altering with development. Many members of a household may be affected, suggesting that a bloodsucking insect is the vector for the disease (Chapter 7.12). In North Africa there is an unexplained female predominance. Drug triggers include penicillamine and other drugs with sulfhydryl groups.

Clinical features

This disease only affects the skin; the mucosae are spared. The face and upper trunk are commonly affected (Chapter 7.12, Fig. 1). The superficial layers of the skin split, giving coin-sized red scaly lesions. The diagnosis is made by histology showing superficial splitting of the epidermis. Direct and indirect immunofluorescence show binding to the surface of the epidermal cells (Fig. 23.4.5), and ELISA can also demonstrate antibodies to desmoglein 1.

Treatment

Initial treatment is with very potent topical steroids, and in all but the mildest cases systemic steroids (prednisolone 20–60 mg). In severe cases immunosuppressants may be required. The disease runs a prolonged course, but most patients eventually remit. It is likely that the presence of endemic foci will lead to the identification of an environmental trigger for this autoimmune disease.

Paraneoplastic pemphigus

This rare condition was not recognized until the 1980s, previous cases having been misdiagnosed as severe drug reactions or pemphigus.

Aetiology, genetics, pathogenesis, and pathology

The condition occurs in the setting of myeloproliferative disorders, in some cases linked to treatment with fludarabine, other malignancies, or Castleman’s syndrome. There are autoantibodies to plakins, which are components of the desmosomes (Fig. 23.4.1), in the skin, transitional epithelium, and other epithelia.

Clinical features

The patients present with severe mucosal disease with erosions and ulceration of the oropharynx, and often also the eyes and genitalia. Skin involvement with tense blisters on the palms and soles, and around the nails, is characteristic. There may be generalized involvement, with denuding of large areas, or occasionally a lichenoid type of eruption. There may be involvement of multiple organs, and respiratory disease may be a late cause of death. Often the patient is known to have lymphoproliferative disease or other malignancy.

Histology shows splitting low in the epidermis. Immunofluo-rescence shows antibodies binding to epidermal cells and the basement membrane zone of skin and the transitional epithelium of rat bladder. The patient will require investigation for underlying lymphoma, other malignancy, or Castleman’s disease.

Treatment

Treatment is directed at the underlying condition, combined with immunosuppression to reduce the skin and mucosal disease. The prognosis is poor, and most patients die.

Subepidermal diseases: the pemphigoid group and others

The subepidermal blistering diseases are the pemphigoid group: bullous pemphigoid, pemphigoid gestationis (see Chapter 14.13), mucous membrane pemphigoid, linear IgA disease and also, epidermolysis bullosa acquisita, and dermatitis herpetiformis. This group is characterized by the presence of autoantibodies to structural components of the basement membrane zone (Fig. 23.4.2 and Tables 23.4.1 and 23.4.2) that result in separation of the epidermis/epithelium from the dermis/mesenchyme, so that the blister roofs are thick, and intact blisters are seen. Dermatitis herpetiformis is the exception, and involves antibodies to epidermal transglutaminases.

Bullous pemphigoid

This is the most common blistering disease in the West.

Aetiology, genetics, pathogenesis, and pathology

The trigger for bullous pemphigoid is unknown, although in a few patients drugs or local trauma to the skin, e.g. an operation or radiotherapy, may initiate the disease. The disease is mediated by IgG autoantibodies to BP230 (bullous pemphigoid antigen 1; dystonin) and BP180 (bullous pemphigoid antigen 2; collagen XVII), components of the hemidesmosome (Fig. 23.4.2). Animal models have shown the antibodies to be pathogenic, and in the closely related condition pemphigoid gestationis (see Chapter 14.13), the transplacental transmission of the disease to the neonate has confirmed pathogenicity in humans. The combination of the autoantibody with the target antigen triggers an inflammatory cascade, the binding of complement, and separation of the epidermis from the dermis, visible as a blister.

Bullous pemphigoid occurs at a rate of 7 to 30 per million. It is a disease of older people, and there is an association with neurological disease, particularly multiple sclerosis in younger patients, and dementia, cardiovascular disease and Parkinson’s disease in older patients.

Clinical features

The first symptom is itching. There may be a long prodromal period of weeks to years, with itching, transient urticarial lesions, or eczematous patches. When the blisters appear the diagnosis is obvious. Tense clear blisters, which may be several centimetres in size, arise from normal skin or large raised red areas (Fig. 23.4.6). The eruption is symmetrical and typically flexural, often around the groins and inner thighs, and may be attributed to a catheter rash. The mouth may have asymptomatic blisters and erosions.

Fig. 23.4.6 Large blisters, vesicles, and red plaques in bullous pemphigoid.

Fig. 23.4.6
Large blisters, vesicles, and red plaques in bullous pemphigoid.

The diagnosis is made clinically, and confirmed by histopathology performed on a small fresh blister, ideally taken within a 4 mm punch biopsy. This shows a subepidermal blister with intact epidermis overlying it. Direct immunofluorescence testing of perilesional skin, and indirect immunofluorescence testing of serum or blister fluid (useful in patients with mental incapacity) demonstrates the binding of IgG antibodies and complement C3 to the basement membrane (Fig. 23.4.7), with binding to the epidermal side of salt-split skin. An ELISA to detect BP180 antibodies is available in some centres.

Fig. 23.4.7 IgG autoantibodies binding to the basement membrane zone in bullous and mucous membrane pemphigoid.

Fig. 23.4.7
IgG autoantibodies binding to the basement membrane zone in bullous and mucous membrane pemphigoid.

Treatment

In the United Kingdom there are national guidelines for treatment (see ‘Further reading’). Topical steroids are the standard treatment, combined if necessary with anti-inflammatory antibiotics (tetracyclines or erythromycin) or systemic steroids (prednisolone 20–60 mg). Immunosuppressants are added if control is difficult, azathioprine or mycophenolate mofetil most commonly, and rarely immune therapy such as IVIG, plasmapheresis, or rituximab. The aim of treatment is to suppress the disease so the patient is comfortable, the occasional blister indicating that the patient is not being over treated. The treatment is slowly tapered once the disease has been controlled. The disease usually remits within 3 to 5 years, but may be more prolonged. Mortality and morbidity are significant, and are related to steroid and immunosuppressive therapy.

With the ageing population, bullous pemphigoid will become a greater problem, and rapid safer treatments would be a great advantage. It is likely that future biological therapies will revolutionize treatment.

Mucous membrane pemphigoid (previously cicatricial pemphigoid)

This is a rare blistering disease. The patients present to multiple specialities: dermatology, oral medicine, ophthalmology, otolaryngology, and gynaecology. An international consensus in 2002 defined the disease.

Aetiology, genetics, pathogenesis, and pathology

The disease is mediated by IgG and IgA autoantibodies to BP180, BP230, or α‎6β‎4 integrin subunits in the hemidesmosome, or to laminin 5 or collagen VII in the adhesion complex (Table 23.4.1, Fig. 23.4.2). A dual IgG and IgA response is associated with a poorer prognosis. Experimental models have confirmed the pathogenicity of the antibodies. The combination of the antibody with antigen triggers an inflammatory cascade that results in separation of the epidermis/epithelium from the dermis/mesenchyme, and scarring.

Mucous membrane pemphigoid occurs at a rate of 1 per million, in middle aged and older people, although cases have been described in children and teenagers. There is an association with autoimmune disease, and laminin 5 mucous membrane pemphigoid has been associated with malignancy.

Clinical features

The disease predominately affects the mucosal surfaces, usually several sites, and there may additionally be skin involvement. The oral mucosa is often the first affected, with desquamative gingivitis (Fig. 23.4.8), shedding of the epithelium of the gums, giving a bright red appearance, and blisters and erosions on the buccal mucosa and the palate. This makes eating painful, and patients may lose weight. There may be hoarseness, choking, and coughing because of involvement of the oropharynx and larynx; involvement of the trachea can lead to stridor, and because of the risk of asphyxiation a tracheostomy may be necessary. Eye involvement presents with conjunctivitis and scarring, leading to symblepharon and blindness (Fig. 23.4.9), which can be rapid. Blistering and scarring of the genitals can interfere with sexual function and micturition. Skin involvement is often localized, and repeated blistering at the same site causes scarring.

Fig. 23.4.8 Desquamative gingivitis of the gums.

Fig. 23.4.8
Desquamative gingivitis of the gums.

Fig. 23.4.9 End stage ocular disease, showing scarring and symblepharon.

Fig. 23.4.9
End stage ocular disease, showing scarring and symblepharon.

The diagnosis is made clinically, and is difficult to confirm. Histology should be performed on a fresh blister. Perilesional mucosa or skin shows basement membrane antibodies on direct immunofluorescence, and serum for indirect immunofluorescence demonstrates low titre antibodies. On salt-split skin the antibodies bind to the epidermal side of the split (BP180, BP230, α‎6β‎4 integrin subunits) or to the dermal side (laminin 5, collagen VII). An ELISA is available to detect BP180 antibodies.

Treatment

A Cochrane review revealed that the evidence base for treatment was small. The international consensus discussed treatment, which is often disappointing. Topical steroids are helpful for symptom relief; systemic therapy is usually needed. Systemic steroids, anti-inflammatory antimicrobials (dapsone, sulfonamides, tetracyclines, or erythromycin), immunosuppressants, and azathioprine are most commonly used, but the best evidence is for cyclophosphamide, immunomodulators, IVIG, plasmapheresis, and rituximab. The aim of treatment is to suppress the disease to make the patient comfortable and prevent catastrophic scarring.

The disease runs a very prolonged course over decades, although it may burn out in some patients. Morbidity from mucosal scarring is significant, and is difficult to prevent even with aggressive treatment.

Linear IgA disease (linear IgA bullous dermatosis, chronic bullous disease of childhood)

This is an uncommon blistering disease in the West, and is unusual in being mediated by IgA antibodies.

Aetiology, genetics, pathogenesis, and pathology

The trigger in a few patients is drugs (e.g. vancomycin, diclofenac) or infections. The disease is mediated by IgA autoantibodies to BP180 and its physiologically shed ectodomain, BP230, and LAD285, components of the hemidesmosome (Fig. 23.4.2). It is strongly associated with the autoimmune haplotype HLA B8, DR3.

Linear IgA disease occurs at a rate of 0.5 per million. It is a disease of young children, often preschool, and there is a second peak in older people. There are large series of children from northern Africa, South Africa, and Sri Lanka.

Clinical features

Usually the onset is abrupt, with either blisters or red lesions; in adults there may be scattered groups of small papulovesicles. The lesions are typically annular, with blistering at the edges (Fig. 23.4.10). The symptoms are burning and itching. Involvement of the genitals is common in young children, and the trunk is usually affected. The mouth may have blisters and erosions.

Fig. 23.4.10 Annular blistering lesions in linear IgA disease.

Fig. 23.4.10
Annular blistering lesions in linear IgA disease.

The diagnosis is usually made clinically, confirmed by histopathology performed on a small fresh blister. Normal skin tested by direct immunofluorescence, and serum tested by indirect immunofluorescence demonstrate the binding of IgA antibodies to the basement membrane.

Treatment

Antimicrobials are the mainstay of treatment (dapsone or the sulfonamides sulfamethoxypyridazine and sulfapyridine), but some patients respond to anti-inflammatory antibiotics (tetracyclines or erythromycin). Rarely, systemic steroids or immunosuppressants are required. The disease usually remits within 3 to 5 years, but may be more prolonged.

Epidermolysis bullosa acquisita

This is one of the rarest blistering diseases.

Aetiology, genetics, pathogenesis, and pathology

Epidermolysis bullosa acquisita is sometimes associated with inflammatory bowel disease. The disease is mediated by IgG autoantibodies to collagen VII, the anchoring fibril (Fig. 23.4.6), which are pathogenic in animal models. Epidermolysis bullosa acquisita occurs at a rate of less than 0.25 per million in Western Europe. It may be more common in other regions.

Clinical features

Usually the onset is abrupt, with typically mechanobullous blisters (i.e. induced by trauma) on the hands, feet, knees and elbows. The tense blisters heal with scarring and milia (small keratin inclusion bodies) (Fig. 23.4.11). The nails may be scarred and destroyed. Mucosal involvement may be prominent, and some patients have a mucous membrane pemphigoid phenotype.

Fig. 23.4.11 Blisters, scarring, milia, and nail damage.

Fig. 23.4.11
Blisters, scarring, milia, and nail damage.

The diagnosis is made clinically and confirmed by histopathology. Direct immunofluorescence and indirect immunofluorescence testing demonstrate the binding of IgG antibodies to the basement membrane and the dermal side of split skin (Fig. 23.4.12). The demonstration of antibodies to collagen VII is essential for diagnosis.

Fig. 23.4.12 IgG antibodies binding to the dermal side of the basement membrane zone of split skin.

Fig. 23.4.12
IgG antibodies binding to the dermal side of the basement membrane zone of split skin.

Treatment

Treatment is difficult, and a Cochrane review found almost no reports. Dapsone or sulfonamides (sulfamethoxypyridazine or sulfapyridine) with systemic steroids can be effective, but immunosuppressants or IVIG are usually required. The disease is severe and prolonged in most cases, with scarring impairing function.

Dermatitis herpetiformis

This is a manifestation of coeliac disease, although the connection was unrecognized until the 1960s.

Aetiology, genetics, pathogenesis, and pathology

Dermatitis herpetiformis is gluten dependent (see Chapter 15.10.3). However, the mechanism by which gluten causes the skin to blister is unclear. The only autoantibodies that distinguish it from coeliac disease are IgA epidermal transglutaminases, and it may be an immune complex-mediated disease. There is a strong association with HLA DQ2 or 7, and 10% of patients have a family history of dermatitis herpetiformis or coeliac disease. The frequency of this condition is highest in western Ireland, Scandinavia, and Hungary. It is rare in non-European populations. Methods to reduce the incidence of coeliac disease would be predicted to reduce the incidence of dermatitis herpetiformis.

Clinical features

The onset is usually sudden in young adults, although childhood cases are common in Italy and Hungary, and older people can present with it. Small, intensely itchy papules and vesicles develop on the extensor surfaces of the knees, elbows, buttocks, and trunk. In partially controlled disease the lesions are often found on the scalp and chin. The lesions are so intensely itchy that it is rare to see an intact blister. There may be other autoimmune diseases present.

Histology of a fresh lesion shows papillary microabscesses filled with neutrophils. Direct immunofluorescence testing demonstrates granular deposits of IgA in the papillary dermis (Fig. 23.4.13), which are essential for diagnosis. As in coeliac disease, antiendomysial and antitransglutaminase antibodies should be sought, and the patient investigated for malabsorption and other autoimmune diseases.

Fig. 23.4.13 Characteristic granular IgA deposits in the papillary dermis.

Fig. 23.4.13
Characteristic granular IgA deposits in the papillary dermis.

Treatment

The treatment of choice is a gluten-free diet (see Chapter 15.10.3) although the malabsorption improves within weeks, the skin will not usually clear until after 2 years of strict gluten avoidance. The ingestion of gluten causes recurrence of the itching and lesions. Dapsone or sulfonamides (sulfamethoxypyridazine or sulfapyridine) will switch off the disease in 24 to 48 h, and may be slowly reduced as the gluten-free diet takes effect. Remission is dependent on strict gluten avoidance, and those electing not to have gluten-free diet will need lifelong treatment. There is an increased susceptibility to lymphoma.

Further reading

Anhalt GJ, et al. (1990). Paraneoplastic pemphigus. An autoimmune mucocutaneous disease associated with neoplasia. N Engl J Med, 20, 1729–35.Find this resource:

Aoki V, et al. (2004). Environmental risk factors in endemic pemphigus foliaceus (fogo selvagem). J Investig Dermatol Symp Proc, 9, 34–40.Find this resource:

Chan LS, et al. (2002). The first international consensus on mucous membrane pemphigoid: definition, diagnostic criteria, pathogenic factors, medical treatment, and prognostic indicators. Arch Dermatol, 138, 370–9.Find this resource:

Collin P, Reunala T (2003). Recognition and management of the cutaneous manifestations of celiac disease: a guide for dermatologists. Am J Clin Dermatol, 4, 13–20.Find this resource:

Fry L, et al. (1968). Effect of gluten-free diet on dermatological, intestinal, and haematological manifestations of dermatitis herpetiformis. Lancet, 16, 557–61.Find this resource:

Giudice GJ, et al. (1993). Bullous pemphigoid and herpes gestationis autoantibodies recognize a common non-collagenous site on the BP180 ectodomain. J Immunol, 151, 5742–50.Find this resource:

Harman KE, Albert S, Black MM (2003). Guidelines for the management of pemphigus vulgaris. Br J Dermatol, 149, 926–37.Find this resource:

Khumalo N, et al. (2005). Interventions for bullous pemphigoid. Cochrane Database Syst Rev, 3, CD002292.Find this resource:

Kirtschig G, et al. (2003). Interventions for mucous membrane pemphigoid and epidermolysis bullosa acquisita. Cochrane Database Syst Rev, 1, CD004056.Find this resource:

Liu Z, et al. (1993). A passive transfer model of the organ-specific autoimmune disease, bullous pemphigoid, using antibodies generated against the hemidesmosomal antigen, BP180. J Clin Invest, 92, 2480–8.Find this resource:

Stanley JR, Amagai M (2006). Pemphigus, bullous impetigo, and the staphylococcal scalded-skin syndrome. N Engl J Med, 26, 1800–10.Find this resource:

Takahashi Y, et al. (1985). Experimentally induced pemphigus vulgaris in neonatal BALB/c mice: a time-course study of clinical, immunologic, ultrastructural, and cytochemical changes. J Invest Dermatol, 84, 41–6.Find this resource:

Wojnarowska F, et al. (1988). Chronic bullous disease of childhood, childhood cicatricial pemphigoid, and linear IgA disease of adults. A comparative study demonstrating clinical and immunopathologic overlap. J Am Acad Dermatol, 19, 792–805.Find this resource:

Wojnarowska F, et al. (2002). British Association of Dermatologists guidelines for the management of bullous pemphigoid. Br J Dermatol, 147, 214–21.Find this resource: