Blistering skin diseases

Learning objectives
Introduction
Inherited blistering diseases
Immunobullous eruptions
Management
Activity

Learning objectives

• Recognise and classify blistering skin diseases

Introduction

Blisters are accumulations of fluid within or under the epidermis. Diagnosis depends on the site of the intercellular split as shown in the table below.

Blisters and the site of intercellular split

Site of blister	Characteristics	Differential diagnosis	Image
Subcorneal	Very thin roof breaks easily	Impetigo, miliaria, SSSS	Miliaria
Intra-epidermal	Thin roof ruptures to leave denuded surface	Acute eczema, varicella, herpes simplex, pemphigus	Eczema
Subepidermal	Tense roof often remain intact	Bullous pemphigoid, dermatitis herpetiformis, erythema multiforme, TEN, friction blisters	Systemic lupus erythematosus

SSSS: Staphylococcal scalded skin syndrome
TEN: Toxic epidermal necrolysis

Imherited blistering diseases

Epidermolysis bullosa (EB) refers to a group of inherited disorders in which there are mutations in specific keratin proteins (EB simplex), hemidesmosomes (junctional EB), anchoring filaments or type VII collagen (dystrophic EB). Minor trauma results in blisters and erosions, the split site and severity depending on the specific defect.

Varying presentations of epidermolysis bullosa

Immunobullous eruptions

There are at least 9 distinct immunobullous diseases due to autoantibodies directed at differing components of the desmosome complex. Skin biopsy and direct immunofluorescence are diagnostic and there may be detectable circulating skin antibodies. High dose corticosteroids and immunosuppressive medication may be required for control.

Bullous pemphigoid

Bullous pemphigoid is the most common immunobullous disease and affects the elderly. Early signs include various subacute itchy rashes on any site, particularly the flexures (submamammary, inguinal):

• Dermatitis-like: dry or exudative discoid eczema
• Urticaria-like: erythematous urticated plaques
• Non-specific: patchy erythema and/or dryness

Eventually (days to weeks) the plaques evolve into subepidermal bullae, or these may arise from apparently normal skin.

• Tense fluid-filled clear or haemorrhagic blisters
• Erosions and crusted lesions
• Excoriations and bruising

Purulent lesions may or may not indicate secondary infection (staphylococcal and/or streptococcal), and in such cases spreading erythema may or may not be due to cellulitis.

Varying presentations of bullous pemphigoid

Dermatitis herpetiformis

Dermatitis herpetiformis mostly affects young adults but may present at any age as a chronic prurigo. It mainly affects scalp, elbows, buttocks, knees and shoulders. Diagnosis is made by skin biopsy and rapid improvement on dapsone. Signs include:

• Papules
• Vesicles
• Crusted excoriations

Despite distressing itch, signs may be quite subtle (hence few photographs available!).

Dermatitis herpetiformis (DH) is associated with gluten-sensitive enteropathy in most cases (at least 85%) although this may be asymptomatic. Symptoms (in 10%) include:

• Bloating
• Abdominal pain
• Diarrhoea
• Weight loss
• Failure to thrive

Dermatitis herpetiformis

Pemphigus

Pemphigus has at least 7 subtypes caused by pathogenic IgG antibodies to intraepidermal cell adhesion molecules. It is diagnosed by clinical presentation and skin biopsy. The most common subtypes are:

• Pemphigus vulgaris
• Pemphigus foliaceus

Pemphigus vulgaris is potentially fatal; it usually presents with acute or subacute extensive oral ulceration followed by widespread cutaneous denudation. It appears to be particularly common in middle-aged patients from the Indian subcontinent.

Pemphigus foliaceus affects the elderly and presents with erosions affecting primarily seborrhoeic areas (scalp, face, chest). It is much less severe than pemphigus vulgaris.

Pemphigus may be precipitated by:

• Drugs (with or without antibody formation): penicillamine, captopril, enalapril and others
• Neoplasia: lymphoma, bronchogenic squamous cell carcinoma and others

Pemphigus

Oral pemphigus	Pemphigus vulgaris	Pemphigus foliaceus
Paraneoplastic pemphigus

Other immunobullous diseases

Other rare immunobullous diseases include:

• Pemphigoid gestationis: bullous eruption of pregnancy (autoantibodies directed against BP180 antigen)
• Cicatricial (benign mucosal) pemphigoid: blisters affecting mouth, nose, eyelids and genitocrural sites that form scars (autoantibodies directed against anchoring filaments)
• Epidermolysis bullosa acquisita: blistering following trauma (autoantibodies directed against NC1 domain of type VII collagen)
• Linear IgA dermatosis: annular blistering

Rare immunobullous diseases

Pemphigoid gestationis

Cicatricial pemphigoid

Epidermolysis bullosa acquisita

Linear IgA dermatosis

Investigations

Skin biopsy and direct immunofluorescence (DIF) are crucial for diagnosis of immunobullous diseases.

Disease	Biopsy features	DIF
Bullous pemphigoid	Subepidermal oedema/blister Mixed perivascular infiltrate with eosinophils	Linear IgG, C3 in BMZ (lamina lucida)
Dermatitis herpetiformis	Subepidermal vesicles Mixed papillary infiltrate with eosinophils	Granular IgA in tips of papillae
Pemphigus vulgaris	Suprabasal acantholytic vesicle (tombstone pattern) Mixed perivascular infiltrate with eosinophils	IgG within suprabasal intercellular spaces
Pemphigus foliaceus	Subcorneal acantholytic vesicle (tombstone pattern) Mixed perivascular infiltrate with eosinophils	IgG within upper epidermal intercellular spaces
Paraneoplastic pemphigus	Suprabasal acantholytic vesicle (tombstone pattern) Keratinocyte necrosis Mixed perivascular infiltrate with eosinophils	IgG within epidermal intercellular spaces and BMZ
Pemphigoid gestationis	Spongiotic dermatitis Subepidermal oedema/blister Mixed perivascular infiltrate with eosinophils	Linear C3 in BMZ (lamina lucida)
Cicatricial pemphigoid	Subepidermal blister Mixed perivascular infiltrate with plasma cells and eosinophils	Linear IgG, C3 in BMZ (lamina lucida)
Epidermolysis bullosa acquisita	Subepidermal blister Sparse inflammatory infiltrate	Linear IgG, C3 in BMZ (upper dermis)
Linear IgA dermatosis	Subepidermal blister Mixed papillary/perivascular infiltrate with eosinophils	Linear IgA, C3 in BMZ

BMZ: basement membrane zone
EM: electron microscopy

Other tests

Specific immunoreactive proteins detected using histochemistry on skin biopsies are beyond the scope of this article, and they are not evaluated in routine clinical practice.

There may be circulating ‘skin antibodies’ in immunobullous diseases. These are detected by indirect immunofluoresce of serum.

Dermatitis herpetiformis

Additional investigations to detect gluten enteropathy should include:

• Serum IgA autoantibodies to reticulin, gliadin and/or endomysium
• Iron and folate (malabsorption can be detected in 20% patients with DH)
• Refer to gastroenterologist for small bowel endoscopy and biopsy

Management

Dermatitis herpetiformis

• Dapsone: doses of 50-300mg daily rapidly controls itching and blistering
• Gluten-free diet: required long term for control (avoid barley, rye, and wheat)
• Refer to Coeliac Society for help

Other immunobullous diseases

Control of immunobullous diseases can be very challenging and is best left to a dermatologist. Maintenance therapy is usually required for years if not lifelong and is likely to result in significant complications.

• Systemic steroids: prednisone 40 - 100mg daily; pulsed IV methyl prednisolone.
  • Bone prophylaxis requires DEXA scan, calcium and biphosphonates
  • May precipitate diabetes, hypertension etc
• Ultrapotent topical steroids
  • Unsuitable for widespread disease
• Tetracyclines: doxycycline or minocycline 200mg daily
• Niacinamide
• Other antibiotics: dapsone, salazopyrin, erythromycin
• Immunosuppressive agents: azathioprine, methotrexate, chlorambucil, cyclosporin, tacrolimus, mycophenolate mofetil, cyclophosphamide
  • Monitor bp and blood (CBC, LFT, Renal function, lipids etc)
• Intravenous immunoglobulin (very expensive)
• Plasma exchange

Activity

Describe the adverse effects of dapsone.

Page 8 of 8. End of course. Back to: Dermatological emergencies course contents.