Bullous disorders (pemphigus, pemphigoid, dermatitis herpetiformis)

Overview

Most blisters are due to infection (herpes, chickenpox, impetigo), insect bites, burns, friction or eczema (pompholyx). A small group are due to autoantibodies against the proteins that hold skin together (immunobullous diseases) or to inherited defects of those proteins (epidermolysis bullosa).

The key to every question is the level of the split:

• Intraepidermal (within the epidermis) → thin roof → flaccid blisters and erosions → pemphigus.
• Subepidermal (below the epidermis) → thick roof → tense blisters → pemphigoid, dermatitis herpetiformis, linear IgA disease.

Investigations in blistering disease

• Skin biopsy from the edge of a fresh blister for histology (level of split, acantholysis, inflammatory cells).
• Direct immunofluorescence (DIF) on perilesional (normal-looking) skin shows where antibodies are bound. This is the key test.
• Indirect immunofluorescence and ELISA on serum detect circulating antibodies (e.g. anti-desmoglein, anti-BP180); titres in pemphigus follow disease activity.
• Tzanck smear from a blister base: rounded, separated acantholytic cells in pemphigus; multinucleated giant cells in herpes.

Pemphigus

Pemphigus vulgaris

Who: adults, usually in middle age, more common in people from the Indian subcontinent and Ashkenazi Jews. It is rare but potentially fatal without treatment.

Cause: IgG autoantibodies (mainly IgG4) against desmoglein 3 (and often desmoglein 1), proteins of the desmosomes that join keratinocytes. Cells separate (acantholysis) just above the basal layer.

Clinical features:

• Oral erosions are common and are the first sign in up to half of patients; painful, slow-healing ulcers in the mouth, often for months before skin lesions.
• Other mucosa: eyes, nose, larynx, genitals.
• Flaccid blisters on normal-looking skin that burst easily, leaving large, painful, weeping erosions and crusts (scalp, face, chest, flexures).
• Nikolsky sign positive: gentle sideways pressure on normal-looking skin shears off the epidermis.
• Asboe-Hansen (bulla spread) sign: pressing on a blister makes it spread sideways.
• Usually not itchy but painful.

Drug-induced pemphigus: penicillamine, captopril and other thiol drugs; usually foliaceus type.

Other forms

• Pemphigus foliaceus: antibodies only to desmoglein 1, which is present in the upper epidermis but not in oral mucosa, so the mouth is spared. Very superficial: crusted, scaly erosions on the face, scalp and upper trunk rather than intact blisters. Endemic form in Brazil (fogo selvagem).
• Paraneoplastic pemphigus: severe, painful oral ulceration and a mixed rash with an underlying lymphoproliferative cancer (non-Hodgkin lymphoma, CLL, Castleman disease, thymoma).

Management

• High-dose systemic corticosteroids (oral prednisolone) to gain control.
• Steroid-sparing drugs for maintenance: azathioprine, mycophenolate mofetil, cyclophosphamide, methotrexate.
• Rituximab (anti-CD20 monoclonal antibody): now widely used early, giving long remissions and allowing lower steroid doses.
• Intravenous immunoglobulin or plasma exchange in resistant disease.
• Supportive care: wound care like a burn, fluids, nutrition, mouthwashes and analgesia, treat secondary infection, and bone protection while on steroids.

Bullous pemphigoid (BP)

Who: the commonest autoimmune blistering disease in the West; mainly people over 60. Linked to neurological disease (dementia, stroke, Parkinson disease) and some drugs (e.g. gliptins, diuretics).

Cause: IgG autoantibodies against the hemidesmosome proteins BP180 (type XVII collagen) and BP230. Complement is activated, eosinophils gather, and the epidermis separates from the dermis (subepidermal split).

Clinical features:

• Often begins with an itchy urticarial or eczema-like rash (pre-bullous phase) for weeks or months.
• Then large, tense, fluid-filled or blood-stained blisters on red, urticated skin, especially on the lower abdomen, inner thighs, groin, flexures and forearms.
• Blisters do not burst easily; erosions heal without scarring.
• Nikolsky sign negative.
• Mucosal involvement is uncommon and usually mild.
• Blood eosinophilia is common.

Management:

• Very potent topical steroid (clobetasol) to the whole body or to lesions: effective and safer than tablets in the frail elderly.
• Oral prednisolone (about 0.5 mg/kg/day) for widespread disease, tapered, with azathioprine or mycophenolate as steroid-sparing agents.
• Tetracyclines (doxycycline) with nicotinamide are a gentler option.
• Drain large blisters with a sterile needle, leaving the roof in place.
• Disease often settles within a few years, though relapse is common. Mortality is raised mainly because patients are old and treatment has side effects.

Variants of pemphigoid

• Mucous membrane (cicatricial) pemphigoid: mainly mucosa; scarring of the eyes (fusion of eyelids, symblepharon, blindness), mouth, larynx and genitals.
• Pemphigoid gestationis: itchy urticarial plaques and blisters starting around the umbilicus in pregnancy or just after delivery; may recur in later pregnancies.

Pemphigus vulgaris versus bullous pemphigoid

Dermatitis herpetiformis (DH)

What it is: the skin form of coeliac disease (gluten-sensitive enteropathy). Both are triggered by dietary gluten in genetically predisposed people (HLA-DQ2/DQ8).

Clinical features:

• Intensely itchy, grouped (herpetiform) small vesicles and papules.
• Symmetrical on extensor surfaces: elbows, knees, buttocks, shoulders and scalp.
• Blisters are usually scratched away, so the doctor often sees only excoriations and crusts.
• More common in men; usually starts in young adults.
• Nearly all have villous atrophy on small-bowel biopsy, but most have no gut symptoms.

Investigations:

• Skin biopsy: subepidermal blister with neutrophil micro-abscesses in the dermal papilla tips.
• DIF: granular IgA deposits in the dermal papillae (the diagnostic test).
• Serology: anti-tissue transglutaminase IgA (TG2) and anti-endomysial antibodies; antibodies to epidermal transglutaminase (TG3) are specific for DH.

Management:

• Strict gluten-exclusion diet for life: treats both skin and gut, and lowers the risk of small-bowel lymphoma. After about 2 years on a strict diet, drugs can often be stopped.
• Dapsone: relieves itch within days and is the classic drug of choice while the diet takes effect.
• Sulfapyridine if dapsone is not tolerated.

Dapsone side effects:

• Dose-related haemolysis in everyone (mild) and severe haemolysis in G6PD deficiency: check G6PD before starting.
• Methaemoglobinaemia (grey-blue lips and breathlessness).
• Agranulocytosis, hepatitis, peripheral neuropathy, and dapsone hypersensitivity syndrome (DRESS).
• Monitor blood counts regularly.

Linear IgA disease

• IgA antibodies against basement membrane proteins; affects children (chronic bullous disease of childhood) and adults.
• Blisters in rings or rosettes around a central crust: the "string of pearls" (or cluster of jewels) sign.
• Can be drug-induced, especially by vancomycin.
• DIF: linear IgA along the basement membrane.
• Treated with dapsone.

Epidermolysis bullosa (inherited)

Children with severe forms are sometimes called "butterfly children". Treatment is supportive: protect the skin, care for wounds, nutrition and cancer surveillance.

Blistering emergencies to distinguish

SJS and toxic epidermal necrolysis (TEN)

• Severe drug reactions (occasionally Mycoplasma) causing widespread death of the epidermis, usually 1–2 weeks after starting the drug.
• Common culprits: allopurinol, anticonvulsants (carbamazepine, phenytoin, lamotrigine), sulphonamides (co-trimoxazole), nevirapine, NSAIDs (oxicams), and antibiotics.
• Prodrome of fever and malaise, then painful dusky red skin, atypical targets, flaccid blisters, positive Nikolsky sign ("wet wallpaper" skin) and erosions of two or more mucosal sites (mouth, eyes, genitals).

• Management: stop the drug at once; admit to ICU or burns unit; manage like a burn (fluids, warming, nutrition, wound care, infection control, eye care); ciclosporin, IVIG or steroids are debated.
• Mortality of TEN is about 30–50%.
• HLA-B\*15:02 testing before carbamazepine in people of Han Chinese or Thai descent reduces risk.

Staphylococcal scalded skin syndrome (SSSS) versus TEN

Erythema multiforme

• Target (iris) lesions with three zones, typically on the hands, feet and extensors; acral.
• Usually triggered by herpes simplex (commonest) or Mycoplasma, rather than drugs.
• EM minor: little or no mucosal disease. EM major: one mucosal site involved.
• Self-limiting; treat the trigger; suppressive aciclovir for recurrent HSV-related EM.

Quick revision

• Intraepidermal = flaccid (pemphigus). Subepidermal = tense (pemphigoid, DH, linear IgA).
• Pemphigus vulgaris: anti-desmoglein 3 IgG, oral erosions first, Nikolsky positive, intercellular IgG; steroids plus rituximab or azathioprine.
• Pemphigus foliaceus: desmoglein 1; mouth spared; drugs such as penicillamine.
• Bullous pemphigoid: over 60, itchy tense blisters, BP180/BP230, linear IgG and C3; very potent topical steroid or prednisolone.
• DH: coeliac disease; elbows, knees, buttocks; granular IgA in papillae; gluten-exclusion diet and dapsone; check G6PD.
• Linear IgA: string of pearls; vancomycin; dapsone.
• SJS under 10%, overlap 10–30%, TEN over 30%; stop the drug; SCORTEN.
• SSSS spares mucosa; TEN involves it.

Written by The House Job from standard references (Kumar and Clark's Clinical Medicine).

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