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Blistering Diseases

Irene LeighProfessor Cellular and Molecular

Medicine, Centre CutaneousResearch,ICMS

Blistering Diseases: Definitions

• Blister Collection of clear fluid• Bulla Blister>5mm diameter• Vesicle Blister<5mm diameter• Crust Dried exudate on skin • Nikolsky sign Shearing normal epidermis

Basement membrane zone• Plasma membrane: basal keratinocytehemidesmosome• Lamina Lucida• Lamina Densa

– Type IV collagen• Anchoring fibrils

– Type VII collagen

DESMOSOME

GAP JUNCTION

ADHERENS JUNCTION

INTRAEPIDERMAL JUNCTIONS

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Blisters

• SubcornealUnder stratum corneum

• IntraepidermalWithin or between keratinocytes

• SubepidermalBasement membrane zone

Pathomechanisms of Blistering• Epidermal oedema(spongiosis causing

separation of keratinocytes) E• Epidermal necrosis eg erythema multiforme E• Damage to intercellular connections eg

pemphigus E• Basal Cell degeneration eg Lupus

erythematosus E• Damage to basal cell membrane • eg pemphigoid S

• Dermal damage eg dermatitis herpetiformis S

Causes of Blistering Disorders

• Congenital• Acquired

InfectionTraumaAutoimmune

• Idiopathic

Congenital Blistering Conditions

• Epidermolysis Bullosa• Dominant dystrophic(DDEB)• Recessive dystrophic• Simplex• Junctional

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Recessive Dystrophic Recessive Dystrophic EpidermolysisEpidermolysis BullosaBullosa

Collagen VII (LH7.2)

Gene therapy for RDEBGene therapy for RDEB

EX vivo: Take skin biopsyGrow skin cellsPut back defective geneApply skin sheets to ulcerated areas

Protein therapyApply type VII collagen to wounds

Delivery membrane

Project BE 96-3524 - Artificial skin

Laboratorygrownepithelial graft

Acquired Blistering conditions

InfectiousAutoimmuneOthers

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Infective Blistering Diseases

• Impetigo– Young children– Honey coloured crusts– Staphylococcus or streptococcus

• Staphylococcal scalded skin syndrome– Staphyloccoccal exotoxin– Intraepidermal damage– Mortality– Antistaphylococcal treatment

Bullous impetigo

SSSSSSSS

Rx: topical or oral antibiotics

Rx: intravenous flucloxacillinNasal Naseptin for family and baby

Toxic epidermal necrolysis(TEN)

• Rare cutaneous reaction– Drugs eg anticonvulsants,antibiotics– Infection– Malignancy eg lymphoma

• Subepidermal damage gives bullae and necrosis• Nikolsky positive• Mucosae involved• Extremely ill(25% mortality)• Supportive care, intravenous IgG

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Autoimmune diseases

Organ specific autoimmune diseaseMediated by pathogenic

auoantibodies to specific tissue antigens

Autoimmune Blistering #1Pemphigus Vulgaris

• Rare M=F middle age• Intraepidermal split due to keratinocyte

separation• Associated with autoimmune disorders e.g.

myasthenia gravis, SLE, thymoma• Drug history• Mucosal involvement often predates skin lesions• Nikolsky sign positive• 100% mortality if untreated, 25% if treated• painful erosions, ill patients, +/- flaccid bullae

Pemphigus vulgaris: Autoantibodies to desmosomal protein desmoglein 3

DesmoDesmossomeome (contains desmoglein(contains desmoglein--3)3)IgGIgG antibodyantibody ComplementComplement

BMBM

Acantholysis

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Pemphigus vulgaris- intraepidermal blister,tombstoning and acantholysis

IgG autoantibody binds to intercellular space in suprabasal epidermis

Treatment

• High dose systemic steroids (60-80 mg prednisolone daily)

• Usually also need other immuno-suppressive agents – e.g. azathioprine or mycophenolate mofetil

• Treatment usually needs to be continued for years

Immunological Blistering Conditions #2Bullous Pemphigoid

• Elderly M+F• Subepidermal bullae often predated by itchy urticated

areas on limb girdles• Tense blisters last several days• Mucosal lesions unusual, patients well• May resolve spontaneously, good prognosis

Bullous pemphigoid

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Bullous pemphigoid : supepidermal blister with eosinophilic infiltrate and inflammation

Bullous pemphigoid: autoantibodies to epidermal basement membrane zone

Antigen is bullous pemphigoid antigen(1/2) hemidesmosome protein

Indirect Immunofluorescence using BP patient serum on salt –split normal skin

Treatment of BP

• Good prognosis• Potent topical steroids• Systemic steroids –

prednisolone (30-40 mg)• Steroid sparing agent

• Azathioprine – check TPMT levels• Dapsone – check G6PD levels

Pemphigoid Gestationis

• Rare eruption of pregnancy (hydatiform mole and choriocarcinoma)

• Associated with other immune disorders?cancer• Papules, subdermal bullae itchy++• Onset any time in pregnancy, around umbilicus then

towards thighs• Positive immunofluorescence• Topical or systemic steroids• NOT the same as polymorphic eruption of pregnancy

(begins in striae in primips, negative immunofluorescence)

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Pemphigoid gestationis Dermatitis Herpetiformis

• Age 20-40 2M:1F• intensely itchy vesicles on extensor

surfaces of elbows, knees, buttocks• Gluten sensitive enteropathy +/-

clinical features of coeliac disease• Histology and IMF (IgA in dermal

papillae)

Dermatitis Herpetiformis DH - Investigations• Skin biopsy

– H&E– Direct IMF

• Bloods – Anti-endomysial antibodies – correlate with disease activity

• GI investigations– Flattening of the villi in the proximal small intestine– Jejunal biopsy shows changes similar to coeliac

disease

DH - Treatment

• Gluten free diet– Often poorly tolerated– May take time to respond

• Dapsone– Check G6PD levels before starting– Regular FBC, LFTs (haemolytic anaemia,

dapsone hypersensitivity rxn.)

Chronic Bullous Disease ofChildhood (Linear IgA Disease-

adults)

Often misdiagnosed as Often misdiagnosed as bullousbullous impetigoimpetigoBlisters in flexures and on Blisters in flexures and on limbslimbs‘‘String of pearlsString of pearls’’Linear Linear IgAIgA deposition on deposition on BMZBMZRx: Rx: DapsoneDapsone, erythromycin, erythromycin

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Miscellaneous blistering conditions

• Pompholyx eczema• Viral infections• Heat/cold/sunburn/trauma• Diabetic bullae• Blisters in drug overdose and coma• Insect bites• Cardiac failure• Drug reactions• Contact dermatitis• Phytophotodermatitis

Porphyria Cutanea Tarda

• Rare photosensitive disorder (but commonest of the porphyrias)

• Alchololic middle aged men, females on OCP• Disturbance of haem. biosynthesis => excess

uroporphyrin (urine fluoresces in Wood’s light)• Scarring, milia, hypertrichosis in sun exposed

skin• ↑ risk of heptocellular carcinoma and lymphoma• Management - avoid sun, alcohol, oestrogens• Low dose chloroquine, reduce iron stores

Porphyria Cutanea Tarda Investigations in Blistering Conditions

• Biopsy– histology– immunofluorescence– electron microscopy

• Blood tests– circulating antibodies– FBC, U&E, viral serology

• Swab MC+S, viral EM• Genetic investigation if appropriate

Summary•Blisters occur from a variety of pathological mechanisms•The clinical presentation depends on the level within the skin that the blister cleavage occurs•Many blistering diseases are very serious and require expert diagnosis often biopsy•Specialised tests include Direct and Indirect Immunofluorescence on frozen skin biopsies