blistering - edel · 1 blistering diseases irene leigh professor cellular and molecular medicine,...
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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