Blistering diseases

Professor Danka Švecová MD, PhD.

Dept. of Dermatovenerology

Faculty of Medicine Comenius University

Classification of blistering diseases

• Hereditary epidermolytic epidermoplysis

• Pemphigus diseases

• Pemphigoid diseases

• Dermatitis herpetiformis

• Bullous diseases in childhood

Establishment of the diagnosis

• History

• Clinical findings

• Blister smear cytology (Tzank´s test)

• Histopathology

• Direct and indirect immunofluorescent examination,

ELISA

• General examination

• Immunoblotting

• Antigenmapping

Hereditary epidermolysis

• Inherited disease

• After mechanical injury production of blister on the

skin and/or mucous membrane

• Sometimes spontaneous production of blisters

Site of discontinuity

• Epidermolysis bullosa simplex

• Junctional epidermolysis bullosa

• Dystrophic epidermolysis bullosa

Hereditary epidermolysis

Epidermolysis bullosa simplex

Inheritance autosomal dominant pattern

• Epidermolysis bullosa simplex generalisata

• Epidermolysis bullosa simplex localisata

Hereditary epidermolysis

Epidermolysis bullosa simplex generalisata

Inheritance autosomal dominant pattern, ↑ men,

the most common disease of the group, incidence of 1:50 000 births

Pathogenesis mutations in the genes for keratins 5 and 14 → trauma and heat, increased friction, sweating→ extensive epidermal damage → intraepidermal blisters

Hereditary epidermolysis

Epidermolysis bullosa simplex generalisata

Clinical findings at birth – area of mechanical stress –the entire body tends to have fragile skin –

blisters → heels, buttocks, elbows, shoulders, occiput → widespread erosions → heal without scaring, transient milia,

mucous membrane are not affected,

common- palmoplantar keratoderma, hyperhidrosis

Epidermolysis bullosa simplex generalisata

Histopathology intraepidermal epidermolytic blister-

BM komponents on the basis of blister

Prognosis may improve during puberty, the tendency

to form blisters easily remains, warm weather →

impairment

Inheritance prognosis 50% susceptibility, guidance

Therapy glucocorticoids (Prednison), soft shoes,

antiperspirants, open the blister without removing

the roof.

Epidermolysis bullosa simplex generalisata

Epidermolysis bullosa simplex generalisata

Epidermolysis bullosa simplex localisata

of the hands and feets

Inheritance autosomal dominant pattern

During infancy 1/3 intraoral blisters from sucking

on the bottle,

free of symptoms until teenagers or young adults →in warm weather, hard manual labor, sports, hiking → severe blisters →

discrepancy between the degree of mechanical stress and the development of blisters.

Epidermolysis bullosa simplex localisata

of the hands and feets

Pathogenesis the same as in EBS generalisata

Clinical findings hands and feet acute blisters and erosions

Histopatghologyintraepidermal epidermolytic blister, EM- dyskeratosis

Course healing without scars, cold weather remission

Therapy soft shoes, antiperspirants, desinfection

Pemphigus diseases

• Pemphigus vulgaris, pemphigus vegetans

• Pemphigus foliaceus, pemphigus erythematosus

• Paraneoplastic pemphigus

Pemphigus vulgaris

Occurence uncommon, 30-60 years of age, transiently in infants of affected mothers, rarely in children and elderly

Etiopathogenesis autoimmune disease autoantigens in desmosomes (cell-cell adherence)

desmoglein3 (Dsg3)-expressed through the epidermis and strongly in mucosa.

Reduction of cell-cell adherence → acantholysis;

desmoglein1 (Dsg1)

Correlation of the disease severity and the autoantibody titer, predicting the course of disease.

Pemphigus vulgaris

Clinical findings insidious onset, no predilection sites, flaccid clear blister → inflamed erosion → centrally crusts mayform as the blister spread peripherally;

↑80% begins in the mouth – blisters break rapidly →painful erosions (misdiagnosed), ocular mucosa →chronic conjuctivitis, chronic blepharitis

Nikolsky sign I in the vicinity of the blisterwhen push the upper layers of theepidermis → it releases away

Nikolsky sign II the spreading of an intactblister laterally when gentle pressure isapplied

Symptoms erosions are painful, in the mouth – eating is difficult

Pemphigus vulgaris

Laboratory findings anti-Dsg3 autoantibody ELISA (only mucosa is affected), anti-Dsg3+ anti-Dsg1 autoAb ELISA (both mucosa and skin are affected), titer correlate with severity of disease.

Blister smear cytology acantholytic cells (Tzank cells)

Histology str.basale – intraepidermal blister

Direct immunofluorescent examination (DIF) perilesional skin deposits of IgG4 and complement components (C1q,C4,C3)

Indirect (IIF) autoAb titer correlates with severity of disease

Course-unpredictable, without systemic corticosteroids fatal over a 1-3-years period.

Pemphigus vulgaris

DIF

Pemphigus vulgaris

Pemphigus vulgaris

DifDg bullous pemphigoid, dermatitis herpetiformis,

bullous toxic exanthema, bullous erythema

multiforme, porphyria cutanea tarda;

Oral cavity - aphthae, erosive lupus erythematosus,

erosive lichen ruber

Pemphigus vulgaris

Therapy the mainstay – corticosteroids, immunosupresive

agents.

Start - Prednison 1.0mg/kg daily, maintenance dose in the

range of 5-15mg/daily

Corticosteroid-sparing agents – azathioprime (50-200 mg),

cyclophosphamide (50-200mg), methotrexate (15-30 mg

once weekly), cyclosporine A, plazmapheresis, IVIG

(high-dose intravenous immunoglobulin G)

Topical noneroded lesions corticosteroids, attention to

secondary infections, oral cavity antibacterial and

anesthetic agents.

Pemphigus vegetans

Variant of pemphigus with localized papillomatous

vegetations, the target antigen – desmoglein 1 and 3

Clinical findings intertriginous patterns; the eroded patches

do not heal → develop papillomatous growths or

vegetations → axilla, groin, perianal region, female

genitalia, nasolabial folds and corners of the mouth;

erosion can dry→warty surface, painful fissures

Histopathology suprabasilar acantholysis with acanthosis

and papillomatosis, intraepidermal eosinophils

Prognosis may envolve into pemphigus vulgaris, therapy -

resistant

Pemphigus vegetans

Diagnosis as in pemphigus vulgaris

DifDg condylomata lata, vegetating

form of bullous pemphigoid,

acantosis nigricans, jododerma,

bromoderma

Therapy corticosteroids,

vegetations – intralesional

corticoisteroids, surgical

debridment, soft x-rays, antibiotic

therapy

Pemphigus foliaceus

Very superficial acantholysisproducing more erosions thanblisters

Occurence very uncommon, lessfrequent than pemphigus vulgaris, the most common type of pemphigus in children

Etiopathogenesis the major antigendesmoglein1 (Dsg1)

expressed primarily in the upperlevels of the epidermis →

none mucosal lesions

Pemphigus foliaceus

Clinical findings typically starts on the scalp, face, sternum or lateral site of the chest and thorax,

broad flat blisters→ easily rupture and evolve sheets of scales as puff pastry

the upper layer of epidermis is actually floating on a bed of serum- weeping and crusting →bacterial colonization may lead to a foul smell;

may resemble erytroderma;

Nikolského sign I positive

Pemphigus foliaceus

Histopathology acantholysis in upper

str.spinosum or str.corneum,

acanthosis and papillomatosis,

some dyskeratotic keratinocytes

Blister smear cytology acantholytic

cells (Tzank cells)

Course chronic of waves, children –

spontaneous healing,

photosensitive disease

DifDg seborrheic dermatitis,

subacute lupus erythematosus

Therapy just as in pemphigus

vulgaris, dapson

Pemphigus erythematosus

Variant of pemphigus foliaceus overlaps with lupus erythematosus

Etiopathogenesis clinically resembles lupus erythematosus →

a small group of patients have immunological markers for both diseases, triggers →light, drugs

Clinical findings as in pemphigus foliaceus, erythematous patches on the sun-exposed areas → face (resembles lupus erythematosus or seborrheic dermatitis), scalp, V-shape;

oral mucosa is not involved.

Pemphigus erythematosus

Variant of pemphigus foliaceus which overlaps with lupus erythematosus

Etiopathogenesis resembles lupus erythematosus →

a small group of patients have immunological markers for both diseases;

→ trigger – light, drugs

Clinical findings as in pemphigus foliaceus,

erythematous patches on the sun-exposed area → face, V-shape

(resembles lupus erythematosus or seborrheic dermatitis)

not involved: oral mucosa

Pemphigus erythematosus

Histopathology superficial acantholysis,

in addition → basal layer vacuolar degeneration, thickened BM

Blister smear cytology acantholytic and dyskeratotic keratinocytes, many leukocytes

Pemphigus erythematosus

Diagnosis

DIF: IgG Ab as in pemphigus vulgaris, BM – lupus band

test 50-70% positive (systemic LE)

IIF: ANA 80% in serum, highly specific LE Ab (anti-DNA, --

-Sm, -Ro, not found →repetion at 2-4-week intervals

Course transition to pemphigus foliaceus, rare →

development to systemic LE, rare→myastenia gravis,

thymomas

DifDg seborrheic dermatitis, LE

Therapy moderate dosages of systemic corticosteroids

+antimalarials and dapsone

Topical th- corticosteroids, sun protection

Pemphigus paraneoplasticus

Uncommon disorder

→ underlying hematologic neoplasms as non-Hodgkin lymphoma, chronic lymphocytic leukemia

Etiopathogenesis unclear

→ the tumor induces synthesis of autoAb reacting with a variety of epithelial structures, directed against components of hemidesmosomes and keratinocytes.

→ autoAb against Dsg3, Dsg 1 (2/3 of cases), desmoplakin I and II, envoplakin, plakoglobin, BPAG1 (bullous pemphigoid Ag) and other epithelial antigens.

Pemphigus paraneoplasticus

Clinical findings

sites of predilection:

oral erosions → severe, hemorghagic, painful;

palms an soles → blisters typicly involved;

conjunctiva; perianal region; genitalia; nailfolds; upper aspects of the trunk, extremities →

Nikolsky sign may be positive

Cutaneous lesions →polymorphic lesions

resembling pemphigus vulgaris; pemphigus foliaceus; lichen planus; graft versus host disease; erythema multiforme; Steven-Johns syndrome;

pulmonaly involvement – bronchiolitis obliterans →death

Pemphigus paraneoplasticus

Diagnosis

Histopathology polymorphism, suprabasilar acantholysis, vacuolar basal layer damage

DIF IgG deposition as in pemphigus vulgaris,

false-negative tests are common – multiple biopses;

BM- deposition of IgG and complement

IIF pemphigus-like antibodies

Course and prognosis depends on the underlying tumor, benign tumors after removing →dramatic improvement

Therapy is difficult, corticosteroids less effective, IVIG, rituximab.

Pemphigoid diseases

• Bullous pemphigoid

• Cicatricial pemphigoid

• Pemphigois gestationis

Bullous pemphigoid

Occurence disease of elderly, mean age 76 years, rarelyin childhood

Etiopathogenesis autoimmune disorder – target Ag-hemidesmosomes → the split in the upper part oflamina lucida (just beneath the basal layer

→BPAG2 (BP180) transmembrane component of hemidesmosomes

→BPAG1 (BP230) inner plaques of hemidesmosomes

> 95% of patients have Ab against BPAG2,and BPAG1

-16-20% paraneoplastic syndroma (ca prostate, mammae, bronchus),

- Triggers → medication:antihypertensive agents, diuretics (furosemide), some antidiabetics; UV; x-rayradiation

Bullous pemphigoid

Clinical findings –

side of neck, axilla, groin, upper inner aspects of the thighs, abdomen;

→large tense irregular blister, within the urticarial plaques or on normal skin, bizarre configuration containing blood and serum, many cm in diameter;

→ erosions with blister formation at their periphery, resulting rosettes of blisters- typical

→ bloody crusts (superficial dermal vessels are exposed)

→ Nikolsky sign negative (only near the blister could be positive)

Bullous pemphigoid

Localized bullous pemphigoidlimited blisters on a given region – elderly –

localization: shins and scalp

occasionally may develop generalized lesions after a period of time

Therapy →topical corticosteroids

Bullous pemphigoid

Signs – pruritus in the begining

Diagnosis:

Histopathology - subepidermal

blister, roof the entire

epidermis, the blister fluid –

fibrin, Eo

Smear blister cytology negative

DIF – perilesional skin – thick

line deposition of IgG (IgG2,

IgG4), C3

IIF 80%, ELISA 90% → sAb anti- BP180, BP230

Bullous pemphigoid

Course chronic, mortality

before corticosteroids 40%,

nowadays 23%; tends to

relent or even remit after a

period of years

DifDg pemphigus vulgaris,

dermatitis herpetiformis,

epidermolysis bullosa

aquisita, erythema

multiforme;

Localized form – bullous

arthropod bite reactions,

bullous disease of diabetes

mellitus

Bullous pemphigoid

Therapy corticosteroids in moderate

dosage 40-80mg, corticosteroid-

sparing agents, antibiotics

plasmapheresis;

topical – corticosteroids

Cicatricial pemphigoid

Rare, elderly, more common in women

Etiopathogenesis

several entity,

autoimmune disease

→antigen or a complex of antigens of BM zone;

atrophy is not clear (Ags in lamina lucida may play role in epidermal wound healing)

Cicatricial pemphigoid

Clinical findings

only 25% of patients have cutaneous lesions;

> 90% oral lesions;

60-70% ocular lesions

Skin lesions- hyperpigmented

atrophic patches, in scalp the blisters →pseudopelade,

ocular lesions- chronic scaring conjunctivitis with progressive subconjunctival fibrosis, synechia formation between bulbar and palpebral conjunctiva, blindness, dry eye,

oral lesions – mucosa can be peeled away, scars - difficult chewing and swallowing

Cicatricial pemphigoid

Diagnosis:

Smear blister cytology negative

DIF 50-60% linear IgG, C3,IgA in BM zone

IIF 50% positive

Course chronic, 20-60% blindness, oral mucosa – painful, interfering with eating and drinking, rarely → squamous cell ca in mucosal scaring

DifDg pemhigus vulgaris, lichen ruber erosivus, M.Behcet, lupus erythematodes chronicus erosivus

Therapy corticosteroids + immunosuppressive agent; oral mucosa – dapson, retinoids, cyclosporine A, topical th –corticosteroids intralesional, topical, surgical treatment

Pemphigoid gestationis (previously: herpes gestationis)

Exclusively limited to pregnancy, 2nd or 3th trimester, recurs in subsequent pregnancies, can be triggered by oral contraceptives

Etiopathogenesis target antigen BPAG2, positive in placenta, IgG antibodies are pathogenic against BM (herpes gestationis factor), Ab cross placenta – cause self-limited disease in infants;

HLA association →

HLA DR3 (75%)

HLA DR4 (50%)

both (35-40%)

father HLA DR2 (50%).

Pemphigoid gestationis

Clinical findings

initial lesions –urticarial on the abdomen, can generalized, palms and soles→ deep tense painful blisters, sparing face and mucous membranes.

Lesions are identical to bullous pemphigoid, more pruritic.

5% of infants neonatal develop pemphigoid,

10% have erythematous macules or papules,

spontaneous resolution within weeks.

Pemphigoides gestationis

Symptoms severe pruritus, fever, malaise

Diagnosis

Smear blister cytology ↑ Eo, acantholytic cells negative

Histopathology subepidermal blisters, numerous intraepidermal microblisters, inflammatory cells, Eo infiltration

DIF C3 in BM zone, 50% IgG and IgA, placental BM similar changes

IIF IgG1, activate complement

Pemphigoides gestationis

Prognosis

can be triggered by oral contraceptives, recurs in subsequent pregnancies,

few menstrual flares,

placental insufficiency;

prematurity;

rare spontaneous abortions;

rare stillborn infants

Pemphigoides gestationis

DifDg drug hypersensitivity

exantema, erythema

exsudativum multiforme,

dermatitis herpetiformis

Therapy corticosteroids in low

dosage, pyridoxin (400-900

mg/daily)

Topical therapy

corticosteroids,

antipruriginous and

antiseptic agents, zinc oxide

shake lotions

Dermatitis herpetiformis

Epidemiology relatively common, onset in adolescence or young adulthood (30.-40 years), male to female ratio (3:2)

Etiopathogenesis very strong HLA predisposition HLA-A1(75%), -B8(88%) HLA DR3 (95%), glutensensitive entheropaty,

→10% have gastrointestinal symptoms;

→60-70% have villous atrophy and lymphocytic infiltrates in small bowel biopsy.

Dermatitis herpetiformis

Etiopathogenesis

Autoantibody IgA directed against number of target antigens,

→tissue transglutaminase (coeliac disease) and

→epidermal transglutaminase (DH)

→ IgA to gliadin, reticulin, smoth muscle endomysium.

→IgA endomysial (DH 80%), (coeliac diseases 95%)correlate with gut disease

→sensitivity to halogen salts (potassium iodide)

Dermatitis herpetiformis

Clinical findings starts slowly or explode over a short time localisation →knees, elbows (the most classic sites), shoulder girdle, scalp, buttocks;

typically polymorphous lesions - pruritic erythematous macules and papules, urticarial, vesicular- small grouped (herpetiform) blisters on erythematous base

Symptoms intense pruritus, even pain

Dermatitis herpetiformis

Diagnosis

Smear blister cytology acantholytic cells negative, ↑Eo

Histopathology subepidermal blisters, papillary microabsecess at the periphery, ↑Eo, Neu

DIF granular deposits

of IgA in the demal papillae (perilesional skin), C3;

10% of clinically typical DH have linear deposition of IgA

IIF is not positive

Dermatitis herpetiformis

Course and prognosis

chronic, risk for intestinal lymphoma,

risk for variety of autoimmune diseases

Therapy dapson (hematologic monitoring of methemoglobin (a deficiency in glucose-6-phosphate dehydrogenase (G6PD).

therapy is longterm – several years,

gluten- free diet, antihistaminines.

Topical th – corticosteroids

Linear IgA dermatosis

Not a single clinical disease

Etiopathogenesis many target antigens, the main antigen BPAG2 and more often proteolytic fragments of this; BPAG1,

lack of HLA antigens and gluten-sensitive entheropathy

Clinical findings (4 types)

→10% of clinically typical dermatitis herpetiformis have linear deposition of IgA, oral lesions.

→chronic bullous disease of childhood – large blisters with rosette pattern.

→large blisters on urticarial base as in bullous pemphigoid.

→mucous membrane erosions as in cicatrical pemphigoid

.

Linear IgA dermatosisHistopathology subepidermal blisters, the picture matches

whatever clinical disease is mimicked

DIF linear band of IgA at the BM zone

IIF 60% IgA directed against wide spectrum of antigens

Linear IgA dermatosis

Therapy in general – condition resembles bullouspemphigoid reponds better to corticoisteroids, resemblesdermatitis herpetiformis responds to sulfone