Dept. of Dermatovenerology Faculty of Medicine Comenius ...
Transcript of Dept. of Dermatovenerology Faculty of Medicine Comenius ...
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
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