Vesiculo-Bullous Disorders

Dr. Srisukhirthi
Contents

• Vesiculo-bullous disorders • Herpes gestationis

• Classification • Linear IgA disease
• Genetic blistering disorders • Chronic bullous disease of
• Epidermolysis bullosa simplex childhood
• Junctional epidermolysis bullosa • Dermatitis herpetiformis
• Dystrophic epidermolysis bullosa
• Epidermolysis bullosa acquisita
• Autoimmune blistering disorders
• Approach to vesiculobullous
• Pemphigus group of disorder
disorders
• Bullous pemphigoid
• MCQs
• Cicatricial pemphigoid
• Photo Quiz
Definitions

• Vesiculo-Bullous Disorders

• Primary event : Blistering in the form of vesicle or bullae

• Vesicles and Bullae : Visible accumulations of fluid within or beneath

the epidermis

− Vesicles are small, less than 0.5 cm in diameter

− Bullae, which may be of any size over 0.5 cm

Classification of Vesiculo-bullous Disorders

Vesiculo-bullous
disorders

Inherited/Genetic blistering Acquired/Autoimmune

disorders blistering disorders
Acquired or Autoimmune Blistering Disorders

• Intraepidermal- Pemphigus • Subepidermal- pemphigoid

group group
• Pemphigus foliaceous • Bullous Pemphigoid
• Pemphigus erythematosus • Cicatricial Pemphigoid
• Endemic pemphigus • Pemphigoid gestationis
• Pemphigus herpetiformis • Linear IgA disease / Chronic
• Suprabasal blisters Bullous Disease of Childhood
• Pemphigus vulgaris • Dermatitis herpetiformis
• Pemphigus vegetans • Epidermolysis bullosa acquisita
• Paraneoplastic pemphigus
• IgA Pemphigus – SCD/IEN types
Pemphigus

• Pemphigus : Derived from the Greek word “Pemphix” which means

blister or bubble

• Pemphigus : A group of autoimmune blistering diseases of the skin

and mucous membranes

• Histology : Intra-epidermal blisters due to the loss of cell–cell

adhesion & separation of keratinocytes (Acantholysis)

• Immunopathology : In-vivo bound & circulating IgG autoantibodies

directed against the epidermal cadherins (calcium-dependent cell-
cell adhesion molecules) found on the cell surface of keratinocytes
Pemphigus - Types & Variants

• Pemphigus vulgaris
− Variant : Pemphigus vegetans
• Pemphigus foliaceus
− Variant : Pemphigus herpetiformis
− Variant : Pemphigus erythematosus
− Variant : Endemic pemphigus
• Paraneoplastic pemphigus
• Drug-Induced pemphigus
• Intercellular IgA dermatosis
− Variant : IgA Pemphigus foliaceus
− Variant : Subcorneal pustular dermatosis
Pemphigus Vulgaris

• Epidemiology
− Disease of middle age (India-Younger age)
− Ashkenazi Jews - Increased susceptibility
− Male & female - Equally affected
• Etiology
− Target antigens: Desmoglien-3 (Desmoglein-1 in few patients)
Pathogenesis

Circulating IgG4 Pemphigus autoantibodies bind to desmoglein-3 & -1

found in desmosomes which are present on the keratinocyte cell
membrane

Lysis of intercellular cement substance

Acantholysis

Intra-epidermal blister
Blister cavity consists of mainly acantholytic cells
Target Antigens in Pemphigus Gp
Pemphigus Vulgaris-
Sites : Oral cavity, groins, genitals, axillae, scalp, face, neck

Mucosal erosions in
Flaccid bullae & erosions
Pemphigus vulgaris
Pemphigus Vulgaris - Clinical Features

• Nikolsky sign: Lack of cohesion within the epidermis, causes its upper
layers easily move laterally with slight pressure or rubbing in active
patients with pemphigus
• Bulla-spread sign (Asboe–Hansen sign): Gentle pressure on an intact
bulla forces the fluid to spread under the skin away from the site of
pressure, due to the lack of cohesion
of keratinocytes
• Can be fatal due secondary bacterial
infections or fluid & electrolyte
imbalance (loss of epidermal barrier
Bulla-spread sign
function)
Pemphigus Vegetans

• A rare vegetative variant of pemphigus vulgaris

• Flaccid blisters erosions fungoid vegetations or
papillomatous proliferations
• Intertriginous areas & scalp, face
• Tongue : cerebriform-like changes
• Two subtypes :
− Neumann type - Severe
− Hallopeau type - Mild Vegetating plaque in the
retro-auricular region
Diagnosis

• Tzanck smear
− Acantholytic cell - Large round cell with hyperchromatic nucleus &
perinuclear halo due to peripheral condensation of cytoplasm
• Histopathology
− Supra basal cleft with acantholytic cells
− Tomb stone appearance
− Perivascular infiltrate of lymphocytes, neutrophils
• Immunofluorescence
− Intercellular IgG and C3 deposits showing (Fishnet or Honey-comb
pattern)
• ELISA to detect IgG antibodies
 Suprabasal blister with acantholytic
cells in the cleft

Tzanck smear showing

Acantholytic cells

DIF showing IgG deposition in the intercellular

regions causing the ‘fish-net pattern’
Treatment of Pemphigus Vulgaris &
Its Variants

• Steroids : 1.5-2 mg/kg/day

• Dexamethasone - Cyclophosphamide pulse (DCP)- 100 mg Dexa in 500

ml of 5% Dextrose on 3 consecutive days, Cyclophosphamide 500 mg
IV along with Dexa only on the 1st day
Repeat pulse every 4 weeks

• Methyl-prednisolone pulse

• Anti metabolites : Azathioprine, MMF, Cyclophosphamide

Treatment of Pemphigus Vulgaris &
Its Variants

• IV Ig – 2g/Kg per cycle divided over 3-5 days

• Dapsone 100-300 mg/d (Steroid sparing agent)

• Nicotinamide 1.5 g/d and Tetracycline 2 g/d combination

• Antimalarials

• Cyclosporine 3-6 mg/Kg

• Rituximab-anti-CD20 monoclonal Ab – 375 mg/m2 once a week for 4

weeks

• Others : Plasmapheresis, extracorporeal photopheresis

Pemphigus Foliaceus

Scaly crusted erosions in

Subcorneal blistering
Seborrheic distribution
Pemphigus Erythematosus
(Senear–Usher Syndrome)

• Pemphigus erythematosus - a localized variant of pemphigus foliaceus

• Typical scaly and crusted lesions- malar region and in other

‘seborrheic’ areas; Oral mucosa rarely involved
Pemphigus Herpetiformis

• Rare and atypical variant of pemphigus

• Resembles dermatitis herpetiformis in its early phase
• Widespread clusters of pruritic papules and vesicles develop on an
erythematous background
• Most patients with herpetiform pemphigus have a clinical variant of
pemphigus foliaceus and the remainder may have a variant of
pemphigus vulgaris
• Eosinophilic spongiosis & subcorneal pustules without acantholysis
histologically
• IgG autoantibodies directed against the cell surfaces of keratinocytes
• Target antigen : Dsg1 in most cases & Dsg3 in others
Endemic Pemphigus Foliaceus
Fogo Selvagem (Wildfire)

• Endemic to certain parts of South America (Brazil, Columbia etc)

• Common in children and young adults

• Risk factor? Arthropod bite (Black fly - Simuliidae)

• Initial lesions are flaccid bullae; Nikolsky sign +ve

• Head & neck involved first

• Burnt appearance & burning sensation - reason for the name Fogo
selvagem, Portuguese for ‘wildfire’

• Mucous membranes - not involved

• Histologically and immunologically - identical to PF

Treatment of Pemphigus Foliaceus &
Its Variants

• Potent topical or intra-lesional steroids

• Oral Prednisolone 20-40 mg/day

• Azathioprine

• Cyclophosphamide

• Hydroxychloroquine 200 mg bid

• IVIg

• Dapsone 100 mg/day

Drug-Induced Pemphigus

penicillamine and captopril

• With penicillamine, pemphigus foliaceus is seen more commonly than

pemphigus vulgaris

• Both penicillamine and captopril contain sulfhydryl groups that are

speculated to interact with the sulfhydryl groups in Dsg1 and Dsg3
Paraneoplastic Pemphigus

• Associated with underlying neoplasms, both malignant & benign

• Commonly associated neoplasms - NHL, CLL, Castleman's disease,
malignant and benign thymomas
• Earliest presenting sign - Intractable stomatitis, persists and resistant
to therapy
• Most patients - severe pseudo-membranous conjunctivitis which may
produce scarring
• Esophageal, nasopharyngeal, vaginal, labial and penile mucosal
lesions may also be seen
• Polymorphic cutaneous lesions-flaccid or tense bullae, EMF-like;
Palms & soles involved (c.f. PV)
• Treatment : Rx of the neoplasm; Usually refractory to all treatments
IgA Pemphigus

• In middle-aged or elderly
• Two types : The subcorneal pustular dermatosis (SPD) &
intraepidermal neutrophilic (IEN)
• In the SPD type, IgA autoantibodies - Upper epidermal surfaces, while
in the IEN type, IgA autoantibodies - Throughout the entire epidermis
• Flaccid vesicles or pustules coalesce to form an annular pattern with
crusts in the center of the lesion
• Common sites - Axilla and groin, mucous membrane involvement is
rare, pruritus is a significant symptom
• Immunologic evaluation is essential to differentiate the SPD type
from classic subcorneal pustular dermatosis
• Treatment : Dapsone, Etretinate, Isotretinoin, PUVA,
Immunosuppressives, plasmapheresis and Colchicine
Pemphigoid Group – Autoantigens
Bullous Pemphigoid

• Epidemiology
• Most common subepidermal blistering disorder
• Disease of the elderly
• Chronic disease, with spontaneous exacerbations & remissions, with
significant morbidity
• Etiology
• Target Antigens : Present in hemidesmosomes which are components
of junctional adhesion complexes that promote dermo-epidermal
cohesion
− BPAg1 or BP230 (230 kDa) &
− BPAg 2 or BP180 or Type VII Collagen (180 kDa)
Pathogenesis of Bullous Pemphigoid

Circulating anti-BP 180 and anti-BP 230 antibodies bind

to the target Ags within the DEJ

Activate the complement pathway & release chemoattractants

Recruitment of eosinophils and neutrophils

Release of destructive proteolytic enzymes

BMZ separates

Sub-epidermal blister is formed

Clinical Features of Bullous Pemphigoid

• Cutaneous manifestations - Polymorphic

• Non-bullous phase - Prodrome for several weeks - Pruritus,
eczematous, papular or urticarial lesions
• Tense vesicles & bullae containing clear fluid on normal or
erythematous base → on rupture form denuded areas with tendency
to heal spontaneously
• Nikolsky’s sign : negative
• Sites : Symmetrical distribution lower abdomen, inner thighs, groins,
flexural aspect of limbs. Mucosal surfaces are involved in 10-40%
cases
• Association : Malignancy, diabetes, ulcerative colitis, multiple
sclerosis
Bullous Pemphigoid

Tense Bullae Tense Vesicles

Diagnosis

• Tzanck smear : Plenty of eosinophils, few neutrophils but no

acantholytic cells
• Histopathology :
− Epidermis - normal
− Sub epidermal bulla filled with fibrin and eosinophils
− Dermis shows infiltrate of eosinophils, mononuclear cells and
neutrophils
• DIF/IIF :
− C3, IgG, IgA, IgM seen along BMZ and in circulation
− ELISA
Bullous Pemphigoid

Sub-epidermal blister with the DIF showing linear C3

lumen containing eosinophils deposition at the BMZ
Treatment

• Topical : Steroids
• Systemic : Steroids 40-80 mg/day & tapered when disease under control
− Dapsone
− Tetracycline and Nicotinamide
− Immunosuppressants
− Plasmapheresis & IV Gamma globulins
− Rituximab, IV Ig
• Prognosis :
− Benign self-limiting disease lasting from months to year
− Mortality rate less after advent of steroids
− Most common cause of death is usually some underlying associated
disease
Cicatricial Pemphigoid

• Rare blistering disorder, results in

permanent scarring of the affected area
• Mucosal lesions predominate-oro-pharynx,
nasopharynx, conjunctiva, larynx,
genitalia & esophagus
• Sequelae include oropharyngeal adhesions,
esophageal strictures, stridor, introital
shrinkage, symblepharon and ‘statue eye’
• Histology : Subepithelial bullae, similar to BP
• DIF : Linear C3, IgG, fibrinogen, occasionally IgM/IgA at basement
membrane in 90%
• IIF : Linear at basement membrane in 20%
CBDC- Chronic Bullous Disease of Childhood (CBDC)

Bullae In Circular (Annular)

Arrangement
Dermatitis Herpetiformis (DH)

• Intensely pruritic, chronic, recurrent, papulovesicular disease

• Underlying gluten-sensitive enteropathy - may be asymptomatic
• Onset usually between 20-55 Years
• Mainly males
• External factors: Gluten containing diet like wheat, barley, oats and
rye
• Antigen: Gut epithelial antigen cross reacts with skin
• Antibodies: IgA directed against gliadin and autoantigens like reticulin
and endomysium
• C3, IgG, IgM may be seen
Dermatitis Herpetiformis (DH)

• Pruritus - first & predominant symptom

• Symmetrical eruption of grouped erythematous papules and
papulovesicles rapidly excoriated - intact vesicles are difficult
to demonstrate
• Extensor aspects of limbs (elbows and knees), buttocks, natal cleft,
shoulders, upper back , face and scalp
• Oral lesions are common but asymptomatic
• Provocation of lesions occurs with iodides
• Differential Diagnosis :
− Scabies, Prodromal phase of Bullous pemphigoid, prurigo, papular
urticaria, neurotic excoriations etc
Dermatitis Herpetiformis

Symmetric, grouped Excoriations and post-

papulovesicles on the elbows inflammatory changes
Management of DH

• Investigation
• Histology of intact vesicles reveals neutrophilic microabscesses at the
tips of dermal papillae
• Direct immunofluorescence on clinically normal skin (buttocks) -
granular IgA deposits in dermal papillae
• Treatment
• Strict gluten free diet
• Dapsone 100-200 mg/day
• Sulphapyridine 1.5 g/ day
• Tetracycline with nicotinamide
• Colchicine when the above drugs are contraindicated
Thank You