(CHRONIC VESICOBULLOUS DERMATOSES)

BULLOUS SKIN DISEASES

dr. Kristo A. Nababan, SpKK

(CHRONIC VESICOBULLOUS DERMATOSES)

BULLOUS SKIN DISEASES

DEFINITION: Chronic blistering/vesicobullous dermatoses characterized by vesicles and bullae CLASSIFICATION: 1. Pemphigus : 1.1 P. vulgaris 1.2 P. erythematosus 1.3 P. foliaceus 1.4 P. vegetans: - Neumann type - Hallopeau type 2. Bullous pemphigoid 3. Dermatitis herpetiformis 4. Chronic bullous disease of childhood 5. Cicatricial pemphigoid 6. Pemphigoid gestationis 7. Epidermolysis bullosa

1. PEMPHIGUS
DEFINITION: A group of diseases characterized by chronic, flaccid, intraepidermal bullae, and can be fatal CLASSIFICATION: 4 type of Pemphigus: 1.1 Pemphigus vulgaris 1.2 Pemphigus erythematosus 1.3 Pemphigus foliaceus 1.4 pemphigus vegetans CHARACTERISTIC: Flaccid, easily ruptured bullae Nikolsky sign (+) Acantholysis (+) Ig G antibody: epidermal intracellular

1.1 PEMPHIGUS VULGARIS

EPIDEMIOLOGY: Most common type (80% cases) Worldwide, no race predilection Male = female Age: 4th and 5th decade any age, children ETIOLOGY: Unknown Autoimmune Associated with: LES, Bullous pemphigoid, Myasthenia gravis, Thymoma, Pernicious anemia PATHOGENESIS: Loss of cohesion between cells (Acantholysis) Ig G AB (+) 0n the keratinocyte surface

CLINICAL FEATURES: Poor general condition Initial sign & symptom: erosions & crusts: oral cavity, all mucous membrane with skuamous epithelial or scalp months (60%) Flaccid, easily ruptured bullae erosions crusts Nikolsky sign (+) Painful: erosion skin. Pruritus () Healing lesions: hypopigmented / hyperpigmented without scar HISTOPATHOLOGY: Suprabasal intraepidermal bullae Epidermal cells: acantholysis on the base of bullae DIFFERENTIAL DIAGNOSIS: 1. Dermatitis herpetiformis 2. Bullous pemphigoid

Differential Between Pemphigus Vulgaris (PV), Bullous Pemphigoid (BP) & Dermatitis Herpetiformis (DH)
PV
Etiology Age of onset Symptom Skin sign Nikolsky sign Predilection site Autoimmune 30-60 years Pruritus (-) Flaccid bullae + Generalized

BP
Autoimmune (?) Elderly Pruritus (-) Tense bullae Abdomen, flexor forearms, groin, medial thighs 10-40% Dermo-epidermal cleft, sub epidermal bullae, especially eosinophils Band-like Ig G on the basal membrane Corticosteroid: Prednisone 40-60 mg/day

DH
? Children or adult Pruritus (+++) Grouped, tense vesicles Symmetric, nuchal, shoulders, posterior axilla, extensor arms, sacrum, buttock Rare Sub epidermal cleft, especially neutropils Granular Ig A on the dermal papillae + + B8, DW3 DDS (Diamino Difenil Sulfon) 200300 mg/day

Mucous membrane & oral cavity involvement Histopatology

60% Intraepidermal bullae

Direct immunofluorecence Enteropathy Gluten-sensitive HLA Therapy

Complement Ig G on the dermis Corticosteroid: Prednisone 60-150 mg/day, cytostatic

TREATMENT: SYSTEMIC a. Corticosteroid (Prednisone/Dexamethasone) Dose: 60-150 mg/day 0r 3 mg/kg body weigh/day Dexamethasone I.M/I.V keep electrolyte fluid balance b. Corticosteroid + Cytostatic (Cyclophosphamide, azathioprine) c. Plasmapheresis d. Cyclosporine TOPICAL: Erosion Silver sulfadiazine PROGNOSIS: Death caused by sepsis & electrolyte imbalance Corticosteroid therapy better prognosis

1.2 PEMPHIGUS ERYTHEMATOSUS (SENEAR-USHER SYNDROME)

CLINICAL FEATURES: Good general condition Few skin lesions initially, including: well-defined erythematous macula with scale and crust on the face (butterfly), flaccid bullae Localized on the seborrheic areas generalized, lesion sometimes on the mucous membrane Lesion: may remains for months, often with remission Can change to Pemphigus vulgaris or foliaceus HISTOPATOLOGY: Identically with pemphigus foliaceus Old lesion: follicular hyperkeratosis, acanthosis, diskeratosis Direct immunofluorecence: Ab intracellular & basal membrane

DIFFERENTIAL DIAGNOSIS: 1. Dermatitis herpetiformis 2. Bullous pemphigoid 3. Lupus erythematosus 4. Seborrheic dermatitis TREATMENT: Corticosteroid: Prednisone 60 mg/day tapering off
PROGNOSIS: Better than Pemphigus vulgaris

1.3 PEMPHIGUS FOLIACEUS

CLINICAL FEATURES: Age: adult 40-50 years Symptom: not severe as P.vulgaris Chronic, temporary remission Lesion: vesicles/bullae, with scale & crust, exudative rupture erosion. Characteristic: generalized, erythema with large scale (>>>), flaccid bullae (<), foul odor Localization: scalp, face, upper chest symmetric in all part of the body. Oral lesion: rare Nikolsky sign (+)

HISTOPATOLOGY: Acantholysis: upper epidermal & stratum granulosum Bullae cleft: sub corneal DIFFERENTIAL DIAGNOSIS: Erythroderma Seborrheic dermatitis PROGNOSIS: Chronic disease

1.4 PEMPHIGUS VEGETANS

Benign variety of Pemphigus vulgaris Uncommon disease (rare) Classification: 2 types: A. Neumann type B. Hallopeau type

CLINICAL FEATURES: ~ P.vulgaris Younger Predilection: face, aksilla, external genital, other intertrigo areas Characteristic: flaccid bullae erosion papillomatous vegetation & proliferation (especially on the intertrigo area) Oral lesion always (+) Longer course & more acute than P.vulgaris Can be fatal

Neumann type

HISTOPATHOLOGY: Initial lesions = P.vulgaris Papillary proliferation with direction to upper portion Intraepidermal abscesses containing eosinophils

Hallopean Type

CLINICAL FETURES: Chronic & fatal Primary lesion: coalescent pustules extend to periphery vegetation cover the large area (aksilla & perineum) Mouth / oral lesion: velvet-like granulomatosis HISTOPATOLOGY: Initial lesion = Neumann type Suprabasal acantholysis with eosinophils Vegetative lesion epidermal hyperplasia + chronic eosinophilic abscess papillomatosis + hyperkeratosis, abscess (-)

TREATMENT: = P.vulgaris
PROGNOSIS: Hallopeau better prognosis

2. BULLOUS PEMPHIGOID
DEFINITION: Chronic disease, thick-walled bullae, erythema ETIOLOGY: Not clear, autoimmunity ??? CLINICAL FEATURES: Good general condition All ages, especially in elderly Skin lesion: bullae + vesicles, tense + erythema rupture bullae erosion Predilection: aksilla, arms (flexor), groin, mouth (20%)

HISTOPATOLOGY: early dermo-epidermal cleft Sebepidrmal bullae Eosinophil (+) IMMUNOLOGY: Ig G and C3 like band on BMZ DIFFERENTIAL DIAGNOSIS: 1. P. vulgaris 2. D. herpetiformis TREATMENT: 1. Corticosteroid: 40-80 mg/day, tapering off 2. Corticosteroid + Cytostatic 3. DDS: 200 300 mg/day 4. Tetracycline (3 x 500 mg/day) + Niacinamide (3 x 500 mg/day) PROGNOSIS: rare spontaneous remission

3. DERMATITIS HERPETIFORMIS (MORBUS DUHRING)

DEFINITION: Chronic disease, polymorph (symmetric, grouped vesicles), pruritus (+++) ETIOLOGY: Not well known
PATHOGENESIS: Gluten (Ag) small bowel (neutrophil as effectors) Iodium remission & exacerbation Small bowel skin abnormality (?)

CLINICAL FEATURES: Children & adult (especially 3rd decade) Slowly course, chronic residif, life time, spontaneous remission 10-15% case Good general condition, pruritus (+++) Predilection: back, sacrum, buttock, extensor upper arms, around elbow & knee Lesions: erythema, papule, vesicles, vesicles/bullae: symmetric, grouped Characteristic: tense vesicles , arsinate /sirsinate formation Intestine disorders:

90%: gluten sensitive-enteropathy (Jejunum & ileum) Mononuclear infiltrate on the lamina propia Vili atrophy mucous epithelial cells of flat small bowel 1/3 case: steatorrhea gluten-free diet better condition

HISTOPATOLOGY: Neutrophils on the dermal papilla Sub epidermal cleft

LABORATORY: Hyperoesinophilia: >40% (peripheral blood) Eosinophils 20-90% (vesicle/bulla fluid) IMMUNOLOGY: Granular dermal papilla Ig A on the lesion and normal skin (standard test DH) C3 (+) HLA-BB (85%), HLA DW3 (90%) DIFFERENTIAL DIAGNOSIS: 1. P. vulgaris 2. Bullous pemphigoid 3. Chronic Bullous Disease of Childhood (CBDC)

TREATMENT: 1. Drug of choice: DDS (Diamino Difenilsulfon)

Dose: 200-300 mg/day better condition 50 mg/day 2 days /1 week CI: Deficiency G6PD

2. 3.

Sulfapiridine: Dose: 1-4 gr/day Free-gluten diet:

Can reduce D/ drug Intestine disorders Skin disorders

PROGNOSIS: Chronic residif disease

4. Chronic Bullous Disease of Childhood (CBDC)

Intermediate form between Bullous pemphigoid & Dermatitis herpetiformis called Dermatoses linear Ig A In children CBDC DEFINITION: dermatoses in children, bulla & linear Ig A SINONIM: linear Ig A dermatoses of children ETIOLOGY: unknown CLINICAL FEATURES:
Preschool age ( 4 years) General condition: good Pruritus () Sudden remission & exacerbation Skin lesion: tense vesicles or bullae (>>) with normal/erythematous background, grouped, generalized Mucous membrane (+) Enteropathy (-)

HISTOPATHOLOGY: Sub epidermal bullae neutrophils/eosinopils Microabscess (neutrophils) on the dermal papilla
IMMUNOLOGY: Deposit linear Ig A & C3 (basal membrane), (2/3 cases) HLA B8 (30% cases) DIFFERENTIAL DIAGNOSIS: 1. Dermatitis herpetiformis 2. Bullous pemphigoid TREATMENT: Sulfapiridine 150 mg/kg/day DDS or corticosteroid or combination

5. CICATRICIAL PEMPHIGOID
DEFINITION: CP is a chronic bullous dermatoses, with main clinical features as bulla cicatrix on the mucosa , mouth & conjunctiva SINONIM: CP = Benign mucosal pemphigoid or Ocular pemphigoid EPIDEMIOLOGY: Rare disease CLINICAL FEATURES: General condition: good; very rare remission Mucous abnormality: mouth 90%, conjunctiva 66% nasal, pharynx , larynx, esophagus, genitalia Ocular symptoms: burning sensation, photophobia, mucoid secretions corneal opacity blindness Nasal mucosal nasal obstruction Pharynx mucosal laryngeal scar & stenosis Skin (30%) tense bulla: inguinal & extremity generalized

HISTOPATHOLOGY: = Bullous pemphigoid IMMUNOLOGY: IF Ab (+) & C (+) on the basal membrane linearly (Ig G) DIFFERENTIAL DIAGNOSIS: 1. Pemphigus vulgaris 2. Oral lichen planus 3. Erythema multiforme 4. Behcet disease 5. Desquamation gingivitis TREATMENT: Prednisone: 0 mg/day with tapering off Or immunosuppressive: MTX, Ciclophosphamide, Azathioprine

6. HERPES GESTATIONIS
DEFINITION: Dermatoses, grouped polymorph lesion, arises in pregnancy, remission after delivered SINONIM: Pemphigus gravidarum, Hydro gravidarum

EPIDEMIOLOGY: Child bearing woman Incidence: 1/10.000 PATHOGENESIS: Unknown > herpes viruses Hormonal trigger factor (when pregnant, menses, estrogen & progestin therapy 1973 immunology mechanism

CLINICAL FEATURE: Prodrome: fever, malaise, nausea, headache Before eruption very itch & burning sensation Lesion: papulo-vesicle, grouped, polymorph (erythema, edema, papule, tense bullae) Intermediate small vesicles, plaque wheal, vesicles, grouped, erosion & crust Pruritus (+++) Attacking time: often on 2nd semester (5th & 6th month). The earliest: 2nd week pregnancy, the latest: after delivered / 1st menses Predilection: abdomen, extremities (palms & soles) all the body, asymmetric + face and legs edema Mucous membrane () Ruptured bulla excoriation, crust Healing: - hyperpigmentation - scar tissues

LABORATORY: Leucocytosis Eosinophilia (50%) HISTOPATHOLOGY: bulla containing eosinophil on the sub epidermal layer IMMUNOLOGY: DIF: C3 & Ig G on the basal membrane DIFFERENTIAL DIAGNOSIS: 1. Dermatitis gravidarum 2. Prurigo gestationis 3. Impetigo herpetiformis 4. Dermatitis herpetiformis 5. Bullous pemphigoid TREATMENT: Prednisone 20-40 mg/day with tapering off be careful: neonatal adrenal failure Fetal death & prematurity Antihistamine or topical steroid Azathioprine + Prednisone depend on the illness

PROGNOSIS: Complication: Mother : pruritus, secondary infection, often repeated on the next pregnancy Baby: fetal death, prematurity

7. Epidermolysis Bullosa
DEFINITION: genetic chronic bullous disease, recessive and dominant autosomal Spontaneously or caused minor trauma, which bulla not too epidermal SINONIM: Mechanobullous disease EPIDEMIOLOGY: Incidence 1 : 50.000

CLASSIFICATION: I. EB without scar tissue II. EB with scar tissue

EPIDERMOLYSIS BULLOSA WITHOUT SCAR TISSUE

Type Genetic trait
Dominant autosomal

Clinical Features

Pathogenesis

Electron/ immunofluorecence Microscope

Intraepidermal bulla caused by basal cells cytolysis, vacuolitic & basal cells degenerations Intraepidermal bulla upper basal cells, usually on the spinosum cells

EB simplex

Early after born on the traumatic area Clear/hemorrhagic bullae Free mucosa 20% nail involvement

Presumed: cytolysis enzyme producing and temperature change-sensitive abnormal protein producing Presumed: collagenproduction enzyme deficiency: Galactosylhydroxylysis Glucosyltransferase Hemidesmosome deficiency not good plaque attachment Presumed: skin fetal attachment to amnion (cynomart band)

Recurrent EB on the hand & feet (WeberCockayne disease) Junctional EB (Herlitz disease) (EB letalis) Bart Syndrome (Localized absence of the skin with blistreing & nail dystrophy)

Dominant autosomal

Age of onset: 1-2 years or before adolescent Clear bulla on the palms/soles, knee orelbow Can be associated with hyperhydrosis Onset at birth or soon after birth Generalized bulla (pals and soles spare) especially on the head and around mouth Often fatal Erosion on the mouth, extensor,areas intertriginous areas,nuchal and buttock Nail involvement (+) Spontaneously remission Patient remains normal

Recessive autosomal

Bulla located on the upper basal membrane, between bullous pemphigoid laminin & antigen Bulla develop on the basal membrane dermal with epidermal erosion

Dominant autosomal

EPIDERMOLYSIS BULLOSA WITH SCAR TISSUE

Type
EBD dominant EB dermatoses

Genetic trait
DA

Clinical features
Onset: when baby start to crawl. Bulla on the traumatic site (extremities). Slow healing scar tissue. Mucosa involvement 20%. Nail involvement 80%. Teeth & hair involvement rare Onset: newborn. Spontaneous bulla generalized. Mucosal and nail involvement (+). MR (+), growth disorders. Healed with scar, dystrophic, deformity (finger contracture)
Onset: adolescent/adult. Localization: knee, elbow, oral mucosa (traumatic site). Nail involvement (+). Hypersensitivity associations (?)

Pathogenesis
Reduce of anchoring fibril

Microscope / immnofluorecence
Bulla under basal membrane, decrease of anchoring fibril without collagen degeneration

EBD recessive

DA

Increase of collagen activity

Bulla under basal membrane, absence of the anchoring fibril, collagen degeneration

Acquired EB

Non-hereditary

Collagen VII gen mutation. Anchoring fibril component

Bulla under basal membrane

Based on bulla location on the dermo-epidermal junction

1.
1.1 Common form 1.1.1 Localized EBS on the hand ang feet (Weber Cockayne) 1.1.2 Generalized EBS (Koebner) 1.1.3 EBS herpetiformis (Bowling-Meara) 1.2 Uncommon form 1.2.1 EBS with muscle atrophy 1.2.2 Superficial EBS 1.2.3 Kallin syndrome 1.2.4EBS with mottled pigmentation 1.2.5 Fatal recessive autosomal EBS 2.1 Common variant form 2.2 Letal form (Gravis, Herlitz) 2.3 Non-letal (Mitis, Non-Herlitz) 2.4 Inverse EB 3.1 Dominant dystrophic (dermolysis) 3.2 Generalized recessive dystrophic 3.3 Localized recessive dystrophic 3.4 Variant form

EB simplex

2.

Junctional EB

3.

Dystrophic EB

CLINICAL FEATURES: Bulla develop on the traumatic-easily site Clear bulla, little tense, sometimes hemorrhagic HISTOPATHOLOGY: Bulla on the epidermal or dermal
CARE & TREATMENT: Avoid trauma/friction Bulla can be stab with sterile needle and leave the roof Lesion on the oral mucosa soft/liquefy food KeepeEnvironment temperature cool enough No ideal and satisfied therapy
Systemic corticosteroid (severe cases) Vitamin E: 600-1600 IU/day Diphenylhydantoin: 2,5 5 mg/kg/day, max: 300 mg/day Topical steroid & antibiotic