Blistering diseases - Levin Flashcards
By definition, what is a blister?
In the skin, where do blisters occurr
Name the types of blisters
A blister is a seperation between layers of the skin
Intraepidermal - between the layers of the epidermis
Subepidermal - beneath the epidermis
Vesicle - a blister less than 1cm
Bulla - a blister greater than 1cm
What holds the skin together?
Desmosomes - connect adjacent keratinocytes in the epidermis
Hemidesmosomes - connect cells in the basal layer to the basement membrane
What are the types of blistering disorders?
Genetic - Epidermolysis bullosa caused by mutations in basal layer keratins and hemidesmosomal proteins
Infectious - Staphylococcal scalded skin syndrome, bullous cellulitis, Herpes simplex virus, Varicella zoster virus
Traumatic/physical causes - Friction blister, coma bulla, burns (including sunburn), cryotherapy
External contactants - Contact dermatitis (poison ivy), chemical burns, vesicants (e.g. blister beetle juice)
Drug reaction - Stevens Johnson Syndrome, Toxic Epidermal Necrolyis
Metabolic - Porphyria cutanea tarda
Autoimmune Disease - Pemphigus vulgaris, pemphigus foliaceus, bullous pemphigoid, dermatitis herpetiformis, linear IgA bullous dermatosis
What are the classifications of the blister by the level of the skin
Subcorneal: Subcorneal pustular dermatosis of Sneddon and Wilkinson
Granular layer: Staphylococcal scalded skin syndrome
Upper spinous layer: Pemphigus foliaceus
Spinous layer: Friction blister
Lower spinous layer: Pemphigus vulgaris
Basal layer: Epidermolysis bullosa simplex
Subepidermal: Bullous pemphigoid, dermatitis herpetiformis, linear IgA bullous dermatosis, epidermolysis bullosa acquisita, junctional and dystrophic epidermolysis bullosa
Staphylococcal scalded skin sydrome
Who does it usually affect
what is the typical history of patients with this syndrome
Staph positive on culture
May precede respiratory infection
Prodrome of malaise, fever, irritability and very tender skin
What is the clinical presentation of Staphylococcal Scalded Skin Syndrome?
- Rapid course: Erythema spreads from head to entire body within hours; develops wrinkled appearance within a day and then sloughs, leaving behind moist denuded skin and crust
- Over 3-5 days, scaling and desquamation occurs
- Spares palms, soles and mucous membranes
- After 1-2 weeks healing occurs w/o scarring
What is the pathophysiology of Staphylococcal Scalded Skin sydrome?
- Staphylococcus aureus at distant focus (nose, pharynx, ear, umbilicus)
- Blisters are sterile (unlike bullous impetigo)
- Epidermolytic toxins A and B; produced by Group II S. aureus Phages (types 3A, 3C, 55, 71)
- Toxins cleave Desmoglein 1, a desmosomal protein in the upper spinous layer, leading to an intra-epidermal blister
- Toxins cleared by the kidneys (neonates, adults with renal failure have poor clearance)
The differential for staphylococcal scalded skin syndrome includes:
Toxic epidermal necrolysis
Kawasaki’s disease
Viral exanthem
Toxic shock syndrome
What is Nikolsky’s sign and in what diseaes is it seen?
It is seen in Staphylococcal scalded skin sydrome - and it is when lateral pressure on unblistered skin induces a new blister (skin peels off)
What is Asboe-Hansen’s sign and in what disease is it seen?
It is seen in Staphylococcus Scalded Skin Syndrome - it is when pressure on top of a blister causes it to extend into normal appearing skin
What is the pathology seen in Staphylococcal Scalded Skin Syndrome?
Oral treatment with a beta-lactamase resistant penicillin or cephalosporin antibiotic for 1 week is usually sufficient
Apply bland emollients to skin
Isolate patient from other infants to prevent spread of Staph.
What is the treatment of Staphylococcal Scalded Skin Syndrome?
What are the three main types of Pemphigus?
What causes pemphigus
Pemphigus vulgaris (can be severe)
Pemphigus foliaceus (milder one)
Paraneoplastic pemphigus (can be severe)
Pemphigus is caused by lack of cohesion between keratinocytes (acantholysis) and mediated by IgG antibodies to desmosomal proteins
Rare and often fatal
Which group of people is mostly affected by pempigus vulgaris?
Adults 5th (40s) and 6th decade (50s)
Jewish and Mediterranean descent
HLA DR4, DR6 DQ1
What are the clinical features of pemphigus vulgaris
Classic - development of oral and other mucous membrane erosions
Most also develop large, flaccid bullae arising from normal apprearing skin, contain clear to hemorrhagic fluid; rapidly rupture to form erosion/crusts
The bullae may begin in mouth; groin, scalp, face, neck, axillae, genital area
Nikolsky’s sign positive
What is the pathology of Pemphigus vulgaris?
Acontholysis - dissociation of keratinocytes
Acontholysis is at the suprabasilar level - its an intraepidermal blister
Non-inflammatory
Only the basal cell layer remains at the floor of the blister “row of tombstones”
Explain the differences in indirect and direct immunoflourescence in pemphigus vulgaris
- Direct IF
- Fluorescently labelled Abs to IgG are applied to patient’s skin biopsy specimen
- These Abs detect presence of patient’s IgG deposits within their own epidermis directed against DSG-3 and often DSG-1
- Intercellular staining throughout epidermis appears as a “chicken wire fence”
- Indirect IF:
- patient’s serum containing IgG to desmoglein- 3 (and often DSG-1) is applied to an epithelial substrate such as monkey esophagus
- Circulating IgG levels correlate with disease activity
What is the treatment for Pemphigus vulgaris?
Systemic corticosteroids (prednisone)
Steroid sparing agents: azathioprine, cyclophosphamide, mycophenolate mofetil
Plasmapheresis, Intravenous immunoglobulin G (IVIG)
Rituximab: an anti-CD20 monoclonal antibody that decreases pathogenic IgG production
Which group of people get Pemphigus foliaceus
Adults, 40-50 years
An endemic type occurs in Brazil
What is the clinical presentation of pemphigus foliaceus?
Small flaccid bullae, rupture as soon as they appear; crusting and bleeding
Scal, face and trunk affected
Mucosal lesion are NOT a feaure (different from p. vulgaris)
Evolves into localized or generalized exfoliation; burning pruritis
Nikolsky’s sign is present
This is the milder form of pemphigus
What is the pathology of pemphigus foliaceus
Acantholysis in upper epidermis, granular layer
Subcorneal blister
Immunoflourescence in pempigus foliaceus
Direct IF: intercellular IgG in upper epidermis
ELISA: Antibodies to Desmoglein 1, NOT Desmoglein 3
Contrast to Pemphigus vulgaris: Abs to DSG-3 +/- DSG-1
What are the antibody profiles in pemphigus
Pemphigus foliaceus?
Pemphigus vulgaris (oral lesions only)
Pemphigus vulgaris (oral and skin lesions)
Pemphigus foliaceus - Demoglein 1
Pemphigus vulgaris (oral lesions only) - Desmoglein 3
Pemphigus vulgaris (oral and skin lesions) - Desmoglein 1 and 3
What is the treatment of pemphigus foliaceus?
Treatment is the same as pemphigus vulgaris:
Systemic corticosteroids (prednisone) - However topical steroid can also be used since this is a milder disease
Steroid sparing agents: azathioprine, cyclophosphamide, mycophenolate mofetil
Plasmapheresis, Intravenous immunoglobulin G (IVIG)
Rituximab: an anti-CD20 monoclonal antibody that decreases pathogenic IgG production
What is bullous pemphigoid - pathophysiology
It is an autoimmune subepidermal blistering disease involving autoantibodies to hemidesmosomal proteins
More common and better prognosis than pempigus vulgaris
It is associated with HLA class II DQB1*0301 in Caucasians
Who is most likely to have bullous pemphigoid?
Its most common in the elderly
What is the clinical presentation of bullous pemphigoid?
Generalized symmetric intensely pruritic eruption with widespread tense blisters (unlike pemphigus which has flaccid blisters)
Early stage may be urticarial (hives) or eczematous, rather than bullous
Lower legs, thighs, groin area, flexor surfaces of forearms
20-30% have mucosal involvement
Does not scar
Nikolsky’s sign negative
Often self-limited (5-6 year period); may come and go for years
Typically not life threatening
What is the pathology of Bullous pemphigoid
Subepidermal split
Inflammatory blister cavity with eosinophils
Bullous Pemphigoid immunostaining
DIRECT IMMUNOFLUORESCENCE
- LINEAR STAINING for IgG and C3 along basement membrane zone
INDIRECT IMMUNOFLUORESCENCE
- 70% have circulating IgG
- Level does not correlate with disease activity (IN CONTRAST TO PEMPHIGUS)
What are the bullous pemphigoid antigens?
Bullous pemphigoid antigen 1 is a 230 kD protein in the hemidesmosomal plaque
Bullous pemphigoid antigen 2 is a 180 kD protein, also called type XVII collagen, that makes up anchoring filaments
How do you treat bullous pemphigoid
TREATMENT: Suppress inflammation; wait for remission (unlike pemphigus)
- Oral and topical steroids
- Tetracycline/niacinamide
- Immunosuppressive agents (azathioprine, mycophenolate moffetil)
Who is mostly affected by dermatitis herpitiformis?
Most common in Northern Europeans
Usual onset at 20-40 years old
What is the clinical presentation of dermatitis herpitiformis?
An intensely pruritic subepidermal blistering disease associated with gluten sensitivity (celiac disease) and IgA Abs against tissue transglutaminase
- >90% have gluten-sensitive enteropathy on small bowel biopsy
- 20% are symptomatic with celiac disease
- Increased risk of intestinal lymphoma (3%) and thyroid disease
Associated with HLA DQ2A1*05B1*02
Clinical presentation:
- Symmetrical, grouped vesicles (often excoriated) on extensor surfaces, scalp, neck, posterior axillary folds, buttocks
- No mucous membrane involvement
- Intense burning and itching
- Nikolsky’s sign negative
What is the pathogenesis of dermatitis herpitiformis?
What are the histological features?
Antigenic stimulation by gluten leads to inflammation and IgA antibodies
IgA Abs bind to epidermal transglutaminase and form IgA-immune complexes that are deposited in skin
Complement activated inflammation leads to neutrophils in dermal papillae
Histology:
- Subepidermal vesicles
- Neutrophils in groups at the dermal papillae +/- eosinophils
Where should immunoflourescence be taken
What do you see?
Direct IF should be taken from peri-lesional skin
IgA in a granular pattern at the dermal papillae
How do you treat dermatitis herpetiformis
Dapsone: Its an antineutrophilic agent. Highly effective
Gluten-free diet alone can cause remission, though this may take months to years; reduces risk of intestinal lymphoma
Epidermolysis bullosa
What is it?
What are the types?
A group of inherited blistering disorders
Three main types:
- Simplex: Split occurs in basal cell layer –> Keratins 5 and 14 defect (intermediate filament proteins expressed in basal layer)
- Junctional: Split within basement membrane zone –> laminin 5; alpha-6, beta-4 integrins; type XVII collagen defects
- Dystrophic: Split beneath basement membrane –> type VII collagen defect
Epidermolysis bullosa
Clinical presentation
Treatment
Clinical presentations - vary widely from very mild localized variants EM simplex (Weber-Cockayne) to universally fatal generalized types (Herlitz Junctional type)
There is also a recessive dystrophic type - it has a risk of sqaumous cell carcinoma (usually cause of death)
Treatment is largely supportive and consists of specialized dressings and wound care
Future treatments: gene therapy?
