02-25 Bullous Disorders

Question 1

This lecture focuses on auto-immune and hereditary forms of bullous diseaes.

What are some other causes?

• Bullae of the diabetic
• Coma blisters
• Friction blisters
• Bullous drug eruptions
• Bullous insect bite reactions
• Post burn
• Edema blisters
• Infx (Strep, staph)
• Herpes

Question 2

acantholysis

Answer 2

• disruptions of the desmosomes
• results in intraepidermal blisters (bullae)
• Alterations in desmosomes typically cause flaccid bullae which easily rupture
  
  • so you might only see the erosions/p popping in clinic

Question 3

Desmosomes

• Structure & Fxn
• Appearance
• Chemical Composition
• Clinical Correlations

Answer 3

• Structure & Fxn:
  
  1. keratinocyte-keratinocyte adhesion
  2. Provides resistance to mechanical stress
  3. Provides slow but strong adhesion
  4. ↑ in size and # as keratinocytes migrate upward
• Apperance:
  
  • Seen as “spines” or “prickles” on histo, particularly in stratum spinosum
• Chemical Composition
  
  1. Complex of cell adhesion proteins and linking proteins
     
     1. Cadherins: Calcium-dependent cell-cell adhesion molecule
        
        • (1) Desmosomal cadherins: Desmogleins 1&3
        • (2) Transmembrane proteins
     2. Linking proteins
        
        • (1) Cytoplasmic proteins
        • (2) Attach to intracellular keratin cytoskeleton filaments

Question 4

3 fxs of BM zone (a.k.a. dermal-epidermal jct)

Answer 4

1. attachment
2. permeabiity barrier (w/ stratum corneum)
3. tissue repair

Question 5

Levels of epidermal Basement MEmbrane

• fxn?

Answer 5

1. Basal keratinocyte
   
   • deep side of basal keratinocyte plasma membrane + hemidesmosome attaching to lamina lucida fibrils
   • Contains bullous pemphigoid antigens
2. Lamina lucida
   
   • weakest portion of BM zone
   • test for dz there w/ salt split
   • BP-AG-180 (anchoring filament) is antigen in bullous pemphigoid
3. Lamina densa
   
   • considered the BM “proper”
   • Type IV collagen (mutations could cause blistering pathology)
4. Sublamina Densa
   
   • Adheres via anchoring fibrils & plaques to connect BM proper (i.e. lamina densa) to collagen in dermis
   • Type VII Collagen

Question 6

What is this dz, general name

Answer 6

Pemphigous

• Presentation
• Flaccid clear-fluid-filled or hemorrhagic bullae
• Whole category of diseases

Question 7

DZ: Pemphigous vulgaris

• Epidemiology
• Presentation
• Natural Hx
• Path Dx

Answer 7

Epidemiology

• Ages 50-60s, but can occur at any age
• 5/million, U.S.
• M = F
• Ashkenazi Jews and Mediterranean ancestry (16-32/million)

Presentation

• usually presents w/ oral lesions
• also see flaccid bullae → erosion → hyperpigmentation after healing (but no scar)
  
  • blisters above the lamina lucida do not scar
• internal organs not involved
• Nikolsky sign: can push a whole layer of skin over
• Asboe Hanser sign: pressure on an intact bulla makes it spread out

Natural Hx

• Much more serious than bullous pemphigous
• 80-90% mortality w/o tx!
• Infx, big protein requirements
• Used to be commonly fatal
• Still refractory to treatment

Path Dx - take a sample just lateral to the erosion

• HISTO (see pic) :
  
  1. Tombstoning
  2. Intraepidermal split
  3. Acantholysis
• Direct IF: chicken wire pattern
• Indirect IF: pt’s serum + anti-human Ab-Ab + monkey esophagus (or other strat squam); incubate together; if pt has Abs in serum, will attack
  
  • Titer: correlates with dz activity

Tx

• prednisone 1-2mg/kg/d X 6w → add steroid-sparing agent slow taper = gold std
• rituximab is #2 tx
• immunosuppressants
  
  • MMF
  • Azathioprine
  • Cyclosporine

Question 8

Pemphigous vulgaris Pathophysiology

Answer 8

• anti-Dsg3 auto-immunity

Question 9

DZ: Pemphigous foliaceous

• Presentation
• Pathophys

Answer 9

Variant Presentation of Pemphigous vulgaris w/ more benign course

Presentation

• very superficial bullae
• enlarge: extensive areas of moist, red, edematous, exfoliated, heaped-up skin
• Oral mucosa rarely involved
• more on scalp and ?
• more

Pathophysiology

• Anti-Dsg1 (split high than vulgaris)

Histo

• see pic, contrasting the two

Question 10

DZ: Fogo selvagem

Answer 10

Variant Presentation of Pemphigous vulgaris

• Brazilians, endemic
• ?Cross rxn w/ black fly

Question 11

paraneoplastic pemphigous

Answer 11

Variant Presentation of Pemphigous vulgaris

• most commonly w/ thymoma; also see with NHL (40%) and CLL (23%)
• painful oral lesions + truncal eruptions
• both occular (injected) and lip involvement (crusted and hemorrhage)
• rash that looks like erythema multiforme

Question 12

Drugs that induce pemphigous

Answer 12

Penicillamine* and captopril

*immunosuppresssant drug used to treat RA that is a metabolite of penicillin but has not abx effects

Question 13

Pemphigous foliaceous vs. Pemphigous vulgaris: Which is which?

Answer 13

• Left: foliaceous
• Right: vulgaris

Question 14

DZ: Dx of this pic?

• Pathophys?
• Natural Hx?
• Presentation?
• Histopath?
• IF Findings?
• Tx?
• Prognosis?

Answer 14

Pathophys

• Autoimmune dz w/ antigens* to hemidesmosomes → Abs/complement/cytokines → sep of dermis and epidermis
  
  • *BPAg1 & BPAg2 (Collagen XVII)

Natural Hx

• Much more common than pemphigus (10/ mil vs. 1/mil)
• Elderly–Average age 65-75
  
  • > 80% older than 60

Presentation

• Large, tense, bullae
• Groin, axillae, thighs, flexor forearms
• Negative Nikolsky
  
  • Actually see many bullae vs. mostly erosions in pemphigous
• Early dz often hive like
• ITCHY!!!!
• Oral involvement: 20%

Histopath

• (See attached photo)
• NO acantholysis
• Subepidermal blister with eosinophils
• Routine biopsy often NOT diagnostic

IF Findings

• Direct IF:
  
  • Linear BM staingin with anit-C3 and anti-IgG
• Indirect IF (pt’s serum + monkey esophagous, squamous cells)
  
  • serum titers have no correlation w/ dz burden

Treatment

• Potent topical steroids for limited disease
• Prednisone 0.5-1 mg/kg/day
• Rituximab
• Immunosuppressants (often in combo w/ steroids)
  
  • MMF (mycophenolate mofetil = CellCept)
  • Azathioprine
  • MTX

Prognosis

• Actually clears (in 5-6 years, i.e. slowly) vs. pemphigous

Question 15

Nikolsky sign

Answer 15

provider can can push a whole layer of skin over

positive in Pemphigous, negative in bullous pemphigoid

Question 16

Asboe Hanser sign

Answer 16

pressure on an intact bulla makes it spread out

positive in Pemphigous, negative in bullous pemphigoid

Question 17

Blisters cause scars when lesions go how deep?

Answer 17

• blisters above the lamina lucida do not scar
• blisters below it do

Question 18

DZ: Epidermolysis bullosa Overview

• Natural Hx
• Presentation

Answer 18

Natural HX

• rare disorder w/ both AD and AR inheritance form
• Varied mutations and clinical presentations

Presentation

• characterized by blistering at sites of trauma
• Heterogeneous presentation (mild to life-threatening) classified by:
  
  • Where blister arises in skin
  • Genetic mode of transmission
  • Clinical phenotype
  • See notes for pathophys and presentation details of each kind
• Four forms:
  
  • Mechanical fragility – minimal traction induces
  • Tense-clear fluid filled blisters
  • Erosions and crusts
  • Scarring
• Variable findings:
  
  • nail changes, milia,
  • scarring alopecia

Treatment

1. Avoidance of trauma and attempting to maintain a cool ambient temperature.
2. Treatment is primarily supportive in severe cases
   
   • Antibiotics as necessary, either topically or systemically
   • Surgical procedures such as esophageal dilatation or “degloving” of mitten deformities of the
     hands in severe recessive dystrophic epidermolysis bullosa
   • Good dental care for oral involvement
   • Nutritional supplement (iron and/or protein) if indicated.

Question 19

Salt Split Skin Technique

Answer 19

• Bullous pemphigoid can be differentiated from Pemphigous conditions by incubating skin biopsy sample in 1 mol/L salt before DIF.
• This induces cleavage through lamina lucida.
• DIF on salt-split skin reveals:
  
  • IgG on blister roof (epidermal side of split skin) in patients with bullous pemphigoid
  • (IgG on blister floor in CP and EBA) not dzs we covered

Question 20

Disruption of desmosomes vs. Disruption of BM

Answer 20

Alterations in desmosomes

1. Disruption of desmosomes causes cells to round and separate, called acantholysis on H&E
2. Results in intraepidermal blisters
3. Alterations in desmosomes typically cause flaccid bullae which easily rupture

Alterations in the basement membrane zone typically:

1. Disruption of basement membrane zone causes a split at the dermal-epidermal junction
2. Results in subepidermal blisters
3. Alterations in the basement membrane zone typically cause tense bullae
4. Identifying the autoantigen through immunofluorescence is important in confirming a clinical
   dx of a 1° bullous disorder
5. Immunofluorescence can be performed both on skin (direct) and serum (indirect) samples

Question 21

DZ: Cicatricial pemphigoid

Answer 21

• Variant of Bullous pemphigoid*
  a. k.a. mucous membrane pemphigoid
• Involves mucous membranes, particularly oral mucosa and conjunctiva with skin involvement in only 25% of cases. Can result in blindness. Little tendency toward remission. Severe disease responds best to cyclophosphamide

Question 22

DZ: Gestational pemphigoid

Answer 22

bullous pemphigoid during pregnancy or postpartum period