Vesiculobullous Disease

Question 1

List the 2 vesiculobullous diseases

Answer 1

1. Bullous Pemphigoid

2. Pemphigus Vulgaris

Question 2

Define vesiculobullous disease

Answer 2

• Uncommon chronic skin disorders caused by autoantibodies against various cutaneous proteins
• Significant quality of life issues

Question 3

Epidemiology of bullous pemphigoid (BP)

Answer 3

• Bullous pemphigoid occurs equally in males and females.
• More prevalent in elderly patients.
• Usually in patients > 65 years of age with other comorbidities
• Median age of onset is 68-82

Question 4

Causes of BP

Answer 4

• A drug, an injury, or skin infection can trigger the onset of disease
• There are HLA associations indicating genetic predisposition to the disease

Question 5

Drug causes of BP

Answer 5

• furosemide
• captopril
• penicillamine
• antibiotics

Question 6

Pathophysiology of BP

Answer 6

• Bullous pemphigoid is associated with the production of autoantibodies (IgG, +/- IgE immunoglobulins) targeting the basement membrane
• The binding of the autoantibodies to the proteins at the basement membrane stimulates destructive inflammatory cascade, predominantly mast cells and eosinophils

Question 7

Name the 2 BP antigens that are autoantibody targets

Answer 7

Antibodies directed against 2 antigens: BP180 and BP230

Question 8

Why is the basement membrane important in BP?

Answer 8

The basement membrane is important for the adhesion of the epidermis to the dermis, and so when targeted, leads to a separation (blister) in this space

Question 9

What is the result of autoantibodies targeting the basement membrane in BP?

Answer 9

Results in the separation of the epidermis from the dermis forming a subepidermal blister

Question 10

How does BP present on clinical exam?

Answer 10

• Prodromal erythematous, pruritic urticarial or papular eruption.
• Pruritus can be severe**

Question 11

Where are the lesions with BP?

Answer 11

• Lesions usually bilateral and symmetric

- Predilection for groin, axillae, trunk, legs and flexural forearms.

Question 12

What is the timeline for BP lesions?

Answer 12

-Evolves in weeks to months to bullae: small expanding to large, tense bullae, which rupture forming erosions.

Question 13

Are the mucous membranes involved in BP?

Answer 13

• yes, but involvement rare - less than 10-20%

- if there is involvement, generally oral cavity.

Question 14

Dx of BP

Answer 14

• Diagnosis is made based upon clinical, histologic, and IF features
• Most cases diagnosis confirmed by a skin biopsy (2 kinds: H&E + DIF)

Question 15

Explain the H&E biopsy for BP

Answer 15

• biopsy of lesional skin (involved skin)
• report would reveal: “subepidermal blister with an inflammatory cell infiltrate containing eosinophils in the superficial dermis the presence of C3 deposition along the epidermal basement membrane zone”
• used for the confirmation of the diagnosis

Question 16

Explain the DIF biopsy for BP

Answer 16

• Direct immunofluorescence (DIF) staining of normal-appearing perilesional skin (uninvolved skin)
• Reveals linear IgG &/or complement C3 along basement membrane

Question 17

What other test for dx of BP?

Answer 17

ELISA test for detection of circulating antigen specific, BP180 and BP230,IgG and IgE antibodies is available.

Question 18

What is involved with DIF biopsy?

Answer 18

• Refrigerated in Michel’s media
• The antibodies IgG fluoresce neon green for pathologist
• Necessity in diagnosis of blistering diseases
• If perilesional (noninvolved skin) sample is taken, recommend > 3.0 mm away from blister edge

Question 19

Tx of bullous pemphigoid

Answer 19

• treatment is directed at reducing the inflammatory response and autoantibody production*
• Goal of therapy is to decrease blister formation
• Use immunosuppressing systemic therapy
• Promote healing of blisters and erosions (wound care, prevent /treat secondary infections)
• Determine the minimal dose of medication necessary to control the disease process.
• Clear patient of blisters with high dose medication, then slow taper

Question 20

For specific bullous pemphigoid tx…

Answer 20

See Dr. Letassy’s handout :)

Question 21

Prognosis of BP

Answer 21

• Characterized by a waxing and waning course
• Occasional spontaneous remission in the absence of treatment
• Localized disease often resolves spontaneously, but spontaneous remission can even occur in patients with more generalized disease
• One study reported that 8 of 30 adults with bullous pemphigoid went into remission after approximately 15 months (range, 3–38 months) of active disease

Question 22

Pemphigus Vulgaris (PV) epidemiology

Answer 22

• Equal frequency in men and women
• Usually 5th and 6th decades (slightly younger than BP)
• MC in Jewish and those of Mediterranean descent and from Middle East

Question 23

Etiology of PV

Answer 23

Autoimmune blistering disease with IgG autoantibodies directed against desmogleins 3 and 1

Question 24

What are desmogleins?

Answer 24

desmosomal proteins that help the keratinocytes in the epidermis attach to each other

Question 25

Which PV lesions dominate with autoantibodies towards Dsg3?

Answer 25

mucosal lesions dominate

Question 26

Which PV lesions dominate with autoantibodies towards both Dsg1 and 3?

Answer 26

mucocutaneous disease

Question 27

What do autoantibodies towards Dsg1 and 3 cause in PV?

Answer 27

**acantholysis – separation of the skin

Question 28

Clinical presentation of PV

Answer 28

- Characterized by painful mucosal erosions and thin-walled (i.e. more flaccid, not as tense), easily ruptured bullae - Blisters typically arise on normal-appearing skin but can be erythematous skin * *No preceding urticarial stage line in BP - Because PV blisters are fragile, MC for skin lesions observed to be erosions resulting from broken blisters

Question 29

Clinical findings in PV - sign - location of 1st involvement

Answer 29

+ Nikolsky sign – epidermis easily shears away from underlying dermis with pressure, twisting or rubbing -usually appears first in the mouth (60% cases) or at site of skin injury

Question 30

Other mucosal involvement with PV

Answer 30

Mucosal involvement usually oral cavity but may involve nasal mucosa, pharynx, larynx, esophagus, conjunctiva, and genitals

Question 31

Define pemphigus foliaceus

Answer 31

- no mucosal lesions; scaly, crusted lesions on an erythematous base - Also called superficial pemphigus as occurs higher in epidermis

Question 32

Dx of PV

Answer 32

- Made by histology from lesional skin + confirmatory immunochemical study via direct immunofluorescence or Enzyme-Linked Immunosorbent Assay - Histology shows acantholysis with intraepidermal blister formation

Question 33

What does PV show on DIF?

Answer 33

staining reveals “chicken wire” pattern of intercellular IgG deposited in perilesional skin bound to the cell surface of keratinocytes

Question 34

ELISA for PV

Answer 34

Autoantibodies against desmoglein 3 &/or, desmoglein 1

Question 35

PV prognosis

Answer 35

- Prior to glucocorticoid therapy, PV was almost always fatal from malnutrition, dehydration and sepsis - Still a disease associated with a significant morbidity and mortality, now approximately 10% or less mortality - Infection +/- immunosuppression of tx is often the cause of death - Remission is possible +/- relapses

Question 36

Tx of PV

Answer 36

- No FDA approved treatments - Approach to tx varies widely - Topical steroids may suffice for localized dz - Systemic glucocorticoids is mainstay; 2.0 mg/kg/day single daily dose - Once disease activity is controlled, tapering prednisone to as low a dose as possible is the goal

Question 37

Tx of PV continued...

Answer 37

- If continued relapses with daily prednisone dose of 10 mg or higher, adjunctive immunosuppressive agents should be considered - Mucosal disease may benefit from the use of glucocorticoid elixirs as a swish and spit or dental trays to help apply class I corticosteroid gels or ointments to the gingiva

Question 38

Considerations when using immunosuppressive therapy for PV

Answer 38

- Monitor all patients closely for potential side effects- blood count, liver and kidney laboratory abnormalities, gastrointestinal ulcer disease, high blood pressure, diabetes, glaucoma, cataracts, osteoporosis, and infection - Consider potential incidence of malignancies that might be associated  - Consider risks of infertility and teratogenicity

Question 39

For specific PV tx...

Answer 39

See Dr. Letassy's handout :)