Lec 20 Oral mucosa: vesiculo-bullous disease

These are organ specific, autoimmune blistering diseases where antibodies target specific
antigens either in the epithelium or beneath it in the basement membrane. This results in
blister formation either within the epithelium (intra-epithelial) or beneath the epithelium
(sub-epithelial). Blisters rapidly rupture due to trauma to leave large shallow ulcers. These
conditions include:

(a) Intra-epithelial bullous disease

• Pemphigus
(b) Sub-epithelial bullous diseases
• Pemphigoid
• Dermatitis herpetiformis
• Epidermolysis bullosa aquisita

Pemphigus

Mean age of onset 40 - 60 years, can occur under 20 years; equal sex predilection,
but more common in the Jewish (Ashkenazi) population. Oral lesions can occur up
to a year in advance of skin lesions and before the advent of effective therapy the
disease was fatal. Incidence ~ 0.5-3.2 per 100,000.

Clinical Features:

Oral - Fragile intraepithelial bullae quickly burst to form

spreading superficial erosions on any mucosal
surface.
- Pain and difficulty in eating and swallowing is typical.
Skin - Bullae as per oral; initial sites - areas of friction
Nikolsky’s sign positive.

Pathogenesis
• Antibodies are present in the patient’s blood.
• These recognise one of the binding proteins that keep epithelial cells
together.
• The binding protein is part of the desmosomal complex (desmoglein
3).
• When the antibody sticks to desmoglein 3 the epithelial cells
separate. This is known as acantholysis and results in the formation of
an intra-epithelial bulla
• If the skin and oral mucosa is involved there are antibodies against
desmoglein 1 and desmoglein 3.

Antibody against desmoglein 3 causes cells to separate (acantholysis)

Desmosome containing desmoglein 3

Histopathology.
Intra-epithelial separation resulting in a bulla. Basal epithelial cells remain at
the base of the bullae and separated epithelial cells (Tzank cells) may be
present in the blister fluid. There is a minimal host response unless the
surface epithelium breaks down.

Diagnosis

Biopsy: - Perilesional and/or normal tissue. Blood in plain tube.

- Send to lab fresh or frozen (do not fix).

In the laboratory:

• Freeze half the biopsy for immunofluorescence test

• Fix the other half for routine histology

 • Direct immunofluorescence test: used to determine whether auto-

antibodies (IgG, IgM ( C3) are present in the patient's epithelium.

• Indirect immunofluorescence test : used to determine whether there

are autoantibodies in the patient’s serum. Present in 80-90% patients.

Epithelium

- Pemphigus Vulgaris

• Most Common.

• Antibodies mainly against desmoglein 3.

- Pemphigus Foliaceous

• Less common

• Lesions more superficial

• Antibodies mainly against desmoglein 1.

- Paraneoplastic Pemphigus

• Associated with a neoplasm elsewhere

• Usually lymphoma or chronic lymphocytic

leukaemia.
• Extremely serious with a high morbidity and

mortality.

Management - Exclude cancer

- Systemic immunosuppression

Prednisolone +/- azathioprine

Other immunosuppresants or plasmaphoresis

Pemphigoid

Two forms: - Bullous pemphigoid

Mucous membrane pemphigoid (cicatricial

pemphigoid)

Both characterised by sub-epithelial bullae and are autoimmune disorders

Bullous pemphigoid (BP)

Sub-epithelial autoimmune blistering condition of the skin. Also affects the

oral mucosa and other mucous membranes in >30% of cases. Auto-

antibodies are directed against BP180 (BPAG1) and BP230 (BPAG2) in the

hemidesmosomes that attach basal keratinocytes to the underlying

basement membrane and connective tissue.

Systemic - Lesions primarily affect skin.

 - Bullae may be preceded by non-specific

erythematous rash

Oral - Bullae and large shallow ulcers may affect any

mucosal surface

- Desquamative gingivitis common

Mucous membrane pemphigoid (MMP)

Chronic, blistering disease mainly affecting the mucous membranes of the

mouth, eye, nose and vagina. Female to male ratio 2:1; mean age 60 years.

Oral lesions commonly, but other mucosal sites frequently affected. Skin

rarely involved. Ulcers, particularly of the eyes, may heal with scarring when

the name cicatricial pemphigoid is used. Auto-antibodies are directed

against BP180 (BPAG1), laminin 5 and α6β4 in the hemidesmosomes that

attach basal keratinocytes to the underlying basement membrane and

connective tissue.

Oral - Bullae rupture to form irregular shallow ulcers of

any mucosal surface

- Ulcers are painful, last weeks or months

- Desquamative gingivitis common (>90% of cases)

 Ocular - 25% of patients with oral lesions

- Eyes may be severely damaged by scarring –

Cicatricial Pemphigoid.

subconjunctival fibrosis  conjunctivitis + erosion  scarring between

bulbar and palpebral conjunctiva  adhesions = symblepharons 

entropion and trichiasis  xerophthalmos  blindness

Diagnosis- Biopsy: - Perilesional and/or normal tissue.

o Send to lab fresh or frozen (do not fix).

o Routine histology

• - Direct immunofluorescence to show linear IgG and C3

pattern within the basement membrane zone (90%

patients)

Serum: - Indirect immunofluorescence positive in 5% of

patients (70% using salt split skin technique)

Management -Systemic or topical steroids are the mainstay of treatment

- Sulphonamides or Dapsone may be an effective

alternative to systemic steroids

Occular examination is essential

Dermatitis herpetiformis (DH

This autoimmune disorder is associated with coeliac disease and is the result

of hypersensitivity to gluten (found in wheat). In many patients the bowel

symptoms may be minimal.

Clinical

Intense itchy rash and blisters affecting the skin in young adults and

occasionally children. Backs of knees, elbows, trunk and buttocks are

particularly affected. Oral manifestations are very uncommon but include

erythematous areas, erosions and purpuric lesions particularly affecting the

buccal mucosa.

Histopathology and pathogenesis.

There is sub-epithelial separation resulting in sub epithelial bullae. IgA is

deposited at the basement membrane zone at the tips of the connective

tissue papillae and complement is deposited. This attracts neutrophils.

Management.

Removal of gluten from the diet.

Dapsone.

Epidermolysis bullosa (EB)

Hereditary blistering mucocutaneous disorders, inherited as either autosomal

dominant (AD) or autosomal recessive forms (AR). 25 different forms are

recognised, some much more severe than others. Defect is in the

attachment mechanism of the epithelial cells either to each other or to the

underlying connective tissue and as such, three main types exist:-

Simplex (AD)

Junctional (AR)

Dystrophic (AD + AR)

EB Simplex - keratin gene defect

blistering of hands and feet which heal without scarring

oral involvement uncommon

EB Junctional - defect of hemidesmosomes

(EB Letalis) severe blistering at birth, often resulting in death

from sloughing of skin during passage through birth

canal

if survives birth oral lesions common, both erosions

and enamel hypoplasia

EB Dystrophic - defect in type VII collagen

 AD - mild, where erosions occur is on skin in areas of

trauma and orally gingival erythema and loss of

sulcus depth

AR - severe mucosal involvement

lesions on skin in sites of trauma

deformity of hands and feet

variable survival depending on type

Diagnosis - biopsy

Management - genetic counselling

oral hygiene, diet, fluoride

Erythema Multiforme (EM)

• Clinical: uncommon disorder affecting the skin and mucous membranes.

Lesions affecting the oral cavity are characterised by bullae which rupture

to leave shallow, grey, haemorrhagic.ulcers. It is usually the anterior parts

of mouth that are affected. Lips show characteristic haemorrhagic

crusting. Episodes may be recurrent and last up to 14 days. There is a

typical skin rash composed of target lesions usually on extremities. If

severe patients may require admission to hospital.

• Aetiology and Pathogenesis: may be precipitated by drugs:

(e.g.sulphonamides, barbiturates) but other agents including viruses

 (particularly herpes) and foodstuffs are important. Most cases of

recurrent EM are precipitated by preceding herpes infection. Lesions are

the result of a cell mediated immune reaction to herpes virus DNA

expressed by epithelial cells.

• Diagnosis – is usually made on clinical grounds especially accompanying

skin rash and association with drugs and herpes. Rarely biopsy.

• Treatment – is mainly symptomatic but admission to hospital may be

necessary for severe cases if there is dehydration and difficulty in eating

and drinking; Antiviral agents and corticosteroids helpful.