Immune-Mediated

Lesions of the Oral

Cavity

Murtaza Kharodawala, MD

Faculty Advisor: Matthew Ryan, MD

Grand Rounds Presentation

The University of Texas Medical Branch

Department of Otolaryngology

April 26, 2006

Introduction

• Oral cavity lesions are a common

presenting complaint in Otolaryngology

• Immune mediated lesions of the oral cavity

may involve other sites and may be life-

threatening

– Acute, chronic and/or recurrent vesicle,

bullae, erosion/ulceration of oral cavity

Overview

• Lichen Planus

• Mucous Membrane Pemphigoid

• Bullous Pemphigoid

• Pemphigus Vulgaris

• Linear IgA Disease

Definitions

• Vesicle: circumscribed

collection of free fluid

up to 0.5 cm in

diameter

• Bulla: circumscribed

collection of free fluid

greater than 0.5 cm in

diameter

Definitions

• Erosion: a focal loss of

epidermis which does

not include the

dermoepidermal

juction. Heals without

scar.

• Ulcer: focal loss of

epidermis and dermis.

Heals with scar.

Definitions

• Direct immunofluorescence: Labelled

antibodies are used for detection of

specific antigens

• Indirect immunofluorescence: Labelled

antibodies (to other antibodies) are used

for detection of antibody-antigen complex

• Activation of inflammatory cascade by cell-

mediated means and/or antibody

deposition and complex formation with

antigen

– Chemotaxis

– Complement activation

– Leukocyte Degranulation

• Proteolytic enzymes that destroy the basement

membrane, resulting in separation of the epidermis

and dermis

Diagnosis: Biopsy!

Lichen Planus

• Idiopathic inflammatory disorder of skin and mucous membranes

• Mucosal disease may occur without cutaneous involvement – Present in sixth decade

– F:M 2:1

– Greater than half involve oral cavity, mostly on buccal mucosa

– Asymptomatic or painful

• Pathogenesis: – May be T-cell mediated immune response to unknown cause

– No autoantibodies found

– IgG, IgM, IgA, and complement deposition as well as fibrin and fibrinogen present in BMZ

Lichen Planus

• Clinical Features: – Classified as reticular, plaque-like, atrophic, papular,

erosive, and bullous • Reticular: appear dendritic, lacy, in a white arborizing pattern

with or without erythema and ulceration

– Wickhams striae: whitish lines of epidermal thickening

– Negative Nikolsky sign: pressure over lesion does not result in extension of fluid into surrounding normal epidermis/mucosa

– Koebner phenomenon: lesions develop in previous sites of trauma

– Malignant transformation to oral SCCA in 0.8%

Lichen Planus Reticular, lace-like pattern

From: Eisen: Oral Diseases, 11(6).November

2005.338-349

Lichen Planus

Atrophic

Lichen Planus

Lichen Planus

Erythematous LP

with reticular

pattern

From: Eisen: Oral Diseases, 11(6).November 2005.338-349

Lichen Planus

• Erosive

Lichen Planus

• Erosive

From: Eisen: Oral Diseases, 11(6).Novermber

2005.338-349

Lichen Planus

Desquamative

gingivitis

From: Eisen: Oral Diseases, 11(6).Novermber 2005.338-349

Lichen Planus

• Diagnosis

– Clinical

– Biopsy!

Lichen Planus

• Histology:

– Loss of rete pegs,

epidermal

thickening,

lymphocytic

infiltration

Lichen Planus

• Direct

immunofluorescence:

– Ovoid deposits of IgG,

IgA, IgM, and

complement in BMZ

From: Immunodermatology Test Result Images, University of

Utah Health Sciences Center website, April 18, 2006.

Lichen Planus

• Usually self limited (8-12 months)

• 50% may recur

• Medical Therapy – Topical, intralesional, and systemic steroids

• Triamcinolone (orabase)

• Intralesional methylpred (20-40mg)

• Oral prednisone (recurrence when tapered)

– Dapsone (50-150 mg daily)

– Resistant, debilitating disease: • Plaquenil

• Azathioprine

• Isotretinoin

• Acitretin

• Autoimmune bullous disease generally in the elderly – Most occurs after 60 years of

age

• Pathophysiology – Antibodies (IgG) to bullous

pemphigoid antigens 230 (cytoplasmic) and 180 (transmembrane) of basal cell desmosomes

– IgG found circulating and bound within lamina lucida

Bullous Pemphigoid

Bullous Pemphigoid

• Clinical Features: – Oral blisters (24%)

– Localized erythema or urticarial plaque which advances to form tense bullae

– Negative Nikolsky sign: Firm pressure on the blister will not result in extension into normal skin

– Generalized: abdomen, groin, flexor surfaces, palms and soles

– Erode within a week to leave eroded bases

– Heals rapidly (unlike pemphigus)

– May be associated with trauma, radiation, vaccination, and systemic medications (furosemide, diazepam, spironolactone)

– No increased risk of malignancy

– Vesicular, vegetative, generalized erythroderma, urticarial, and nodular variants

Bullous Pemphigoid

Bullous Pemphigoid

Cutaneous tense bullae

Bullous Pemphigoid

• Diagnosis:

– Circulating eosinophilia

– Elevated serum IgE

– Biopsy!

Bullous Pemphigoid

Histology:

Cleavage between

epidermal and dermal

junction with presence of

eosinophils and to a lower

extent neutrophils

Bullous Pemphigoid

Bullous Pemphigoid

Direct Immunofluorescence and Electron Microscopy

IgG and/or C3, and to lesser extent IgA, IgM, and fibrin

present in a linear fashion at the BMZ

Indirect

Immunofluorescence

Bullous Pemphigoid

Bullous Pemphigoid

• Untreated BP may remain localized and

undergo spontaneous remission or

become generalized

• Generalized BP has poor prognosis

– Mortality at 1 year up to 19% with treatment

– Mortality without treatment 24%

– Remission: 30% at 2 years, 50% at 3 years

• Medical Therapy – Antibiotics: tetracyline, erythromycin

– Topical steroids (Clobetasol propionate cream 0.05%)

– Systemic steroids (Prednisone 0.5-1 mg/kg/day)

– Dapsone (50-200 mg/day)

– Sulfapyridine (500-1500 mg/day)

– Azathioprine (1-2.5 mg/kg/day)

– Mycophenolate Mofetil (0.5-1 gm twice daily)

– Cyclophosphamide

– Methotrexate (5-12.5 mg/week)

– Cyclosporine

– Tacrolimus

– Chlorambucil

– IVIG

– Plasmapheresis

Bullous Pemphigoid

• AKA Cicatricial Pemphigoid

• Autoimmune blistering disease resulting in ulceration and often scarring – Variant of localized pemphigoid

– Adults 40-60 years

– Female to male 2:1 ratio

• Pathophysiology: – Autoantibodies to antigens within the lamina lucida of the BMZ

– Bullous pemphigoid hemidesmosomal antigen 180

– BPAG2

– Laminen 5

– β 4 Integrin subunit

Mucous Membrane Pemphigoid

• Clinical Features: – Oral cavity (85%) and eyes (65%) are most common sites

involved

– Gingiva (90%), palate, less often buccal mucosa

– Characterized by erythema, painful vesicle or bullae formation followed by rupture leaving ulcers

– Negative Nikolsky sign

– Ulcers heal in 7-10 days

– Vermilion not involved (in contrast to pemphigus)

– Laryngeal involvement (8%) – Hoarseness

– Ocular manifestations: • Conjunctivitis to blindness

• Corneal ulceration, opacification

• Fibrous conjuctival adhesions (fixed globe)

• Decreased tearing

• Blindness in up to 20% affected

– Skin lesions (25%): face, neck scalp, genetalia

Mucous Membrane Pemphigoid

Mucous Membrane Pemphigoid

Mucous Membrane Pemphigoid

Mucous Membrane Pemphigoid

Mucous Membrane Pemphigoid

Mucous Membrane Pemphigoid

Laryngeal Stenosis

From: Boedeker: Ann Otol Rhinol Laryngol. 112(3): Mar 2003: 271-275

Mucous Membrane Pemphigoid

Mucous Membrane Pemphigoid

• Diagnosis:

– Biopsy!

Mucous Membrane Pemphigoid

Mucous Membrane Pemphigoid

Histology:

Separation of

epithelium from

underlying

tissue at

lamina lucida

*Pemphigus

has cleavage

at the spinous

layer of

epithelium

Mucous Membrane Pemphigoid

Direct

immunofluorescence:

Linear deposits of IgG,

IgA, and C3 at BMZ in

continuous pattern

• Medical Therapy – Debridement and wound care

– Dexamethasone elixir oral rinse

– Fluconinide gel

– Triamcinolone (Orabase)

– Intralesional (5-10 mg/ml) and systemic steroids (prednisone 0.75-1 mg/kg/day)

– Dapsone (75-200 mg daily)

– Cyclophosphamide (1.5-2.5 mg/kg/day)

– Mitomycin C

– Tacrolimus

Mucous Membrane Pemphigoid

• Medical Therapy – IVIG

– Plasmapheresis

– Eyes: lubrication and antibiotic gtt

• Surgical Intervention – May be needed in cases involving the eyes, larynx,

and esophagus due to scarring • Blindness

• Laryngeal stenosis

• Esophageal stricture

– Ideally when disease is in remission

Mucous Membrane Pemphigoid

Pemphigus Vulgaris

• Autoimmune bullous disease of skin and

mucous membranes

– Related to pemphigus foliaceus (differs by level of

acantholysis in epithelium)

– Other members of pemphigus family are

paraneoplastic pemphigus (lymphoma) and drug-

induced pemphigus (penicillamine)

• 1-5 cases per million per year

– Onset in sixth decade

– M=F

Pemphigus Vulgaris

• Pathophysiology: – Genetically predisposed

individuals and exogenous factor (antigen mimicking desmosomal protein)

– Autoantibodies that bind to desmosomal components resulting in acantholysis

– Cell-cell adhesion • Desmoglein 1, Dsg1 (skin)

• Desmoglein 3, Dsg3 (oral and skin)

Pemphigus Vulgaris

• Clinical Features – Mucosal involvement in 50%

• Soft palate 80%

• Eye

• Esophageal mucosa

– Painful oral erosions preceding skin blisters

• Scalp, face, axilla

– If untreated, become generalized

– Positive Nikolsky sign: pressure over intact bullae results in fluid dissection laterally into the surrounding midepidermis

– Erosions last for weeks before healing with brownish hyperpigmentation

– Associated with Myasthenia gravis and thymoma

Pemphigus Vulgaris

Collapsed

bullae over

buccal mucosa

Pemphigus Vulgaris

Pemphigus Vulgaris

Pemphigus Vulgaris

Erosive gingivitis

Pemphigus Vulgaris

Pemphigus Vulgaris

Pemphigus Vulgaris

Conjunctival

and scleral

involvement

Pemphigus Vulgaris

• Diagnosis:

– Biopsy!

Pemphigus Vulgaris

Histology:

Intraepidermal bulla and

acantholysis with

detachment of basal cells

from each other but still

attached to BMZ.

Moderate eosinophil

infiltration

Pemphigus Vulgaris

Pemphigus Vulgaris

Pemphigus Vulgaris

Direct

Immunofluorescence:

IgG against Dsg3

present in

intercellular space in

stratum spinosum

Pemphigus Vulgaris

• Avoid sunlight

• Mortality high if untreated (50% at 2 years, 100% at 5 years) – With treatment 10%

• Medical Therapy: – *Oral steroids (Prednisone 0.5-1 mg/kg/day)

– Topical steroids (Clobetasol propionate 0.05% BID)

– Cyclophosphamide 1.5 mg/kg/day (most effective) • Bone marrow suppression, hemorrhagic cystitis, bladder fibrosis and carcinoma,

lymphoma

– Azathioprine 1.5-2.5 mg/kg/day • Bone marrow suppression, hepatotoxic, malignancy

– IVIG monotherapy or as adjuvant

– Chlorambucil

– Mycophenolate mofetil

– Dapsone

– Cyclosporine

– Tetracycline

– May stop when clinically free of disease and negative direct immunofluorescence

• Remission in 75% after 10 years

Linear IgA Disease

• Acquired or idiopathic, autoimmune, blistering disorder – Incidence 0.6 per 100,000

– 2:1 Female to male ratio

• Two clinical types: (share histologic and immunologic findings) – Chronic dermatosis of childhood in first decade

– Adult linear IgA disease, peak 60-65 years

• Pathophysiology: – Resembles Dermatitis Herpetiformis

– IgA deposits below lamina densa of BMZ or within the lamina lucida, or both

– Multiple antigens with multiple binding sites on each antigen

– Bullous pemphigoid antigen BP180 and extracellular domain LAD1

– Gluten sensitivity in 25-33%

– Associated with RA, UC, immune glomerulonephritis, malignancy

– Drugs, including Vancomycin

Linear IgA Disease

• Clinical Features:

– Vesiculobullous lesions may be present over

entire body including oral mucosa and

conjuctiva

– Lesions may be painful and/or pruritic

– Negative Nikolsky sign

Linear IgA Disease

From: ORegan: Arch Otolaryngol Head Neck Surg, 130(4).April 2004.469–472

Desquamative Gingivitis

Linear IgA Disease

From: ORegan: Arch Otolaryngol Head Neck Surg, 130(4).April 2004.469–472

Buccal Ulceration

Linear IgA Disease

Ocular Findings: conjunctivitis,

fibrosis, scarring

From: Klein: Linear IgA Dermatosis. Emedicine, Jun 23, 2003.

Linear IgA Disease

• Diagnosis

– Elevated ESR and circulating IgA

– Biopsy!

Linear IgA Disease

From: ORegan: Arch Otolaryngol Head Neck Surg, 130(4).April 2004.469–472

Histology:

Separation of

the epidermis

and dermis with

eosinophils in

subepithelial

split

Linear IgA Disease

From: ORegan: Arch Otolaryngol Head Neck Surg, 130(4).April 2004.469–472

Direct

Immunofluorescence:

Linear subepithelial

band of IgA deposition

Linear IgA Disease

• Medical Therapy

– Topical and systemic steroids (usually not

effective)

– Dapsone 25-150 mg daily

• Peripheral Motor Neuropathy

• Hemolytic Anemia

– Sulfapyridine 500-1500 mg daily

– Colchicine, Tetracylcine, Nicotinamide

• Many cases resolve spontaneously

Disorder Biopsy site Bx by DIF Serum by

IDIF

Lichen Planus Edge of involved

skin

Mult Ig, C, fibrin in

cytoid bodies in

epidermis with

fibrin around rete

pegs

None

Bullous

Pemphigoid

Erythematous

perilesional skin

IgG and/or C3 in

BMZ found in

linear pattern

IgG in BMZ

Mucous

Membrane

Pemphigoid

Erythematous

perilesional skin

IgG and/or C3 in

BMZ in linear

pattern

IgG and IgA in

BMZ

Pemphigus Erythematous

perilesional skin

IgG in Intercellular

area of stratum

spinosum

Mult antibodies in

stratum spinosum

Linear IgA Perilesional skin

IgG and/or C3 at

BMZ in linear

pattern

IgA in BMZ

Bibliography

Habif: Clinical Dermatology, 4th ed., Copyright © 2004 Mosby, Inc.

Cummings: Otolaryngology: Head & Neck Surgery, 4th ed., Copyright © 2005 Mosby, Inc.

Eisen et al. Oral lichen planus: clinical features and management. Oral Diseases 2005;11:338-

349.

Boedeker et al. Cicatricial pemphigoid in the upper aerodigestive tract: diagnosis and management

in severe laryngeal stenosis. Ann Otol Rhinol Laryngol 2003;112:271-275.

Sacher et al. Cicatricial pemphigoid. Am J Clin Dermatol 2005;6:93-103.

O’Regan et al. Linear IgA disease presenting as desquamative gingivitis. Arch Otolaryngol Head

and Neck Surgery 2004;130:469-472.

Ruocco et at. Life-threatening bullous dermatoses: pemphigus vulgaris. Clinics in Dermatol

2005;23:223-226.

Yeh et al. Blistering disorders: diagnosis and treatment. Dermatol Therapy 2003;16:214-223.

Kirtschig et al. Management of Bullous Pemphigoid. Am J Clin Dermatol 2004;5:319-326.