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 lifethreatening – 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 cellmediated 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

Lichen Planus

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

Lichen Planus Atrophic

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

Bullous Pemphigoid • 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 • 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

Bullous Pemphigoid Indirect Immunofluorescence

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

Bullous Pemphigoid • 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

Mucous Membrane 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 Laryngeal Stenosis

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

Mucous Membrane Pemphigoid

Mucous Membrane Pemphigoid

Mucous Membrane Pemphigoid • Diagnosis: – Biopsy!

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

Mucous Membrane Pemphigoid • 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

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 druginduced 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 Desquamative Gingivitis

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

Linear IgA Disease Buccal Ulceration

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

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 Histology: Separation of the epidermis and dermis with eosinophils in subepithelial split

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

Linear IgA Disease Direct Immunofluorescence: Linear subepithelial band of IgA deposition

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

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

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

Perilesional skin

IgG and/or C3 at BMZ in linear pattern

IgA in BMZ

Disorder

Linear IgA

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;11:338349. 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.