BDS 10037 Oral Ulceration - Immunologically Mediated Disease PDF

BDS 10037 Oral ulceration – Immunologically-mediated disease Oral ulceration – Immunologically-mediated disease Aims: •The aim of this lecture is to detail the clinical, diagnostic and therapeutic aspects of immunologically mediated disease Objectives: On completion of this lecture, the student sh...

BDS 10037 Oral ulceration – Immunologically-mediated disease Oral ulceration – Immunologically-mediated disease Aims: •The aim of this lecture is to detail the clinical, diagnostic and therapeutic aspects of immunologically mediated disease Objectives: On completion of this lecture, the student should be able to: •Understand the clinical manifestations of oral pemphigus, pemphigoid, erythema multiforme and oral lichen planus •Have an awareness of the spectrum of immunobullous disease that can affect the oral mucosa Classification of Oral Ulceration 1) Trauma Typically physical; Radiotherapy and chemotherapy-associated disease more common than before; chemical is uncommon. 2) Infection Typically viral (HSV, VZV; T. pallidum; short term, well defined features) 3) Immunologically-mediated Typically autoimmune; also autoinflammatory (e.g. Behcet’s; FPAPA) Can be a feature of vasculitic or granulomatous disease 4) Haematological/gastroenterological reflects an anaemia or neutropenia 5) Malignancy Typically OSCC (but many others can occur) 6) Iatrogenic Mechanisms of above 7) Recurrent aphthous stomatitis Probably the most common of all causes of mouth ulcers 8) Others Connective tissue disease (e.g. epidermolysis bullosa; Ehler Danlos syndrome etc) Pathogenic mechanisms of immunologically-mediated diseases: I. Autoimmune diseases: 1. 2. 3. 4. 5. 6. Pemphigus group Pemphigoid group IgA dermatoses Oral lichen planus* Lupus erythematosus Others Immunobullous disorders II. Hypersensitivity: Orofacial granulomatosis III. Anti-inflammatory: Behcet’s disease. IV. Immunodeficiency: A. Primary immunodeficiency e.g. congenital immunodeficiency B. Secondary immunodeficiency e.g. HIV ,drugs, haematological, malignancy V. Poorly defined: 1. RAS* 2. Erythema multiforme *Dominate Oral Medicine practice I. Autoimmune mucocutaneous diseases • A heterogeneous group characterised by the presence of circulating and/or tissue bound autoantibodies that target structural components of skin and mucosae. 1. Pemphigus group (PV). 2. Pemphigoid group (MMP, BP). 3. Ig A dermatoses. 4. Oral lichen planus. 5. Lupus erythematosus. 6. Others • N.B. Oral disease is dominated by PV & MMP 1) Pemphigus group A. B. C. D. E. Pemphigus vulgaris (PV) (very common) Pemphigus vegetans (rare) Paraneoplastic autoimmune multiorgan pemphigus. IgA pemphigus Drug-induced: Sulfhydryl radical: captopril, Penicillamine Non-thiol drugs: phenol, rifampicin, diclofenac 1) Pemphigus Vulgaris Definition: • A common chronic fatal autoimmune disease. • Affects skin and mucous membrane (mucocutaneous) Pathogenesis: • IgG autoantibodies attack part of epithelial desmosomes called desmoglein-3 (Dsg 3) that maintains the integrity of the epithelium. • This leads to : a. Loss of adhesion between epithelial cells (acantholysis) b. Degeneration of epithelial cells (acantholytic cells/ Tzanck cells). • A suprabasillar split occurs forming flaccid Intra epithelial vesicle/bullae. • Complement system does not have a role in the pathogenesis (therefore there is no red halo around lesion). Suprabasal split causing Intra epithelial vesicle Clinical Features: • Age: Females aged 40-60 are predominantly affected. • Site: involve any mucosal surfaces e.g. hard/soft palate, buccal, labial mucosae, lateral aspects of the tongue • In 50-70% of cases oral Lesions appear first then spread widely on the skin. Oral Manifestation: • Fragile & flaccid intra-epithelial vesicles/bullae on normal looking mucosa. • They soon rupture leaving superficial Erosions: 1. 2. 3. 4. Multiple & large map-like lesion with red bleeding surface. Irregular margin with tissue tags (ragged edges). The margin has no inflammatory halo. Painful & tender. • Extension of the lesion on the vermillion border of the lip is covered by bloody crust. • Desquamative gingivitis. Skin • Bulla soon rupture to form painful erosion and the lesions continue to expand over weeks to months, until large areas of the skin become denuded. Positive Nikolsky’s sign : • When a tongue blade is used to rub oral mucosa with gentle pressure the outer layer of the epithelium is rubbed off, or a bulla develops. Course • General symptoms of cachexia & weight loss. • Fluid loss & septicemia (death) • Healing without scarring ,within weeks ,months or years. Diagnosis: A) History: Painless vesicles that become painful on rupture with loss of weight & cachexia. B) Clinical examination: • Superficial ulcer on normally looking mucosa without inflammatory halo. • +ve Nikolsky’s sign. C) Special investigations: 1. Biopsy from fresh bullae shows suprabasal cleft & intraepithelial vesicles containing Tzanck cells. 2. Indirect immunofluorescent test to detect the presence of circulating autoantibodies in serum of patient. Circulating Ig G1 and Ig G4 autoantibodies are indicative of active disease while Ig G2 imply remission. 3. Direct immunofluorescent test Positive reaction in the epithelial tissue (not circulating) forming honey comb pattern indicating presence of tissue autoantibodies. Treatment : 1. Systemic corticosteroids Prednisone 60-100 mg/day. 2. Topical corticosteroids: for skin and oral lesions. 3. Azathioprine: immunosuppressive drug used with corticosteroids to reduce side effect of high doses of steroids for long periods. 4. Antifungal drugs: for 1 week for every 4 weeks of steroid therapy. 5. Systemic antibiotics: to control secondary infection. Dental Implications • Avoid pressure by holding the mirror with force against the cheek. • Steroids on long term can induce adrenal atrophy and adrenal crisis is liable to occur in dental clinic. • Immunosuppressive drug so patient may suffer of infection. • Mostly diagnosed by the dentist since oral lesions are first to appear (better prognosis). Drugs used for treatment of PV in the literature First line Azathioprine Mycophenolate mofetil Chlorambucil Cyclophosphamide Ciclosporin Methotrexate (low dose only) New agents Cholinergic agonists Protease inhibitors Second line Gold Dapsone Etretinate Prostaglandin E2 Minocycline Tacrolimus (topical and systemic) Plasmapheresis Extracorporeal photophoresis IV immunoglobulin Rituximab (anti-CD20) • No strong evidence that any topical agent will be effective for local disease • Uncertainty remains as to what constitutes the most effective and safe systemic therapy B. Pemphigus vegetans • Two variants: Hallopeau (pustules) and Neuman (flaccid bullae) • Oral involvement in up to 88%: ulceration, irregular vegetation & pustules may give rise to “cerebroform tongue” • Any oral site may be affected • Dsg1 and Dsg3 antibodies present C. Paraneoplastic autoimmune multi-organ syndrome (PAMS) • More recognised than in the past • 66% reflect haematological malignancy; Non-Hodgkin’s lymphoma, CLL, Castleman’s disease. • Also with sarcomas, lung malignancy, thymoma and OSCC. • Clinical features similar to PV but can mimic mucocutaneous pemphigoid, erythema multiforme, lichen planus or chronic GvHD. • Labial involvement is suggested to be common • Bronchiolar involvement may lead to early death. • Immunohistochemistry may include “lichenoid features” as well as those of PV • Circulating antibodies to Dsg1, Dsg3, envoplakin, periplakin, BP180 and alpha-2macroglobulin-like protease inhibitor. • Therapy should be directed towards the underlying malignancy 2) Pemphigoid group • Immunologically-mediated disease with auto antibodies attack the basement membrane zone (BMZ) Types • • • • • Mucous membrane pemphigoid (MMP) (BPAG2 - 180KD). Bullous pemphigoid (BP) (BPAG2 and / or BPAG1) Anti-laminin 5 Anti-integrins Anti-anchoring filaments Bolognia et al., Elsevier 2003 Benign mucous membrane Bullous pemphigoid pemphigoid (BP) (MMP) Autoantibody against MMP Autoantibody against BP 1)Etiology antigen on BMZ at a lower antigen on BMZ at lamina level of lamina lucida lucida. Adult & old age (50-70 Y) Older (over 60 Y) 2)Onset Age More in females 3)Sex Both Males & females 4) Oral mucosa Common Not common palate, gingiva, i.Desquamative gingivitis i. Desquamative gingivitis buccal mucosa (90%) and tongue ii. Chronic multiple shallow ii. Ulcers similar to MMP. ulcer (10 %). Positive Nikolsky's sign Positive Nikolsky’s sign. MMP 5)Other Eyes: Initial: unilateral irritation, mucosal photophobia, epiphora Lesions Later: symblepharon, ankyoblepharon, entropion & trichiasis scarring of lacrimal duct blindness. 6)Skin lesion BP NO EYE LESIONS ii.Trachea, larynx and esophagus Bullae, ulcerated crusted lesions on Urticarial rashes then Face, neck, trunk, extremities (25%) bullae develop on extremities & abdomen. *heal by scar. *Skin lesion usually follows oral *Skin lesion usually lesions. follows oral lesions. Benign mucous membrane pemphigoid (MMP) MMP 7) Investigations a)Histopathology Subepithelial bullae separation of BMZ b) ImmunoLinear deposits at BMZ fluorescence test of IgG (97%), C3 (78%), IgA (27%), IgM (12%) a)Direct from perilesional mucosa b)Indirect Circulating antibody only in 10 % of cases BP Linear deposits at BMZ of IgG and C3. Circulating antibody detectable (70%) Treatment & oral considerations of MMP & BP • Consider appropriate referral with respect to eyes, skin, genitalia • Topical corticosteroids. • Systemic corticosteroids for initial disease control • Corticosteroid-sparing immunosuppressant (similar to PV) • Antimicrobials (limited evidence for oral disease no systematic review of therapy). • Tends to initially respond to topical therapies. • Remission uncommon • Complications of therapy may be considerable I. Autoimmune mucocutaneous diseases 1. Pemphigus group (PV). 2. Pemphigoid group (MMP, BP). 3. Ig A dermatoses. 4. Oral lichen planus. 5.Lupus erythematosus. 6.Others 3) IgA Dermatoses a) Dermatitis herpetiformis • Associated with gluten sensitive enteropathy. • Painful oral erosions • Pruritic papulovesicular eruptions • Cutaneous vesicles on an urticated base • IgA at dermal papillae with circulating epidermal transglutaminase 3 b) Linear IgA disease • • • • • Rarely (15%) associated with GSE. A single case secondary to penicillin has been reported. Oral lesions are uncommon but mimic BMMP. IgA in linear pattern at BMZ. Therapy is usually dapsone or sulphapyridine 4) Lichen Planus Extra-oral Lichen Planus: • 15% of individuals with OLP have cutaneous LP as purple polygonal pruritic papules, dystrophic nails with genital ocular, nasal, laryngeal, oesophageal lesions. • Females - 20% Males - 5% • Lichen planopilaris leading to scarring alopecia. • Disease may be split into: 1. Oral Lichen planus 2. Oral Lichenoid drug reaction 3. Oral Lichenoid contact lesion 4. Oral lichenoid lesion Oral lichen planus (OLP) • Occurs in 0.5-2% of the population • Occurs in 4th-8th decades • 60% women; 2-3% children • Europeans / Indians > Chinese / Malay • Bilateral at buccal, labial mucosae, gingiva, tongue. • Immune-mediated (T-cell) but exact trigger is not known. • Clinical types (white Wickham’s striae): 1. Reticular 2. Papular/Plaque-like 3. Atrophic 4. Erosive (ulcerative) 5. Bullous Oral Lichenoid drug reaction: Drugs associated with Lichenoid Reactions: 1. 2. 3. 4. 5. Beta-blockers ACE inhibitors Diuretics Methyldopa Oral hypoglycaemics 6. NSAID 7. Gold salts 8. Penicillamine 9. Anti-malarials 10. Allopurinol Oral Lichenoid contact lesion: • It is a form of oral contact hypersensitivity reactions. • Individual is sensitized to a component of the dental material. • Amalgam alloy, nickel, mercury, gold, bis-GMA. • Lesion is confined to area of mucosa in direct contact with restoration. Management of oral lichen planus • Not curative • Drugs are given for: 1. Reduction of inflammation 2. Reduction of pain 3. Prevention of complications 1-Double blind studies, 2-Clinical series, 3-Case reports • Majority of therapies have not been evaluated in randomised controlled trials. • Lack of strong evidence supporting efficacy of any therapy. • Currently, no strong evidence that therapy alters the risk of malignant transformation in either direction. Long term complications of oral lichen planus • Oral disease is lifelong for the majority • Increased risk of malignancy rate controversial (0.3 - 6.5%) no clinical or pathological predictors • OSCC can arise in non-affected sites • Malignant transformation not related to tobacco or alcohol use or HPV 16/18 carriage. • Recurrences More tumours in cohort studies New primary vs recurrence • Aggressive tumours Early nodal involvement, Inflammatory process pro-invasive • Survival rates – unclear Early studies showed poor outcomes Larger cohorts show better outcomes Histopathological review is essential if there is any likelihood of dysplastic change All patients should be informed of the potential risk of malignant transformation 5) Lupus erythematosus (local & systemic variants) •Ulceration & oral lesions similar to that of OLP. • “Sun ray” &“honeycomb” patterns also possible. • Labial mucosa is suggested as a common site. • Lesions may affect the palate (less common than in OLP) • Lesions are often unilateral • Desquamative gingivitis. • Ulceration may be due to haemolytic anaemia or autoimmune neutropenia in SLE • Treatment similar to that OLP • Manage the underlying disease 6) Other autoimmune disorders a) Dermatomyositis • Ulceration of tongue, buccal mucosae & palate (with white patches) • Desquamative gingivitis • Myositis may cause swelling of the tongue, floor of mouth & dysphagia. • Risk of non-Hodgkin’s lymphoma b) Hematologic disorders: • Pernicious anaemia due to antibodies to gastric parietal cells (lack of intrinsic factor and vitamin B12 deficiency). • Autoimmune haemolytic anaemia • Autoimmune neutropenia (can be part of SLE) Pathogenic mechanisms of immunologically-mediated diseases: I. Autoimmune diseases: 1. 2. 3. 4. 5. 6. Pemphigus group Pemphigoid group IgA dermatoses Oral lichen planus* Lupus erythematosus Others Immunobullous disorders II. Hypersensitivity: Orofacial granulomatosis III. Anti-inflammatory: Behcet’s disease. IV. Immunodeficiency: A. Primary immunodeficiency e.g. congenital immunodeficiency B. Secondary immunodeficiency e.g. HIV ,drugs, haematological, malignancy V. Poorly defined: 1. RAS* 2. Erythema multiforme *Dominate Oral Medicine practice Erythema Multiforme (EM) Definition: • Acute, immunologically-mediated, mucocutaneous disease. • Characterized by vesicles and bullae formation. • 30% of cases are prone to recurrence (winter & spring). • Age: common in infants, children and young adults (<30 y). Etiology: • Mainly initiated by :1. Drugs: e.g. penicillin, sulphonamides, barbiturates, & carbamazepine. 2. Infection: e.g. HSV “Herpes associated EM”. 3 Clinical Features: 1) Minor erythema multiforme (80%) 2) Major erythema multiforme : a) Steven Johnson’s syndrome. b) Toxic epidermal necrolysis (TEN). 3) Chronic erythema multiforme. •Rare. •Immunocompromised patients. 1) Erythema Multiforme Minor Involves skin & oral mucosa without any systemic manifestation. Onset: Sudden/Acute. Oral Lesion: • Vesicles which rupture leaving ulcers. • Ulcers: Large, deep, irregular, hemorrhagic, surrounded by erythema. • Labial mucosa : extensively eroded & denuded of epithelium. • Vermillion border shows characteristic “bloody crusted appearance”. • Tongue: enlargement with indentation & ulceration. • Desquamative gingivitis. Symptoms: • Pain, inability to eat, dysphagia & increased salivation. Skin lesion appear in 3 different forms. 1) Dull red maculopapular lesions: • On the back of the extremities & neck. 2) Iris or target lesions (targetoid): • More common on the back of the hands & wrists. • Three zones: 1. A central area of erythema. 2. A middle paler zone of edema. 3. An outer ring of erythema with a well-defined edge. 3) Vesiculo-bullous lesions 2) Erythema Multiforme Major A) Stevens Johnson’s Syndrome: • One of the Mucocutaneous-occular syndrome • Involves skin, mouth, eyes & genitalia. Onset: • “Prodrome” sudden with fever, headache ,malaise, anorexia. • Fever may persist 4-5 days, after 1 week patient appears very ill. • After 24-48 hours severe vesiculo-bullous lesions develop. 1) Oral lesion: like EM minor. 2) Skin lesion : like EM minor. a) Maculopapular and iris or target lesions. b) Vesiculo-bullous lesions are severe & may end in extensive skin sloughing which may cause death due to 2ry infection or electrolyte imbalance. 3) Eye : conjunctivitis, corneal ulceration, may lead to scarring & blindness. 4) Urogenital: Urethritis in male and vaginal ulcers in females. B) Toxic epidermal necrolysis (TEN) “Lyell’s syndrome” • A rare syndrome representing most severe form of EM. • Mainly due to drug reaction. • Vesiculo-bullous lesion & detachment of the epidermis. • Resembling scalding i.e. burn with hot steam. • The patient is very ill & has rising fever. • High morbidity rate due to loss of body fluid, electrolyte imbalance & 2ry infection. • Patient may survive. • The patient best treated in burn hospital. Course : • It is self limiting disease. • Lesions heal with no scar unless there is 2ry infection. • The lesions persist for 2-3 weeks in the minor form • The lesions persist for > 4 weeks in major & chronic EM. • May be fatal in the major form. • Blindness if the eyes are involved by corneal ulceration. Diagnosis: 1) History: • Sudden rapid onset of vesiculo-bullous lesions on skin/oral mucosa develop within 1-2 days in minor type. • Fever & prodromal features in major type. • Recurrence 2) Clinical examination: • The character and distribution of oral lesions are typical. • Target skin lesions if present facilitate the diagnosis. 3) Special Investigation: • There are no laboratory tests to diagnose EM. Management: a. Mild Cases: Supportive/palliative treatment i.e. soft or liquid diet. b. Moderate-severe Cases: • Systemic steroids. • Systemic antibiotic to control secondary infection. • An ophthalmological opinion if the eye is involved. c. Severe cases may need hospital’s admission Mucocutaneous ocular syndromes A group of diseases that show characteristic oral, skin and eye lesions including: 1. Behcet’s disease (syndrome) 2. Reiter’s disease (syndrome) 3. Stevens Johnson syndrome. Key points of immunologically-mediated diseases: • Oral lichen planus is the most common immune-driven disorder of the oral mucosa • Immune-driven disease of the mouth tends to be autoimmune in basis and hence is most likely in middle-to-late aged females • Immunobullous disease is usually mucous membrane pemphigoid or pemphigus vulgaris • Therapy of immune-drive disease is aimed at reducing the oral ulceration and associated pain but may require to be life-long • Oral lichen planus has a small, but real, malignant potential that is unrelated to the clinical presentation of the lichen planus • Always refer patients to specialists when you suspect there is immunologically mediated oral disease. Reading material Students are advised to review any relevant teaching provided in the first year. In addition they are advised to read relevant sections of the following texts: 1. Odell E.W. Cawson’s Essentials of Oral Pathology and Oral Medicine. 9th Edition. Elsevier, 2017 pp 453 2. Robinson M et al. Soames’ and Southam’s Oral Pathology. 5th edition. Oxford University Press, 2018 pp 41-47, 212 3. Scully C. Oral and Maxillofacial Medicine Churchill Livingstone 2008 pp 207-210, 229-232, 261-278 Oral ulceration – Immunologically-mediated disease Aims: •The aim of this lecture is to detail the clinical, diagnostic and therapeutic aspects of immunologically mediated disease Objectives: On completion of this lecture, the student should be able to: •Understand the clinical manifestations of oral pemphigus, pemphigoid, erythema multiforme and oral lichen planus •Have an awareness of the spectrum of immunobullous disease that can affect the oral mucosa