Dr.

Tahani Abualteen

Vesiculobullous diseases
Vesiculobullous diseases: Diseases that result in collection of clear fluid (blisters) within or below the epithelium Blisters are classified into (vesicles and bullae) Vesicles: o Fluid filled lesion o Smaller in size o Mostly arise intra-epithelially Bullae: o Fluid filled lesion o Larger in size o Mostly arise sup- epithelially Vesiculobullous diseases are present as oral ulceration following rupture of the vesicles & bullae Classification of vesiculobullous diseases: o Vesiculobullous diseases are classified into 2 major groups depending on the histological location of the lesions: o Intraepithelial vesiculobullous diseases (lesions form within the epithelium): Intraepithelial vesiculobullous diseases are classified into 2 groups depending on the mechanism of formation of the lesion Acantholytic lesions: - Pemphigus vulgaris ** Lesions are produced by breakdown of intercellular attachments (desmosomes) between epithelial cells Non-acantholytic lesions: - Viral infections of the oral mucosa (e.g. ballooning degeneration in herpetic infections) ** Lesions are produced by death and rupture of groups of epithelial cells Pemphigoid Erythema multiforme Dermatitis herpetiformis Linear IgA disease Epidermolysis bullosa Angina bullosa hemorrhagica (oral blood blisters) Bullous lichen planus

o Subepithelial vesiculobullous diseases (lesions form between the epithelium & lamina propria):

History is important o Duration (ulceration lasts weeks to months) o Recurrence o Other lesions: skin, eye, genital lesions o Systemic manifestations o Certain types may be associated with medications
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Pemphigus vulgaris: Pemphigus is a group of uncommon autoimmune blistering diseases of which Pemphigus vulgaris is the most common type Classified as intraepithelial acantholytic vesiculobullous disease Clinical features: o Present in middle age o More common in women than in men o More common in certain ethnic groups, particularly Ashkenazi Jews, where there may be a genetic link o Characterized by widespread bullous eruptions involving the skin and mucous membranes o Oral mucosa is involved in nearly all patients and in about 50% of cases is the site of initial lesions o Bullae are fragile (since they are intra-epithelial & not covered with a thick layer of tissue) and so, they readily rupture forming crusted areas on the skin and irregular, ragged mucosal ulcers o Any part of the oral mucosa may be involved, but the soft palate, buccal mucosa, and lips are most frequently affected o There may be also a desquamative gingivitis (a clinical term indicating sloughing and ulceration of attached gingiva that might be a manifestation of different diseases) o Bullae are produced as a result of acantholysis and this process extends laterally in the surrounding epithelium, often for a considerable distance o As a result, gentle lateral pressure to the mucosa in an involved area Nikolsky's sign can lead to the formation of a bulla (Nikolsky's sign) ** Rubbing the oral mucosa gently with a blunt instrument may result (within minutes) in vesicles or bullae formation; and this indicates the presence of immune mechanisms (like Ab attached to desmosomes) that are waiting for maybe a minor trauma to cause damage Histopathological features: o Intraepithelial separation o Cleft-like spaces produced by acantholysis in stratum spinosum cells just above basal cell layer o Basal cells forming the base of the lesion remain attached to the lamina propria o Little subepithelial inflammatory cell infiltration until the lesion ruptures o Acantholytic stratum spinosum cells are small and rounded and contain enlarged hyper-chromatic nuclei (the so called Tzanck cells)

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Pathogenesis: o Autoimmune disease autoantibodies against desmosomes ** Desmosome is a junctional complex mediating cell-cell contact ** Desmosome = intercellular attachment plaque + intercellular adhesion protein Intercellular attachment s of epithelial cells are mediated ** Desmogleins are important by desmosomes comprising opposing attachment plaques intercellular adhesion proteins (P) and intercellular adhesion proteins ** Autoantibodies to desmoglein 3 are found in Pemphigus limited to mucosal sites ** Autoantibodies to desmoglein 1 and desmoglein 3 are found Pemphigus involving skin and mucosa o There's strong evidence that IgG autoantibodies against the intercellular proteins of the desmosomes (Ab-Ag complex) are responsible for the acantholysis but the mechanism by which this occurs is unclear! however, it is likely to involve the activity of proteineases Diagnosis: o Immunological studies are important in establishing the diagnosis and may be helpful in monitoring the progression of the disease o Indirect immunoflourescence: Circulating autoantibodies (IgG) to desmosomes can be demonstrated in the serum of patients Their titer is related to the severity of the disease and monitoring the titer over time may be helpful in disease monitoring and response to treatment Circulating autoantibodies may not be detected in all patients (especially in the early stages of the disease) o Direct immunoflourescence: Detection of antibodies while in their place using another florescent antibody Biopsy of peri-lesional mucosa to detect the binding of autoantibodies (IgG) to desmosomes ** IgG autoantibodies can be detected within the epithelial thickness producing a characteristic fish-net pattern Positive in all patients

Other forms of Pemphigus include: o P. vegetans o Drug induced o Paraneoplastic (associated with some malignancies, e.g. leukemia and lymphoma)

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Pemphigoid: Pemphigoid is a group of autoimmune blistering diseases characterized by the production of autoantibodies against hemidesmosomes and basement membrane (which mediate attachment between epithelium and underlying connective tissue) Classified as subepithelial vesiculobullous disease The different subtypes and their clinical manifestations most likely reflect damage to different target antigens, however, they can be divided into 2 groups clinically:

Attachment op epithelium to connective tissue is mediated by hemidesmosomes (HD) and proteins of basement membrane zone (BMZ)

o Bullous Pemphigoid (involving skin mainly) o Mucous membrane Pemphigoid (involving mucosa mainly) ** Oral manifestations occur in almost all patients with mucous membrane Pemphigoid group, but they are very uncommon in bullous Pemphigoid Mucous membrane (cicatrical) Pemphigoid: o Etiology: the most common target antigen in mucous membrane Pemphigoid with oral manifestations is a Transmembrane protein bridging the hemidesmosomes and the basement membrane together known as BP antigen 2 o Clinical features: More common in women than in men Oral mucosa is almost always affected (either alone or in association with other mucosae) Bullae occur anywhere on the oral mucosa ** But over 90% of cases involve the gingiva where the condition presents as desquamative gingivitis ** In some patients, desquamative gingivitis is the only manifestation, and thus the condition is then called oral Pemphigoid Bullae are tense and tough (unlike those of Pemphigus vulgaris) since they consist of full thickness-epithelium and thus they remain intact for few days When bullae rupture, they give rise to erosions which heal slowly, sometimes with scarring (hence the other name cicatrical Pemphigoid) Bullae are produced as a result of acantholysis and this process extends laterally in the surrounding epithelium, often for a considerable distance As a result, gentle lateral pressure to the mucosa in an involved area can lead to the formation of a bulla (Nikolsky's sign)
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Extraoral lesions: - Mucosa of nose, larynx, pharynx, esophageous, and genitalia - Skin - Conjunctiva: may cause blindness ** Ocular involvement is the most serious complication with scarring leading to opacity of the cornea and blindness Subepithelial separation (separation of the full thickness of the epithelium from the lamina propria) Initially, there's no evidence of an inflammatory reaction in the lamina propria Later on, as the bulla develops, there's infiltration by variable numbers of neutrophils & Eosinophils around and within the developing bulla Peri-vascular lymphocytic infiltrate in the lamina propria Release of proteases from neutrophils and Eosinophils enhances bulla formation in the basement membrane zone Immunological studies are important in establishing the diagnosis and may be helpful in monitoring the progression of the disease Indirect immunoflourescence: Circulating autoantibodies (IgG) to basement membrane antigens were seldom identified in the past by routine techniques, but using the modern techniques, they can now be detected in the serum of about 80% of patients - Their titer is related to the severity of the disease and monitoring the titer over time may be helpful in disease monitoring and response to treatment Direct immunoflourescence: Biopsy of peri-lesional mucosa to detect the binding of autoantibodies (IgG) to basement membrane zone Shows linear deposition of IgG and C3 in the basement membrane Positive in all patients -

o Histopathological features:

o Diagnosis:

o Treatment: topical and/or systemic corticosteroids o Prognosis: good, but monitor eye lesions

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Erythema multiforme: A disease of sudden onset involving skin and mucous membranes and has a wide range of clinical presentations (hence the name multiforme) Clinical features: o Mainly in young adults o More common in males than in females o There may or may not be a Prodromal phase with upper respiratory infection, headache, malaise, nausea o Severity of the disease varies considerably In its severe form, the Stevens-Johnson syndrome, there's widespread involvement of the skin and oral, genital, and ocular mucosae ** Ocular involvement can lead to conjunctiva scarring and visual impairment Milder forms may involve the oral mucosa (with or without skin lesions) or the skin alone may be involved o Disease tends to subside after 10-14 days but recurrence may occur o Recurrent Erythema multiforme is associated in particular with recurrent attacks of herpes simplex virus infection o Skin lesions: Have variety of forms, including: erythematous maculopapular rashes and vesiculobullous eruptions in addition to the characteristic diagnostic target or iris lesions Target "iris" lesions consist of concentric rings of varying Erythema, in the center of which may be an intact or ruptured and crusted bulla Hands and feet are most commonly involved o Oral lesions: Involve any part of the mucosa Lips and anterior parts of the mouth are most commonly affected Appearance of lesions varies with time Erythematous patches are quickly followed by vesiculobullous eruptions which rapidly breakdown into erosions as the bullae disintegrate Erosions on the lips are associated with bleeding and crusting Circumoral crusting hemorrhagic lesions are an important sign to reach clinical diagnosis Pathogenesis: o Unknown (not fully understood)
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o Has been suggested that the disease represents a type III hypersensitivity reaction and that the manifestations maybe related to deposition of immune complexes in which the antigen may be of drug, bacterial, or viral origin o Ag - Ab complexes have been detected in Erythema Multiforme and in some cases they have been associated with HSV infection ** Ag - Ab complexes deposition complement activation neutrophils chemotaxis Vasculitis epithelial damage o Many precipitating factors have been identified including drugs (especially sulphonamides & penicillin) and preceding infection (especially herpes simplex infection) o Many cases appear to arise spontaneously Diagnosis: o Diagnosis is primarily clinical o Microscopic features are not diagnostic May result in intraepithelial or subepithelial separation No autoantibodies, so negative direct & indirect immunoflourescence Treatment and prognosis: o o o o Remove causative drugs, if any Topical and systemic corticosteroids May be recurrent May benefit from prophylactic acyclovir

Dermatitis herpetiformis: A chronic, intensely pruritic autoimmune blistering disease of skin Classified as sub-epithelial vesiculobullous disease Primarily skin disease, but oral manifestations are variable and range from symptomless erythematous areas to extensive erosions About 90% of patients with dermatitis herpetiformis have gluten hypersensitivity Biopsy shows: subepithelial separation and granular accumulation of neutrophils Direct immunoflourescence studies show granular deposits of IgA in the tips of the connective tissue papillae together with some complement component, principally C3 Indirect immunoflourescence studies are negative Pathogenesis: activation of complement system and neutrophils chemotaxis

Linear IgA disease: Rare autoimmune blistering disease of skin Classified as subepithelial vesiculobullous disease Primarily skin disease, but oral involvement is occasional Clinically, this disease overlaps with dermatitis herpetiformis & bullous Pemphigoid (differential diagnoses) About 30% of patients with Linear IgA disease have gluten hypersensitivity
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Biopsy shows: subepithelial separation Direct immunoflourescence studies show linear IgA along basement membrane Indirect immunoflourescence studies show the circulating autoantibodies (IgA) to basement membrane antigens in the serum of about 30% of patients

Epidermolysis Bullosa: The inherited forms of Epidermolysis bullosa form a complex group of syndromes They are due to mutation in the genes coding either for specific keratins in the basal epithelial layer (resulting in intraepithelial separation) or for various collagens and other attachment proteins in the basement membrane (resulting in subepithelial separation) Clinical features: o Skin lesions: Formation of skin bullae which may manifest at birth or shortly afterwards Extreme fragility of the skin Bullae usually develop in response to minimal trauma or pressure but they may arise spontaneously Hands, feet, knees, elbows are common sites Bullae tend to heal slowly with scarring which can result in claw-like deformity of the hands

o Oral lesions: Oral and other mucosae may be involved Bullae tend to heal slowly with scarring which can result in difficulty in eating, speaking, and swallowing as a result of involvement of the mouth, larynx and pharynx Oral lesions may appear in neonates in response to suckling, and later on minimal trauma from tooth brushing and routine dental treatment can cause serious consequences Bullae rupture to leave painful erosions and subsequent scarring can restrict the opening of the mouth, movement of lips and tongue, and cause obliteration of the sulci Effective oral hygiene may be impossible and rampant caries add to the dental complications
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TYPES OF EPIDERMOLYSIS BULLOSA: o o o o Simplex localized skin lesions; oral lesions, good prognosis Dystrophic dominant nails; oral lesions; scarring; fair prognosis Dystrophic recessive severe skin and oral lesions, scarring, abnormal teeth, poor prognosis Junctional severe skin and oral lesions, abnormal teeth, fatal

Treatment: o Avoid trauma o Antibiotics, corticosteroids Prognosis: o Simplex: good o Recessive & Junctional: fatal

Epidermolysis bullosa acquisita: Uncommon autoimmune blistering disease Acquired in adult life Classified as subepithelial vesiculobullous disease Lesions arise mostly on the trauma-prone areas, such as: elbows and knees Oral lesions may occur Biopsy shows: subepithelial separation Direct immunoflourescence studies show linear deposition of IgG and C3 in the basement membrane Indirect immunoflourescence studies show the circulating autoantibodies (IgG) to basement membrane antigens in the serum of about 30-40% of patients

Angina Bullosa Hemorrhagica (oral blood blister): Spontaneous blood filled bullae Occasionally develop on the oral mucosa Usually solitary Middle aged or elderly Occur on any part of the oral mucosa Soft palate is the most commonly involved Cause is unknown, but bullae may be related to trauma Biopsy shows: subepithelial separation No autoantibodies, so negative direct & indirect immunoflourescence

Treatment of non-microbial mucositis with corticosteroids: Mouth rinse o Triamcinolone acetonide Ointment o Triamcinolone acetonide o Fluocinonide (Lidex)
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o Clobetasol Systemic Steroids o Prednisone o Contraindicated in certain systemic diseases Intralesional Steroids Triamcinolone acetonide, inject 10-40 mg Anesthetize area before injection of steroid

Differential diagnosis of subepithelial separation: 1234567Pemphigoid Bullous lichen planus Linear IgA disease Dermatitis herpetiformis Epidermolysis bullosa (both forms) Erythema multiforme Angina bullosa hemorrhagica

Differential diagnosis of desquamative gingivitis: 12345Mucous membrane Pemphigoid Pemphigus vulgaris Erosive lichen planus Allergic reaction Drug induced

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