6- vesiculobullous diseases

7/30/2019 6- Vesiculobullous Diseases

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Dr. Tahani Abualteen

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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 lesiono Smaller in sizeo Mostly arise intra-epithelially

Bullae:o Fluid filled lesiono Larger in sizeo 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 histologicallocation 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

o Subepithelial vesiculobullous diseases(lesions form between the epithelium & lamina propria): Pemphigoid Erythema multiforme Dermatitis herpetiformis Linear IgA disease Epidermolysis bullosa Angina bullosa hemorrhagica (oral blood blisters) Bullous lichen planus

History is importanto Duration (ulceration lasts weeks to months)o Recurrenceo Other lesions: skin, eye, genital lesionso Systemic manifestationso 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 ageo More common in women than in meno More common in certain ethnic groups, particularly

Ashkenazi Jews, where there may be a genetic link

o Characterized by widespread bullous eruptions involvingthe skin and mucous membranes

o Oral mucosa is involved in nearly all patients and in about50% of cases is the site of initial lesions

o Bullae are fragile (since they are intra-epithelial & notcovered 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 softpalate, buccal mucosa, and lips are most frequently

affected

o There may be also a desquamative gingivitis (a clinicalterm 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 thisprocess extends laterally in the surrounding epithelium,

often for a considerable distance

o As a result, gentle lateral pressure to the mucosa in an involved areacan lead to the formation of abulla (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 ofimmune mechanisms (like Ab

attached to desmosomes) that are waiting for maybe a minor trauma to cause damage

Histopathological features:o Intraepithelial separationo Cleft-like spaces produced by acantholysis in stratum spinosum cellsjust above basal cell layero Basal cells forming the base of the lesion remain

attached to the lamina propria

o Little subepithelial inflammatory cell infiltrationuntil the lesion ruptures

o Acantholytic stratum spinosum cellsare small androunded and contain enlarged hyper-chromatic

nuclei (the so called Tzanck cells)

Nikolsky's sign


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Intercellular attachment s of epithelial cells are mediated

by desmosomes comprising opposing attachment plaques

(P) and intercellular adhesion proteins

Pathogenesis:o Autoimmune diseaseauto-

antibodies against desmosomes

** Desmosome is a junctional complex

mediating cell-cell contact** Desmosome = intercellular

attachment plaque + intercellular

adhesion protein

** Desmogleins are important

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 thedesmosomes (Ab-Ag complex) are responsible for the acantholysisbut 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 earlystages of the disease)

o Direct immunoflourescence:- Detection of antibodies while in their place

using another florescent antibody

- Biopsy of peri-lesional mucosa to detect thebinding of autoantibodies (IgG) to desmosomes** IgG autoantibodies can be detected within

the epithelial thicknessproducing a

characteristic fish-net pattern

- Positive in all patients Other forms of Pemphigus include:

o P. vegetanso Drug inducedo 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 vesiculobullousdisease

The different subtypes and their clinicalmanifestations most likely reflect damage to

different target antigens, however, they can be

divided into 2 groups clinically:

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

oClinical features: More common in women than in men Oral mucosa is almost always affected (either alone or

in association with other mucosae)

Bullae occuranywhere 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 onlymanifestation, and thus the condition is then called oral

Pemphigoid

Bullae are tense and tough (unlike those of Pemphigusvulgaris) since they consist offull thickness-epithelium

and thus they remain intact for few days

When bullae rupture, they give rise to erosions whichheal slowly, sometimes with scarring (hence the other

name cicatrical Pemphigoid)

Bullae are produced as a result of acantholysis andthis 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 theformation of abulla (Nikolsky's sign)

Attachment op epithelium to connective tissue is

mediated by hemidesmosomes (HD) and proteins of

basement membrane zone (BMZ)


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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

complicationwith scarring leading to

opacity of the cornea and blindness

o Histopathological features: Subepithelial separation (separation of the full

thickness of the epithelium from the lamina

propria)

Initially, there's no evidence of aninflammatory reaction in the lamina propria

Later on, as the bulla develops, there'sinfiltration by variable numbers ofneutrophils

& Eosinophils around and within the developing

bulla

Peri-vascular lymphocytic infiltrate in thelamina propria

Release of proteases from neutrophils andEosinophils enhances bulla formation in the

basement membrane zone

o Diagnosis: 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 timemay 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 thebasement membrane

- Positive in all patientso Treatment: topical and/or systemic corticosteroidso Prognosis: good, but monitor eye lesions


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Erythema multiforme: A disease ofsudden onset involving skin and mucous membranes and has a wide range of clinical

presentations (hence the name multiforme)

Clinical features:o Mainly in young adultso More common in males than in femaleso 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 alonemay be involved

o Disease tends to subside after 10-14 days but recurrence may occuro 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 ofconcentric rings of varying Erythema, in the center ofwhich may be an intact or ruptured and crusted bulla

Hands and feet are most commonly involvedo 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 bleedingand crusting

Circumoral crusting hemorrhagic lesions are animportant 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 themanifestations 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 havebeen associated with HSV infection** Ag - Ab complexes deposition complement activation neutrophils chemotaxisVasculitis 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 clinicalo Microscopic features are not diagnostic

May result in intraepithelial or subepithelialseparation

No autoantibodies, so negative direct &indirect immunoflourescence

Treatment and prognosis:o Remove causative drugs, if anyo Topical and systemic corticosteroidso May be recurrento May benefit from prophylactic acyclovir

Dermatitis herpetiformis: A chronic, intensely pruriticautoimmune blistering diseaseof 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 ofskin 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 deformityof 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 responseto 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 ofthe 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 Simplexlocalized skin lesions; oral lesions, good prognosiso Dystrophic dominantnails; oral lesions; scarring; fair prognosiso Dystrophic recessivesevere skin and oral lesions, scarring, abnormal teeth, poor prognosiso Junctionalsevere skin and oral lesions, abnormal teeth, fatal

Treatment:o Avoid traumao Antibiotics, corticosteroids

Prognosis:o Simplex: goodo 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 basementmembrane 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

oTriamcinolone acetonide

o Fluocinonide (Lidex)


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o Clobetasol Systemic Steroids

o Prednisoneo Contraindicated in certain systemic diseases

Intralesional Steroids Triamcinolone acetonide, inject 10-40 mg Anesthetize area before injection of steroid

Differential diagnosis of subepithelial separation:

1- Pemphigoid2- Bullous lichen planus3- Linear IgA disease4-

Dermatitis herpetiformis

5- Epidermolysis bullosa (both forms)6- Erythema multiforme7- Angina bullosa hemorrhagica

Differential diagnosis of desquamative gingivitis:

1- Mucous membrane Pemphigoid2- Pemphigus vulgaris3- Erosive lichen planus4- Allergic reaction5- Drug induced

6- vesiculobullous diseases

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