Topic 11. Autoimmune Bullous Skin Diseases

7/28/2019 Topic 11. Autoimmune Bullous Skin Diseases

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Efi. Gelerstein 2011

Topic 11. Autoimmune bullous skin diseases

Blisters are accumulations of fluid within or under the epidermis. The appearance of a blister is determined by the level at which it forms. Subepidermal blisters occur between the dermis and the epidermis

- Thick roof, tense and intact.- May contain blood.

Intraepidermal blisters appear within the prickle cell layer of the epidermis- Thin roofs and rupture easily to leave an oozing denuded surface

Sub-corneal blisters form just beneath the stratum corneum at the outermost edge of the viableepidermis, and therefore have even thinner roofs.

Bullous disorders of immunological origin

1. Pemphigus group intraepidermal blister2. Pemphigoid group subepidermal blister3. Dermatitis Herpetiformis Duhring (DHD) subepidermal blister

Pemphigus

Pemphigus is severe and potentially life-threatening disease. There are two main types:

1. Pemphigus vulgaris most common, of all cases, and formost of the deaths.

2. Pemphigus vegetans rare variant of pemphigus vulgaris. Other types:

1. Superficial pemphigus generalized foliaceus type andlocalized erythematosus type.

2. Pemphigus-like reaction from drug reaction3. para-neoplastic pemphigustumor associated


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Cause

Autoimmune diseases Pathogenic IgG antibodies bind to antigens within the epidermis. The main antigens:

1. Desmoglein 3 (in pemphigus vulgaris)2. Desmoglein 1 (in superficial pemphigus)

- Both are cell-adhesion molecules of the cadherin family found in desmosomes. The antigenantibody reaction interferes with adhesion, causing the keratinocytes to fall apart

Presentation

Flaccid blisters of the skin and mouth Blisters rupture, by widespread painful erosions. 1stmouth lesions Shearing stresses on normal skin can cause new erosions (+Nikolsky sign). In the vegetans variantheaped up cauliflower-like weeping areas are

present in the groin and body folds.

The blisters in pemphigus foliaceusare superficial, and rupture easily;clinical picture is dominated more by weeping and crusting erosions than by

blisters. In the rarerpemphigus erythematosus, the facial lesions are often pink, dry,

and scaly.Course

Prolonged course, even with treatment Superficial pemphigus is less severe. With modern treatments, most patients can live relatively normal lives, with

occasional exacerbations.

Complications

Complications are inevitable with the high doses of steroids andimmunosuppressive drugs

Side-effects of treatment are now the leading cause of death. Infections of all types are common. The large areas of denudation may become infected and smelly, and severe oral ulcers make eating

painful.

Differential diagnosis

Widespread erosions: pyoderma, impetigo, epidermolysis bullosa or ecthyma. Mouth ulcers: aphthae, Behcets disease or a herpes simplex infection.


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Investigations

Biopsy vesicles are intraepidermal, with rounded keratinocytes floating freely within the blistercavity (acantholysis).

Direct immunofluorescence of adjacent normal skin shows intercellular epidermal deposits of IgGand C3

Serum: Contains antibodies that bind to the desmogleins in the desmosomes of normal epidermis, sothat indirect immunofluorescence can also be used to confirm the diagnosis.

The titre of these antibodies correlates loosely with clinical activity and may guide changes in thedosage of systemic steroids.

Pemphigus is more attacking than Pemphigoid and needs higher doses of steroids to control it.

Treatment

1. Corticosteroids 2-3 mg/kg prednisoneuntil secession of new blister formation-rapid Reduction - slow tapering of dose to minimal maintenance dose

2. Concomitant Immunosuppressive Therapy Azathioprine100-150 mg/day-tapering of dose to 100-50 mg/day (steroid sparing effect) Second line treatments: MTX, cyclophosphamide, plasmapheresis, gold therapy

3. Topical therapy4. Correction of fluid and electrolyte imbalance5. Monitoring! drug-related side effects drug-induced adverse effects

Subepidermal immunobullous disorders:

Pemphigoid

Autoimmune disease Serum contains antibodies that bind in vitro to normal skin at the

basement membrane zone

The IgG antibodies bind to two main antigens:- BP230 (within the cellular part of the hemidesmosome) most common- BP180 (a transmembrane molecule with one end within the hemidesmosome and the other bound

to the lamina lucida).

Complement is then activated inflammatory cascade mast cells degranulation, liberating avariety of inflammatory mediators.

Presentation

Chronic, usually itchy, blistering disease, mainly affecting the elderly. The tense bullae can arise from normal skin but usually do so from urticarial plaques The flexures are often affected; the mucous membranes usually are not. The Nikolsky test is negative. (Nikolsky's sign is positive when slight rubbing of the skin results in

exfoliation of the skin's outermost layer)


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Course

Pemphigoid is usually self-limiting and treatment can often be stopped after 12 years

Complications

Causes much discomfort and loss of fluid from ruptured bullae. Systemic steroids and immunosuppressive agents side effects The validity of a possible association with internal malignancy is still debated.

Differential diagnosis

May look like other bullous diseases, especially:

1. Epidermolysis bullosa acquisita2. Bullous lupus erythematosus3. Dermatitis herpetiformis4. Pemphigoid gestationis5. Bullous erythema multiforme6. Linear IgA bullous disease.

Investigations

Histology: Subepidermal blister often filled with eosinophils. Direct immunofluorescence: linear band ofIgG and C3 along the basement membrane zone Indirect immunofluorescence: IgG antibodies that react with the basement membrane zone

Treatment

Acute phase Prednisoloneorprednisoneat a dosage of 4060 mg/day is usually needed to control the eruption. Immunosuppressive agents may also be required. The dosage is reduced as soon as possible, and patients end up on a low maintenance regimen of

systemic steroids, taken on alternate days until treatment is stopped.

For unknown reasons,Tetracyclinesand niacinamidehelp some patients.IgA pemphigus

Vesiculo-pustular skin symptoms Histology: mild acantholysis, neutrophils DIF: IgA, IC reaktivits Therapy:Dapsone, steroids, colchicin

Linear IgA bullous disease

Clinically similar to pemphigoid, but affects children as well as adults. Blisters arise on urticarial plaques, and are more often grouped, and on extensor surfaces string of pearls sign- the presence of blistering around the rim of polycyclic urticarial lesions. Associated with linear deposits of IgA and C3 at the basement membrane zone The disorder responds well to oral dapsone


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Cicatricial pemphigoid

Autoimmune skin disease showing IgG and C3 deposition at thebasement membrane zone

The antigens are often as in pemphigoid, but sometimes other aretargeted such as laminin 5 (in anchoring filaments).

Blisters and ulcers occur mainly on mucous membranes such as theconjunctivae, the mouth and genital tract may lead to blindness!

Lesions heal with scarring: around the eyes blindness condition tends to persist and treatment is relatively ineffective

Epidermolysis Bullosa Acquisita (EBA)

This can also look like pemphigoid, but has two important extra features:- many of the blisters are a response to trauma and arise on otherwise normal skin- Milia are a feature of healing lesions (tiny spheroidal epithelial cyst lying superficially w/i skin)

Autoantibodies to type VII collagen in anchoring fibrils Antigen lies on the dermal side of the lamina densa (pemphigoid antigensepidermal side ) Associated with IBD (Crohns disease) Linear deposits of IgG&C3 Poor response to steroids and cytotoxic Plasmapheresis, hdIVIg

Therapy

50-100 mg/dayprednisone 100-150 mg/dayAzathioprine topical steroid

Dermatitis Herpetiformis Duhrings disease (DHD) Very itchy chronic subepidermal vesicular disease Vesicles erupt in groups as in herpes simplex - hence the name

herpetiformis.

Cause

Gluten-sensitive enteropathy ( diarrhea, constipation or malnutrition) Granular deposits of IgA and C3 in the superficial dermis under the basement membrane zone

induce inflammation separates the epidermis from the dermis.

These deposits clear slowly after the introduction of a gluten-free diet.Presentation

The extremely itchy, grouped vesicles and urticated papules develop particularly over the elbowsand knees, buttocks and shoulders.

They are often broken by scratching before they reach any size. A typical patient therefore showsonly grouped excoriations, sometimes with eczema-like changes added by scratching.


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Course

The condition typically lasts for decades. iodide sensitivity , gluten sensitive enteropathy

Therapy

Dapsone 100-200 mg/day, reduced to 25-50 mg/daymaintenance

Gluten-free diet-slow response Sulfapyridine 1-1.5 g/day if dapsone contraindicated or not tolerated Sulfone therapy: G-6-PD deficiency, Methemoglobinaemia

Laboratory and special examinations in autoimmune blistering diseases

Dermatopathology-light microscopy Immunofluorescence-DIF & IIF Salt-split skin (1M NaCl, separation within the lamina lucida) Western blotting ELISA

Topic 11. Autoimmune Bullous Skin Diseases

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