Autoimmune blistering diseases http:www.srrsh.com Autoimmune blistering diseases Pemphigus Pemphigoid Dermatitis herpetiformis (Duhring) Dr. Kejian Zhu Sir Run Run Shaw Hospital

Blister---classification Intraepithelial vesicles: Acantholytic vesicles: the break down of specialized attachments (desmosomes) Nonacantholytic vesicles: the death or the rupture of the group of cells, usually seen in viral infections Subepithelial vesicles:

Autoimmune blistering diseases Diseases with intraepidermal blistering (pemphigus-group) Pemphigus vulgaris Pemphigus vegetans Pemphigus foliaceus Pemphigus erythematosus Paraneoplastic pemphigus Drug-induced pemphigus Neonatal pemphigus Intercellular IgA dermatosis Brazilian pemphigus

Autoimmune blistering diseases Diseases with subepidermal blistering (pemphigoid group) Bullous pemphigoid (BP) Herpes gestationis Cicatricial pemphigoid Epidermolysis bullosa acquisita Dermatitis herpetiformis (Duhring) Linear IgA bullous dermatosis (LAD) Bullous SLE

Diseases with intraepidermal blistering (pemphigus-group) Pemphigus vulgaris Pemphigus vegetans Pemphigus foliaceus Pemphigus erythematosus

Outline Middle-aged and elderly people are most commonly affected Flaccid blisters Two main groups: vulgaris & foliaceus Nikolsky’s sign and Tzanck test are positive Autoimmune diseases Acantholytic intraepidermal blistering is produced by autoantibodies against desmoglein Anti-desmoglein antibodies are detected by ELISA In vivo IgG deposition and IgG antibodies are observed by immunofluorescence Oral steroids & immunosuppressants are mainly administered.

Adhesion of keratinocytes Keratinocytes are firmly adhered by desmosomes. Transmembrane adhesion molecules in the cadherin superfamily, such as desmoglein 1 (Dsg 1), Dsg3, and desmocolin cadherin (DC), are important to intercellular adhesion. In pemphigus, autoantibodies are produced against Dsg1 and Dsg3, some of whose molecular functions are disturbed. This causes acantholysis.

Acantholysis Acantholysis: dissociation of intercellular connections in the epidermis. As dissociation progresses, epidermal cleavage and blistering occurs. Acantholytic cells: deformed keratinocytes become spherical from loss of intercellular connection within the blisters.

Tzanck test Tzanck test is a kind of cytological diagnosis method. It is induced by applying a slide glass to the bottom of a broken blister and staining the adhered cellular components in Giemsa for observation under a light microscope. Tzanck cells are acantholytic cells observed in pemphigus. Tzanck cells can also be observed in blisters of herpes simplex and herpes zoster, ballooning cells produced by viral infection.

Nikolsky’s sign Nikolsky's sign: blistering or exfoliation of the skin’s outmost layer produced by slight rubbing of the normal-looking skin It is positive in pemphigus, epidermolysis bullosa, staphylococcal scalded-skin syndrome (SSSS), and toxic epidermal necrolysis (TEN). Nikolsky's sign is useful in differentiating between pemphigus vulgaris (where it is present or positive) and bullous pemphigoid (where it is absent) When the blisters are pressed without breaking, the fluid contents extend to the peripheral normal skin around the blisters (blister diffusion phenomena, or false Nikolsky’s sign)

Pemphigus vulgaris Pemphigus vegetans Pemphigus foliaceus Pemphigus erythematosus

Outline The most common variety of pemphigus The disease most frequently occurs in the middle-aged and elderly. The disease is caused by autoantibodies against desmoglein 3, which is a desmosomal adhesion factor in keratinocytes. Acantholytic blisters form immediately above epidermal basal cells。 It tends to manifest as oral enanthema. Nikolsky’s sign is positive. Oral steroids and immunosuppressants are the first-line treatment.

Clinical features Most frequently affects the middle-aged and elderly Erosions and ulcers develop acutely in the oral mucosa in 70-80% of cases Blisters of various sizes occur on normal skin, easily rupture to form erosions and crusts Painful, esp. when touched Anywhere on the body, esp. at sites of pressure and friction (back, buttocks and feet) Nikolsky’s sign When widespread, electrolyte abnormalities due to loss of body fluid or hypoprotein Be fatal when there is secondary infection

Workup Pathology: acantholysis, intraepidermal blistering, leaving one basal layer at the bottom Immunofluorescence: intercellular in vivo IgG deposition ELISA: anti-Dsg3 IgG Ab, sometimes also anti-Dsg1 IgG Ab

Diagnosis Clinical features Pathology Immunofluorescence ELISA DDx: bullous pemphigoid, impetigo, bullous drug eruption, dermatitis herpetiformis, erythema multiforme, Stevens-Johnson syndrome, etc.

Treatment Systemic application of steroids is the first-line treatment (0.5-1.0mg/kg/d). Taper off to a maintenance dose or until it can be discontinued. Immunosuppressants (mycophenolate mofetil, CTX, AZT, MTX, cyclosporine) may be used. In intractable cases, plasma exchange therapy and IVIG can be performed. Antibiotics, fluid transfusion, nutrition management are conducted supplementarily.

Pemphigus vulgaris Pemphigus vegetans Pemphigus foliaceus Pemphigus erythematosus

Clinical features A subtype of pemphigus vulgaris, the most uncommon variety of pemphigus Characterized by the formation of vesicles and erosions that do not re-epithelialize but gradually proliferate and elevate Frequently occurs on areas of friction (axillary fossa, umbilical fossa, periphery of the oculonasal and perioral regions) and exposure (face, neck, scalp) Oral mucosa is often involved Strong odor

Workup Pathology: suprabasal cell acantholysis, downward proliferation of rete ridges Immunofluoscence: intercellular deposition of IgG and C3 Culture: bacteria and/or candida

Diagnosis Vesicles and erosions Areas of friction, exposure Proliferate and elevate Suprabasal cell acantholysis DDx: chronic pyoderma and fungal granuloma, Hailey-Hailey disease, condyloma acuminatum, etc.

Treatment The same as for pemphigus vulgaris Treat local infections Consider topical and systemic antibiotics Consider antifungal agents for candida Surgical excision of large vegetative growths Better prognosis than pemphigus vulgaris

Pemphigus vulgaris Pemphigus vegetans Pemphigus foliaceus Pemphigus erythematosus

Outline Autoantibodies are produced exclusively against Dsg 1 Acantholysis and blistering are seen in the superficial epidermis (in the granular cell layer) Fragile blisters, scaling and erosion, accompanied by crusts Lesions are not/occasionally produced in the mucosa Examinations and treatments are the same as for pemphigus vulgaris. The steroid dosage is usually less than for pemphigus vulgaris

Clinical features Most commonly affects the middle-aged and elderly Extremely fragile flaccid vesicles Some of the blisters dry to become leafy and to exfoliate successively The face, head, back and chest are most commonly affected When spreads over the whole body, it resembles exfoliative erythroderma Mucosa is not or occasionally involved Nikolsky’s sign is positive

Workup Pathology: acantholytic blistering is found in the epidermal upper layer. Immunofluorescence: intercellular in vivo IgG deposition is observed ELISA: anti-desmoglein 1 antibodies

Diagnosis Clinical features Pathology Immunofluorescence ELISA DDx: pemphigus vulgaris, pemphigus erythematosus, drug-induced bullous disease, paraneoplastic pemphigus, etc.

Treatment The same as for pemphigus vulgaris Oral steroid dosage may be less than that for pemphigus vulgaris In limited involvement cases, topical steroid are sufficient

Pemphigus vulgaris Pemphigus vegetans Pemphigus foliaceus Pemphigus erythematosus

Clinical features A subtype of pemphigus foliaceus Occurs most commonly in the middle-aged and elderly Frequently affects the seborrheic zones (head, face, chest and back) The mucosa is not involved Involvement of SLE is seen in some cases

Workup Pathology: intraepidermal superficial bullae within the granular layer or just below it. Acantholysis may occur in the blister floor or roof. Immunofluorescence: linear deposits of IgG and C3 in the intercellular space of the epidermis May have lab abnormalities of SLE

Diagnosis Clinical features Pathology Immunofluorescence DDx: paraneoplastic pemphigus, seborrheic dermatitis, lupus erythematosus, pemphigus foliaceus, etc.

Treatment The same as for pemphigus foliaceus

Diseases with subepidermal blstering (pemphigoid group) Bullous pemphigoid (BP) Dermatitis herpetiformis (Duhring)

Outline Subepidermal blistering occurs as a result of autoantibody action against epidermal basement membrane structural proteins Blisters are tense and do not rupture easily Divided into pemphigoid, linear IgA bullous dermatosis, epidermolysis bullosa acquisita, dermatitis herpetiformis, herpes gestations, etc. Immunofluorescence is useful for diagnosis Steroids and dapsone are applied

Basement membrane zone the area corresponding to the dermo-epidermal junction stains with periodic acid-Schiff consists of the basal cell plasma membrane the lamina lucida the basal lamina the sub-basal lamina fibrous components acts as a mechanical barrier and penetration of substance between dermis and epidermis

Bullous pemphigoid (BP) Dermatitis herpetiformis

pathogenesis Autoantibodies are produced against hemidesmosome, type XVII collagen (BP180) and BP230 in the epidermal basement membranes, which leads to blistering. Autoantibodies against BP180 play a major role.

Outline Autoantibodies against hemidesmosomes The major pathogenic antigen is type XVII collagen (BP180). The roof of the blister has the full thickness of the epidermis Elderly people account for the majority of cases Characterized by subepidermal blisters Blisters do not rupture easily Oral steroids are effective

Clinical features The elderly are more commonly affected Multiple relatively large and severe tense blisters form immediately Often accompanied by edematous erythema Much less invasively to the mucous membranes (20% involved) The general condition is favourable May be complicated by malignant tumors

Workup Pathology: subepidermal blistering, accompanied by eosinophilic infiltration Immunofluorescence: linear IgG and C3 deposition in the basement membranes ELISA: autoantibodies against type XVII collagen (BP180) proteins High IgE values and elevated levels of eosinophils in peripheral blood

Diagnosis Clinical features Pathology Immunofluorescence ELISA DDx: drug-induced bullous disorders, epidermolysis bullosa, epidermolysis bullosa acquisita, erythema multiforme, dermatitis herpetifomis, linear IgA dermatosis, etc.

Treatment Oral steroids (0.5mg/kg/d) Gradually reduced Combination therapy of Immunosuppressants (CTX), DDS, tetracyclines and nicotinic-acid amide are also useful Avoid secondary infections Nutrition management is important for elderly Topical steroid application may be sufficient in mild cases Plasma exchange therapy and IVIG may also be used in severe cases

Bullous pemphigoid (BP) Dermatitis herpetiformis

Outline Characterized by extremely intense itching and irritation, chronically recurrent erythema and vesicles Vesicles tend to form circular patterns Common in Caucasians, rare in Asians Granular IgA deposition in the dermal papillary Gluten-induced enteropathy develops as a complication Oral dapsone is effective

Gluten composed of the sticky, storage proteins found in wheat exist conjoined with starch in the same grass-related grains, notably wheat, rye and barley

Pathogenesis IgA antibodies against tissue transglutaminase The granular IgA deposition in the skin is an immuno-complex

Clinical features Extremely intense itching Erythema and urticarial lesions Vesicles in a ring-shaped pattern Scratch and resulted crusts Heal with abnormal pigmentation or depigmentation Appear symmetrically on the entire body, esp. on the elbows, knees and buttocks Gluten-induce enteropathy is found in more than 90% of cases

Workup Pathology: subepidermal blistering, micro-abscesses of neutrophils in dermal papillary Immunofluorescence: granular IgA deposition in the dermal papillary

Diagnosis Clinical features Pathology Immunofluorescence DDx: linear IgA bullous dermatosis, bullous pemphigoid, herpes gestationis, erythema multiforme, ect.

Treatment Dapsone is effective Gluten-free diet antihistamines