1.2.5 Pemphigus Vulgaris

F = M: 30-60 years. Incidence of 2-7 new cases per million per year. Ethnic variation with much higher incidence in Ashkenazi Jewish patients.

Loss of cell adhesions between keratinocytes (acantholysis) and subsequent blister formation through impairment of desmosome function, by circulating autoantibodies against desmosomal proteins (desmogleins 1 and 3).

• Pemphigus vulgaris: onset with oral painful erosions in more than 50% of cases, later superficial, fragile and flaccid blisters with rapid transition to crusted erosions. The lesions usually develop in non-inflammed skin. Nikolski’s signs positive (Nikolski I: blisters induced by rubbing normal skin. Nikolski II: existing blisters extend with lateral pressure). Mucosal lesions clinically are painful erosions of different sized characterized by an irregular and ill-defined border, localized in the oral cavity, especially at the buccal and palatine mucosa. The primary skin lesions are flaccid, thin-walled, easily ruptured blisters developing usually in non-inflammed skin. Nikolski’s signs positive (Nikolski I: blisters induced by rubbing normal skin. Nikolski II: existing blisters extend with lateral pressure). The fluid in the bullae is clear at the early stages, and then may become hemorrhagic, turbid, seropurulent. When the bullae are ruptured, they form painful erosions with oozing and bleeding, and they can be covered by crusts.

• Pemphigus vegetans: a very rare variant of pemphigus vulgaris clinically characterized by flaccid blisters and/or pustules that become erosions, ultimately progressing to vegetating plaques, especially in the intertriginous areas.

• Pemphigus foliaceus: rare variant where blister levels so superficial that blisters are extremely unstable and rarely intact. It manifests with impetigo-like crusted erosions usually on an erythematosus base, and usually starts in seborrheic areas. Mucosae are usually spared. Transition into exfoliative erythroderma.

• Pemphigus erythematosus: a localized variant of pemphigus foliaceus in the malar region of the face and in the other seborrheic areas.

• Pemphigus herpetiformis: variant of pemphigus vulgaris that clinically resembles dermatitis herpetiformis or linear immunoglobulin A bullous dermatosis.

• IgA pemphigus: Painful and pruritic vesiculopustular eruptions. Intraepidermal IgA deposits. Two distinct subtypes are subcorneal pustular dermatosis (anti-desmocollin 1 antibodies) and intraepidermal neutrophilic dermatosis (anti-desmoglein antibodies).

• Paraneoplastic pemphigus: very rare. Associated with an underlying neoplasm, most frequently non-Hodgkin lymphoma and chronic lymphocytic leukemia. Clinically is characterized by severe stomatitis with erosions and ulcerations in the oropharynx that extent to vermillion lip. In most cases, a severe pseudomembranous conjunctivitis is present. Paraneoplastic autoimmune multi- organ syndrome (PAMS) has been coined to account for the variable non-bullous cutaneous manifestation and additional systemic findings, such as bronchiolitis obliterans. Serum auto- antibodies against several desmosomal components (desmogleins, desmocollins, plakoglobin).

Direct immunofluorescence (DIF): identification of in vivo bound intra-epidermal, intercellular IgG or IgA autoantibodies in the skin biopsy.

Indirect immunofluorescence (IIF): identification in patient’s serum of circulating IgG autoantibodies against stratified squamous epithelium (monkey esophagus, rat or rabbit urinary bladder epithelium).

ELISA or immunoblot or detection of autoantibodies against desmosomal proteins in serum. Antinuclear antibodies may be detected in pemphigus erythematosus.

Intraepidermal clefts secondary to acantholysis. Eosinophilic spongiosis is characteristic.

Chronic, progressive. If untreated, fatal in high percentage of cases.

Tzanck test: direct identification of acantholytic cells in smear of blister content (smear, Giemsa stain). Histology to disclose the level of epidermal acantholysis. The demonstration of IgG or IgA autoantibodies directed against the cell surface of keratinocytes is the gold standard for the diagnosis. To demonstrate the autoantibodies, the methods are direct immunofluorescence (DIF), indirect immunofluorescence (IIF), immunoprecipitation, immunoblotting, and ELISA. Immunoblot/ ELISA: antibodies anti-desmoglein 1 and 3 autoantibodies in serum.

• Mucosal and erosive oral lesions: acute herpetic stomatitis, aphthous stomatitis, erosive lichen planus, erythema multiforme major or Stevens-Johnson syndrome, fixed drug reaction, systemic lupus erythematosus, mucous membrane pemphigoid.

• Skin lesions: other autoimmune bullous diseases, erythema multiforme, Hailey-Hailey disease, Grover disease, staphylococcal scalded skin syndrome (SSSS), toxic epidermal necrolysis (TEN).

Systemic: rituximab, long-term immunosuppressive therapy (corticosteroids and steroid sparing agents, such as azathioprine, methotrexate, cyclophosphamide). Rituximab, the current first line treatment, is a B-cell depleting monoclonal anti-CD20 antibody, and is administered usually by two separate intravenous infusions of 1 g. In general, a long-lasting beneficial effect is seen, and it can be repeated after months. A humanized affinity-matured IgG4-kappa monoclonal antibody with high affinity for the neonatal Fc and Bruton’s tyrosine kinase (BTK) inhibitors receptor seem promising., Systemic corticosteroid therapy: prednisone or prednisolone, with an initial dosage of 1 mg/kg/day or high dose pulse corticosteroids (1 g/day for 3 days). Immunosuppressive agents (azathioprine), combined with corticosteroids, may results in a gaining early control of the disease. Therapy initially high-dose, then tapered over many months to years. In refractory cases or special cases high dose intravenous immunoglobulins can be used.

Topical: general wound care.