Bullae are elevated, fluid-filled blisters ≥ 10 mm in diameter.
Pemphigus vulgaris usually occurs in middle-aged patients, affecting men and women in equal numbers. Rarely, cases have been reported in children. One variant, paraneoplastic pemphigus, can occur in patients who have malignant or benign tumors, most commonly non-Hodgkin lymphoma Non-Hodgkin Lymphomas Non-Hodgkin lymphomas are a heterogeneous group of disorders involving malignant monoclonal proliferation of lymphoid cells in lymphoreticular sites, including lymph nodes, bone marrow, the... read more .
Pemphigus vulgaris is characterized by IgG autoantibodies directed against the calcium-dependent cadherins desmoglein 3 and sometimes desmoglein 1 ( 1 General reference Pemphigus vulgaris is an uncommon, potentially fatal, autoimmune disorder characterized by intraepidermal blisters and extensive erosions on apparently healthy skin and mucous membranes. Diagnosis... read more ). Paraneoplastic pemphigus has autoantibodies directed against these desmoglein antigens as well as others (eg, envoplakin, peiplakin, desmoplakin 1 and 2, BP-Ag 1). These transmembrane glycoproteins affect cell-cell adhesion and signaling between epidermal cells. Acantholysis (loss of intercellular adhesion with consequent epidermal blister formation) results from either direct inhibition of desmoglein function by autoantibody binding or from autoantibody-induced cell signaling that results in down-regulation of cell-cell adhesion. The autoantibodies are present in both serum and skin during active disease. Any area of stratified squamous epithelium may be affected, including mucosal surfaces (see figure Skin cleavage levels in pemphigus and bullous pemphigoid Skin cleavage levels in pemphigus and bullous pemphigoid ).
Skin cleavage levels in pemphigus and bullous pemphigoid
Pemphigus foliaceus blisters form in the superficial layers of the epidermis. Pemphigus vulgaris blisters can form at any epidermal level but typically form in the lower aspects of the epidermis. Bullous pemphigoid blisters form subepidermally (lamina lucida of the basement membrane zone). In this figure, the basement membrane zone is disproportionately enlarged to display its layers.
Pemphigus (vulgaris, foliaceus, or both) may coexist with certain central nervous system (CNS) disorders, especially dementia, epilepsy, and Parkinson disease. Desmoglein 1 is present in CNS neurons (and in all epithelial cells), and an immunologic cross-reaction between epithelial and CNS isoforms has been suggested.
1. Russo I, De Siena FP, MD, Saponeri A, et al: Evaluation of anti-desmoglein-1 and anti-desmoglein-3 autoantibody titers in pemphigus patients at the time of the initial diagnosis and after clinical remission. Medicine (Baltimore) 96(46):e8801, 2017. doi: 10.1097/MD.0000000000008801
Symptoms and Signs of Pemphigus Vulgaris
Flaccid bullae, which are the primary lesions of pemphigus vulgaris, cause widespread and painful skin, oral, and other mucosal erosions. About half of patients have only oral erosions, which rupture and remain as chronic, painful lesions for variable periods. Often, oral lesions precede skin involvement. Dysphagia and poor oral intake are common because lesions also may occur in the upper esophagus. Cutaneous bullae typically arise in normal-appearing skin, rupture, and leave a raw area with crusting. Itching is usually absent. Erosions often become infected. If large portions of the body are affected, fluid and electrolyte loss may be significant.
A rare variant called pemphigus vegetans occurs primarily in intertriginous areas and oral mucosa with vegetating cauliflower-like plaques.
Diagnosis of Pemphigus Vulgaris
Biopsy with immunofluorescence testing
Pemphigus vulgaris should be suspected in patients with unexplained chronic mucosal ulceration, particularly if they have bullous skin lesions. This disorder must be differentiated from other disorders that cause chronic oral ulcers and from other bullous dermatoses (eg, pemphigus foliaceus Pemphigus Foliaceus Pemphigus foliaceus is an autoimmune blistering disorder in which lack of adhesion in the superficial epidermis result in cutaneous erosions. Diagnosis is by skin biopsy and direct immunofluorescence... read more , bullous pemphigoid Bullous Pemphigoid Bullous pemphigoid is a chronic autoimmune skin disorder resulting in generalized, pruritic, bullous lesions in older patients. Mucous membrane involvement is rare. Diagnosis is by skin biopsy... read more , mucous membrane pemphigoid Mucous Membrane Pemphigoid Mucous membrane pemphigoid is the designation given to a heterogeneous group of rare chronic autoimmune disorders that tend to cause waxing and waning bullous lesions of the mucous membranes... read more , drug eruptions Drug Eruptions and Reactions Drugs can cause multiple skin eruptions and reactions. The most serious of these are discussed elsewhere in THE MANUAL and include Stevens-Johnson syndrome and toxic epidermal necrolysis, hypersensitivity... read more , toxic epidermal necrolysis Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) Stevens-Johnson syndrome and toxic epidermal necrolysis are severe cutaneous hypersensitivity reactions. Drugs, especially sulfa drugs, antiseizure drugs, and antibiotics, are the most common... read more , erythema multiforme Erythema Multiforme Erythema multiforme is an inflammatory reaction, characterized by target or iris skin lesions. Oral mucosa may be involved. Diagnosis is clinical. Lesions spontaneously resolve but frequently... read more , dermatitis herpetiformis Dermatitis Herpetiformis Dermatitis herpetiformis is an intensely pruritic, chronic, autoimmune, papulovesicular cutaneous eruption strongly associated with celiac disease. Typical findings are clusters of intensely... read more , bullous contact dermatitis Contact Dermatitis Contact dermatitis is inflammation of the skin caused by direct contact with irritants (irritant contact dermatitis) or allergens (allergic contact dermatitis). Symptoms include pruritus and... read more ).
Two clinical findings, both reflecting lack of epidermal cohesion, that are somewhat specific for pemphigus vulgaris are the following:
Nikolsky sign: Upper layers of epidermis move laterally with slight pressure or rubbing of skin adjacent to a bulla.
Asboe-Hansen sign: Gentle pressure on intact bullae causes fluid to spread away from the site of pressure and beneath the adjacent skin.
The diagnosis of pemphigus vulgaris is confirmed by biopsy of lesional and surrounding (perilesional) normal skin. Immunofluorescence testing shows IgG autoantibodies against the keratinocyte's cell surface. Serum autoantibodies to desmoglein 1 and desmoglein 3 transmembrane glycoproteins can be identified via direct immunofluorescence, indirect immunofluorescence, and enzyme-linked immunosorbent assay (ELISA).
Prognosis for Pemphigus Vulgaris
Without treatment, pemphigus vulgaris is often fatal, usually within 5 years of disease onset. Systemic corticosteroid and immunosuppressive therapy has improved prognosis, but death may still result from complications of therapy.
Treatment of Pemphigus Vulgaris
Corticosteroids, oral or IV
Sometimes plasma exchange or IV immune globulin (IVIG)
Referral to a dermatologist with expertise in treating this disorder is recommended. Hospitalization is required initially for all but the most minor cases. Cleansing and dressing of open skin lesions is similar to that done to treat partial-thickness burns Initial wound care (eg, reverse isolation, hydrocolloid or silver sulfadiazine dressings).
Treatment of pemphigus vulgaris is aimed at decreasing production of pathogenic autoantibodies. The mainstay of treatment is systemic corticosteroids. Some patients with few lesions may respond to oral prednisone 20 to 30 mg once a day, but most require 1 mg/kg once a day as an initial dose. Some clinicians begin with even higher doses, which may slightly hasten initial response but do not appear to improve outcome. If new lesions continue to appear after 5 to 7 days, IV pulse therapy with methylprednisolone 1 g once a day can be tried.
Once no new lesions have appeared for 7 to 10 days, corticosteroid dose should be tapered monthly by about 10 mg/day (tapering continues more slowly once 20 mg/day is reached). A relapse requires a return to the starting dose. If the patient has been stable after a year, a trial without treatment can be attempted but must be closely monitored.
Immunosuppressants such as rituximab ( 1 Treatment references Pemphigus vulgaris is an uncommon, potentially fatal, autoimmune disorder characterized by intraepidermal blisters and extensive erosions on apparently healthy skin and mucous membranes. Diagnosis... read more ), methotrexate, cyclophosphamide, azathioprine, gold, mycophenolate mofetil, or cyclosporine can reduce the need for corticosteroids and thus minimize the undesirable effects of long-term corticosteroid use. Rituximab combined with systemic corticosteroids is an alternative first-line treatment ( 2 Treatment references Pemphigus vulgaris is an uncommon, potentially fatal, autoimmune disorder characterized by intraepidermal blisters and extensive erosions on apparently healthy skin and mucous membranes. Diagnosis... read more ). Plasma exchange and high-dose IV immune globulin to reduce antibody titers have also been effective.
1. Craythorne EE, Mufti G, DuVivier AW: Rituximab used as a first-line single agent in the treatment of pemphigus vulgaris. J Am Acad Dermatol 65(5):1064–1065, 2011. doi: 10.1016/j.jaad.2010.06.033
2. Joly P, Maho-Vaillant M, Prost-Squarcioni C, et al: First-line rituximab combined with short-term prednisone versus prednisone alone for the treatment of pemphigus (Ritux 3): A prospective, multicentre, parallel-group, open-label randomised trial. Lancet 389(10083):2031–2040, 2017. doi: 10.1016/S0140-6736(17)30070-3
About half of patients with pemphigus vulgaris have only oral lesions.
Use Nikolsky and Asboe-Hansen signs to help clinically differentiate pemphigus vulgaris from other bullous disorders.
Confirm the diagnosis by immunofluorescence testing of skin samples.
Treat with systemic corticosteroids, with or without other immunosuppressive therapies (drugs, IV immune globulin, or plasma exchange).
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