ICD-9: 694.4 ○ ICD-10: L10
A serious, acute or chronic, bullous autoimmune disease of skin and mucous membranes based on acantholysis.
Two major types: pemphigus vulgaris (PV) and pemphigus foliaceus (PF).
PV: flaccid blisters on skin and erosions on mucous membranes. PF: scaly and crusted skin lesions.
PV: suprabasal acantholysis. PF: subcorneal acantholysis.
IgG autoantibodies to desmogleins, transmembrane desmosomal adhesion molecules.
Serious and often fatal unless treated with immunosuppressive agents.
PV: Rare, more common in Jews and people of Mediterranean descent (See Table 6-2). In Jerusalem the incidence is estimated at 16 per million, whereas in France and Germany it is 1.3 per million.
PF: Also rare but endemic in rural areas in Brazil (fogo selvagem), where the prevalence can be as high as 3.4%.
TABLE 6-2CLASSIFICATION OF PEMPHIGUS |Favorite Table|Download (.pdf) TABLE 6-2 CLASSIFICATION OF PEMPHIGUS
|Pemphigus vulgaris |
|Pemphigus foliaceus |
|Paraneoplastic pemphigus: associated with malignancy |
|IgA pemphigus: subcorneal pustular dermatosis and intraepidermal neutrophilic IgA dermatitis |
40–60 years; fogo selvagem also in children and young adults.
Equal incidence in males and in females, but predominance of females with PF in Tunisia and Colombia.
Etiology and Pathogenesis
An autoimmune disorder. Loss of cell-to-cell adhesion in the epidermis (acantholysis). Occurs as a result of circulating antibodies of the IgG class, which bind to desmogleins, transmembrane glycoproteins in the desmosomes, members of the cadherin superfamily. In PV, desmoglein 3 (in some, also desmoglein 1). In PF, desmoglein 1. Autoantibodies interfere with calcium-sensitive adhesion function and thus induce acantholysis.
usually starts in the oral mucosa, and months may elapse before skin lesions occur. Less frequently, there may be a generalized, acute eruption of bullae from the beginning. No pruritus but burning and pain in erosions. Painful and tender mouth lesions may prevent adequate food intake. Epistaxis, hoarseness, dysphagia. Weakness, malaise, weight loss.
Vesicles and bullae with serous content, flaccid (flabby) (Fig. 6-9), easily ruptured, and weeping (Fig. 6-10), arising on normal skin, randomly scattered, discrete. Localized (e.g., to mouth or circumscribed skin area), or generalized with a random pattern. Extensive erosions bleed easily (Fig. 6-11), crusts particularly on scalp. Since blisters rupture so easily, only painful erosions in many patients (Fig. 6-11).
Pemphigus vulgaris This is the classic initial lesion: flaccid, easily ruptured bulla on normal-appearing skin. Ruptured vesicles lead to erosions that subsequently crust as seen in the two smaller lesions.
Pemphigus vulgaris Widespread confluent flaccid blisters on the lower back of a 40-year-old male who had a generalized eruption including scalp and mucous membranes. The eroded lesions are extremely painful.
Pemphigus vulgaris Widespread confluent erosions that are very painful and bleed easily in a 53-year-old male. There are hardly any intact blisters because they are so fragile and break easily. The blood tracts go sideways because the patient had been lying on his right side before the photograph was taken.
Nikolsky Sign. Dislodging of normal-appearing epidermis by lateral finger pressure in the vicinity of lesions, which leads to an erosion. Pressure on bulla leads to lateral extension of blister.
Sites of Predilection. Scalp, face, chest, axillae, groin, umbilicus. In bedridden patients, there is extensive involvement of back (Fig. 6-11).
Bullae rarely seen, erosions of mouth (see Section 35) and nose, pharynx and larynx, vagina.
Pemphigus Foliaceus has no mucosal lesions and starts with scaly, crusted lesions on an erythematous base, initially in seborrheic areas.
Most commonly on face, scalp, upper chest, and abdomen. Scaly, crusted erosions on an erythematous base (Fig. 6-12). In early or localized disease, sharply demarcated in seborrheic areas; may stay localized or progress to generalized disease and exfoliative erythroderma. Initial lesion also a flaccid bulla, but this is rarely seen because of superficial location (see dermatopathology below).
Pemphigus foliaceus The back of this patient is covered by scaly crusts and superficial erosions.
Pemphigus Vegetans (PVeg) (See Table 6-2). A PV variant. Usually confined to intertriginous regions, perioral area, neck, and scalp. Granulomatous vegetating purulent plaques that extend centrifugally. In these patients, there is a granulomatous response to the autoimmune damage of PV (Fig. 6-13).
Pemphigus vegetans Papillomatous, cauliflower-like, oozing growths in the groin and pubis of a 50-year-old man.
Drug-Induced PV. Clinically identical to sporadic PV. Several different drugs implicated, most significantly, captopril and D-penicillamine.
Brazilian Pemphigus (Fogo Selvagem). A distinctive form of PF endemic to south central Brazil. Clinically, histologically, and immunopathologically identical to PF. Patients improve when moved to urban areas but relapse after returning to endemic regions. Probably related to an arthropod-borne infectious agent, with clustering similar to that of the black fly—simulium nigrimanum. More than 1000 new cases per year are estimated to occur in the endemic regions.
Pemphigus Erythematosus (PE). Synonym: Senear-Usher syndrome. A localized variant of PF largely confined to seborrheic sites. Erythematous, crusted, and erosive lesions in the “butterfly” area of the face, forehead, and presternal and interscapular regions. May have antinuclear antibodies.
Drug-Induced Pemphigus PF. As in PV, associated with D-penicillamine and less frequently by captopril and other drugs. In most, but not all, instances, the eruption resolves after termination of therapy with the offending drug.
Neonatal Pemphigus. Very rare, transplacental transmission from diseased mother; spontaneous resolution.
This is a disease sui generis and is discussed in Section 19.
PV: Light microscopy (select early small bulla or, if not present, margin of larger bulla or erosion): Separation of keratinocytes, suprabasally, leading to split just above the basal cell layer and vesicles containing separated, rounded-up (acantholytic) keratinocytes. PF: Superficial form with acantholysis in the granular layer of the epidermis.
Direct immunofluorescence (IF) staining reveals IgG and often C3 deposited in lesional and paralesional skin in the intercellular substance of the epidermis. In PE Ig and complement deposits also found at the dermal epidermal junction.
Autoantibodies (IgG) detected by indirect IF or ELISA. Titer usually correlates with activity of disease. In PV, autoantibodies against a 130-kDa glycoprotein, desmoglein 3, located in desmosomes of keratinocytes. In PF, autoantibodies to a 160-kDa intercellular (cell surface) antigen, desmoglein 1, in desmosomes of keratinocytes.
Diagnosis and Differential Diagnosis
Difficult problem if only mouth lesions are present. Aphthae, mucosal lichen planus, erythema multiforme. Differential diagnosis includes all forms of acquired bullous diseases (see Table 6-3). Biopsy of the skin and mucous membrane, direct IF, and demonstration of circulating autoantibodies confirm a high index of suspicion.
TABLE 6-3DIFFERENTIAL DIAGNOSIS OF IMPORTANT BULLOUS DISEASES |Favorite Table|Download (.pdf) TABLE 6-3 DIFFERENTIAL DIAGNOSIS OF IMPORTANT BULLOUS DISEASES
|Disease ||Skin Lesions ||Mucous Membranes ||Distribution |
|PV ||Flaccid bullae on normal skin, erosions ||Almost always involved, erosions ||Anywhere, localized or generalized |
|PF ||Crusted erosions, occasionally flaccid vesicles ||Rarely involved ||Exposed, seborrheic regions or generalized |
|PVeg ||Granulating plaques, occasionally vesicles at margin ||As in PV ||Intertriginous regions, scalp |
|Bullous pemphigoid ||Tense bullae on normal and erythematous skin; urticarial plaques and papules ||Mouth involved in 10–35% ||Anywhere, localized or generalized |
|EBA ||Tense bullae and erosions, noninflammatory or BP-, DH- or LAD-like presentation ||May be severely involved (oral esophagus, vagina) ||Traumatized regions or random |
|Dermatitis herpetiformis ||Grouped papules, vesicles, urticarial plaques, crusted ||None ||Predilection sites: elbows, knees, gluteal, sacral, and scapular areas |
|Linear IgA dermatosis ||Annular, grouped papules, vesicles, and bullae ||Oral erosions and ulcers, conjunctival erosions and scarring ||Anywhere |
|Disease ||Histopathology ||Immunopathology/Skin ||Serum |
|PV ||Suprabasal acantholysis ||IgG intercellular pattern || |
IgG AB to intercellular substance of epidermis (IIF)
ELISA: AB to desmoglein 3 W desmoglein 1
|PF ||Acantholysis in granular layer ||IgG, intracellular pattern || |
IgG AB to intercellular substance of epidermis (IIF)
ELISA: AB to desmoglein 1 only
|PVeg ||Acantholysis ± intraepidermal neutrophilic abscesses, epidermal hyperplasia ||As in PV ||As in PV |
|Bullous pemphigoid ||Subepidermal blister ||IgG and C3 linear at BMZ ||IgG AB to BMZ (IIF); directed to BPAG1 and BPAG2 |
|EBA ||Subepidermal blister ||Linear IgG at BMZ ||IgG AB to BMZ (IIF) directed to type VII collagen (ELISA, Western blot) |
|Dermatitis herpetiformis ||Papillary microabscesses, subepidermal vesicle ||Granular IgA in tips of papillae ||Antiendomysial antibodies |
|Linear IgA dermatosis ||Subepidermal blister with neutrophils ||Linear IgA at BMZ ||Low titers of IgA AB against BMZ |
In most cases, the disease inexorably progresses to death unless treated aggressively with immunosuppressive agents. The mortality rate has been markedly reduced since treatment has become available. Currently, morbidity mainly related to glucocorticoids and immunosuppressive therapies.
Requires expertise and experience. Treatment to be performed by dermatologist.
2–3 mg/kg body weight of prednisone until cessation of new blister formation and disappearance of Nikolsky sign. Then rapid reduction to about half the initial dose until patient is almost clear, followed by very slow tapering of dose to minimal effective maintenance dose.
Concomitant Immunosuppressive Therapy
Immunosuppressive agents are given concomitantly for their glucocorticoid-sparing effect:
Azathioprine, 2–3 mg/kg body weight until complete clearing; then tapered.
Methotrexate, either orally or IM at doses of 25–35 mg/wk. Dose adjustments are made as with azathioprine.
Cyclophosphamide, 100–200 mg daily, with reduction to maintenance doses of 50–100 mg/d. Alternatively, cyclophosphamide “bolus” therapy with 1000 mg IV once a week or every 2 weeks in the initial phases, followed by 50–100 mg/d po as maintenance.
Mycophenolate mofetil (1 g twice daily).
Plasmapheresis, in conjunction with glucocorticoids and immunosuppressive agents.
High-dose intravenous immunoglobulin (IVIG) (2 g/kg body weight every 3–4 weeks) has glucocorticoid-sparing effects.
Rituximab (monoclonal antibody to CD20) targets B cells, the precursors of (auto) antibody-producing plasma cells. Given as intravenous therapy once a week for 4 weeks shows dramatic effects in some and at least partial remission in other patients. Serious infections may be seen.
Cleansing baths, wet dressings, topical and intralesional glucocorticoids, antimicrobial therapy in documented bacterial infections. Correction of fluid and electrolyte imbalance.
Clinical, for improvement of skin lesions and development of drug-related side effects. Laboratory monitoring of pemphigus antibody titers and for hematologic and metabolic indicators of glucocorticoid- and/or immunosuppressive-induced adverse effects.