Chapter 055. Immunologically Mediated Skin Diseases (Part 2) Pemphigus Vulgaris Pemphigus refers to a group of autoantibody-mediated intraepidermal blistering diseases characterized by loss of cohesion between epidermal cells (a process termed acantholysis). Manual pressure to the skin of these patients may elicit the separation of the epidermis (Nikolsky's sign). This finding, while characteristic of pemphigus, is not specific to this group of disorders and is also seen in toxic epidermal necrolysis, Stevens-Johnson syndrome, and a few other skin diseases. Pemphigus vulgaris (PV) is a mucocutaneous blistering disease that predominates in patients >40 years. PV typically begins on mucosal surfaces; it often progresses to a mucocutaneous disease in which fragile, flaccid blisters rupture to produce extensive denudation of the skin (Fig. 55-1). PV typically involves the mouth, scalp, face, neck, axilla, groin, and trunk. PV may be associated with severe skin pain; some patients experience pruritus as well. Lesions usually heal without scarring, except at sites complicated by secondary infection or mechanically induced dermal wounds. Postinflammatory hyperpigmentation is usually present at sites of healed lesions for some time. Figure 55-1 Pemphigus vulgaris. A. Pemphigus vulgaris demonstrating flaccid bullae that are easily ruptured, resulting in multiple erosions and crusted plaques. B. Pemphigus vulgaris almost invariably involves the oral mucosa and may present with erosions involving the gingiva, buccal mucosa, palate, posterior pharynx, or the tongue. (B, Courtesy of Robert Swerlick, MD.) Biopsies of early lesions demonstrate intraepidermal vesicle formation secondary to loss of cohesion between epidermal cells (i.e., acantholytic blisters). Blister cavities contain acantholytic epidermal cells, which appear as round homogeneous cells containing hyperchromatic nuclei. Basal keratinocytes remain attached to the epidermal basement membrane, hence blister formation is within the suprabasal portion of the epidermis. Lesional skin may contain focal collections of intraepidermal eosinophils within blister cavities; dermal alterations are slight, often limited to an eosinophil-predominant leukocytic infiltrate. Direct immunofluorescence microscopy of lesional or intact patient skin shows deposits of IgG on the surface of keratinocytes; deposits of complement components are typically found in lesional but not uninvolved skin. Deposits of IgG on keratinocytes are derived from circulating autoantibodies directed against cell- surface autoantigens. Such circulating autoantibodies can be demonstrated in 80– 90% of PV patients by indirect immunofluorescence microscopy; monkey esophagus is the optimal substrate for these studies. Patients with PV have IgG autoantibodies directed against desmogleins (Dsgs), transmembrane desmosomal glycoproteins that belong to the cadherin family of calcium-dependent adhesion molecules. Such autoantibodies can be precisely quantitated by enzyme-linked immunosorbent assay (ELISA). Patients with early PV (i.e., mucosal disease) have only IgG autoantibodies directed against Dsg3; patients with advanced PV (i.e., mucocutaneous disease) have IgG autoantibodies directed against both Dsg3 and Dsg1. Experimental studies have shown that autoantibodies from patients with PV are pathogenic (i.e., responsible for blister formation) and that their titer correlates with disease activity. Recent studies have shown that the anti-Dsg autoantibody profile in these patients' sera as well as the tissue distribution of Dsg3 and Dsg1 determine the site of blister formation in patients with pemphigus. Coexpression of Dsg3 and Dsg1 by epidermal cells protects against pathogenic IgG directed against either cadherin but not pathogenic autoantibodies directed against both. PV can be life-threatening. Prior to the availability of glucocorticoids, the mortality ranged from 60–90%; the current mortality is ~5%. Common causes of morbidity and mortality are infection and complications of treatment with glucocorticoids. Bad prognostic factors include advanced age, widespread involvement, and the requirement for high doses of glucocorticoids (with or without other immunosuppressive agents) for control of disease. The course of PV in individual patients is variable and difficult to predict. Some patients achieve remission, while others may require long-term treatment or succumb to complications of their disease or its treatment. The mainstay of treatment is systemic glucocorticoids. Patients with moderate to severe PV are usually started on prednisone, 1 mg/kg per day. If new lesions continue to appear after 1–2 weeks of treatment, the dose may need to be increased. Many regimens combine an immunosuppressive agent with systemic glucocorticoids for control of PV. The most frequently used are azathioprine (2–2.5 mg/kg per day), mycophenolate mofetil (20–35 mg/kg per day), or cyclophosphamide (1–2 mg/kg per day). Patients with severe, treatment-resistant disease may derive benefit from plasmapheresis [six high-volume exchanges (i.e., 2–3 liters per exchange) over ~2 weeks], IV immunoglobulin (2 g/kg over 3–5 days every 6–8 weeks), or rituximab (375 mg/m 2 per week x 4). It is important to bring severe or progressive disease under control quickly to lessen the severity and/or duration of this disorder. . Chapter 055. Immunologically Mediated Skin Diseases (Part 2) Pemphigus Vulgaris Pemphigus refers to a group of autoantibody -mediated intraepidermal blistering diseases characterized. disorders and is also seen in toxic epidermal necrolysis, Stevens-Johnson syndrome, and a few other skin diseases. Pemphigus vulgaris (PV) is a mucocutaneous blistering disease that predominates in. produce extensive denudation of the skin (Fig. 55-1). PV typically involves the mouth, scalp, face, neck, axilla, groin, and trunk. PV may be associated with severe skin pain; some patients experience