Answer: A.

Pemphigus vulgaris (PV) is the most common of the group of autoimmune bullous diseases characterized by intraepithelial blister formation.17,18 PV is a rare autoimmune disease with an incidence of approximately 0.42 per 100,000 people in the United States. The incidence is much higher in some Ashkenazi Jewish populations and in Eastern countries, such as China, Japan, Malaysia, and India. The disease affects men and women equally and has a mean age of onset of 50 to 60 years; however, it has also been reported in children and the elderly.17,19 PV is a potentially life-threatening disease with a high mortality rate if untreated (50% at 2 years, 100% at 5 years).20

PV is characterized by the deposition of IgG antibodies against desmoglein 3 (Dsg3, a 130kDa protein) and desmoglein 1 (Dsg1) found in the mucous epithelium and in skin desmosomes, causing loss of cell-cell adhesion as well as keratinocyte acantholysis, both of which combine to form the blisters that are observed clinically.2,3,20,21

The onset and course of pemphigus vulgaris depend on the interaction between predisposing and inducing factors.17 Medications, pesticides, malignancies, ultraviolet radiation, and stress have all been associated with the development of PV.18 Viral infections, especially of herpetic origin, may trigger a PV outbreak or complicate its clinical course.17 Physical agents (ultraviolet or ionizing radiation, thermal or electrical burns, surgery, and cosmetic procedures), contact allergens (organophosphate pesticides), dietary factors (foods that contain allyl compounds), and emotional stress are less commonly associated but still have been reported to cause PV.17

Clinically, patients present with small flaccid blisters that almost immediately rupture leaving crusted erosions.3 Mucous membranes are usually affected first and present with painful, nonhealing oral erosions and fragile blisters.13,20,22 Evaluation of patients with only oral involvement may be difficult, as intact bullae are difficult to find due to mastication or trauma. Oral lesions often precede skin findings by several months. Skin involvement is characterized by a diffuse eruption of flaccid blisters and erosions localized to the face, scalp, extremities, and flexural surfaces.22 Traditionally, patients with PV will have a positive Nikolsky sign. If left untreated, PV can be fatal secondary to complications associated with the disruption of the protective skin barrier, which results in uncontrolled protein and fluid loss as well as the development of opportunistic infections.13

The diagnosis of PV is accomplished through a combination of clinical findings, histopathology, and immunohistochemistry. Diagnosis is confirmed by DIF assay, indirect immunofluorescence (IIF) assay, or ELISA to Dsg1 and Dsg3 recombinant fusion proteins.22 DIF reveals deposition of IgG and C3 binding to the keratinocyte cell surface in the mid and lower or entire epidermis of the perilesional skin or mucosa. An ELISA kit for detection and titration of circulating anti-Dsg3 and anti-Dsg1 antibodies has recently become available to aid in diagnosis.2,23 Additionally, recent studies looking at the human leukocyte antigen typing of affected individuals have identified pemphigus-prone genes in the patient’s genotype.23 However, despite the multiple tools available, there are currently no uniformly accepted criteria for the diagnosis of PV.3

The differential diagnosis for PV includes BP, pemphigus foliaceus, pemphigus herpetiformis, dermatitis herpetiformis, and IgA pemphigus. BP is characterized by pruritic, tense blisters localized to the flexural aspects of the extremities and the trunk. Unlike that seen in PV, most patients with BP do not suffer from oral involvement and they will have a negative Nikolsky sign.3 More information regarding the differentiation between BP and PV is included in the Table. Pemphigus foliaceus, an acquired autoimmune blistering disease, can be differentiated from PV by the lack of mucosal lesions and the absence of anti-Dsg3 antibodies.3,24,25 

Pemphigus herpetiformis can be differentiated from PV histologically by the presence of spongiosis and microabscesses in the mid or subcorneal epidermis, mostly without acantholysis. Pemphigus herpetiformis typically presents as gyrate or annular erythematous lesions with clusters of small or abortive vesicles and/or pustules, frequently in herpetiform patterns.11,26

Dermatitis herpetiformis presents as pruritic, excoriated papulovesicles, often in a grouped pattern. Unlike PV, DIF assay in dermatitis herpetiformis shows granular IgA and C3 in the tips of the dermal papillae, and IIF assay shows IgA antibodies against endomysium.11

IgA pemphigus is a vesiculopustular disease in which the skin lesions initially appear as tense bullae but typically evolve into translucent, fluid-filled blisters, which may be confused for PV.27 However, patients with IgA pemphigus usually present with annular plaques that have collarette-like scaling.11

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First-line treatment for patients with PV includes systemic corticosteroids, either alone or in combination with corticosteroid-sparing immunosuppressive agents.28 Prednisone or deflazacort are initially given at a high dosage (100-200 mg/d) and can be used with azathioprine (2.5 mg/kg/d), cyclophosphamide (1-3 mg/kg/d), or mycophenolate mofetil (1 g twice per day). As the patient begins to improve clinically, the steroid dose can be gradually tapered as tolerated.23 Additionally, topical preparations of epidermal growth factor or pimecrolimus seem to decrease the time required for healing of erosions.29 Treatment should be continued for several years; thus, the side effects of the steroid and immunosuppressive therapy are more likely to affect mortality and morbidity than the disease itself.23 In general, any therapy strategy should weigh the benefits vs the risks of the treatment protocol for each patient.29 For patients in remission, the ingestion of any unnecessary drugs and sun exposure are discouraged as they may increase the risk of a pemphigus relapse.20

Following presentation to the clinic, the patient presented in this case underwent biopsy of his lesions, the findings of which were consistent with a diagnosis of PV. Treatment with high-dose prednisone and azathioprine was initiated; as the patient’s blisters subsided, the doses of each were tapered. The patient’s symptoms are currently well controlled with no recent flares.

Jessica Sheu, BA, is a medical student; Joan Fernandez, BS, is a medical student; and Christopher Rizk, MD, is a dermatology resident at the Baylor College of Medicine, Houston, Texas.

References

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