Pemphigus vulgaris (PV) is a life-threatening immunobullous disorder affecting the mucous membranes and skin. PV together with pemphigus foliaceus (PF), immunoglobulin A (IgA) pemphigus, and paraneoplastic pemphigus (PNP) make up the pemphigus group of autoimmune blistering diseases characterized by intraepidermal acantholysis and antidesmosomal antibodies.11 This is in contrast to the pemphigoid autoimmune blistering diseases, in which the body creates subepidermal blisters and antibodies against the basement membrane zone.12 The term pemphigus (pemphix, the Greek term for pustule) originally encompassed all mucocutaneous blistering diseases until the discovery of autoantibodies in patients with pemphigus in the 1960s and 1970s.13,14
Although rare, PV is the most common of the pemphigus variants, with an incidence of 1 to 5 per million people per year.15 It occurs most commonly in adults, with disease onset at 40 to 60 years of age, and affects men and women equally. A higher prevalence is seen in patients of Ashkenazi Jewish, Indian, and Mediterranean descent.15,16 The genetic component of PV is strengthened further by higher susceptibility in patients with specific human leukocyte antigen allele variants (DR4, DR14, DRB1).17
The pathophysiology of PV is rooted in the formation of IgG autoantibodies against desmoglein, a transmembrane glycoprotein of desmosomes.11,18 Binding of these antibodies to the apical surface of keratinocytes leads to disruption of acantholysis, resulting in intraepithelial blistering.17 The type of antibody helps to differentiate mucosal PV (antidesmoglein 3), mucocutaneous PV (antidesmoglein 1 and 3), and PF (antidesmoglein 1).17,18 In contrast, IgA pemphigus (subcorneal pustular dermatosis) is characterized by IgA antibodies against the desmosomal protein desmocollin 1.17 Severity of PV has been linked to levels of antidesmoglein antibodies.19 Investigators have theorized that UV radiation, drug exposure (antibiotics, nonsteroidal anti-inflammatory drugs), and diet are precipitating or exacerbating factors for PV.17
Most patients with PV initially present with persistent, quickly eroding mucosal ulcerations followed by cutaneous manifestations. Of the mucosal surfaces, the oral mucosa — notably the buccal mucosa, gingiva, tongue, hard and soft palate — is most commonly involved.11,16-18 PV lesions are extremely painful, and patients experience dysphagia, hoarseness (laryngeal involvement), malnutrition, and weight loss.17,18 Other mucous membranes can be affected, including conjunctiva, esophagus, nose, anus, vulva, vagina, and cervix.17,18
Weeks to months after the appearance of mucosal PV, patients develop erythematous macules that eventually evolve into flaccid, nonpruritic blisters that easily rupture to form bloody erosions. Commonly affected areas include the chest and back, scalp, and intertriginous areas, such as axilla or skin folds of the breast, with the palms and soles generally spared.11,17,18 The Nikolsky sign (applying tangential pressure adjacent to a lesion induces a blister) is a frequently used, somewhat-specific diagnostic sign.17 PV occasionally can involve the nails, causing discoloration, paronychia, onychorrhexis, hemorrhage, and onycholysis.18 A small but important subset of individuals with PV presents with predominant cutaneous symptoms and little to no mucosal involvement.11
The diagnosis of PV relies heavily on well-sampled lesional and perilesional biopsies.11,17 The histologic hallmark of PV is intraepithelial cleavage with acantholysis. Basal keratinocytes remain attached along the basement membrane zone, producing characteristic “tombstone” morphology on H&E staining. Direct immunofluorescence reveals deposition of IgG antidesmoglein antibodies along the apical surface of epidermal keratinocytes. Circulating antibodies also are detectable through indirect immunofluorescence and enzyme-linked immunosorbent assay (ELISA).11,17,18
The differential diagnosis for PV includes several other autoimmune blistering diseases.17,18 PF, a superficial variant of pemphigus, also presents with cutaneous lesions in a seborrheic distribution and also may have a positive Nikolsky sign. Mucosal involvement typically is absent and antidesmoglein 1 is the predominant antibody.11 In IgA pemphigus, patients present with subacute development of vesicles that evolve into pustules with accompanying erythematous plaques. Immunofluorescence reveals IgA, rather than IgG, antibodies.18 Bullous pemphigoid is the most common blistering autoimmune disease. Unlike PV, patients with bullous pemphigoid present at an older age (>80 years), with highly pruritic, tense, fluid-filled blisters most commonly appearing on flexural surfaces. Mucosal involvement is rare and Nikolsky sign is negative. Biopsy reveals subepidermal splitting with inflammation of the upper dermis, and IgG antibodies directed against hemidesmosomal proteins bullous pemphigoid antigen 180 (BP180) and BP230 can be visualized at the dermal-epidermal junction by immunofluorescence.12,16 Other conditions in the differential include drug-induced pemphigus, familial benign pemphigus (Hailey-Hailey disease), or PNP.17
The mucocutaneous lesions seen in patients with PV also can occur with several other conditions.17,18 Oral lesions seen early in the disease could suggest erosive lichen planus, herpetic gingivostomatitis, or aphthous ulcers.18 Cervical mucosal lesions can be misinterpreted as cervical dysplasia on Papanicolaou test.17 The cutaneous symptoms can resemble erythema multiforme or Stevens-Johnson syndrome.17,18 A thorough patient history, physical examination, and biopsy with histology and immunofluorescence can help eliminate these items from the differential and provide a definitive diagnosis of PV. However, the overlap in the early symptoms with other conditions commonly results in diagnosis being delayed until there is cutaneous involvement and the patient already has seen several different specialists, such as dentists, oral surgeons, gynecologists, and otolaryngology-head and neck surgeons.11
First-line treatment for PV has been systemic/topical steroids aimed at inducing remission (suppressing active disease, minimizing formation of new lesions, and allowing existing lesions to heal during a consolidation period).20 The second phase of PV management, remission maintenance, involves keeping the patient on a disease-free course. Oral steroids are tapered during this phase to minimize side effects and replaced with immunosuppressant therapy (azathioprine, mycophenolate, dapsone, methotrexate, or cyclophosphamide).11 Rituximab, a monoclonal anti-CD20 B-cell antibody, has been found to be effective in treating pemphigus by reducing the amount of circulating autoantibodies. Other treatments for PV include newer B-cell therapies, IVIG, immunoadsorption, and a highly promising chimeric autoantigen receptor T-cell therapy.18 Although treatment has helped reduce the high mortality associated with PV (more than 70%), these treatments are not benign, and patients risk complications ranging from simple skin infections to life-threatening systemic infection after immunosuppression.20
The patient in this case underwent lesional skin biopsy for H&E staining, perilesional skin biopsy for direct immunofluorescence, and serum collection for ELISA and indirect immunofluorescence. The results of the testing confirmed the diagnosis of PV, and the patient was started on systemic corticosteroids and followed closely. After a week of therapy, the patient had no new lesions and the corticosteroids were tapered slowly.
Table. PLEVA vs Pemphigus Vulgaris
Riyad N. H. Seervai, BA, BS, and Eleanor Johnson, BA, are medical students at Baylor College of Medicine, and Christopher Rizk, MD, is a certified dermatologist at Elite Dermatology in Houston, Texas.
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