An Unusual Presentation of Pemphigus Vulgaris

Pemphigus vulgaris (PV) is a potentially life-threatening autoimmune disease targeting the skin and mucous membranes. The disease is characterized by acantholysis, or the disruption of the adhesion of the keratinocytes.^1,2 Although oral and pharyngeal involvement is very common, esophageal involvement is reported to be less common and is mostly confined to case reports and case series. Esophageal involvement usually manifests as odynophagia and dysphagia, and hematemesis is rare. Here, we report a case of PV involving the esophagus that presented as hematemesis and required endoscopic intervention for hemostasis.

Case Report

A 55-year-old Indian woman with a history of rheumatoid arthritis, PV, gastroesophageal reflux disease, and osteoporosis presented to the emergency room with several episodes of hematemesis. The patient was diagnosed with PV in 1996 when she presented with odynophagia and was found to have oral and esophageal lesions. She was treated successfully with prednisone and subsequently fared well, aside from being briefly hospitalization for a hematemesis episode in 1999, for which she was treated with high-dose prednisone and azathioprine (Imuran, Prometheus). Her disease remained quiescent, and she stopped taking prednisone and azathioprine in 2003, on her own. She has never had cutaneous involvement.

The patient had been feeling well until several hours prior to her presentation to the emergency room, when she suddenly developed multiple episodes of hematemesis while at a family gathering. She experienced no odynophagia, dysphagia, nausea, retching, or abdominal pain, and she had no history of alcohol or nonsteroidal anti-inflammatory drug use. Her medications included omeprazole (Prilosec, AstraZeneca) 20 mg daily as well as weekly doses of alendronate (Fosamax, Merck).

On presentation, her vital signs were stable and she was not orthostatic. Although physical examination did not reveal cutaneous lesions, it was remarkable for three small erosions on her buccal mucosa. Laboratory examinations revealed a hemoglobin level of 12.8 g/dL as well as a normal platelet count, international normalized ratio, and partial thromboplastin time. Esophagogastroduoden oscopy revealed circumferential erythema and excoriation involving nearly the entire esophagus, from 2 cm below the upper esophageal sphincter to the gastroesophageal junction (Figure 1). There were also several areas suggestive of ruptured blisters. At the gastroesophageal junction, a 1.5-cm ulcer with active oozing of fresh blood was visible (Figure 2). Tree endoclips were applied, resulting in good hemostasis (Figure 3). Histologic and cytologic examination of the specimens obtained by brushing and biopsy revealed reparative and reactive-appearing squamous cells with suprabasal acantholysis, as well as several tombstone-appearing squamous cells and positive direct immunofluorescence for immunoglobulin (Ig) G. These findings are consistent with PV and (Figures 4 and 5). There was no evidence of viral inclusions.

Figure 1.

Endoscopic image showing diffuse excoriation of the esophageal mucosa with mucosal sloughing.

Figure 2.

Endoscopic image of actively bleeding ulcer at gastroesophageal junction.

Figure 3.

Gastroesophageal junction ulcer after application of 3 endoclips.

Figure 4.

Light microscopy image showing classic suprabasal acantholysis.

Figure 5.

Direct immunoflourescence image showing intercellular immunoglobulin G deposits in the esophageal mucosa.

The patient was initially started on intravenous meth-ylprednisolone (Solu-Medrol, Pharmacia and Upjohn) 30 mg every 8 hours, along with esomeprazole (Nexium, AstraZeneca) 40 mg orally twice a day. She was able to tolerate a regular diet and did not experience further bleeding. Subsequently, her steroids were switched to 80 mg of oral prednisone daily, and she was discharged 48 hours later in stable condition.

Discussion

Pemphigus comes from the Greek word “pemphix,” meaning “bubble,” in reference to the blisters that are characteristic of the disease. PV is a rare condition, with a reported incidence ranging from 0.75–5 cases per million per year to 0.5–3.2 cases per 100,000 per year, depending on the population, with an increased incidence among people of Jewish and Mediterranean descent.^3,4 PV is a chronic autoimmune disorder characterized by bullous lesions and fluid-filled blisters that erupt on the skin and mucous membranes. These lesions tend to rupture quickly, leaving painful erosions. The disease tends to occur in middle-aged and slightly older individuals, with both sexes affected equally.

At the cellular level in PV, autoantibodies, usually IgG, are directed against the intercellular adhesion molecules, of which the desmosomal cadherins desmoglein 1 and 3 are best characterized. However, additional antigens such as the novel epithelial acetylcholine receptors alpha 9 and pemphaxin may play a role in the disease.^5,6 As a result, a loss of cohesion occurs between cells in the epidermis, causing the suprabasal acantholysis visible on light microscopy. Further verification of the diagnosis can be made by direct immunofluorescence, which reveals intercellular deposits of immunoreactants in the epidermis, and indirect immunofluorescence, which reveals immunoreactants circulating in the serum.

Interestingly, in PV, oral lesions precede skin lesions in roughly 70% of patients. In patients who already display skin lesions, oral lesions are encountered in approximately 90% of cases.⁷ The incidence of esophageal involvement is not known precisely. Although previously reported to be uncommon, case studies have revealed a significant per-centage of both symptomatic and asymptomatic patients with both microscopic and macroscopic involvement.^7,8,9 Asymptomatic esophageal involvement is likely more prevalent than previously recognized. This finding is not surprising, considering that oral, esophageal, and skin mucosa are all composed of stratified squamous epithelium. From a purely histologic standpoint, it seems logical that one area would not be spared over another.

Esophageal involvement in PV usually manifests as dysphagia or odynophagia. Typical endoscopic findings include esophageal erythema with blisters and erosions, which can involve the entire esophagus. Reports of esophageal PV in the literature have cited white plaques and exfoliation of the mucosa,^10–12 but bleeding from esophageal pemphigus appears to be quite rare.

Several interesting aspects of this case deserve mention. First, gastrointestinal bleeding, as part of the presentation of PV, is much less common than symptoms such as dysphagia or odynophagia; however, this is our patient's second presentation with only hemate-mesis. Second, although our patient had diffuse esopha-geal involvement, she had only 3 small oral lesions and no skin or other mucocutaneous lesions (including genital lesions). This finding is similar to previous reports in the literature that found esophageal involvement to be more common in women, many of whom did not have skin lesions when the esophageal involvement was discovered.¹³

In addition, our patient was also taking long-term bisphosphonates for osteoporosis. Despite the histologic examination showing no evidence of alendronate-associ-ated injury, it is conceivable that the concomitant use of this medication with alendronate resulted in damaging effects on her esophageal mucosa. Histologic findings of alendronate-associated esophageal injury have included nonspecific inflammatory exudates, the presence of polar-izable crystalline foreign material (in 60% of cases), and multinucleated giant cells (in 30% of cases).¹⁴

Initial treatment of PV consists of corticosteroids, which usually result in a fairly rapid response. The usual initial steroid dose is 1 mg/kg body weight of prednisone or its equivalent. This dose can be tapered according to patient response; however, the majority of patients require long-term maintenance therapy to sustain remission. Immunosuppressive agents can be used in severe or steroid-refractory cases. The most commonly used adjuvant agents include azathioprine (4 mg/kg/day) and cyclophosphamide (Cytoxan, Bristol-Myers Squibb; 2–3mg/kg/day).^15,16 Currently, the mortality rate for PV patients is approximately 5%; however, prior to the use of corticosteroids and immunosuppressives, the disease was frequently fatal.^17–19 Referral to a dermatologist for initial evaluation and continued follow-up is strongly recommended.