Herpes Esophagitis in the Setting of Immunosuppression From Pemphigus Vulgaris Therapy

Pemphigus vulgaris (PV) is a chronic autoimmune intraepithelial bullous disease caused by pathogenic IgG antibodies at the intraepidermal cell-surface proteins desmoglein 1 (DSG1) and desmoglein 3 (DSG3), which are members of the cadherin superfamily of desmosomal proteins and are involved in keratinocyte adhesion. Autoantibody binding to these molecules leads to the loss of cell-cell adhesion in the epithelial suprabasilar layer, producing flaccid blisters on an erythematous base with a positive Nikolsky sign.¹ The blisters frequently rupture, leaving painful nonscarring erosions with the potential for secondary infection.

The clinical phenotype of PV is directly related to the autoantibody profile. Clinically, PV often is mucosal dominant on presentation with painful oropharyngeal involvement and associated IgG antibodies against DSG3. Progression to cutaneous disease, such as on the scalp or axillae, is accompanied by a shift in IgG antibodies against both DSG1 and DSG3.^2,3

Combination therapy with prednisone and mycophenolate mofetil (MMF) has proven to be an effective method of controlling the signs and symptoms of PV⁴; however, the immunosuppressive effects of these medications put the patient at risk for a host of opportunistic infections. Herpes simplex virus (HSV) has been associated with PV lesions of the oral mucosa, though a clear-cut relationship between these 2 entities has yet to be established.⁵ Herpes simplex virus has likewise been confirmed in therapy-resistant exacerbations of PV.⁶ Herpes esophagitis is a rare consequence of treatment with prednisone and MMF that is primarily encountered in patients with a history of solid organ transplantation⁷ and rarely has been reported in PV patients undergoing therapeutic immunosuppression.

Acute odynophagia in patients undergoing systemic treatment of active PV warrants prompt endoscopic evaluation to rule out esophageal pemphigus or superinfection. We report the case of a 35-year-old man with stable but poorly controlled PV who was undergoing systemic treatment and experienced rapid deterioration due to herpes esophagitis from immunosuppression.

Case Report

A 35-year-old man was referred to our clinic for evaluation of blisters on the scalp, oral mucosa, and proximal upper and lower extremities of 4 months’ duration. A biopsy performed by his primary care physician within a month of onset of symptoms was reportedly suggestive of PV; although no direct immunofluorescence had been performed, serum indirect immunofluorescence was highly positive for IgG antibodies toward DSG3 and to a lesser extent DSG1. The blisters failed to improve with a 2-week prednisone taper completed 1 month prior to presentation. The patient was not currently taking any other medications. He had a remote history of fever blisters but no other dermatologic issues.

Initial examination revealed flaccid bullae on an erythematous base involving the posterior scalp as well as tender white erosions to shallow ulcers on the tongue and hard and soft palates. A Tzanck smear (modified Wright-Giemsa stain) of these erosions confirmed acantholytic mucosal cells. Punch biopsies of lesional and perilesional skin from the scalp were obtained for histopathologic confirmation and immunofluorescence. An acantholytic dermatosis with a tombstone pattern along the basement membrane was present on hematoxylin and eosin staining, and direct immunofluorescence was positive for IgG and C3 in an intraepidermal lacelike pattern, confirming a diagnosis of PV.

Despite starting an oral regimen of high-dose corticosteroids (prednisone 80 mg once daily), no improvement was noted at 2-week follow-up. He had developed flaccid blisters on the left axillae and mildly worsened oral erosions. He also reported moderate difficulty eating due to pain with swallowing. Mycophenolate mofetil (500 mg twice daily) was added as combination therapy with the prednisone.

One week later, the patient was unable to eat or drink due to worsening odynophagia. He was admitted as an inpatient for treatment with intravenous methylprednisolone (120 mg every 8 hours) and MMF (1000 mg daily). The gastroenterology department was consulted and an esophagogastroduodenoscopy revealed diffuse areas of denuded and friable mucosa with an overlay of white exudate (Figure 1). Cytology performed on esophageal brushings revealed viral cytopathic changes confirming herpes esophagitis (Figure 2). No esophageal viral cultures were taken. The patient was started on intravenous acyclovir (800 mg 4 times daily), leading to rapid resolution of the odynophagia. He was discharged after 4 days with a course of oral acyclovir (400 mg 4 times daily for 14 days). Tzanck smears and HSV cultures of oral lesions performed immediately following discharge were negative. Combination therapy with MMF (500 mg twice daily) and a slow taper of prednisone (down to 5 mg once daily) was continued past 1 year without flare of his cutaneous disease.

Figure 1. An upper endoscopy showed eroded esophageal mucosa with a white exudate.

Figure 2. Multinucleated giant cells from esophageal brushings were seen on cytology (Papanicolaou, original magnification ×20).