Journal of Dermatology for Physician Assistants

The official journal of the Society of Dermatology Physician Assistants

Something is Afoot: Case of Pemphigus Vulgaris Mimicking Infections

By Cynthia Faires Griffith, MPAS, PA-C; Loderick Matthews, BS; and Rosemary Son, MPAS, PA-C, RD

ABSTRACT
This case of a gentleman with a chronic foot lesion and onychodystrophy illustrates one of the various forms that pemphigus vulgaris can take. We present diagnostic testing, including histology, direct immunofluorescence testing (DIF), and indirect immunofluorescence (IIF). We discuss the incidence of pemphigus, the variants of pemphigus, and the treatment objectives in this patient population

CLINICAL VIGNETTE
A 46-year-old Black man presented to the dermatology outpatient clinic for a purported foot infection present for 8 months. Initially the rash was only on the tops of the toes and spread over time to the entire medial side of his left foot (Figure 1). He was seen by another dermatology provider and treated with numerous antibiotics and antifungals including trimethoprim/ sulfamethoxazole, doxycycline, amoxicillin-clavulanate, fluconazole, itraconazole, and topical mupirocin and clobetasol.

Simultaneously the patient also developed painful oral ulcers, lip swelling, and dysphagia (Figure 2). He endorsed recent unintentional weight loss of 27 pounds, which he attributed to pain with eating. Attempted treatments included intraoral topical tacrolimus ointment and oral suspension of lidocaine, diphenhydramine, aluminum hydroxide, and magnesium hydroxide; these made little difference. The patient also described a rash on his genitals around the time the oral ulcers started, which resolved spontaneously.

Diagnosis. A punch biopsy for histopathology was taken from the edge of the plaque on the left foot (Figure 3). Normal appearing skin within 1 cm of the plaque on the left foot was punch biopsied with 4 mm punch for direct immunofluorescence (DIF). The patient’s serum (blood) was taken for indirect immunofluorescence (IIF) for autoantibodies against skin.

Histopathology showed focal intraepidermal acantholysis with acanthosis and hyperkeratosis and lymphocytes, eosinophils, and neutrophils in the epidermis and dermis. The epidermis showed verucous and pseudoepitheliomatous changes. DIF revealed IgG deposition on epidermal cell surfaces; IIF was positive for epidermal antibodies (Figure 4). Enzyme-linked immunoassay (ELISA) was below the level of detection for anti-DSG1 IgG and was 174 U/ml for anti-DSG3 IgG. Interpretation of ELISA is as follows:

DSG1
• <14: negative
• 14-20: indeterminate
• >20: positive

DSG3
• <9: negative
• 9-20: indeterminate
• >20: positive

Due to clinicopathologic correlation and serum findings, the patient was diagnosed with pemphigus vulgaris (PV).

DISCUSSION
Pemphigus is a family of acquired autoimmune blistering diseases with an estimated annual incidence of two new cases per million citizens in Europe.2 The term pemphigus derives from “pemphix,” the Greek word for blister.1 Pemphigus is a group of diseases that can be further categorized into variants (Table 1). PV and pemphigus foliaceus account for 90 to 95% of pemphigus diagnoses.1 It often takes months for the disease to be diagnosed as was the case with this patient. Pemphigus typically presents during the fourth to sixth decades of life.

In PV, autoantibodies damage desmosomal subunits (desmogleins DSG1 and/or DSG3), which normally facilitate cell-cell adhesion. As a result, epidermal intercellular adhesion is compromised, leading to flaccid blisters. These easily shear and progress to erosions.

Patients with PV present with oral erosions and weight loss as a result of pain with eating and drinking. The most affected areas are the buccal and palatine mucosa, lips, and gingivae. Oral lesions extend peripherally. Patients can also have cutaneous erosions, bran-like crusts, or easily sheared flaccid blisters.

How pathophysiology translates into clinical presentation. There are a significant number of DSGs in the hair follicle; therefore, most patients with pemphigus have scalp lesions, though our patient did not.2
Reported triggers (or inciting events) for pemphigus include medications (especially penicillin and captopril), pesticides, metal vapor, ultraviolet light, ionizing radiation, burns, surgery, and stress.3-5

Other dermatologic conditions may clinically resemble pemphigus variants (Table 2).

Diagnostic testing. Assessment of the clinical presentation in conjunction with both the patient’s blood and skin for serum antibodies and antibodies bound to the skin or mucous membranes is required to distinguish PV from other superficial blistering dermatoses including pemphigus variants.1

Biopsy for histopathology should be taken from an edge of a plaque or erosion and placed in formalin (Figure 3). The pathologist will inspect the specimen to determine at what level the skin is separating to cause blister formation; in the case of PV this will be intraepidermal. In bullous pemphigoid, the blister formation will be subepidermal. More specifically, histology will show suprabasal acantholysis: loss of coherence between the epidermal cells at a layer above the basal layer of the epidermis.6 Acantholysis at the granular layer of the epidermis is characteristic of pemphigus foliaceous, distinguishing it from PV.

A biopsy of perilesional skin (unaffected skin within 1 cm of the erosion) can be sampled with punch biopsy and placed in Michel’s transport medium for DIF (Figure 3).

DIF testing looks for in-situ autoantibodies and immunoreactants in skin to identify the type and location of deposit within skin. The specimen is washed free of the Michel’s transport media, frozen, cross sectioned, and incubated with fluorescein isothiocyanate (FITC) or other fluorophore conjugated antibodies to IgG, IgA, IgM, C3c, and fibrinogen. The slides are then examined to look for the deposition and pattern of IgG, IgA, IgM, C3, and fibrinogen. DIF for patients with pemphigus will present with a deposit of IgG or IgA and/or C3 on the plasma membrane of basal epidermal keratinocytes.6

Other blistering diseases can present with a variety of deposits in different locations and patterns (e.g., staining of the epidermal basement membrane can be characteristic of epidermolysis bullosa acquisita or bullous pemphigoid, among other autoimmune diseases).

Another test that can be done to gain further evidence for the diagnosis of PV is IIF testing (Figure 5). In IIF, the patient’s serum is incubated on monkey esophagus epithelium substrate, which has abundant DSG1 and DSG3 expressed to determine if IgG or IgA autoantibodies are present.6 After the initial serum incubation, the slides are washed in phosphate buffered saline (PBS) and then incubated with a FITC-conjugated anti-Human IgG or IgA. As with DIF testing, a positive result in IIF v. monkey esophagus will also demonstrate a “chicken wire” pattern of staining. This test is excellent in determining if a patient has autoantibodies against DSG1 and 3 as opposed to the 1M NaCl split human skin assay because the in human salt split skin the DSG1 and 3 antigens are enmeshed with keratinocytes and do not allow easy access to the binding site by the autoantibodies in the patient’s serum. In contrast, monkey esophagus has abundant DSG1 and 3 expressed at its surface.

Another test that can aid in the diagnosis of pemphigus is the DSG1 and DSG3 ELISA. In this test the patient’s blood is placed into a well coated with DSG1 or 3. If present, the patient’s autoantibodies against DSG1 or 3 will bind with the respective desmogleins in the wells. Then, an IgG antibody against the DSG 1 or 3 autoantibodies is added to the wells to highlight their presence. Another substrate is added to quantify the number of antibody complexes and at the end of a complex chemical reaction, the liquid in the wells will turn from clear to blue. Then, a 1 normal solution of H2SO4 is added, causing the color to change from blue to yellow at which point the ELISA plate reader measures the absorbance of light passed through the solution. The raw numbers of optical density are plugged into a manufacturer-provided formula and converted to a unit per ml. This number corresponds to either a negative, indeterminate, or positive result.

Treatment Considerations. Objectives for therapy are to promote healing of the erosions, improve patient’s functional status, including ability to eat, and prevent new blisters/erosions.6

The first-line treatments are systemic (typically oral) corticosteroids at 0.5mg to 1.5 mg/kg/d and more recently rituximab infusions. There are numerous side effects with oral corticosteroid use including weight gain and osteoporosis; therefore, treatment with the smallest dose of steroid for the shortest duration is recommended to minimize adverse events. Rituximab (intravenous) has been an effective treatment allowing more rapid tapering of corticosteroids. There are two regimens for treatment: either 1000 mg x 2 (2 weeks apart) or 375 mg/m2 x 4 (one week apart). If patient relapses, rituximab can be administered again as early as six months after initial treatment.6 Topical steroids are helpful for the oral erosions. The gel vehicle tends to be best tolerated for patients.

In patients that require steroid-sparing treatments, the following can be used:6

• Azathioprine: 1-3 mg/kg/d
• Mycophenolate mofetil: 30mg/kg/d-45 mg/kg/d
• Intravenous immunoglobulin (IVIG): 2g/kg over 2-5 d/mo

CONCLUSION
This patient was treated with rituximab infusions 1000 mg twice two weeks apart with plans for a 500 mg infusion six months after his initial treatment.

He had remission of his symptoms right after rituximab but then had a recurrence of his symptoms 2.5 months after treatment. The patient was started on mycophenolate mofetil 500 mg twice daily and prednisone 20 mg daily for two weeks then 10 mg daily for two weeks. The patient was also using clobetasol ointment mixed with 40% urea twice daily on his feet, magic mouthwash four times daily, and fluocinonide gel twice daily. He had oral candidiasis requiring treatment over his previous treatment course.

Acknowledgments
The authors appreciate the work of Dr. Marjatta Son to create Figure 5, Visual representation of Indirect Immunofluorescence on Monkey Esophagus.

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Cynthia Faires Griffith, MPAS, PA-C, is a Dermatology Physician Assistant at UT Southwestern Medical Center in Dallas, Texas, where she also earned her Masters of Physician Assistant Studies. Ms. Griffith is the co-founder of the UT Southwestern High-Risk Skin Cancer Transplant Clinic, a twice-monthly clinical initiative to serve patients who are immunosuppressed after solid organ or bone marrow transplant. She also practices general adult medical dermatology. She is Dermatology Grand Rounds Department Editor for the Journal of Dermatology for Physician Assistants (JDPA) and is a guest lecturer in the UT Southwestern PA program and a lecturer at local, regional, and national conferences. She is a member of the Texas Academy of Physician Assistants, the Society for Dermatology Physician Assistants, and the American Academy of Physician Assistants. She was awarded UT Southwestern’s PA of the Year in 2017. When not practicing, Ms. Griffith is an avid sailor, marathoner, and long-distance cyclist.

Loderick A. Matthews, BS, is a research associate in the Cutaneous Immunopathology Laboratory in the Department of Dermatology at the University of Texas Southwestern Medical Center in Dallas, Texas. Loderick frequently contributes fluorescent microscopy photographs to case studies presented by residents and faculty at the Department of Dermatology Grand Rounds. When Loderick is not in the lab, he is a runner, cyclist, and a working musician.

Rosemary Son, MPAS, PA-C, RD, is a Dermatology Physician Assistant at UT Southwestern Medical Center in Dallas, Texas where she earned her MPAS as well. She spends the majority of her time taking care of medical dermatology patients at the dermatology clinic at Parkland, the safety net hospital for Dallas County. Prior to this she worked as a registered dietitian specializing in weight loss surgery. In her free time, she enjoys endurance horseback riding, cooking for friends, gardening, and reading literature.

Disclosure: The authors have disclosed no potential conflicts of interest, financial or otherwise, relating to the content of this article.

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