Introduction
Pemphigus foliaceus (PF) is an autoimmune blistering disorder characterized by scaly,
crusted, cutaneous erosions without mucous membrane involvement, typically in a seborrheic
distribution.
1
Rarely, PF can present with generalization and even exfoliative erythroderma. Lesions
originate from disruption of desmoglein-1 (DSG-1) by auto-antibody production, resulting
in acantholysis in the stratum granulosum. PF is the second most common form of pemphigus
disease behind pemphigus vulgaris (PV), which is characterized by mucous membrane
involvement and auto-antibody production against desmoglein-3 (DSG-3) and sometimes
DSG-1.
1
,
2
PF is often initially misdiagnosed as various common dermatologic conditions, which
can lead to a delay in correct diagnosis of months to even years.
3
In this case report, we discuss a Latino patient with a histology consistent with
PF whose serum was suggestive of PV with no evidence of typical PV mucosal or cutaneous
manifestations.
Case report
A 41-year-old Latino man with no prior medical history presented with a 1-year history
of exquisitely painful violaceous nodules on the face and ears, in addition to nonscarring
scalp alopecia (Fig 1). He denied any oral or genital lesions. Of note, he had previously
presented to urgent care, where he was diagnosed with scalp folliculitis and treated
with topical and oral antibiotics for 3 months. Differential diagnosis included bullous
impetigo, dissecting cellulitis, PF, sarcoidosis, and Kaposi's sarcoma.
Fig 1
Photos from the initial clinic visit demonstrating violaceous nodules on the face
and nonscarring scalp alopecia.
At his dermatology appointment, a biopsy was obtained from a ear nodule showing acanthosis
with acantholysis of the granular cell layer, with direct immunofluorescence revealing
intercellular deposition of IgG and complement component 3 within the epidermis, consistent
with PF (Fig 2). Serology testing revealed not only a profound elevation of DSG-1
autoantibodies (174; normal, <20), but also an aberrant expression of DSG-3 autoantibodies
(28; normal, <28). In addition, a test for antinculear antibodies was positive, speckled
at 1:160.
Fig 2
DIF revealing intercellular deposition of IgG and complement component 3 within the
epidermis, consistent with a diagnosis of PF. DIF, Direct Immunofluorescence; PF,
pemphigus foliaceus.
The patient was started on 40 mg of prednisone daily with plans to start rituximab.
At his 1-month follow-up, he was noted to have more significant painful erosions on
the scalp and persistence of painful nodules and violaceous thin plaques on his ears
and face, respectively (Fig 3). Bacterial swabs revealed bacterial superinfection
with methicillin-sensitive Staphylococcus aureus and Klebsiella species. He was started
on mycophenolate given reluctance to proceed with rituximab due to fear of increased
susceptibility to COVID-19 and trimethoprim-sulfamethoxazole (800-160 mg once daily
for 2 weeks) for superinfection with reduction of his prednisone dose with plans for
close monitoring of clinical symptoms and follow-up.
Fig 3
Photos from the 1-month follow-up visit with persistence of violaceous nodules and
plaques with worsening scalp erosions.
Discussion
Diagnosing PF is frequently a diagnostic challenge and often misdiagnosed as bullous
impetigo, dissecting cellulitis of the scalp, inflammatory seborrheic dermatitis,
among other common dermatologic conditions.
3
In this case, the patient initially endorsed draining scalp pustules, resulting in
a diagnosis of folliculitis. However, despite appropriate treatment for this condition,
he continued to develop new scalp and face lesions, highlighting that PF may mimic
other common dermatologic conditions, in particular when the scalp is involved.
Additionally, bacterial swabs performed at his follow-up visit revealed bacterial
superinfection with methicillin-sensitive Staphylococcus aureus and Klebsiella, showing
that PF may also occur concomitantly with other common dermatologic conditions. Though
no data are available on the prevalence of superinfection in PF specifically, a study
by Aghmiyuni et al
4
found that 59.1% of PV patients had co-existing S. aureus infection, followed by Staphylococcus
epidermidis at 28.1%. Diagnostic workup should include a thorough medical history
(including medications), comprehensive mucosal and cutaneous exams, lesional biopsy
for hematoxylin-eosin–staining, perilesional biopsy for direct immunofluorescence,
serum collection for enzyme-linked immunosorbent assay, and bacterial and fungal cultures
due to the high prevalence of superinfection.
Because of facial involvement, pemphigus erythematosus (PE) was also considered. PE,
or Senear-Usher syndrome, is a controversial disease process with variable diagnostic
criteria. It can be considered a subtype of PF and has been described as a localized
or early-stage variant with mixed features of systemic lupus erythematosus and PF
that can involve the malar regions. Serologic evaluation may demonstrate antinuclear
antibodies titers, as in this case. However, histologic discordance was not consistent
with PE. Immunoreactants were not deposited in the expected granular deposition, and
keratinocyte nuclear fluorescence was not seen.
5
Another layer of complexity in diagnosis was skin of color. Few case reports discuss
the cutaneous presentation of PF in patients with skin of color.
3
Due to the violaceous and infiltrative appearance of the patient's lesions, Kaposi
sarcoma and sarcoidosis were considered, which could potentially delay diagnosis and
result in unnecessary and expensive additional testing. It is important to recognize
that erythema in darker-pigmented individuals can appear violaceous and that epidermal
death can appear dusky or gray.
6
,
7
Another layer of difficulty was management of PF during the COVID-19 pandemic. Though
rituximab was offered, the patient had concerns beginning immunosuppression due to
the unclear safety of rituximab affecting susceptibility to the viral infection. It
is also uncertain whether disease-modifying therapy would hamper the effectiveness
of any future COVID-19 vaccines and blunt antibody production.
8
Additionally, serologies showed not only a profound elevation of DSG-1 autoantibodies,
but also an aberrant expression of DSG-3 autoantibodies, without mucosal or cutaneous
manifestations of PV. Though it is more commonly reported for PV patients to develop
PF, there have been case reports of patients with an established diagnosis of PF developing
PV months or several years later.
2
,
9
,
10
This is theoretically due to epitope spreading, where in the initial stage, solely
anti-DSG1 autoantibodies are present.
9
,
10
During the disease course, DSG3 may be released from injured tissue, leading to recognition
and production of anti-DSG3 antibodies. It is plausible that this patient may have
been caught in this transition period from PF to PV. Patients with PF are usually
treated less aggressively than PV. Given this patient's clinical and histopathologic
discordance with serological findings and lack of response to systemic prednisone,
we suggest this patient and those with similar presentations be monitored closely
and treated more aggressively.
Conclusion
PF is a rare and difficult clinical diagnosis to make, increasingly obscured in patients
with skin of color. Awareness of differences in presentation is necessary to ensure
expedient diagnosis and avoid delays in treatment. In addition, increased awareness
of transition of PF to PV and vice versa can assist in approaching treatment decisions.
Conflicts of interest
None disclosed.