Dear Editor,
1
With the advent of immune checkpoint blockade as a novel therapeutic modality in the
treatment of various malignancies, there has been an accompanying rise in immune‐related
adverse events (irAEs).
1
Bullous pemphigoid (BP) can be a particularly difficult irAE to manage in oncologic
patients. Here, we report the clinical case of a 59‐year‐old woman with a history
of cervical cancer and pembrolizumab‐induced bullous pemphigoid successfully managed
with dupilumab.
A 59‐year‐old woman with a history of cervical cancer presented with progressive,
pruritic, blistering eruption of two months' duration. On admission, her examination
was notable for near erythroderma with scattered tense and eroded blisters overlying
blanching edematous orange‐pink plaques on the abdomen, back, arms, legs, and face,
as demonstrated in Figure 1. She had no mucosal involvement. Five weeks prior to the
onset of the blistering eruption, she had been initiated on pembrolizumab, a programmed
cell death protein‐1 (PD‐1) inhibitor, for adjuvant treatment of stage IIB cervical
cancer. Skin biopsy demonstrated a subepidermal blister with superficial perivascular
infiltrate and occasional interstitial eosinophils; direct immunofluorescence yielded
linear staining of the dermal–epidermal junction with IgG and C3. The clinical and
histopathologic findings in conjunction with the timeline of pembrolizumab initiation
supported a diagnosis of pembrolizumab‐induced bullous pemphigoid.
FIGURE 1
Pembrolizumab‐induced bullous pemphigoid demonstrated on the patient's bilateral lower
extremities with scattered tense bullae on a pink erythematous base at various stages
of rupture and erosion
Due to the severity of her eruption, the patient's pembrolizumab was discontinued.
She was initiated on intravenous methylprednisolone at a dose of 1 mg/kg/day divided
twice daily, transitioned to oral prednisone after 5 days, and gradually tapered to
a dose of 0.5 mg/kg/day over 2 weeks while inpatient. She was subsequently discharged
with plans for a slow prednisone taper over the ensuing 2 months. Following discharge,
she experienced numerous flares requiring repeated courses of high‐dose oral prednisone.
Over a period of 8 months, she failed numerous additional agents, including oral doxycycline
100 mg twice daily, oral niacinamide 500 mg twice daily, oral dapsone 75 mg daily,
topical bethamethasone diproprionate 0.05% ointment, and triamcinolone 0.1% ointment.
Additional immunosuppressive agents, such as mycophenolate mofetil, were not pursued
due to her recent malignancy. Due to the refractory nature of the patient's disease,
she began treatment with dupilumab 300 mg subcutaneous injection administered every
other week in conjunction with a steroid taper beginning at 60 mg/day (0.75 mg/kg/day).
Over the subsequent 2 months, she ceased to develop new blisters, and her maintenance
prednisone was weaned to 5 mg/day. Five months into dupilumab therapy, she had an
extended stint at a skilled nursing facility (SNF), during which she missed four doses
of dupilumab while on a prednisone maintenance dose of 5 mg/day, and experienced a
severe flare of her bullous pemphigoid. Upon re‐initiation of dupilumab, oral doxycycline
100 mg twice daily, and a prednisone course of 60 mg/day tapered down to 10 mg/day
over 4 weeks, she again attained clearance, and has remained clear for an additional
6 months.
Immune checkpoint inhibitor (ICI) induced bullous pemphigoid is a rare, severe cutaneous
irAE. BP has been associated with the use of programmed cell death protein‐1(PD‐1),
programmed death ligand‐1(PD‐L1), and cytotoxic T‐lymphocyte‐associated protein‐4(CTLA‐4)
inhibitors.
2
Formal guidelines for the management of ICI‐induced BP are not yet available, and
treatment recommendations are currently based on experience from case reports and
series. The current first‐line treatment for ICI‐induced BP includes the discontinuation
of the ICI, and initiation of topical corticosteroids.
3
Other treatment options include systemic corticosteroids, minocycline, doxycycline,
nicotinamide, methotrexate, omalizumab, and rituximab.
3
Many of the traditional agents utilized in the treatment of BP, such as mycophenolate
mofetil or azathioprine,
4
are relatively contraindicated in these patients due to their concurrent malignancies.
Dupilumab, an interleukin‐4 (IL‐4) alpha receptor antagonist that modulates signaling
in both the IL‐4 and IL‐13 pathways, is being explored as a novel therapeutic in the
treatment of BP.
5
,
6
Recent studies have demonstrated increased frequencies of IL‐4‐ and IL‐13‐producing
cells in the peripheral blood of patients with BP.
7
Relative to traditional immunosuppressive agents such as mycophenolate mofetil, high‐dose
corticosteroids, and azathioprine, dupilumab has lower risks of systemic immunosuppression.
In this case, our patient was treated concomitantly with dupilumab, systemic prednisone,
and topical corticosteroids, so her therapeutic response cannot be solely attributed
to dupilumab; however, since receiving dupilumab in a sustained fashion, she has been
able to wean off her systemic prednisone without additional flares. It is also notable
that removal of dupilumab therapy resulted in recrudescence of her disease. As demonstrated
by this case, dupilumab may prove a useful and safe tool in oncologic patients suffering
from ICI‐induced bullous pemphigoid.
AUTHOR CONTRIBUTIONS
Samantha Pop and Robert Smith obtained the data used in this case study and were responsible
for reviewing and editing the manuscript. Daniel Strock drafted the original manuscript
and was involved in the review, editing, and submission of the manuscript.
CONFLICT OF INTEREST
The authors have no conflicts of interest to report.
CONSENT FOR FIGURE PUBLICATION
The patient designated in this case study consented the following:
“I consent for these photographs to be used in medical publications, including medical
journals, textbooks, and electronic publications. I understand that the image may
be seen by members of the general public, in addition to scientists and medical researchers
that regularly use these publications in their professional education. Although these
photographs will be used without identifying information such as my name, I understand
that it is possible that someone may recognize me. I also agree for my image to be
shown for teaching purposes to be used for my medical record.” Signed and witnessed
3/2/2022.