Dupilumab for the treatment of pembrolizumab-induced bullous pemphigoid: A case report.

Dear Editor,

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). 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. 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. Other treatment options include systemic corticosteroids, minocycline, doxycycline, nicotinamide, methotrexate, omalizumab, and rituximab. Many of the traditional agents utilized in the treatment of BP, such as mycophenolate mofetil or azathioprine, 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. , Recent studies have demonstrated increased frequencies of IL‐4‐ and IL‐13‐producing cells in the peripheral blood of patients with BP. 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.