Two rare cases of bullous pemphigoid associated with immune checkpoint inhibitors

Abstract

Bullous pemphigoid is a rare and severe adverse reaction to immune-checkpoint inhibitors that can be life-threatening. Here, we present two cases of bullous pemphigoid secondary to nivolumab and ipilimumab+nivolumab therapy, respectively. Both cases presented months after discontinuation of immunotherapy. Our first case highlights the life-threatening nature of bullous pemphigoid due to its potential to cause laryngeal oedema. Our second case illustrates that cytotoxic T-lymphocyte-associated protein-4 inhibitors can rarely lead to bullous pemphigoid, in addition to programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1) inhibitors. Both cases emphasise the importance of skin examinations and dermatological follow-up for patients during and even after discontinuation of immunotherapy.

Background

Immune checkpoint inhibitors (ICIs) belong to a class of antineoplastic immunotherapeutic agents that are used to treat a wide range of solid-organ malignancies.¹ While ICIs are highly effective cancer treatments, they can cause various immune-related adverse events (irAEs), with cutaneous irAEs (irCAEs) being the most common.¹ Bullous pemphigoid (BP) is an autoimmune blistering disease that is a rare and potentially life-threatening irCAE. ICI-induced BP is usually associated with PD-1 or PD-L1 inhibitors and presents during immunotherapy.

Here, we report two cases of ICI-induced BP that occurred months after discontinuation of immunotherapy and discuss a review of the literature, importance of early detection and treatment challenges.

Case 1

Case presentation

A woman in her 60s with a history of metastatic melanoma presented to our dermatology clinic with a blistering eruption on her left chest and right thigh that appeared 1 month prior. She finished her 1-year course of nivolumab 2 months prior. She had not recently discontinued any other medicaitions and her only current medications were amlodpine for hypertension and atorvastatin for hyperlipidaemia.

Four years prior, the patient was diagnosed with acral lentiginous melanoma on the left plantar heel that was excised with negative margins. Two years after her initial diagnosis, the melanoma had metastasised to her left lower leg. Wide-excision and sentinel lymph node dissection were performed, with pathology revealing negative margins and no lymph node metastases. The patient was started on adjuvant nivolumab therapy 480 mg every 4 weeks for 52 weeks. Seven months after starting nivolumab, the patient developed immunotherapy-induced vitiligo.

In the dermatology clinic, skin examination was remarkable for a 1×1.5 cm eroded plaque with hyperpigmentation along the rim most notable at the 10 o’clock position on her left chest (figure 1).

Figure 1.

Bullous pemphigoid. Representative clinical image from left chest.

Investigations

Punch biopsies were performed, and histopathology showed focal mild spongiosis with an underlying band-like infiltrate composed mostly of lymphocytes focally obscuring the dermal-epidermal junction (DEJ) as well as a subepidermal split (figure 2). Direct immunofluorescence (DIF) showed linear staining at the DEJ with IgG and C3, which confirmed the diagnosis of BP.

Figure 2.

Bullous pemphigoid. H&E-stained section from left chest.

Differential diagnosis

The patient’s recent discontinuation of nivolumab and skin condition led to suspicion of nivolumab-induced BP.

Treatment

Treatment for the BP was initiated with two times per day doxycycline 100 mg and clobetasol 0.05% ointment, along with daily niacinamide 500 mg.

One month after being seen in the dermatology clinic, the patient was found to have metastatic melanoma of her left calf. The tumour was excised, and she was started on adjuvant trametinib by her oncologist.

Outcome and follow-up

Two months after initially presenting to the dermatology clinic, the patient was hospitalised for odynophagia, dysphagia and mild haemoptysis. CT scan revealed laryngeal oedema and flexible laryngoscopy showed erythematous lesions of the pharynx and supraglottis, bulla on the epiglottis, and interarytenoid inflammation that was consistent with BP. Due to concerns of airway obstruction, the patient was immediately started on intravenous dexamethasone 10 mg every 8 hours. Her symptoms improved and she was discharged 2 days later with prednisone 40 mg daily for 7 days and amoxicillin–clavulanate 875–125 mg two times per day for 4 days.

On follow-up visit with her primary care provider, the patient’s odynophagia and dysphagia were improving, and her skin lesions had resolved. However, at dermatology follow-up 4 months later, her BP was flaring with erosions on her chest, back and bilateral extremities. In addition to her previous treatment of doxycycline, niacinamide and clobetasol, the patient was started on dapsone 50 mg two times per day and predinose 30 mg taper over 6 weeks.

Case 2

Case presentation

A man in his 80s with a history of renal cell carcinoma (RCC) was referred to our dermatology clinic after presenting to the hospital with a diffuse blistering eruption. He was diagnosed with RCC 1 year ago that was treated with right nephrectomy and nivolumab-ipilimumab adjuvant therapy. Nivolumab–ipilimumab therapy was stopped after eight rounds due to the patient developing diabetes mellitus and an unspecified skin eruption. Three months later after immunotherapy discontinuation, the patient developed diffuse bullae on his trunk and extremities which required hospitalisation. He had not recently started or discontinued any other medicaitions and his current medications were amlodpine for hypertension, insulin for type II diabetes melitus, and levothyroxine for hypothyroidism.

In the dermatology clinic, skin examination showed multiple 1–2 cm eroded papules with surrounding erythema and multiple crusted thin plaques across the trunk and extremities affecting 10% of body surface area (figures 3 and 4).

Figure 3.

Bullous pemphigoid. Representative clinical image from left chest.

Figure 4.

Bullous pemphigoid. Representative clinical image from left thigh.

Investigations

In the hospital, punch biopsies were performed, and histopathological examination revealed eosinophilic spongiosis and a perivascular and interstitial mixed cell infiltrate containing numerous eosinophils (figure 5). DIF showed linear staining at the DEJ with IgG and C3. The patient was diagnosed with BP and referred to our dermatology clinic.

Figure 5.

Bullous pemphigoid. H&E-stained section from right abdomen.

Differential diagnosis

The patient’s recent discontinuation of nivolumab–ipilimumab therapy and skin condition led to suspicion of nivolumab-induced BP.

Treatment

After discharge from the hospital, the patient was started on prednisone 10 mg two times per day which was tapered down to 5 mg daily. In the dermatology clinic, he was continued on prednisone 5 mg daily, and he was started on two times per day doxycycline 100 mg and clobetasol 0.05% ointment. Additionally, he was recommended to take daily vitamin D 800 U, calcium 1200 mg, famotidine 20 mg and niacinamide 500 mg. He was not initially started on further immunosuppressive or nephrotoxic medications due to his history RCC, concern for recurrence and history of right nephrectomy. His BP failed to improve, and he continued to have new bullae formation, so dapsone 50 mg daily was started and prednisone was slowly tapered and discontinued over 2 months. One month after initiating dapsone, the frequency was increased to 50 mg two times per day due to lack of improvement.

Outcome and follow-up

Currently, the patient’s BP has slightly improved, but is not controlled and he continues to have new bullae. Weekly complete blood counts (CBCs) since initiating dapsone showed his haemoglobin had decreased from 117 g/L to 99 g/L over the course of 3 weeks. Due to concerns about dapsone-induced methaemoglobinaemia, the dose of dapsone was not increased. The patient continues to be monitored with weekly CBCs and monthly dermatology visits. If BP remains uncontrolled on higher doses of dapsone, we will consider switching to intravenous immune globulin.

Discussion

BP is an autoimmune subepidermal blistering skin disease that is due to antibodies against components of the DEJ of skin and adjacent mucous membranes.² BP usually arises in older adults and presents with a prodromal non-bullous phase of widespread urticarial plaques that evolve into tense blisters.² However, there are non-bullous and atypical variants where patients may only have localised bulla formation, eczematous lesions or even an absence of skin changes with only pruritus.^{2 3} Risk factors for BP include old age, neurological diseases such as dementia and Parkinson’s disease and certain drugs.³ Drug-induced BP as been associated with 89 different medications, with ICIs, gliptins, loop diuretics, penicillin and its derivatives showing the strongest evidence.⁴ The only medication taken by either of our patient that has a likely or probable association with BP was the ICI.⁴ While ICI-induced BP is a rare occurrence, it has been well documented in the literature.

ICIs are powerful anticancer therapies that are the first-line treatment for several solid-organ malignancies. These drugs are monoclonal antibodies that target cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), PD-1 or PD-L1, and lead to cytotoxic T-cell activation and prevent cancer cells from evading the immune system. There are currently two types of ICIs: CTLA-4 inhibitors such as ipilimumab, and PD-1 or PD-L1 inhibitors such as pembrolizumab, nivolumab, and cemiplimab or atezolizumab, avelumab and durvalumab, respectively.¹ Activating antitumour immune responses can lead to numerous irAEs that may involve any organ. The most common irCAEs, occurring in 18%–34% of patients on PD-1/PD-L1 inhibitors and 43%–45% on CTLA-4 inhibitors.¹ The majority of irCAEs are usually self-limited and can be managed with topical agents alone; these include psoriasiform, eczematous and lichenoid dermatoses.^{5 6} In contrast, BP is a rare, potentially life-threatening irCAE that often requires systemic treatment and discontinuation of immunotherapy.⁷

Cutaneous adverse events with CTLA-4 inhibitors are twice as common with PD-1/PD-L1 inhibitors⁸; however, only 2.4% of all reported cases of ICI-induced BP are due to anti-CTLA-4 therapy and 3.9% are due to combined anti-PD-1 and anti-CTLA-4 therapy.⁷ The considerably fewer reported cases of BP with CTLA-4 inhibitor use suggests that ICI-induced BP may be more specific to anti‐PD‐1/PD‐L1 therapy. As described, case 2 adds to the limited number of cases of BP induced by anti-PD-1 and anti-CTLA-4 combination therapy and is the only reported case in which the diagnosis was not melanoma. We conducted a literature review on all reported cases of BP induced by CTLA-4 inhibitors, combination anti-PD-1 and anti-CTLA-4 therapy and CTLA-4 inhibitor therapy after PD-1/PD-L1 inhibitor therapy (table 1).

Table 1.

Summary of BP case associated with CTLA-4 inhibitor therapy

Sex/ age	Diagnosis	Agent	Onset	Management	Outcome of BP	Study
M/80	RCC	Ipilimumab +nivolumab	1 year after initiation, 3 months after cessation	Prednisone 5 mg daily, dapsone 50 mg two times per day, doxycycline 100 mg two times per day, clobetasol 0.05% ointment two times per day	Ongoing	Current
M/63	Mucosal melanoma	Ipilimumab +nivolumab	17 days after initiation	Doxycycline, intravenous methylprednisolone 1 mg/kg/1 day, intravenous rituximab 1000 mg once	Ongoing	Wesolow et al, 202114
M/57	Melanoma	Ipilimumab +nivolumab	2 months after initiation	Systemic steroids 1 g/kg, two rituximab (1000 mg) infusions, intravenous Ig 2 mg/kg	Ongoing	Povilaityte et al, 202115
M/76	Melanoma	Ipilimumab +nivolumab	12 months after initiation	Oral prednisone, topical corticosteroids (TCS)	Ongoing	Morris et al, 202016
M/82	Melanoma	Ipilimumab +Nivolumab	6 months after initiation	Systemic steroids, mycophenolate mofetil 1500 mg/day, clobetasol 0.05%, diphenhydramine	Ongoing	Schwartzman et al, 202017
F/76	Uveal melanoma	Ipilimumab +Nivolumab	60 weeks after initiation	TCS Prednisolone 15 mg/day	Resolved	Sadik et al, 202018
M/72	Melanoma	Ipilimumab	10 weeks after initiation, 1 week after cessation	Prednisolone 40 mg/day, TCS	Ongoing	Hanley et al, 201819
M/35	Melanoma	7 cycles of nivolumab, then ipilimumab	After 2 cycles of ipilimumab	TCS	Resolved	Kuwatsuka et al, 201820
M/56	Melanoma	Ipilimumab	After 2 cycles of ipilimumab	Systemic steroids	Resolved	Cavalcante et al, 201521

BP, bullous pemphigoid; CTL4-4, cytotoxic T-lymphocyte-associated protein-4; RCC, renal cell carcinoma.

Like typical cases of BP, ICI-induced BP classically presents with a prodromal non-bullous phase of pruritus and non-specific cutaneous eruption, followed by generalised or localised tense blisters, but atypical presentations are also reported.^{5 9 10} The heterogenous presentation of BP and the fact that pruritus is one of the most common low-grade irCAEs makes the diagnosis challenging. There should be a high suspicion of BP and low threshold for skin biopsy when pruritus or skin eruptions are refractory to topical corticosteroids.⁵ Both clinical and immunopathological features are necessary for diagnosis.² Histological examination and DIF will typically show subepidermal bulla with eosinophilic infiltrate and linear deposits of IgG and C3 at the DEJ.^{5 10} ELISA for circulating antibodies against BP180 and BP230 can help confirm the diagnosis, determine disease severity and monitor treatment response.⁵

Treatment of ICI-induced BP is challenging and may result in discontinuation of immunotherapy in up to 70% of cases.^{7 9} Treatment recommendations are based on the Common Terminology Criteria for Adverse Events (CTCAE) V.5.0, which grades the severity of bullous dermatoses based on symptoms, impact on activities of daily living (ADL) and percentage of body surface area (BSA) covered with blisters (table 2).^{5 11} Rituximab is the most used medication for steroid-refractory BP; other treatments include omalizumab, methotrexate, dapsone, plasma exchange and intravenous immunoglobulin.^{1 7 10} There is concern for reduced efficacy of immunotherapy and risk of cancer recurrence with use of immunosuppressive medications. This was a particular concern in our patient in case 2, so we initiated dapsone instead of more conventional treatments. Our patient also underwent a right nephrectomy for his RCC, so nephrotoxic medications like methotrexate could not be used. Additionally, irCAE development after ICI therapy is strongly associated with response to ICI therapy and patient survival,¹² and development of BP after PD-1 therapy has been associated with an improved tumour response in retrospective studies,¹³ though prospective studies are needed to validate this hypothesis.⁶

Table 2.

CTCAE V.5.0 treatment recommendations for bullous dermatoses

CTCAE grade	Description	Treatment recommendations
1	<10% BSA, asymptomatic	Continue ICI; high potency TCS two times per day
2	10%–30% BSA; painful blisters; limiting instrumental ADL	Hold ICI; high-potency TCS; doxycycline 100 mg two times per day; niacinamide 500 mg two times per day; consider systemic corticosteroids (prednisone 0.5–1 mg/kg/day) if rapidly progressive; consider rituximab if refractory
3	>30% BSA; limiting self-care ADL;	Hold ICI; high-potency TCS; doxycycline 100 mg two times per day; niacinamide 500 mg two times per day; systemic corticosteroids (prednisone 0.5–1 mg/kg/day); attempt steroid taper after 2 weeks; consider rituximab if refractory
4	>30% BSA; associated with fluid or electrolyte abnormalities	Hospital admission; permanently discontinue ICI; prednisone 1–2 mg/kg or equivalent dose of intravenous methylprednisolone for 2 weeks with slow taper; doxycycline 100 mg two times per day; niacinamide 500 mg two times per day; consider rituximab if refractory

ADL, activities of daily living; BSA, body surface area; CTCAE, Common Terminology Criteria for Adverse Events; ICI, immune checkpoint inhibitor; TCS, topical corticosteroids.

While mucous membranes are only involved in 10%–30% of ICI-induced BP cases,^{5 7 10} involvement of the larynx may be life-threatening since it can lead to inflammation and oedema that may develop into airway obstruction, as evidenced in our first case. Thus, prompt recognition of ICI-induced BP is critical to prevent or reduce interruptions in cancer treatment and to prevent life-threatening sequela of BP. Over 92% of cases of BP developed during immunotherapy with the average time interval of 22 weeks between ICI initiation and BP onset.⁷ Patients on immunotherapy are closely followed by their oncologists and monitored for irAEs. However, the onset of BP in both of our patients occurred after discontinuation of immunotherapy. While this is an extremely rare occurrence that has only been previously reported in the literature 10 times, patients can still develop severe sequela of BP even years after immunotherapy.⁷ Thus, it is important for patients to have regular dermatological follow-up to evaluate for irCAEs even after immunotherapy discontinuation.

Learning points.

• Patients on both anti-PD-1/PD-L1 and anti-cytotoxic T-lymphocyte-associated protein-4 immunotherapy are susceptible to life threatening cutaneous immune-related adverse events such as bullous pemphigoid.

• There should be a high suspicion of bullous pemphigoid (BP) and low threshold for skin biopsy when pruritus or skin eruptions in patients on immune checkpoint inhibitors (ICIs) are refractory to topical corticosteroids.

• ICI-induced BP can occur months to years after discontinuation of ICIs and patients should have regular dermatological follow-up during and after discontinuation of immunotherapy.

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