Immune Checkpoint Inhibitor-Induced Bullous Pemphigoid: Successful Treatment with Dupilumab while Maintaining Immunotherapy

Abstract

Introduction

Immune checkpoint inhibitors (ICIs) represent a new class of antitumor agents in oncology. Their use has been associated with a specific safety profile, known as immune-related adverse events (irAEs), with dermatological toxicities being the most frequently encountered.

Case Report

We report the case of a bullous pemphigoid (BP) in a metastatic melanoma patient, treated with ipilimumab and nivolumab. This immune-mediated toxicity was controlled by using dupilumab as a steroid-sparing therapy, allowing the reintroduction of immunotherapy without relapse.

Conclusion

This case illustrates the complexity of managing some dermatological irAEs and the need for better treatment strategies. Dupilumab is a promising agent for cutaneous irAEs, including ICI-BP. To our knowledge, our case is the first one in which a rechallenge with an ICI was attempted after a dupilumab treatment for an ICI-BP.

Introduction

Immune checkpoint inhibitors (ICIs) are a new class of antitumor agents in oncology, revolutionizing anticancer therapy since 2010 [1, 2]. They work by disrupting the immune homeostasis and overactivating the immune system. Their use has been linked to a specific safety profile, known as immune-related adverse events (irAEs) [1]. T-cell activation contributes to the development of irAEs, by causing the generation of inflammatory cytokines and B-cell-mediated autoantibodies. The incidence of irAEs differs depending on the monoclonal antibody used (anti-CTLA4 or anti-PD-1/L1), either alone or in combination, and represents a significant drawback in clinical practice [3].

Dermatological toxicities are the most prevalent irAEs, occurring in up to 30 to 50% of patients receiving ICIs. The most frequently seen are maculopapular rash, lichenoid dermatitis, psoriasis, and vitiligo [4]. Autoimmune bullous diseases have been reported with an incidence of 1–5%, with bullous pemphigoid (BP) being the most frequent. Its treatment often requires prolonged immunosuppression by systemic steroids, with the risk of jeopardizing ICI’s efficacy.

We report the case of BP in a metastatic melanoma patient, treated with ipilimumab and nivolumab. The control of the skin disease was obtained by using dupilumab as a steroid-sparing therapy and allowing the reintroduction of nivolumab without relapse.

Case Report

In 2022, a 62-year-old woman, without significant comorbidities, was diagnosed with metastatic melanoma of unknown primary, BRAF wild-type, with pulmonary and brain metastasis. After stereotactic radiotherapy of the brain lesions, combined ipilimumab and nivolumab was started.

Following the first administration, the patient developed a grade 2 according to Common Terminology Criteria for Adverse Events (CTCAE) v5.0 (Table 1) skin rash, with an itchy and erythematous eruption, covering almost 30% of body surface area, managed with topical moisturizers. Two weeks after the second administration, the skin rash progressed to grade 3, with the appearance of tense large clear blisters, located on the abdomen, back, arms, and legs, involving almost 70% of body surface area (Fig. 1a, b). No mucosal involvement was observed. Due to the development of a grade 3 skin eruption, immunotherapy was discontinued. The histopathological examination of skin biopsies revealed the presence of a subepidermal bullous detachment, together with a mixed neutrophilic and eosinophilic infiltrate (Fig. 2a, b). Direct immunofluorescence microscopy confirmed linear deposits of IgG and complement component 3 at the dermo-epidermal junction, with a negative result for IgA and IgM. The circulating specific BP – antibodies, targeting the BP180 (BP180NC16 ELISA) and BP230 (BP230NC16 ELISA) antigens, had an initial elevated value – 106.40 U/mL (N < 9) and 6.8 U/mL (N < 9), respectively. The immunoglobulin (Ig) E levels reached a concentration of more than 5,000 kU/L (N < 103), and hypereosinophilia was also observed.

Table 1.

Grading of bullous dermatitis according to the CTCAE, reproduced from the US National Cancer Institute, CTCAE v5.0, 2017 [5]

CTCAE term	Grade 1	Grade 2	Grade 3	Grade 4	Grade 5
Bullous dermatitis	Asymptomatic; blisters covering	Blisters covering 10–30% BSA; painful blisters; limiting instrumental ADL	Blisters covering >30% BSA; limiting self-care ADL	Blisters covering >30% BSA; associated with fluid or electrolyte abnormalities; ICU care or burn unit indicated	Death

BSA, body surface area.

Fig. 1.

a, b Close-up view of the postero-superior left thorax (a) and of the anterior face of the legs (b) showing tense bullae, erosions, and crusted lesions on a erythematous background, consistent with a BP.

Fig. 2.

a, b Hematoxylin and eosin stain demonstrating subepidermal blistering with a neutrophilic and eosinophilic infiltration.

The diagnosis of immune-mediated BP was retained. As a topical steroid treatment was inefficient, systemic steroids were introduced (prednisone 0.6 mg/kg/day) and the BP was controlled within 2 weeks. At that time, a new oncological assessment revealed a partial response of the lung metastases, with a decrease in size of the bilateral pulmonary nodules and no new brain lesions. The reintroduction of ICI was indicated.

To obtain a rapid withdrawal from steroids and to avoid their potential negative interaction with ICI, we proposed a suitable steroid-sparing approach to minimize the use of high-dose steroids. Dupilumab was initiated at the recommended loading dose of 600 mg, followed by 300 mg every other week. BP lesions significantly ameliorated, allowing reducing prednisone at 10 mg/day within 6 weeks.

Nivolumab was reintroduced in monotherapy and was continued for 7 months, while dupilumab and 10 mg of prednisone were maintained during this period, without experiencing any new relapse of BP. At that time, as the oncological assessment showed a complete remission, the patient was put on surveillance. Interestingly, serum anti-BP 180 antibody and total IgE levels decreased significantly, but remained above the normal range.

The chronological summary of ICI-BP is presented in Table 2. The CARE Checklist has been completed by the authors for this case report, and it is attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000547431).

Table 2.

Evolution of ICI-BP: clinical events, serological markers, and therapeutic interventions

​	1 Feb 2023	1 Mar 2023	15 Mar 2023	22 Mar 2023	5 Apr 2023	19 Apr 2023	26 Apr 2023	24 May 2023	7 Jun 2023	21 Jun 2023	11 Jul 2023	23 Aug 2023	28 Jun 2023	26 Jul 2023	17 Jan 2024
Nivolumab IV – 3 mg/kg	220 mg	220 mg	Immunotherapy paused										220 mg	220 mg/14 days
Ipilimumab IV – 1 mg/kg	75 mg	75 mg											​
Skin status	​		BP flare			No PB lesion
Skin biopsy/hematoxylin-eosin	​		Interface dermatitis with eosinophils; cleavage at the DEJ	​
Skin biopsy/DIF	​		Linear IgG deposition along the DEJ
Circulating BP-180 antibodies – N < 10 UI/mL	​		106.4 UI/mL	​			93.5 UI/mL	55.5 UI/mL	​	54.8 UI/mL	51.6 UI/mL	67.9 UI/mL	​
Circulating BP-230 antibodies – N < 10 UI/mL	​		6.8 UI/mL	​			3.5 UI/mL	2.8 UI/mL		2.6 UI/mL	1.9 UI/mL	2.5 UI/mL	​
Total IgE – N < 103.0 kU/L	​		>5,000	​			1,830	870		652	​
Eosinophils, G/L	100 G/L	800 G/L	200 G/L	​			0	0		100 G/L	200 G/L	​
Prednisone	​		​	40 mg/day	Tapering from 35 to 15 mg/day				10 mg/day and tapering to definitive withdrawal				​
Dupilumab SQ (every 14 days)	​		​	​	​	​	600 mg SQ	​

DIF, direct immunofluorescence.

Discussion

The reported incidence of ICI-induced BP varies between 0.3% and 3.8% across publications [6]. The occurrence of BP as an irAE is increasing due to the rising usage of ICIs in cancer. The median age of the patient is around 70 years, generally lower than the age in the classic type. The median time between ICI initiation and BP diagnosis is around 5 months [6]. In our case, the use of dual immunotherapy can explain the early onset of BP after only 5 weeks. BP typically manifests as a pruritic rash followed by tense blistering on the trunk and limbs, with mucosal involvement in less than 20% and generally limited to the oral mucosa [7].

Although the pathogenesis of ICI-BP is not completely understood, it remains an antibody-mediated immune disease, characterized by autoantibodies directed against components of the basement membrane of the skin. Mainly, IgG autoantibodies bind to the components of the hemidesmosome adhesion complex, BP230 and BP180 antigens. The antigen-antibody interaction results in an increase of interleukin (IL)-3, IL-5, and IL-13 and of eosinophils in blood and in BP lesions, as well as a raised IgE serum level, leading to the formation of the subepidermal blisters [8].

In general, patients are treated according to the severity of BP eruption, as classified according to the CTCAE [7]. While mild and moderate BP (grade 1/2) can be managed with topical corticosteroids, more severe or persistent toxicities (grade 3/4) require oral corticosteroids. In corticosteroid-dependent or relapsing cases, other immunosuppressive drugs may be proposed, such as methotrexate, azathioprine, and mycophenolate mofetil, which are immunosuppressants and may not be recommended in situations as they can induce cancer recurrence. More recently, some biological therapies have been added to this therapeutic arsenal, such as rituximab, omalizumab, and dupilumab [1–4, 6–9]. Our patient presented a mild ICI-induced BP, rapidly evolving to a more severe form despite topical corticosteroids. In our case, oral prednisolone at 0.6 mg/kg was started.

Dupilumab is a fully recombinant IgG4 monoclonal antibody, targeting IL-4 receptor alpha, that inhibits the signaling of type 2 inflammatory cytokines, IL-4 and IL-13 [9]. Dupilumab has demonstrated significant and clinical improvement of type 2 inflammation, pruritus, and skin lesions like prurigo nodularis, atopic dermatitis (AD), and chronic spontaneous urticaria, and is used in these diseases routinely. ICI-BP lesions showed a high IL-4 and IL-13 expression, similar to conventional autoimmune PB or AD [10]. In recent years, several series have shown the efficacy of dupilumab in the treatment of patients with resistant BP or with contraindications for corticosteroids [11]. A global, randomized, double-blind, placebo-controlled phase 2/3 trial, the LIBERTY-ADEPT study, is actually assessing the efficacy and safety of dupilumab as a corticoid-sparing therapy in patients with moderate-to-severe BP [12].

Kuo et al. [13] reported a high efficiency and safety profile of dupilumab in several immune-related cutaneous AEs demonstrating a promising place as an alternative to steroids for these patients. In a study published in 2024, Macagno and colleagues [14] also evaluated the safety profile of dupilumab. They conducted a retrospective analysis on patients with a cancer diagnosis and moderate-to-severe AD treated with dupilumab at Turin University’s dermatology clinic. Only 1 of 24 patients in the report stopped taking dupilumab because of conjunctivitis. There were no further adverse events mentioned. These studies supported the use of dupilumab as the recommended treatment for individuals with moderate-to-severe AD and BP and a history of cancer, in line with the most recent International Eczema Council recommendation [14].

Our case is the first to describe a rapid reduction of steroids and a reintroduction of anti-PD1 while maintaining dupilumab. This strategy did not compromise the antitumor immunity and enabled our patient to achieve a complete response.

Conclusion

This case illustrates the complexity of managing some dermatological irAEs and the need for better treatment strategies that are effective and safe without interfering with ICI response. Dupilumab is a promising agent of cutaneous irAEs, including ICI-BP, particularly for patients when immunosuppressive therapy is contraindicated. To our knowledge, our case is the first one in which a rechallenge with an ICI was attempted after a dupilumab treatment for an ICI-BP.

Statement of Ethics

This research was conducted ethically in accordance with the World Medical Association Declaration of Helsinki. Written informed consent was obtained from the patient for publication of this case report, included identifying details like individual age, gender, illness, and any accompanying images. Ethical approval is not required for this case report in accordance with local guidelines.

Conflict of Interest Statement

The authors have no conflict of interest to declare.

Funding Sources

This study did not require any funding.

Author Contributions

Florea Cristina-Maria: conceptualization, collecting literature data, and writing – original draft, review, and editing; Berthod Grégoire: obtaining patient consent, data curation, conceptualization, validation, and writing – review and editing; Parmentier Laurent: validation and writing – review and editing; Abdou Mohamed: conceptualization and interpretation of pathological data, ensuring accurate diagnostic classification, and integration of histological findings into the overall clinical analysis.

Funding Statement

This study did not require any funding.

Data Availability Statement

All data generated or analyzed during this study are included in this article and its online supplementary material. Further inquiries can be directed to the corresponding author.