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Year : 2020  |  Volume : 65  |  Issue : 3  |  Page : 214-216
Nivolumab-induced bullous pemphigoid managed without drug withdrawal

Department of Dermatology, Germans Trias I Pujol University Hospital, Universitat Autònoma De Barcelona, Badalona, Spain

Date of Web Publication14-Apr-2020

Correspondence Address:
Mónica Munera-Campos
Department of Dermatology, Germans Trias I Pujol University Hospital, Universitat Autonoma De Barcelona, Carretera De Canyet, S/N, 08916 Badalona, Barcelona
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijd.IJD_321_18

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The widespread use of anti-programmed cell death receptor-1 (PD-1) agents has shed light to unusual immune-related adverse effects, especially affecting the skin. We report a case of bullous pemphigoid secondary to nivolumab therapy for metastatic renal carcinoma with a previously unreported complete response to clobetasol ointment alone. The autoimmune blistering disease was successfully treated without oral corticosteroids, and the anti-PD-1 agent could be maintained without recurrence of the skin lesions. Topical therapy remains a good option in selected, mild-to-moderate cases of induced bullous pemphigoid.

Keywords: Anti-programmed cell death receptor-1, bullous pemphigoid, nivolumab, renal carcinoma, topical treatment

How to cite this article:
Munera-Campos M, Plana-Pla A, Rivera N, Boada A, Ferrándiz C. Nivolumab-induced bullous pemphigoid managed without drug withdrawal. Indian J Dermatol 2020;65:214-6

How to cite this URL:
Munera-Campos M, Plana-Pla A, Rivera N, Boada A, Ferrándiz C. Nivolumab-induced bullous pemphigoid managed without drug withdrawal. Indian J Dermatol [serial online] 2020 [cited 2021 May 12];65:214-6. Available from:

   Introduction Top

Immune checkpoint inhibitors, such as nivolumab, have revolutionized the treatment of some metastatic tumors, such as melanoma or lung cancer. However, up to 40% of patients may develop immune-related adverse events affecting the skin.[1] Autoimmune blistering diseases have infrequently been described.

We report a case of bullous pemphigoid appeared shortly after the second dose of nivolumab and managed without drug withdrawal.

   Case Report Top

A 62-year-old man presented at our department with a 1-month history of a generalized and pruritic eruption. The patient had no previous history of autoimmune or inflammatory skin conditions. Medical history was significant for metastatic renal carcinoma previously treated with sunitinib and everolimus, none of which were effective. Treatment with nivolumab (3 mg/kg intravenously every 2 weeks), started 1 month before the eruption, achieved a good response of his oncologic disease.

On examination, the skin showed numerous hemorrhagic crusted papules and plaques especially affecting the trunk [Figure 1]a, and two active bullous lesions were present on the dorsum of his right arm [Figure 1]b. Skin biopsy of an intact lesion showed a subepidermal blister [Figure 2]a with a dermal lymphocytic infiltrate with numerous eosinophils [Figure 2]b. A linear deposition of C3 (+++) and immunoglobulin G (++) at the dermo-epidermal junction was shown on direct immunofluorescence [Figure 2]c. The enzyme-linked immunosorbent assay for BP180 autoantibody was positive, with a negative BP230. These changes were consistent with the clinical impression of bullous pemphigoid.
Figure 1: Clinical features. Crusted papules and plaques on the trunk (a) and active bulla on the right arm (b)

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Figure 2: Histopathological and immunological features. Histopathological features include a subepidermal blister (H and E, ×40) (a) with eosinophil infiltration (H and E, ×200) (b). Direct immunofluorescence for C3 shown linear deposition at the dermal-epidermal junction (Immunofluorescence stain, ×100) (c)

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As the patient had shown good response and the adverse event was tolerable, nivolumab was maintained, and treatment for bullous pemphigoid was started with clobetasol ointment followed by a progressive reduction to a weekly maintenance therapy. The response was complete with topical steroid. No relapse was observed with the following nivolumab administrations.

   Discussion Top

Nivolumab is a monoclonal antibody that specifically targets the programmed cell death receptor-1 (PD-1), thus improving the T-cell-mediated antitumor response. Dermatologic toxicities are among the more frequent adverse events of these drugs.[2]

To our knowledge, more than 20 cases of bullous pemphigoid in patients receiving anti-PD-1 agents have been reported, 10 of them induced by nivolumab, 12 by pembrolizumab, and 1 by durvalumab.[1],[2],[3],[4],[5],[6],[7] The association of bullous pemphigoid with cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) inhibitors, such as ipilimumab remains controversial, as reported cases appeared in association with anti-PD-1 therapy, but no cases have been reported with CTLA-4 inhibitors alone.[2] While bullous pemphigoid has mostly been described in the setting of immunotherapy for metastatic melanoma, lung cancer, and urothelial carcinoma,[2] there is only one other case reported in a patient with metastatic renal carcinoma, which required drug withdrawal.[8]

Although pathogenesis is not fully understood, it is hypothesized that anti-PD-1/programmed cell death ligand-1 (PD-L1) blockade may result in a loss of tolerance and the development of T-cells against BP180. Moreover, a humoral response may result from the activation of B-cell germinal center secondary to an interaction between PD-1/PD-L1 expressing B-cells and PD-1+ follicular helper cells.[9]

A potential association between bullous pemphigoid with an improved survival in patients receiving anti-PD-1 inhibitors has been suggested. However, response rates in these patients (41.7%) seem to be similar to that reported in the literature, and induced-bullous pemphigoid does not seem to be a marker of a better response.[2],[4]

The persistence and the severity of bullous pemphigoid lesions led to therapy discontinuation in previous reports.[2],[4],[7],[9] In general, treatment includes topical and oral steroids,[2] but other therapies, including omalizumab[4] and rituximab,[6] have also been used. In our case, nivolumab could be maintained as clobetasol ointment alone achieved a complete response.

   Conclusion Top

As new indications of anti-PD-1 therapies in other neoplasms arise, an increase is expected in the number of immune-related adverse events, including autoimmune skin diseases. Thus, awareness and close monitoring of dermatological toxicities is crucial to ensure an adequate management. Immunotherapy withdrawal is not always mandatory and should be individualized. Topical therapy remains a good option in selected, mild-to-moderate cases.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

   References Top

Garje R, Chau JJ, Chung J, Wanat K, Zakharia Y. Acute flare of bullous pemphigus with pembrolizumab used for treatment of metastatic urothelial cancer. J Immunother 2018;41:42-4.  Back to cited text no. 1
Anastasopoulou A, Papaxoinis G, Diamantopoulos P, Christofidou E, Benopoulou O, Stratigos A, et al. Bullous pemphigoid-like skin lesions and overt eosinophilia in a patient with melanoma treated with nivolumab: Case report and review of the literature. J Immunother 2018;41:164-7.  Back to cited text no. 2
Kuwatsuka Y, Iwanaga A, Kuwatsuka S, Okubo Y, Murayama N, Ishii N, et al. Bullous pemphigoid induced by ipilimumab in a patient with metastatic malignant melanoma after unsuccessful treatment with nivolumab. J Dermatol 2018;45:e21-2.  Back to cited text no. 3
Damsky W, Kole L, Tomayko MM. Development of bullous pemphigoid during nivolumab therapy. JAAD Case Rep 2016;2:442-4.  Back to cited text no. 4
Rofe O, Bar-Sela G, Keidar Z, Sezin T, Sadik CD, Bergman R, et al. Severe bullous pemphigoid associated with pembrolizumab therapy for metastatic melanoma with complete regression. Clin Exp Dermatol 2017;42:309-12.  Back to cited text no. 5
Sowerby L, Dewan AK, Granter S, Gandhi L, LeBoeuf NR. Rituximab treatment of nivolumab-induced bullous pemphigoid. JAMA Dermatol 2017;153:603-5.  Back to cited text no. 6
Shen J, Chang J, Mendenhall M, Cherry G, Goldman JW, Kulkarni RP, et al. Diverse cutaneous adverse eruptions caused by anti-programmed cell death-1 (PD-1) and anti-programmed cell death ligand-1 (PD-L1) immunotherapies: Clinical features and management. Ther Adv Med Oncol 2018;10:1758834017751634.  Back to cited text no. 7
Kwon CW, Land AS, Smoller BR, Scott G, Beck LA, Mercurio MG, et al. Bullous pemphigoid associated with nivolumab, a programmed cell death 1 protein inhibitor. J Eur Acad Dermatol Venereol 2017;31:e349-50.  Back to cited text no. 8
Naidoo J, Schindler K, Querfeld C, Busam K, Cunningham J, Page DB, et al. Autoimmune bullous skin disorders with immune checkpoint inhibitors targeting PD-1 and PD-L1. Cancer Immunol Res 2016;4:383-9.  Back to cited text no. 9


  [Figure 1], [Figure 2]


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