Bullous pemphigoid associated with the use of nivolumab in a patient with metastatic melanoma: a case report.

ABSTRACT

Benefits of immunotherapy within modern oncology are evident, especially when evaluating survival, morbidity and systemic effects in the treatment of neoplastic tumors. However, adverse events have been described in association with checkpoint inhibitors. We aim to describe a case of bullous pemphigoid in a patient with metastatic melanoma treated with nivolumab. A 62-year-old male diagnosed with metastatic melanoma and BRAF mutation who underwent surgical resection started nivolumab and during the 40th cycle presented dermatological lesions compatible with bullous pemphigoid. After confirmation with biopsy, corticosteroid therapy was adopted and remission of the lesions was observed followed by relapse after immunotherapy reintroduction. Even though checkpoint inhibitors express several advantages over conventional systemic agents, these drugs seem to exert toxic effects that may manifest as skin lesions. Bullous pemphigoid diagnosis, which requires careful clinical investigation, should be considered when patients present dermatologic symptoms after treatment with nivolumab.

RESUMO

Os benefícios da imunoterapia na oncologia moderna são evidentes, com vantagens significativas quanto à avaliação de sobrevida, morbidade e efeitos sistêmicos no tratamento de tumores neoplásicos. No entanto, eventos adversos têm sido associados ao uso de inibidores de check- point. Neste estudo, objetivou-se descrever um caso de penfigoide bolhoso em um paciente com melanoma metastático tratado com nivolumabe. Um homem de 62 anos com diagnóstico de melanoma metastático com mutação BRAF, submetido à ressecção cirúrgica, iniciou nivolumabe e durante o 40º ciclo, apresentou lesões dermatológicas compatíveis com penfigoide bolhoso. Após confirmação de biópsia, foi adotada terapia com corticosteróides e observada remissão das lesões, seguida de recidiva após reintrodução da imunoterapia. Embora os inibidores de checkpoint expressem várias vantagens sobre os agentes sistêmicos convencionais, tais medicamentos parecem exercer efeitos tóxicos que podem manifestar-se como lesões na pele. O diagnóstico de penfigoide bolhoso, o qual requer cuidadosa investigação clínica, deve ser considerado quando os pacientes apresentarem sintomas dermatológicos após tratamento com nivolumabe.

Keywords:

Pemphigoid - Bullous - Nivolumab - Melanoma

Descritores:

Penfigoide bolhoso - Nivolumabe - Melanoma

AUTHOR'S CONTRIBUTION

Diego Lopes Paim Miranda: Collection and assembly of data, Conception and design, Data analysis and interpretation, Manuscript writing.

Leilah Andrade Alves: Collection and assembly of data, Conception and design, Data analysis and interpretation, Manuscript writing.

Dyonatas Rodrigues da Mata: Collection and assembly of data, Conception and design, Data analysis and interpretation, Manuscript writing.

Nathanael Pinheiro: Data analysis and interpretation, Provision of study materials or patient.

Anete Olivieri Pessoa da Silva: Data analysis and interpretation.

Luciana Castro Garcia Landeiro: Collection and assembly of data, Conception and design, Final approval of manuscript, Manuscript writing, Provision of study materials or patient.

Publication History

Received: 28 September 2019

Accepted: 03 April 2020

Article published online:
21 May 2020

• REFERENCES

• Sosman JA. Overview of the management of advanced cutaneous melanoma. . UpToDate [Internet]. 2019; [cited 2019 Aug 01]. Available from: https://www.uptodate.com/contents/overview-of-the-management-of-advanced-cutaneous-melanoma
• Hodi FS, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Cowey CL. et al Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol 2018; Nov; 19 (11) 1480-1492
• Schachter J, Ribas A, Long GV, Arance A, Grob JJ, Mortier L. et al Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet 2017; Oct; 390 (10105): 1853-1862
• Lopez AT, Geskin L. A case of nivolumab-induced bullous pemphigoid: review of dermatologic toxicity associated with programmed cell death protein-1/programmed death ligand-1 inhibitors and recommendations for diagnosis and management. Oncologist 2018; Oct; 23 (10) 111926
• Siegel J, Totonchy M, Damsky W, , Berk-Krauss, Castiglione Junior F, Sznol M. et al Bullous disorders associated with anti-PD-1 and antiPD-L1 therapy: A retrospective analysis evaluating the clinical and histopathologic features, frequency, and impact on cancer therapy. J Am Acad Dermatol 2018; Dec; 79 (06) 1081-1088
• Haanen JBAG, Robert C. Immune checkpoint inhibitors. Prog Tumor Res 2015; 55-66
• Tocheva AS, Mor A.. Checkpoint inhibitors: applications for autoimmunity. Curr Allergy Asthma Rep 2017; Sep; 17 (10) 72
• Seidel JA, Otsuka A, Kabashima K. Anti-PD-1 and anti-CTLA-4 therapies in cancer: mechanisms of action, efficacy, and limitations. Front Oncol 2018; Mar; 8: 86
• Aggarwal P. Disproportionality analysis of bullous pemphigoid adverse events with PD-1 inhibitors in the FDA Adverse Event Reporting System. Expert Opin Drug Saf 2019; Jul; 18 (07) 62333
• Khair DO, Bax HJ, Mele S, Crescioli S, Pellizzari G, Khiabany A. et al Combining immune checkpoint inhibitors: established and emerging targets and strategies to improve outcomes in melanoma. Front Immunol 2019; Mar; 10: 453
• Curry JL, Tetzlaff MT, Nagarajan P, Drucker C, Diab A, Hymes SR. et al Diverse types of dermatologic toxicities from immune checkpoint blockade therapy. J Cutan Pathol 2017; Feb; 44 (02) 158-176
• Anastasopoulou A, Papaxoinis G, Diamantopoulos P, Christodifou 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; Apr; 41 (03) 164-167
• Schadendorf D, Hodi FS, Robert C, Weber JS, Margolin K, Hamid O. et al Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. J Clin Oncol 2015; Jun; 33 (17) 1889-1894
• Lopez AT, Khanna T, Antonov N, Audrey-Bayan C, Geskin L. A review of bullous pemphigoid associated with PD-1 and PD-L1 inhibitors. Int J Dermatol 2018; Jun; 57 (06) 664-669
• Murrell DF, Ramirez-Quizon M. Management and prognosis of bullous pemphigoid. . UpToDate [Internet]. 2019; [cited 2019 Aug 01]. Available from: https://www.uptodate.com/contents/management-and-prognosis-of-bullous-pemphigoid
• Abdel-Wahab N, Shah M, Suarez-Almazor ME. Adverse events associated with immune checkpoint blockade in patients with cancer: a systematic review of case reports. PLoS ONE 2016; Jul; 11 (07) e0160221
• Long H, Zhang G, Wang L, Liu Q. Eosinophilic skin diseases: a comprehensive review. Clin Rev Allergy Immunol 2016; Apr; 50 (02) 189-213
• Leiferman KM. Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid. . UpToDate [Internet]. 2019; [cited 2019 Aug 01]. Available from: https://www.uptodate.com/contents/clinical-features-anddiagnosis-of-bullous-pemphigoid-and-mucousmembrane-pemphigoid
• Joly P, Roujeau JC, Benichou J, Delaporte E, D'Incan M, Dreno B. et al A comparison of two regimens of topical corticosteroids in the treatment of patients with bullous pemphigoid: a multicenter randomized study. J Invest Dermatol 2009; Jul; 129 (07) 1681-1687