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Dermatologic Reactions to Immune Checkpoint Inhibitors

Skin Toxicities and Immunotherapy

Abstract

The development of immune checkpoint inhibitors [monoclonal antibodies targeting cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), programmed cell death protein 1 (PD-1) or programmed death ligand 1 (PD-L1)] represents a major breakthrough in cancer therapy. Although they present a favorable risk/benefit ratio, immune checkpoint blockade therapies have a very specific safety profile. Due to their unique mechanism of action, they entail a new spectrum of adverse events that are mostly immune related [immune-related adverse events (irAEs)], notably mediated by the triggering of cytotoxic CD4+/CD8+ T cell activation. Cutaneous toxicities appear to be one of the most prevalent irAEs, both with anti-PD-1 and anti-CTLA-4 agents or with the newly developed anti-PD-L1 agents, which corresponds to a class effect. They are observed in more than one-third of the treated patients, mainly in the form of a maculopapular rash (eczema-like spongiotic dermatitis) and pruritus. A wide range of other dermatologic manifestations can also occur, including lichenoid reactions, psoriasis, acneiform rashes, vitiligo-like lesions, autoimmune skin diseases (e.g., bullous pemphigoid, dermatomyositis, alopecia areata), sarcoidosis or nail and oral mucosal changes. In addition, the use of anti-CTLA-4 and anti-PD-1 therapies in combination is associated with the development of more frequent, more severe and earlier cutaneous irAEs compared to single agents. In most cases, these dysimmune dermatologic adverse events remain self-limiting and readily manageable. Early recognition and adequate management, however, are critical to prevent exacerbation of the lesions, to limit treatment interruption and to minimize quality of life impairment. This review describes the variable clinical and histopathologic aspects of dermatologic irAEs induced by immune checkpoint inhibitors. Appropriate treatment and counseling are also proposed, with a step-by-step approach for optimized management by both practicing oncologists and dermatologists.

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References

  1. Rapoport BL, van Eeden R, Sibaud V, Epstein JB, Klastersky J, Aapro M, et al. Supportive care for patients undergoing immunotherapy. Support Care Cancer. 2017. https://doi.org/10.1007/s00520-017-3802-9 (Epub ahead of print).

    Article  PubMed  Google Scholar 

  2. Postow MA, Callahan MK, Wolchok JD. Immune checkpoint blockade in cancer therapy. J Clin Oncol. 2015;33:1974–82.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  3. Naidoo J, Page DB, Li BT, Connell LC, Schindler K, Lacouture ME, et al. Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. Ann Oncol. 2015;26:2375–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Weber JS, Hodi FS, Wolchok JD, Topalian SL, Schadendorf D, Larkin J, et al. Safety profile of nivolumab monotherapy: a pooled analysis with advanced melanoma. J Clin Oncol. 2017;35:785–92.

    CAS  PubMed  Article  Google Scholar 

  5. Weber JS, Kähler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol. 2012;30:2691–7.

    CAS  PubMed  Article  Google Scholar 

  6. Hassel JC, Heinzerling L, Aberle J, Bähr O, Eigentler TK, Grimm MO, et al. Combined immune checkpoint blockade (anti-PD-1/anti-CTLA-4): evaluation and management of adverse drug reactions. Cancer Treat Rev. 2017;57:36–49.

    CAS  PubMed  Article  Google Scholar 

  7. Haanen JBAG, Carbonnel F, Robert C, Kerr KM, Peters S, Larkin J, et al. Management of toxicities from immunotherapy: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017;28:iv119–42.

    CAS  PubMed  Article  Google Scholar 

  8. Champiat S, Lambotte O, Barreau E, Belkhir R, Berdelou A, Carbonnel F, et al. Management of immune checkpoint blockade dysimmune toxicities: a collaborative position paper. Ann Oncol. 2016;27:559–74.

    CAS  PubMed  Article  Google Scholar 

  9. Sibaud V, Meyer N, Lamant L, Vigarios E, Mazieres J, Delord JP. Dermatologic complications of anti-PD-1/PD-L1 immune checkpoint antibodies. Curr Opin Oncol. 2016;28:254–63.

    CAS  PubMed  Article  Google Scholar 

  10. Freeman-Keller M, Kim Y, Cronin H, Richards A, Gibney G, Weber JS, et al. Nivolumab in resected and unresectable metastatic melanoma: characteristics of immune-related adverse events and association with outcomes. Clin Cancer Res. 2016;22:886–94.

    CAS  PubMed  Article  Google Scholar 

  11. Curry JL, Tetzlaff MT, Nagarajan P, Drucker C, Diab A, Hymes SR. Diverse types of dermatologic toxicities from immune checkpoint blockade therapy. J Cutan Pathol. 2017;44:158–76.

    PubMed  Article  Google Scholar 

  12. Belum VR, Benhuri B, Postow MA, Hellmann MD, Lesokhin AM, Segal NH, et al. Characterisation and management of dermatologic adverse events to agents targeting the PD-1 receptor. Eur J Cancer. 2016;60:12–25.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372:320–30.

    CAS  PubMed  Article  Google Scholar 

  14. Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373:23–34.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  15. Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015;372:2521–32.

    CAS  PubMed  Article  Google Scholar 

  16. Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 2013;369:134–44.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  17. Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369:122–33.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. Postow MA, Chesney J, Pavlick AC, Robert C, Grossman K, McDermott D, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015;372:2006–17.

    PubMed  PubMed Central  Article  Google Scholar 

  19. Hofmann L, Forschner A, Loquai C, Goldinger SM, Zimmer L, Ugurel S, et al. Cutaneous, gastrointestinal, hepatic, endocrine, and renal side effects of anti-PD-1 therapy. Eur J Cancer. 2016;60:190–209.

    CAS  PubMed  Article  Google Scholar 

  20. Sanlorenzo M, Vujic I, Daud A, Algazi A, Gubens M, Luna SA, et al. Pembrolizumab cutaneous adverse events and their association with disease progression. JAMA Dermatol. 2015;151:1206–12.

    PubMed  PubMed Central  Article  Google Scholar 

  21. Minkis K, Garden BC, Wu S, Pulitzer MP, Lacouture ME. The risk of rash associated with ipilimumab in patients with cancer: a systematic review of the literature and meta-analysis. J Am Acad Dermatol. 2013;69:e121–8.

    CAS  PubMed  Article  Google Scholar 

  22. Hua C, Boussemart L, Mateus C, Routier E, Boutros C, Cazenave H, et al. Association of vitiligo with tumor response in patients with metastatic melanoma treated with pembrolizumab. JAMA Dermatol. 2016;152:45–51.

    PubMed  Article  Google Scholar 

  23. Hwang SJ, Carlos G, Wakade D, Byth K, Kong BY, Chou S, et al. Cutaneous adverse events (AEs) of anti-programmed cell death (PD)-1 therapy in patients with metastatic melanoma: a single-institution cohort. J Am Acad Dermatol. 2016;74:455–61.

    PubMed  Article  Google Scholar 

  24. Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366:2455–65.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. Peters S, Gettinger S, Johnson ML, Jänne PA, Garassino MC, Christoph D, et al. Phase II trial of atezolizumab as first-line or subsequent therapy for patients with programmed death-ligand 1-selected advanced non-small-cell lung cancer (BIRCH). J Clin Oncol. 2017;35:2781–9.

    PubMed  Article  PubMed Central  Google Scholar 

  26. Balar AV, Galsky MD, Rosenberg JE, Powles T, Petrylak DP, Bellmunt J, et al. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet. 2017;389:67–76.

    CAS  PubMed  Article  Google Scholar 

  27. Rittmeyer A, Barlesi F, Waterkamp D, Park K, Ciardiello F, von Pawel J, et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet. 2017;389:255–65.

    PubMed  Article  Google Scholar 

  28. Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, et al. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med. 2017. https://doi.org/10.1056/nejmoa1709937 (Epub ahead of print).

    PubMed  Article  Google Scholar 

  29. Lacouture ME, Wolchok JD, Yosipovitch G, Kähler KC, Busam KJ, Hauschild A. Ipilimumab in patients with cancer and the management of dermatologic adverse events. J Am Acad Dermatol. 2014;71:161–9.

    CAS  PubMed  Article  Google Scholar 

  30. Shi VJ, Rodic N, Gettinger S, Leventhal JS, Neckman JP, Girardi M, et al. Clinical and histologic features of lichenoid mucocutaneous eruptions due to anti-programmed cell death 1 and anti-programmed cell death ligand 1 immunotherapy. JAMA dermatol. 2016;152:1128–36.

    PubMed  Article  PubMed Central  Google Scholar 

  31. Goldinger SM, Stieger P, Meier B, Micaletto S, Contassot E, French LE, et al. Cytotoxic cutaneous adverse drug reactions during anti-PD-1 therapy. Clin Cancer Res. 2016;22:4023–9.

    CAS  PubMed  Article  Google Scholar 

  32. Chou S, Hwang SJ, Carlos G, Wakade D, Fernandez-Penas P. Histologic Assessment of lichenoid dermatitis observed in patients with advanced malignancies on antiprogramed cell death-1 (anti-PD-1) Therapy With or Without Ipilimumab. Am J Dermatopathol. 2017;39:23–7.

    PubMed  Article  Google Scholar 

  33. Perret RE, Josselin N, Knol AC, Khammari A, Cassecuel J, Peuvrel L, et al. Histopathological aspects of cutaneous erythematous-papular eruptions induced by immune checkpoint inhibitors for the treatment of metastatic melanoma. Int J Dermatol. 2017;56:527–33.

    CAS  PubMed  Article  Google Scholar 

  34. Schaberg KB, Novoa RA, Wakelee HA, Kim J, Cheung C, Srinivas S, et al. Immunohistochemical analysis of lichenoid reactions in patients treated with anti-PD-L1 and anti-PD-1 therapy. J Cutan Pathol. 2016;43:339–46.

    PubMed  Article  Google Scholar 

  35. Joseph RW, Cappel M, Goedjen B, Gordon M, Kirsch B, Gilstrap C, et al. Lichenoid dermatitis in three patients with metastatic melanoma treated with anti-PD-1 therapy. Cancer Immunol Res. 2015;3:18–22.

    PubMed  Article  Google Scholar 

  36. Tetzlaff MT, Nagarajan P, Chon S, Huen A, Diab A, Omar P, et al. Lichenoid dermatologic toxicity from immune checkpoint blockade therapy: a detailed examination of the clinicopathologic features. Am J Dermatopathol. 2017;39:121–9.

    PubMed  Article  Google Scholar 

  37. Guggina LM, Yanes DA, Choi JN. Inverse lichenoid drug eruption associated with nivolumab. JAAD Case Rep. 2016;3:7–9.

    PubMed  PubMed Central  Article  Google Scholar 

  38. Sibaud V, Eid C, Belum VR, Combemale P, Barres B, Lamant L, et al. Oral lichenoid reactions associated with anti-PD-1/PD-L1 therapies: clinicopathological findings. J Eur Acad Dermatol Venereol. 2017. https://doi.org/10.1111/jdv.14284 (Epub ahead of print).

    PubMed  Article  PubMed Central  Google Scholar 

  39. Chia PL, John T. Severe psoriasis flare after anti-programmed death ligand 1 (PD-L1) therapy for metastatic non-small cell lung cancer (NSCLC). J Immunother. 2016;39:202–4.

    CAS  PubMed  Article  Google Scholar 

  40. Gutzmer R, Koop A, Meier F, Hassel JC, Terheyden P, Zimmer L, et al. Programmed cell death protein-1 (PD-1) inhibitor therapy in patients with advanced melanoma and preexisting autoimmunity or ipilimumab-triggered autoimmunity. Eur J Cancer. 2017;75:24–32.

    CAS  PubMed  Article  Google Scholar 

  41. Menzies AM, Johnson DB, Ramanujam S, Atkinson VG, Wong ANM, Park JJ, et al. Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab. Ann Oncol. 2017;28:368–76.

    CAS  PubMed  Article  Google Scholar 

  42. Johnson DB, Sullivan RJ, Ott PA, Carlino MS, Khushalani NI, Ye F, et al. Ipilimumab therapy in patients with advanced melanoma and preexisting autoimmune disorders. JAMA Oncol. 2016;2:234–40.

    PubMed  Article  Google Scholar 

  43. Bonigen J, Raynaud-Donzel C, Hureaux J, Kramkimel N, Blom A, Jeudy G, et al. Anti-PD1-induced psoriasis: a study of 21 patients. J Eur Acad Dermatol Venereol. 2017;31:e254–7.

    CAS  PubMed  Article  Google Scholar 

  44. Ruiz-Bañobre J, Abdulkader I, Anido U, León L, López-López R, García-González J. Development of de novo psoriasis during nivolumab therapy for metastatic renal cell carcinoma: immunohistochemical analyses and clinical outcome. APMIS. 2017;125:259–63.

    PubMed  Article  CAS  Google Scholar 

  45. Tanaka R, Okiyama N, Okune M, Ishitsuka Y, Watanabe R, Furuta J, et al. Serum level of interleukin-6 is increased in nivolumab-associated psoriasiform dermatitis and tumor necrosis factor-α is a biomarker of nivolumab recativity. J Dermatol Sci. 2017;86:71–3.

    CAS  PubMed  Article  Google Scholar 

  46. Totonchy MB, Ezaldein HH, Ko CJ, Choi JN. Inverse psoriasiform eruption during pembrolizumab therapy for metastatic melanoma. JAMA Dermatol. 2016;152:590–2.

    PubMed  Article  Google Scholar 

  47. Dulos J, Carven GJ, van Boxtel SJ, Buddenkotte J, McDonald I, Aubert J, et al. PD-1 blockade augments Th1 and Th17 and suppresses Th2 responses in peripheral blood from patients with prostate and advanced melanoma cancer. J Immunother. 2012;35:169–78.

    CAS  PubMed  Article  Google Scholar 

  48. Law-Ping-Man S, Martin A, Briens E, Tisseau L, Safa G. Psoriasis and psoriatic arthritis induced by nivolumab in a patient with advanced lung cancer. Rheumatology. 2016;55:2087–9.

    PubMed  Article  Google Scholar 

  49. Ruiz-Bañobre J, Pérez-Pampín E, García-González J, Gómez-Caamaño A, Barón-Duarte FJ, López-López R, et al. Development of psoriatic arthritis during nivolumab therapy for metastatic non-small cell lung cancer, clinical outcome analysis and review of the literature. Lung Cancer. 2017;108:217–21.

    PubMed  Article  Google Scholar 

  50. Vivar KL, Deschaine M, Messina J, Divine JM, Rabionet A, Patel N, et al. Epidermal programmed cell death-ligand 1 expression in TEN associated with nivolumab therapy. J Cutan Pathol. 2017;44:381–4.

    PubMed  Article  Google Scholar 

  51. Saw S, Lee HY, Ng QS. Pembrolizumab-induced Stevens-Johnson syndrome in non-melanoma patients. Eur J Cancer. 2017;81:237–9.

    CAS  PubMed  Article  Google Scholar 

  52. Hwang SJ, Carlos G, Wakade D, Sharma R, Fernandez-Penas P. Ipilimumab-induced acute generalized exanthematous pustulosis in a patient with metastatic melanoma. Melanoma Res. 2016;26:417–20.

    PubMed  Article  Google Scholar 

  53. Page B, Borradori L, Beltraminelli H, Yawalkar N, Hunger RE. Acute generalized exanthematous pustulosis associated with ipilimumab and nivolumab. J Eur Acad Dermatol Venereol. 2017. https://doi.org/10.1111/jdv.14282 (Epub ahead of print).

    PubMed  Article  Google Scholar 

  54. Voskens CJ, Goldinger SM, Loquai C, Robert C, Kaehler KC, Berking C, et al. The price of tumor control: an analysis of rare side effects of anti-CTLA-4 therapy in metastatic melanoma from the ipilimumab network. PLoS One. 2013;8:e53745.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  55. Jour G, Glitza IC, Ellis RM, Torres-Cabala CA, Tetzlaff MT, Li JY, et al. Autoimmune dermatologic toxicities from immune checkpoint blockade with anti-PD-1 antibody therapy: a report on bullous skin eruptions. J Cutan Pathol. 2016;43:688–96.

    PubMed  Article  Google Scholar 

  56. Gulley JL, Rajan A, Spigel DR, Iannotti N, Chandler J, Wong DJL, et al. Avelumab for patients with previously treated metastatic or recurrent non-small-cell lung cancer (JAVELIN Solid Tumor): dose-expansion cohort of a multicentre, open-label, phase 1b trial. Lancet Oncol. 2017;18:599–610.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. Heery CR, O’Sullivan-Coyne G, Madan RA, Cordes L, Rajan A, Rauckhorst M. Avelumab for metastatic or locally advanced previously treated solid tumours (JAVELIN Solid Tumor): a phase 1a, multicohort, dose-escalation trial. Lancet Oncol. 2017;18:587–98.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  58. Munoz J, Guillot B, Girard C, Dereure O, Du-Thanh A. First report of ipilimumab-induced Grover disease. Br J Dermatol. 2014;171:1236–7.

    CAS  PubMed  Article  Google Scholar 

  59. Koelzer VH, Buser T, Willi N, Rothschild SI, Wicki A, Schiller P, et al. Grover’s-like drug eruption in a patient with metastatic melanoma under ipilimumab therapy. J Immunother Cancer. 2016;4:47.

    PubMed  PubMed Central  Article  Google Scholar 

  60. Uemura M, Faisal F, Haymaker C, McQuail N, Sirmans E, Hudgens CW, et al. A case report of Grover’s disease from immunotherapy-a skin toxicity induced by inhibition of CTLA-4 but not PD-1. J Immunother Cancer. 2016;4:55.

    PubMed  PubMed Central  Article  Google Scholar 

  61. Ito J, Fujimoto D, Nakamura A, Nagano T, Uehara K, Imai Y, et al. Aprepitant for refractory nivolumab-induced pruritus. Lung Cancer. 2017;109:58–61.

    PubMed  Article  Google Scholar 

  62. Yin ES, Totonchy MB, Leventhal JS. Nivolumab-associated vitiligo-like depigmentation in a patient with acute myeloid leukemia: A novel finding. JAAD Case Rep. 2017;3:90–2.

    PubMed  PubMed Central  Article  Google Scholar 

  63. Uenami T, Hosono Y, Ishijima M, Kanazu M, Akazawa Y, Yano Y, et al. Vitiligo in a patient with lung adenocarcinoma treated with nivolumab: A case report. Lung Cancer. 2017;109:42–4.

    PubMed  Article  Google Scholar 

  64. Dai J, Belum VR, Wu S, Sibaud V, Lacouture ME. Pigmentary changes in patients treated with targeted anticancer agents: a systematic review and meta-analysis. J Am Acad Dermatol. 2017. https://doi.org/10.1016/j.jaad.2017.06.044.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Nakamura Y, Tanaka R, Asami Y, Teramoto Y, Imamura T, Sato S, et al. Correlation between vitiligo occurrence and clinical benefit in advanced melanoma patients treated with nivolumab: a multi-institutional retrospective study. J Dermatol. 2017;44:117–22.

    CAS  PubMed  Article  Google Scholar 

  66. Larsabal M, Marti A, Jacquemin C, Rambert J, Thiolat D, Dousset L, et al. Vitiligo-like lesions occurring in patients receiving anti-programmed cell death-1 therapies are clinically and biologically distinct from vitiligo. J Am Acad Dermatol. 2017;76:863–70.

    PubMed  Article  Google Scholar 

  67. Nakamura Y, Teramoto Y, Asami Y, Matsuya T, Adachi JI, Nishikawa R, Yamamoto A. Nivolumab therapy for treatment-related vitiligo in a patient with relapsed metastatic melanoma. JAMA Dermatol. 2017;153:942–4.

    PubMed  Article  Google Scholar 

  68. Zamani MR, Aslani S, Salmaninejad A, Javan MR, Rezaei N. PD-1/PD-L and autoimmunity: a growing relationship. Cell Immunol. 2016;310:27–41.

    CAS  PubMed  Article  Google Scholar 

  69. 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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  70. Kwon CW, Land AS, Smoller BR, Scott G, Beck LA, Mercurio MG. Bullous pemphigoid associated with nivolumab, a programmed cell death 1 protein inhibitor. J Eur Acad Dermatol Venereol. 2017. https://doi.org/10.1111/jdv.14143.

    Article  PubMed  Google Scholar 

  71. Sowerby L, Dewan AK, Granter S, Gandhi L, LeBoeuf NR. Rituximab treatment of nivolumab-induced bullous pemphigoid. JAMA Dermatol. 2017. https://doi.org/10.1001/jamadermatol.2017.0091.

    PubMed  Article  Google Scholar 

  72. Damsky W, Kole L, Tomayko MM. Development of bullous pemphigoid during nivolumab therapy. JAAD Case Rep. 2016;2:442–4.

    PubMed  PubMed Central  Article  Google Scholar 

  73. Rofe O, Bar-Sela G, Keidar Z, Sezin T, Sadik CD, Bergman R. Severe bullous pemphigoid associated with pembrolizumab therapy for metastatic melanoma with complete regression. Clin Exp Dermatol. 2017;42:309–12.

    CAS  PubMed  Article  Google Scholar 

  74. Russo I, Sacco G, Frega S, Polo V, Pasello G, Alaibac M. Immunotherapy-related skin toxicity: bullous pemphigoid in a lung adenocarcinoma patient treated with the anti-PDL1 antibody atezolizumab. Eur J Dermatol. 2017;27:205–8.

    PubMed  Google Scholar 

  75. Beck KM, Dong J, Geskin LJ, Beltrani VP, Phelps RG, Carvajal RD, et al. Disease stabilization with pembrolizumab for metastatic acral melanoma in the setting of autoimmune bullous pemphigoid. J Immunother Cancer. 2016;4:20.

    PubMed  PubMed Central  Article  Google Scholar 

  76. Brunet-Possenti F, Mignot S, Deschamps L, Descamps V. Antiepidermis autoantibodies induced by anti-PD-1 therapy in metastatic melanoma. Melanoma Res. 2016;26:540–3.

    CAS  PubMed  Article  Google Scholar 

  77. Sheik S, Goddard AL, Luke JJ, Donahue H, Todd DJ, Werchniak A, et al. Drug-induced dermatomyositis following ipilimumab therapy. JAMA Dermatol. 2015;151:195–9.

    Article  Google Scholar 

  78. Yamaguchi Y, Abe R, Haga N, Shimizu H. A case of drug-associated dermatomyositis following ipilimumab therapy. Eur J dermatol. 2016;26:320–1.

    CAS  PubMed  Google Scholar 

  79. Bilen MA, Subudhi SK, Gao J, Tannir NM, Tu SM, Sharma P. Acute rhabdomyolysis with severe polymyositis following ipilimumab-nivolumab treatment in a cancer patient with elevated anti-striated muscle antibody. J Immunother Cancer. 2016;4:36.

    PubMed  PubMed Central  Article  Google Scholar 

  80. Le burel S, Champiat S, Routier E, Aspeslagh S, Albiges L, Szwebel TA, et al. Onset of connective tissue disease following anti-PD-1/PD-L1 cancer immunotherapy. Ann Rheum Dis. 2017;76:43–50.

    Article  CAS  Google Scholar 

  81. Gambichler T, Strutzmann S, Tannapfel A, Susok L. Paraneoplastic acral vascular syndrome in a patient with metastatic melanoma under immune checkpoint blockade. BMC Cancer. 2017;17:327.

    PubMed  PubMed Central  Article  Google Scholar 

  82. Vigarios E, Epstein JB, Sibaud V. Oral mucosal changes induced by anticancer targeted therapies and immune checkpoint inhibitors. Support Care Cancer. 2017;25:1713–39.

    PubMed  Article  Google Scholar 

  83. Cappelli LC, Gutierrez AK, Baer AN, Albayda J, Manno RL, Haque U, et al. Inflammatory arthritis and sicca syndrome induced by nivolumab and ipilimumab. Ann Rheum Dis. 2017;76:43–50.

    CAS  PubMed  Article  Google Scholar 

  84. Cotliar J, Querfeld C, Boswell WJ, Raja N, Raz D, Chen R. Pembrolizumab-associated sarcoidosis. JAAD Case Rep. 2016;2:290–3.

    PubMed  PubMed Central  Article  Google Scholar 

  85. Suozzi KC, Stahl M, Ko CJ, Chiang A, Gettinger SN, Siegel MD, Bunick CG. Immune-related sarcoidosis observed in combination ipilimumab and nivolumab therapy. JAAD Case Rep. 2016;2:264–8.

    PubMed  PubMed Central  Article  Google Scholar 

  86. Berthod G, Lazor R, Letovanec I, Romano E, Noirez L, Mazza Stalder J, et al. Pulmonary sarcoid-like granulomatosis induced by ipilimumab. J Clin Oncol. 2012;30:e156–9.

    PubMed  Article  Google Scholar 

  87. Danlos FX, Pagès C, Baroudjian B, Vercellino L, Battistella M, Mimoun M, et al. Nivolumab-induced sarcoid-like granulomatous reaction in a patient with advanced melanoma. Chest. 2016;149:e133–6.

    PubMed  Article  Google Scholar 

  88. Kim C, Gao J, Shannon VR, Siefker-Radtke A. Systemic sarcoidosis first manifesting in a tattoo in the setting of immune checkpoint inhibition. BMJ Case Rep. 2016. https://doi.org/10.1136/bcr-2016-216217.

    Article  PubMed  PubMed Central  Google Scholar 

  89. Martínez Leboráns L, Esteve Martínez A, Victoria Martínez AM, Alegre de Miquel V, Berrocal Jaime A. Cutaneous sarcoidosis in a melanoma patient under ipilimumab therapy. Dermatol Ther. 2016;29:306–8.

    PubMed  Article  Google Scholar 

  90. Reule RB, North JP. Cutaneous and pulmonary sarcoidosis-like reaction associated with ipilimumab. J Am Acad Dermatol. 2013;69:e272–3.

    PubMed  Article  Google Scholar 

  91. Birnbaum MR, Ma MW, Fleisig S, Packer S, Amin BD, Jacobson M, McLellan B. Nivolumab-related cutaneous sarcoidosis in a patient with lung adenocarcinoma. JAAD Case Rep. 2017;3:208–11.

    PubMed  PubMed Central  Article  Google Scholar 

  92. Lomax AJ, McGuire HM, McNeil C, Choi CJ, Hersey P, Karikios D. Immunotherapy-induced sarcoidosis in patients with melanoma treated with PD-1 checkpoint inhibitors: case series and immunophenotypic analysis. Int J Rheum Dis. 2017. https://doi.org/10.1111/1756-185x.13076 (Epub ahead of print).

    PubMed  Article  Google Scholar 

  93. Celada LJ, Rotsinger JE, Young A, Shaginurova G, Shelton D, Hawkins C, et al. Programmed death-1 inhibition of phosphatidylinositol 3-kinase/AKT/mechanistic target of rapamycin signaling impairs sarcoidosis CD4+ T cell proliferation. Am J Respir Cell Mol Biol. 2017;56:74–82.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  94. Pintova S, Sidhu H, Friedlander PA, Holcombe RF. Sweet’s syndrome in a patient with metastatic melanoma after ipilimumab therapy. Melanoma Res. 2013;23:498–501.

    PubMed  Article  Google Scholar 

  95. Gormley R, Wanat K, Elenitsas R, Giles J, McGettigan S, Schuchter L, et al. Ipilimumab-associated Sweet syndrome in a melanoma patient. J Am Acad Dermatol. 2014;71:e211–3.

    PubMed  Article  Google Scholar 

  96. Kyllo RL, Parker MK, Rosman I, Musiek AC. Ipilimumab-associated Sweet syndrome in a patient with high-risk melanoma. J Am Acad Dermatol. 2014;70:e85–6.

    PubMed  Article  Google Scholar 

  97. 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;11:e0160221.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  98. Dika E, Ravaioli GM, Fanti PA, Piraccini BM, Lambertini M, Chessa MA, et al. Cutaneous adverse effects during ipilimumab treatment for metastatic melanoma: a prospective study. Eur J Dermatol. 2017;27:266–70.

    PubMed  Google Scholar 

  99. Garon EB, Rizvi NA, Hui R, Leighl N N, Balmanarkian AS, Eden JP, et al. Pembrolizumab for the treatment of non-small–cell lung cancer. N Engl J Med. 2015;372:2018–28.

    PubMed  Article  Google Scholar 

  100. McDermott DF, Sosman JA, Sznol M, Massard C, Gordon MS, Hamid O, et al. Atelizumab, an anti-programmed death-ligand 1 antibody, in metastatic renal cell carcinoma: long term safety, clinical activity, and immune correlates from a phase Ia study. J Clin Oncol. 2016;34:833–42.

    CAS  PubMed  Article  Google Scholar 

  101. Bousquet E, Zarbo A, Tournier E, Chevreau C, Mazieres J, Lacouture ME, et al. Development of papulopustular rosacea during nivolumab therapy for metastatic cancer. Acta Derm Venereol. 2017;97:539–40.

    PubMed  PubMed Central  Article  Google Scholar 

  102. Tetzlaff MT, Jazaeri AA, Torres-Cabala CA, Korivi BR, Landon GA, Nagarajan P, et al. Erythema-nodosum panniculitis mimicking disease recurrence: a novel toxicity from immune checkpoint blockade therapy. Report of two patients. J Cutan Pathol. 2017. https://doi.org/10.1111/cup.13044 (Epub ahead of print).

    Article  PubMed  Google Scholar 

  103. Freites-Martinez A, Kwong BY, Rieger KE, Coit DG, Colevas AD, Lacouture ME. Eruptive keratoacanthomas associated with pembrolizumab therapy. JAMA Dermatol. 2017;153:694–7.

    PubMed  PubMed Central  Article  Google Scholar 

  104. Sibaud V, David I, Lamant L, Resseguier S, Radut R, Attal J, et al. Acute skin reaction suggestive of pembrolizumab-induced radiosensitization. Melanoma Res. 2015;25:555–8.

    CAS  PubMed  Article  Google Scholar 

  105. Zarbo A, Belum VR, Sibaud V, Oudard S, Postow MA, Hsieh JJ, et al. Immune-related alopecia (areata and universalis) in cancer patients receiving immune checkpoint inhibitors. Br J Dermatol. 2017;176:1649–52.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  106. Rivera N, Boada A, Bielsa MI, Fernández-Figueras MT, Carcereny E, Moran MT, et al. Hair repigmentation during immunotherapy treatment with an anti-programmed cell death 1 and anti-programmed cell death ligand 1 agent for lung cancer. JAMA Dermatol. 2017. https://doi.org/10.1001/jamadermatol.2017.2106 (Epub ahead of print).

    PubMed  Article  PubMed Central  Google Scholar 

  107. Shenoy N, Esplin B, Barbosa N, Wieland C, Thanarajasingam U, Markovic S. Pembrolizumab induced severe sclerodermoid reaction. Ann Oncol. 2017;28:432–3.

    CAS  PubMed  Article  Google Scholar 

  108. Dasanu CA, Lippman SM, Plaxe SC. Persistently curly hair phenotype with the use of nivolumab for squamous cell lung cancer. J Oncol Pharm Pract. 2017;23:638–40.

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Acknowledgements

I thank Dr. Emilie Tournier and Prof. Laurence Lamant (Pathology Department, Cancer University Institute) for providing histopathology figures.

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Correspondence to Vincent Sibaud.

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The author has received consulting fees or honorarium from pharmaceutical companies (Bristol-Myers-Squibb, Pierre Fabre, Novartis, Roche, GSK).

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Sibaud, V. Dermatologic Reactions to Immune Checkpoint Inhibitors. Am J Clin Dermatol 19, 345–361 (2018). https://doi.org/10.1007/s40257-017-0336-3

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