Dermatological adverse events of immune checkpoint inhibitors

Dermatological adverse events of immune checkpoint inhibitors

Kevin Yang1, Khurram Yusuf2

1Dermatology, UAB School of Medicine, Birmingham, AL 35294
2Kendriya Vidyalaya, Jabalpur, MP 482004, India

Treatment with immune checkpoint inhibitors is a landmark in the treatment of melanoma and other cancers. These treatments have been very effective and have increased the survival of cancer patients. The promise of immunotherapy also comes with a variety of adverse events. One of the common sites of immune related adverse events (irAEs) is skin. The cutaneous irAEs present a unique challenge to the success of immunotherapy. It is important to diagnose and understand the mechanism related to these cutaneous irAEs to increase the effectiveness of immune checkpoint inhibitor therapy. In this review, we have characterized the various cutaneous irAEs associated with immune checkpoint inhibitor therapies and their possible mechanisms.

Keywords:checkpoint inhibitors, immunotherapy, adverse events

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How to cite this article:
Kevin Yang, Khurram Yusuf. Dermatological adverse events of immune checkpoint inhibitors.American Journal of Dermatological Research and Reviews, 2020, 3:33. DOI: 10.28933/ajodrr-2020-09-1805


1. O’Day SJ, Hamid O, Urba WJ. 2007. Targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4): a novel strategy for the treatment of melanoma and other malignancies, Cancer 110(12): 2614-27.
2. Fong L, Small EJ. 2008. Anti-cytotoxic T-lymphocyte antigen-4 antibody: the first in an emerging class of immunomodulatory antibodies for cancer treatment. J Clin Oncol. 26(32): 5275-83.
3. Zitvogel L, Kroemer G. 2012. Targeting PD-1/PD-L1 interactions for cancer immunotherapy, Oncoimmunology 1(8): 1223-5.
4. Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H et al. 2000. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation, J Exp Med. 192(7):1027-34.
5. Quirk SK, Shure AK, Agrawal DK. 2015. Immune-mediated adverse events of anticytotoxic T lymphocyte-associated antigen 4 antibody therapy in metastatic melanoma, Translational research : J Lab Clin Med. 166(5):412-24.
6. Sibaud V. 2018. Dermatologic Reactions to Immune Checkpoint Inhibitors : Skin Toxicities and Immunotherapy, Am J Clin Dermatol. 19(3):345-361.
7. Thebeau M, Rubin K, Hofmann M, Grimm J, Weinstein A, Choi JN. 2017. Management of skin adverse events associated with immune checkpoint inhibitors in patients with melanoma: A nursing perspective. J Am Assoc Nurse Pract 29(5):294-303.
8. Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, Hassel JC et al. 2015. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 372(4): 320-30.
9. Weber JS, Kahler KC, Hauschild A (2012). Management of immune-related adverse events and kinetics of response with ipilimumab, Am Soc Clin Oncol. 30(21):2691-7.
10. Curry JL, Tetzlaff MT, Nagarajan P, et al. 2017. Diverse types of dermatologic toxicities from immune checkpoint blockade therapy. J Cutan Pathol. 44(2):158-176.
11. Jaber SH, Cowen EW, Haworth LR, et al. 2006. Skin reactions in a subset of patients with stage IV melanoma treated with anti-cytotoxic T-lymphocyte antigen 4 monoclonal antibody as a single agent. Arch Dermatol. 142(2):166-172.
12. Geisler AN, Phillips GS, Barrios DM, et al. 2020. CME Part II: Immune checkpoint inhibitor-related dermatologic adverse events. J Am Acad Der-matol. S0190-9622(20)30963-4.
13. Sibaud V, Meyer N, Lamant L, Vigarios E, Mazi-eres J, Delord JP. 2016. Dermatologic compli-cations of anti-PD-1/PD-L1 immune checkpoint antibodies. Curr Opin Oncol. 28(4):254-263.
14. Sibaud V. 2018. Dermatologic reactions to im-mune checkpoint inhibitors: skin toxicities and immunotherapy. Am J Clin Dermatol. 2018;19(3):345-361.
15. Sanlorenzo M, Vujic I, Daud A, et al. 2015. Pem-brolizumab cutaneous adverse events and their association with disease progression. JAMA Dermatol. 151(11):1206-1212.
16. Tetzlaff MT, Nagarajan P, Chon S, et al. 2017. Lichenoid dermatologic toxicity from immune checkpoint blockade therapy: A detailed exami-nation of the clinicopathologic features. Am J Dermatopathol. 39(2):121-129.
17. Phillips GS, Wu J, Hellmann MD, et al. 2019. Treatment outcomes of immune-related cutane-ous adverse events. J Clin Oncol. 37(30):2746-2758.
18. Kaunitz GJ, Loss M, Rizvi H, et al. 2017. Cutane-ous eruptions in patients receiving immune checkpoint blockade: Clinicopathologic analysis of the nonlichenoid histologic pattern. Am J Surg Pathol. 41(10):1381-1389.
19. de Golian E, Kwong BY, Swetter SM, Pugliese SB. 2016. Cutaneous complications of targeted melanoma therapy. Curr Treat Options Oncol.17 (11):57.
20. Lacouture M, Sibaud V. 2018. Toxic side effects of targeted therapies and immunotherapies af-fecting the skin, oral mucosa, hair, and nails. Am J Clin Dermatol.19 (Suppl1):31-39.
21. Schaberg KB, Novoa RA, Wakelee HA, et al. 2016. Immunohistochemical analysis of lichenoid reactions in patients treated with anti-PD-L1 and anti-PD-1 therapy. J Cutan Pathol. 43:339-346.
22. Hua C, Boussemart L, Mateus C, et al. 2016. As-sociation of vitiligo with tumor response in pa-tients with metastatic melanoma treated with pembrolizumab. JAMA Dermatol. 152(1):45-51.
23. Teulings HE, Limpens J, Jansen SN, et al. 2015. Vitiligo-like depigmentation in patients with stage III-IV melanoma receiving immunotherapy and its association with survival: a systematic review and meta-analysis. J Clin Oncol. 33(7):773-781.
24. Quaglino P, Marenco F, Osella-Abate S, et al. 2010. Vitiligo is an independent favourable prognostic factor in stage III and IV metastatic melanoma patients: results from a single institu-tion hospital-based observational cohort study. Ann Oncol. 21(2):409-414.
25. Phillips GS, Wu J, Hellmann MD, et al. 2019. Treatment outcomes of immune-related cutane-ous adverse events. J Clin Oncol. 37 (30):2746-2758.
26. Larsabal M, Marti A, Jacquemin C, et al. 2017. Vitiligo-like lesions occurring in patients receiv-ing anti-programmed cell death-1 therapies are clinically and biologically distinct from vitiligo. J Am Acad Dermatol. 76(5):863-870.
27. Liu RC, Consuegra G, Chou S, Fernandez Penas P. 2019. Vitiligo-like depigmentation in oncology patients treated with immunotherapies for non-melanoma metastatic cancers. Clin Exp Derma-tol. 44(6):643-646.
28. Lolli C, Medri M, Ricci M, et al. 2018. Vitiligo-like lesions in a patient treated with nivolumab for re-nal cell carcinoma. Medicine (Baltimore). 97(52):e13810.
29. Anastasopoulou A, Papaxoinis G, Diamantopoulos P, Christofidou E, Benopoulou O, Stratigos A, Gogas H. 2018. Bullous pemphigoid-like skin lesions and overt eosinophilia in a patient with melanoma treated with nivolumab: case report and review of the literature, Journal of immunotherapy (Hagerstown, Md. : 1997) 41(3) :164-167.
30. Lomax AJ, Ge L, Anand S, McNeil C, Lowe P. 2016. Bullous pemphigoid-like reaction in a patient with metastatic melanoma receiving pembrolizumab and previously treated with ipilimumab, The Austral J Dermatol. 57(4):333-335.
31. Parakh S, Nguyen R, Opie JM, Andrews MC. 2017. Late presentation of generalised bullous pemphigoid-like reaction in a patient treated with pembrolizumab for metastatic melanoma. Australas J Dermatol. 58(3):e109-e112.
32. Sowerby L, Dewan AK, Granter S, Gandhi L, LeBoeuf NR (2017). Rituximab treatment of nivolumab-induced bullous pemphigoid. JAMA Dermatol. 153(6) : 603-605.
33. Ridpath AV, Rzepka PV, Shearer SM, Scrape SR, Olencki TE, Kaffenberger BH. 2018. Novel use of combination therapeutic plasma exchange and rituximab in the treatment of nivolumab-induced bullous pemphigoid. Int J Dermatol. 57 (11):1372-1374.
34. Naidoo J, Schindler K, Querfeld C, Busam K, Cunningham J, Page DB et al. 2016. Autoimmune bullous skin disorders with immune checkpoint inhibitors targeting PD-1 and PD-L1, Cancer Immunol Res. 4(5): 383-9.
35. Chen WS, Tetzlaff MT, Diwan H, Jahan-Tigh R, Diab A, Nelson K et al. 2018. Suprabasal acantholytic dermatologic toxicities associated checkpoint inhibitor therapy: A spectrum of immune reactions from paraneoplastic pemphigus-like to Grover-like lesions, J Cutaneous Pathol. 45(10):764-773.
36. Lopez AT, Khanna T, Antonov N, Audrey-Bayan C, Geskin L. 2018. A review of bullous pemphi-goid associated with PD-1 and PD-L1 inhibitors. Int J Dermatol. 57(6):664-669.
37. Barbosa NS, Wetter DA, Wieland CN, Shenoy NK, Markovic SN, Thanarajasingam U. 2017. Scleroderma Induced by Pembrolizumab: A Case Series. Mayo Clin Proc. 92(7):1158-1163.
38. Tjarks BJ, Kerkvliet AM, Jassim AD, Bleeker JS. 2018. Scleroderma-like skin changes induced by checkpoint inhibitor therapy, J Cutaneous Pathol. 45(8):615-618.
39. Naidoo J, Page DB, Li BT et al. 2015. Toxicities of the anti‐PD‐1 and anti‐PD‐L1 immune check-point antibodies. Ann Oncol. 26: 2375– 91.
40. Belum VR, Benhuri B, Postow MA et al. 2016. Characterization and management of dermato-logic adverse events to agents targeting the PD‐1 receptor. Eur J Cancer. 60: 12-25.
41. Zarbo A, Belum VR, Sibaud V, et al. 2017. Im-mune-related alopecia (areata and universalis) in cancer patients receiving immune checkpoint in-hibitors. Br J Dermatol. 176(6):1649-1652.
42. Nishimura H, Nose M, Hiai H, Minato N, Honjo T. 1999. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encod-ing an ITIM motif-carrying immunorecep-tor. Immunity. 11: 141–151.
43. Ceeraz S, Nowak EC, Burns CM, Noelle RJ. 2014. Immune checkpoint receptors in regulating im-mune reactivity in rheumatic disease. Arthritis Res Ther. 16, 1–12.
44. Lu K.-L, Wu M.-Y, Wang C.-H, Wang C.-H, Hung H.-L, Cung W.-H, Chen C.-B. 2019. The role of immune checkpoint receptors in regulating im-mune reactivity in lupus. Cells 8, 1213.
45. Arnaud L, Lebrun-Vignes B, Salem J.-E. 2019. Checkpoint inhibitor-associated immune arthri-tis. Ann Rheum Dis. 78, e68.
46. Ruiz-Banobre J, Abdulkader I, Anido U, Leon L, Lopez-Lopez R, Garcia-Gonzalez J. 2017. Development of de novo psoriasis during nivolumab therapy for metastatic renal cell carcinoma: immunohistochemical analyses and clinical outcome. APMIS 125(3):259-263.
47. Chia PL, John T. 2016. Severe psoriasis flare after anti-programmed death ligand 1 (PD-L1) therapy for metastatic non-small cell lung cancer (NSCLC). J Immunother (Hagerstown, Md. : 1997) 39(5):202-4.
48. Phadke SD, Ghabour R, Swick BL, Swenson A, Milhem M, Zakharia Y. 2016. Pembrolizumab therapy triggering an exacerbation of preexisting autoimmune disease: a report of 2 patient cases. J Investig Med High Impact Case Rep. 4(4):2324709616674316.
49. Johnson DB, Sullivan RJ, Ott PA, Carlino MS, Khushalani NI, Ye F et al. 2016. Ipilimumab therapy in patients with advanced melanoma and preexisting autoimmune disorders. JAMA Oncol. 2(2):234-40.
50. Bonigen J, Raynaud-Donzel C, Hureaux J, Kramkimel N, Blom A, Jeudy G et al. 2017. Anti-PD1-induced psoriasis: a study of 21 patients. JEADV 31(5):e254-e257.
51. Voudouri D, Nikolaou V, Laschos K, Charpidou A, Soupos N, Triantafyllopoulou I et al. 2017. Anti-PD1/PDL1 induced psoriasis, Curr Prob Cancer 41(6) : 407-412.
52. Bronstein Y, Ng CS, Hwu P, Hwu WJ. 2011. Radiologic manifestations of immune-related adverse events in patients with metastatic melanoma undergoing anti-CTLA-4 antibody therapy. AJR Am J Roentgenol. 197(6):W992-w1000.
53. Tirumani SH, Ramaiya NH, Keraliya A, Bailey ND, Ott PA, Hodi FS. Et al. 2015. Radiographic profiling of immune-related adverse events in advanced melanoma patients treated with ipilimumab, Cancer Immunol Res. 3(10): 1185-92.
54. Birnbaum MR, Ma MW, Fleisig S, Packer S, Amin BD, Jacobson M, McLellan BN. 2017. Nivolumab-related cutaneous sarcoidosis in a patient with lung adenocarcinoma, JAAD Case Reports 3(3):208-211.
55. Firwana B, Ravilla R, Raval M, Hutchins L, Mahmoud F. 2017. Sarcoidosis-like syndrome and lymphadenopathy due to checkpoint inhibitors, J Oncol Pharm Pract. 23(8):620-624.
56. Danlos FX, Pages C, Baroudjian B, Vercellino L, Battistella M, Mimoun M et al. 2016. Nivolumab-induced sarcoid-like granulomatous reaction in a patient with advanced melanoma. Chest 149(5):e133-6.
57. Yatim N, Mateus C, Charles P. 2018. Sarcoidosis post-anti-PD-1 therapy, mimicking relapse of metastatic melanoma in a patient undergoing complete remission, La Revue de medecine interne 39(2):130-133.
58. Gantz M, Butler D, Goldberg M, Ryu J, McCalmont T, Shinkai K. 2017. Atypical features and systemic associations in extensive cases of Grover disease: a systematic review. J Am Acad Dermatol. 77:952–7.
59. Vastarella M, Fabbrocini G, Sibaud V. 2020. Hy-perkeratotic skin adverse events induced by an-ticancer treatments: a comprehensive re-view. Drug Saf. 43(5):395-408.
60. Collins LK, Chapman MS, Carter JB, Samie FH. 2017. Cutaneous adverse effects of the immune checkpoint inhibitors. Curr Probl Cancer. 41(2):125-128.
61. Coleman EL, Olamiju B, Leventhal JS. The life-threatening eruptions of immune checkpoint in-hibitor therapy. Clin Dermatol. 2020;38(1):94-104.
62. Hwang A, Iskandar A, Dasanu A. 2019. Stevens-Johnson Syndrome manifesting late in the course of pembrolizumab therapy. J Oncol Pharm Pract. 25 (6): 1520-1522.
63. Saw S, Lee HY, Ng QS. 2017. Pembrolizumab-induced Stevens-Johnson syndrome in non-melanoma patients. Eur J Cancer, 81:237-239
64. Wei SC, Levine JH, Cogdill AP, Zhao Y, Anang NAS, Andrews MC et al. 2017. Distinct cellular mechanisms underlie anti-CTLA-4 and anti-PD-1 checkpoint blockade. Cell 170(6):1120-1133.e17.
65. Postow MA, Sidlow R, Hellmann MD. 2018. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med. 378(2) :158-168.
66. Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD. et al. 2015. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 373(1) : 23-34.
67. Barber DL, Wherry EJ, Masopust D et al. 2006. Restoring function in exhausted CD8 T cells dur-ing chronic viral infection. Nature. 439(7077):682-687.
68. Osorio JC, Ni A, Chaft JE, et al. 2017. Antibody-mediated thyroid dysfunction during T-cell checkpoint blockade in patients with non-small-cell lung cancer. Ann Oncol. 28(3):583-589.
69. Terme M. et al. 2011. IL-18 induces PD-1-dependent immunosuppression in can-cer. Cancer Res. 71:5393–5399.
70. Fanoni D, et al. 2011. New monoclonal antibod-ies against B-cell antigens: possible new strate-gies for diagnosis of primary cutaneous B-cell lymphomas. Immunol Lett. 134:157–160.
71. Velu V, et al. 2009. Enhancing SIV-specific im-munity in vivo by PD-1 blockade. Nature. 458:206–210.
72. Pardoll DM. 2012. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 12(4):252-264.