Published date: Sep 16 2024

Journal Title: Journal of Ophthalmic and Vision Research

Issue title: July–Sep 2024, Volume 19, Issue 3

Pages: 368–380

DOI: 10.18502/jovr.v19i3.15047

Zahra Souri - z.souri@bio.ui.ac.ir - https://orcid.org/0000-0003-2800-8998

Farzad Pakdel - fapakdel@gmail.com - https://orcid.org/0000-0001-7392-6056

Immune checkpoints (ICPs) are essential regulators of the immune system, ensuring a delicate balance between self-tolerance and autoimmune responses. ICP therapy is a rapidly growing cancer treatment strategy that inhibits the interaction between ICPs and their ligands. This biological interaction increases the ability of the immune system in combating cancer. However, in some cases, the use of these agents may lead to immune hyperactivity and, subsequently, autoimmune diseases. Graves’ disease (GD), thyroid eye disease (TED), and orbital myopathy are complex autoimmune disorders characterized by the production of autoantibodies. The emergence of these treatment-related adverse events underscore the critical need for a deeper understanding of the immune-checkpoint axis in autoimmune diseases. In this review article, we provide a comprehensive survey of the biological mechanisms of ICPs that are most frequently targeted in cancer therapy, including CTLA-4, PD-1, PDL-1, and LAG3. Furthermore, we investigate the latest scientific findings on the adverse events associated with the inhibition of these ICPs. This paper will particularly focus on the potential risks these complications pose to ocular and orbital tissues, which are a concern in the context of cancer treatment.

1. Tison A, Garaud S, Chiche L, Cornec D, Kostine M. Immune-checkpoint inhibitor use in patients with cancer and pre-existing autoimmune diseases. Nat Rev Rheumatol 2022;18:641–656.

2. Ibis B, Aliazis K, Cao C, Yenyuwadee S, Boussiotis VA. Immune-related adverse effects of checkpoint immunotherapy and implications for the treatment of patients with cancer and autoimmune diseases. Front Immunol 2023;14:1197364.

3. Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science 2018;359:1350–1355.

4. Souri Z, Wierenga AP, Kroes WG, van der Velden PA, Verdijk RM, Eikmans M, et al. LAG3 and its ligands show increased expression in high-risk uveal melanoma. Cancers (Basel) 2021;13:4445–4457.

5. Johnson DB, Nebhan CA, Moslehi JJ, Balko JM. Immunecheckpoint inhibitors: Long-term implications of toxicity. Nat Rev Clin Oncol 2022;19:254–267.

6. Yokoyama R, Sato Y, Nakamura F, Kagemoto K, Mitsui Y, Okamoto K, et al. Efficacy of immune checkpoint inhibitors in patients with anorectal melanoma in association with immune-related adverse events: A case series. Clin J Gastroenterol 2023;16:842–847.

7. Thomas B, Burns M, Pervanas H, Ciurescu D, Dima L. Nivolumab/relatlimab-rmbw: A novel dual combination therapy to treat adult and pediatric patients with unresectable or metastatic melanoma. Am J Ther 2023;30:e526–34.

8. Huber RM. Neoadjuvant therapy with immune checkpoint inhibitors in operable nonsmall cell lung cancer. Curr Opin Oncol 2024;36:29–34.

9. Esfahani K, Meti N, Miller WH Jr, Hudson M. Adverse events associated with immune checkpoint inhibitor treatment for cancer. CMAJ 2019;191:E40–6.

10. Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, et al.; KEYNOTE-006 investigators. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med 2015;372:2521–2532.

11. Weber JS, Kähler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol 2012;30:2691–2697.

12. Owen CN, Bai X, Quah T, Lo SN, Allayous C, Callaghan S, et al. Delayed immune-related adverse events with anti-PD-1-based immunotherapy in melanoma. Ann Oncol 2021;32:917–925.

13. Sagiv O, Kandl TJ, Thakar SD, Thuro BA, Busaidy NL, Cabanillas M, et al. Extraocular muscle enlargement and thyroid eye disease-like orbital inflammation associated with immune checkpoint inhibitor therapy in cancer patients. Ophthalmic Plast Reconstr Surg 2019;35:50–52.

14. Horisberger K, Portenkirchner C, Rickenbacher A, Biedermann L, Gubler C, Turina M. Long-term immune-related adverse events after discontinuation of immunotherapy. Immunotherapy 2021;13:735–740.

15. Byun DJ, Wolchok JD, Rosenberg LM, Girotra M. Cancer immunotherapy - Immune checkpoint blockade and associated endocrinopathies. Nat Rev Endocrinol 2017;13:195–207.

16. Barroso-Sousa R, Barry WT, Garrido-Castro AC, Hodi FS, Min L, Krop IE, et al. Incidence of endocrine dysfunction following the use of different immune checkpoint inhibitor regimens: A systematic review and meta-analysis. JAMA Oncol 2018;4:173–182.

17. Muir CA, Clifton-Bligh RJ, Long GV, Scolyer RA, Lo SN, Carlino MS, et al. Thyroid immune-related adverse events following immune checkpoint inhibitor treatment. J Clin Endocrinol Metab 2021;106:e3704–13.

18. Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Lao CD, et al. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med 2019;381:1535–1546.

19. de Filette J, Andreescu CE, Cools F, Bravenboer B, Velkeniers B. A systematic review and meta-analysis of endocrine-related adverse events associated with immune checkpoint inhibitors. Horm Metab Res 2019;51:145–156.

20. Dyck L, Mills KH. Immune checkpoints and their inhibition in cancer and infectious diseases. Eur J Immunol 2017;47:765–779.

21. Brunet JF, Denizot F, Luciani MF, Roux-Dosseto M, Suzan M, Mattei MG, et al. A new member of the immunoglobulin superfamily—CTLA-4. Nature 1987;328:267–270.

22. Brunner MC, Chambers CA, Chan FK, Hanke J, Winoto A, Allison JP. CTLA-4-mediated inhibition of early events of T cell proliferation. J Immunol 1999;162:5813–5820.

23. Tivol EA, Borriello F, Schweitzer AN, Lynch WP, Bluestone JA, Sharpe AH. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 1995;3:541–547.

24. Linsley PS, Greene JL, Brady W, Bajorath J, Ledbetter JA, Peach R. Human B7-1 (CD80) and B7-2 (CD86) bind with similar avidities but distinct kinetics to CD28 and CTLA-4 receptors. Immunity 1994;1:793–801.

25. van der Merwe PA, Bodian DL, Daenke S, Linsley P, Davis SJ. CD80 (B7-1) binds both CD28 and CTLA-4 with a low affinity and very fast kinetics. J Exp Med 1997;185:393– 403.

26. Schwartz JC, Zhang X, Fedorov AA, Nathenson SG, Almo SC. Structural basis for co-stimulation by the human CTLA- 4/B7-2 complex. Nature 2001;410:604–608.

27. Linsley PS, Bradshaw J, Greene J, Peach R, Bennett KL, Mittler RS. Intracellular trafficking of CTLA-4 and focal localization towards sites of TCR engagement. Immunity 1996;4:535–543.

28. Egen JG, Allison JP. Cytotoxic T lymphocyte antigen-4 accumulation in the immunological synapse is regulated by TCR signal strength. Immunity 2002;16:23–35.

29. Read S, Greenwald R, Izcue A, Robinson N, Mandelbrot D, Francisco L, et al. Blockade of CTLA-4 on CD4+CD25+ regulatory T cells abrogates their function in vivo. J Immunol 2006;177:4376–4383.

30. Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 2000;192:1027–1034.

31. Latchman Y, Wood CR, Chernova T, Chaudhary D, Borde M, Chernova I, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol 2001;2:261–268.

32. Loke P, Allison JP. PD-L1 and PD-L2 are differentially regulated by Th1 and Th2 cells. Proc Natl Acad Sci USA 2003;100:5336–5341.

33. Kisielow M, Kisielow J, Capoferri-Sollami G, Karjalainen K. Expression of lymphocyte activation gene 3 (LAG-3) on B cells is induced by T cells. Eur J Immunol 2005;35:2081– 2088.

34. Triebel F, Jitsukawa S, Baixeras E, Roman-Roman S, Genevee C, Viegas-Pequignot E, et al. LAG-3, a novel lymphocyte activation gene closely related to CD4. J Exp Med 1990;171:1393–1405.

35. Baixeras E, Huard B, Miossec C, Jitsukawa S, Martin M, Hercend T, et al. Characterization of the lymphocyte activation gene 3-encoded protein. A new ligand for human leukocyte antigen class II antigens. J Exp Med 1992;176:327–337.

36. Huard B, Tournier M, Hercend T, Triebel F, Faure F. Lymphocyte-activation gene 3/major histocompatibility complex class II interaction modulates the antigenic response of CD4+ T lymphocytes. Eur J Immunol 1994;24:3216–3221.

37. Huard B, Mastrangeli R, Prigent P, Bruniquel D, Donini S, El-Tayar N, et al. Characterization of the major histocompatibility complex class II binding site on LAG-3 protein. Proc Natl Acad Sci USA 1997;94:5744–5749.

38. Souri Z, Wierenga AP, Mulder A, Jochemsen AG, Jager MJ. HLA expression in uveal melanoma: An indicatorof malignancy and a modifiable immunological target. Cancers (Basel) 2019;11:1132.

39. Souri Z, Wierenga AP, van Weeghel C, van der Velden PA, Kroes WG, Luyten GP, et al. Loss of BAP1 is associated with upregulation of the NFkB pathway and increased HLA class I expression in uveal melanoma. Cancers (Basel) 2019;11:1102.

40. Souri Z, Jochemsen AG, Versluis M, Wierenga AP, Nemati F, van der Velden PA, et al. HDAC inhibition increases HLA class I expression in uveal melanoma. Cancers (Basel) 2020;12:3690.

41. Guy C, Mitrea DM, Chou PC, Temirov J, Vignali KM, Liu X, et al. LAG3 associates with TCR-CD3 complexes and suppresses signaling by driving co-receptor-Lck dissociation. Nat Immunol 2022;23:757–767.

42. Chung LY, Tang SJ, Wu YC, Sun GH, Liu HY, Sun KH. Galectin-3 augments tumor initiating property and tumorigenicity of lung cancer through interaction with β- catenin. Oncotarget 2015;6:4936–4952.

43. Wang J, Sanmamed MF, Datar I, Su TT, Ji L, Sun J, et al. Fibrinogen-like protein 1 is a major immune inhibitory ligand of LAG-3. Cell 2019;176:334–347.e12.

44. Bae J, Lee SJ, Park CG, Lee YS, Chun T. Trafficking of LAG-3 to the surface on activated T cells via its cytoplasmic domain and protein kinase C signaling. J Immunol 2014;193:3101–3112.

45. Nagasaki J, Togashi Y. A variety of ‘exhausted’ T cells in the tumor microenvironment. Int Immunol 2022;34:563– 570.

46. Banerjee S, Nahar U, Dahiya D, Mukherjee S, Dey P, Gupta R, et al. Role of cytotoxic T cells and PD-1 immune checkpoint pathway in papillary thyroid carcinoma. Front Endocrinol (Lausanne) 2022;13:931647.

47. Vaddepally RK, Kharel P, Pandey R, Garje R, Chandra AB. Review of indications of FDA-approved immune checkpoint inhibitors per NCCN guidelines with the level of evidence. Cancers (Basel) 2020;12:738.

48. Korman AJ, Garrett-Thomson SC, Lonberg N. The foundations of immune checkpoint blockade and the ipilimumab approval decennial. Nat Rev Drug Discov 2022;21:509–528.

49. Guo Z, Zhang R, Yang AG, Zheng G. Diversity of immune checkpoints in cancer immunotherapy. Front Immunol 2023;14:1121285.

50. Kamali AN, Bautista JM, Eisenhut M, Hamedifar H. Immune checkpoints and cancer immunotherapies: Insights into newly potential receptors and ligands. Ther Adv Vaccines Immunother 2023;11:25151355231192043.

51. Chalan P, Di Dalmazi G, Pani F, De Remigis A, Corsello A, Caturegli P. Thyroid dysfunctions secondary to cancer immunotherapy. J Endocrinol Invest 2018;41:625–638.

52. Kotwal A, Kottschade L, Ryder M. PD-L1 inhibitor-induced thyroiditis is associated with better overall survival in cancer patients. Thyroid 2020;30:177–184.

53. Zhou N, Velez MA, Bachrach B, Gukasyan J, Fares CM, Cummings AL, et al. Immune checkpoint inhibitor induced thyroid dysfunction is a frequent event post-treatment in NSCLC. Lung Cancer 2021;161:34–41.

54. Arnaud-Coffin P, Maillet D, Gan HK, Stelmes JJ, You B, Dalle S, et al. A systematic review of adverse events in randomized trials assessing immune checkpoint inhibitors. Int J Cancer 2019;145:639–648.

55. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010;363:711–723.

56. Motzer RJ, Rini BI, McDermott DF, Redman BG, Kuzel TM, Harrison MR, et al. Nivolumab for metastatic renal cell carcinoma: Results of a randomized phase II trial. J Clin Oncol 2015;33:1430–1437.

57. Robert C, Ribas A, Wolchok JD, Hodi FS, Hamid O, Kefford R, et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: A randomised dose-comparison cohort of a phase 1 trial. Lancet 2014;384:1109–1117.

58. Min L, Vaidya A, Becker C. Thyroid autoimmunity and ophthalmopathy related to melanoma biological therapy. Eur J Endocrinol 2011;164:303–307.

59. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012;366:2443–2454.

60. Topalian SL, Sznol M, McDermott DF, Kluger HM, Carvajal RD, Sharfman WH, et al. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol 2014;32:1020–1030.

61. Ryder M, Callahan M, Postow MA, Wolchok J, Fagin JA. Endocrine-related adverse events following ipilimumab in patients with advanced melanoma: A comprehensive retrospective review from a single institution. Endocr Relat Cancer 2014;21:371–381.

62. 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;372:320–330.

63. 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.

64. Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, et al.; KEYNOTE-001 Investigators. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 2015;372:2018–2028.

65. 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;366:2455–2465.

66. McDermott DF, Sosman JA, Sznol M, Massard C, Gordon MS, Hamid O, et al. Atezolizumab, an anti–programmed death-ligand 1 antibody, in metastatic renal cell carcinoma: Long-term safety, clinical activity, and immune correlates from a phase I a study. J Clin Oncol 2016;34:833–842.

67. Tawbi HA, Schadendorf D, Lipson EJ, Ascierto PA, Matamala L, Castillo Gutiérrez E, et al.; RELATIVITY- 047 Investigators. Relatlimab and nivolumab versus nivolumab in untreated advanced melanoma. N Engl J Med 2022;386:24–34.

68. Sukik A, Mohamed S, Habib MB, Sardar S, Tanous B, Tahtouh R, et al. The unusual late-onset graves’ disease following Hashimoto’s related hypothyroidism: A case report and literature review. Case Rep Endocrinol 2020;2020:5647273.

69. Bartalena L, Piantanida E, Gallo D, Ippolito S, Tanda ML. Management of Graves’ hyperthyroidism: Present and future. Expert Rev Endocrinol Metab 2022;17:153–166.

70. Nabi M, Noor R, Zahid A, Zulfiqar T, Khalid A, Ri S. Grave’s disease: Pathophysiology of a model autoimmune disease. Arch Microbiol 2022;6:149–164.

71. Ueda H, Howson JM, Esposito L, Heward J, Snook H, Chamberlain G, et al. Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 2003;423:506–511.

72. Han S, Zhang S, Zhang W, Li R, Li Y, Wang Z, et al. CTLA4 polymorphisms and ophthalmopathy in Graves’ disease patients: association study and meta-analysis. Hum Immunol 2006;67:618–626.

73. Takahashi M, Kimura A. HLA and CTLA4 polymorphisms may confer a synergistic risk in the susceptibility to Graves’ disease. J Hum Genet 2010;55:323–326.

74. Borodic G, Hinkle DM, Cia Y. Drug-induced graves disease from CTLA-4 receptor suppression. Ophthalmic Plast Reconstr Surg 2011;27:e87–8.

75. Azmat U, Liebner D, Joehlin-Price A, Agrawal A, Nabhan F. Treatment of ipilimumab induced Graves’ disease in a patient with metastatic melanoma. Case Rep Endocrinol 2016;2016:2087525.

76. Gan EH, Mitchell AL, Plummer R, Pearce S, Perros P. Tremelimumab-induced Graves hyperthyroidism. Eur Thyroid J 2017;6:167–170.

77. Brancatella A, Viola N, Brogioni S, Montanelli L, Sardella C, Vitti P, et al. Graves’ disease induced by immune checkpoint inhibitors: A case report and review of the literature. Eur Thyroid J 2019;8:192–195.

78. Yamada H, Okajima F, Onda T, Fujimori S, Emoto N, Sugihara H. New-onset graves’ disease after the initiation of nivolumab therapy for gastric cancer: A case report. BMC Endocr Disord 2020;20:132.

79. Moore GH, Rootman DB. Orbital inflammatory disease management. Expert Rev Ophthalmol 2016;11:415–428.

80. Ludgate M, Baker G. Unlocking the immunological mechanisms of orbital inflammation in thyroid eye disease. Clin Exp Immunol 2002;127:193–198.

81. Bawazeer A, Rahali W, Alsharif A, Alshehri M, Maksood L, Babkier A, et al. Idiopathic orbital inflammation treated with rituximab monotherapy. Cureus 2023;15:e33614.

82. Srivastava A, Al-Zubidi N, Appelbaum E, Gombos DS, Nader ME, Gidley PW, et al. Immune-related oral, otologic, and ocular adverse events. Adv Exp Med Biol 2020;1244:295–307.

83. Gan L, Chen H, Liu X, Zhang L. Ophthalmic immune-related adverse events associated with immune checkpoint inhibitors. Front Immunol 2023;14:1130238.

84. Mohammadi P, Hesari M, Chalabi M, Salari F, Khademi F. An overview of immune checkpoint therapy in autoimmune diseases. Int Immunopharmacol 2022;107:108647.

85. Bahn RS. Graves’ ophthalmopathy. N Engl J Med 2010;362:726–738.

86. Bartalena L, Fatourechi V. Extrathyroidal manifestations of Graves’ disease: A 2014 update. J Endocrinol Invest 2014;37:691–700.

87. Chin YH, Ng CH, Lee MH, Koh JW, Kiew J, Yang SP, et al. Prevalence of thyroid eye disease in Graves’ disease: A meta-analysis and systematic review. Clin Endocrinol (Oxf) 2020;93:363–374.

88. Ueland HO, Neset MT, Methlie P, Ueland GÅ, Pakdel F, Rødahl E. Molecular biomarkers in thyroid eye disease: A literature review. Ophthalmic Plast Reconstr Surg 2023;39:S19–S28.

89. Tanda ML, Piantanida E, Liparulo L, Veronesi G, Lai A, Sassi L, et al. Prevalence and natural history of Graves’ orbitopathy in a large series of patients with newly diagnosed graves’ hyperthyroidism seen at a single center. J Clin Endocrinol Metab 2013;98:1443–1449.

90. Hiromatsu Y, Eguchi H, Tani J, Kasaoka M, Teshima Y. Graves’ ophthalmopathy: Epidemiology and natural history. Intern Med 2014;53:353–360.

91. Ionescu IC, van Trotsenburg PA, Paridaens D, Tanck M, Mooij CF, Cagienard E, et al. Pediatric Graves’ orbitopathy: A multicentre study. Acta Ophthalmol 2022;100:e1340–8.

92. Kahaly GJ, Petrak F, Hardt J, Pitz S, Egle UT. Psychosocial morbidity of Graves’ orbitopathy. Clin Endocrinol (Oxf) 2005;63:395–402.

93. Potvin AR, Pakdel F, Saeed P. Dysthyroid optic neuropathy. Ophthalmic Plast Reconstr Surg 2023;39:S65–S80.

94. Kashkouli MB, Alemzadeh SA, Aghaei H, Pakdel F, Abdolalizadeh P, Ghazizadeh M, et al. Subjective versus objective dry eye disease in patients with moderatesevere thyroid eye disease. Ocul Surf 2018;16(4):458–462.

95. Pakdel F, Sullivan TJ, Pirmarzdashti N. Pathophysiology of autoimmune orbital diseases and target therapy for orbital inflammatory and neoplastic diseases. Transl Autoimmun 2022;4:105–120.

96. Bartalena L, Baldeschi L, Dickinson AJ, Eckstein A, Kendall-Taylor P, Marcocci C, et al. Consensus statement of the European group on Graves’ orbitopathy (EUGOGO) on management of Graves’ orbitopathy. Thyroid 2008;18:333–346.

97. Kashkouli MB, Heidari I, Pakdel F, Jam S, Honarbakhsh Y, Mirarmandehi B. Change in quality of life after medical and surgical treatment of graves’ ophthalmopathy. Middle East Afr J Ophthalmol 2011;18:42–47.

98. Bahmani-Kashkouli M, Pakdel F, Astaraki A, Hashemi M, Honarbakhsh Y, Mirarmandehi B, et al. Quality of life in patients with thyroid eye disease. J Ophthalmic Vis Res 2009;4:164–168.

99. Kashkouli MB, Kaghazkanani R, Heidari I, Ketabi N, Jam S, Azarnia S, et al. Bilateral versus unilateral thyroid eye disease. Indian J Ophthalmol 2011;59:363–366.

100. Pakdel F, Ghazavi R, Heidary R, Nezamabadi A, Parvizi M, Haji Safar Ali Memar M, et al. Effect of selenium on thyroid disorders: Scientometric Analysis. Iran J Public Health 2019;48:410–420.

101. Barrio-Barrio J, Sabater AL, Bonet-Farriol E, Velázquez- Villoria Á, Galofré JC. Graves’ ophthalmopathy: VISA versus EUGOGO classification, assessment, and management. J Ophthamol 2015;2015:249125.

102. Ban Y, Davies TF, Greenberg DA, Kissin A, Marder B, Murphy B, et al. Analysis of the CTLA-4, CD28, and inducible costimulator (ICOS) genes in autoimmune thyroid disease. Genes Immun 2003;4:586–593.

103. Goyal I, Pandey MR, Sharma R, Chaudhuri A, Dandona P. The side effects of immune checkpoint inhibitor therapy on the endocrine system. Indian J Med Res 2021;154:559– 570.

104. McElnea E, Ní Mhéalóid Á, Moran S, Kelly R, Fulcher T. Thyroid-like ophthalmopathy in a euthyroid patient receiving Ipilimumab. Orbit 2014;33:424–427.

105. Dalvin LA, Shields CL, Orloff M, Sato T, Shields JA. Checkpoint inhibitor immune therapy: Systemic indications and ophthalmic side effects. Retina 2018;38:1063–1078.

106. Liu Z, Liu Y, Liu M, Gong Q, Shi A, Li X, et al. PD-L1 inhibits T cell-induced cytokines and hyaluronan expression via the CD40-CD40L pathway in orbital fibroblasts from patients with thyroid associated ophthalmopathy. Front Immunol 2022;13:849480.

107. Berrih-Aknin S, Frenkian-Cuvelier M, Eymard B. Diagnostic and clinical classification of autoimmune myasthenia gravis. J Autoimmun 2014;48–49:143–148.

108. Dresser L, Wlodarski R, Rezania K, Soliven B. Myasthenia gravis: Epidemiology, pathophysiology and clinical manifestations. J Clin Med 2021;10:2235.

109. Virameteekul S, Charoensri S, Sawanyawisuth K, Tiamkao S. Concurrence of myasthenia gravis and thyroid disorders: A retrospective database study. J ASEAN Fed Endocr Soc 2019;34:153–157.

110. Amin S, Aung M, Gandhi FR, Pena Escobar JA, Gulraiz A, Malik BH. Myasthenia gravis and its association with thyroid diseases. Cureus 2020;12:e10248.

111. Masood I, Yasir M, Aiman A, Kudyar RP. Autoimmune thyroid disease with myasthenia gravis in a 28-year-old male: A case report. Cases J 2009;2:8766.

112. Mangaraj S, Choudhury AK, Mohanty BK, Baliarsinha AK. Neurological manifestations of Graves’ disease: A case report and review of the literature. J Neurosci Rural Pract 2016;7:153–156.

113. Salhi H, Ajdi F. [Hypothyroidism and myasthenia: A case study]. Pan Afr Med J 2019;34:59.

114. Becquart O, Lacotte J, Malissart P, Nadal J, Lesage C, Guillot B, et al. Myasthenia gravis induced by immune checkpoint inhibitors. J Immunother 2019;42:309–312.

115. Suzuki S, Ishikawa N, Konoeda F, Seki N, Fukushima S, Takahashi K, et al. Nivolumab-related myasthenia gravis with myositis and myocarditis in Japan. Neurology 2017;89:1127–1134.

116. Maeda O, Yokota K, Atsuta N, Katsuno M, Akiyama M, Ando Y. Nivolumab for the treatment of malignant melanoma in a patient with pre-existing myasthenia gravis. Nagoya J Med Sci 2016;78:119–122.

117. Dugena O, Zheng C, Taylor J, Wong A. Pembrolizumabinduced myasthenia gravis: literature review of ocular manifestations and a refractory case. J Immunother 2022;45:267–273.

118. Kamo H, Hatano T, Kanai K, Aoki N, Kamiyama D, Yokoyama K, et al. Pembrolizumab-related systemic myositis involving ocular and hindneck muscles resembling myasthenic gravis: A case report. BMC Neurol 2019;19:184.

119. Liu Q, Ayyappan S, Broad A, Narita A. Pembrolizumabassociated ocular myasthenia gravis. Clin Exp Ophthalmol 2019;47:796–798.

120. Michels KL, Karagianis Do AG, Simon SS. Pembrolizumabassociated diplopia secondary to idiopathic orbital inflammatory syndrome. J Clin Ophthalmol 2019;3:150.

121. Lorenzo CJ, Fitzpatrick H, Campdesuner V, George J, Lattanzio N. Pembrolizumab-induced ocular myasthenic crisis. Cureus 2020;12:e9192.

122. Garcez D, Clara AI, Moraes-Fontes MF, Marques JB. A Challenging case of eyelid ptosis and diplopia induced by pembrolizumab. Cureus 2022;14:e28330.

123. Jeyakumar N, Etchegaray M, Henry J, Lelenwa L, Zhao B, Segura A, et al. The terrible triad of checkpoint inhibition: A case report of myasthenia gravis, myocarditis, and myositis induced by cemiplimab in a patient with metastatic cutaneous squamous cell carcinoma. Case Reports Immunol 2020;2020:5126717.

124. Garibaldi M, Calabrò F, Merlonghi G, Pugliese S, Ceccanti M, Cristiano L, et al. Immune checkpoint inhibitors (ICIs)-related ocular myositis. Neuromuscul Disord 2020;30:420–423.

125. Tian CY, Ou YH, Chang SL, Lin CM. Pembrolizumabinduced myasthenia gravis-like disorder, ocular myositis, and hepatitis: A case report. J Med Case Rep 2021;15:244.

126. Jebaraj AP, Etheridge TJ, Winegar BA, Marx DP. Ipilimumab-related orbitopathy: A case report. Orbit 2022:1–5.