1932

Abstract

Immune checkpoint inhibitors (CPIs) reverse immune suppression that is thought to allow malignant growth. Despite remarkable efficacy in a subset of cancers, their use is accompanied by immune-related adverse events, including endocrinopathies such as hypophysitis, thyroid dysfunction, diabetes, and adrenalitis. These conditions are heterogenous, with differing incidence across CPI types, but are unified by the acuity and extremity of tissue-specific organ failure. Their occurrence may be associated with beneficial tumor control. Further understanding of the risk factors and mechanisms of these endocrine immunotoxicities can help optimize CPI use as well as improve understanding of spontaneous autoimmune diseases.

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2021-01-27
2024-04-25
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Literature Cited

  1. 1. 
    June CH, Warshauer JT, Bluestone JA 2017. Is autoimmunity the Achilles’ heel of cancer immunotherapy. Nat. Med. 23:5540–47
    [Google Scholar]
  2. 2. 
    Postow MA, Sidlow R, Hellmann MD 2018. Immune-related adverse events associated with immune checkpoint inhibitors. N. Engl. J. Med. 378:2158–68
    [Google Scholar]
  3. 3. 
    Boutros C, Tarhini A, Routier E et al. 2016. Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination. Nat. Rev. Clin. Oncol. 13:8473–86
    [Google Scholar]
  4. 4. 
    Faje AT, Lawrence D, Flaherty K et al. 2018. High-dose glucocorticoids for the treatment of ipilimumab-induced hypophysitis is associated with reduced survival in patients with melanoma. Cancer 124:183706–14
    [Google Scholar]
  5. 5. 
    Kotwal A, Kottschade L, Ryder M 2020. PD-L1 inhibitor-induced thyroiditis is associated with better overall survival in cancer patients. Thyroid 30:2177–84
    [Google Scholar]
  6. 6. 
    Yamauchi I, Sakane Y, Fukuda Y et al. 2017. Clinical features of nivolumab-induced thyroiditis: a case series study. Thyroid 27:7894–901
    [Google Scholar]
  7. 7. 
    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. 28:3583–89
    [Google Scholar]
  8. 8. 
    Walunas TL, Lenschow DJ, Bakker CY et al. 1994. CTLA-4 can function as a negative regulator of T cell activation. Immunity 1:5405–13
    [Google Scholar]
  9. 9. 
    Freeman GJ, Long AJ, Iwai Y 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. 192:71027–34
    [Google Scholar]
  10. 10. 
    Wing K, Onishi Y, Prieto-Martin P et al. 2008. CTLA-4 control over Foxp3+ regulatory T cell function. Science 322:5899271–75
    [Google Scholar]
  11. 11. 
    Jain N, Nguyen H, Chambers C et al. 2010. Dual function of CTLA-4 in regulatory T cells and conventional T cells to prevent multiorgan autoimmunity. PNAS 107:41524–28
    [Google Scholar]
  12. 12. 
    Okazaki T, Chikuma S, Iwai Y et al. 2013. A rheostat for immune responses: the unique properties of PD-1 and their advantages for clinical application. Nat. Immunol. 14:121212–18
    [Google Scholar]
  13. 13. 
    Iwai Y, Ishida M, Tanaka Y et al. 2002. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. PNAS 99:1912293–97
    [Google Scholar]
  14. 14. 
    Barber DL, Wherry EJ, Masopust D et al. 2006. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439:7077682–87
    [Google Scholar]
  15. 15. 
    Rui J, Deng S, Arazi A et al. 2017. β cells that resist immunological attack develop during progression of autoimmune diabetes in NOD mice. Cell Metab 25:3727–38
    [Google Scholar]
  16. 16. 
    Osum KC, Burrack AL, Martinov T et al. 2018. Interferon-gamma drives programmed death-ligand 1 expression on islet β cells to limit T cell function during autoimmune diabetes. Sci. Rep. 8:18295
    [Google Scholar]
  17. 17. 
    Garcia-Diaz A, Shin DS, Moreno BH et al. 2017. Interferon receptor signaling pathways regulating PD-L1 and PD-L2 expression. Cell Rep 19:61189–1201
    [Google Scholar]
  18. 18. 
    Hui E, Cheung J, Zhu J et al. 2017. T cell costimulatory receptor CD28 is a primary target for PD-1-mediated inhibition. Science 355:63321428–33
    [Google Scholar]
  19. 19. 
    Kamphorst AO, Wieland A, Nasti T et al. 2017. Rescue of exhausted CD8 T cells by PD-1-targeted therapies is CD28-dependent. Science 355:63321423–27
    [Google Scholar]
  20. 20. 
    Young A, Quandt Z, Bluestone JA 2018. The balancing act between cancer immunity and autoimmunity in response to immunotherapy. Cancer Immunol. Res. 6:121445–52
    [Google Scholar]
  21. 21. 
    Tivol EA, Borriello F, Schweitzer AN et al. 1995. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 3:5541–47
    [Google Scholar]
  22. 22. 
    Waterhouse P, Penninger JM, Timms E et al. 1995. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science 270:5238985–88
    [Google Scholar]
  23. 23. 
    Wang J, Yoshida T, Nakaki F et al. 2005. Establishment of NOD-Pdcd1−/− mice as an efficient animal model of type I diabetes. PNAS 102:3311823–28
    [Google Scholar]
  24. 24. 
    Nishimura H, Nose M, Hiai H et al. 1999. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 11:2141–51
    [Google Scholar]
  25. 25. 
    Nishimura H. 2001. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science 291:5502319–22
    [Google Scholar]
  26. 26. 
    Hammers HJ, Plimack ER, Infante JR et al. 2017. Safety and efficacy of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma: the CheckMate 016 study. J. Clin. Oncol. 35:343851–58
    [Google Scholar]
  27. 27. 
    Wolchok JD, Chiarion-Sileni V, Gonzalez R et al. 2017. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N. Engl. J. Med. 377:1345–56
    [Google Scholar]
  28. 28. 
    Dougan M, Pietropaolo M. 2020. Time to dissect the autoimmune etiology of cancer antibody immunotherapy. J. Clin. Investig. 130:151–61
    [Google Scholar]
  29. 29. 
    Pai C-CS, Simons DM, Lu X et al. 2018. Tumor-conditional anti-CTLA4 uncouples antitumor efficacy from immunotherapy-related toxicity. J. Clin. Investig. 129:1349–63
    [Google Scholar]
  30. 30. 
    Read S, Greenwald R, Izcue A et al. 2006. Blockade of CTLA-4 on CD4+CD25+ regulatory T cells abrogates their function in vivo. J. Immunol. 177:74376–83
    [Google Scholar]
  31. 31. 
    Lühder F, Höglund P, Allison JP et al. 1998. Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) regulates the unfolding of autoimmune diabetes. J. Exp. Med. 187:3427–32
    [Google Scholar]
  32. 32. 
    Ansari MJI, Salama AD, Chitnis T et al. 2003. The programmed death-1 (PD-1) pathway regulates autoimmune diabetes in nonobese diabetic (NOD) mice. J. Exp. Med. 198:163–69
    [Google Scholar]
  33. 33. 
    Fife BT, Guleria I, Gubbels Bupp M et al. 2006. Insulin-induced remission in new-onset NOD mice is maintained by the PD-1–PD-L1 pathway. J. Exp. Med. 203:122737–47
    [Google Scholar]
  34. 34. 
    Stamatouli AM, Quandt Z, Perdigoto AL et al. 2018. Collateral damage: insulin-dependent diabetes induced with checkpoint inhibitors. Diabetes 67:81471–80
    [Google Scholar]
  35. 35. 
    Tsang VHM, McGrath RT, Clifton-Bligh RJ et al. 2019. Checkpoint inhibitor-associated autoimmune diabetes is distinct from type 1 diabetes. J. Clin. Endocrinol. Metab. 104:115499–506
    [Google Scholar]
  36. 36. 
    Quandt Z, Young A, Anderson M 2020. Immune checkpoint inhibitor diabetes mellitus: a novel form of autoimmune diabetes. Clin. Exp. Immunol. 200:2131–40
    [Google Scholar]
  37. 37. 
    Barroso-Sousa R, Barry WT, Garrido-Castro AC et al. 2018. Incidence of endocrine dysfunction following the use of different immune checkpoint inhibitor regimens. JAMA Oncol 4:2173–82
    [Google Scholar]
  38. 38. 
    Faje A. 2016. Immunotherapy and hypophysitis: clinical presentation, treatment, and biologic insights. Pituitary 19:182–92
    [Google Scholar]
  39. 39. 
    Grover S, Rahma OE, Hashemi N et al. 2018. Gastrointestinal and hepatic toxicities of checkpoint inhibitors: algorithms for management. ASCO Educational Book DS Dizon, N Pennel, HS Rugo 13–19
    [Google Scholar]
  40. 40. 
    Iwama S, De Remigis A, Callahan MK et al. 2014. Pituitary expression of CTLA-4 mediates hypophysitis secondary to administration of CTLA-4 blocking antibody. Sci. Transl. Med. 6:230230ra45
    [Google Scholar]
  41. 41. 
    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. 33:7773–81
    [Google Scholar]
  42. 42. 
    Johnson DB, Balko JM, Compton ML et al. 2016. Fulminant myocarditis with combination immune checkpoint blockade. N. Engl. J. Med. 375:181749–55
    [Google Scholar]
  43. 43. 
    Oh DY, Cham J, Zhang L et al. 2017. Immune toxicities elicited by CTLA-4 blockade in cancer patients are associated with early diversification of the T-cell repertoire. Cancer Res 77:61322–30
    [Google Scholar]
  44. 44. 
    Perez-Ruiz E, Minute L, Otano I et al. 2019. Prophylactic TNF blockade uncouples efficacy and toxicity in dual CTLA-4 and PD-1 immunotherapy. Nature 569:7756428–32
    [Google Scholar]
  45. 45. 
    Kotwal A, Haddox C, Block M et al. 2019. Immune checkpoint inhibitors: an emerging cause of insulin-dependent diabetes. BMJ Open Diabetes Res. Care 7:1e000591
    [Google Scholar]
  46. 46. 
    Lu J, Yang J, Liang Y et al. 2019. Incidence of immune checkpoint inhibitor-associated diabetes: a meta-analysis of randomized controlled studies. Front. Pharmacol. 10:1453
    [Google Scholar]
  47. 47. 
    Wright JJ, Salem J, Johnson DB et al. 2018. Increased reporting of immune checkpoint inhibitor-associated diabetes. Diabetes Care 41:Sep.150–51
    [Google Scholar]
  48. 48. 
    de Filette JMK, Pen JJ, Decoster L et al. 2019. Immune checkpoint inhibitors and type 1 diabetes mellitus: a case report and systematic review. Eur. J. Endocrinol. 181:3363–74
    [Google Scholar]
  49. 49. 
    Tan MH, Iyengar R, Mizokami-Stout K et al. 2019. Spectrum of immune checkpoint inhibitors-induced endocrinopathies in cancer patients: a scoping review of case reports. Clin. Diabetes Endocrinol. 5:1 https://doi.org/10.1186/s40842-018-0073-4
    [Crossref] [Google Scholar]
  50. 50. 
    Perdigoto AL, Quandt Z, Anderson M et al. 2019. Checkpoint inhibitor-induced insulin-dependent diabetes: an emerging syndrome. Lancet Diabetes Endocrinol 8587:199–11
    [Google Scholar]
  51. 51. 
    Akturk HK, Kahramangil D, Sarwal A et al. 2019. Immune checkpoint inhibitor-induced type 1 diabetes: a systematic review and meta-analysis. Diabet. Med. 36:1075–81
    [Google Scholar]
  52. 52. 
    Clotman K, Janssens K, Specenier P et al. 2018. Programmed cell death-1 inhibitor-induced type 1 diabetes mellitus. J. Clin. Endocrinol. Metab. 103:93144–54
    [Google Scholar]
  53. 53. 
    Atkinson MA. 2012. The pathogenesis and natural history of type 1 diabetes. Cold Spring Harbor Perspect. Med. 2:11a007641
    [Google Scholar]
  54. 54. 
    Marchand L, Thivolet A, Dalle S et al. 2019. Diabetes mellitus induced by PD-1 and PD-L1 inhibitors: description of pancreatic endocrine and exocrine phenotype. Acta Diabetol 56:4441–48
    [Google Scholar]
  55. 55. 
    Ishikawa K, Shono-Saito T, Yamate T et al. 2017. A case of fulminant type 1 diabetes mellitus, with a precipitous decrease in pancreatic volume, induced by nivolumab for malignant melanoma: analysis of HLA and CTLA-4 polymorphisms. Eur. J. Dermatol. 27:2184–85
    [Google Scholar]
  56. 56. 
    Bingley PJ. 2010. Clinical applications of diabetes antibody testing. J. Clin. Endocrinol. Metab. 95:125–33
    [Google Scholar]
  57. 57. 
    Brahmer JR, Lacchetti C, Schneider BJ et al. 2018. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology clinical practice guideline. J. Clin. Oncol. 36:171714–68
    [Google Scholar]
  58. 58. 
    Trinh B, Donath MY, Läubli H 2019. Successful treatment of immune checkpoint inhibitor-induced diabetes with infliximab. Diabetes Care 42:9e153–54
    [Google Scholar]
  59. 59. 
    Hansen E, Sahasrabudhe D, Sievert L 2016. A case report of insulin-dependent diabetes as immune-related toxicity of pembrolizumab: presentation, management and outcome. Cancer Immunol. Immunother. 65:6765–67
    [Google Scholar]
  60. 60. 
    Keir ME, Liang SC, Guleria I et al. 2006. Tissue expression of PD-L1 mediates peripheral T cell tolerance. J. Exp. Med. 203:4883–95
    [Google Scholar]
  61. 61. 
    El Khatib MM, Sakuma T, Tonne JM et al. 2015. β-Cell-targeted blockage of PD1 and CTLA4 pathways prevents development of autoimmune diabetes and acute allogeneic islets rejection. Gene Ther 22:5430–38
    [Google Scholar]
  62. 62. 
    Colli ML, Hill JLE, Marroquí L et al. 2018. PDL1 is expressed in the islets of people with type 1 diabetes and is up-regulated by interferons-α and-γ via IRF1 induction. EBioMedicine 36:367–75
    [Google Scholar]
  63. 63. 
    Yoneda S, Imagawa A, Hosokawa Y et al. 2019. T-lymphocyte infiltration to islets in the pancreas of a patient who developed type 1 diabetes after administration of immune checkpoint inhibitors. Diabetes Care 42:7e116–18
    [Google Scholar]
  64. 64. 
    Faje A, Reynolds K, Zubiri L et al. 2019. Hypophysitis secondary to nivolumab and pembrolizumab is a clinical entity distinct from ipilimumab-associated hypophysitis. Eur. J. Endocrinol. 181:3211–19
    [Google Scholar]
  65. 65. 
    Byun DJ, Wolchok JD, Rosenberg LM et al. 2017. Cancer immunotherapy—immune checkpoint blockade and associated endocrinopathies. Nat. Rev. Endocrinol. 13:4195–207
    [Google Scholar]
  66. 66. 
    Heaney AP, Sumerel B, Rajalingam R et al. 2015. HLA markers DQ8 and DR53 are associated with lymphocytic hypophysitis and may aid in differential diagnosis. J. Clin. Endocrinol. Metab. 100:114092–97
    [Google Scholar]
  67. 67. 
    Garon-Czmil J, Petitpain N, Rouby F et al. 2019. Immune check point inhibitors-induced hypophysitis: a retrospective analysis of the French Pharmacovigilance database. Sci. Rep. 9:19419
    [Google Scholar]
  68. 68. 
    Guerrero E, Johnson DB, Bachelot A et al. 2019. Immune checkpoint inhibitor-associated hypophysitis—World Health Organisation VigiBase report analysis. Eur. J. Cancer 113:10–13
    [Google Scholar]
  69. 69. 
    Min L, Hodi FS, Giobbie-Hurder A et al. 2015. Systemic high-dose corticosteroid treatment does not improve the outcome of ipilimumab-related hypophysitis: a retrospective cohort study. Clin. Cancer Res. 21:4749–55
    [Google Scholar]
  70. 70. 
    Tahir SA, Gao J, Miura Y et al. 2019. Autoimmune antibodies correlate with immune checkpoint therapy-induced toxicities. PNAS 116:4422246–51
    [Google Scholar]
  71. 71. 
    Puzanov I, Diab A, Abdallah K et al. 2017. Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. J. Immunother. Cancer 5:95
    [Google Scholar]
  72. 72. 
    Caturegli P, Di Dalmazi G, Lombardi M et al. 2016. Hypophysitis secondary to cytotoxic T-lymphocyte-associated protein 4 blockade: insights into pathogenesis from an autopsy series. Am. J. Pathol. 186:123225–35
    [Google Scholar]
  73. 73. 
    Torino F, Corsello SM, Salvatori R 2016. Endocrinological side-effects of immune checkpoint inhibitors. Curr. Opin. Oncol. 28:4278–87
    [Google Scholar]
  74. 74. 
    Delivanis DA, Gustafson MP, Bornschlegl S et al. 2017. Pembrolizumab-induced thyroiditis: comprehensive clinical review and insights into underlying involved mechanisms. J. Clin. Endocrinol. Metab. 102:82770–80
    [Google Scholar]
  75. 75. 
    Yamauchi I, Yasoda A, Matsumoto S et al. 2019. Incidence, features, and prognosis of immune-related adverse events involving the thyroid gland induced by nivolumab. PLOS ONE 14:5e0216954
    [Google Scholar]
  76. 76. 
    De Filette J, Jansen Y, Schreuer M et al. 2016. Incidence of thyroid-related adverse events in melanoma patients treated with pembrolizumab. J. Clin. Endocrinol. Metab. 101:114431–39
    [Google Scholar]
  77. 77. 
    Pollack RM, Kagan M, Lotem M et al. 2019. Baseline TSH level is associated with risk of anti-PD-1-induced thyroid dysfunction. Endocr. Pract. 25:8824–29
    [Google Scholar]
  78. 78. 
    Sbardella E, Tenuta M, Sirgiovanni G et al. 2020. Thyroid disorders in programmed death 1 inhibitor-treated patients: Is previous therapy with tyrosine kinase inhibitors a predisposing factor. Clin. Endocrinol. 92:3258–65
    [Google Scholar]
  79. 79. 
    Al Mushref M, Guido PA, Collichio FA et al. 2020. Thyroid dysfunction, recovery, and prognosis in melanoma patients treated with immune checkpoint inhibitors: a retrospective review. Endocr. Pract. 26:136–42
    [Google Scholar]
  80. 80. 
    Kurimoto C, Inaba H, Ariyasu H et al. 2020. Predictive and sensitive biomarkers for thyroid dysfunctions during treatment with immune-checkpoint inhibitors. Cancer Sci 111:51468–77
    [Google Scholar]
  81. 81. 
    Brancatella A, Viola N, Brogioni S et al. 2019. Graves’ disease induced by immune checkpoint inhibitors: a case report and review of the literature. Eur. Thyroid J. 8:4192–95
    [Google Scholar]
  82. 82. 
    Kobayashi T, Iwama S, Yasuda Y et al. 2018. Patients with antithyroid antibodies are prone to develop destructive thyroiditis by nivolumab: a prospective study. J. Endocr. Soc. 2:3241–51
    [Google Scholar]
  83. 83. 
    Toi Y, Sugawara S, Sugisaka J et al. 2019. Profiling preexisting antibodies in patients treated with anti-PD-1 therapy for advanced non-small cell lung cancer. JAMA Oncol 5:3376–83
    [Google Scholar]
  84. 84. 
    O'Malley G, Lee HJ, Parekh S et al. 2017. Rapid evolution of thyroid dysfunction in patients treated with nivolumab. Endocr. Pract. 23:101223–31
    [Google Scholar]
  85. 85. 
    Fröhlich E, Wahl R. 2017. Thyroid autoimmunity: role of anti-thyroid antibodies in thyroid and extra-thyroidal diseases. Front. Immunol. 8:521
    [Google Scholar]
  86. 86. 
    Mazarico I, Capel I, Giménez-Palop O et al. 2019. Low frequency of positive antithyroid antibodies is observed in patients with thyroid dysfunction related to immune check point inhibitors. J. Endocrinol. Investig. 42:121443–50
    [Google Scholar]
  87. 87. 
    Ma C, Hodi FS, Giobbie-Hurder A et al. 2019. The impact of high-dose glucocorticoids on the outcome of immune-checkpoint inhibitor-related thyroid disorders. Cancer Immunol. Res. 7:71214–20
    [Google Scholar]
  88. 88. 
    Jacobson EM, Huber A, Tomer Y 2009. The HLA gene complex in thyroid autoimmunity: from epidemiology to etiology. J. Autoimmun. 30:1–258–62
    [Google Scholar]
  89. 89. 
    Angell TE, Min L, Wieczorek TJ et al. 2018. Unique cytologic features of thyroiditis caused by immune checkpoint inhibitor therapy for malignant melanoma. Genes Dis 5:146–48
    [Google Scholar]
  90. 90. 
    de Filette J, Andreescu C, Cools F et al. 2019. A systematic review and meta-analysis of endocrine-related adverse events associated with immune checkpoint inhibitors. Horm. Metab. Res. 51:3145–56
    [Google Scholar]
  91. 91. 
    Iqbal I, Khan MAA, Ullah W et al. 2019. Nivolumab-induced adrenalitis. BMJ Case Rep 12:11e231829
    [Google Scholar]
  92. 92. 
    Hanna RM, Selamet U, Bui P et al. 2018. Acute kidney injury after pembrolizumab-induced adrenalitis and adrenal insufficiency. Case Rep. Nephrol. Dial. 8:2171–77
    [Google Scholar]
  93. 93. 
    Min L, Ibrahim N. 2013. Ipilimumab-induced autoimmune adrenalitis. Lancet Diabetes Endocrinol 1:3e15
    [Google Scholar]
  94. 94. 
    Paepegaey A-C, Lheure C, Ratour C et al. 2017. Polyendocrinopathy resulting from pembrolizumab in a patient with a malignant melanoma. J. Endocr. Soc. 1:6646–49
    [Google Scholar]
  95. 95. 
    Trainer H, Hulse P, Higham CE et al. 2016. Hyponatraemia secondary to nivolumab-induced primary adrenal failure. Endocrinol. Diabetes Metab. Case Rep. 2016:16–0108
    [Google Scholar]
  96. 96. 
    Akarca FK, Can O, Yalcinli S et al. 2017. Nivolumab, a new immunomodulatory drug, a new adverse effect; adrenal crisis. Turkish J. Emerg. Med. 17:4157–59
    [Google Scholar]
  97. 97. 
    Bacanovic S, Burger IA, Stolzmann P et al. 2015. Ipilimumab-induced adrenalitis. Clin. Nucl. Med. 40:11e518–19
    [Google Scholar]
  98. 98. 
    Shariff AI, D'Alessio DA. 2018. Primary adrenal insufficiency from immune checkpoint inhibitors. AACE Clin. Case Rep. 4:3e232–34
    [Google Scholar]
  99. 99. 
    Grouthier V, Lebrun-Vignes B, Moey M et al. 2020. Immune checkpoint inhibitor-associated primary adrenal insufficiency: WHO VigiBase report analysis. Oncologist 25:1–6
    [Google Scholar]
  100. 100. 
    Mitchell AL, Pearce SHS. 2012. Autoimmune Addison disease: pathophysiology and genetic complexity. Nat. Rev. Endocrinol. 8:5306–16
    [Google Scholar]
  101. 101. 
    Charmandari E, Nicolaides NC, Chrousos GP 2014. Adrenal insufficiency. Lancet 383:99352152–67
    [Google Scholar]
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