Endocrinol Metab.  2021 Apr;36(2):312-321. 10.3803/EnM.2021.1007.

Clinical Characteristics, Management, and Potential Biomarkers of Endocrine Dysfunction Induced by Immune Checkpoint Inhibitors

• Iwama S
• Kobayashi T
• Arima H

• KMID: 2515457
• DOI: http://doi.org/10.3803/EnM.2021.1007

Abstract

Immune-related adverse events (irAEs) affecting the endocrine glands are among the most frequent irAEs induced by immune checkpoint inhibitors (ICIs) and include hypopituitarism, primary adrenal insufficiency, thyrotoxicosis, hypothyroidism, hypoparathyroidism, and type 1 diabetes mellitus. Since the incidence and clinical features of endocrine irAEs vary according to the ICI used, it is important to understand the characteristics of these irAEs and to manage each one appropriately. Since some endocrine irAEs, including adrenal crisis and diabetic ketoacidosis, are potentially life-threatening, predicting the risk of endocrine irAEs before their onset is critical. Several autoantibodies have been detected in patients who develop endocrine irAEs, among which anti-thyroid antibodies may be predictive biomarkers of thyroid dysfunction. In this review, we describe the clinical features of each endocrine irAE induced by ICIs and discuss their potential biomarkers, including autoantibodies.

Keyword

Hypopituitarism; Hypophysitis; Adrenal insufficiency; Thyrotoxicosis; Hypothyroidism; Hypoparathyroidism; Diabetes mellitus, type 1; Immune checkpoint inhibitors; Autoantibodies

Reference

1. Brahmer JR, Lacchetti C, Schneider BJ, Atkins MB, Brassil KJ, Caterino JM, et al. 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. 2018; 36:1714–68.

2. Puzanov I, Diab A, Abdallah K, Bingham CO 3rd, Brogdon C, Dadu R, et al. Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. J Immunother Cancer. 2017; 5:95.

3. Arima H, Iwama S, Inaba H, Ariyasu H, Makita N, Otsuki M, et al. Management of immune-related adverse events in endocrine organs induced by immune checkpoint inhibitors: clinical guidelines of the Japan Endocrine Society. Endocr J. 2019; 66:581–6.

4. Zhai Y, Ye X, Hu F, Xu J, Guo X, Zhuang Y, et al. Endocrine toxicity of immune checkpoint inhibitors: a real-world study leveraging US Food and Drug Administration adverse events reporting system. J Immunother Cancer. 2019; 7:286.

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

6. Chang LS, Barroso-Sousa R, Tolaney SM, Hodi FS, Kaiser UB, Min L. Endocrine toxicity of cancer immunotherapy targeting immune checkpoints. Endocr Rev. 2019; 40:17–65.

7. Faje AT, Lawrence D, Flaherty K, Freedman C, Fadden R, Rubin K, et al. High-dose glucocorticoids for the treatment of ipilimumab-induced hypophysitis is associated with reduced survival in patients with melanoma. Cancer. 2018; 124:3706–14.

8. Kobayashi T, Iwama S, Yasuda Y, Okada N, Okuji T, Ito M, et al. Pituitary dysfunction induced by immune checkpoint inhibitors is associated with better overall survival in both malignant melanoma and non-small cell lung carcinoma: a prospective study. J Immunother Cancer. 2020; 8:e000779.

9. Osorio JC, Ni A, Chaft JE, Pollina R, Kasler MK, Stephens D, et al. Antibody-mediated thyroid dysfunction during Tcell checkpoint blockade in patients with non-small-cell lung cancer. Ann Oncol. 2017; 28:583–9.

10. Yamauchi I, Yasoda A, Matsumoto S, Sakamori Y, Kim YH, Nomura M, et al. Incidence, features, and prognosis of immune-related adverse events involving the thyroid gland induced by nivolumab. PLoS One. 2019; 14:e0216954.

11. 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; 4:173–82.

12. Caturegli P, Di Dalmazi G, Lombardi M, Grosso F, Larman HB, Larman T, et al. Hypophysitis secondary to cytotoxic Tlymphocyte-associated protein 4 blockade: insights into pathogenesis from an autopsy series. Am J Pathol. 2016; 186:3225–35.

13. Dillard T, Yedinak CG, Alumkal J, Fleseriu M. Anti-CTLA- 4 antibody therapy associated autoimmune hypophysitis: serious immune related adverse events across a spectrum of cancer subtypes. Pituitary. 2010; 13:29–38.

14. Zhao C, Tella SH, Del Rivero J, Kommalapati A, Ebenuwa I, Gulley J, et al. Anti-PD-L1 treatment induced central diabetes insipidus. J Clin Endocrinol Metab. 2018; 103:365–9.

15. Okano Y, Satoh T, Horiguchi K, Toyoda M, Osaki A, Matsumoto S, et al. Nivolumab-induced hypophysitis in a patient with advanced malignant melanoma. Endocr J. 2016; 63:905–12.

16. Cho KY, Miyoshi H, Nakamura A, Kurita T, Atsumi T. Hyponatremia can be a powerful predictor of the development of isolated ACTH deficiency associated with nivolumab treatment [Letter to the Editor]. Endocr J. 2017; 64:235–6.

17. Kanie K, Iguchi G, Bando H, Fujita Y, Odake Y, Yoshida K, et al. Two cases of atezolizumab-induced hypophysitis. J Endocr Soc. 2017; 2:91–5.

18. Min L, Hodi FS, Giobbie-Hurder A, Ott PA, Luke JJ, Donahue H, et al. Systemic high-dose corticosteroid treatment does not improve the outcome of ipilimumab-related hypophysitis: a retrospective cohort study. Clin Cancer Res. 2015; 21:749–55.

19. Iwama S, De Remigis A, Callahan MK, Slovin SF, Wolchok JD, Caturegli P. Pituitary expression of CTLA-4 mediates hypophysitis secondary to administration of CTLA-4 blocking antibody. Sci Transl Med. 2014; 6:230ra45.

20. Iwama S, Arima H. Anti-pituitary antibodies as a marker of autoimmunity in pituitary glands. Endocr J. 2020; 67:1077–83.

21. Tahir SA, Gao J, Miura Y, Blando J, Tidwell RSS, Zhao H, et al. Autoimmune antibodies correlate with immune checkpoint therapy-induced toxicities. Proc Natl Acad Sci U S A. 2019; 116:22246–51.

22. Ricciuti A, De Remigis A, Landek-Salgado MA, De Vincentiis L, Guaraldi F, Lupi I, et al. Detection of pituitary antibodies by immunofluorescence: approach and results in patients with pituitary diseases. J Clin Endocrinol Metab. 2014; 99:1758–66.

23. Iwata N, Iwama S, Sugimura Y, Yasuda Y, Nakashima K, Takeuchi S, et al. Anti-pituitary antibodies against corticotrophs in IgG4-related hypophysitis. Pituitary. 2017; 20:301–10.

24. Lupi I, Manetti L, Raffaelli V, Grasso L, Sardella C, Cosottini M, et al. Pituitary autoimmunity is associated with hypopituitarism in patients with primary empty sella. J Endocrinol Invest. 2011; 34:e240–4.

25. Iwama S, Welt CK, Romero CJ, Radovick S, Caturegli P. Isolated prolactin deficiency associated with serum autoantibodies against prolactin-secreting cells. J Clin Endocrinol Metab. 2013; 98:3920–5.

26. Lupi I, Brancatella A, Cosottini M, Viola N, Lanzolla G, Sgro D, et al. Clinical heterogeneity of hypophysitis secondary to PD-1/PD-L1 blockade: insights from four cases. Endocrinol Diabetes Metab Case Rep. 2019; 2019:EDM-19–0102.

27. Lanzolla G, Coppelli A, Cosottini M, Del Prato S, Marcocci C, Lupi I. Immune checkpoint blockade anti-PD-L1 as a trigger for autoimmune polyendocrine syndrome. J Endocr Soc. 2019; 3:496–503.

28. Yano S, Ashida K, Sakamoto R, Sakaguchi C, Ogata M, Maruyama K, et al. Human leucocyte antigen DR15, a possible predictive marker for immune checkpoint inhibitor-induced secondary adrenal insufficiency. Eur J Cancer. 2020; 130:198–203.

29. Inaba H, Ariyasu H, Iwakura H, Ueda Y, Kurimoto C, Uraki S, et al. Comparative analysis of human leucocyte antigen between idiopathic and anti-PD-1 antibody induced isolated adrenocorticotropic hormone deficiency: a pilot study. Clin Endocrinol (Oxf). 2019; 91:786–92.

30. Min L, Ibrahim N. Ipilimumab-induced autoimmune adrenalitis. Lancet Diabetes Endocrinol. 2013; 1:e15.

31. Trainer H, Hulse P, Higham CE, Trainer P, Lorigan P. Hyponatraemia secondary to nivolumab-induced primary adrenal failure. Endocrinol Diabetes Metab Case Rep. 2016; 2016:EDM-16–0108.

32. Yanase T, Tajima T, Katabami T, Iwasaki Y, Tanahashi Y, Sugawara A, et al. Diagnosis and treatment of adrenal insufficiency including adrenal crisis: a Japan Endocrine Society clinical practice guideline [Opinion]. Endocr J. 2016; 63:765–84.

33. Kobayashi T, Iwama S, Yasuda Y, Okada N, Tsunekawa T, Onoue T, et al. Patients with antithyroid antibodies are prone to develop destructive thyroiditis by nivolumab: a prospective study. J Endocr Soc. 2018; 2:241–51.

34. Yamauchi I, Sakane Y, Fukuda Y, Fujii T, Taura D, Hirata M, et al. Clinical features of nivolumab-induced thyroiditis: a case series study. Thyroid. 2017; 27:894–901.

35. Okada N, Iwama S, Okuji T, Kobayashi T, Yasuda Y, Wada E, et al. Anti-thyroid antibodies and thyroid echo pattern at baseline as risk factors for thyroid dysfunction induced by anti-programmed cell death-1 antibodies: a prospective study. Br J Cancer. 2020; 122:771–7.

36. Kurihara S, Oikawa Y, Nakajima R, Satomura A, Tanaka R, Kagamu H, et al. Simultaneous development of Graves’ disease and type 1 diabetes during anti-programmed cell death-1 therapy: a case report. J Diabetes Investig. 2020; 11:1006–9.

37. McMillen B, Dhillon MS, Yong-Yow S. A rare case of thyroid storm. BMJ Case Rep. 2016; 2016:214603.

38. Ma C, Hodi FS, Giobbie-Hurder A, Wang X, Zhou J, Zhang A, et al. The impact of high-dose glucocorticoids on the outcome of immune-checkpoint inhibitor-related thyroid disorders. Cancer Immunol Res. 2019; 7:1214–20.

39. Basak EA, van der Meer JWM, Hurkmans DP, Schreurs MWJ, Oomen-de Hoop E, van der Veldt AAM, et al. Overt thyroid dysfunction and anti-thyroid antibodies predict response to anti-PD-1 immunotherapy in cancer patients. Thyroid. 2020; 30:966–73.

40. Neppl C, Kaderli RM, Trepp R, Schmitt AM, Berger MD, Wehrli M, et al. Histology of nivolumab-induced thyroiditis. Thyroid. 2018; 28:1727–8.

41. Kimbara S, Fujiwara Y, Iwama S, Ohashi K, Kuchiba A, Arima H, et al. Association of antithyroglobulin antibodies with the development of thyroid dysfunction induced by nivolumab. Cancer Sci. 2018; 109:3583–90.

42. Kotwal A, Haddox C, Block M, Kudva YC. Immune checkpoint inhibitors: an emerging cause of insulin-dependent diabetes. BMJ Open Diabetes Res Care. 2019; 7:e000591.

43. Piranavan P, Li Y, Brown E, Kemp EH, Trivedi N. Immune checkpoint inhibitor-induced hypoparathyroidism associated with calcium-sensing receptor-activating autoantibodies. J Clin Endocrinol Metab. 2019; 104:550–6.

44. Umeguchi H, Takenoshita H, Inoue H, Kurihara Y, Sakaguchi C, Yano S, et al. Autoimmune-related primary hypoparathyroidism possibly induced by the administration of pembrolizumab: a case report. J Oncol Pract. 2018; 14:449–51.

45. Lupi I, Brancatella A, Cetani F, Latrofa F, Kemp EH, Marcocci C. Activating antibodies to the calcium-sensing receptor in immunotherapy-induced hypoparathyroidism. J Clin Endocrinol Metab. 2020; 105:dgaa092.

46. Win MA, Thein KZ, Qdaisat A, Yeung SJ. Acute symptomatic hypocalcemia from immune checkpoint therapy-induced hypoparathyroidism. Am J Emerg Med. 2017; 35:1039.

47. Dadu R, Rodgers TE, Trinh VA, Kemp EH, Cubb TD, Patel S, et al. Calcium-sensing receptor autoantibody-mediated hypoparathyroidism associated with immune checkpoint inhibitor therapy: diagnosis and long-term follow-up. J Immunother Cancer. 2020; 8:e000687.

48. Trinh B, Sanchez GO, Herzig P, Laubli H. Inflammation-induced hypoparathyroidism triggered by combination immune checkpoint blockade for melanoma. J Immunother Cancer. 2019; 7:52.

49. Baden MY, Imagawa A, Abiru N, Awata T, Ikegami H, Uchigata Y, et al. Characteristics and clinical course of type 1 diabetes mellitus related to anti-programmed cell death-1 therapy. Diabetol Int. 2018; 10:58–66.

50. Stamatouli AM, Quandt Z, Perdigoto AL, Clark PL, Kluger H, Weiss SA, et al. Collateral damage: insulin-dependent diabetes induced with checkpoint inhibitors. Diabetes. 2018; 67:1471–80.

51. Tsiogka A, Jansky GL, Bauer JW, Koelblinger P. Fulminant type 1 diabetes after adjuvant ipilimumab therapy in cutaneous melanoma. Melanoma Res. 2017; 27:524–5.

52. Imagawa A, Hanafusa T, Miyagawa J, Matsuzawa Y. A novel subtype of type 1 diabetes mellitus characterized by a rapid onset and an absence of diabetes-related antibodies. Osaka IDDM Study Group. N Engl J Med. 2000; 342:301–7.

53. Kawasaki E, Maruyama T, Imagawa A, Awata T, Ikegami H, Uchigata Y, et al. Diagnostic criteria for acute-onset type 1 diabetes mellitus (2012): report of the committee of Japan Diabetes Society on the research of fulminant and acute-onset type 1 diabetes mellitus. J Diabetes Investig. 2014; 5:115–8.

54. Imagawa A, Hanafusa T, Awata T, Ikegami H, Uchigata Y, Osawa H, et al. Report of the committee of the Japan Diabetes Society on the research of fulminant and acute-onset type 1 diabetes mellitus: new diagnostic criteria of fulminant type 1 diabetes mellitus (2012). J Diabetes Investig. 2012; 3:536–9.

55. Yoneda S, Imagawa A, Hosokawa Y, Baden MY, Kimura T, Uno S, et al. T-lymphocyte infiltration to islets in the pancreas of a patient who developed type 1 diabetes after administration of immune checkpoint inhibitors. Diabetes Care. 2019; 42:e116–8.