Skip to content
2000
Volume 26, Issue 1
  • ISSN: 1871-5303
  • E-ISSN: 2212-3873

Abstract

Background

Immune Checkpoint Inhibitor (ICPi) therapy has revolutionized cancer treatment but can lead to immune-related adverse events (irAE), including thyroid dysfunction. The impact of ICPi on patients with pre-existing autoimmune thyroid diseases (PATD), particularly the development of Graves' disease, remains poorly understood.

Case Presentation

We provide the first complete case of Graves' disease with ICPi therapy in a patient who already had Hashimoto's thyroiditis. The patient, a 52-year-old male, was diagnosed with lung adenocarcinoma and received Atezolizumab. Clinical evaluation revealed hyperthyroidism, confirmed by elevated thyroid hormones and autoantibodies (TRAb and TSAb). The patient was managed with methimazole and demonstrated a transient hyperthyroid phase followed by persistent hypothyroidism. Only 16 confirmed cases of Graves' disease induced by ICPi were reported. We conducted a review to investigate the clinical characteristics, risk factors, and prognosis trends associated with ICPi-induced Graves disease in PTAD patients. Additionally, changes in thyroid function and autoantibodies during and after ICPi treatment are examined.

Conclusion

This case underscores the importance of monitoring thyroid function and autoantibodies in patients with PATD undergoing ICPi therapy. The findings suggest distinct differences in the humoral immune response between ICPi-induced and spontaneous Graves' disease, necessitating further research into autoantibody dynamics and their relationship with cellular immunity in these patients.

This is an open access article published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode
Loading

Article metrics loading...

/content/journals/emiddt/10.2174/0118715303317264250116095028
2025-02-10
2026-02-18
Loading full text...

Full text loading...

/deliver/fulltext/emiddt/26/1/EMIDDT-26-E18715303317264.html?itemId=/content/journals/emiddt/10.2174/0118715303317264250116095028&mimeType=html&fmt=ahah

References

  1. WrightJ.J. PowersA.C. JohnsonD.B. Endocrine toxicities of immune checkpoint inhibitors.Nat. Rev. Endocrinol.202117738939910.1038/s41574‑021‑00484‑333875857
    [Google Scholar]
  2. ChiloiroS. BianchiA. GiampietroA. MilardiD. De MarinisL. PontecorviA. The changing clinical spectrum of endocrine adverse events in cancer immunotherapy.Trends Endocrinol. Metab.20223328710410.1016/j.tem.2021.10.00934895977
    [Google Scholar]
  3. Ramos-CasalsM. Sisó-AlmirallA. Immune-related adverse events of immune checkpoint inhibitors.Ann. Intern. Med.20241772ITC17ITC3210.7326/AITC20240220038346306
    [Google Scholar]
  4. WangS.J. DouganS.K. DouganM. Immune mechanisms of toxicity from checkpoint inhibitors.Trends Cancer20239754355310.1016/j.trecan.2023.04.00237117135
    [Google Scholar]
  5. TisonA. GaraudS. ChicheL. CornecD. KostineM. Immune-checkpoint inhibitor use in patients with cancer and pre-existing autoimmune diseases.Nat. Rev. Rheumatol.2022181164165610.1038/s41584‑022‑00841‑036198831
    [Google Scholar]
  6. SparksJ.A. Pre-existing autoimmune diseases and immune checkpoint inhibitors for cancer treatment: Considerations about initiation, flares, immune-related adverse events, and cancer progression.Rheum. Dis. Clin. North Am.202450214715910.1016/j.rdc.2024.01.00138670718
    [Google Scholar]
  7. SumimotoH. NodaS. KoideH. DoukeY. SakaiK. NishikawaA. TomiokaA. HoriM. NakatoH. KimuraY. TokudaA. TakanoA. TeramotoK. MurataS. DaigoY. Pre-existing autoimmune disease as a risk factor for immune-related adverse events in cancer patients receiving immune checkpoint inhibitors.PLoS One2024197e030699510.1371/journal.pone.030699539012903
    [Google Scholar]
  8. KehlK.L. YangS. AwadM.M. PalmerN. KohaneI.S. SchragD. Pre-existing autoimmune disease and the risk of immune-related adverse events among patients receiving checkpoint inhibitors for cancer.Cancer Immunol. Immunother.201968691792610.1007/s00262‑019‑02321‑z30877325
    [Google Scholar]
  9. ZhangK. KongX. LiY. WangZ. ZhangL. XuanL. PD-1/PD-L1 inhibitors in patients with preexisting autoimmune diseases.Front. Pharmacol.20221385496710.3389/fphar.2022.85496735370736
    [Google Scholar]
  10. IwamaS. KobayashiT. YasudaY. ArimaH. Immune checkpoint inhibitor-related thyroid dysfunction.Best Pract. Res. Clin. Endocrinol. Metab.202236310166010.1016/j.beem.2022.10166035501263
    [Google Scholar]
  11. LuD. YaoJ. YuanG. GaoY. ZhangJ. GuoX. Immune checkpoint inhibitor-related new-onset thyroid dysfunction: A retrospective analysis using the US FDA adverse event reporting system.Oncologist2022272e126e13210.1093/oncolo/oyab04335641200
    [Google Scholar]
  12. WiersingaW.M. PoppeK.G. EffraimidisG. Hyperthyroidism: Aetiology, pathogenesis, diagnosis, management, complications, and prognosis.Lancet Diabetes Endocrinol.202311428229810.1016/S2213‑8587(23)00005‑036848916
    [Google Scholar]
  13. Petranović OvčaričekP. GörgesR. GiovanellaL. Autoimmune thyroid diseases.Semin. Nucl. Med.202454221923610.1053/j.semnuclmed.2023.11.00238044176
    [Google Scholar]
  14. GrixtiL. LaneL.C. PearceS.H. The genetics of Graves’ disease.Rev. Endocr. Metab. Disord.202425120321410.1007/s11154‑023‑09848‑838108994
    [Google Scholar]
  15. PitoiaF. TrimboliP. New insights in thyroid diagnosis and treatment.Rev. Endocr. Metab. Disord.20242511310.1007/s11154‑023‑09859‑538041785
    [Google Scholar]
  16. LeeS.Y. PearceE.N. Hyperthyroidism.JAMA2023330151472148310.1001/jama.2023.1905237847271
    [Google Scholar]
  17. LanzollaG. MarinòM. MenconiF. Graves disease: Latest understanding of pathogenesis and treatment options.Nat. Rev. Endocrinol.2024201164766010.1038/s41574‑024‑01016‑539039206
    [Google Scholar]
  18. AzmatU. LiebnerD. Joehlin-PriceA. AgrawalA. NabhanF. Treatment of ipilimumab induced Graves’ disease in a patient with metastatic melanoma.Case Rep. Endocrinol.201620161410.1155/2016/208752526881150
    [Google Scholar]
  19. de FiletteJ. JansenY. SchreuerM. EveraertH. VelkeniersB. NeynsB. BravenboerB. Incidence of thyroid-related adverse events in melanoma patients treated with pembrolizumab.J. Clin. Endocrinol. Metab.2016101114431443910.1210/jc.2016‑230027571185
    [Google Scholar]
  20. GanE.H. MitchellA.L. PlummerR. PearceS. PerrosP. Tremelimumab-induced graves hyperthyroidism.Eur. Thyroid J.20176316717010.1159/00046428528785544
    [Google Scholar]
  21. NarayenG. LiebD. Pembrolizumab-related graves' disease: A rare adverse effect of an anti-PD-1 antibody cancer immunotherapy.J. Endocr. Soc.20193Suppl 1SAT-58410.1210/js.2019‑SAT‑584
    [Google Scholar]
  22. BrancatellaA. ViolaN. BrogioniS. MontanelliL. SardellaC. VittiP. MarcocciC. LupiI. LatrofaF. Graves’ disease induced by immune checkpoint inhibitors: A case report and review of the literature.Eur. Thyroid J.20198419219510.1159/00050182431602361
    [Google Scholar]
  23. YajimaK. AkiseY. A case report of Graves’ disease induced by the anti-human programmed cell death-1 monoclonal antibody pembrolizumab in a bladder cancer patient.Case Rep. Endocrinol.201920191510.1155/2019/231403231772785
    [Google Scholar]
  24. IadarolaC. CroceL. QuaquariniE. TeragniC. PintoS. BernardoA. FonteR. MarinòM. RotondiM. ChiovatoL. Nivolumab induced thyroid dysfunction: Unusual clinical presentation and challenging diagnosis.Front. Endocrinol.2019981310.3389/fendo.2018.0081330705667
    [Google Scholar]
  25. YamadaH. OkajimaF. OndaT. FujimoriS. EmotoN. SugiharaH. New-onset graves’ disease after the initiation of nivolumab therapy for gastric cancer: A case report.BMC Endocr. Disord.202020113210.1186/s12902‑020‑00613‑532847555
    [Google Scholar]
  26. KuriharaS. OikawaY. NakajimaR. SatomuraA. TanakaR. KagamuH. ShimadaA. Simultaneous development of Graves’ disease and type 1 diabetes during anti-programmed cell death-1 therapy: A case report.J. Diabetes Investig.20201141006100910.1111/jdi.1321231926048
    [Google Scholar]
  27. PeiffertM. Cugnet-AnceauC. DalleS. ChikhK. AssaadS. DisseE. RaverotG. Borson-ChazotF. Abeillon-du PayratJ. Graves’ disease during immune checkpoint inhibitor therapy (a case series and literature review).Cancers2021138194410.3390/cancers1308194433920721
    [Google Scholar]
  28. ReddyC. ZenaM. Title: Case of hyperthyroidism in a patient on Anti-PD-1 (programmed cell death receptor-1 blocking antibody) therapy caused by destructive thyroiditis followed by Graves’ disease.J. Endocr. Soc.20215Suppl. 1A968A96910.1210/jendso/bvab048.1979
    [Google Scholar]
  29. AlqaisiS. RahmanA. A rare case of pembrolizumab-associated Graves’ disease.Cureus2023152e3469610.7759/cureus.3469636909047
    [Google Scholar]
  30. MuirC.A. WoodC.C.G. Clifton-BlighR.J. LongG.V. ScolyerR.A. CarlinoM.S. MenziesA.M. TsangV.H.M. Association of antithyroid antibodies in checkpoint inhibitor–associated thyroid immune–related adverse events.J. Clin. Endocrinol. Metab.20221075e1843e184910.1210/clinem/dgac05935104870
    [Google Scholar]
  31. ChiengJ.H.L. HtetZ.W. ZhaoJ.J. TaiE.S. TayS.H. HuangY. WongA. YangS.P. Clinical presentation of immune-related endocrine adverse events during immune checkpoint inhibitor treatment.Cancers 20221411268710.3390/cancers1411268735681667
    [Google Scholar]
  32. KimbaraS. FujiwaraY. IwamaS. OhashiK. KuchibaA. ArimaH. YamazakiN. KitanoS. YamamotoN. OheY. Association of antithyroglobulin antibodies with the development of thyroid dysfunction induced by nivolumab.Cancer Sci.2018109113583359010.1111/cas.1380030230649
    [Google Scholar]
  33. WangQ. WuT. ZhaoR. LiY. ChenX. ShenS. ZhangX. Development and validation of a prediction model for thyroid dysfunction in patients during immunotherapy.Endocr Pract20243010943950
    [Google Scholar]
  34. ZhouX. IwamaS. KobayashiT. AndoM. ArimaH. Risk of thyroid dysfunction in PD-1 blockade is stratified by the pattern of TgAb and TPOAb positivity at baseline.J. Clin. Endocrinol. Metab.202310810e1056e106210.1210/clinem/dgad23137084392
    [Google Scholar]
  35. MarianiG. TonaccheraM. GrossoM. OrsoliniF. VittiP. StraussH.W. The role of nuclear medicine in the clinical management of benign thyroid disorders, Part 1: Hyperthyroidism.J. Nucl. Med.202162330431210.2967/jnumed.120.24317033008929
    [Google Scholar]
  36. TywanekE. MichalakA. ŚwirskaJ. ZwolakA. Autoimmunity, new potential biomarkers and the thyroid gland—The perspective of Hashimoto’s thyroiditis and its treatment.Int. J. Mol. Sci.2024259470310.3390/ijms2509470338731922
    [Google Scholar]
  37. KriegerC.C. KahalyG.J. AzamA. Klubo-GwiezdzinskaJ. NeumannS. GershengornM.C. Graves’ autoantibodies exhibit different stimulating activities in cultures of thyrocytes and orbital fibroblasts not reflected by clinical assays.Thyroid2022321909634714162
    [Google Scholar]
  38. StanM.N. Algeciras-SchimnichA. MurthyV. ThapaP. ArakiN. Diagnostic utility of a new assay for thyroid stimulating immunoglobulins in Graves’ disease and thyroid eye disease.Thyroid202232217017610.1089/thy.2021.029934714163
    [Google Scholar]
  39. KahalyG.J. DianaT. KanitzM. FrommerL. OlivoP.D. Prospective trial of functional thyrotropin receptor antibodies in Graves disease.J. Clin. Endocrinol. Metab.20201054e1006e101410.1210/clinem/dgz29231865369
    [Google Scholar]
  40. NapolitanoG. BucciI. Di DalmaziG. GiulianiC. Non-conventional clinical uses of TSH receptor antibodies: The case of chronic autoimmune thyroiditis.Front. Endocrinol.20211276908410.3389/fendo.2021.76908434803929
    [Google Scholar]
  41. NallaP. YoungS. SandersJ. CarterJ. AdlanM.A. KabelisK. ChenS. FurmaniakJ. Rees SmithB. PremawardhanaL.D.K.E. Thyrotrophin receptor antibody concentration and activity, several years after treatment for Graves’ disease.Clin. Endocrinol.201990236937410.1111/cen.1390830485487
    [Google Scholar]
  42. BukhariS. HenickB.S. WinchesterR.J. LerrerS. AdamK. GartshteynY. ManiarR. LinZ. Khodadadi-JamayranA. TsirigosA. SalvatoreM.M. LagosG.G. ReinerS.L. DallosM.C. MathewM. RizviN.A. MorA. Single-cell RNA sequencing reveals distinct T cell populations in immune-related adverse events of checkpoint inhibitors.Cell Rep. Med.20234110086810.1016/j.xcrm.2022.10086836513074
    [Google Scholar]
  43. YasudaY. IwamaS. SugiyamaD. OkujiT. KobayashiT. ItoM. OkadaN. EnomotoA. ItoS. YanY. SugiyamaM. OnoueT. TsunekawaT. ItoY. TakagiH. HagiwaraD. GotoM. SugaH. BannoR. TakahashiM. NishikawaH. ArimaH. CD4 + T cells are essential for the development of destructive thyroiditis induced by anti–PD-1 antibody in thyroglobulin-immunized mice.Sci. Transl. Med.202113593eabb749510.1126/scitranslmed.abb749533980577
    [Google Scholar]
  44. KotwalA. GustafsonM.P. BornschleglS. KottschadeL. DelivanisD.A. DietzA.B. GandhiM. RyderM. Immune checkpoint inhibitor-induced thyroiditis is associated with increased intrathyroidal T lymphocyte subpopulations.Thyroid202030101440145010.1089/thy.2020.007532323619
    [Google Scholar]
  45. TaylorJ. GandhiA. GrayE. ZaenkerP. Checkpoint inhibitor immune-related adverse events: A focused review on autoantibodies and B cells as biomarkers, advancements and future possibilities.Front. Immunol.20231399143310.3389/fimmu.2022.99143336713389
    [Google Scholar]
  46. Vargas-UricoecheaH. Molecular mechanisms in autoimmune thyroid disease.Cells202312691810.3390/cells1206091836980259
    [Google Scholar]
  47. InabaH. De GrootL.J. AkamizuT. Thyrotropin receptor epitope and human leukocyte antigen in Graves’ disease.Front. Endocrinol.2016712010.3389/fendo.2016.0012027602020
    [Google Scholar]
  48. MullerI. WillisM. HealyS. NasserT. LovelessS. ButterworthS. ZhangL. DramanM.S. TaylorP.N. RobertsonN. DayanC.M. LudgateM.E. Longitudinal characterization of autoantibodies to the thyrotropin receptor (TRAb) during alemtuzumab therapy: Evidence that TRAb may precede thyroid dysfunction by many years.Thyroid201828121682169310.1089/thy.2018.023230351224
    [Google Scholar]
  49. DwivediS.N. KalariaT. BuchH. Thyroid autoantibodies.J. Clin. Pathol.2023761192810.1136/jcp‑2022‑20829036270794
    [Google Scholar]
  50. HuX. WangL. ShangB. WangJ. SunJ. LiangB. SuL. YouW. JiangS. Immune checkpoint inhibitor-associated toxicity in advanced non-small cell lung cancer: An updated understanding of risk factors.Front. Immunol.202314109441410.3389/fimmu.2023.109441436949956
    [Google Scholar]
/content/journals/emiddt/10.2174/0118715303317264250116095028
Loading
/content/journals/emiddt/10.2174/0118715303317264250116095028
Loading

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test