Thyroid dysfunction in patients treated with the immune checkpoint inhibitor nivolumab: different clinical features

Giuseppe Giuffrida, Alfredo Campennì, Francesco Trimarchi, Rosaria M. Ruggeri


Rationale. Immune Checkpoint Inhibitors (ICIs) are approved for some advanced neoplasms, increasing survival. ICIs block inhibitor receptors cytotoxic T lymphocyte antigen 4 (CTLA4) and programmed death-1 (PD-1) and trigger T cell-mediated immunity against tumor. Their action is accompanied by several immunity-related adverse events (IRAEs), also involving the endocrine system (pituitary, thyroid, adrenals). We report two different cases of thyrotoxicosis following administration of the anti-PD-1 nivolumab. Patients. Patient 1, M, 75 years-old, treated for non-small cell lung carcinoma (NSCLC) since September 2016, with euthyroid multinodular goiter. In January 2017 (12 weeks from baseline), he developed frank hyperthyroidism, with positive TSH-receptor antibodies (TRAb) and thyroperoxidase antibodies (TPOAb). A Tc99m thyroid scintiscan showed diffuse uptake and “cold” areas. After nivolumab withdrawal, treatment with metimazole (MMI) 5 mg per day was started and euthyroidism was resumed, so to restart the drug in May 2017. Patient 2, M, 80 years-old, treated for a left-eye choroid melanoma since January 2017, with euthyroid nodular goiter. In April 2017 (6 weeks from baseline), thyrotoxicosis was detected, with positive thyroglobulin antibodies (Tg-Ab, 244 IU/ml, nv <4) and no scintiscan uptake, as in destructive thyroiditis. Scalar-dose prednisone was initiated, and after 3 months TSH was >4.5 µIU/ml (subclinical hypothyroidism). Patient was treated with replacement doses of levothyroxine (LT-4), and continued nivolumab infusions. Conclusions. Two forms of thyrotoxicosis were reported: the first with thyroid hyperfunction and positive TRAb, the latter as a destructive thyroiditis. In both cases (mean onset after 9 weeks), the moderate severity and the appropriate management of endocrine IRAEs allowed treatment continuation.


immune checkpoint inhibitors; autoimmunity; autoimmune thyroid diseases

Full Text:



Kim, R., Emi, M., Tanabe, K. (2007) Cancer immunoediting from immune surveillance to immune escape. Immunology, 121:1-14.

Wang, X. B., Zheng, C. Y., Giscombe, R. et al. (2001) Regulation of surface and intracellular expression of CTLA4 oh human peripheral T-cells. Scandinavian J Immunol, 54:453-458.

Torino F., Corsello S.M., Salvatori R. (2016) Endocrinological side-effects of immune checkpoint inhibitors. Curr Opin Oncol, 28:278-287.

Hodi,, F.S., O’Day S.J., McDermott, D.F. et al. (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med, 363:711-723.

Brahmer, J.R., Tykodi, S.S., Chow, L.Q. et al. (2012) Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med, 366:2455-2465.

Robert, C., Thomas, L., Bondarenko, I. et al. (2011) Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med, 364:2517-26.

Weber, J.S., D’Angelo, S.P., Minor, D. et al. (2015) Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (Check-Mate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol, 16:375-84.

Hofmann, L., Forschner, A., Loquai, C. et al. (2016) Cutaneous, gastrointestinal, hepatic, endocrine, and renal side-effects of anti-PD-1 therapy. Eur J Cancer, 60:190-209.

U.S. Department Of Health And Human Services NIoH, National Cancer Institute. (2009) Common Terminology Criteria for Adverse Events v4.0 (CTCAE) [updated (v4.03: June 14, 2010) May 28, 2009].

Horvat, T. Z., Adel, N. G., Dang, T. O. et al. (2015) Immune-related adverse events, need for systemic immunosuppression, and effects on survival and time to treatment failure in patients with melanoma treated with ipilimumab at memorial sloan kettering cancer center. J Clin Oncol, 33:3193-3198.

Eigentler, T.K., Hassel, J.C., Berking, C. et al. (2016) Diagnosis, monitoring and management of immune-related adverse drug reactions of anti-PD1 antibody therapy. Cancer Treatment Rev, 45;7-18.

Herbst R.S., Baas P., Kim D. Et al. (2016) Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet, 387:1540–1550.

Joshi, M.N., Whitelaw, B.C., Palomar, M.T.P. et al. (2016) Immune checkpoint inhibitor-related hypophysitis and endocrine dysfunction. Clin Endocrinol, 85:331-339.

EMA, European Public Assessment Report Nivolumab-BMS (EMA/CHMP/392114/2015).

Robert, C., Schachter, J., Long, G.V. et al. (2015) Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med, 372:2521-32.

Tanaka, R., Fujisawa, Y., Maruyama, H. et al. (2016) Nivolumab-induced thyroid dysfunction. Jpn J Clin Oncol 46:575–579.

Yamauchi, I., Sakane, Y., Fukuda, Y. et al. (2017) Clinical features of nivolumab-induced thyroiditis: a case series study. Thyroid, 27:894-901.



  • There are currently no refbacks.

Copyright (c) 2017 Giuseppe Giuffrida, Alfredo Campennì, Francesco Trimarchi, Rosaria M. Ruggeri

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.