Tremelimumab-Induced Graves Hyperthyroidism
Open accessAbstract
Tremelimumab and ipilimumab are monoclonal antibodies directed against the extracellular domain of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and have been used as immunotherapies against immune checkpoints that suppress T-cell activation. Anti-CTLA-4 antibody-based therapies have been shown to be effective in treating various cancers including metastatic melanoma. However, a few immune-related adverse events including hypophysitis and thyroid disorder have been reported, mostly developed within the first year of receiving treatment. We report a case of tremelimumab-induced Graves hyperthyroidism in a 55-year-old man who was diagnosed with metastatic melanoma after 8 years of tremelimumab therapy. He had no personal or family history of thyroid or autoimmune diseases. His biochemical profile was in keeping with Graves disease, with raised serum free thyroid hormones, suppressed thyroid-stimulating hormone concentration, and raised thyrotropin receptor antibody level. He was treated with carbimazole as part of the block and replace therapy, without complications. Tremelimumab therapy was temporarily discontinued and recommenced when he was rendered biochemically euthyroid. There has been no further relapse of Graves hyperthyroidism since the discontinuation of block and replace therapy. The mechanistic profile of anti-CTLA-4-induced thyroid dysfunction and the long-term endocrine safety of this therapeutic approach remain unclear. It is important to monitor thyroid functions in patients receiving anti-CTLA-4 therapies, as their effects on endocrine systems could be more latent or prolonged than the data from current clinical trials suggest. Antithyroid drug therapy was safe and effective alongside anti-CTLA-4 therapy without compromising antitumour treatment efficacy.
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In the literature, only nine cases of ICPi-induced Graves' hyperthyroidism and seven cases of induced Graves' orbitopathy have been described, associated with anti-PD-1 or anti-CTLA-4 treatment or their combination, with only one patient presenting both thyrotoxicosis and orbitopathy.
“To the best of our knowledge at the time of writing, only nine cases of ICPi-induced Graves’ hyperthyroidism and seven cases of induced Graves’ orbitopathy have been described in the literature, associated with anti-PD-1 or anti-CTLA-4 treatment or their combination (Table 3), with only one patient presenting with both thyrotoxicosis and orbitopathy [19,29,30,31,35,36,37,38,39,40,41,42,43,44].”
From Graves’ Disease during Immune Checkpoint Inhibitor Therapy (A Case Series and Literature Review) (2021) · cites this paper as [36]
The Clinical Case reports Graves hyperthyroidism after tremelimumab, an anti-CTLA-4 treatment, and the Discussion mentions ipilimumab-associated Graves ophthalmopathy and thyrotoxicosis. Neither section provides the claimed totals of nine hyperthyroidism cases and seven orbitopathy cases, addresses anti-PD-1 or combination treatment, or establishes that only one patient had both conditions. Page numbers are not available for these indexed passages. (LLM, conf=0.85)
Experimental — accuracy not yet measuredCases of immune checkpoint inhibitor-associated diabetes mellitus in patients on CTLA-4 monotherapy are very rare.
“whereas reports of cases on CTLA-4 monotherapy are very rare”
From Endocrine toxicities of immune checkpoint inhibitors (2021) · cites this paper as [67]
About 97% of reported cases of immune checkpoint inhibitor-associated diabetes mellitus have occurred in patients treated with anti-PD-1/PD-L1 agents or combination therapy.
“Approximately 97% of all reported ICI-DM cases have arisen with anti-PD-1/PD-L1 or combination treated patients”
From Endocrine toxicities of immune checkpoint inhibitors (2021) · cites this paper as [67]
In a case series of 10 patients, autoantibody-negative patients did not develop autoantibodies up to 32 months after diagnosis.
“In one case series of 10 patients, auto-antibody negative patients did not subsequently develop auto-antibodies as far as 32 months after diagnosis67”
From Endocrine toxicities of immune checkpoint inhibitors (2021) · cites this paper as [67]
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Cites
Improved Survival with Ipilimumab in Patients with Metastatic Melanoma
Hodi, F. S., O'Day, S. J., McDermott, D. F., Weber, R. W., Sosman, J. A., Haanen, J. B., Gonzalez, R., Robert, C., Schadendorf, D., Hassel, J. C., et al. (2010) · New England Journal of Medicine · doi:10.1056/nejmoa1003466 · Cited by 15,155 · see citing works
Ipilimumab plus Dacarbazine for Previously Untreated Metastatic Melanoma
Robert, C., Thomas, L., Bondarenko, I., O'Day, S., Weber, J., Garbe, C., Lebbe, C., Baurain, J.-F., Testori, A., Grob, J.-J., et al. (2011) · New England Journal of Medicine · doi:10.1056/nejmoa1104621 · Cited by 4,496 · see citing works
CTLA-4 can function as a negative regulator of T cell activation
Walunas, T. L., Lenschow, D. J., Bakker, C. Y., Linsley, P. S., Freeman, G. J., Green, J. M., Thompson, C. B., & Bluestone, J. A. (1994) · Immunity · doi:10.1016/1074-7613(94)90071-x · Cited by 2,222 · see citing works
Read, S., Malmström, V., & Powrie, F. M. (2000) · The Journal of Experimental Medicine · doi:10.1084/jem.192.2.295 · Cited by 2,206 · see citing works
Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease
Ueda, H., Howson, J. M. M., Esposito, L., Heward, J., Snook, Chamberlain, G., Rainbow, D. B., Hunter, K. M. D., Smith, A. N., Di Genova, G., et al. (2003) · Nature · doi:10.1038/nature01621 · Cited by 2,175 · see citing works
A new member of the immunoglobulin superfamily—CTLA-4
Brunet, J., Denizot, F., Luciani, M., Roux-Rouquié, M., Suzan, M., Mattéi, M., & Golstein, P. (1987) · Nature · doi:10.1038/328267a0 · Cited by 1,307 · see citing works
Carreno, B. M., & Collins, M. A. (2002) · Annual Review of Immunology · doi:10.1146/annurev.immunol.20.091101.091806 · Cited by 895 · see citing works
Shared and Distinct Genetic Variants in Type 1 Diabetes and Celiac Disease
Smyth, D. J., Plagnol, V., Walker, N. M., Cooper, J. D., Downes, K., Yang, J. H. M., Howson, J. M. M., Stevens, H. E., McManus, R., Wijmenga, C., et al. (2008) · New England Journal of Medicine · doi:10.1056/nejmoa0807917 · Cited by 738 · see citing works
Bertrand, A., Kostine, M., Barnetche, T., Truchetet, M.-E., & Schaeverbeke, T. (2015) · BMC Medicine · doi:10.1186/s12916-015-0455-8 · Cited by 704 · see citing works
Mechanisms of Immune Evasion by Tumors
Drake, C. G., Jaffee, E. M., & Pardoll, D. M. (2006) · Advances in immunology · doi:10.1016/s0065-2776(06)90002-9 · Cited by 690 · see citing works
Ribas, A., Camacho, L. H., Lopez-Berestein, G., Pavlov, D., Bulanhagui, C. A., Millham, R., Comin-Anduix, B., Reuben, J. M., Seja, E., Parker, C. A., et al. (2005) · Journal of Clinical Oncology · doi:10.1200/jco.2005.01.109 · Cited by 591 · see citing works
Ryder, M., Callahan, M., Postow, M. A., Wolchok, J., & Fagin, J. A. (2014) · Endocrine-Related Cancer · doi:10.1530/erc-13-0499 · Cited by 439 · see citing works
Blockade of CTLA-4 on CD4+CD25+ regulatory T cells abrogates their function in vivo
Read, S., Greenwald, R., Izcue, A., Robinson, N., Mandelbrot, D., Francisco, L., Sharpe, A. H., & Powrie, F. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.177.7.4376 · Cited by 434 · see citing works
Zhernakova, A., Stahl, E. A., Trynka, G., Raychaudhuri, S., Festen, E. A. M., Franke, L., Westra, H.-J., Fehrmann, R. S. N., Kurreeman, F. A. S., Thomson, B. P., et al. (2011) · PLoS Genetics · doi:10.1371/journal.pgen.1002004 · Cited by 355 · see citing works
Calabrò, L., Morra, A., Fonsatti, E., Cutaia, O., Amato, G., Giannarelli, D., Giacomo, A. M. D., Danielli, R., Altomonte, M., Mutti, L., et al. (2013) · The Lancet Oncology · doi:10.1016/s1470-2045(13)70381-4 · Cited by 353 · see citing works
Alemtuzumab treatment of multiple sclerosis: long-term safety and efficacy
Tuohy, O., Costelloe, L., Hill-Cawthorne, G., Bjornson, I., Harding, K., Robertson, N., May, K., Button, T., Azzopardi, L., Kousin-Ezewu, O., et al. (2015) · Journal of Neurology, Neurosurgery & Psychiatry · doi:10.1136/jnnp-2014-307721 · Cited by 238 · see citing works
The cytotoxic T lymphocyte antigen-4 is a major Graves' disease locus
Vaidya, B. (1999) · Human Molecular Genetics · doi:10.1093/hmg/8.7.1195 · Cited by 216 · see citing works
Kim, R., Emi, M., & Tanabe, K. (2006) · Immunology · doi:10.1111/j.1365-2567.2006.02430.x · Cited by 191 · see citing works
Thyroid autoimmunity and ophthalmopathy related to melanoma biological therapy
Min, L., Vaidya, A., & Becker, C. (2011) · European Journal of Endocrinology · doi:10.1530/eje-10-0833 · Cited by 179 · see citing works
Daniels, G. H., Vladic, A., Brinar, V., Zavalishin, I., Valente, W., Oyuela, P., Palmer, J., & Margolin, D. H. (2014) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2013-2201 · Cited by 150 · see citing works
Endocrinological side-effects of immune checkpoint inhibitors
Torino, F., Corsello, S. M., & Salvatori, R. (2016) · Current Opinion in Oncology · doi:10.1097/cco.0000000000000293 · Cited by 138 · see citing works
Zatloukal, P., Heo, D. S., Park, K., Kang, J., Butts, C., Bradford, D. S., Graziano, S. L., Huang, B., & Healey, D. I. (2009) · Journal of Clinical Oncology · doi:10.1200/jco.2009.27.15_suppl.8071 · Cited by 125 · see citing works
CTLA-4 is expressed by human monocyte-derived dendritic cells and regulates their functions
Laurent, S., Carrega, P., Saverino, D., Piccioli, P., Camoriano, M., Morabito, A., Dozin, B., Fontana, V., Simone, R., Mortara, L., et al. (2010) · Human Immunology · doi:10.1016/j.humimm.2010.07.007 · Cited by 121 · see citing works
McNeel, D. G., Smith, H. A., Eickhoff, J. C., Lang, J. M., Staab, M. J., Wilding, G., & Liu, G. (2011) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-011-1193-1 · Cited by 103 · see citing works
Thyroid-Like Ophthalmopathy in a Euthyroid Patient Receiving Ipilimumab
McElnea, E., Ní Mhéalóid, Á., Moran, S., Kelly, R., & Fulcher, T. (2014) · Orbit · doi:10.3109/01676830.2014.949792 · Cited by 93 · see citing works
Molecular Pathways: Immune Checkpoint Antibodies and their Toxicities
Cousin, S., & Italiano, A. (2016) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-15-2569 · Cited by 83 · see citing works
Furugaki, K., Shirasawa, S., Ishikawa, N., et al. (2004) · Journal of Human Genetics · doi:10.1007/s10038-003-0120-5 · Cited by 73 · see citing works
Millward, M., Underhill, C. R., Lobb, S., McBurnie, J., Meech, S. J., Gómez-Navarro, J., Marshall, M. A., Huang, B., & Mather, C. B. (2013) · British Journal of Cancer · doi:10.1038/bjc.2013.227 · Cited by 67 · see citing works
Treatment of Ipilimumab Induced Graves’ Disease in a Patient with Metastatic Melanoma
Azmat, U., Liebner, D., Joehlin-Price, A., Agrawal, A., & Nabhan, F. (2016) · Case Reports in Endocrinology · doi:10.1155/2016/2087525 · Cited by 59 · see citing works
de Jong, V. M., Zaldumbide, A., van der Slik, A. R., Laban, S., Koeleman, B. P. C., & Roep, B. O. (2015) · Genes and Immunity · doi:10.1038/gene.2015.51 · Cited by 31 · see citing works
Flagged first, then by citations
Research works printed but not linked: 3
- Cousin S, Italiano A: Molecular pathways: im- mune checkpoint antibodies and their toxici- ties. Clin Cancer Res 2016;22: 4550-4555.
- Torino F, Corsello SM, Salvatori R: Endocri- nological side-effects of immune checkpoint inihibitors. Curr Opin Oncol 2016;28: 278- 287.
- Min L, Vaidya A, Becker C: Thyroid autoim- munity and ophthalmopathy related to mela- noma biological therapy. Eur J Endocrinol 2011;164: 303-307.
Cited by
Sorted by citations
Endocrine toxicities of immune checkpoint inhibitors
Wright, J. J., Powers, A. C., & Johnson, D. B. (2021) · Nature Reviews Endocrinology · doi:10.1038/s41574-021-00484-3 · Cited by 441 · see citing works
de Filette, J., Andreescu, C., Cools, F., Bravenboer, B., & Velkeniers, B. (2019) · Hormone and Metabolic Research · doi:10.1055/a-0843-3366 · Cited by 381 · see citing works
Tan, M. H., Iyengar, R., Mizokami-Stout, K., Yentz, S., MacEachern, M. P., Shen, L. Y., Redman, B., & Gianchandani, R. (2019) · Clinical Diabetes and Endocrinology · doi:10.1186/s40842-018-0073-4 · Cited by 172 · see citing works
Graves’ Disease during Immune Checkpoint Inhibitor Therapy (A Case Series and Literature Review)
Peiffert, M., Cugnet-Anceau, C., Dalle, S., Chikh, K., Assaad, S., Disse, E., Raverot, G., Borson-Chazot, F., & Abeillon-du Payrat, J. (2021) · Cancers · doi:10.3390/cancers13081944 · Cited by 33 · see citing works
Nivolumab Induced Thyroid Dysfunction: Unusual Clinical Presentation and Challenging Diagnosis
Iadarola, C., Croce, L., Quaquarini, E., Teragni, C., Pinto, S., Bernardo, A., Fonte, R., Marinò, M., Rotondi, M., & Chiovato, L. (2019) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00813 · Cited by 33 · see citing works
Yajima, K., & Akise, Y. (2019) · Case Reports in Endocrinology · doi:10.1155/2019/2314032 · Cited by 13 · see citing works
- Authors
- Gan, E. H., Mitchell, A. L., Plummer, R., Pearce, S., & Perros, P.
- Affiliations
- Centre for Life (GB)
- Corresponding author
- Gan, Earn H.
- Venue
- European Thyroid Journal
- Publisher
- Bioscientifica
- Published
- 2017-03-14
- Volume
- 6
- Issue
- 3
- Pages
- 167-170
- ISSN
- 2235-0640 (ISSN-L)
- 2235-0802
- PMC
- PMC5527187
- OpenAlex
- W2606361632
- Cited by
- 58
- References
- 30
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 7 · 2023: 5 · 2022: 10 · 2021: 8 · 2020: 6 · 2019: 9 · 2018: 6 · 2017: 1
- FWCI
- 2.65
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- European Thyroid Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Newcastle University ePrints (Newcastle Univesity)
- Funders
- National Institute for Health and Care Research (CL-2014-01-002, CL-2014-01-001)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Health Sciences › Medicine › Neurology › Autoimmune Neurological Disorders and Treatments
- Keywords
- tremelimumab, Graves' hyperthyroidism, CTLA-4 blockade, immune checkpoint inhibitors, immune-related adverse events, metastatic melanoma, TSH receptor antibodies, carbimazole, thyroid dysfunction
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