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Thyroid autoimmunity and ophthalmopathy related to melanoma biological therapy
Open accessAbstract
OBJECTIVE: Ipilimumab is a fully human MAB against cytotoxic T-lymphocyte antigen 4 (CTLA4). CTLA4 negatively regulates immune cell activation. In patients with metastatic melanoma, ipilimumab increases survival time and induces complete remission in some patients. However, immune-related adverse events including endocrinopathies have been reported. Bevacizumab, an angiogenesis inhibitor, has been used in combination with ipilimumab in patients with advanced melanoma. PATIENTS AND METHODS: In this study, we report three patients who received ipilimumab alone or combined with bevacizumab therapy and developed thyroiditis, and the first report of euthyroid Graves' ophthalmopathy. RESULTS: Case 1 is a 51-year-old female who presented with severe eye pain, proptosis, and periorbital edema. Laboratory results revealed normal TSH, elevated thyroid antibodies but low titer of anti-TSH receptor antibody. Imaging was consistent with Graves' ophthalmopathy. Cases 2 and 3 were referred for hyperthyroidism, and workup revealed thyroiditis. These three cases suggest that patients with advanced melanoma treated with ipilimumab +/- bevacizumab may be susceptible to a variety of thyroid disorders. CONCLUSIONS: Anti-CTLA4 therapy has shown promising results in treating advanced malignancy such as melanoma and renal carcinoma. A number of endocrinopathies, including thyroid disorders, may develop during ipilimumab therapy. The association of bevacizumab with endocrinopathies is not clear, although a few reports suggest a link to hypothyroidism. All patients on ipilimumab and/or bevacizumab therapy should be monitored for signs or symptoms of thyroiditis.
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In the citing paper
“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 [30]
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In the citing paper
“In the literature, initially only induced Graves’ orbitopathy (GO) without thyrotoxicosis were described in patients undergoing Ipilimumab (anti-CTLA-4) treatment [29,30,31].”
From Graves’ Disease during Immune Checkpoint Inhibitor Therapy (A Case Series and Literature Review) (2021) · cites this paper as [30]
In the citing paper
“has been increasing in recognition and diagnosis.66”
From Endocrine toxicities of immune checkpoint inhibitors (2021) · cites this paper as [66]
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“whereas reports of cases on CTLA-4 monotherapy are very rare”
From Endocrine toxicities of immune checkpoint inhibitors (2021) · cites this paper as [66]
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“though diabetes has developed several months after ICI cessation 66”
From Endocrine toxicities of immune checkpoint inhibitors (2021) · cites this paper as [66]
In the citing paper
“Most patients develop ICI-DM while on therapy”
From Endocrine toxicities of immune checkpoint inhibitors (2021) · cites this paper as [66]
In the citing paper
“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 [66]
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Metadata
- Authors
- Min, L., Vaidya, A., & Becker, C.
- Affiliations
- Brigham and Women's Hospital (US)
- Corresponding author
- Becker, Carolyn
- ORCID
- Venue
- European Journal of Endocrinology
- Publisher
- Oxford University Press (OUP)
- Published
- 2011-02
- Volume
- 164
- Issue
- 2
- Pages
- 303-307
- ISSN
- 0804-4643 (ISSN-L)
- 1479-683X
- PMC
- PMC4080629
- OpenAlex
- W2127446775
- Cited by
- 179
- References
- 22
- Citations by year
- 2026: 4 · 2025: 8 · 2024: 5 · 2023: 6 · 2022: 12 · 2021: 8 · 2020: 17 · 2019: 17 · 2018: 24 · 2017: 21 · 2016: 14 · 2015: 14 · 2014: 4 · 2013: 18 · 2012: 1
- FWCI
- 3.96
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- European Journal of Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (F32HL104776)
- National Institute of Diabetes and Digestive and Kidney Diseases (T32DK007529)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (K08HD070957)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Health Sciences › Medicine › Ophthalmology › Ophthalmology and Eye Disorders
- Keywords
- ipilimumab, bevacizumab, melanoma, CTLA-4 blockade, immune-related adverse events, thyroiditis, Graves' ophthalmopathy, hyperthyroidism, hypothyroidism, TSH receptor antibodies, endocrine disorders, immune checkpoint inhibitors
- MeSH terms
- Ipilimumab, Adult, Antibodies, Monoclonal, Female, Humans, Male, Melanoma, Middle Aged, Skin Neoplasms, Thyroiditis, Autoimmune, Graves Ophthalmopathy
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