Thyroid autoimmunity and ophthalmopathy related to melanoma biological therapy
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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 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 [30]
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredInitially only induced Graves' orbitopathy without thyrotoxicosis were described in patients undergoing Ipilimumab treatment.
“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]
Recognition and diagnosis of immune checkpoint inhibitor-associated diabetes mellitus have been increasing.
“has been increasing in recognition and diagnosis.66”
From Endocrine toxicities of immune checkpoint inhibitors (2021) · cites this paper as [66]
Cases 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 [66]
Diabetes has developed several months after cessation of immune checkpoint inhibitor therapy.
“though diabetes has developed several months after ICI cessation 66”
From Endocrine toxicities of immune checkpoint inhibitors (2021) · cites this paper as [66]
Most patients develop immune checkpoint inhibitor-associated diabetes mellitus while still on therapy.
“Most patients develop ICI-DM while on therapy”
From Endocrine toxicities of immune checkpoint inhibitors (2021) · cites this paper as [66]
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 [66]
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- 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 › Pathology and Forensic Medicine › 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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