Thyroid autoimmunity and ophthalmopathy related to melanoma biological therapy

in European Journal of Endocrinology
(Correspondence should be addressed to C Becker; Email: cbbecker@partners.org)

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.

Abstract

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.

Introduction

Cytotoxic T-lymphocyte antigen 4 (CTLA4) is a checkpoint molecule present on the cell surface of activated T-lymphocytes. It counterbalances the T-cell activation mediated by CD28, a positive immune response regulator. As a result, the proliferation of T-lymphocytes and secretion of interleukin 2 are inhibited (1). Ipilimumab is a fully human MAB against CTLA4. Clinical studies have revealed a variety of immune-related adverse events (IRAEs) associated with ipilimumab therapy, including endocrinopathies. The most common endocrinopathy has been hypophysitis. In a large series of 163 patients with advanced melanoma or renal cell cancer, eight patients developed autoimmune hypophysitis while receiving ipilimumab (2). The incidence of autoimmune hypophysitis in anti-CTLA4 clinical trials ranges from 0 to 17% (3). Thyroiditis has been listed as an adverse event, but details are scant (3). Bevacizumab is a humanized MAB that acts as an anti-angiogenic agent by directly inhibiting vascular endothelial growth factor (VEGF) and is widely used in advanced malignancies (4). In this study, we report three patients with advanced melanoma who received ipilimumab with or without bevacizumab and developed autoimmune thyroiditis or ophthalmopathy.

Case report

Case 1

A 51-year-old female with a 4-year history of stage IV melanoma was hospitalized for acute onset of severe eye pain, conjunctivitis, proptosis, and periorbital edema. Ipilimumab (10 mg/kg) therapy was initiated 2 months before hospitalization. She had no history of thyroid disease and was euthyroid at baseline with TSH 3.7 (normal range: 0.5–5 mIU/l) and free thyroxine (T4) 1.1 (normal range 0.93–1.7 ng/dl; Table 1). After receiving four doses of ipilimumab at 10 mg/kg, she developed the eye symptoms mentioned above. Physical examination revealed bilateral proptosis, conjunctival redness, and periorbital edema. Hertel exophthalmometry showed OD 23 mm and OS 23 mm (normal range 12–22 mm) indicating mild proptosis. Intraocular pressures were slightly increased (OD 24 mmHg and OS 20 mmHg, normal range: 10–20 mmHg). Thyroid examination was negative for goiter, nodules, or tenderness. Her laboratory studies revealed high anti-TPO antibody (662 IU/ml, n<20) and thyroglobulin antibody (148.5 IU/ml, n<3.9), though her thyroid function tests remained normal with TSH 1.01 and free T4 1.1 (normal range: 0.8–1.8 ng/dl; Table 1). Computed tomography of the brain and orbital magnetic resonance imaging showed bilateral thickening of extraocular muscles compatible with Graves' ophthalmopathy. Ipilimumab was discontinued. She received i.v. Solu-Medrol 1 g daily for 3 days and subsequently a course of oral prednisone. Her symptoms and ophthalmopathy resolved initially following treatment with glucocorticoids but relapsed 2 months later as prednisone was tapered. High-dose i.v. Solu-Medrol was again initiated. She received i.v. Solu-Medrol 100 mg daily for the first day followed by 250 mg every 6 h for a total of 12 doses. Prednisone 100 mg p.o. twice daily with slow taper was initiated after finishing the course of i.v. Solu-Medrol. Her ocular symptoms persisted 5 months later. The levels of anti-TPO and thyroglobulin antibodies remained elevated though decreased significantly over 1 year. Thyroid-stimulating immunoglobulin was not initially checked but was 1.4 (normal range <1.3) 17 months after initial presentation. She has subsequently been able to stop glucocorticoids with almost complete resolution of ocular symptoms and signs.

Table 1

Laboratory values before and after ipilimumab therapy.

Case 1Case 2Case 3
BeforeAfterBeforeAfterBeforeAfterReference range
TSH3.681.011.131.011.030.060.5–5 mIU/l
Free thyroxine index19.84–11
Free thyroxine1.11.80.8–1.8 ng/dl
TPO662.1145.7600–20 IU/ml
Thyroglobulin antibody148.5UD15.3UD4.90–3.9 IU/ml
TSI1.40–1.3
TSH-BII9%0–16%

–, not measured; UD, undetectable.

Case 2

A 48-year-old male with advanced melanoma was enrolled in a clinical trial with combined therapy of ipilimumab (10 mg/kg) and bevacizumab (7.5 mg/kg). He had no history of thyroid disease (Table 2). His baseline TSH was 1.13 mIU/l with negative anti-thyroglobulin antibodies (Table 1). Following two infusions of ipilimumab and bevacizumab, his TSH declined to 0.01 mIU/l. He denied symptoms of hyper- or hypothyroidism, though physical examination revealed hand tremor. Thyroid examination was unremarkable. Laboratory studies revealed elevated T4 and strongly positive anti-TPO and anti-thyroglobulin antibodies (Table 1). A radioiodine-123 thyroid uptake showed low uptake of 0.9% at 6 h (normal range 7–15%) consistent with a thyroiditis. He had not received any iodinated contrast in the previous 2 months. We observed him without treatment, and 3 weeks later, his T4 normalized. His TSH increased to 7.78 mIU/l 3 months after presentation and remained high with the most recent TSH 9.46, consistent with an autoimmune thyroiditis (Fig. 1).

Table 2

Summary of demographics, thyroid disorders, preexisting endocrine diseases, and imaging studies.

Case 1Case 2Case 3
Age (years)514828
GenderFemaleMaleFemale
Total doses of ipilimumab423
Pre-existing endocrinopathyNoneNoneNone
Ipilimumab-related endocrinopathyEuthyroid Grave's ophthalmopathyThyroiditisThyroiditis
Endocrine therapyGlucocorticoidsNoneNone
Imaging studies
 MRI of pituitaryNormalNormalNormal
 MRI of orbitDiffuse ocular muscle thickening
 I-123 thyroid uptakeLow
 FDG-PET scanMild and diffuse thyroid uptakeMild and diffuse thyroid uptakeDiffuse FDG uptake associated with slightly enlarged thyroid gland

–, not done.

Figure 1

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Figure 1

Change in TSH in cases 2 and 3 before and after ipilimumab therapy.

Citation: European Journal of Endocrinology 164, 2; 10.1530/EJE-10-0833

Case 3

A 28-year-old female received surgery, radiation therapy, and systematic chemotherapy with interferon-α and autologous tumor cell vaccine for advanced melanoma. She enrolled in a clinical trial with ipilimumab (10 mg/kg)/bevacizumab (7.5 mg/kg) after her disease progressed. She received the interferon-α therapy for 6 months. She was clinically euthyroid during the therapy. Her levels of TSH were normal before and after interferon-α therapy. The interferon-α treatment was completed 2 years before ipilimumab therapy. TSH was 1 mIU/ml before the trial and declined to 0.06 mIU/ml after three doses of combined therapy (Table 1). She had not received iodinated contrast in the previous 2 months. Her free T4 was high normal, and anti-TPO antibody was elevated at 60 IU/ml. Physical examination revealed tachycardia without goiter or neck tenderness. Positron emission tomography (PET) scan revealed persistently increased FDG (2-deoxy-2[F-18]fluoro-d-glucose) positive uptake in both thyroid lobes, consistent with a thyroiditis (5, 6, 7). Her TSH normalized 1 month later, increased to 6.19 after 3 months, and 5 months after presentation it normalized to 3.9, consistent with a resolving painless thyroiditis (Fig. 1).

Discussion

These three patients had no history of thyroid disorders and were euthyroid before initiation of ipilimumab alone or combined with bevacizumab therapy (Table 2). Each developed a different thyroid-associated disorder. Although cases 2 and 3 both developed thyroiditis, case 2 progressed to a Hashimoto-type permanent hypothyroidism, while case 3 had findings more typical of a transient, painless thyroiditis. Case 1 has remained euthyroid but developed physical and radiological evidence of bilateral Graves' ophthalmopathy. All cases have no family history of autoimmune endocrinopathies. The onset of abnormalities in all patients occurred relatively quickly, after 2–4 cycles or 6–12 weeks of ipilimumab +/− bevacizumab therapy. The tests for other autoimmune endocrinopathies, especially hypophysitis, were negative in all patients.

Our clinical observations extend the findings of previous studies with ipilimumab. Most recently, Hodi et al. described a phase III study of ipilimumab in patients with metastatic melanoma (8). In addition to an improvement in overall survival, treatment with ipilimumab was associated with thyroid disorders or abnormal thyroid function tests in ∼2% of the study population. Interestingly, several studies have reported a positive correlation between clinical response to anti-CTLA4 therapy and IRAEs (9, 10, 11, 12).

Case 1 had striking ocular symptoms and signs. The imaging studies were consistent with Graves' ophthalmopathy. She had a slightly elevated thyroid-stimulating antibody over 1 year after presentation but low titer of TSH-binding inhibitory immunoglobulins of 9% (ref 0–16%) and normal thyroid function tests (Table 1) suggesting euthyroid Graves' ophthalmopathy. Up to 5% of patients with Graves' ophthalmopathy are euthyroid or hypothyroid and have low titers of anti-TSH receptor antibodies at the time of presentation (13). To our knowledge, this is the first case of euthyroid Graves' ophthalmopathy associated with ipilimumab therapy.

CTLA4 gene polymorphisms have been associated with autoimmune thyroid diseases (AITD) including Graves' disease and Hashimoto's thyroiditis (14, 15). A recent meta-analysis supported these associations (16). Sanderson et al. (11) performed polymorphism analysis in a small anti-CTLA4 clinical trial and observed that the GG allele in JO33 that encodes three alleles correlating with the level of CTLA4 expression on T-cells is related to higher risk of developing autoimmunity with CTLA4 blockade, while the GG allele is associated with low CTLA4 expression. There are controversies about the correlation of CTLA4 polymorphisms with Graves' ophthalmopathy. Early studies from a UK team suggested the association of CTLA4 gene polymorphism with increased incidence of Graves' ophthalmopathy (17, 18). Studies in different populations were inconsistent (19). A meta-analysis failed to find a significant association of CTLA4 single nucleotide polymorphism (SNP) with Graves' ophthalmopathy (20).

Management of ipilimumab-related endocrinopathies can be challenging since glucocorticoids are usually used as anti-inflammatory agents. As the goal of anti-CTLA4 therapy is to stimulate an immune response against cancer cells, treating the patients with glucocorticoids as in Case 1 theoretically reverses the anti-cancer benefit of CTLA4 blockade. Interestingly, the accumulated evidence suggests that systemic steroid administration does not significantly alter the anti-tumor activity of CTLA4 blockade (2, 12, 21). Blansfield et al. reported that a glucocorticoid therapy protocol with i.v. dexamethasone 4 mg every 6 h for 7 days and then rapidly tapered to replacement doses of hydrocortisone appeared to have no adverse impact on tumor response (2). In this report, case 1 had been on chronic high-dose glucocorticoid treatment for her ophthalmopathy, yet her melanoma remains in remission.

Two of our patients received combination therapy with bevacizumab and ipilimumab. A recent retrospective study revealed a relation of bevacizumab therapy and hypothyroidism in children with primary CNS tumor (22). However, there are no details describing the possible etiology for hypothyroidism in these patients. Based on animal studies, the mechanism of anti-VEGF-related hypothyroidism is associated with capillary regression in the thyroid gland rather than autoimmune thyroiditis (23). Since all of our reported patients had significantly high TPO antibodies and received ipilimumab, it is possible that the thyroiditis was related to the independent effects of this medication. Alternatively, an independent and/or synergistic effect of bevacizumab on thyroid function cannot be excluded.

In conclusion, we have described three patients with advanced melanoma who developed autoimmune thyroiditis or Graves' ophthalmopathy early in the course of ipilimumab +/− bevacizumab therapy. Further research on the relationship between polymorphisms of CTLA4 and autoimmunity may be useful in identifying populations at highest risk for AITD and other endocrinopathies while on anti-CTLA4 therapy. Identifying the possible association of CTLA4 polymorphism with ipilimumab-related autoimmune endocrinopathies may help to unveil the mechanism and pathogenesis of these disorders. Based on the recent findings supporting the efficacy of ipilimumab in treating patients with advanced melanoma (8), we expect that more patients with advanced malignancies will receive this therapy. This may result in increased autoimmune-related endocrinopathies. For now, we recommend that all patients on ipilimumab alone or combined with bevacizumab therapy have baseline thyroid function tests and careful monitoring for new onset of thyroid disease, particularly during the first 3 months of treatment.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

Acknowledgements

We thank Dr Frank S Hodi and Dr Philip A Friedlander for referring the patients to our endocrine clinic.

References

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    BoehmSRothermundtCHessDJoergerM. Antiangiogenic drugs in oncology: a focus on drug safety and the elderly – a mini-review. Gerontology201056303309doi:10.1159/000262450.

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    KarantanisDBogsrudTVWisemanGAMullanBPSubramaniamRMNathanMAPellerPJBahnRSLoweVJ. Clinical significance of diffusely increased 18F-FDG uptake in the thyroid gland. Journal of Nuclear Medicine200748896901doi:10.2967/jnumed.106.039024.

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    SandersonKScotlandRLeePLiuDGroshenSSnivelyJSianSNicholGDavisTKelerTYellinMWeberJ. Autoimmunity in a phase I trial of a fully human anti-cytotoxic T-lymphocyte antigen-4 monoclonal antibody with multiple melanoma peptides and Montanide ISA 51 for patients with resected stages III and IV melanoma. Journal of Clinical Oncology200523741750doi:10.1200/JCO.2005.01.128.

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    UedaHHowsonJMEspositoLHewardJSnookHChamberlainGRainbowDBHunterKMSmithANDi GenovaGHerrMHDahlmanIPayneFSmythDLoweCTwellsRCHowlettSHealyBNutlandSRanceHEEverettVSminkLJLamACCordellHJWalkerNMBordinCHulmeJMotzoCCuccaFHessJFMetzkerMLRogersJGregorySAllahabadiaANithiyananthanRTuomilehto-WolfETuomilehtoJBingleyPGillespieKMUndlienDERonningenKSGujaCIonescu-TirgovisteCSavageDAMaxwellAPCarsonDJPattersonCCFranklynJAClaytonDGPetersonLBWickerLSToddJAGoughSC. Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature2003423506511doi:10.1038/nature01621.

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    VaidyaBOakesEJImrieHDickinsonAJPerrosPKendall-TaylorPPearceSH. CTLA4 gene and Graves' disease: association of Graves' disease with the CTLA4 exon 1 and intron 1 polymorphisms, but not with the promoter polymorphism. Clinical Endocrinology200358732735doi:10.1046/j.1365-2265.2003.01778.x.

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    HanSZhangSZhangWLiRLiYWangZXieYMaoY. CTLA4 polymorphisms and ophthalmopathy in Graves' disease patients: association study and meta-analysis. Human Immunology200667618626doi:10.1016/j.humimm.2006.05.003.

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    Change in TSH in cases 2 and 3 before and after ipilimumab therapy.

References

1

ChambersCAKuhnsMSEgenJGAllisonJP. CTLA-4-mediated inhibition in regulation of T cell responses: mechanisms and manipulation in tumor immunotherapy. Annual Review of Immunology200119565594doi:10.1146/annurev.immunol.19.1.565.

2

BlansfieldJABeckKETranKYangJCHughesMSKammulaUSRoyalRETopalianSLHaworthLRLevyCRosenbergSASherryRM. Cytotoxic T-lymphocyte-associated antigen-4 blockage can induce autoimmune hypophysitis in patients with metastatic melanoma and renal cancer. Journal of Immunotherapy200528593598doi:10.1097/01.cji.0000178913.41256.06.

3

DillardTYedinakCGAlumkalJFleseriuM. Anti-CTLA-4 antibody therapy associated autoimmune hypophysitis: serious immune related adverse events across a spectrum of cancer subtypes. Pituitary2010132938doi:10.1007/s11102-009-0193-z.

4

BoehmSRothermundtCHessDJoergerM. Antiangiogenic drugs in oncology: a focus on drug safety and the elderly – a mini-review. Gerontology201056303309doi:10.1159/000262450.

5

KarantanisDBogsrudTVWisemanGAMullanBPSubramaniamRMNathanMAPellerPJBahnRSLoweVJ. Clinical significance of diffusely increased 18F-FDG uptake in the thyroid gland. Journal of Nuclear Medicine200748896901doi:10.2967/jnumed.106.039024.

6

YasudaSShohtsuAIdeMTakagiSTakahashiWSuzukiYHoriuchiM. Chronic thyroiditis: diffuse uptake of FDG at PET. Radiology1998207775778.

7

LiuY. Clinical significance of thyroid uptake on F18-fluorodeoxyglucose positron emission tomography. Annals of Nuclear Medicine2009231723doi:10.1007/s12149-008-0198-0.

8

HodiFSO'DaySJMcDermottDFWeberRWSosmanJAHaanenJBGonzalezRRobertCSchadendorfDHasselJCAkerleyWvan den EertweghAJLutzkyJLoriganPVaubelJMLinetteGPHoggDOttensmeierCHLebbeCPeschelCQuirtIClarkJIWolchokJDWeberJSTianJYellinMJNicholGMHoosAUrbaWJ. Improved survival with ipilimumab in patients with metastatic melanoma. New England Journal of Medicine2010363711723doi:10.1056/NEJMoa1003466.

9

AttiaPPhanGQMakerAVRobinsonMRQuezadoMMYangJCSherryRMTopalianSLKammulaUSRoyalRERestifoNPHaworthLRLevyCMavroukakisSANicholGYellinMJRosenbergSA. Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4. Journal of Clinical Oncology20052360436053doi:10.1200/JCO.2005.06.205.

10

BeckKEBlansfieldJATranKQFeldmanALHughesMSRoyalREKammulaUSTopalianSLSherryRMKleinerDQuezadoMLowyIYellinMRosenbergSAYangJC. Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4. Journal of Clinical Oncology20062422832289doi:10.1200/JCO.2005.04.5716.

11

SandersonKScotlandRLeePLiuDGroshenSSnivelyJSianSNicholGDavisTKelerTYellinMWeberJ. Autoimmunity in a phase I trial of a fully human anti-cytotoxic T-lymphocyte antigen-4 monoclonal antibody with multiple melanoma peptides and Montanide ISA 51 for patients with resected stages III and IV melanoma. Journal of Clinical Oncology200523741750doi:10.1200/JCO.2005.01.128.

12

WeberJThompsonJAHamidOMinorDAminARonIRidolfiRAssiHMaraveyasABermanDSiegelJO'DaySJ. A randomized, double-blind, placebo-controlled, phase II study comparing the tolerability and efficacy of ipilimumab administered with or without prophylactic budesonide in patients with unresecTable stage III or IV melanoma. Clinical Cancer Research20091555915598doi:10.1158/1078-0432.CCR-09-1024.

13

BahnRS. Graves' ophthalmopathy. New England Journal of Medicine2010362726738doi:10.1056/NEJMra0905750.

14

UedaHHowsonJMEspositoLHewardJSnookHChamberlainGRainbowDBHunterKMSmithANDi GenovaGHerrMHDahlmanIPayneFSmythDLoweCTwellsRCHowlettSHealyBNutlandSRanceHEEverettVSminkLJLamACCordellHJWalkerNMBordinCHulmeJMotzoCCuccaFHessJFMetzkerMLRogersJGregorySAllahabadiaANithiyananthanRTuomilehto-WolfETuomilehtoJBingleyPGillespieKMUndlienDERonningenKSGujaCIonescu-TirgovisteCSavageDAMaxwellAPCarsonDJPattersonCCFranklynJAClaytonDGPetersonLBWickerLSToddJAGoughSC. Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature2003423506511doi:10.1038/nature01621.

15

ChistiakovDATurakulovRI. CTLA-4 and its role in autoimmune thyroid disease. Journal of Molecular Endocrinology2003312136doi:10.1677/jme.0.0310021.

16

KavvouraFKAkamizuTAwataTBanYChistiakovDAFrydeckaIGhaderiAGoughSCHiromatsuYPloskiRWangPWBednarczukTChistiakovaEIChojmMHewardJMHirataniHJuoSHKarabonLKatayamaSKuriharaSLiuRTMiyakeIOmraniGHPawlakETaniyamaMTozakiTIoannidisJP. Cytotoxic T-lymphocyte associated antigen 4 gene polymorphisms and autoimmune thyroid disease: a meta-analysis. Journal of Clinical Endocrinology and Metabolism20079231623170doi:10.1210/jc.2007-0147.

17

VaidyaBImrieHPerrosPDickinsonJMcCarthyMIKendall-TaylorPPearceSH. Cytotoxic T lymphocyte antigen-4 (CTLA-4) gene polymorphism confers susceptibility to thyroid associated orbitopathy. Lancet1999354743744doi:10.1016/S0140-6736(99)01465-8.

18

VaidyaBOakesEJImrieHDickinsonAJPerrosPKendall-TaylorPPearceSH. CTLA4 gene and Graves' disease: association of Graves' disease with the CTLA4 exon 1 and intron 1 polymorphisms, but not with the promoter polymorphism. Clinical Endocrinology200358732735doi:10.1046/j.1365-2265.2003.01778.x.

19

BednarczukTGopinathBPloskiRWallJR. Susceptibility genes in Graves' ophthalmopathy: searching for a needle in a haystack?Clinical Endocrinology200767319doi:10.1111/j.1365-2265.2007.02854.x.

20

HanSZhangSZhangWLiRLiYWangZXieYMaoY. CTLA4 polymorphisms and ophthalmopathy in Graves' disease patients: association study and meta-analysis. Human Immunology200667618626doi:10.1016/j.humimm.2006.05.003.

21

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