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Feb 25, 2024
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Abstract
Graves' Orbitopathy (GO), also known as thyroid eye disease or thyroid-associated orbitopathy is characterized by inflammation, ocular muscle hypertrophy, adipogenesis, and oedema (due to glycosaminoglycan accumulation). This condition leads to remodeling, tissue expansion, and/or fibrosis within the fibroadipose tissue or extraocular muscles of the orbit. GO manifests as an extrathyroidal aspect of autoimmune thyroid diseases in both Grave's disease (GD) and Hashimoto's thyroiditis.
The pathophysiological foundation of GO entails the infiltration of B cells, T cells, and CD34+ fibroblasts in the orbit. B cells generate IGF (insulin-like growth factor), wherein IGF and TRab (Thyroid-Receptor antibodies) stimulate the IGF receptor complex and thyrotropin receptor (respectively) on the surface of CD34+ cells which triggers orbital tissue expansion, orbital protrusion, optic nerve compression, and eyeball displacement, resulting in exophthalmos.
GO progress through an active phase (characterized by inflammation with visible manifestations), followed by a plateau phase (stabilization of GO manifestations), and a gradual resolution of distinctive residual signs and symptoms (inactive phase). This entire process spans between 18-24 months in untreated patients, where disease manifestations significantly depend on the phase during which the disease is identified.
GO therapy is intended to shorten the active phase and supress its residual eye manifestations during the inactive phase. In general, GO therapy is categorized into general and disease severity-specific approaches.
GO therapy often falls short of providing satisfactory results, prompting need of surgery to address lingering clinical manifestations. This review presents the latest insights into the pathogenesis and treatment of GO for better management and outcomes.
Article Details
This work is licensed under a Creative Commons Attribution 4.0 International License.
How to Cite
Ujianto, M., Sari, F., & Rakhman, M. F. (2024). Unveiling Modern Strategies for Diagnosing and Treating Grave Orbitopathy. Jurnal Klinik Dan Riset Kesehatan, 3(2), 89-106. https://doi.org/10.11594/jk-risk.03.2.4
References
1. Bartalena L, Kahaly GJ, Baldeschi L, Dayan CM, Eckstein A, Marcocci C, et al. The 2021 European Group on Graves’ orbitopathy (EUGOGO) clinical practice guidelines for the medical management of Graves’ orbitopathy. Eur J Endocrinol. 2021;185(4):G43–67.
2. González-García A, Sales-Sanz M. Treatment of Graves’ ophthalmopathy. Med Clínica (English Ed. 2021;156(4):180–6.
3. Macovei ML, Azis Ű, Gheorghe A, Burcea M. A systematic review of euthyroid Graves’ disease (Review). Exp Ther Med. 2021;22(5).
4. Kahaly GJ, Diana T, Glang J, Kanitz M, Pitz S, König J. Thyroid stimulating antibodies are highly prevalent in Hashimoto’s thyroiditis and associated orbitopathy. J Clin Endocrinol Metab. 2016;101(5):1998–2004.
5. Hou TY, Wu SB, Kau HC, Tsai CC. The role of oxidative stress and therapeutic potential of antioxidants in graves’ ophthalmopathy. Biomedicines. 2021;9(12):1–14.
6. Ren Z, Zhang H, Yu H, Zhu X, Lin J. Roles of four targets in the pathogenesis of graves’ orbitopathy. Heliyon. 2023;9(9):e19250.
7. Savitri AD, Sutjahjo A, Soelistijo SA, Baskoro A. Comparison of thyroid stimulating hormone receptor antibody (Trab) in graves’ disease patients with and without ophtalmopathy. New Armen Med J. 2019;13(4):39–46.
8. Subekti I, Boedisantoso A, Moeloek ND, Waspadji S, Mansyur M. Association of TSH receptor antibody, thyroid stimulating antibody, and thyroid blocking antibody with clinical activity score and degree of severity of Graves ophthalmopathy. Acta Med Indones. 2012;44(2):114–21.
9. Bartalena L, Piantanida E, Gallo D, Lai A, Tanda ML. Epidemiology, Natural History, Risk Factors, and Prevention of Graves’ Orbitopathy. Front Endocrinol (Lausanne). 2020;11(November):1–10.
10. Bartalena L, Tanda ML. Current concepts regarding Graves’ orbitopathy. J Intern Med. 2022;292(5):692–716.
11. Smith TJ. New advances in understanding thyroid-associated ophthalmopathy and the potential role for insulin-like growth factor-I receptor. F1000Research. 2018;7(0):1–9.
12. Muñoz-Ortiz J, Sierra-Cote MC, Zapata-Bravo E, Valenzuela-Vallejo L, Marin-Noriega MA, Uribe-Reina P, et al. Prevalence of hyperthyroidism, hypothyroidism, and euthyroidism in thyroid eye disease: A systematic review of the literature. Syst Rev. 2020;9(1).
13. Turck N, Eperon S, De Los Angeles Gracia M, Obéric A, Hamédani M. Thyroid-associated orbitopathy and biomarkers: Where we are and what we can hope for the future. Dis Markers. 2018;2018.
14. Whitacre CC. Sex differences in autoimmune disease. Nat Immunol. 2001;2(9):777–80.
15. Vermeulen A, Kaufman JM, Goemaere S, Van Pottelberg I. Estradiol in elderly men. Aging Male. 2002;5(2):98–102.
16. Orwoll E, Lambert LC, Marshall LM, Phipps K, Blank J, Barrett-Connor E, et al. Testosterone and estradiol among older men. J Clin Endocrinol Metab. 2006;91(4):1336–44.
17. Chailurkit LO, Aekplakorn W, Ongphiphadhanakul B. The relationship between circulating estradiol and thyroid autoimmunity in males. Eur J Endocrinol. 2014;170(1):63–7.
18. Khong JJ, Finch S, De Silva C, Rylander S, Craig JE, Selva D, et al. Risk factors for graves’ orbitopathy; The australian thyroid-associated orbitopathy research (ATOR) study. J Clin Endocrinol Metab. 2016;101(7):2711–20.
19. Mathur C, Singh S, Sharma S. Prevalence and risk factors of thyroid-associated ophthalmopathy among Indians. Int J Adv Med. 2016;3(3):662–5.
20. Lat AMM, Jauculan MC, Sanchez CA, Jimeno C, Sison-Peña CM, Pe-Yan MR, et al. Risk factors associated with the activity and severity of graves’ ophthalmopathy among patients at the university of the Philippines Manila-Philippine general hospital. J ASEAN Fed Endocr Soc. 2017;32(2):151–7.
21. Xia N, Zhou S, Liang Y, Xiao C, Shen H, Pan H, et al. CD4+ T cells and the Th1/Th2 imbalance are implicated in the pathogenesis of Graves’ ophthalmopathy. Int J Mol Med. 2006;17(5):911–6.
22. Fang S, Lu Y, Huang Y, Zhou H, Fan X. Mechanisms That Underly T Cell Immunity in Graves’ Orbitopathy. Front Endocrinol (Lausanne). 2021;12(April):1–17.
23. Huang Y, Fang S, Li D, Zhou H, Li B, Fan X. The involvement of T cell pathogenesis in thyroid-associated ophthalmopathy. Eye. 2019;33(2):176–82.
24. Salvi M, Covelli D. B cells in Graves’ Orbitopathy: more than just a source of antibodies? Eye. 2019;33(2):230–4.
25. Tang F, Chen X, Mao Y, Wan S, Ai S, Yang H, et al. Orbital fibroblasts of Graves’ orbitopathy stimulated with proinflammatory cytokines promote B cell survival by secreting BAFF. Mol Cell Endocrinol. 2017;446:1–11.
26. Chen G, Ding Y, Li Q, Li Y, Wen X, Ji X, et al. Defective Regulatory B Cells Are Associated with Thyroid-Associated Ophthalmopathy. J Clin Endocrinol Metab. 2019;104(9):4067–77.
27. Fang S, Huang Y, Liu X, Zhong S, Wang N, Zhao B, et al. Interaction between CCR6 + TH17 cells and CD34 + fibrocytes promotes inflammation: Implications in graves’ orbitopathy in Chinese population. Investig Ophthalmol Vis Sci. 2018;59(6):2604–14.
28. Wang Y, Chen Z, Wang T, Guo H, Liu Y, Dang N, et al. A novel CD4+ CTL subtype characterized by chemotaxis and inflammation is involved in the pathogenesis of Graves’ orbitopathy. Cell Mol Immunol. 2021;18(3):735–45.
29. Smith TJ. Potential Roles of CD34 + Fibrocytes Masquerading as Orbital Fibroblasts in Thyroid-Associated Ophthalmopathy. J Clin Endocrinol Metab. 2018;104(2):581–94.
30. Douglas RS, Gianoukakis AG, Kamat S, Smith TJ. Aberrant Expression of the Insulin-Like Growth Factor-1 Receptor by T Cells from Patients with Graves’ Disease May Carry Functional Consequences for Disease Pathogenesis. J Immunol. 2007;178(5):3281–7.
31. Douglas RS, Naik V, Hwang CJ, Afifiyan NF, Gianoukakis AG, Sand D, et al. B Cells from Patients with Graves’ Disease Aberrantly Express the IGF-1 Receptor: Implications for Disease Pathogenesis. J Immunol. 2008;181(8):5768–74.
32. Tsui S, Naik V, Hoa N, Hwang CJ, Afifiyan NF, Sinha Hikim A, et al. Evidence for an Association between Thyroid-Stimulating Hormone and Insulin-Like Growth Factor 1 Receptors: A Tale of Two Antigens Implicated in Graves’ Disease. J Immunol. 2008;181(6):4397–405.
33. Pritchard J, Horst N, Cruikshank W, Smith TJ. Igs from Patients with Graves’ Disease Induce the Expression of T Cell Chemoattractants in Their Fibroblasts. J Immunol. 2002;168(2):942–50.
34. Fernando R, Caldera O, Smith TJ. Therapeutic IGF-I receptor inhibition alters fibrocyte immune phenotype in thyroid-associated ophthalmopathy. Proc Natl Acad Sci U S A. 2021;118(52):1–10.
35. Smith TJ, Hoa N. Immunoglobulins from patients with graves’ disease induce hyaluronan synthesis in their orbital fibroblasts through the self-antigen, insulin-like growth factor-I receptor. J Clin Endocrinol Metab. 2004;89(10):5076–80.
36. Niedermeier M, Reich B, Gomez MR, Denzel A, Schmidbauer K, Göbel N, et al. CD4+ T cells control the differentiation of Gr1+ monocytes into fibrocytes. Proc Natl Acad Sci U S A. 2009;106(42):17892–7.
37. Abe R, Donnelly SC, Peng T, Bucala R, Metz CN. Peripheral Blood Fibrocytes: Differentiation Pathway and Migration to Wound Sites. J Imminol. 2001;166(12):7566–7562.
38. Fernando R, Grisolia ABD, Lu Y, Atkins S, Smith TJ. Slit2 Modulates the Inflammatory Phenotype of Orbit-Infiltrating Fibrocytes in Graves’ Disease. J Immunol. 2018;200(12):3942–9.
39. Kanda H, Tateya S, Tamori Y, Kotani K, Hiasa K ichi, Kitazawa R, et al. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity1. Kanda H, Tateya S, Tamori Y, Kotani K, Hiasa K, Kitazawa R, Kitazawa S, Miyachi H, Maeda S, Egashira K, others. MCP-1 contributes to m. J Clin Invest. 2006;116(6):1494.
40. Zhang X, Liu Z, Li W, Kang Y, Xu Z, Li X, et al. MAPKs/AP-1. not NF-κB, is responsible for MCP-1 production in TNF-α-activated adipocytes. Adipocyte. 2022;11(1):477–86.
41. Luo X, Gao ZX, Lin SW, Tong ML, Liu LL, Lin LR, et al. Recombinant Treponema pallidum protein Tp0136 promotes fibroblast migration by modulating MCP-1/CCR2 through TLR4. J Eur Acad Dermatology Venereol. 2020;34(4):862–72.
42. Xin Z, Hua L, Yang YL, Shi TT, Liu W, Tuo X, et al. A pathway analysis based on genome-wide DNA methylation of Chinese patients with graves’ orbitopathy. Biomed Res Int. 2019;2019.
43. Cao JM, Wang N, Hou SY, Qi X, Xiong W. Epigenetics effect on pathogenesis of thyroid-associated ophthalmopathy. Int J Ophthalmol. 2021;14(9):1441–8.
44. Matheis N, Lantz M, Grus FH, Ponto KA, Wolters D, Brorson H, et al. Proteomics of orbital tissue in thyroid-associated orbitopathy. J Clin Endocrinol Metab. 2015;100(12):E1523–30.
45. Zhu FF, Yang LZ. Bioinformatic analysis identifies potentially key differentially expressed genes and pathways in orbital adipose tissues of patients with thyroid eye disease. Acta Endocrinol (Copenh). 2019;15(1):1–8.
46. Lee JY, Gallo RA, Ledon PJ, Tao W, Tse DT, Pelaez D, et al. Integrating differential gene expression analysis with perturbagen-response signatures may identify novel therapies for thyroid-associated orbitopathy. Transl Vis Sci Technol. 2020;9(9):1–12.
47. Palareti G, Legnani C, Cosmi B, Antonucci E, Erba N, Poli D, et al. Comparison between different D-Dimer cutoff values to assess the individual risk of recurrent venous thromboembolism: Analysis of results obtained in the DULCIS study. Int J Lab Hematol. 2016;38(1):42–9.
48. Kwak EA, Pan CC, Ramonett A, Kumar S, Cruz-Flores P, Ahmed T, et al. βIV-spectrin as a stalk cell-intrinsic regulator of VEGF signaling. Nat Commun. 2022;13(1).
49. Tamura K, Miyata K, Sugahara K, Onishi S, Shuin T, Aso T. Identification of EloA-BP1. a novel Elongin A binding protein with an exonuclease homology domain. Biochem Biophys Res Commun. 2003;309(1):189–95.
50. Boyer DS, Rippmann JF, Ehrlich MS, Bakker RA, Chong V, Nguyen QD. Amine oxidase copper-containing 3 (AOC3) inhibition: a potential novel target for the management of diabetic retinopathy. Int J Retin Vitr. 2021;7(1):1–12.
51. Park BS, Im HL, Yoon NA, Tu TH, Park JW, Kim JG, et al. Developmentally regulated GTP-binding protein-2 regulates adipocyte differentiation. Biochem Biophys Res Commun. 2021;578:1–6.
52. Bunker RD, Bulloch EMM, Dickson JMJ, Loomes KM, Baker EN. Structure and function of human xylulokinase, an enzyme with important roles in carbohydrate metabolism. J Biol Chem. 2013;288(3):1643–52.
53. Besant PG, Attwood P V. Histone H4 histidine phosphorylation: Kinases, phosphatases, liver regeneration and cancer. Biochem Soc Trans. 2012;40(1):290–3.
54. Bolz H, Ramírez A, Von Brederlow B, Kubisch C. Characterization of ADAMTS14. a novel member of the ADAMTS metalloproteinase family. Biochim Biophys Acta - Gene Struct Expr. 2001;1522(3):221–5.
55. Qazi S, Jit BP, Das A, Karthikeyan M, Saxena A, Ray MD, et al. BESFA: bioinformatics based evolutionary, structural & functional analysis of prostrate, Placenta, Ovary, Testis, and Embryo (POTE) paralogs. Heliyon. 2022;8(9):e10476.
56. Raz A, Nakahara S. Biological Modulation by Lectins and Their Ligands in Tumor Progression and Metastasis. Anticancer Agents Med Chem. 2008;8(1):22–36.
57. Kaur S, Van Bergen NJ, Verhey KJ, Nowell CJ, Budaitis B, Yue Y, et al. Expansion of the phenotypic spectrum of de novo missense variants in kinesin family member 1A (KIF1A). Hum Mutat. 2020;41(10):1761–74.
58. Lim HI, Hajjar KA. Annexin A2 in fibrinolysis, inflammation and fibrosis. Int J Mol Sci. 2021;22(13):1–14.
59. Jung IH, Jung DWE, Chung YY, Kim KS, Park SW. Iroquois Homeobox 1 Acts as a True Tumor Suppressor in Multiple Organs by Regulating Cell Cycle Progression. Neoplasia (United States). 2019;21(10):1003–14.
60. Luo B, Feng S, Li T, Wang J, Qi Z, Zhao Y, et al. Transcription factor HOXB2 upregulates NUSAP1 to promote the proliferation, invasion and migration of nephroblastoma cells via the PI3K/Akt signaling pathway. Mol Med Rep. 2022;25(6):1–10.
61. Langeh U, Singh S. Targeting S100B Protein as a Surrogate Biomarker and its Role in Various Neurological Disorders. Curr Neuropharmacol. 2020;19(2):265–77.
62. Zhang C, Li T, Chiu KY, Wen C, Xu A, Yan CH. FABP4 as a biomarker for knee osteoarthritis. Biomark Med. 2018;12(2):107–18.
63. Li J, Guo C, Wu J. The Agonists of Peroxisome Proliferator-Activated Receptor-γ for Liver Fibrosis. Drug Des Devel Ther. 2021;15:2619–28.
64. Blom JMC, Ottaviani E. Immune-Neuroendocrine Interactions: Evolution, Ecology, and Susceptibility to Illness. Med Sci Monit Basic Res. 2017;23:362–7.
65. Saini DK, Karunarathne WKA, Angaswamy N, Saini D, Cho JH, Kalyanaraman V, et al. Regulation of Golgi structure and secretion by receptor-induced G protein βγ complex translocation. Proc Natl Acad Sci U S A. 2010;107(25):11417–22.
66. Liu Y, Feng Q, Miao J, Wu Q, Zhou S, Shen W, et al. C-X-C motif chemokine receptor 4 aggravates renal fibrosis through activating JAK/STAT/GSK3β/β-catenin pathway. Oncol Lett. 2018;16:3976–82.
67. He W, Yang T, Gong XH, Qin RZ, Zhang XD, Liu WD. Targeting CXC motif chemokine receptor 4 inhibits the proliferation, migration and angiogenesis of lung cancer cells. Oncol Lett. 2018;16(3):3976–82.
68. Rogero MM, Calder PC. Obesity, inflammation, toll-like receptor 4 and fatty acids. Nutrients. 2018;10(4):1–19.
69. Kumari A, Silakari O, Singh RK. Recent advances in colony stimulating factor-1 receptor/c-FMS as an emerging target for various therapeutic implications. Biomed Pharmacother. 2018;103(April):662–79.
70. Fayyaz S, Japtok L, Schumacher F, Wigger D, Schulz TJ, Haubold K, et al. Lysophosphatidic Acid Inhibits Insulin Signaling in Primary Rat Hepatocytes via the LPA 3 Receptor Subtype and is Increased in Obesity. Cell Physiol Biochem. 2017;43(2):445–56.
71. Shano S, Hatanaka K, Ninose S, Moriyama R, Tsujiuchi T, Fukushima N. A lysophosphatidic acid receptor lacking the PDZ-binding domain is constitutively active and stimulates cell proliferation. Biochim Biophys Acta - Mol Cell Res. 2008;1783(5):748–59.
72. Goldsmith ZG, Ha JH, Jayaraman M, Dhanasekaran DN. Lysophosphatidic Acid Stimulates the Proliferation of Ovarian Cancer Cells via the gep Proto-Oncogene Gα12. Genes Cancer. 2011;2(5):563–75.
73. Du B, Wang Y, Yang M, He W. Clinical features and clinical course of thyroid-associated ophthalmopathy: a case series of 3620 Chinese cases. Eye. 2021;35(8):2294–301.
74. Li X, Li S, Fan W, Rokohl AC, Ju S, Ju X, et al. Recent advances in graves ophthalmopathy medical therapy: a comprehensive literature review. Int Ophthalmol. 2023;43(4):1437–49.
75. Maheshwari R, Weis E. Thyroid associated orbitopathy. Indian J Ophthalmol. 2012;60(2):87–93.
76. Gontarz-Nowak K, Szychlińska M, Matuszewski W, Stefanowicz-Rutkowska M, Bandurska-Stankiewicz E. Current knowledge on graves’ orbitopathy. J Clin Med. 2021;10(1):1–23.
77. Muralidhar A, Das S, Tiple S. Clinical profile of thyroid eye disease and factors predictive of disease severity. Indian J Ophthalmol. 2020;68(8):1629–34.
78. Davies MJ, Dolman PJ. Levator Muscle Enlargement in Thyroid Eye Disease-Related Upper Eyelid Retraction. Ophthal Plast Reconstr Surg. 2017;33(1):35–9.
79. Rashad R, Pinto R, Li E, Sohrab M, Distefano AG. Thyroid eye disease. life. 2022;12(2):2084.
80. Bahn RS. Graves’ Ophthalmopathy-Mechanism of Disease. N Engl J Med. 2010;362(8):726-38.
81. Prummel MF, Bakker A, Wiersinga WM, Baldeschi L, Mourits MP, Kendall-Taylor P, et al. Multi-center study on the characteristics and treatment strategies of patients with Graves’ orbitopathy: The first European Group on Graves’ Orbitopathy experience. Eur J Endocrinol. 2003;148(5):491–5.
82. Soroudi AE, Goldberg RA, McCann JD. Prevalence of asymmetric exophthalmos in Graves orbitopathy. Ophthal Plast Reconstr Surg. 2004;20(3):224–5.
83. Daumerie C, Duprez T, Boschi A. Long-term multidisciplinary follow-up of unilateral thyroid-associated orbitopathy. Eur J Intern Med. 2008;19(7):531–6.
84. Strianese D, Piscopo R, Elefante A, Napoli M, Comune C, Baronissi I, et al. Unilateral proptosis in thyroid eye disease with subsequent contralateral involvement: Retrospective follow-up study. BMC Ophthalmol. 2013;13(1).
85. Eckstein AK, Lösch C, Glowacka D, Schott M, Mann K, Esser J, et al. Euthyroid and primarily hypothyroid patients develop milder and significantly more asymmetrical Graves ophthalmopathy. Br J Ophthalmol. 2009;93(8):1052–6.
86. Mourits MP. Diagnosis and Differential Diagnosis of Graves’ Orbitopathy. In: Wiersinga WM, Kahaly GJ, editors. Graves’ Orbitopathy. 3rd ed. Basel: Karger; 2017. p. 74.
87. Hutchings KR, Fritzhand SJ, Esmaeli B, Koka K, Zhao J, Ahmed S, et al. Graves’ Eye Disease: Clinical and Radiological Diagnosis. Biomedicines. 2023;11(2).
88. Mourits MP. Diagnosis of Graves’ Orbitopathy. In: Gooris PJ, Mourits MP, Bergsma J, editors. Surgery in and around the Orbit. Breda: Springer Cham; 2023. p. 271–277.
89. Tortora F, Cirillo M, Ferrara M, Belfiore MP, Carella C, Caranci F, et al. Disease activity in graves’ ophthalmopathy: Diagnosis with orbital MR imaging and correlation with clinical score. Neuroradiol J. 2013;26(5):555–64.
90. Chng CL, Seah LL, Khoo DHC. Ethnic differences in the clinical presentation of Graves’ ophthalmopathy. Best Pract Res Clin Endocrinol Metab. 2012;26(3):249–58.
91. Barrio-Barrio J, Sabater AL, Bonet-Farriol E, Velázquez-Villoria Á, Galofré JC. Graves’ ophthalmopathy: VISA versus EUGOGO classification, assessment, and management. J Ophthalmol. 2015;2015.
92. Hoang TD, Stocker DJ, Chou EL, Burch HB. 2022 Update on Clinical Management of Graves’ Disease and Thyroid Eye Disease. J Pediatr. 2022;51(2):287–304.
2. González-García A, Sales-Sanz M. Treatment of Graves’ ophthalmopathy. Med Clínica (English Ed. 2021;156(4):180–6.
3. Macovei ML, Azis Ű, Gheorghe A, Burcea M. A systematic review of euthyroid Graves’ disease (Review). Exp Ther Med. 2021;22(5).
4. Kahaly GJ, Diana T, Glang J, Kanitz M, Pitz S, König J. Thyroid stimulating antibodies are highly prevalent in Hashimoto’s thyroiditis and associated orbitopathy. J Clin Endocrinol Metab. 2016;101(5):1998–2004.
5. Hou TY, Wu SB, Kau HC, Tsai CC. The role of oxidative stress and therapeutic potential of antioxidants in graves’ ophthalmopathy. Biomedicines. 2021;9(12):1–14.
6. Ren Z, Zhang H, Yu H, Zhu X, Lin J. Roles of four targets in the pathogenesis of graves’ orbitopathy. Heliyon. 2023;9(9):e19250.
7. Savitri AD, Sutjahjo A, Soelistijo SA, Baskoro A. Comparison of thyroid stimulating hormone receptor antibody (Trab) in graves’ disease patients with and without ophtalmopathy. New Armen Med J. 2019;13(4):39–46.
8. Subekti I, Boedisantoso A, Moeloek ND, Waspadji S, Mansyur M. Association of TSH receptor antibody, thyroid stimulating antibody, and thyroid blocking antibody with clinical activity score and degree of severity of Graves ophthalmopathy. Acta Med Indones. 2012;44(2):114–21.
9. Bartalena L, Piantanida E, Gallo D, Lai A, Tanda ML. Epidemiology, Natural History, Risk Factors, and Prevention of Graves’ Orbitopathy. Front Endocrinol (Lausanne). 2020;11(November):1–10.
10. Bartalena L, Tanda ML. Current concepts regarding Graves’ orbitopathy. J Intern Med. 2022;292(5):692–716.
11. Smith TJ. New advances in understanding thyroid-associated ophthalmopathy and the potential role for insulin-like growth factor-I receptor. F1000Research. 2018;7(0):1–9.
12. Muñoz-Ortiz J, Sierra-Cote MC, Zapata-Bravo E, Valenzuela-Vallejo L, Marin-Noriega MA, Uribe-Reina P, et al. Prevalence of hyperthyroidism, hypothyroidism, and euthyroidism in thyroid eye disease: A systematic review of the literature. Syst Rev. 2020;9(1).
13. Turck N, Eperon S, De Los Angeles Gracia M, Obéric A, Hamédani M. Thyroid-associated orbitopathy and biomarkers: Where we are and what we can hope for the future. Dis Markers. 2018;2018.
14. Whitacre CC. Sex differences in autoimmune disease. Nat Immunol. 2001;2(9):777–80.
15. Vermeulen A, Kaufman JM, Goemaere S, Van Pottelberg I. Estradiol in elderly men. Aging Male. 2002;5(2):98–102.
16. Orwoll E, Lambert LC, Marshall LM, Phipps K, Blank J, Barrett-Connor E, et al. Testosterone and estradiol among older men. J Clin Endocrinol Metab. 2006;91(4):1336–44.
17. Chailurkit LO, Aekplakorn W, Ongphiphadhanakul B. The relationship between circulating estradiol and thyroid autoimmunity in males. Eur J Endocrinol. 2014;170(1):63–7.
18. Khong JJ, Finch S, De Silva C, Rylander S, Craig JE, Selva D, et al. Risk factors for graves’ orbitopathy; The australian thyroid-associated orbitopathy research (ATOR) study. J Clin Endocrinol Metab. 2016;101(7):2711–20.
19. Mathur C, Singh S, Sharma S. Prevalence and risk factors of thyroid-associated ophthalmopathy among Indians. Int J Adv Med. 2016;3(3):662–5.
20. Lat AMM, Jauculan MC, Sanchez CA, Jimeno C, Sison-Peña CM, Pe-Yan MR, et al. Risk factors associated with the activity and severity of graves’ ophthalmopathy among patients at the university of the Philippines Manila-Philippine general hospital. J ASEAN Fed Endocr Soc. 2017;32(2):151–7.
21. Xia N, Zhou S, Liang Y, Xiao C, Shen H, Pan H, et al. CD4+ T cells and the Th1/Th2 imbalance are implicated in the pathogenesis of Graves’ ophthalmopathy. Int J Mol Med. 2006;17(5):911–6.
22. Fang S, Lu Y, Huang Y, Zhou H, Fan X. Mechanisms That Underly T Cell Immunity in Graves’ Orbitopathy. Front Endocrinol (Lausanne). 2021;12(April):1–17.
23. Huang Y, Fang S, Li D, Zhou H, Li B, Fan X. The involvement of T cell pathogenesis in thyroid-associated ophthalmopathy. Eye. 2019;33(2):176–82.
24. Salvi M, Covelli D. B cells in Graves’ Orbitopathy: more than just a source of antibodies? Eye. 2019;33(2):230–4.
25. Tang F, Chen X, Mao Y, Wan S, Ai S, Yang H, et al. Orbital fibroblasts of Graves’ orbitopathy stimulated with proinflammatory cytokines promote B cell survival by secreting BAFF. Mol Cell Endocrinol. 2017;446:1–11.
26. Chen G, Ding Y, Li Q, Li Y, Wen X, Ji X, et al. Defective Regulatory B Cells Are Associated with Thyroid-Associated Ophthalmopathy. J Clin Endocrinol Metab. 2019;104(9):4067–77.
27. Fang S, Huang Y, Liu X, Zhong S, Wang N, Zhao B, et al. Interaction between CCR6 + TH17 cells and CD34 + fibrocytes promotes inflammation: Implications in graves’ orbitopathy in Chinese population. Investig Ophthalmol Vis Sci. 2018;59(6):2604–14.
28. Wang Y, Chen Z, Wang T, Guo H, Liu Y, Dang N, et al. A novel CD4+ CTL subtype characterized by chemotaxis and inflammation is involved in the pathogenesis of Graves’ orbitopathy. Cell Mol Immunol. 2021;18(3):735–45.
29. Smith TJ. Potential Roles of CD34 + Fibrocytes Masquerading as Orbital Fibroblasts in Thyroid-Associated Ophthalmopathy. J Clin Endocrinol Metab. 2018;104(2):581–94.
30. Douglas RS, Gianoukakis AG, Kamat S, Smith TJ. Aberrant Expression of the Insulin-Like Growth Factor-1 Receptor by T Cells from Patients with Graves’ Disease May Carry Functional Consequences for Disease Pathogenesis. J Immunol. 2007;178(5):3281–7.
31. Douglas RS, Naik V, Hwang CJ, Afifiyan NF, Gianoukakis AG, Sand D, et al. B Cells from Patients with Graves’ Disease Aberrantly Express the IGF-1 Receptor: Implications for Disease Pathogenesis. J Immunol. 2008;181(8):5768–74.
32. Tsui S, Naik V, Hoa N, Hwang CJ, Afifiyan NF, Sinha Hikim A, et al. Evidence for an Association between Thyroid-Stimulating Hormone and Insulin-Like Growth Factor 1 Receptors: A Tale of Two Antigens Implicated in Graves’ Disease. J Immunol. 2008;181(6):4397–405.
33. Pritchard J, Horst N, Cruikshank W, Smith TJ. Igs from Patients with Graves’ Disease Induce the Expression of T Cell Chemoattractants in Their Fibroblasts. J Immunol. 2002;168(2):942–50.
34. Fernando R, Caldera O, Smith TJ. Therapeutic IGF-I receptor inhibition alters fibrocyte immune phenotype in thyroid-associated ophthalmopathy. Proc Natl Acad Sci U S A. 2021;118(52):1–10.
35. Smith TJ, Hoa N. Immunoglobulins from patients with graves’ disease induce hyaluronan synthesis in their orbital fibroblasts through the self-antigen, insulin-like growth factor-I receptor. J Clin Endocrinol Metab. 2004;89(10):5076–80.
36. Niedermeier M, Reich B, Gomez MR, Denzel A, Schmidbauer K, Göbel N, et al. CD4+ T cells control the differentiation of Gr1+ monocytes into fibrocytes. Proc Natl Acad Sci U S A. 2009;106(42):17892–7.
37. Abe R, Donnelly SC, Peng T, Bucala R, Metz CN. Peripheral Blood Fibrocytes: Differentiation Pathway and Migration to Wound Sites. J Imminol. 2001;166(12):7566–7562.
38. Fernando R, Grisolia ABD, Lu Y, Atkins S, Smith TJ. Slit2 Modulates the Inflammatory Phenotype of Orbit-Infiltrating Fibrocytes in Graves’ Disease. J Immunol. 2018;200(12):3942–9.
39. Kanda H, Tateya S, Tamori Y, Kotani K, Hiasa K ichi, Kitazawa R, et al. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity1. Kanda H, Tateya S, Tamori Y, Kotani K, Hiasa K, Kitazawa R, Kitazawa S, Miyachi H, Maeda S, Egashira K, others. MCP-1 contributes to m. J Clin Invest. 2006;116(6):1494.
40. Zhang X, Liu Z, Li W, Kang Y, Xu Z, Li X, et al. MAPKs/AP-1. not NF-κB, is responsible for MCP-1 production in TNF-α-activated adipocytes. Adipocyte. 2022;11(1):477–86.
41. Luo X, Gao ZX, Lin SW, Tong ML, Liu LL, Lin LR, et al. Recombinant Treponema pallidum protein Tp0136 promotes fibroblast migration by modulating MCP-1/CCR2 through TLR4. J Eur Acad Dermatology Venereol. 2020;34(4):862–72.
42. Xin Z, Hua L, Yang YL, Shi TT, Liu W, Tuo X, et al. A pathway analysis based on genome-wide DNA methylation of Chinese patients with graves’ orbitopathy. Biomed Res Int. 2019;2019.
43. Cao JM, Wang N, Hou SY, Qi X, Xiong W. Epigenetics effect on pathogenesis of thyroid-associated ophthalmopathy. Int J Ophthalmol. 2021;14(9):1441–8.
44. Matheis N, Lantz M, Grus FH, Ponto KA, Wolters D, Brorson H, et al. Proteomics of orbital tissue in thyroid-associated orbitopathy. J Clin Endocrinol Metab. 2015;100(12):E1523–30.
45. Zhu FF, Yang LZ. Bioinformatic analysis identifies potentially key differentially expressed genes and pathways in orbital adipose tissues of patients with thyroid eye disease. Acta Endocrinol (Copenh). 2019;15(1):1–8.
46. Lee JY, Gallo RA, Ledon PJ, Tao W, Tse DT, Pelaez D, et al. Integrating differential gene expression analysis with perturbagen-response signatures may identify novel therapies for thyroid-associated orbitopathy. Transl Vis Sci Technol. 2020;9(9):1–12.
47. Palareti G, Legnani C, Cosmi B, Antonucci E, Erba N, Poli D, et al. Comparison between different D-Dimer cutoff values to assess the individual risk of recurrent venous thromboembolism: Analysis of results obtained in the DULCIS study. Int J Lab Hematol. 2016;38(1):42–9.
48. Kwak EA, Pan CC, Ramonett A, Kumar S, Cruz-Flores P, Ahmed T, et al. βIV-spectrin as a stalk cell-intrinsic regulator of VEGF signaling. Nat Commun. 2022;13(1).
49. Tamura K, Miyata K, Sugahara K, Onishi S, Shuin T, Aso T. Identification of EloA-BP1. a novel Elongin A binding protein with an exonuclease homology domain. Biochem Biophys Res Commun. 2003;309(1):189–95.
50. Boyer DS, Rippmann JF, Ehrlich MS, Bakker RA, Chong V, Nguyen QD. Amine oxidase copper-containing 3 (AOC3) inhibition: a potential novel target for the management of diabetic retinopathy. Int J Retin Vitr. 2021;7(1):1–12.
51. Park BS, Im HL, Yoon NA, Tu TH, Park JW, Kim JG, et al. Developmentally regulated GTP-binding protein-2 regulates adipocyte differentiation. Biochem Biophys Res Commun. 2021;578:1–6.
52. Bunker RD, Bulloch EMM, Dickson JMJ, Loomes KM, Baker EN. Structure and function of human xylulokinase, an enzyme with important roles in carbohydrate metabolism. J Biol Chem. 2013;288(3):1643–52.
53. Besant PG, Attwood P V. Histone H4 histidine phosphorylation: Kinases, phosphatases, liver regeneration and cancer. Biochem Soc Trans. 2012;40(1):290–3.
54. Bolz H, Ramírez A, Von Brederlow B, Kubisch C. Characterization of ADAMTS14. a novel member of the ADAMTS metalloproteinase family. Biochim Biophys Acta - Gene Struct Expr. 2001;1522(3):221–5.
55. Qazi S, Jit BP, Das A, Karthikeyan M, Saxena A, Ray MD, et al. BESFA: bioinformatics based evolutionary, structural & functional analysis of prostrate, Placenta, Ovary, Testis, and Embryo (POTE) paralogs. Heliyon. 2022;8(9):e10476.
56. Raz A, Nakahara S. Biological Modulation by Lectins and Their Ligands in Tumor Progression and Metastasis. Anticancer Agents Med Chem. 2008;8(1):22–36.
57. Kaur S, Van Bergen NJ, Verhey KJ, Nowell CJ, Budaitis B, Yue Y, et al. Expansion of the phenotypic spectrum of de novo missense variants in kinesin family member 1A (KIF1A). Hum Mutat. 2020;41(10):1761–74.
58. Lim HI, Hajjar KA. Annexin A2 in fibrinolysis, inflammation and fibrosis. Int J Mol Sci. 2021;22(13):1–14.
59. Jung IH, Jung DWE, Chung YY, Kim KS, Park SW. Iroquois Homeobox 1 Acts as a True Tumor Suppressor in Multiple Organs by Regulating Cell Cycle Progression. Neoplasia (United States). 2019;21(10):1003–14.
60. Luo B, Feng S, Li T, Wang J, Qi Z, Zhao Y, et al. Transcription factor HOXB2 upregulates NUSAP1 to promote the proliferation, invasion and migration of nephroblastoma cells via the PI3K/Akt signaling pathway. Mol Med Rep. 2022;25(6):1–10.
61. Langeh U, Singh S. Targeting S100B Protein as a Surrogate Biomarker and its Role in Various Neurological Disorders. Curr Neuropharmacol. 2020;19(2):265–77.
62. Zhang C, Li T, Chiu KY, Wen C, Xu A, Yan CH. FABP4 as a biomarker for knee osteoarthritis. Biomark Med. 2018;12(2):107–18.
63. Li J, Guo C, Wu J. The Agonists of Peroxisome Proliferator-Activated Receptor-γ for Liver Fibrosis. Drug Des Devel Ther. 2021;15:2619–28.
64. Blom JMC, Ottaviani E. Immune-Neuroendocrine Interactions: Evolution, Ecology, and Susceptibility to Illness. Med Sci Monit Basic Res. 2017;23:362–7.
65. Saini DK, Karunarathne WKA, Angaswamy N, Saini D, Cho JH, Kalyanaraman V, et al. Regulation of Golgi structure and secretion by receptor-induced G protein βγ complex translocation. Proc Natl Acad Sci U S A. 2010;107(25):11417–22.
66. Liu Y, Feng Q, Miao J, Wu Q, Zhou S, Shen W, et al. C-X-C motif chemokine receptor 4 aggravates renal fibrosis through activating JAK/STAT/GSK3β/β-catenin pathway. Oncol Lett. 2018;16:3976–82.
67. He W, Yang T, Gong XH, Qin RZ, Zhang XD, Liu WD. Targeting CXC motif chemokine receptor 4 inhibits the proliferation, migration and angiogenesis of lung cancer cells. Oncol Lett. 2018;16(3):3976–82.
68. Rogero MM, Calder PC. Obesity, inflammation, toll-like receptor 4 and fatty acids. Nutrients. 2018;10(4):1–19.
69. Kumari A, Silakari O, Singh RK. Recent advances in colony stimulating factor-1 receptor/c-FMS as an emerging target for various therapeutic implications. Biomed Pharmacother. 2018;103(April):662–79.
70. Fayyaz S, Japtok L, Schumacher F, Wigger D, Schulz TJ, Haubold K, et al. Lysophosphatidic Acid Inhibits Insulin Signaling in Primary Rat Hepatocytes via the LPA 3 Receptor Subtype and is Increased in Obesity. Cell Physiol Biochem. 2017;43(2):445–56.
71. Shano S, Hatanaka K, Ninose S, Moriyama R, Tsujiuchi T, Fukushima N. A lysophosphatidic acid receptor lacking the PDZ-binding domain is constitutively active and stimulates cell proliferation. Biochim Biophys Acta - Mol Cell Res. 2008;1783(5):748–59.
72. Goldsmith ZG, Ha JH, Jayaraman M, Dhanasekaran DN. Lysophosphatidic Acid Stimulates the Proliferation of Ovarian Cancer Cells via the gep Proto-Oncogene Gα12. Genes Cancer. 2011;2(5):563–75.
73. Du B, Wang Y, Yang M, He W. Clinical features and clinical course of thyroid-associated ophthalmopathy: a case series of 3620 Chinese cases. Eye. 2021;35(8):2294–301.
74. Li X, Li S, Fan W, Rokohl AC, Ju S, Ju X, et al. Recent advances in graves ophthalmopathy medical therapy: a comprehensive literature review. Int Ophthalmol. 2023;43(4):1437–49.
75. Maheshwari R, Weis E. Thyroid associated orbitopathy. Indian J Ophthalmol. 2012;60(2):87–93.
76. Gontarz-Nowak K, Szychlińska M, Matuszewski W, Stefanowicz-Rutkowska M, Bandurska-Stankiewicz E. Current knowledge on graves’ orbitopathy. J Clin Med. 2021;10(1):1–23.
77. Muralidhar A, Das S, Tiple S. Clinical profile of thyroid eye disease and factors predictive of disease severity. Indian J Ophthalmol. 2020;68(8):1629–34.
78. Davies MJ, Dolman PJ. Levator Muscle Enlargement in Thyroid Eye Disease-Related Upper Eyelid Retraction. Ophthal Plast Reconstr Surg. 2017;33(1):35–9.
79. Rashad R, Pinto R, Li E, Sohrab M, Distefano AG. Thyroid eye disease. life. 2022;12(2):2084.
80. Bahn RS. Graves’ Ophthalmopathy-Mechanism of Disease. N Engl J Med. 2010;362(8):726-38.
81. Prummel MF, Bakker A, Wiersinga WM, Baldeschi L, Mourits MP, Kendall-Taylor P, et al. Multi-center study on the characteristics and treatment strategies of patients with Graves’ orbitopathy: The first European Group on Graves’ Orbitopathy experience. Eur J Endocrinol. 2003;148(5):491–5.
82. Soroudi AE, Goldberg RA, McCann JD. Prevalence of asymmetric exophthalmos in Graves orbitopathy. Ophthal Plast Reconstr Surg. 2004;20(3):224–5.
83. Daumerie C, Duprez T, Boschi A. Long-term multidisciplinary follow-up of unilateral thyroid-associated orbitopathy. Eur J Intern Med. 2008;19(7):531–6.
84. Strianese D, Piscopo R, Elefante A, Napoli M, Comune C, Baronissi I, et al. Unilateral proptosis in thyroid eye disease with subsequent contralateral involvement: Retrospective follow-up study. BMC Ophthalmol. 2013;13(1).
85. Eckstein AK, Lösch C, Glowacka D, Schott M, Mann K, Esser J, et al. Euthyroid and primarily hypothyroid patients develop milder and significantly more asymmetrical Graves ophthalmopathy. Br J Ophthalmol. 2009;93(8):1052–6.
86. Mourits MP. Diagnosis and Differential Diagnosis of Graves’ Orbitopathy. In: Wiersinga WM, Kahaly GJ, editors. Graves’ Orbitopathy. 3rd ed. Basel: Karger; 2017. p. 74.
87. Hutchings KR, Fritzhand SJ, Esmaeli B, Koka K, Zhao J, Ahmed S, et al. Graves’ Eye Disease: Clinical and Radiological Diagnosis. Biomedicines. 2023;11(2).
88. Mourits MP. Diagnosis of Graves’ Orbitopathy. In: Gooris PJ, Mourits MP, Bergsma J, editors. Surgery in and around the Orbit. Breda: Springer Cham; 2023. p. 271–277.
89. Tortora F, Cirillo M, Ferrara M, Belfiore MP, Carella C, Caranci F, et al. Disease activity in graves’ ophthalmopathy: Diagnosis with orbital MR imaging and correlation with clinical score. Neuroradiol J. 2013;26(5):555–64.
90. Chng CL, Seah LL, Khoo DHC. Ethnic differences in the clinical presentation of Graves’ ophthalmopathy. Best Pract Res Clin Endocrinol Metab. 2012;26(3):249–58.
91. Barrio-Barrio J, Sabater AL, Bonet-Farriol E, Velázquez-Villoria Á, Galofré JC. Graves’ ophthalmopathy: VISA versus EUGOGO classification, assessment, and management. J Ophthalmol. 2015;2015.
92. Hoang TD, Stocker DJ, Chou EL, Burch HB. 2022 Update on Clinical Management of Graves’ Disease and Thyroid Eye Disease. J Pediatr. 2022;51(2):287–304.