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 Table of Contents  
Year : 2020  |  Volume : 10  |  Issue : 3  |  Page : 174-180

Progress in the pathogenesis of thyroid-associated ophthalmopathy and new drug development

Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China

Date of Submission31-Mar-2020
Date of Acceptance12-Apr-2020
Date of Web Publication17-Jul-2020

Correspondence Address:
Dr. Huifang Zhou
Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, 639 Zhizaoju Road, Huangpu, Shanghai
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/tjo.tjo_18_20

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Thyroid-associated ophthalmopathy (TAO) is the most common extrathyroidal manifestation of toxic diffuse goiter (Graves' disease), also known as Graves' ophthalmopathy/orbitopathy. As an organ-specific autoimmune disease, the pathogenesis of TAO is still unclear. In recent years, great progress has been made in revealing the mechanism of TAO. Various biological and immunosuppressive agents have emerged in an endless stream, showing encouraging results. Strengthening the basic research, establishing ideal animal models, deeply understanding the pathogenesis, and developing novel targeted drugs are of great significance to guide the clinical diagnosis and management of TAO and improve the prognosis of patients.

Keywords: Immunotherapy, new drug development, thyroid-associated ophthalmopathy

How to cite this article:
Huang Y, Fang S, Zhang S, Zhou H. Progress in the pathogenesis of thyroid-associated ophthalmopathy and new drug development. Taiwan J Ophthalmol 2020;10:174-80

How to cite this URL:
Huang Y, Fang S, Zhang S, Zhou H. Progress in the pathogenesis of thyroid-associated ophthalmopathy and new drug development. Taiwan J Ophthalmol [serial online] 2020 [cited 2021 Jun 18];10:174-80. Available from: https://www.e-tjo.org/text.asp?2020/10/3/174/290025

Yazhuo Huang and Sijie Fang contributed equally to this work

  Introduction Top

Thyroid-associated ophthalmopathy (TAO), also known as Graves' ophthalmopathy/orbitopathy, the most common extrathyroidal manifestation of Graves' disease (GD), is found in 25%–50% of patients with GD. TAO also occurs in 2% of patients with chronic thyroiditis and in a small number of people with normal thyroid function.[1] Previous studies showed that TAO is a tissue-specific autoimmune disorder, which is affected by many factors such as heredity, immunity, and environmental elements.[1],[2] The clinical manifestations of TAO are complex, including eyelid retraction, exophthalmos, diplopia, restrictive strabismus, exposed keratitis, and dysthyroid optic neuropathy.[3],[4] TAO is divided into an early active stage and a late chronic inactive stage and is classified as mild, moderate-to-severe, and very severe, namely sight-threatening, forms according to the impact of TAO on the quality of life and the risk of vision loss.[5]

Recently, novel hypotheses in the pathogenesis of TAO such as fibrocyte, T-helper (Th) cell 17, and insulin-like growth factor-1 receptor (IGF-1R) are being confirmed. As a result, the development of therapeutic strategies for TAO based on immunologic perspective is rising. A variety of immunosuppressants and biological agents have shown great clinical potentials. In this review, we summarized the latest theories of pathogenesis and the emerging new drugs to provide insights into future management of TAO.

  Autoantigens Top

Thyroid-stimulating hormone receptor (TSHR) is the first recognized autoantigen of TAO, which is expressed on orbital fibroblasts (OFs).[6] In recent years, a number of studies have confirmed that IGF-1R might be another important autoantigen in disease progression. IGF-1R and TSHR overlap in the postreceptor signal transduction, and they synergistically regulate the function of OFs in vitro.[7] Compared with healthy individuals, GD patients have higher IGF-1R expression on the thyroid glands, OFs, and lymphocytes,[8],[9] and IGF-1R is highly expressed on OFs obtained from patients with active TAO. It has been demonstrated that activation of IGF-1R by IGF-1 enables OFs to differentiate into adipocytes and secrete hyaluronic acid.[10],[11],[12] In addition, IGF-1 secreted by OFs plays a pathogenic role through autocrine and paracrine ways.[13]

In order to block TSHR-stimulating production of autoimmune antibodies, researchers developed a monoclonal antibody named K1-70 and carried out a clinical study on its efficacy in controlling hyperthyroidism of GD patients (NCT02904330), which is expected to be completed in 2020.[14] Since there is crosstalk between the pathogenesis of TAO and GD, K1-70 is also a hopeful drug for suppressing the ocular complications. Teprotumumab, a monoclonal blocking antibody of IGF-1R, is originally designed as an antitumor drug. Two randomized, double-blind, placebo-controlled clinical results with global multicenter participation published in 2017 and 2020, respectively, showed that 82.9% of TAO patients had lower exophthalmos (reduction of exophthalmos ≥2 mm) at the 24th week after teprotumumab treatment, whereas the placebo group had a value of 9.5%, while achieving secondary endpoints such as reduced diplopia, improved quality of life, and decreased clinical activity score (CAS). The adverse reactions of teprotumumab are mild, including potential hyperglycemia and hearing loss.[15],[16] At present, teprotumumab has been approved by the US Food and Drug Administration as the first drug for TAO treatment.

  Lymphocytes Top

Both humoral and cellular immunities play important roles in orbital inflammation. Lymphocytes participate in the pathogenesis of TAO through the following pathways: (1) B-cells. B-cells migrate to the orbit and recognize TSHR and/or IGF-1R through B-cell receptors, the first signal for B-cell activation. T-cells bind to CD40 on the surface of B-cells through CD40L, which provides the second signal for B-cell activation. Meanwhile, interleukin (IL) 4 secreted by T-cells is essential for further activation of B-cells and their antibody-class switching.[17],[18] Activated B-cell clones proliferate and differentiate into plasma cells that produce autoantibodies. Autoantibodies in TAO including stimulating, blocking, and neutralizing types recognize and attack OFs, leading to orbital inflammation. (2) T-cells. Antigen-presenting cells recognize TSHR and/or IGF-1R and then activate T-cells. The second signal for T-cell activation is provided by B7 on B-cells and CD28 on the surface of T-cells.[17] Activated T-cells, mainly CD4+ helper T-cells, express adhesion molecules, secrete cytokines, and recruit more lymphocytes, which cause orbital inflammation, adipogenesis and fibrosis of orbital connective tissues, extracellular matrix deposition, and ultimately leading to orbital tissue remodeling.[17]

At present, there are two kinds of antimetabolic drugs that inhibit lymphocytes mycophenolate mofetil (MMF) and methotrexate (MTX). MMF can inhibit the de novo synthesis of guanosine and play an immunosuppressive role by inhibiting lymphocyte proliferation. MMF has been used to treat moderate-to-severe TAO in active stage. The results showed that MMF was superior to glucocorticoid therapy in many aspects with fewer side effects.[19] However, the high price limits wide use of the drug and its long-term efficacy and safety still need to be confirmed by a large number of follow-up clinical studies.[20] MTX is an antifolate antimetabolite that exerts immunosuppressive effect by interfering with the DNA/RNA synthesis of proliferating cells. It has been used in the treatment of glucocorticoid-insensitive TAO patients, showing good results but generally needs a long course of treatment.[21] Other drugs with more accurate targets are currently undergoing clinical trials for a variety of autoimmune diseases. For instance, otelixizumab and teplizumab are used as CD3 antibodies to deplete T-cells, whereas CTLA-4 analogs such as abatacept limit the further activation of T-cells; these drugs have been approved for the treatment of type 1 diabetes and rheumatoid arthritis.[22],[23] CFZ533 is a monoclonal antibody against CD40, which can inhibit the activation of B-cells and has been used in the treatment of myasthenia gravis and Sjogren's syndrome.[24],[25] Furthermore, CFZ533 is currently approved for the treatment of GD (NCT02713256). We speculate that these drugs are expected to be used in TAO treatment in the near future.

As an important part of orbital inflammation, blocking the activation of B-cells is also expected to be used in the treatment of TAO. Rituximab (RTX) is a monoclonal antibody against CD20 on B-cell surface. RTX depletes B-cells and blocks antigen presenting processes, thus inhibiting T-cell activation.[26] As a second-line treatment recommended by the European Group on Graves' Orbitopathy (EUGOGO) guidelines,[5] many studies have focused on the application of RTX in the treatment of TAO, especially in patients who are insensitive or resistant to glucocorticoid therapy.[27] In 2015, Savino et al. reported that intraorbital injection of RTX was safe and effective.[28] Salvi et al. found that intravenous RTX was even better than methylprednisolone in improving eyeball movement, decreasing CAS scores, and reducing surgical rates.[29] However, another research by Stan et al. demonstrated that the effect of treating TAO with RTX was not different from that of the placebo group.[30] In the latter study cohort, patients with longer duration, older age, higher male ratio, and higher levels of autoantibodies may all contribute to the reduction of RTX reactivity. Recently, a study by Chen et al. has shown that the removal of functionally defective B-cells by RTX can eliminate pro-inflammatory B-cells, which is beneficial for the treatment of TAO patients.[31] The EUGOGO guidelines recommend the use of RTX as one of several options for patients who are not sensitive or ineffective with intravenous glucocorticoid therapy.[5] Similar to RTX, belimumab is another monoclonal antibody targeting at the B-cell activating factor and has been used to treat systemic lupus erythematosus. Clinical trail of belimumab for TAO is currently undergoing (EUDRACT 2015-002127-26).[26]

  Cytokines Top

Previous studies have shown that interferon (IFN)-γ-producing Th1 cells are dominant in the active phase of TAO, whereas IL-4-producing Th2 cells are dominant in the inactive phase.[32] In 2008, Huber et al. reported for the first time that the IL23R single-nucleotide polymorphism was related to the occurrence of TAO.[33] Several studies suggested a correlation between IL-17A and TAO development.[34],[35],[36],[37] Our group first confirmed the inflammatory responses in TAO orbital connective tissue mediated by IL-17A-producing Th17 cells[38],[39] and elucidated the regulatory mechanism of pathogenic Th17 cells on the adipogenesis and fibrosis of TAO orbital connective tissues.[40] Xin et al. reported that the methylation of IL-17RE was positively correlated with the CAS of TAO.[41] In addition, the expression of T-cell immunoglobulin and mucin domain-3 on Th17 cells in patients with TAO is reduced, which cannot inhibit the secretion of IFN-γ and IL-17A by Th1 and Th17 cells, respectively.[42],[43] Thus, the local orbital immune responses of TAO might be a complex regulatory process involving multiple T-cell subsets.

IFN-γ, IL-4, IL-17A, and other cytokines form a precise network to coordinately promote the autoimmunity of TAO. IL-2 promotes the proliferation of T-cell clones; IFN-γ upregulates CD40 expression on OFs and releasing of monocyte chemokines;[44] IL-4 activates B-cells; IL-17A and IL-1β stimulate OFs to secrete RANTES or IL-16 through different pathways;[3],[39] TNF-α stimulates OFs to express adhesion molecules.[45] In addition, IL-1β is involved in maintaining the phenotype of Th17 cells and promoting prostaglandin E2 (PGE2) production by OFs.[38],[46],[47] On the one hand, PGE2 stimulates OFs to produce IL-6 through the cyclic AMP pathway[48] and enhances the differentiation and pathogenic phenotype of Th17 cells;[40],[46] meanwhile, PGE2 assists B-cell maturation and antibody-type switching, activates mast cell degranulation, and induces Th2 cell immunity.[45] These are the molecular basis for the application of nonsteroidal anti-inflammatory drugs to inhibit the synthesis of prostaglandin as adjuvant therapy for TAO.

Based on the above cytokine network, many specific therapeutic targets can be applied. Cyclosporine inhibits the calcineurin pathway and reduces the secretion of IL-2 by Th2 cells. Clinical studies have shown that cyclosporine combined with glucocorticoid treatment for moderate-to-severe TAO has a good effect, but cyclosporine alone is not better than glucocorticoid alone, and the specific protocol has yet to be verified by more clinical trial data.[49] Studies have shown that IL-1R antagonists inhibit the production of glycosaminoglycan by OFs [50], but this phenomenon has not been verified in patients with TAO. Tocilizumab (TCZ) is a monoclonal antibody against the human IL-6 receptor. A number of studies have shown that TCZ is safe and effective in treating TAO patients who were glucocorticoid insensitive. TCZ was also demonstrated to block the inflammatory cascade, improve clinical performance, and reduce CAS,[51],[52],[53],[54] but it needs to be further verified in the clinical application. A variety of TNF-α monoclonal antibodies, such as etanercept, infliximab, and adalimumab, have shown good efficacy in TAO,[55],[56],[57] however most studies are case reports and large-scale population based studies have not been carried out. At present, many monoclonal antibodies have been successfully developed IL-17A-producing Th17 cells, including Cosentyx (secukinumab), Taltz (ixekizumab), and Siliq (brodalumab). The indications are psoriasis and mandatory spondylitis. The first Chinese monoclonal antibody of IL-17, SHR-1314, is currently under Phase II clinical trials. However, these anti-IL-17 monoclonal antibodies have not been used in the clinical treatment of TAO. In view of the vital role of Th17 cells in the pathogenesis of TAO, large-scale clinical research needs to be carried out, and it is expected to become an effective therapy.

  Orbital Fibroblasts Top

OFs are the target cells of TAO autoimmune responses. OFs differentiate into adipocytes and myofibroblasts under the stimulation of autoantibodies and cytokines, indicating that OFs have heterogeneous phenotypes and function. It has been revealed that OFs can be divided into two main subgroups: CD90+ OFs, which are prone to differentiate into myofibroblasts, and CD90- OFs, which are mostly transformed into adipocytes.[45],[58] Both types of OFs can synthesize extracellular matrix such as hyaluronic acid and glycosaminoglycan in the inflammatory environment of TAO, leading to orbital connective tissue edema.[59] OFs express a variety of chemokines, such as ICAM-1, MIP-1, CXCL9/10/11, and RANTES,[3],[39],[60],[61] which can recruit T-cells infiltrating into the orbit. Meanwhile, OFs secrete various cytokines, such as IL-1β, IL-6, IL-8, and PGE2, which are involved in regulating the local immune responses in the orbit.[62]

It has been shown that platelet-derived growth factor (PDGF)-AA, AB, and BB are increased in orbital connective tissues of TAO patients, and OFs express PDGF receptor.[63],[64] PDGFs induce the proliferation of OFs, stimulate their production of hyaluronic acid and IL-6,[65],[66],[67] and increase the expression levels of TSHR on OF surface.[68] Tyrosine kinase inhibitors, such as imatinib and nilotinib, can inhibit PDGF transduction signaling by blocking the phosphorylation of PDGF receptor on the surface of OFs. However, these inhibitors have adverse effects such as periorbital edema, peripheral arterial occlusive disease, and cerebrovascular event;[69] thus, the safe dose and efficacy of tyrosine kinase inhibitors need to be further explored.

  Fibrocytes Top

Smith et al. proposed that fibrocytes from peripheral blood are involved in the pathogenesis of TAO. Fibrocytes are derived from bone marrow and are found in very small amounts in peripheral blood. Surface markers of fibrocytes include CD45, CD34, CXCR4, and TSHR. In peripheral blood of GD patients, the proportion of CD34+ fibrocytes increases significantly.[70] When TAO occurs, CD34+ fibrocytes may infiltrate the orbit and differentiate into CD34+ OFs, coexisting with the original CD34- OFs in the orbit. Both CD34+ and CD34- OFs express TSHR and IGF-1R.[71] CD34- OFs in the orbit and CD34+ OFs originated from fibrocytes are mutually regulated. Some studies have pointed out that this regulatory effect may be controlled by Slit2 and AIRE.[72],[73],[74],[75] Our study found that fibrocytes can recruit Th17 cells through the MIP-3/CCR-6 pathway.[76] In addition, TSH and CD40L can induce the secretion of IL-12 of fibrocytes,[77] which might be involved in the induction of Th1 cell immunity or transformation of Th17 cell to Th1 phenotype. Therefore, fibrocytes are also a potential target for precision treatment of TAO.

  Animal Models Top

The establishment of TAO animal model is not only an important means to study and verify the pathogenesis of this immune disorder but also an useful platform for new drug development. Over the years, researchers have carried out a lot of work in this field. Banga et al. constructed plasmids using TSHR subunits and induced TAO murine model successfully.[78],[79],[80] However, due to the large differences in the orbital structure of rodents and human beings, and the proneness of Th2-type immunity in BALB/c mice, the murine model cannot accurately reflect the real inflammatory environment of the human orbit. Hence, it is still challenging to explore animal models of TAO with stable incidence and typical pathological and clinical manifestations.

  Conclusion Top

The onset of TAO involves autoantigens, lymphocytes, OFs, and many other parts. Glucocorticoid therapy is still preferred for patients with very severe and moderate-to-severe TAO, whereas orbital decompression surgery is considered for patients with inactive TAO, all of which are symptomatic approaches. In the last decades, progresses have been made in the field of basic research of TAO, and several potential drugs have been developed, bringing hope for the cure of the disease. However, the problems of how autoimmune tolerance is broken in TAO, the molecular mechanism that promotes fibrocyte differentiation into OFs, and the synergistic effect of different T-cell subsets need to be further studied. The clinical research of many new drugs for TAO is in different process, and their safety and efficacy also need to be clinically evaluated and verified. The establishment of a perfect TAO animal model is also an important part of new drug development. In the future, the basic research of TAO should be reinforced to uncover its pathogenesis, so as to accelerate the development of novel targeted drugs and benefit more patients.

Financial support and sponsorship

The work was supported by the National Natural Science Foundation of China (No. 81970974, 81761168037, 81800695, 81770974), the Shanghai Sailing Program (18YF1412300), and the Research Grant of the Shanghai Science and Technology Committee (17DZ2260100).

Conflicts of interest

The authors declare that there are no conflicts of interest of this paper.

  References Top

Hiromatsu Y, Eguchi H, Tani J, Kasaoka M, Teshima Y. Graves' ophthalmopathy: Epidemiology and natural history. Intern Med 2014;53:353-60.  Back to cited text no. 1
Arnold K, Weetman AP. Cell-mediated immunity in thyroid-associated ophthalmopathy. Orbit 2009;15:159-64.  Back to cited text no. 2
Wang Y, Smith TJ. Current concepts in the molecular pathogenesis of thyroid-associated ophthalmopathy. Invest Ophthalmol Vis Sci 2014;55:1735-48.  Back to cited text no. 3
Hegedüs L, Smith TJ, Douglas RS, Nielsen CH. Targeted biological therapies for Graves' disease and thyroid-associated ophthalmopathy. Focus on B-cell depletion with rituximab. Clin Endocrinol (Oxf) 2011;74:1-8.  Back to cited text no. 4
Bartalena L, Baldeschi L, Boboridis K, Eckstein A, Kahaly GJ, Marcocci C, et al. The 2016 European Thyroid Association/European Group on Graves' Orbitopathy Guidelines for the Management of Graves' Orbitopathy. Eur Thyroid J 2016;5:9-26.  Back to cited text no. 5
Khoo TK, Bahn RS. Pathogenesis of Graves' ophthalmopathy: The role of autoantibodies. Thyroid 2007;17:1013-8.  Back to cited text no. 6
Wiersinga WM. Autoimmunity in Graves' ophthalmopathy: The result of an unfortunate marriage between TSH receptors and IGF-1 receptors? J Clin Endocrinol Metab 2011;96:2386-94.  Back to cited text no. 7
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;178:3281-7.  Back to cited text no. 8
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;181:5768-74.  Back to cited text no. 9
Pritchard J, Han R, Horst N, Cruikshank WW, Smith TJ. Immunoglobulin activation of T cell chemoattractant expression in fibroblasts from patients with Graves' disease is mediated through the insulin-like growth factor I receptor pathway. J Immunol 2003;170:6348-54.  Back to cited text no. 10
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;89:5076-80.  Back to cited text no. 11
Smith TJ. The putative role of fibroblasts in the pathogenesis of Graves' disease: Evidence for the involvement of the insulin-like growth factor-1 receptor in fibroblast activation. Autoimmunity 2003;36:409-15.  Back to cited text no. 12
Song D, Wang R, Zhong Y, Li W, Li H, Dong F. Locally produced insulin-like growth factor-1 by orbital fibroblasts as implicative pathogenic factor rather than systemically circulated IGF-1 for patients with thyroid-associated ophthalmopathy. Graefes Arch Clin Exp Ophthalmol 2012;250:433-40.  Back to cited text no. 13
Sanders P, Young S, Sanders J, Kabelis K, Baker S, Sullivan A, et al. Crystal structure of the TSH receptor (TSHR) bound to a blocking-type TSHR autoantibody. J Mol Endocrinol 2011;46:81-99.  Back to cited text no. 14
Smith TJ, Kahaly GJ, Ezra DG, Fleming JC, Dailey RA, Tang RA, et al. Teprotumumab for thyroid-associated ophthalmopathy. N Engl J Med 2017;376:1748-61.  Back to cited text no. 15
Douglas RS, Kahaly GJ, Patel A, Sile S, Thompson EH, Perdok R, et al. Teprotumumab for the treatment of active thyroid eye disease. N Engl J Med 2020;382:341-52.  Back to cited text no. 16
Lehmann GM, Feldon SE, Smith TJ, Phipps RP. Immune mechanisms in thyroid eye disease. Thyroid 2008;18:959-65.  Back to cited text no. 17
Huang Y, Fang S, Li D, Zhou H, Li B, Fan X. The involvement of T cell pathogenesis in thyroid-associated ophthalmopathy. Eye (Lond) 2019;33:176-82.  Back to cited text no. 18
Bartalena L, Krassas GE, Wiersinga W, Marcocci C, Salvi M, Daumerie C, et al. Efficacy and safety of three different cumulative doses of intravenous methylprednisolone for moderate to severe and active Graves' orbitopathy. J Clin Endocrinol Metab 2012;97:4454-63.  Back to cited text no. 19
Kahaly GJ, Riedl M, König J, Pitz S, Ponto K, Diana T, et al. Mycophenolate plus methylprednisolone versus methylprednisolone alone in active, moderate-to-severe Graves' orbitopathy (MINGO): A randomised, observer-masked, multicentre trial. Lancet Diabetes Endocrinol 2018;6:287-98.  Back to cited text no. 20
Strianese D, Iuliano A, Ferrara M, Comune C, Baronissi I, Napolitano P, et al. Methotrexate for the treatment of thyroid eye disease. J Ophthalmol 2014;2014. doi: 10.1155/2014/128903.  Back to cited text no. 21
Daifotis AG, Koenig S, Chatenoud L, Herold KC. Anti-CD3 clinical trials in type 1 diabetes mellitus. Clin Immunol 2013;149:268-78.  Back to cited text no. 22
Herrero-Beaumont G, Martínez Calatrava MJ, Castañeda S. Abatacept mechanism of action: Concordance with its clinical profile. Reumatol Clin 2012;8:78-83.  Back to cited text no. 23
Behin A, Le Panse R. New pathways and therapeutic targets in autoimmune myasthenia gravis. J Neuromuscul Dis 2018;5:265-77.  Back to cited text no. 24
Gueiros LA, France K, Posey R, Mays JW, Carey B, Sollecito TP, et al. World workshop on oral medicine VII: Immunobiologics for salivary gland disease in Sjögren's syndrome: A systematic review. Oral Dis 2019;25 Suppl 1:102-10.  Back to cited text no. 25
Wiersinga WM. Advances in treatment of active, moderate-to-severe Graves' ophthalmopathy. Lancet Diabetes Endocrinol 2017;5:134-42.  Back to cited text no. 26
Salvi M, Vannucchi G, Beck-Peccoz P. Potential utility of rituximab for Graves' orbitopathy. J Clin Endocrinol Metab 2013;98:4291-9.  Back to cited text no. 27
Savino G, Mandarà E, Gari M, Battendieri R, Corsello SM, Pontecorvi A. Intraorbital injection of rituximab versus high dose of systemic glucocorticoids in the treatment of thyroid-associated orbitopathy. Endocrine 2015;48:241-7.  Back to cited text no. 28
Salvi M, Vannucchi G, Currò N, Campi I, Covelli D, Dazzi D, et al. Efficacy of B-cell targeted therapy with rituximab in patients with active moderate to severe Graves' orbitopathy: A randomized controlled study. J Clin Endocrinol Metab 2015;100:422-31.  Back to cited text no. 29
Stan MN, Garrity JA, Carranza Leon BG, Prabin T, Bradley EA, Bahn RS. Randomized controlled trial of rituximab in patients with Graves' orbitopathy. J Clin Endocrinol Metab 2015;100:432-41.  Back to cited text no. 30
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;104:4067-77.  Back to cited text no. 31
Bahn RS. Graves' ophthalmopathy. N Engl J Med 2010;362:726-38.  Back to cited text no. 32
Huber AK, Jacobson EM, Jazdzewski K, Concepcion ES, Tomer Y. Interleukin (IL)-23 receptor is a major susceptibility gene for Graves' ophthalmopathy: The IL-23/T-helper 17 axis extends to thyroid autoimmunity. J Clin Endocrinol Metab 2008;93:1077-81.  Back to cited text no. 33
Kim SE, Yoon JS, Kim KH, Lee SY. Increased serum interleukin-17 in Graves' ophthalmopathy. Graefes Arch Clin Exp Ophthalmol 2012;250:1521-6.  Back to cited text no. 34
Shen J, Li Z, Li W, Ge Y, Xie M, Lv M, et al. Th1, Th2, and Th17 cytokine involvement in thyroid associated ophthalmopathy. Dis Markers 2015;2015. doi: 10.1155/2015/609593.  Back to cited text no. 35
Wei H, Guan M, Qin Y, Xie C, Fu X, Gao F, et al. Circulating levels of miR-146a and IL-17 are significantly correlated with the clinical activity of Graves' ophthalmopathy. Endocr J 2014;61:1087-92.  Back to cited text no. 36
Huang D, Luo Q, Yang H, Mao Y. Changes of lacrimal gland and tear inflammatory cytokines in thyroid-associated ophthalmopathy. Invest Ophthalmol Vis Sci 2014;55:4935-43.  Back to cited text no. 37
Fang S, Huang Y, Wang S, Zhang Y, Luo X, Liu L, et al. IL-17A exacerbates fibrosis by promoting the proinflammatory and profibrotic function of orbital fibroblasts in TAO. J Clin Endocrinol Metab 2016;101:2955-65.  Back to cited text no. 38
Fang S, Huang Y, Zhong S, Zhang Y, Liu X, Wang Y, et al. IL-17A Promotes RANTES expression, but not IL-16, in orbital fibroblasts via CD40-CD40L combination in thyroid-associated ophthalmopathy. Invest Ophthalmol Vis Sci 2016;57:6123-33.  Back to cited text no. 39
Fang S, Huang Y, Zhong S, Li Y, Zhang Y, Li Y, et al. Regulation of orbital fibrosis and adipogenesis by pathogenic Th17 cells in graves Orbitopathy. J Clin Endocrinol Metab 2017;102:4273-83.  Back to cited text no. 40
Xin Z, Hua L, Shi TT, Tuo X, Yang FY, Li Y, et al. A genome-wide DNA methylation analysis in peripheral blood from patients identifies risk loci associated with Graves' orbitopathy. J Endocrinol Invest 2018;41:719-27.  Back to cited text no. 41
Luo LH, Li DM, Wang YL, Wang K, Gao LX, Li S, et al. Tim3/galectin-9 alleviates the inflammation of TAO patients via suppressing Akt/NF-kB signaling pathway. Biochem Biophys Res Commun 2017;491:966-72.  Back to cited text no. 42
Zhao J, Lin B, Deng H, Zhi X, Li Y, Liu Y, et al. Decreased expression of TIM-3 on Th17 cells associated with ophthalmopathy in patients with Graves' disease. Curr Mol Med 2018;18:83-90.  Back to cited text no. 43
Feldon SE, Park DJ, O'Loughlin CW, Nguyen VT, Landskroner-Eiger S, Chang D, et al. Autologous T-lymphocytes stimulate proliferation of orbital fibroblasts derived from patients with Graves' ophthalmopathy. Invest Ophthalmol Vis Sci 2005;46:3913-21.  Back to cited text no. 44
Dik WA, Virakul S, van Steensel L. Current perspectives on the role of orbital fibroblasts in the pathogenesis of Graves' ophthalmopathy. Exp Eye Res 2016;142:83-91.  Back to cited text no. 45
Fang S, Huang Y, Wang N, Zhang S, Zhong S, Li Y, et al. Insights into local orbital immunity: Evidence for the involvement of the Th17 cell pathway in thyroid-associated ophthalmopathy. J Clin Endocrinol Metab 2019;104:1697-711.  Back to cited text no. 46
Wang HS, Cao HJ, Winn VD, Rezanka LJ, Frobert Y, Evans CH, et al. Leukoregulin induction of prostaglandin-endoperoxide H synthase-2 in human orbital fibroblasts. Anin vitro model for connective tissue inflammation. J Biol Chem 1996;271:22718-28.  Back to cited text no. 47
Raychaudhuri N, Douglas RS, Smith TJ. PGE2 induces IL-6 in orbital fibroblasts through EP2 receptors and increased gene promoter activity: Implications to thyroid-associated ophthalmopathy. PLoS One 2010;5:e15296.  Back to cited text no. 48
Gürdal C, Genç I, Saraç O, Gönül I, Takmaz T, Can I. Topical cyclosporine in thyroid orbitopathy-related dry eye: Clinical findings, conjunctival epithelial apoptosis, and MMP-9 expression. Curr Eye Res 2010;35:771-7.  Back to cited text no. 49
Tan GH, Dutton CM, Bahn RS. Interleukin-1 (IL-1) receptor antagonist and soluble IL-1 receptor inhibit IL-1-induced glycosaminoglycan production in cultured human orbital fibroblasts from patients with Graves' ophthalmopathy. J Clin Endocrinol Metab 1996;81:449-52.  Back to cited text no. 50
Smolen JS, Beaulieu A, Rubbert-Roth A, Ramos-Remus C, Rovensky J, Alecock E, et al. Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): A double-blind, placebo-controlled, randomised trial. Lancet 2008;371:987-97.  Back to cited text no. 51
Pérez-Moreiras JV, Alvarez-López A, Gómez EC. Treatment of active corticosteroid-resistant graves' orbitopathy. Ophthalmic Plast Reconstr Surg 2014;30:162-7.  Back to cited text no. 52
Atienza-Mateo B, Calvo-Río V, Martín-Varillas J, Demetrio-Pablo R, Valls-Pascual E, Valls-Espinosa B, et al. SAT0601 anti-il6-receptor tocilizumab in Graves' orbitopathy. Multicenter study of 29 patients. Ann Rheum Dis 2018;77:1153-54.  Back to cited text no. 53
Perez-Moreiras JV, Gomez-Reino JJ, Maneiro JR, Perez-Pampin E, Romo Lopez A, Rodríguez Alvarez FM, et al. Efficacy of tocilizumab in patients with moderate-to-severe corticosteroid-resistant graves orbitopathy: A randomized clinical trial. Am J Ophthalmol 2018;195:181-90.  Back to cited text no. 54
Paridaens D, van den Bosch WA, van der Loos TL, Krenning EP, van Hagen PM. The effect of etanercept on Graves' ophthalmopathy: A pilot study. Eye (Lond) 2005;19:1286-9.  Back to cited text no. 55
Ayabe R, Rootman DB, Hwang CJ, Ben-Artzi A, Goldberg R. Adalimumab as steroid-sparing treatment of inflammatory-stage thyroid eye disease. Ophthalmic Plast Reconstr Surg 2014;30:415-9.  Back to cited text no. 56
Komorowski J, Jankiewicz-Wika J, Siejka A, Lawnicka H, Kłysik A, Goś R, et al. Monoclonal anti-TNFalpha antibody (infliximab) in the treatment of patient with thyroid associated ophthalmopathy. Klin Oczna 2007;109:457-60.  Back to cited text no. 57
Smith TJ. TSH-receptor-expressing fibrocytes and thyroid-associated ophthalmopathy. Nat Rev Endocrinol 2015;11:171-81.  Back to cited text no. 58
Khoo TK, Coenen MJ, Schiefer AR, Kumar S, Bahn RS. Evidence for enhanced Thy-1 (CD90) expression in orbital fibroblasts of patients with Graves' ophthalmopathy. Thyroid 2008;18:1291-6.  Back to cited text no. 59
Antonelli A, Rotondi M, Ferrari SM, Fallahi P, Romagnani P, Franceschini SS, et al. Interferon-γ-inducible α-chemokine CXCL10 involvement in Graves' ophthalmopathy: Modulation by peroxisome proliferator-activated receptor-γ agonists. J Clin Endocrinol Metab 2006;91:614-20.  Back to cited text no. 60
Antonelli A, Ferrari SM, Fallahi P, Frascerra S, Santini E, Franceschini SS, et al. Monokine induced by interferon gamma (IFNgamma) (CXCL9) and IFNgamma inducible T-cell alpha-chemoattractant (CXCL11) involvement in Graves' disease and ophthalmopathy: Modulation by peroxisome proliferator-activated receptor-gamma agonists. J Clin Endocrinol Metab 2009;94:1803-9.  Back to cited text no. 61
Smith TJ, Hegedüs L. Graves' Disease. N Engl J Med 2016;375:1552-65.  Back to cited text no. 62
van Steensel L, Paridaens D, van Meurs M, van Hagen PM, van den Bosch WA, Kuijpers RW, et al. Orbit-infiltrating mast cells, monocytes, and macrophages produce PDGF isoforms that orchestrate orbital fibroblast activation in Graves' ophthalmopathy. J Clin Endocrinol Metab 2012;97:E400-8.  Back to cited text no. 63
van Steensel L, Paridaens D, Dingjan GM, van Daele PL, van Hagen PM, Kuijpers RW, et al. Platelet-derived growth factor-BB: A stimulus for cytokine production by orbital fibroblasts in Graves' ophthalmopathy. Invest Ophthalmol Vis Sci 2010;51:1002-7.  Back to cited text no. 64
van Steensel L, Hooijkaas H, Paridaens D, van den Bosch WA, Kuijpers RW, Drexhage HA, et al. PDGF enhances orbital fibroblast responses to TSHR stimulating autoantibodies in Graves' ophthalmopathy patients. J Clin Endocrinol Metab 2012;97:E944-53.  Back to cited text no. 65
Virakul S, Dalm VA, Paridaens D, van den Bosch WA, Mulder MT, Hirankarn N, et al. Platelet-derived growth factor-BB enhances adipogenesis in orbital fibroblasts. Invest Ophthalmol Vis Sci 2015;56:5457-64.  Back to cited text no. 66
Virakul S, Heutz JW, Dalm VA, Peeters RP, Paridaens D, van den Bosch WA, et al. Basic FGF and PDGF-BB synergistically stimulate hyaluronan and IL-6 production by orbital fibroblasts. Mol Cell Endocrinol 2016;433:94-104.  Back to cited text no. 67
Virakul S, van Steensel L, Dalm VA, Paridaens D, van Hagen PM, Dik WA. Platelet-derived growth factor: A key factor in the pathogenesis of graves' ophthalmopathy and potential target for treatment. Eur Thyroid J 2014;3:217-26.  Back to cited text no. 68
Kim TD, Rea D, Schwarz M, Grille P, Nicolini FE, Rosti G, et al. Peripheral artery occlusive disease in chronic phase chronic myeloid leukemia patients treated with nilotinib or imatinib. Leukemia 2013;27:1316-21.  Back to cited text no. 69
Douglas RS, Afifiyan NF, Hwang CJ, Chong K, Haider U, Richards P, et al. Increased generation of fibrocytes in thyroid-associated ophthalmopathy. J Clin Endocrinol Metab 2010;95:430-8.  Back to cited text no. 70
Smith TJ, Hegedüs L, Douglas RS. Role of insulin-like growth factor-1 (IGF-1) pathway in the pathogenesis of Graves' orbitopathy. Best Pract Res Clin Endocrinol Metab 2012;26:291-302.  Back to cited text no. 71
Fernando R, Atkins S, Raychaudhuri N, Lu Y, Li B, Douglas RS, et al. Human fibrocytes coexpress thyroglobulin and thyrotropin receptor. Proc Natl Acad Sci U S A 2012;109:7427-32.  Back to cited text no. 72
Fernando R, Lu Y, Atkins SJ, Mester T, Branham K, Smith TJ. Expression of thyrotropin receptor, thyroglobulin, sodium-iodide symporter, and thyroperoxidase by fibrocytes depends on AIRE. J Clin Endocrinol Metab 2014;99:E1236-44.  Back to cited text no. 73
Lu Y, Atkins SJ, Fernando R, Trierweiler A, Mester T, Grisolia AB, et al. CD34- orbital fibroblasts from patients with thyroid-associated ophthalmopathy modulate TNF-α expression in CD34+ fibroblasts and fibrocytes. Invest Ophthalmol Vis Sci 2018;59:2615-22.  Back to cited text no. 74
Smith TJ. Potential roles of CD34+fibrocytes masquerading as orbital fibroblasts in thyroid-associated ophthalmopathy. J Clin Endocrinol Metab 2019;104:581-94.  Back to cited text no. 75
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. Invest Ophthalmol Vis Sci 2018;59:2604-14.  Back to cited text no. 76
Wu T, Mester T, Gupta S, Sun F, Smith TJ, Douglas RS. Thyrotropin and CD40L stimulate interleukin-12 expression in fibrocytes: Implications for pathogenesis of thyroid-associated ophthalmopathy. Thyroid 2016;26:1768-77.  Back to cited text no. 77
Johnson KT, Wiesweg B, Schott M, Ehlers M, Müller M, Minich WB, et al. Examination of orbital tissues in murine models of Graves' disease reveals expression of UCP-1 and the TSHR in retrobulbar adipose tissues. Horm Metab Res 2013;45:401-7.  Back to cited text no. 78
Moshkelgosha S, So PW, Deasy N, Diaz-Cano S, Banga JP. Cutting edge: Retrobulbar inflammation, adipogenesis, and acute orbital congestion in a preclinical female mouse model of Graves' orbitopathy induced by thyrotropin receptor plasmid-in vivo electroporation. Endocrinol 2013;154:3008-15.  Back to cited text no. 79
Berchner-Pfannschmidt U, Moshkelgosha S, Diaz-Cano S, Edelmann B, Görtz GE, Horstmann M, et al. Comparative assessment of female mouse model of Graves' orbitopathy under different environments, accompanied by proinflammatory cytokine and T-cell responses to thyrotropin hormone receptor antigen. Endocrinol 2016;157:1673-82.  Back to cited text no. 80

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