Targeting TSH and IGF-1 Receptors to Treat Thyroid Eye Disease

Graves’ disease (GD) is an autoimmune disease caused in part by thyroid-stimulating antibodies (TSAbs) that activate the thyroid-stimulating hormone receptor (TSHR). In Graves’ hyperthyroidism (GH), TSAbs cause persistent stimulation of thyroid cells leading to continuous thyroid hormone synthesis and secretion. Thyroid eye disease (TED), also called Graves’ orbitopathy, is an orbital manifestation of GD. We review the important roles of the TSHR and the insulin-like growth factor 1 receptor (IGF-1R) in the pathogenesis of TED and discuss a model of TSHR/IGF-1R crosstalk that considers two pathways initiated by TSAb activation of TSHR in the eye, an IGF-1R-independent and an IGF-1R-dependent signaling pathway leading to hyaluronan (HA) secretion in orbital fibroblasts. We discuss current and future therapeutic approaches targeting the IGF-1R and TSHR. Teprotumumab, a human monoclonal anti-IGF-1R-blocking antibody, has been approved as an effective treatment in patients with TED. However, as the TSHR seems to be the primary target for TSAbs in patients with GD, future therapeutic interventions directly targeting the TSHR, e.g. blocking antibodies and small molecule antagonists, are being developed and have the advantage to inhibit the IGF-1R-independent as well as the IGF-1R-dependent component of TSAb-induced HA secretion. Antigen-specific immunotherapies using TSHR peptides to reduce serum TSHR antibodies are being developed also. These TSHR-targeted strategies also have the potential to treat both GH and TED with the same drug. We propose that combination therapy targeting TSHR and IGF-1R may be an effective and better tolerated treatment strategy for TED.

Download Full-text

Updates on the understanding and management of thyroid eye disease

Therapeutic Advances in Ophthalmology ◽

10.1177/25158414211027760 ◽

2021 ◽

Vol 13 ◽

pp. 251584142110277

Author(s):

Clara J. Men ◽

Andrea L. Kossler ◽

Sara T. Wester

Keyword(s):

Autoimmune Diseases ◽

Immune Modulation ◽

Complex Disease ◽

Vision Loss ◽

Treatment Options ◽

Thyroid Stimulating Hormone ◽

Thyroid Eye Disease ◽

Eye Disease ◽

Signaling Complex ◽

Clinical Trial Results

Thyroid eye disease (TED) is a complex disease associated with myriad clinical presentations, including facial disfigurement, vision loss, and decreased quality of life. Traditionally, steroid therapy and/or radiation therapy were commonly used in the treatment of active TED. While these therapies can help reduce inflammation, they often do not have a sustainable, significant long-term effect on disease outcomes, including proptosis and diplopia. Recent advances in our understanding of the pathophysiology of TED have shifted the focus of treatment toward targeted biologic therapies. Biologics have the advantage of precise immune modulation, which can have better safety profiles and greater efficacy compared to traditional approaches. For instance, the insulin-like growth factor-1 receptor (IGF-1R) has been found to be upregulated in TED patients and to colocalize with the thyroid-stimulating hormone receptor (TSHR), forming a signaling complex. Teprotumumab is an antibody targeted against IGF-1R. By inhibiting the IGF-1R/TSHR signaling pathway, teprotumumab may reduce the production of proinflammatory cytokines, hyaluronan secretion, and orbital fibroblast activation in patients with TED. Due to promising phase II and III clinical trial results, teprotumumab has become the first biologic US Food and Drug Administration (FDA)-approved for the treatment of TED. In addition, there are currently ongoing studies looking at the use of antibodies targeting the neonatal Fc receptor (FcRn) in various autoimmune diseases, including TED. FcRn functions to transport immunoglobulin G (IgG) and prevent their lysosomal degradation. By blocking the recycling of IgG, this approach may dampen the body’s immune response, in particular the pathogenic IgG implicated in some autoimmune diseases. Advances in our understanding of the pathophysiology of TED, therefore, are leading to more targeted therapeutic options, and we are entering an exciting new phase in the management of TED. This review will cover recent insights into the understanding of TED pathophysiology and novel treatment options as well as ongoing studies of new potential treatment options for TED.

Download Full-text

Relationship between Serum Thyroid-stimulating Hormone Receptor Autoantibodies and Activity and Severity of Thyroid Eye Disease

Journal of the Korean Ophthalmological Society ◽

10.3341/jkos.2021.62.11.1459 ◽

2021 ◽

Vol 62 (11) ◽

pp. 1459-1464

Author(s):

Je Sang Lee ◽

Si Hyung Lee ◽

Bo Yeon Kim ◽

Sun Young Jang

Keyword(s):

Optic Neuropathy ◽

Clinical Signs ◽

Cross Sectional Study ◽

Thyroid Stimulating Hormone ◽

Thyroid Eye Disease ◽

Eye Disease ◽

Clinical Activity ◽

Cross Sectional ◽

Severity Grading ◽

Stimulating Hormone

Purpose: To study the relationship between the levels of serum thyroid-stimulating hormone (TSH)-receptor autoantibodies (TRAbs) and thyroid eye disease (TED) activity and severity scores.Methods: A cross-sectional study was performed. The medical records of 315 patients diagnosed with TED between March 2014 and December 2019 were reviewed. The clinical activity score (CAS) was used to assess TED activity and a modified NOSPECS score was used for severity grading. The serum TRAb level was measured using two assays: a TSHR binding inhibitory immunoglobulin (TBII) assay and thyroid stimulating immunoglobulin (TSI) bioassay.Results: The TBII and TSI assay results were significantly positively correlated with the CAS (R = 0.113 and 0.211, respectively; p < 0.05), modified NOSPECS score (R = 0.173 and 0.316, respectively; p < 0.05), and proptosis (R = 0.136 and 0.167, respectively; p < 0.05). Both assays demonstrated significant differences in the level of TRAb between patients with and without compressive optic neuropathy or corneal epithelial defects.Conclusions: The levels of TRAbs according to both TBII and TSI assays showed significant correlations with clinical signs of corneal involvement, optic neuropathy, and TED activity and severity.

Download Full-text

SAT-500 Response to Tocilizumab Retreatment in Refractory Thyroid Eye Disease

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.1316 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Daniel Kaplan ◽

Benjamin Erickson ◽

Andrea Kossler ◽

Julie Chen ◽

Chrysoula Dosiou

Keyword(s):

Controlled Trial ◽

Standard Of Care ◽

Thyroid Eye Disease ◽

Eye Disease ◽

Clinical Activity ◽

Current Standard ◽

Compressive Optic Neuropathy ◽

Effective Option ◽

Graves Orbitopathy ◽

Recurrent Inflammation

Abstract Background: The current standard of care for moderate to severe thyroid eye disease (TED) is intravenous methylprednisolone (IVMP), though alternative immunosuppressive options are emerging. In a recent randomized trial, Tocilizumab (TCZ), an anti-IL-6 receptor antibody, demonstrated improved efficacy for corticosteroid-resistant TED compared to placebo. Clinical response to TCZ retreatment, however, has not been previously reported. Clinical case: A 64-year old man presented with progressive diplopia, eyelid retraction and edema and retrobulbar pain. Initial labs revealed TSH 0.221 uIU/mL, free thyroxine (FT4) 1.11 ng/dL, total T3 172 ng/dL and a thyroid stimulating immunoglobulin (TSI) index of 329 (normal < 140). The patient was a former cigarette smoker who had recently transitioned to e-cigarettes. He was treated with 12 weeks of IVMP with improvement in ocular redness and swelling. Three months following completion of treatment, he presented with worsening left sided proptosis, restrictive strabismus, and compressive optic neuropathy (CON) evidenced by deteriorating central acuity and color vision. He underwent urgent surgical decompression for CON with full restoration of visual acuity. He then received a second 12-week course of IVMP with concomitant orbital radiation. Of note, his hyperthyroidism was well controlled with methimazole. Two months after his second IVMP course, he had a third flare of ophthalmic symptoms. He was then treated with TCZ 8 mg/kg (800mg) IV monthly for six months. The patient’s Clinical Activity Score (CAS) improved from 4 to 2 and TSI index decreased from 610 to 92 (normal). He had significant improvement in periorbital edema, caruncle/plica swelling, and conjunctival injection. However, ten months following completion of the TCZ course he again complained of worsening diplopia and left proptosis. Of note, relapse of his TED symptoms was preceded by an increase in TSI from 92 to 300 two months prior. Orbital CT demonstrated progression of left orbitopathy and increased orbital apex crowding. Following these CT findings he was restarted on TCZ, of which he has now completed 5 additional infusions. His CAS has improved from 3 to 2 and TSI index has decreased from 284 to 100. Conclusion: This is the first reported case of response to successive courses of TCZ in relapsing, severe, corticosteroid-resistant TED. TCZ can be an effective option for refractory TED though retreatment may be necessary for recurrent inflammation. Further study of TCZ is required to determine its role in relapsing TED and the optimal duration of therapy needed. References: Perez-Moreiras et al., 2018. Efficacy of Tocilizumab in patients with moderate to severe corticosteroid resistant Graves’ orbitopathy: a randomized controlled trial. Am J Ophthalmol 195:181

Download Full-text

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

Endocrinology ◽

10.1210/en.2013-1576 ◽

2013 ◽

Vol 154 (9) ◽

pp. 3008-3015 ◽

Cited By ~ 52

Author(s):

Sajad Moshkelgosha ◽

Po-Wah So ◽

Neil Deasy ◽

Salvador Diaz-Cano ◽

J Paul Banga

Keyword(s):

Therapeutic Interventions ◽

Preclinical Model ◽

Orbital Tissue ◽

Mri Scans ◽

A Subunit ◽

Graves Orbitopathy ◽

Orbital Muscle ◽

Magnetic Resonance Imaging Mri ◽

Blocking Antibodies

Graves' orbitopathy (GO) is a complication in Graves' disease (GD) but mechanistic insights into pathogenesis remain unresolved, hampered by lack of animal model. The TSH receptor (TSHR) and perhaps IGF-1 receptor (IGF-1R) are considered relevant antigens. We show that genetic immunization of human TSHR (hTSHR) A-subunit plasmid leads to extensive remodeling of orbital tissue, recapitulating GO. Female BALB/c mice immunized with hTSHR A-subunit or control plasmids by in vivo muscle electroporation were evaluated for orbital remodeling by histopathology and magnetic resonance imaging (MRI). Antibodies to TSHR and IGF-1R were present in animals challenged with hTSHR A-subunit plasmid, with predominantly TSH blocking antibodies and were profoundly hypothyroid. Orbital pathology was characterized by interstitial inflammation of extraocular muscles with CD3+ T cells, F4/80+ macrophages, and mast cells, accompanied by glycosaminoglycan deposition with resultant separation of individual muscle fibers. Some animals showed heterogeneity in orbital pathology with 1) large infiltrate surrounding the optic nerve or 2) extensive adipogenesis with expansion of retrobulbar adipose tissue. A striking finding that underpins the new model were the in vivo MRI scans of mouse orbital region that provided clear and quantifiable evidence of orbital muscle hypertrophy with protrusion (proptosis) of the eye. Additionally, eyelid manifestations of chemosis, including dilated and congested orbital blood vessels, were visually apparent. Immunization with control plasmids failed to show any orbital pathology. Overall, these findings support TSHR as the pathogenic antigen in GO. Development of a new preclinical model will facilitate molecular investigations on GO and evaluation of new therapeutic interventions.

Download Full-text

Course of upper eyelid retraction in thyroid eye disease

British Journal of Ophthalmology ◽

10.1136/bjophthalmol-2018-313578 ◽

2019 ◽

Vol 104 (2) ◽

pp. 254-259

Author(s):

Dong Cheol Lee ◽

Stephanie M Young ◽

Yoon-Duck Kim ◽

Kyung In Woo

Keyword(s):

Positive Family History ◽

Thyroid Stimulating Hormone ◽

Thyroid Eye Disease ◽

Eye Disease ◽

Clinical Activity ◽

Eyelid Retraction ◽

Tertiary Institution ◽

Upper Eyelid ◽

Upper Eyelid Retraction ◽

History Of

AimsTo evaluate the natural course of upper eyelid retraction (UER) in patients with thyroid eye disease (TED) and factors affecting its course.MethodsRetrospective non-interventional cohort study in a single tertiary institution from March 2006 to March 2015 on patients with TED with (1) unilateral or bilateral UER within 6 months from initial presentation, and (2) no prior interventions nor surgical treatment for their UER. Main outcomes and measures were mean margin reflex distance 1 (MRD1) and factors associated with UER improvement.ResultsThere were a total of 61 patients and 81 eyes (41 unilateral and 20 bilateral UER). Mean age was 42.3±15.1 years. Mean MRD1 decreased from 6.1 mm at presentation to 4.8 mm at 12 months, and 4.4 mm at 24 months. The proportion of eyes with normalisation of lid height increased from 0% at presentation to 22.2% at 6 months, 37.0% at 12 months and 49.4% at 24 months. Mean time to normalisation of MRD1 was 18.0±12.4 months. A positive family history of TED was found to be associated with a 6.2 times lower likelihood of normalisation. Change in exophthalmometry, clinical activity score and thyroid-stimulating immunoglobulin were significantly correlated to change in MRD1 (p<0.05). There was no correlation between change in MRD1 and thyroid-stimulating hormone receptor antibodies.ConclusionAn improved knowledge of the natural history of UER in TED will allow us to better decide and evaluate the optimal management for such patients.

Download Full-text

STUDIES OF THYROID HORMONE SYNTHESIS IN EXPERIMENTAL AUTOIMMUNE THYROIDITIS

Acta Endocrinologica ◽

10.1530/acta.0.0400297 ◽

1962 ◽

Vol 40 (2) ◽

pp. 297-306 ◽

Cited By ~ 4

Author(s):

W. Hung ◽

R. W. Chandler ◽

M. A. Kyle ◽

R. M. Blizzard

Keyword(s):

Thyroid Hormone ◽

Accumulation Rate ◽

Potassium Thiocyanate ◽

Thyroid Stimulating Hormone ◽

Accumulation Rates ◽

Experimental Autoimmune Thyroiditis ◽

Thyroid Cells ◽

Hormone Synthesis ◽

Thyroid Hormone Synthesis ◽

Thyroid Glands

ABSTRACT Thyroid hormone synthesis in rabbits with experimentally induced thyroiditis is compared with hormone synthesis in normal rabbits and in immunized rabbits receiving thyroid stimulating hormone. The immunized rabbits showed decreased thyroidal accumulation rates for 131I. T. S. H. administration produced an increase in the accumulation rate of immunized animals, but this increase was smaller than that obtained in normal rabbits stimulated with T. S. H. None of the rabbits' thyroids discharged iodide with the administration of potassium thiocyanate. Twenty-four and 48 hours after 131I was administered, chromatography was performed on digested extracts of the thyroid glands. In the digested extracts of thyroids removed from normal rabbits the mono:diiodotyrosine ratio was greater than 1.0 whereas the extracts of thyroids removed from immunized rabbits and normal rabbits stimulated with T. S. H. consistently had a ratio of less than 1.0. Thyroxine was not always present in the thyroids of normal rabbits but was consistently found in the thyroids of the immunized and T. S. H. treated animals. These findings suggest that the remaining thyroid cells in the glands of immunized rabbits are operating under increased T. S. H. stimulation. The experimental thyroiditis of immunized rabbits was similar to Hashimoto's thyroiditis in respect to histological alteration and the presence of anti-thyroid antibodies. 131I accumulation rates, response to potassium thiocyanate, and chromatography studies revealed no correlation between the two groups.

Download Full-text

Molecular regulation of follicle-stimulating hormone synthesis, secretion and action

Journal of Molecular Endocrinology ◽

10.1530/jme-17-0308 ◽

2018 ◽

Vol 60 (3) ◽

pp. R131-R155 ◽

Cited By ~ 14

Author(s):

Nandana Das ◽

T Rajendra Kumar

Keyword(s):

Molecular Mechanisms ◽

Follicle Stimulating Hormone ◽

Thyroid Stimulating Hormone ◽

Α Subunit ◽

Physiological Regulation ◽

Hormone Synthesis ◽

The Common ◽

Blocking Antibodies ◽

Recombinant Human Fsh ◽

Stimulating Hormone

Follicle-stimulating hormone (FSH) plays fundamental roles in male and female fertility. FSH is a heterodimeric glycoprotein expressed by gonadotrophs in the anterior pituitary. The hormone-specific FSHβ-subunit is non-covalently associated with the common α-subunit that is also present in the luteinizing hormone (LH), another gonadotrophic hormone secreted by gonadotrophs and thyroid-stimulating hormone (TSH) secreted by thyrotrophs. Several decades of research led to the purification, structural characterization and physiological regulation of FSH in a variety of species including humans. With the advent of molecular tools, availability of immortalized gonadotroph cell lines and genetically modified mouse models, our knowledge on molecular mechanisms of FSH regulation has tremendously expanded. Several key players that regulate FSH synthesis, sorting, secretion and action in gonads and extragonadal tissues have been identified in a physiological setting. Novel post-transcriptional and post-translational regulatory mechanisms have also been identified that provide additional layers of regulation mediating FSH homeostasis. Recombinant human FSH analogs hold promise for a variety of clinical applications, whereas blocking antibodies against FSH may prove efficacious for preventing age-dependent bone loss and adiposity. It is anticipated that several exciting new discoveries uncovering all aspects of FSH biology will soon be forthcoming.

Download Full-text

A Case of Thyroid Eye Disease Revealed During Secondary Adrenal Insufficiency

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.1858 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A910-A910

Author(s):

Amira Ibrahim ◽

Victoria Loseva

Keyword(s):

Adrenal Insufficiency ◽

Extraocular Muscle ◽

Early Recognition ◽

Thyroid Eye Disease ◽

Eye Disease ◽

Secondary Adrenal Insufficiency ◽

Movement Restriction ◽

Free T4 ◽

Muscle Movement ◽

Graves Orbitopathy

Abstract Introduction: Thyroid eye disease (TED) or Graves’ orbitopathy (GO) is an autoimmune disease of the retro-orbital tissues. GO is mostly associated with hyperthyroidism in 90% of patients; however, it may coexist with hypothyroid conditions in 5% of cases. Clinical Case: A 56-year-old male with a past medical history of autoimmune diseases including hypothyroidism and Ulcerative Colitis on chronic steroid therapy presented to the emergency department with nausea, fatigue, weight loss, and muscle weakness. The patient stated that his glucocorticoids were abruptly discontinued a month prior to his current presentation. On examination, vitals were stable. The patient was somnolent with a depressed mood. He had bilateral periorbital edema and bilateral eyeball protrusion, left more pronounced than right. Extraocular muscle movement revealed a delay in the lateral movement of the left eye causing double vision on exam. He had no starring look or lid lag. The thyroid gland was normal in size and contour. Initial Laboratories revealed a white blood cell count of 6.7 K/mcL (4-10 K/mcL) with 18% eosinophil count (0-5%). Cortisol at 8 AM was 2.9 mcg/dL (4.3 -22.4 mcg/dl). The patient was managed for secondary adrenal insufficiency and restarted immediately on Prednisone. A review of a recent CT scan of the head revealed bilateral proptosis with no signs of compressing lesions. Further thyroid studies revealed TSH of 2.9 mcIU/mL (0.3-3.7 mcIU/mL), free T4 of 0.8 ng/dL (0.75-2.0 ng/dL), free T3 of 1.6 ng/dL (2.4-4.2 ng/dL), TPO antibodies <0.3 IU/mL (0.0-9.0 IU/mL) and TSH receptor antibodies 0.90 IU/L (reference range <1.75 IU/L). The patient was then diagnosed with Hypothyroid Grave’s ophthalmopathy with negative antibodies given the evidence of proptosis on CT and exam revealing extraocular muscle movement restriction causing diplopia. The patient had a unique presentation of TED with hypothyroidism and asymmetric ophthalmic signs that were only manifested after the patient discontinued the prednisone and therefore unmasking the underlying disorder. Fortunately, in June of 2020, the US Food and Drug Administration (FDA) approved Teprotumumab (an insulin-like growth factor 1 [IGF-1] receptor inhibitor) for the treatment of Graves’ orbitopathy based on the findings from two 24-week trials comparing teprotumumab with placebo in 171 patients with active, moderate-to-severe orbitopathy. (1) Our patient was started on Levothyroxine along with Prednisone and referred for ophthalmology evaluation for possible qualification for Teprotumumab treatment. Conclusion: Clinician awareness of the unusual presentations of TED would allow for early recognition and prevention of progression, especially with the recently approved treatment modality. References: (1) Teprotumumab for Thyroid-Associated Ophthalmopathy. Smith TJ Et al. N Engl J Med. 2017;376(18):1748.

Download Full-text