A closer look at the history and science of thyroid eye disease
Thyroid eye disease (TED) is an autoimmune condition in which the body’s immune system attacks the tissues around the eyes, resulting in both physical and emotional effects on a person. Although descriptions of TED can be found in medical writing dating as far back as 1100, it was not until the 1990s that researchers began to uncover key receptors involved in the cause of TED. These discoveries have led to the development of newer treatments focused on targeting these receptors using precision medicine. Advances in our understanding of TED are leading to the development of more targeted therapeutic options and what looks to be a promising new era of care and treatment for people affected by TED
By Barrett Katz, MD, MBA, chief medical officer, Viridian Therapeutics
Thomas Ciulla, MD, MBA, chief development officer, Viridian Therapeutics
Thyroid eye disease (TED) is an autoimmune, inflammatory condition in which the body’s immune system attacks the tissues around and behind the eyes. Not everyone affected by TED will experience the same symptoms, and the impact of each symptom varies for everyone. Common symptoms include bulging and prominence of the eyes, dry eyes, redness of the eyes, swelling tissue around the eyes, double vision, eye lid retraction, and pain in and around the eyes.
diplopia – double vision
euthyroid – normal thyroid hormone levels
exophthalmos – bulging of the eyes along with apparent eyelid retraction
goitre – swelling in the neck
hyperthyroidism – overactive thyroid gland
hypothyroid – low thyroid gland activity
palpitations – sensation of rapid and prominent heartbeat
proptosis – bulging of the eyes
Most often, TED occurs when the thyroid gland is overactive. Approximately 85% of people living with TED also have Graves’ disease, a different autoimmune condition also caused by an overactive thyroid. Given the close association between these two autoimmune conditions, TED is still commonly referred to as Graves’ eye disease, Graves’ ophthalmopathy and Graves’ orbitopathy.1 In rare cases, TED can occur in people who have normal or underactive thyroids.
One of the earliest records describing TED’s hallmark symptom of bulging eyes along with signs of thyroid dysfunction dates to 1110 in the medieval Persian medical encyclopaedia, The Treasure of Khvarazm Shah. In this collection of ten books, Ismail ibn al-Husayn al-Jurjani describes a person with swelling in the neck, rapid heartbeat and bulging of the eyes—three symptoms that we now recognise to be associated with TED.2
Jump then to the 1800s, when we once again find records with similar descriptions that include involvement of the eyes. In 1802, G. Flajani, an Italian anatomist and surgeon at San Spirito Hospital, published results on two people with swelling in the neck and rapid heartbeat, one of whom also had bulging of the eyes.3
A few years later, in 1835, during his clinical lectures at Meath Hospital, Robert James Graves, an Irish physician, described four women with swelling of the neck and rapid heartbeat, one of whom was also noted as having bulging eyes. Subsequently, the London Medical and Surgical Journal published his lectures in 1843, and the collection of symptoms took the name Graves’ disease and Graves’ ophthalmopathy in many English-speaking countries.4 Around the same time, in 1840, Karl Adolph von Basedow, a German physician, independently described this clinical triad of symptoms—swelling in the neck, rapid heartbeat and bulging eyes. As a result, the term Basedow’s syndrome and Basedow oculopathy are commonly used terms in European countries.
Over time scientists have been able to better understand the distinction between TED and Graves’ disease and the importance of how each condition is diagnosed and treated. Today, the term TED is more commonly seen in scientific literature and is gaining public awareness. With this, TED is being diagnosed and treated as a standalone condition separate from Graves’ disease.3,5
We have come a long way since the 1800s in our understanding of the underlying biological drivers of TED, owing primarily to advances in science and technology. The postulated causes of TED have evolved from heart failure and dysfunction of the autonomic nervous system to over-secretion of a pituitary hormone called thyrotropin (or thyroid stimulating hormone, TSH), to production within the pituitary of TSH fragments with eye-affecting properties, to the now more widely accepted explanation of the autoimmune response within the thyroid gland and muscle and fat tissues behind the eyes. This being driven by overactivity of orbital fibroblasts, cells that contribute to the formation of connective tissue.3
In the 1990s, scientists discovered two key biological switches (receptors on cells) in the body believed to be involved in the disease processes of TED as well as a shared biological trigger for these switches. They found increased numbers of insulin-like growth factor-1 receptors (IGF-1R) and TSH receptors (TSHR) on orbital fibroblasts surrounding the eye, both of which are triggered by the same self-produced chemical (autoantigen) called IGF-1.6-10
TED can go unrecognised, especially in people with no apparent signs of abnormal thyroid function. Most people discover they have TED while being treated for an overactive thyroid caused by Graves’ disease. Endocrinologists play an important role in the initial care of people diagnosed with TED, and referrals to TED specialists (ophthalmologists, neuro-ophthalmologists, and oculoplastic surgeons). However, even in the absence of thyroid abnormalities, it is recommended that people who experience any of the common symptoms of TED, such as eye bulging, eye lid swelling, very dry eyes and eye pain, visit an ophthalmologist to evaluate their symptoms to determine if they may have TED. TED is diagnosed through an evaluation of a person’s medical history, physical examination of the eyes and a blood test to check thyroid levels. Imaging tests such as CT (computerised tomography) scan or magnetic resonance imaging (MRI) may also be used to help diagnose the condition.
TED affects all ethnicities and ages, although it commonly occurs mid-adulthood. While TED is five times as common in women, it has been observed that men with TED are more likely to develop a severe form of the condition than are women. Understanding the severity and phases of TED is important in treatment decisions.
The severity of TED is based on multiple factors, including degree of inflammation, double vision, eye bulging and soft tissue changes as well as the impact on the person’s quality of life. Severity is commonly graded on a scale of mild, moderate-to-severe or sight-threatening.11 Regardless of severity, TED is typically considered to be a progressive condition, with an initial active phase, followed by a transition to a secondary chronic phase. The active phase is commonly characterised by inflammation. The chronic phase may feature “quiet” white eyes and ongoing presentation of select symptoms. However, given the variability in the symptoms of TED, there may be considerable variability across the phases of the condition. For example, some people may never experience inflammation, while others may endure a prolonged active phase lasting decades. Some with TED can require therapeutic intervention during the active phase, and others may revert from the chronic phase to an active phase.
For a time, the surgical removal of bone around the eyes was the treatment of choice. This was performed under the premise that the eyes of those severely affected by TED would further bulge, leading to inflammation of the eyes and eventual death from bone infection and resultant meningitis.12 More recently, steroids have been widely used to ease inflammation in the active phase of the condition. Steroids may sometimes be combined with radiation therapy. In the chronic phase of the condition, surgery is still used to correct the bulging of the eyes through removal of bone, creating more space for enlarged muscle and fat and correcting misalignment of the eyes to reduce double vision. Additionally, eyelid retraction surgery is used to improve eyelid position and restore the ability to close the eyes.13 Depending on the condition’s severity, some living with TED have benefited from non-invasive options, such as eye drops to help with dryness and irritation of the eyes and lifestyle changes, such as quitting smoking. Despite advances in our understanding of the biological drivers of TED and surgical innovation over the years, the first FDA-approved treatment for TED did not occur until the winter of 2020.
Following the 1990s-era scientific discovery of key receptors thought to be involved in the cause of TED, the development of newer treatments has focused on targeting these receptors with proteins, such as monoclonal antibodies. Protein-based therapies are medicines engineered forms of naturally occurring proteins and designed to target specific receptors in the body to tailor an immune response. These precision medicines have the potential to be safer and more effective treatment options for people with TED.
Since the mid-1980s, hundreds of monoclonal antibody therapies have been approved by regulatory agencies for the treatment of numerous conditions. 14 In 2020 the FDA approved a monoclonal antibody (antagonist/inhibitor to IGF-1R), for the treatment of people affected by TED. When the IGF-1R antibody attaches to the IGF-1R switch it prevents the self-produced trigger (autoantigen IGF-1) from attaching. This has been shown to affect cell activity and improve TED-related symptoms.15,16 Scientists have studied several antibodies that block IGF-1R in the laboratory and have learned they can attach and block the switch differently and to varying degrees.17
Today, as many as 16 protein-based therapies and potential new treatments for TED are being studied in the laboratory and in clinical trials across the globe. These include inhibition by antagonists of IGF-1R, inhibitors of TSHR, inhibitors of FcRN (neonatal crystallisable fragment receptor), another receptor found inside of cells, and inhibitors of interleukin-6 (IL-6), a chemical produced at the site of inflammation in the body. Many of the studies of these newer protein-based therapies have shown favourable results; however, large clinical trials (phase 3 trials) are still needed to evaluate their safety and effectiveness more fully in treating TED. Advances in our understanding of TED are leading to the development of more targeted therapeutic options and what looks to be a promising new era of care and treatment for people affected by TED.
We are extremely grateful for the individuals who are contributing and have contributed to the development of potential new therapies by participating in clinical studies. Without them, medical research and treatment advances would not be possible.
This article is intended for educational purposes and does not constitute diagnosis or treatment recommendations. Please speak with a healthcare professional for all medical questions.
 Perros P, Hegedüs L, Bartalena L, et al. Graves’ orbitopathy as a rare disease in Europe: a European Group on Graves’ Orbitopathy (EUGOGO) position statement. Orphanet J Rare Dis. Apr 20 2017;12(1):72. doi:10.1186/s13023-017-0625-1
 Nabipour I. Clinical Endocrinology in the Islamic Civilization in Iran. Discussion. Int J Endocrinol Metab. 2003;1(1):e102818.
 Bürgi H. Thyroid Eye Disease: A Historical Perspective. Orbit. 2009/08/01 2009;28(4):226-230. doi:10.1080/01676830903104561
 RJ G. Affections of the thyroid gland. A System of Clinical Medicine. Dublin: Fannin and Co; 1843. p. 674-676.
 Burch H, Perros P, Bednarczuk T, et al. Management of Thyroid Eye Disease: A Consensus Statement by the American Thyroid Association and the European Thyroid Association. Thyroid. Dec 2022;32(12):1439-1470. doi:10.1089/thy.2022.0251
 Pritchard J., Han R., Horst N., Cruikshank W. W., Smith T. J. 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. Jun 15 2003;170(12):6348-54. doi:10.4049/jimmunol.170.12.6348
 Krieger C., Neumann S., Place R., Marcus-Samuels B., M. G. Bidirectional TSH and IGF-1 receptor cross talk mediates stimulation of hyaluronan secretion by Graves’ disease immunoglobins. J Clin Endocrinol Metab. Mar 2015;100(3):1071-7. doi:10.1210/jc.2014-3566
 Smith TJ. Insulin-like growth factor-I regulation of immune function: a potential therapeutic target in autoimmune diseases? Pharmacol Rev. Jun 2010;62(2):199-236. doi:10.1124/pr.109.002469
 Smith TJ, Tsai CC, Shih MJ, et al. Unique attributes of orbital fibroblasts and global alterations in IGF-1 receptor signaling could explain thyroid-associated ophthalmopathy. Thyroid. Sep 2008;18(9):983-8. doi:10.1089/thy.2007.0404
 Douglas RS, Afifiyan NF, Hwang CJ, et al. Increased generation of fibrocytes in thyroid-associated ophthalmopathy. J Clin Endocrinol Metab. Jan 2010;95(1):430-8. doi:10.1210/jc.2009-1614
 Bartalena L, Baldeschi L, Dickinson AJ, et al. Consensus statement of the European group on Graves’ orbitopathy (EUGOGO) on management of Graves’ orbitopathy. Thyroid. Mar 2008;18(3):333-46. doi:10.1089/thy.2007.0315
 Tinker MB. ELECTRO-SURGERY WITH SPECIAL REFERENCE TO GOITRE AND MALIGNANCY. Ann Surg. Oct 1931;94(4):587-91. doi:10.1097/00000658-193110000-00014
 Men CJ, Kossler AL, Wester ST. Updates on the understanding and management of thyroid eye disease. Ther Adv Ophthalmol. Jan-Dec 2021;13:25158414211027760. doi:10.1177/25158414211027760
 Lyu X, Zhao Q, Hui J, et al. The global landscape of approved antibody therapies. Antib Ther. Oct 2022;5(4):233-257. doi:10.1093/abt/tbac021
 Smith TJ, Kahaly GJ, Ezra DG, et al. Teprotumumab for Thyroid-Associated Ophthalmopathy. N Engl J Med. May 04 2017;376(18):1748-1761. doi:10.1056/NEJMoa1614949
 Douglas RS, Kahaly GJ, Patel A, et al. Teprotumumab for the Treatment of Active Thyroid Eye Disease. N Engl J Med. Jan 23 2020;382(4):341-352. doi:10.1056/NEJMoa1910434
 Bedian V, Newell R, Zhao Y, Tsai J, Dickinson B, Foster K. Preclinical Pharmacology, Pharmacokinetics, and Pharmacodynamics of VRDN-001, a Full Antagonist Antibody to the IGF-1 Receptor. 2023;(Manuscript submitted for publication).