Thyroid Eye Disease: A New Name,A New Guide,and A New Era

A New Name

You know it when you see it….this applies to the eyes of patients with Graves' disease. As soon as the patient walks through the door you know whether thyroid eye disease is there or not. You do not need a fancy activity score to help you decide whether the patient has the complication, which may occur in 25–30% of patients. ¹ But you do most certainly need such an assessment if you are going to care for the patient yourself and monitor their response to treatment. Thus, the use of the Clinical Activity Score ² is important in the absence of a disease marker as long as we realize how approximate the assessment is and that it does not reflect the duration of disease.

But how is it that we have known about “goiter” for centuries, but it was not until the 19th century (apart from some ancient reports) that physicians looked, consistently at the eyes of their patients? It is easy enough to notice that our Clinical Fellows are often too glued to their screens to look in a patient's eyes. However, experienced clinicians had to wait until Graves (1834) and von Basedow (1840) spread the news and it became widely recognized. For an excellent review of this history, I recommend an article published in Thyroid by Lindholm and Laurberg. ³ Take note of how Graves described a “newly observed affection of the thyroid gland in females” ^4,5 :

The eyeballs were enlarged so that when she slept or tried to shut her eyes, the lids were incapable of closing. When the eyes were open, the white sclerotic could be seen all around the cornea and a tumor of a horse-shoe shape appeared on the front of the throat exactly in the situation of the thyroid gland.

However, more early reports, not widely circulated, of cases of “goiter with exophthalmos” were first published by the Italians, Giuseppe Flajani and Antonio Giuseppe Testa, in 1802 and 1810, respectively. Before these, and much better recognized, Caleb Hillier Parry, a notable provincial physician from Bath in England, described a case in 1786. This case was not published until 1825, which was still 10 years ahead of the report by Graves. ⁵ And so, since the description of “goiter with exophthalmos” we clinicians spent the next 200 years redescribing the disorder and giving it a series of different but often confusing names, including the following:

Exophthalmos

Since 1999 with the establishment of the European Group on Graves' Orbitopathy (EUGOGO) the term Graves' Orbitopathy gradually became the medical description most used and EUGOGO has done a magnificent job in training clinicians and trying to educate patients about the disease. Their collaborative research has produced an impressive new knowledge base; especially in the treatment arena (see 2021 EUGOGO guidelines for the medical management of GO). ² Science, after all, is the art of measurement and EUGOGO has pioneered the description of facts over opinion but has unfortunately persisted in using the term Graves' Orbitopathy.

Now at last we seem to have entered a new ERA which has landed upon the term “Thyroid Eye Disease” or TED. I wish I could say this came from a multinational conference of endocrinologists, but I believe the driving force has been commercial. Once a specific treatment recently became available for thyroid eyes it had to be explained to patients and much of the nomenclature in use did not ensure public digestion. TED, however, is easy to say and to understand and now you see it all over the media in the United States and it has begun to replace the old terms in the medical/scientific literature. The new edition of UpToDate on TED now uses this term exclusively (for full disclosure—I have to admit I am a coauthor). ⁶

It is not that I am uncomfortable with the old terms. I “grew up” on GO, first meaning Graves' Ophthalmopathy, and then when I became wiser, it meant to me Graves' Orbitopathy, since it is NOT a disorder of the globe but rather the orbit. Now of course, whenever there is a consensus formed there are objections from the left and the right. Despite the rampant confusion, a small number of thyroidologists, and I assume also ophthalmologists, would prefer to keep their patients in the “dark” and keep one of the older terms. So let them! This is not a personal vendetta against people with passion for their interest! EUGOGO does not have to rename itself! Although the American Thyroid Association (ATA) did change its name when times changed (from American Goiter Association). But what is in a name? Well, it is important and for once Shakespeare was incorrect:

What's in a name? That which we call a rose/By any other name would smell as sweet

This was Juliet telling Romeo that a name is nothing but a name. It is a convention with no meaning behind it. How wrong! Look at the problems misnaming and misunderstanding can cause. Words must have meanings that we all can understand. So, congratulations to all of us who agree that Thyroid Eye Disease is the right name for the times!

A New Guide

EUGOGO has released highly informative treatment guidelines from Europe for the past 15 years. ^2,7 In this edition of Thyroid, we are being treated to a new consensus statement on TED. Not only is it from the ATA but also from the European Thyroid Association (ETA, but I note not EUGOGO), suggesting that the world is indeed coming to a consensus not only on the NAME but also on the disorder. This joint statement is designed “to address the clinical assessment, develop criteria for referral to specialty care and treatment, and to focus on medical and surgical treatment in non-pregnant adults (age ≥18 years) with TED.” And it does this with great success. Even though I may strongly disagree with certain statements and recommendations (Since when was retro-orbital radiotherapy a preferred treatment of choice for diplopia?), it is a tour de force in the field and a reference document for us all.

But be warned… By definition, such guides have the capacity for self-growth. Never in the history of mankind has a new guideline been updated by slimming it down. So, this is only the first installment! Every guideline grows larger—we know so much! There is a rather macabre play by Albee, I think, where there is a dead body in a room off stage, which keeps growing as the play continues, pushing in the back wall until by the end of the play there is hardly any room left on stage. The early EUGOGO consensus statement had 15 pages ⁷ and the latest EUGOGO guideline has 25 pages. ² However, the new TED consensus statement in this edition of Thyroid is even longer at 32 pages! Nevertheless, we should congratulate Drs. Burch, Perros, and their team for reaching and producing a consensus for us to all to learn from. And what nomenclature do they use? Thyroid Eye Disease.

A New ERA

The emergence of novel therapies has changed the entire discussion concerning TED and not just its name. There must be at least 7–8 different drugs in various stages of development, ⁸ some of which are discussed in the new consensus statement. This progress has been because of the success of basic science in furthering our understanding of the etiology of this disorder—something the National Institutes of Health should take note of. The new era really began in the laboratory of Sydney Ingbar, who showed that thyrotropin (TSH) and insulin-like growth factor 1 (IGF-1) synergized ⁹ and years later the finding of enhanced TSH receptor expression in retro-orbital fibroblasts ¹⁰ and that the synergism was maintained between TSH and IGF-1 in nonthyroid cells. ¹¹

The subsequent clinical studies using an IGF1-receptor blocking antibody (teprotumumab) produced impressive proptosis reduction in patients with TED—the first drug to successfully achieve this since corticosteroids rarely induced such marked improvement. ¹² Now that this monoclonal antibody is FDA approved in the United States, it is receiving the real test of general use and has opened a totally new era in treatment of a very difficult disorder. Although there are concerns about side effects (such as glucose intolerance and hearing disturbances) and the need for delivery by infusions, these will not be an obstacle to further development of this approach as we learn how to use this and similar drugs.

But it is not yet available outside the United States and so international guides to treatment must take this into account just as the ATA/ETA consensus article does. Furthermore, more treatments are on the way including the potential use of a TSH receptor blocking monoclonal antibody, which may improve the patient's thyroid status as well the eyes with or without IGF1-receptor blockade. ¹³ These are early and exciting days in the treatment of TED, which is likely to be a much more manageable disease in the years to come.

Author's Contributions

T.F.D. is responsible for conceptualization and writing of this article.