LILLY WAGNER: Good afternoon. Welcome, everybody. Thank you so much for joining us in our webinar titled Thyroid Eye Disease Update-- Advances in Medical and Surgical Management.
I am Dr. Lilly Wagner. I'm an ophthalmologist here at the Mayo Clinic in Rochester, Minnesota, and I will be your moderator for today's discussion. We are really excited to have so many of you with us today.
And with that, I would like to introduce our speakers today, Dr. Elizabeth Bradley and Dr. Andrea Tooley, are ophthalmologists here at the Mayo Clinic and my colleagues in oculoplastic surgery. Dr. Marius Stan is an endocrinologist here at Mayo with special interest in thyroid disease. Along with other colleagues in ophthalmology, endocrinology and ENT, we all together take care of patients with thyroid eye disease in our multidisciplinary clinic.
None of us have any relevant financial disclosures with industry for this webinar, and I'm just going to start out, since we have audience participants from all different backgrounds, medical, patients, just interested students and learners, what is thyroid eye disease? Thyroid eye disease is a multisystem autoimmune disease. It is caused by autoantibodies that target the thyroid gland as well as tissues in the orbit, in the eye socket.
In the orbit, these antibodies cause a reaction that results in inflammation, fibrosis, deposition of extracellular matrix, and adipogenesis. And this leads to the typical signs and symptoms of thyroid eye disease, including proptosis, swelling around the eyes, dysfunction of the muscles with double vision and strabismus, and pain, redness, things that patients can see and feel. It follows a very typical time course in many cases, and this is demonstrated by Rundle's Curve.
In general, we have an active phase in the beginning that lasts anywhere between 1 to 3 years. This is when we see all the inflammation and the progressive changes. After this, patients enter a stable phase where they're not progressing anymore, but they may be left with a lot of the problems that the thyroid eye disease caused, like proptosis and double vision. And this is when we have the chance to help patients with rehabilitative surgeries.
When medical treatment is able to target that inflammation early on, we may be able to flatten the curve, have less severe disease, and patients may have less long-term problems and may even need less surgeries. Because of this variation in the severity and the timeline, we see very, very different presentations clinically of TED. They could range anywhere from very mild disease with mainly dry eye problems and cosmetic concerns to severe vision threatening disease, where patients need emergent surgery.
And it depends on the severity and the timeline where patients fall on that spectrum. So with that brief introduction, we're going to dive into our different aspects that we want to cover today. Dr. Stan is going to start us off and give us a brief overview of some basic pathophysiologic mechanisms and the relevance that these antibodies play.
MARIUS STAN: Thank you, Lilly, and happy to join a crew that has made patients with thyroid eye disease visiting with us quite happy with this multidisciplinary approach that we take here. My focus will be on the endocrine perspective, and as we look at the complex pathophysiology that this slide tries to depict, all of us are aware that the antibodies against the TSH receptor are generating the Graves disease, the overactive thyroid, which is many times the first step for these patients.
As the Graves disease is presenting to the endocrinologist, all of us in the endocrine field should be very keen to look for early changes that might be present at the eye level, and that's where the cartoon here depicts the orbital fibroblast which is the target of the antibodies in the orbit generating the changes that Dr. Wagner described earlier. Even if Graves disease is not associated with thyroid eye disease changes, it's important for us as endocrinologists to bring to the patient's attention that these changes can occur over the coming months or sometimes years, even when the thyroid disease has already been settled with one treatment or another.
And when those changes are present, we want them to notify us, and we as endocrinologists try to bring this to the attention of our colleagues in ophthalmology to decide what level of disease is present and what is the appropriate therapy. As we look at these changes, we have to be cautious-- and again, I speak mainly to the endocrine audience that makes a decision about how to treat Graves disease-- about what we know that can affect negatively the eye changes and particularly the use of radioactive iodine. When we try to control hyperthyroidism, we are aware that radioactive iodine is going to lead to an increase in TSH-directed autoantibodies, and that tends to be associated with either development of the novo of eye disease or deterioration of mild disease towards more severe disease.
And that is the perspective that from an endocrine pathway, we have to be aware. And then not only hyper but also hypothyroidism, which we sometimes see, can be associated with eye changes. So Hashimoto's thyroiditis does not mean patients are immune from thyroid eye disease. We should be aware that both ends of the autoimmune thyroid spectrum can lead to the changes that we call thyroid eye disease. And later on, we'll discuss what medical treatments might be available. I will turn it back to Dr. Wagner and come back to the antibodies when you see appropriate, Lilly, but I'll defer to you.
LILLY WAGNER: OK, great. Yes, we can go over some of the aspects of antibodies maybe later when we talk about the workup that we do in clinic where we're now going to turn over to Dr. Tooley. And oftentimes, I get asked by general ophthalmology or optometry colleagues, when do you think I should refer a patient? What should I take care of myself? And maybe you could tell us about when you think that's necessary and what the workup that we do here at Mayo looks like.
ANDREA TOOLEY: Thank you, Lilly, so much for having me. It's really a delight to talk about thyroid disease, which is something we're all so passionate about treating. And it's truly a complex constellation of symptoms.
And I say this to all my patients. There's no one way to diagnose thyroid eye disease. And so if you're seeing a patient that you suspect has thyroid eye disease but it's still unclear to you, I think that's a great reason to send them over to someone who sees a lot of this and can really recognize it.
Thyroid eye disease is one of those syndromes that falls under a great masquerader phenotype or pathology. There can be lots of things where you think maybe just a chronic conjunctivitis or a chronic dry eye, subtle proptosis, subtle lid retraction. All kinds of things can make it really easy to miss thyroid eye disease. In terms of the workup and when to really refer patients, I tend to go in an algorithmic approach.
I start with the thyroid history, and I ask my patients, what's your thyroid history, and when were you hypothyroidism? We know that for the vast majority of our patients, they're going to have a history of being hyperthyroid. But just like Dr. Stan said, don't let that fool you.
Our Hashimoto's hypothyroid or even thyroid patients can still have thyroid disease, but the most common will be hyper. So, start with that thyroid history, and if they fit the clinical picture-- yes, they had a history of hypothyroidism a year or two ago-- then that kind of adds to your checkbox, yes, this is probably thyroid disease. The next question is to ask about the eye history, and I say, when did your eyes start?
And most patients tend to know what that means. They'll say, you know, they really started about six months ago. Or I'll say, when did you notice changes in your eyes?
When did they start getting red or irritated? When did the double vision start? When were things changing?
And patients can usually pinpoint an exact timeframe when the eyes started, and that helps you also understand the pathology and the trajectory of the disease, and it helps you plot them on that Rundle's curve that Dr. Wagner was mentioning. So that's the second thing I add into my bucket of, is this thyroid eye disease? If the thyroid picture fits, if the eye history fits.
And then the next is your clinical assessment, and you can adjunctively add to that with antibody levels and serum testing that we'll talk about more, orbital imaging that we'll talk about more. But your basic exam-- do they have upper lid retraction? Do they have proptosis?
If patients kind of fit the bill for thyroid eye disease and have very mild disease-- slight lid retraction, they've had it for six months, no double vision, and you feel confident managing them-- I think it's fine to keep them under your care. If patients are in what I consider that active phase, meaning symptoms for less than a year, year and a half, I tend to see them on an every three month basis. But if patients are confusing you, if the diagnosis is unclear, or if you think they're severe or progressive symptoms, then always a good idea to refer to a real thyroid eye disease type center.
LILLY WAGNER: That's great. Yes, we certainly see patients where we sometimes feel, that's OK, we can send them back. But we never mind doing that initial evaluation, giving some guidance, discussing options with patients of medical treatment.
And oftentimes, if they have mild disease, they're totally happy to just be observed with supportive treatment and follow with their regular eye doctor, and they can always come back if things get worse. When we see patients here who have at least moderate to severe disease and especially active disease, we try to get them scheduled in our thyroid eye disease-dedicated clinic. Dr. Bradley, can you tell us a little more about how that clinic works, what that day looks like for patients?
ELIZABETH BRADLEY: Yes, thanks, Dr. Wagner. So, the thyroid eye disease clinic is a multidisciplinary clinic that we hold at Mayo about twice a month, and what it looks like from the patient perspective is that they spend their morning seeing multiple subspecialists. They see typically Dr. Stan or one of his colleagues but usually Dr. Stan in endocrinology.
In ophthalmology, they see two different groups. They see either Dr. Wagner or Dr. Tooley or myself in our orbital disease group, and then they see one of our adult strabismus colleagues, typically Dr. Eric Bothun. They are also seen by one of our rhinology colleagues, Dr. Janalee Stokken, shown in the top panel between me and Dr. Stan, and we'll explain that later what role they play in the surgical assessment.
And then patients also undergo standardized medical photography so that we have multiple images in different fields of gaze. And that allows us to get a snapshot of their disease at the entry point to us as well as to follow them over time. And then in the afternoon, patients come back, and they have a wrap up with Dr. Stan and with the orbital surgeon as well as CT imaging if needed if we feel that they're going to be going on to orbital decompression.
And then from the clinician standpoint, what it looks like is again, we're holding these clinics twice a month. The orbital surgeons rotate coverage. Each physician sees the patient independently in the morning, and then we convene over the noon hour for an hour-long meeting where we discuss our new patients as well as any established patients who have come back in the morning. And then again, one of the orbital surgeons is going back and meeting with the patient in person with Dr. Stan to give the patient our overview of next steps. And the thyroid disease clinic, in addition to providing clinical care, also does allow patients' entry into some of the clinical trials and other research that we have going on within the clinic and on our different services.
LILLY WAGNER: Yeah, that was a great overview. I think that last little piece, that afternoon wrap-up visit, which is like the last line on the description here, is really the key piece of the thyroid eye disease clinic, and when I get feedback from patients that seems to be what really empowers them to understand their disease and make informed decisions. So often, after that last wrap up visit, where we go up to the 18th floor and see patients together with Dr. Stan, patients tell us this is the first time I understand what's going on.
I'm not getting different information from my endocrinologist, my primary care doctor, my eye doctor. Everybody tells me one coherent assessment and plan, and I feel good about this decision now. We always present all the options to patients, and it's really up to them to make that informed decision, and it's great to see that most of them feel comfortable to tell us which way they want to go in that wrap-up visit. So that's my favorite part of the TED clinic.
We want to go back from our clinical assessment a little bit more to the basic science of this because this is a really important part also that we explain to patients to help them understand what is happening to them. Dr. Stan, can you tell us a little more about why we check the antibodies? What are they doing? What's the relevance of this?
MARIUS STAN: I agree, Lilly. That was a very nice overview, Elizabeth. Thank you for framing it so well.
And yes, I'm happy to discuss a bit how we look at the antibodies because many of us have probably over the years heard the various terms-- DSI, TRAP, TBII-- and what is the meaning behind them and what's the relevance to this disease. So I took here some cartoons from a publication from Dr. Davis a few years back. And what you're looking at here, you can, for now, ignore the right side.
But the left side, this is the TSH receptor. And you have to imagine the cell membrane is right at this beta subunit level. This is all in the cell membrane, and this is sticking out like a hook.
So now look where we have the antibodies coming in. This green dot that I depicted here is basically the way you have to imagine that a stimulating antibody would lock into the receptor. The TSH would try to do the very same thing, but this is the auto antibody that patients with Graves disease and patients with thyroid eye disease have, and it induces a stimulating signal that is transmitted to the orbital fibroblast, as we said earlier. And then the whole pandora's box opens up with fat accumulation and the glycosaminoglycan, that hyaluronic acid, that stiffens the muscles.
But this is not the only type of antibody. So the next image is where we have a blocking antibody. And we do not measure these directly.
But nevertheless, you have to see this blocking antibody as actually preventing TSH from stimulating. And I'm not sure if you see my mouse or not, but what I'm showing is that empty space is where the stimulation would occur, and that's blocked. So these antibodies actually can block the action of TSH as well as the action of stimulating antibody.
And then the third type of antibody is this gray dot here that actually is what we would call a neutral antibody. Bottom line is that it induces cell death. If there is a sufficient amount of interaction with these neutral antibodies, the signal that happens downstream is actually one of apoptosis.
Patients have a spectrum of these antibodies and one of them will dominate, but over the course of the disease, there might be shifts in which one dominates. So sometimes, we're surprised seeing flares down the road even if the antibody is staying the same titer, let's say. And that might be related to how these changes in the antibody type are happening over course of time.
When you order a test, you will have to keep in mind that if you order-- and I'm working with my technical skills here. If you order what's called TRAB, thyrotropin receptor antibodies, you're basically measuring all these three types-- stimulating, blocking, and neutral. You won't be able to say which one dominates, but you will have the overall titer, and this is the one that's cheapest, fastest, and probably correlates well with the disease for many patients but not all.
This is expressed in international units per liter. So if you get TRAB, you'll get the mixture. If you order TSI, Thyroid Stimulating Immunoglobulin, then you get only that green dot that I showed you earlier-- the most potent and the most highly correlated with disease activity.
That is going to take a little longer. It's about a two day run up for that assay. But it's probably the one that's most sensitive. When the disease is in its early phases, this is the assay that would be most relevant. We have a few more slides here trying to show how these values are able sometimes to predict the course of the disease.
This is data from Germany. Anja Eckstein looked. If the antibodies are over the black line that you see here, that would be more likely that they'll require a more aggressive course, more interventions. Under the gray line, that is titer of antibody.
Most likely, they will have a milder course for their disease. But about 50% of patients were found to be in this gray territory, where there was really no strong correlation one way or the other. I think overall, the antibodies have a useful role.
And keep in mind, some of these patients still have their thyroid disease, and that's highly relevant what the antibodies are doing. Here, I listed a couple of the ways in which antibodies could be utilized in a clinical practice. First of all, as Dr. Tooley was mentioning, they are very helpful when the presentation is atypical. Are we really dealing with thyroid disease or Graves ophthalmopathy?
Some patients are euthyroid. Despite our ability to look back, we just don't find thyroid abnormalities looking for the inflammation and also, as I said, a prognostic role. And I'll turn it back to you, Lilly, for guiding us further.
LILLY WAGNER: Yeah, no. This is great. No, I learned so much from my colleagues in the TED clinic when we worked together.
And this was one of the things that was hard for me to understand when I first came out of training, why patients sometimes have a positive TRAB but a normal TSI. and Dr. Stan did a lot of work explaining to me how there's a mix of antibodies. We really only assess some of them. There may be some that don't even fall under the TRAB test, right, that we don't even know about.
And that's why we don't understand the cause of some patients. We have improving antibody levels but seem to have worsening clinical disease or vice versa. Their antibodies are high, but they really don't look so bad clinically. So there's still a lot to learn, but the antibodies are definitely, I agree, a key piece and diagnosis.
And we can count on one hand, I think, the patients that we've all seen that we think had TED but no positive antibody. So it's extremely rare. So it almost rules it out that they have active TED.
We're going to talk a little bit about imaging next. The labs, the blood tests that patients go to get in the morning, are one piece of the puzzle in our diagnosis and treatment planning. The next one is orbital imaging.
Dr. Tooley, can you talk a little bit about when we get imaging? What does it tell us? How does it affect our decision making?
ANDREA TOOLEY: Yes, so, just like you said, the labs are one piece of the puzzle, and if their labs are negative, especially that TSI and TRAB, highly unlikely we're going to be seeing TED but not impossible. So that's one thing that can really help you with diagnosis.
And the next is imaging. Not every patient needs orbital imaging, but think it's very helpful. If you see orbital changes-- so there's proptosis. There's diplopia. There's lid retraction. and if you're uncertain of the diagnosis or if you're thinking they might be a surgical candidate in the future.
Those are both great reasons to get orbital imaging. It can help you confirm a pattern that correlates with thyroid eye disease. It can help you with surgical planning, and it can help see any type of other orbital pathology that may be confounding the clinical picture.
So when I get orbital imaging, I usually get an orbital CT. You can certainly get an MRI, but it's harder to access. It's more expensive, and we can get all the information we need from a CT.
If you're also thinking about getting an orbital decompression or surgery down the road, a CT will give you that bony anatomy detail, which can be very helpful. You can even get a CT sinus, and we can talk about that more when we're talking about how we partner with ENT. But if you're thinking about orbital decompression, a CT sinus has slightly less cuts, slightly less radiation, a little bit easier to do versus a CT orbit which is a little more detailed but also gives you all the same great information.
So, I personally love a CT orbit. When we look at the different orbital changes that we're seeing in thyroid eye disease, you can categorize them into a muscle predominant or a fat predominant type of orbital expansion. Those adipocytes are adding on the glycosaminoglycans.
They're accumulating fluid. We see edema and swelling. And that can translate into orbital fibroblasts and extraocular muscle enlargement or orbital fat enlargement or a combination of both. So just because you don't see orbital extraocular muscle enlargement and you're only seeing orbital fat enlargement doesn't mean that it's not thyroid eye disease. You can have kind of both.
So if we look at some of these pictures of orbital imaging that I've found, this picture on the top left, you see enlargement of, especially on the right, inferior rectus, medial rectus, superior rectus, a little bit of enlargement maybe of the medial on the left. That goes in a thyroid eye disease pattern, where we expect to see medial, inferior, and superior muscle enlargement before lateral rectus enlargement. One thing I tell everyone who's training with me and something I learned is that if you see lateral rectus enlargement without the other extraocular muscle enlargements, really think twice, and it's unlikely to be thyroid eye disease.
If that lateral rectus is enlarged, the other three muscles need to also be enlarged before you're seeing lateral rectus involvement. The picture, then, on the top right, representative more of that orbital fat expansion with normal appearing muscles, and you can really see that significant proptosis even though the muscles appear relatively normal. Then that bottom left is that real extraocular muscle expansion, where you're seeing the inferior, medial, and superior, but the laterals look relatively normal.
And that's a very typical clinical picture that you'd see with imaging with thyroid eye disease. And then on that axial slice, you can see that muscle belly enlargement with the tendon sparing that we talk about. In thyroid eye disease, our imaging tends to show sparing of the tendons of the extraocular muscles with those bellies really taking on the vast majority of the enlargement. So there's a variety of clinical phenotypes you can see, but that's the general things that we're looking for.
Looking here on this left photo, sometimes you can just see singular muscle enlargement. We have some good studies that show that if one muscle is going to be enlarged, often, it's the superior rectus. So, just because the inferior and the medial is not involved and it's only the superior, that can still be a classic presentation of thyroid disease.
And the last thing is orbital inflammation that you see here on this right image, where you see kind of fluffy infiltrates. The orbit looks a little dirty. There's more of an inflammatory picture.
This is much less typical for a thyroid eye disease picture. So if you're seeing other infiltrative lesions, creepy crawly type lesions, lacrimal gland enlargement, those all can be thyroid eye disease.
But another reason to think twice and use the full picture to put it together and think, is this an inflammatory syndrome, or is this thyroid eye disease, this image here on the right is actually a patient who ended up having IGG4-- related orbital inflammation, who was initially misdiagnosed as thyroid eye disease. So again, a great masquerader. An orbital imaging can really help you in those cases where you're thinking about surgical planning, you're wanting to confirm your diagnosis, or you're just suspicious about the diagnosis in general.
LILLY WAGNER: And of course, that picture, that last one you showed with the IGG4 disease, also has terrible sinus disease, which should tip us off. Of course, patients could have chronic sinusitis and thyroid disease, but yeah. If you see that obscuration of the sinuses, another great reason why we love having ENT on speed dial because something else may be going on.
ANDREA TOOLEY: That's a great point.
LILLY WAGNER: So, in this second half here, as we enter into that in our webinar, we're going to get to our updates and new exciting things that are happening. I think everybody knows now what do to diagnose it, what are all the different ways that patients with TED can present. And now we're going to say what we're going to do to help them.
So we're going to move on to the treatment part and some of the recent developments. We used to really only have one options in terms of medical treatment. Now, things have become more complicated since teprotumumab has become FDA-approved, and many of our referring docs and patients specifically come wanting to hear about these treatment options.
So, Dr. Tooley, who are the good candidates for teprotumumab? Is there still a role of steroids? What do we tell patients in terms of treatments that we have to offer?
ANDREA TOOLEY: This is such a great question, Dr. Wagner, because teprotumumab or TEPEZZA really changed the whole game for treating thyroid eye disease. Like you said, this was FDA approved in 2020. So it's still a very recent medication.
We're learning a lot about teprotumumab as we treat more patients. And the initial studies were really small numbers of patients. And so there's still a lot of big questions about teprotumumab.
But I think it's the most common question that we hear from outside providers or patients. Am I a candidate? Should I be on it? Who should be on it, and how do you choose?
So in general, teprotumumab is an IGF1 receptor antibody, and this really targets the whole cascade of pathophysiologic changes that we're seeing in thyroid eye disease. It's overexpressed on orbital fibroblasts, and so it really targets all of those different changes that Dr. Stan had touched upon. It's an IV infusion that's given every three weeks, and in the initial studies, it was chosen to give eight infusions because that equaled six months.
As we're learning more about teprotumumab, and we'll talk more about this later, the big questions are, do patients truly need eight infusions, or do they need more, or do they need maintenance dosing? And those are big questions that we're investigating, and there's exciting clinical trials that are giving us more data in terms of that. But for now, it's an eight week or eight-time infusion every three weeks.
As we all know, it's extremely expensive, and we've had great luck with insurance coverage, but not everyone is a candidate. And you really have to meet certain criteria to be able to have this covered by insurance. And so that's kind of our overview with teprotumumab.
When you're thinking about patients who might be good candidates for TEPEZZA or teprotumumab, I like to think first about the disease time course. And that's because two reasons. In the initial study for teprotumumab, patients were included if they were within an early course of their disease-- so, less than nine months.
So patients who are what we would consider in the active phase of that Rundle's curve that Dr. Wagner mentioned are really good candidates. There are questions about can we give this for patients who have more chronic, long-term disease. And we're starting to get more data, and patients do seem to have some treatment response.
But my initial thought is that patients who are in a more active phase of their disease are going to overall be more responsive and better candidates for teprotumumab starting off. The next question you want to ask is the side effect profile and understanding your patient's comorbidities and other things that they're dealing with. Are they a very brittle diabetic?
Do they have extremely high blood glucose that is out of control? Are they overall sick or immunocompromised? Are there other things that we need to be considering?
Is this a patient who won't tolerate infusions very well? Are they 90 years old, or are they a healthy 45-year-old with no medical problems? Thinking about that side effect profile is going to be very important, and Dr. Bradley will talk more about the overall side effects, especially hearing loss and any hearing changes, which is something else you want to think about if you're wondering if your patient is a candidate.
So those are the big things that I initially talk to my patient about. And then the last thing is in everything we do as a physician is weighing those risks and those benefits. And so if a patient has very mild disease, is it really worth putting them through an extremely expensive infusion to get a small improvement? I think patients in general with the studies showing a CAS of four or greater or, in my mind, patients who are very distressed by their disease are better candidates than patients who have a more mild or moderate phenotype.
LILLY WAGNER: Yeah, that's great. And the CAS, in case-- and not everyone in the audience is familiar with it-- is our Clinical Activity Score which basically puts people onto that spectrum of mild to severe amount of inflammation, and patients get a number from 0 to 7. 0 is no inflammation, 7 is the worst. And we collect that score on every visit for every TED patient.
It also helps us to determine where they are on the curve, is their score getting better or worse, and would they get a lot of bang for their buck if we put them on anti-inflammatory treatment. So that's a super helpful number to assess if you are an ophthalmologist or optometrist who sees TED patients to tell if they're getting better or worse and if it's time to refer them and if they're a good candidate to treatment. So we're going to go a little bit into the specifics of the study that you mentioned which showed us what the potential benefits are and the potential side effects of TEPEZZA/teprotumumab. And I think, Doctor, were you going to cover that? Or Doctor Bradley here, our next slide shows--
ANDREA TOOLEY: I'll touch on it.
LILLY WAGNER: --study. Yeah.
ANDREA TOOLEY: I'll touch on the optic study a little bit, Dr. Wagner, and then I'll turn it over to Dr. Bradley for her experience clinically. But basically, this was the initial study in New England Journal of Medicine that came out in 2020 and changed everything. We now have some long-term data in the optic X study and then lots of side trials that we'll talk about as well.
But like I said, patients were recruited if they had what was considered active thyroid eye disease, less than nine months with no prior treatment, a wide range of ages in that initial study, clinical activity score greater than four-- so, really quite symptomatic in terms of how the thyroid disease was affecting them. Patients were randomized to get eight infusions of teprotumumab or a placebo. And what you'll see is in terms of proptosis, diplopia, and CAS score, we had very impressive clinical improvement that was all statistically significant. So, proptosis was a greater than two millimeter reduction, and we saw that in 83% of patients, which is huge.
And then diplopia responders, also 68%. Tremendous, and CAS responders as well. So those were the three main metrics that we initially looked at in that optic study.
And the one thing I'll add before turning it over to Dr. Bradley to really give the real-world experience is that these are small numbers, about 80 patients in this initial study. And I think we all were so excited about having something to offer our patients. And now as we're entering kind of year four into seeing what this drug can really do for us, we've learned a lot about the limitations, and I'll pass it over to Dr. Bradley.
ELIZABETH BRADLEY: Yeah, and I'm happy to talk now, and I think Dr. Stan also was going to talk about side effects. Marius, did you want to talk about that before I get into some of the issues with recurrent thyroid eye disease? Or I'd be happy to talk about side effects as well.
MARIUS STAN: I think it's a point that many of us in the field of thyroid eye disease is considering. As you said, Lilly, what's the benefit? What's the risk?
How do we balance that? As an endocrinologist, I'm not surprised that we have to consider side effects because this pathway of blocking the IGF1 receptor is a relevant pathway for many systems. The issues that came along with the use of teprotumumab, one was the development of elevated glucose value-- so, hypoglycemia.
It is probably somewhere in the range of 20% to 30% in real practice even though the clinical trials had it a little lower at maybe 10% to 15%. Fortunately, with good patient selection as maybe, Andrea, you pointed out, diabetes has to be well-controlled up front. Typically, we would want to see an A1C less than eight before patients are started on this treatment.
And then we want to monitor the glucose values after the first two to four infusions, I would say, to make sure that there's no sharp deviation from the level of control that they have before therapy. And occasionally, we would have to add another agent. If they've been on oral agents, the increase in dose seems to be sufficient for most.
But occasionally, we did add insulin on a couple cases. Overall, I think this is managed well as long as a team approach like we're using is in place. So I think the endocrine ophthalmology collaboration works well to keep this at bay.
The challenge that many of us are facing, though, is there's no good prediction for who will run into hearing challenges. And those can be issues along the lines of autophobia, hearing yourself speaking rather loud as if you have water in your ears, the tinnitus, the pressure, but at times actual hearing loss. And it tends to be on the higher frequencies.
So, one should be obtaining a baseline audiogram to understand where we start and then be on the lookout and question the patients about changes that might be developing insidiously and yet be meaningful later on. So we try to repeat an audiogram halfway through a full treatment course. The other issues that many of us might be aware is that patients develop muscle cramps. Those, fortunately, are manageable with hydration, multivitamins, occasionally muscle relaxants.
And GI distress-- I think that's another common factor. Anybody should be screened for inflammatory bowel disease, and if that's present, this drug should not be used if the inflammatory bowel disease is an acute flare. Probably OK to consider it if they've been quiescent, but I'll be very careful about this aspect. And then there are a number of other aspects that we can touch up in the Q&A later if we want to expand on this.
LILLY WAGNER: And you mentioned checking glucose labs. So if someone wanted to get baseline labs and then that second look after two or three infusions, would that be a hemoglobin A1C and a fasting glucose?
MARIUS STAN: Exactly. Good that you're that you're pointing out, as I said, an A1C less than eight would be the door to entry into this trial, but we certainly want to see that the glucose at that point because A1C goes back three months and might not be a very accurate reflection of what's happening over the last couple of weeks. So I want to see that the fasting glucose is also less than 150. Certainly values over 200 would make me very reluctant to start teprotumumab at that point.
LILLY WAGNER: OK, great. So now that we decided maybe that we have a good candidate, Dr. Bradley can tell us a little bit more about what is it that we see in the real world with treatment, how do people do afterwards. Now that we have some patients who finish treatment and we followed them quite some time, we get a better idea of what that time looks like.
ELIZABETH BRADLEY: Thanks, Dr. Wagner. So I have chosen a patient here who really shows us both the promise of TEPEZZA but then also some of its limitations as well. So the patient presented to an outside clinic in February 2020.
So, TEPEZZA was FDA-approved in January 2020. So it's a brand new drug. She presented very soon after that prior to treatment with TEPEZZA and was one of the very early patients to be treated with TEPEZZA.
Had an excellent response. So she started on TEPEZZA very soon after her February presentation, finished treatment that fall of 2020. And then here she is, six months after her last infusion.
She came to see us at that point very much improved in terms of her proptosis and that clinical activity, meaning the amount of inflammation she has. You can see she's got less eyelid edema, erythema, less conjunctival injection, and even allowing for difference in color between the photos. I think you can appreciate that she had a significant improvement in her appearance.
And symptomatically, she felt much better. She did still have dry eye, and she did still feel that her bulging was excessive compared to her baseline. And so she came to us looking for orbital decompression.
And so we took her to the operating room shortly after that February presentation with us. And you saw her for her six week follow up visit, shown on the left here, expecting to go in and see somebody who at that point had fairly quiet eyes and a significant reduction in her proptosis, and we found the opposite. So, she looks inflamed again.
Eyes are very injected. Lids are swollen. And rather than achieving a three to four millimeter proptosis reduction, we actually have worse proptosis than we had before we did the decompression. And put things together in terms of the timing and realized that she was at the right time, about 9 to 12 months after her last TEPEZZA infusion, that she is having reactivation of her disease. And so then we followed her along, and at 4 months after decompression, 11 months after her last TEPEZZA infusion, the inflammation simply continues to worsen.
And then we had many discussions about what the appropriate treatment course was for her at that point. She decided to be retreated with TEPEZZA. And so in October 2022, she at that point had been treated with six more TEPEZZA infusions. She stopped because she developed significant tinnitus, and she also felt that she was having some word finding difficulties that she correlated with the TEPEZZA.
That's not a well-known side effect, but again, when the initial clinical trials have fewer than 100 patients, certainly, it's possible that new side effects emerge as more patients are treated. So, for those symptoms, she was stopped short of the full eight treatments. But after just six treatments, you can see that she's had significant lessening in her proptosis.
She did not get back to that initial wonderful treatment response that she had after the first course. She's got some loosening of the eyelid skin, and she still has some proptosis and lid retraction but undoubtedly is a good bit better after that second course of TEPEZZA. And then that brings us up to the current time, when we last saw her in clinic last month.
So at that point, she was a year out of that second round of TEPEZZA . She is progressing again. So we definitely have increased proptosis and some increased inflammation as well.
So she's having this kind of yo-yo response depending on whether she is actively on TEPEZZA or not. So again, we're early in the days still of TEPEZZA, and in some ways, the treatment raises more questions than it answers. And just to look at that key result from the original New England Journal paper, this is what Dr. Tooley had shown before.
You know, 83% response to proptosis at the 24 week marker versus only 10% with placebo. But again, that was patients who were still-- they were still actively receiving the drug, having just finished their last infusion. The trial investigators did look at their duration of effect. So again, they're reporting 83% of their intention to treat population responded at 24 weeks.
When the investigators followed patients along at 48 weeks, they were reporting 56% of responders maintained the effect. The most recent data that we have comes from the Cleveland Clinic group just published a couple of weeks ago looking at reactivation after teprotumumab treatment for active thyroid eye disease. They reviewed 21 of their patients, and fully 2/3 of their patients unfortunately lost the effect over time.
And in their group, they found that the rebound began at six months but potentially continued all the way through to two years. And most patients were having a full blown disease reactivation, as we saw in our patient. In other words, they were going all the way back to that inflammatory phase.
And the issue that the authors raised is that teprotumumab can significantly delay achievement potentially of the quiescent phase of the disease and therefore readiness for surgical rehabilitation. So again, it's something we're sorting out. Does teprotumumab just insert a period of seeming quiescence until the drug is removed? Do some patients need to be treated every six months or so with one or two infusions? These are all things that we need to out in the months and years ahead.
LILLY WAGNER: Yeah, and I think this just speaks to that wide range of presentations that patients fall on. And the Rundle's curve active part section acknowledges that the active phase can last 1 to 3 years. So of course, someone who's in the active phase for two or three years and only receives eight infusions every three weeks will still be in the active phase when they finish treatment.
And it makes perfect sense that there is going to be some kind of recurrence of disease activity and inflammation. And unfortunately, we don't when we first see patients if they're in the one year or the three year active duration group. So that's going to be something that hopefully one day, we can sort out and predict how long they're going to need anti-inflammatory treatment for.
We are going to look at some of the-- back some of the basic science aspects of things, and Dr. Stan is going to talk us through that. Back to the cellular mechanisms, there's a lot of treatments in the pipeline that recognize some of those underlying processes and try to target them and shut down the inflammatory cascade. Dr. Stan, what are the new things that may be coming out soon that are currently in clinical trial, maybe even with our patient population?
MARIUS STAN: I think it's a very interesting time for thyroid eye disease and in general for thyroid autoimmunity because we shouldn't separate these treatments as being for thyroid eye disease alone. Some of these are probably going to spill over in how we treat Graves disease. But specifics-- so this is one approach that is currently in clinical trials. The product, let's call it, INVT-1401 actually now has a name, batoclimab.
The idea is that all of us, as we have IGGs in circulation, we bring them down into our cells for recycling, and we have a chaperone protein called FCRN. This protein actually is able to protect the IGG. If you look at the cartoon on the left, the binding of FCRN is what chaperones the IGGs back to the cell membrane.
And this is why our IGG lasts about three weeks in circulation. That's the half life that we have for IGG. So if we were able to block this orange FCRN, the IGGs would end up in the lysosome and be degraded, which would certainly decrease their lifespan, if you will.
And that's exactly what this monoclonal antibody is trying to do with the idea that most of the IGGs in an autoimmune individual or individual with autoimmunity are actually autoantibodies that cause harm-- in this case, the TSH receptor autoantibodies. So, this monoclonal antibody will block the FCRM protector, and thus IGGs end up degraded in the lysosomes, intracellular. So we have what we can see on the next slide, the impact on the TSH receptor autoantibodies with batoclimab, this FCRM monoclonal antibody.
You can see the placebo group on the gray line staying pretty much along the baseline prior to the trial. And if we look at the different strengths of the batoclimab drug, we can see a decline. On the y-axis, you see percentage decline in the TRAB.
I mentioned to you as this being the compound of all TSH receptor autoantibodies. And you can see that that hits the 60% decline at the 12 weeks of the cutoff point for this trial. This is not the current trial.
This is the trial that happened in the 2020-2021. And some of you know that that trial was stopped. And the reason for that stoppage had to do with the fact that albumin also uses the same mechanism. And actually, a drop in albumin occurred.
And subsequent to that, an increase in cholesterol synthesis, that's the presumed mechanism, occurred with increase in LDL values. So a reshuffling of the approach to a clinical trial with this drug was devised, how to keep it safe. And that's the current iteration that some of you probably are aware of the new trial with batoclimab trying to again decrease the autoantibodies but at the same time avoid the challenges with cholesterol.
So this is one approach. This is our FCRN monoclonal antibodies, and there's more than one that it's trying to make its way through clinical research. The next approach, which is also a very interesting one, this is, again, the TSH receptor. We discussed this earlier.
And what I want you to see is if I could activate the screen, what's masked here, and I think that action is outside of my technical skill. But bottom line, if this animation were to function, what you would see here is that we would block-- as I showed you earlier, we would be able to use a receptor antibody that blocks the action on the TSH receptor. This is called K-170.
And this K-170 has actually been brought to the clinical arena for a trial in UK with very nice response in patients with Graves disease. And some of these patients also had thyroid eye disease, and their response was very intriguing-- decrease in proptosis, decrease in inflammation. We have actually reported on one such case here from Mayo Clinic.
I'll be brief about this, but basically, this was a patient that had thyroid cancer, lung metastasis, and at the same time had Graves disease with thyroid eye disease. The K-170 was used on a compassionate basis in order to block the stimulation for the lung metastasis. And lo and behold, what was noticed was an improvement in the inflammation score.
You see at baseline six out of seven, a beautiful response, almost no inflammation. You see the quantification of proptosis 21 bilateral and, few months later, a decrease by three millimeters in both eyes again with blocking the TSH receptor which, fortunately, also delayed the progression of her lung metastasis, actually shrunk a number of them because they were stimulated by the presence of ongoing TSH receptor antibodies. And then--
LILLY WAGNER: Dr. Stan, we do want to touch on briefly the surgical management and have a couple of minutes for questions and answers because we do have a few in the chat. But yeah, I think you had one more agent that you wanted to--
MARIUS STAN: I think I'll just say what many in the audience probably know-- the talk about inflammation. Tocilizumab is an IL-6 receptor blocker. I'm not going to review the data.
I'll just say that many of us have heard of the data from Spain, and there are novel agents that aim to tackle exactly the IL-6 receptor, and I expect two if not more clinical trials looking at this target will be happening in the near future. We are involved in one such trial, but there are at least two novel IL-6 blockers. I'll turn it to you, Lilly, because I know I can take too much of everybody's time. So I'll stop here.
LILLY WAGNER: I just-- yeah, we're excited to see the results. I just saw two trial patients today that are in the middle of their treatments, and we're excited to see what comes out of it. Of course, we won't know if they're on treatment or placebo until the end, but you know, either way, we're going to get some good data.
Dr. Tooley, we just wanted to briefly touch for a minute because we have a few good questions that I kind of grouped. Some of them fall in the same categories, but briefly touch on the role of surgery. So, with all this proptosis reduction and positive results, do patients still need surgery?
ANDREA TOOLEY: Yes. So, lots of different surgical options-- I've grouped them into three kind of categories-- decompression, strabismus surgery, and then lid retraction repair, which are kind of our most common categories. Decompression, you can either do acutely for compressive optic neuropathy during the active stage of the disease.
And so if a patient is within that active Rundle's curve within those one to three years and they have evidence of compressive optic neuropathy, then they're eligible for treatment with IV steroids and surgical decompression to protect their vision and the optic nerve. Otherwise, we're generally thinking about doing surgery outside of the active phase, when the inflammation is more quiet. So in that case, we would do a surgical decompression for excess proptosis, exposure keratopathy, lagophthalmos and really just proptosis and cosmesis and making the eye feel more comfortable.
I'll show you a little algorithm for deciding what of decompression to do. Then, of course, strabismus surgery-- we like to do strabismus surgery outside of the active phase when we demonstrated at least six months of stability in extraocular motility measurements. So you really want stability there.
You can couple decompression and strabismus surgery, although the outcomes are a little bit more of a guessing game. But there's been some good data showing that. We don't do that frequently here at Mayo Clinic, but it's an option.
And then finally, lid retraction repair-- I think it's essential to do lid retraction repair outside of the active phase. Otherwise, that lid will go right back up. And so you really want stability.
There are a couple good papers that show that lid retraction actually does slightly improve over the kind of one to three years following the active phase. So if it's very minimal, I would just let the patients wait, and it tends to get a little bit better. But if it is severe and you want to repair the lid retraction as long as the patient is in the quiet phase, I like to do a full thickness laparotomy.
But you could do a graded laparotomy and bring that lid down. It's important to sit the patient up, really look at the lid height, and always aim on the low side because they tend to heal up. And so those are my biggest tips for general surgery.
Quickly with decompression, we talk about doing combined decompression with endoscopic medial wall approach with ENT versus lateral wall, a balance with the medial wall, lateral wall, adding a floor for extra decompression effects, and then a fat decompression, where you're only taking orbital fat. That has the lowest risk of diplopia. It can give you about two to three millimeters of proptosis reduction. And so you really have to decide how much proptosis reduction you're looking for, and then you can customize your decompression based on that.
LILLY WAGNER: That's great. Yeah, so we definitely still do a lot of surgery. And I'm going to try to cover some of our audience questions because they're really awesome and super important points that people want to clarify.
Someone asked if TED is really a multisystem disease. Yes, it is. Patients have eye problems.
They have thyroid problems. They can have dermopathy, which means skin changes, on their lower extremities, which can be really symptomatic for patients. And some patients even have neurologic problems with memory loss. So we don't even understand yet how the whole body is affected, but it's definitely a disease that affects many parts of our body, and we have to look at the patient as a whole.
There's a few quick questions about workup regarding CT. We usually get a CT with no contrast. I don't think adding the contrast is really changing our management. So, CT no contrast is fine.
In terms of labs, somebody asked if all the labs can be normal. Yes, they can all be normal in terms of the thyroid hormones. And like I said, we even had a handful of patients where all the clinical pictures made sense, but they had negative antibodies. And even then, we sometimes diagnosed TEDs.
We had somebody ask about Dr. Bradley's patients, if insurance covered that repeat TEPEZZA treatment. And I believe they did. And I hear that from colleagues out in oculoplastics as well, that usually, if a case is made that they're a good candidate, sometimes repeat treatment will be covered.
Somebody asked about clinical scales. We usually use the CAS, the Clinical Activity Score, which is from the EUGOGO study. And then some of the side effects and comparison to prednisone-- all the TEPEZZA trials have been against placebo. So that's really all the information that we have is how it performs against placebo, not against steroids or other treatments.
I think we've reached the end. We may have the opportunity to answer some of the questions in writing and add that to our recording. We love having so many of you tune in.
It's a really exciting topic, and we are very fortunate here to manage this with such a great team.