Is Long-Term Antithyroid Use the Best Treatment for Graves Disease?

This transcript has been edited for clarity.

Angela Leung, MD, MSc: Welcome to this video commentary about the long-term use of antithyroid drugs in the management of Graves disease. My name is Angela Leung. I'm an adult endocrinologist at the University of California in Los Angeles and the Veterans Affairs Greater Los Angeles Healthcare System.

I'm pleased to moderate this discussion today, and we have two esteemed guests with us. The first is Dr David Cooper. He is a professor of medicine and radiology at the Johns Hopkins University School of Medicine. He's the director of the thyroid clinic there, an internationally known expert for his work in thyroid research, and an esteemed educator and clinician. He's also one of the co-authors of the American Thyroid Association 2016 hyperthyroidism and thyrotoxicosis guideline.

We also have Dr Whitney Goldner, who is a professor of medicine in the Division of Diabetes, Endocrinology, and Metabolism in the Department of Medicine at the University of Nebraska College of Medicine and the University of Nebraska Medical Center. She is the medical director of the Thyroid and Endocrine Tumor Program there, and she is active in the Endocrine Society and the American Thyroid Association. Her clinical and research interests are in thyroid disease, thyroid nodules, and thyroid cancer.

We're very pleased to hold this informal discussion with our two guests today on the long-term management of individuals with Graves disease. With that, let's go ahead and get started.

Dr Goldner, I'll pose the first question to you. Could you give us a brief introduction on the definition of Graves disease and the usual treatment options that you would counsel patients on when you see them in clinic?

Whitney Goldner, MD: Sure. Graves disease is one of the causes of an overactive thyroid or hyperthyroidism; it's often the most common cause. It's an autoimmune condition where the body develops antibodies against itself, specifically against the TSH receptor, or the thyroid-stimulating hormone receptor, on the thyroid gland, which ultimately turns on the thyroid. It continues to make more and more thyroid hormone and often makes the thyroid get bigger, and it doesn't necessarily turn off in response to our normal turn-off mechanisms in the body. That's why people become hyperthyroid and make too much thyroid hormone.

The most common treatment options: We usually think of three main options when we think of how we should treat it. One of them is with medications. They're oral medications that we refer to as antithyroid medications, which is what we're discussing today, which slow down the production of thyroid hormone from the gland itself.

Another option would be treating somebody with radioactive iodine, which in effect will kill many of the thyroid cells in the gland itself so they don't have the ability to make more or excess thyroid hormone. Last would be surgical removal of the gland.

Leung: That's perfect. Among those three options, can you give us a quick overview of your thinking when you decide on and recommend which of the three might be appropriate for which type of patient?

Goldner: I usually think of many different factors when it comes to which option might be best. Really, there's no perfect option for just one person. It's a personalized approach, considering the pros and cons of each approach. If somebody is wanting to first try to get their levels down and take a little bit of time to make a decision, it's always reasonable to start with antithyroid drugs and, in a sense, cool off their levels and bring them — hopefully — back down to normal.

That can be done initially and as a bridge to a more permanent therapy like radioactive iodine or surgery, or it can be used in a more long-term fashion as the ultimate therapy that is being used.

For people who are considering, say, pregnancy relatively soon or they really don't want to use medications long term or be exposed to radioactivity, sometimes surgery is something that people want to consider, which is upfront as their more permanent option. Conversely, for people who do not want to consider surgery and really don't want long-term antithyroid medication, sometimes radioactive iodine can be a great option.

One thing to consider is that I generally don't put radioactive iodine high on my list for people who have involvement of their eyes from their Graves disease. There can be inflammation in the eyes from Graves disease, also by the same type of antibodies. In those people, I think twice before considering radioactive iodine as an option because it can sometimes get worse after treatment with radioactive iodine.

Leung: Certainly there are pros and cons to think about with each of the three treatments. There's certainly no one right answer sometimes, and it involves a good discussion between the patient and the provider to determine which might be the best.

You had hinted that antithyroid drugs are usually the first option for many people. Dr Cooper, what is considered long-term use of antithyroid drugs, and why might that be the definition?

David S. Cooper, MD: We're using the term "antithyroid drugs," but in fact, there really is only one antithyroid drug that we use. Until maybe 10 years ago, we had two antithyroid drugs. One was methimazole, which is the one we continue to use, and the other is called propylthiouracil, or PTU, which was the more common one up until maybe 20 years ago. Because PTU has a higher risk for liver damage, methimazole is now pretty much the only drug that is used unless the person can't take methimazole for one reason or another, or they're pregnant, in which case, PTU or propylthiouracil is used.

Long-term antithyroid drug use really, in this country, applies to methimazole long term. Until maybe 5 years ago or so, long-term antithyroid drug use was considered as taking it for a couple of years and then stopping the drug to see whether the person had what's called a remission.

The concept of a remission was identified back in the 1950s. If a person took an antithyroid drug for even 6 months or 1 year and then they stopped it, sometimes the people stayed normal and didn't have a recurrence or a relapse of their hyperthyroidism. Traditionally, taking the drug for a year or two and then waiting to see what would happen after the drug was stopped — or more recently, to measure those antibodies in the blood that Dr Goldman talked about, to see if they were still there — was the way we would manage this condition.

We would give the drug for a year or two, stop the drug or measure the antibodies, and if it looked like things were going well and the antibodies had disappeared, we would stop the medicine. That was called long-term antithyroid drug.

Now, it turns out that if we give the drug for longer periods of time — something that was actually recommended many years ago but not really endorsed by experts up until relatively recently — it may be that the outcomes are improved in terms of the remission rate. Studies conducted back in the 1990s suggested that it didn't matter how long a person took the drug, whether they took it for 6 months or 12 months or 18 months or even 2 years; the outcomes were the same. That is, the remission rates were really no different no matter how long the person took the drug.

The problem is that there were never any studies that gave the drug for longer than that, for 3 years or 4 years or up to 10 years. There are studies that suggest that long term may mean not 2 years but a decade or even longer potentially. When I think of long term, I mean 5-10 years of treatment.

Leung: We're talking really long term, more than the traditional 18-24 months that have been quoted in many places.

Switching back to you, Dr Goldner. There are pros and cons of using antithyroid drugs, of course, but what would be some of the risks that you quote to your patients when we are initiating something like methimazole for the very first time? What do you monitor?

Goldner: Good question. Sometimes that is a factor that patients take into account when they're trying to decide if this is something that they're going to take long term vs picking one of the other options.

I would say the two things that people think of most often when they think of antithyroid drugs is agranulocytosis, or low white blood cell count, and liver toxicity. Both of those are fairly rare, but they're obviously things that are fairly serious if they do happen. I mentioned them more so that patients are aware that they could potentially happen and to keep an eye out for them, but not to necessarily mean that it's a reason that they shouldn't take them.

In the case of low white blood cell count, all of the most common side effects occur within the first few months of taking it if they happen, but they can happen at any point. If a low white blood cell count happens, then that means the body's not usually able to fight off infection and so sometimes they will present with fever and sore throat, which are the classic symptoms, and a strep throat kind of picture.

When we're starting people on these medications, I usually tell them that if they get that out of the blue, they should not take their next dose and call us. We often will have people go in and get a white blood cell count or a CBC just to make sure that's not the case. There's obviously run-of-the-mill causes for sore throats and fevers — not only strep throat but also COVID-19, as we've all experienced in the past few years.

It doesn't mean that people can't take it, but it's something to be aware of. If it goes unnoticed, then that could be severe, but it is quite rare.

One thing to remember, especially in people who take it long term, is that sometimes people forget the side-effect profile the longer they've been on the medications. I do try to remind them that if they are taking medications long term, there are these side effects to remember if they do develop them at any point in time.

The liver toxicity for methimazole is usually a cholestatic pattern. As Dr Cooper said, not many people are taking PTU anymore except for rare circumstances, and that was more of a hepatitis-type pattern. If people develop any symptoms that are suspicious for that, that would obviously be something that we would want to reevaluate.

Guidelines don't really say that you have to monitor for these abnormal lab tests because they can occur at any time, and are not necessarily predictive if they're normal one time and that this is not going to happen. Although I tend to get baseline tests so that I can compare them if I do end up getting follow-up CBCs or liver function tests later, because if their white blood cell count was already somewhat low to begin with, I don't know if that is truly a change or not. Similarly, with their liver function tests, you want to know their baseline levels. I have a low threshold to repeat those labs either periodically or if they have symptoms that make me worry.

There are other things that I often do mention but don't always see. Sometimes, just like any drug, you can get a rash or skin allergic reactions that don't always require stopping the medication. People can sometimes use antihistamines or it's not bothersome enough, but they notice it. I have occasionally had a few people who get arthralgias or almost like an arthritis-type pain when they start them, but that has been very rare in the many years that I've been prescribing them.

I would say those are probably the most common side effects that we talk about. Long term, there have been case reports of vasculitis, but that is also fairly rare. That's not something that we talk about right up front, because it's not something that's always going to happen. Long term, I do think that would play into the discussion if somebody chooses to take it for decades, as we talked about. It usually is a vasculitis that's mediated by an antibody also.

Leung: I'm curious, Dr Cooper — do you get some baseline labs? The guidelines don't really dictate or advise strongly that we have to, and I maybe don't. I lean toward the other end. I'm just curious for our viewers. Do you, Dr Cooper, get baseline labs?

Cooper: I do. Sometimes you're shocked at how low someone's white blood cell count is, for example, especially in African Americans. In fact, I had a call recently from another physician about this, and it turned out that their baseline white count was really low to start with. Hyperthyroidism itself can cause a low white count, so I think it's really important, personally, to do that.

Liver function tests also can be affected by being hyperthyroid, especially alkaline phosphatase and the transaminases sometimes. I think it's good to have a baseline.

I just wanted to add one thing to what Dr Goldberg said, and that is that these really severe side effects do occur, as she said, usually in the first few months of taking the medicine. Although they could occur later, in the first year or two, it's very, very rare. The vast majority occur upfront within the first few months.

One of the things that needs to be appreciated, though, is that if a person stops taking the medicine and then they have a relapse, let's say, and then they start taking it again a year or two later, it's as if they had never taken it at all. They are still at risk for getting the side effects that they may never have had the first time, the second time, the third time, or the fourth time. When they go off for a period of time, for at least 6-12 months, and then they restart, they can be susceptible to getting those exact same side effects that they never had the first time.

Leung: Great comment. Many patients certainly have that concern when they restart a second time.

If we're thinking about the possibility of long-term use of antithyroid drugs, Dr Cooper, can you comment on what some of the more recent data have shown and maybe even comment on what has been the longest use of antithyroid drugs? Do we have a report about something like that?

Cooper: Sure. As I mentioned, there are some randomized controlled trials that showed that it didn't seem to matter how long people took the drug. These were conducted in the 1990s and the longest time that was analyzed in these studies was 40 months. This is why we came to believe that it didn't really matter how long a person took the drug.

I call this the tyranny of the randomized controlled trial because once those trials were done, we just assumed that they were all correct, and in fact, it didn't really matter how long the person took the drug — the relapse rates were the same. Now we have other data, some of it retrospective and some of it prospective. One randomized trial seems to indicate that, indeed, the longer a person takes the medicine, the more and more likely it is that when they stop taking the medicine, they will have a remission. I won't get into all of the studies, but I just want to mention two.

One is a retrospective analysis of anti-TSH receptor antibody levels in people taking antithyroid drug. This is a study from Japan by Bandai et al, published in 2019, where they measured the antibodies very often during the course of treatment. They found that, yes, antibody levels do go down with treatment. Whether this is due to a direct effect on the immune system of the drugs or whether it's just due to the hyperthyroidism causing an immune dysregulation that then is interrupted by going on the drug and becoming euthyroid, we don't know.

If you wanted to maximize the normalization of the anti-TSH receptor antibodies in a population, it takes 5 years for everybody's antibodies to go down in those people whose antibodies will go down. Of course, there are some people whose antibodies don't go down. There are people who can't be treated with drugs and then stop the drugs. They need to be on the drug because the antibodies are still there or they have to move on to some definitive treatment. There's a proportion of patients, maybe 40% of all patients with Graves disease, who will have a long-term remission. Up to 5 years of continuous treatment is necessary for that group of people to have normalization of their anti-TSH receptor antibodies.

The other thing I was going to mention is a randomized trial from Iran by Azizi et al, where a group of patients were treated with methimazole for 18 months, and then half of them stopped the treatment and the other half went on to continue the treatment for 5-10 years, and they were followed prospectively for 48 months. They found that the recurrence rate in the group that took the medicine for 18 months was about 50%, which is what we expect, but the recurrence rate in patients who took the drug for 5-10 years and then stopped was 15%.

This, I think, is very powerful evidence that if you just stick with the program and give the medicine for a much longer period of time than you might think, then a larger number of people will achieve what we call a remission and not need to be on any medicine at all.

There are studies where people have taken it for decades, and even when the TSH receptor antibodies are undetectable, people continue to take the medicine indefinitely because they're either worried about a recurrence or are just happy taking a small dose of medicine. Again, in that group of people, the relapse rates when they do stop are about 15%-20%. After taking the medicine for 10-20 years, about 80% of people overall will have a remission.

Leung: Thank you so much. That's exactly the quote that I provide to my patient counseling: You have about a 30%-50% chance of remission a couple of years out, 2 or 3 years out. It's worth a try.

Dr Goldner, maybe I'll let you have the last word. Who are the ideal patients in whom to try long-term antithyroid drugs for people with Graves disease? Does it matter on age, comorbidities, gender, life stage? Who would be the perfect, ideal candidates?

Goldner: That's a good question. I feel like my answer has changed over the years. When there was more of a push toward everybody having radioactive iodine and it was less, I guess, favorable or there weren't the data yet as far as long-term antithyroid drugs, I felt like we tried to get people to make a little bit more of a permanent decision. They took the antithyroid drugs more as that bridge to therapy and then tried to pick something more permanent.

Over the years, I would say that really, people representing all ages and of all situations are potentially interested in the longer antithyroid drug treatment. It used to be that I considered patients who are older with multiple comorbidities, where I felt like one of the more permanent therapies like radioactive iodine or surgery, maybe they weren't a candidate for that. Doing long-term antithyroid drug treatment as, basically, the least disruptive thing to do and the most stable thing to do for people was my preference because they could hopefully normalize their levels without needing other interventions.

I think that same approach applies to people at younger ages and with fewer comorbidities. I find now that sometimes on the opposite end of the spectrum, if they're younger patients — in their late teens and early twenties — and they really are not looking to do something permanent, they want that chance of remission and to be able to not take a medicine at all if they have a relatively smaller gland, they don't have much ophthalmopathy, their levels aren't real high, and they're able to be controlled on antithyroid drugs.

I think that there are many people who may want that chance to see if they go into remission on antithyroid drugs and maybe may not have to take thyroid hormone or antithyroid drugs. That is something that has changed over time.

The people that I think are not candidates are people who have suspicious nodules and you're concerned about a malignancy, who would probably benefit more from surgical removal, because that would be taking care of not only the hypothyroidism but also the suspicious nodule. As I mentioned before, I take into account whether they have eye disease when making these decisions.

Almost every person would be a candidate for longer-term antithyroid drugs if they would like to try medications rather than something a little bit more permanent before making their decision. The one group who I would say probably not to do it in are those people who already have, say, liver dysfunction or already have very low white blood cell counts, and you're concerned that any reduction might be might be detrimental for them. Those would be people that I'd have a very serious conversation with about risks and benefits. Not that they couldn't use it, but I think they would need a little bit closer monitoring.

This is a personalized decision. In many people, I start with an antithyroid drug, and they don't need to make that more permanent decision or decide what they're going to do long term until they feel a little better and their levels are normalized. Then we can continue to discuss the pros and cons.

Leung: It is certainly a nuanced decision to be made on an individual basis. Dr Cooper, any last words about who might be the ideal candidates and who to avoid? Anything you want to add to Dr Goldner's comments?

Cooper: I would just say that I think that, as she said, anybody theoretically could fit into this program of long-term drug therapy. There have been studies where people have been asked, just theoretically, "What would you want to do, what are your preferences, what are the things you value and things you don't value?" People have voted with their feet. What people mostly want now is antithyroid drug therapy because of (A) the holy grail that they're going to have a remission and (B) they don't want to be on thyroid hormone and not have a thyroid. That's just something that people don't want. So I think most people would be candidates for this.

I would also say that our mindset should be changed a little bit. In many patients, we can think about anti-drug therapy the way we think about a statin or an antihypertensive drug. In other words, this is just a medicine the person is taking to keep a chronic disease that they have under control. That's why you can think about it and give it for 5-10 years without really worrying so much. Most people who go on long-term therapy are well controlled on small doses of medicine and there's essentially no toxicity. I'll also mention that it may be that there are other things that can be done to improve the remission rate.

I just wanted to mention immunotherapy. Obviously, Graves disease has its basis in an aberrant immune system. One of the things that's been studied recently — and there was a paper just this month — is using rituximab at the start of treatment of Graves disease with antithyroid drugs. In other words, one rituximab infusion seems to maybe improve the remission rate after a course of antithyroid drug therapy.

As time goes on, for the younger people who are listening in, I'm sure that things will be different 10 or 15 or 20 years from now in terms of how we manage Graves disease, in terms of getting at the cause, the aberrant immune response, rather than just treating it with the treatments that we've been discussing today, which have been around for 75-100 years. There's nothing new yet, but I hope that there will be new treatments and we'll be able to manage it with much less toxicity and worry in the future.

Leung: Certainly. Unfortunately, this video commentary didn't allow us time to explore some of the newer immunomodulators, which are certainly on the horizon; there is a wonderful promise for therapies in the years ahead.

I want to thank our viewers. Thank you so much for joining us for this video commentary on the use of long-term antithyroid drugs in the management of patients with Graves disease. We hope it's been informative in your care of patients with Graves disease, which, as a reminder, is the most common cause of hyperthyroidism worldwide. Thank you again and have a wonderful day.

Goldner: Thank you.

Cooper: Thank you.

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