Melanie Cole, MS (Host): Welcome to UF Health Med EdCast with UF Health Shands Hospital. I'm Melanie Cole and today we have two University of Florida College of Medicine physicians for you in a panel highlighting hereditary hemorrhagic telangiectasia. Joining me is Dr. Jeb Justice. He's an Associate Professor of Otolaryngology, the Division Chief of Rhinology and Skull Based Surgery, and the Co-Director of the UF HH Center of Excellence. And Dr. Ali Ataya. He's an Associate Professor of Medicine in the Division of Pulmonary and Critical Care Medicine, and he's the Director of the UF HHT Center of Excellence. Doctors, thank you so much for joining us to discuss this very important topic. So Dr. Ataya, I'd like to start with you.

How prevalent is HHT, and give us a little outline of the pathophysiology of it, how it informs your treatment strategies.

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Ali Ataya, MD: Thank you for having us. HHT is a rare genetic disease. We believe it affects anywhere between 1 in 3,000 to 1 in 5,000 individuals. It's inherited in an autosomal dominant matter, so it means every parent has a 50 percent chance of passing it on to their children. And the most prevalent manifestations that we see in patients is usually nosebleeds that substantially affect their quality of life, as well as internal organ manifestations of these abnormal vessel formations, what we call AVMs, that occur in the skin and other internal organs. And, we've worked on creating a multidisciplinary center here at UF between myself and Dr. Justice to help treat these patients and the various manifestations of their disease.

Jeb M Justice, MD: So thanks, thanks again for having us. Excited to talk about HHT. We call it HHT for short because the other words are too hard for us to say. Hereditary hemorrhagic telangiectasia, or as I was taught in medical school, Osler-Weber-Rendu, the original name after three of the physicians who originally published on this disease over a hundred years ago.

Host: Well, then, Dr. Justice, why don't you jump right in with the exciting treatment modalities. What's changed since the last time we had this discussion? Tell us a little bit about how this is evolving.

Jeb M Justice, MD: The interesting thing about HHT is in the past we had multiple different treatment. And I'm going to speak mainly in the area of procedural and surgical treatments. Of course, from a medical standpoint, we always want to humidify the nose, moisturize the nose. We use multiple ointments and topical therapies to try to decrease the amount that the airflow hits the tissue. 'Cause that's actually the main thing that causes the vessels to form abnormally and to bleed. But if we move more into the realm of procedural treatment, some of them are considered surgery, some of them are procedures that we can do in the clinic.

In the past, one of the mainstays of treatment was laser and that was primarily done in the operating room. It works for smaller lesions, but not for bigger high flow lesions. And it's a bit of a burdensome setup. As you can imagine, you got to have the laser, everyone in the room has to wear eye protection for the risk of damage to the eyes.

And if you're not trained really well in the laser, and you hit the vessel in the wrong spot, you can actually cause bleeding. For bigger lesions, starting 15 to 20 years ago, we would use things like bipolar electrocautery or radiofrequency ablation, and those do have a role. But remember, anything with cauterization like this can cause tissue damage.

And if we're too aggressive with that, we can cause a hole in the nasal septum, which is called a nasal septum perforation. So one of the exciting treatments, which in the world is not a new treatment, it's called sclerotherapy, which has been used on lymphatic malformations in children, as well as varicose veins in adults.

Has been tried in the HHT world in the last 10 to 15 years with super exciting results. So sclerotherapy, we use a detergent. There's multiple options. I use something called sotradecol or sodium tetradecyl sulfate. And we actually mix it with air to form a foam and it's injected directly into the vessel.

It causes endothelial disruption causing the vessel to clot off and kind of collapse on itself. The really exciting thing about it, is that it's safe, it's highly effective, and it does not cause the tissue damage that we see with some of the other treatments like cauterization. One of the other main advantages of sclerotherapy is that it can be done in the clinic under local anesthesia, which avoids patients having to get unnecessary general anesthesia and avoids the cost of going to the operating room.

Sclerotherapy originally, had one concerning outcome about 12 to 15 years ago. And I want to be real specific with this is that the detergent was mixed with saline and injected submucosally on the lateral wall, actually leading to one case of blindness, immediate blindness. But since then, since we've been mixing it with air and not injecting submucosally, but rather injecting directly into the vessel, there's been no reported cases of blindness.

But that's an important thing to counsel your patients upon. As we've mentioned before, in our first podcast, the HHT community is very close knit, whether that be through Cure HHT, their national and international organization, or through social media. And so a lot of times when we start to talk about sclerotherapy with a patient, they've heard about this and are quite concerned.

So it's important that we listen to the patient's concerns, talk to them about the difference in techniques that we're using, and about the safety and efficacy of the sclerotherapy.

Now, moving to different things other than sclero, which we've done in a few patients is nasal septal splints. Now, these are silastic splints that have typically been used for packing the nose after, let's say a septum surgery, like a septoplasty for a deviated septum. But if we cut them in a certain way and suture them into the nose such that the patient can still breathe, if you actually cover up the lining of the septum with these splints, the telangiectasias will shrink and go away and the bleeding stops.

And we have over 10 patients that we've had splints in place for over nine months, and they tolerated them quite well. Their bleeding has decreased. And most of them have gone from being anemic to not anemic anymore. There are also other options that we offer including, mechanical gels, as well as a couple of medications.

One's called doxycycline, which people will hear this and say, well, why do you give an antibiotic for nosebleeds? It's just a lucky side effect of doxycycline. It blocks a protein called MMP9 or matrix metalloproteinase 9, which is involved in the formation of blood vessels. And so there's a certain population of the HHT patients who actually respond dramatically to doxycycline.

Some do and some don't. We don't really know why. We've actually done research to see if the genetic mutation predicts response to doxycycline. And so far it does not look like that it does.

Host: Dr. Ataya, would you like to weigh in on what you see are some of the most exciting and you can respond to Dr. Justice as well?

Ali Ataya, MD: Absolutely. Patients are aware that currently, as of now, we don't have any FDA approved treatments, medical treatments for epistaxis in HHT. So, it's amazing to what extent patients will go to try off label medications, whether on their own or through experts or getting advice from other patients.

So, when technology and procedures like sclerotherapy that Dr. Justice offers, has become available; we've seen a very drastic interest by patients to who've traveled from quite a distance from out of state and sometimes out of the country to come and get sclerotherapy treatments because it's quite effective.

And as Dr. Justice mentioned, in combination with certain like easy therapies like doxycycline, for example, which is a simple antibiotic that's easy to prescribe with low side effect profile; some patients may have some important and drastic responses that will help them. And then of course those who don't respond or need more aggressive treatments for more severe nosebleeds, we have other options for them.

Enrolling them in clinical trials, providing them more aggressive medical therapies, or in some cases even some infusions like, bevacizumab or Avastin infusions. So we have multiple modalities to offer for patients because while

nosebleeds don't really result in mortality in most patients, they do significantly, in fact, affect their quality of life for a lot of these patients. So it's important to help improve that for them.

Host: Dr. Justice, you mentioned some of the different treatment modalities, doxycycline and sclerotherapy and splints, and you mentioned a few things. What about special situations where patients may need to be on a blood thinner, which obviously may exacerbate their nosebleeds? What do you do in that case?

Jeb M Justice, MD: So a great question. and I should add, one thing I forgot to mention is that schlerotherapy does not have to be done primarily or solely in the nose or the nasal cavity. A subset of the HHT patients will have abnormal vessels on their tongue, their lips, inside their mouth, on their hard palate. And we've also done sclerotherapy on those lesions in different sites with great success.

Now, it's true, we have over 200 patients, 200 HHT patients in our HHT Center of Excellence here at University of Florida, and almost 40 of them, have some condition that would, in normal circumstances, indicate them to be on a blood thinner, whether that's atrial fibrillation or history of a blood clot or something like that.

And as you can imagine, these patients who already bleed every day, if you give them a blood thinner, how potentially disastrous that can be. And so some of those patients, we actually have to keep them off the blood thinner, which puts them at risk for clotting or another serious outcome. Or if it's very, very risky to keep them off, that's a situation where I might offer sclerotherapy or splints to a patient before offering the typical medical treatments like, ointments and stuff like that. So if we can eliminate most of the lesions with sclerotherapy or get someone to keep their splints in, let's say for six to 12 months while they're on their blood thinner. This can allow them to reduce their risk of, let's say, having an adverse outcome from atrial fibrillation while they're on a blood thinner, or if they're having to withhold their blood thinner.

So those are some unique situations. We try to have multidisciplinary care, to get the best quality of life outcomes for our patients.

Ali Ataya, MD: I would like to add that, not every patient with HHT who goes on a blood thinner necessarily ends up having a bleeding. Surprisingly, the data shows 50 percent may have an increase in their bleeding and 50 percent may not. That said, we try not to take risks. I'm sure patients themselves, are aware of the risks and they don't want to fall into that 50 percent group that bleed more.

So any intervention we do early before going on blood thinners or being more aggressive in their therapy, goes a long way. However, unfortunately, despite our best efforts, some patients are just not candidates for blood thinners, just because of their refractory bleeding. So those are some exceptional situations that we deal with.

Host: Dr. Ataya, tell us about some emerging pharmacologic therapies or other systemic treatments that may show promise in altering disease progression. What's on the horizon?

Ali Ataya, MD: Well, there's been a lot of interest recently in medical therapies, various medical therapies in HHT. One of the therapies we've been using for a while is infusion of Avastin or bevacizumab. It's a VEGF inhibitor, an infusion that we provide every other week initially for a few doses, then once every few months.

And, patients improve pretty remarkably on this infusion with a significant improvement in their nosebleeds. However, as you can imagine, it does require multiple visits for an infusion center. It does require adherence as well as possibility of some side effect profile. However, we reserve it some of the sickest patients who have refractory bleeding.

But, more recently, you know, some clinical trials have been exploring the use of oral agent medications to reduce or improve nosebleeds. And UF was one of the centers, part of the recently published clinical trial, PATH HHT, that was just published in the New England Journal of Medicine. And what they studied was a drug called pomalidomide.

It's an immunomodulator drug, which can help stabilize AVMs

in the nose and improve nosebleeds. And sure enough, the enrollment for the study was abruptly stopped early due to the benefits seen in patients who were receiving the medication. The results were just published showing that improvement not just in these intensity, but duration of nosebleed.

So, this is one of the first large randomized clinical trials in HHT using newer oral agents. On the horizon, we have a few other medications. One ongoing trial is a phase 3 trial for pazopanib, a similar oral medication that can reduce nosebleeds. And there are recent, companies that are investigating newer agents, like, there's a pharmaceutical company, Vaderis, with VAD-004 molecule that may help not only reduce nosebleeds, but shrink telangiectasias that these patients develop. And another company called Diagonal Therapeutics that's exploring new modality of treating HHT. So it's an exciting time to see newer therapies come to market that we may one day have an FDA approved drug for these patients.

Host: Dr. Justice, what's exciting for you? What do you see happening?

Jeb M Justice, MD: So exactly what Dr. Ataya mentioned. So now we've had clinical trial evidence that there are multiple more medical options and some clinical trials that are going to be getting started soon with what Dr. Ataya mentioned. Beause in my world, surgery is not really a cure.

The old school procedure that cures their nosebleeds is called the Young's Procedure, but that involves us suturing the nostrils closed which as you can imagine makes unable to breathe through their nose, unable to smell, they're obligate mouth breathers and patients we used to really only do that for people who were having life threatening bleeds or needing blood transfusions. In my practice, that's why we switched over to doing the splints because they cover most of the problematic mucosa on the septum and they're reversible and removable and the patient can still breathe a little bit. But the biggest game changer in my world.

So in the last two to three years has been sclerotherapy because these patients who we used to have to take to the operating room every time, put them under general anesthesia and offer them surgical treatments that had only short duration of improvement. I'm seeing longer duration of improvement. I'm seeing that a lot of times the vessels are not growing back, whereas when we do cauterization or laser, the vessels will typically grow back in the same spots.

With sclerotherapy, it doesn't seem to do that as much. And the fact that we can do this in the clinic, has been a total game changer for patients. Like Dr. Ataya said, we've had patients come from Chicago, Nashville, Atlanta, Miami, and even different countries just to get sclero here.

Host: I'd love for you each to have a chance for a final thought here because this is such an enlightening conversation. Dr. Justice, starting with you here, what would you like the key takeaways to be as far as future directions, goals, counseling families on the hereditary nature of the disease itself? What would you like the key takeaways to be for other providers?

Jeb M Justice, MD: So, we're lucky that we have a multidisciplinary team here, led by Dr. Ataya. We have ENT. We have GI specialists who are dedicated to HHT, as well as interventional radiology, neurosurgery, genetic counseling. The biggest takeaway for me is that, Dr. Ataya and I are very easy to contact.

You know, our contact info is on our website. We're very responsive. If physicians want to get patients in, we try to get them in as soon as possible, because we know that the HHT can be debilitating for quality of life, and we also want to get people managed early so that they can help their family members.

A lot of our patients have family members with HHT all over the country, and we've gotten some really positive feedback about them spreading the word about the new treatments. And so, for the referring doctors, we'll try to work with you as much as possible. And we'll try to be as responsive as possible.

Host: Dr. Ataya, last word to you. What would you like the key messages to be for other providers about what you're doing there at UF Health Shands Hospital?

Ali Ataya, MD: I'd like to echo what Dr. Justice just mentioned. We are very fortunate having access to a multidisciplinary team of experts, where our focus is our patients and improving their quality of life and providing top quality care. So, our goal here is to try to reach as many patients as possible, and we would recommend that.

And early referral for patients suspected of having HHT. Our job is to collaborate with physicians around the state and even outside the state who have patients, so we can provide the best care for them. And as Dr. Justice mentioned, we are very easy to get a hold of. Our information is online and any questions anyone may have, they can feel free to reach out so we can help support them and support their patients.

Host: Thank you both so much for joining us today. What a great discussion this was and to learn more about this and other healthcare topics at UF Health Shands Hospital, please visit innovation. ufhealth. org. And to listen to more podcasts from our experts, please visit ufhealth.org/medmatters. That concludes today's episode of UF Health Med EdCast with UF Health Shands Hospital. Please also remember to subscribe, rate, and review UF Health Med EdCast on Apple Podcasts, Spotify, iHeart, and Pandora. I'm Melanie Cole. Thanks so much for joining us today.