Ocular Graft-versus-Host Disease: Advances in the Diagnosis and Management

Transcription:

Hello, my name is Jordan Sexton, and I'll be your moderator for this workshop.

Welcome to the workshop, Ocular Graft-versus-Host Disease, Advances in Diagnosis and Management.

Before we begin, I'd like to thank Incyte, whose support helped make this workshop possible.It's now my pleasure to introduce our speaker, Dr. Jessica Ciralsky.

[00:21] Dr. Ciralsky is a cornea, cataract, and ocular surface specialist at Weill Cornell Medicine with a clinical focus on dry eye and related conditions, including graft-versus-host disease.

Over the past 16 years, she has collaborated with the bone marrow transplant teams at both Weill Cornell and Memorial Sloan Kettering to care for patients suffering from ocular GVHD.

Please join me in welcoming Dr. Ciralsky.

[00:49] Dr. Ciralsky: Thank you so much. Wonderful. I think this is live. Okay, great.

I'm Dr. Jessica Ciralsky, as you heard, and I'm going to be talking about ocular graft-versus-host disease, something near and dear to my heart, and advances in diagnosis and management.

I am a Weill Cornell doctor here in New York City, and I specialize in dry eye and graft-versus-host, among other things that I do. I have no relevant financial disclosures.

[01:24] I want to dive right into it. For most of you on the call, you are probably well aware of the manifestations of ocular graft-versus-host.  But how common is it?

How often am I seeing this in my practice or your doctors in their practices?

The incidence varies widely.

If you look at the studies and people that look at this, it can be anywhere from 10% to 90%.

[01:49] But if you break it down, about half of the patients that get a bone marrow transplant go on to get ocular graft-versus-host. 

But if you develop another type of graft-versus-host disease, chronic, like skin graft-versus-host or GI graft-versus-host, the amount of eye manifestations jumps from 50% to 60% to 90%. So huge number of patients get graft-versus-host, particularly if you have it elsewhere, if you have graft-versus-host elsewhere.

[02:22] When we're talking about this, I'm mainly referring to chronic manifestations of it, not the acute. The acute is like right after you get the transplant, the eyes have problems. That's less than 10%. We'll briefly talk about that. But most of what we're talking about is the chronic manifestations that you may see. And I'll jump right into that in the next slide.

Sometimes the eyes can actually be the first affected organ.

You can have nothing else going on, but you come in with dry eye.

[02:54] And it's estimated to be about a quarter of the patient's 22% presented with new onset dry eye after their bone marrow transplant. I'm sorry about that.

With dry eye and inflammation without any features of systemic graft-versus-host. In terms of the ocular surface, the ocular surface is typically what is affected.

And the ocular surface is really everything that you can see when you look at your eye, right?You've got the eyelids. You've got the conjunctiva. That's the white part of the eye.

You can see the iris in this picture. It's blue, but there's a clear dome you can't see in the 2D picture that sort of vaults over that iris.

[03:36] So the cornea, the conjunctiva, the white part, the eyelids, these are the parts that are mainly involved.

In terms of the system and how tears are made, if you look in the second picture, the picture on the right, there is that sort of purple, sorry, pinkish area that's called the lacrimal gland on the upper left side of the second picture. That's where your tears are produced.

That's your lacrimal gland. And then the tears are produced. They wet your eye. And then they drain down the system that goes into your nose.

We call that the nasolacrimal duct, the system of the nasolacrimal system. And what can actually happen to the eyes? Well, it can affect all of the different parts of the eyes.

[04:17] The eyelids, usually we're talking about blepharitis, inflammation of the eyelids, or meibomian gland dysfunction. Sometimes you can get scarring. We call that cicatricial changes where the eyelids sort of bend out or bend in. The conjunctiva can get red with conjunctivitis.

You can even get these little membranes on there that can be really uncomfortable. The cornea can get filaments. These are little dry spots, scratches. It can even go on to have a hole in the cornea in the most extreme cases.

Typically, we're dealing with lacrimal gland dysfunction. You're not making enough tears.

Then occasionally, you can get some inflammation inside the eye. We call that uveitis.

[05:02] The impact of ocular graft-versus-host should not be underestimated. They've done some studies on this, and the impact of severe dry eye on a patient's life was comparable to moderate to severe chest pain.

For the most severe cases, it was thought to be worse than a disabling hip fracture. So really powerful in terms of a patient's quality of life.

[05:25] I think it's really important to understand it, to get it treated well, and to arm you with the knowledge so you know how to be an advocate.

In terms of what happens when you come to the eye doctor, we're going to examine you. We're going to look at the eye. There are lots of different ways to do this.

[05:43] Many times we will use a dye, a special dye, like either a green one called lissamine green or a yellowish one called fluorescein that helps highlight these dry spots.

You can see in the pictures on the bottom right, it's a fluorescein study that's dotting all those little dry spots. All those little yellow dots are all dry spots across that eye.

In the bottom left figure, that is lissamine green, you can see the conjunctiva is staining and has some dry spots. We can also look at how quickly tears evaporate, because if you make tears, but they evaporate too quickly, you don't really get the benefit of wetting properties that you want.

[06:22] And in the upper right-hand corner, those little arrows are pointing to the oil glands that are not producing healthy oil.  And healthy oil is one of the main components of tears.

[06:33] We may also do some testing, some dry eye testing for you.

These are a multitude of tests that may be available in your doctor's office. Sometimes in the middle bottom picture, we are doing a Schirmer's test. How many tears do you make in five minutes?

We can look at the oil glands on the bottom right picture and see how healthy these are. The top left picture tells me what the quality of the tears are. Some of them will tell me if they're inflamed.

And so we have lots of different tools to give us both objective measurements as well as sort of things that we can grade when we look at you under a microscope.

[07:16] What does it look like when we're examining a patient with graft-versus-host?

Well, again, in the acute setting, I only have one slide on this because I think this affects a very limited amount of people. Many times this is treated fairly easily in those first couple weeks or months after your transplant.

But some people can get conjunctivitis. That first picture, you see a red eye. The second picture, the white part of the eye can be swollen. We call that chemosis.

[07:47] The third picture is when you're getting those membranes I was alluding to. These can be really irritating. People don't like how they feel.

Then in the last picture, that's actually a scratch on the eye. A scratch on the eye can be extremely painful and actually dangerous if not treated quickly.

[08:06] What about the chronic? How do we look at this?

There was an international group that looked at chronic ocular graft-versus-host, and they held these working meetings of ophthalmologists that specialize in this to come up with a consensus as to how we look at patients with graft-versus-host in this chronic period so that we can better communicate with our bone marrow transplant team so we can better treat our patients. 

And essentially, we're putting in that yellow dye we call fluorescein. This is the left-hand column that you see. And we're grading how many of those little spots do we see? Is it really dry? Is it just a little bit dry? And we give a grade to it.

[08:48] The conjunctival injection score means how red is the eye? Zero is none. One's a little bit pink. two is really red. And then not shown here, but we do a survey that people can take to tell us how dry they feel they are and how it affects you in a given day. 

And then a Schirmer's test, which is that little strip that I showed in the previous picture to tell us how many tears do you make in a given five minutes. And after we take the survey, the testing, and the two pictures We come up with a little graph. We give numbers associated to it, and we can kind of tell, is this not graft-versus-host in the eyes? Is it probable? Is it definite? And you can see that you don't need as many points. If you look on that bottom row, if you already have graft-versus-host elsewhere in the body, you just need a little bit in the eyes for it to cross over to that probable.

[09:48] So that's a big determinant. Do you already have graft-versus-host? And then do you have that would push me to think this is in the eye.

[09:59] Let me teach you just a little bit about tears. We have three main components of a tear. The top one is the lipid layer, like oil. The middle one, the big chunk of the tear is made up of water. Then the inner layer is made of mucin, like a mucus layer.

The mucin layer is the least important for the purpose of what we're discussing. Most people's mucin layer is pretty normal in ocular graft-versus-host, except in rare situations. Usually what is happening in our patients is that they don't make enough tears.

[10:33] So the water is decreased and/or the lipid layer is abnormal. Think about that as if you make enough tears, but the lipid is not sort of holding it against your eye. It's evaporating too quickly. So, you make plenty of tears, but they're not staying on your eye to wet it appropriately.

So you get dry eye because of the evaporative component. It's not wetting the way it should, or it's not staying around as long as we want it to.

[11:01] So when I think about treating ocular graft-versus-host, I usually think about it locally, right?

Rather than immediately calling your bone marrow transplant team and adding more oral medicines, immune suppressing medicines, we have a lot of tools in our belt to try to do organ-specific treatment first, eye treatments first.

I may occasionally call them and ask for their help, but most of the time I can handle most of the ocular treatments with ocular, most of the ocular symptoms with ocular treatments.

[11:33] The three main goals, as you saw from that picture before, when we're talking about tears, I want to bring the lubrication back to your eyes.

I want to keep those eyes moist. I want to help the oil be healthy to slow the evaporation of the tears. Then we know from all of our studies, dry eye is inflammatory. So we have to also work with inflammation.

[11:54] As I talk to my patients about this, a lot of what I talk about is the step ladder approach.

We're going to try something. We're going to see how it goes. Then we're going to go up the ladder. I don't like to throw the whole kitchen sink at you. I want to try what I think you need.

And then if it's not enough, we'll add to it. Because many of these treatments have a little bit of a period of onset.

[12:15] You have to wait to get all the steps right. You know, a lot of patients come to me, and they're like, well, I've tried that. Well, I've tried that. To be honest with you, a lot of it is the order in which you do it, right?

We put a medication like cyclosporine on you, but your eyes are super inflamed. You didn't tolerate it.

It's maybe the order in which we gave you that medication regimen that made you intolerant of it instead of a true allergy or that it didn't work.

Maybe it's how we approach you. And so I think that's really important to emphasize as we think about this.

[12:48] Every patient is different and we need to tailor our approach to you individually.

But for broad strokes, thinking about what we do, this is from dry eye management. We call it the DEWS dry eye treatment regimen. This holds true for not graft-versus-host only. It can be for all dry eye treatment algorithms.

Essentially, when you think about that step ladder, here is a four-pronged step ladder approach. Many things exist within each prong. It's not one thing.

[13:23] But step one is sort of what I like to refer to as the natural approach, right? We're going to modify your local environment. You know, maybe you're sleeping with a fan on you and we need to move the fan. We may change some of the medications, some of the offending oral medications.

If you're on an allergy medicine, that's drying you out. We need to change that.

[13:43] We may give you some of the over-the-counters you know artificial tears artificial tears come in different thicknesses and we may do things like warm compresses or lid wipes and then if that's not adequate we keep those and we add to it and so this is the bulk of what we do this is step two or the rung of the ladder you know the next rung of the ladder maybe we change those artificial tears to not have preservatives. 

Maybe we're doing something with the tear ducts. Maybe we're giving you topical medications that are prescriptions or even some treatments in the office. And I'll go through these in more detail. I just want sort of the broad strokes from these busy slides.

[14:26] If that doesn't work, maybe we're giving you oral medicines or special tears made from your blood or specialized contact lenses. And if all of that doesn't work, sometimes we go on to things like steroids, and surgical treatments. And so, let's break this down into something that is a little more tailored to each individual category here. 

So artificial tears, gels, and ointments. I like to differentiate that many times when you go to the store, you see that huge row of artificial tears. You have no idea what to buy. And so, I would like to explain to my patients that there's different thicknesses of tears. There's tears that are just like water drops. Those only last like 15, 20 minutes. So many people have to reintroduce those throughout the day.

A gel is a little thicker and might last a couple hours, and an ointment can last you all night.

So a lot of patients come in, they're like, I put tears in before bed, but I wake up dry. Well, the tears are gone, you know, probably an hour after you've slept. And so that's not going to last you all night. And so, thinking about all of the different formulations, there are different ones over the counter when we think about the natural approach. And then we're going to get into things like lid hygiene and oil gland treatments and then inflammatory treatments.

[15:50] So let's start with the lubrication. Again, as you walk into the drugstore and you see all these, try to differentiate. You know, what's a tear, what's a gel, what's an ointment, and what am I looking for? And then does it come in a bottle, or does it come in these individual vials you see on the right? Typically, traditionally, bottles have preservatives. The individual ones don't. I know nowadays you can buy a bottle that's preservative-free. And if you look closely, you can find that.

But traditionally, the individual ones we know do not have preservatives. And often if you look for those, you know you're buying a preservative-free one. Preservative-free tears are really important if you're using something more than six times a day because the preservative in an artificial tear could be toxic to the eye if you use it too many times.

[16:37] And so many times, one of the first things I do is switch out your artificial tear. Although this isn't the big workhorse for what we want, it's still a supplemental medication that's important and important to do correctly.

[16:51] A lot of people come in, and they are really dry when they wake up in the middle of the night or first thing in the morning. These nighttime ointments in the left picture, like I said, can last all night.

You know, you put a little bit in, a little ribbon before bed.  If you wake up to go to the bathroom, you have to put a little bit more in. The problem with these is it blurs your vision. So it really has to be the last thing you do before you go to sleep.

[17:15] They also make these goggles. A lot of people like goggles instead of ointment. If the ointment is too sticky, you don't like how it feels. And these goggles create a little moisture barrier to keep your eyes moist all night.

But find a way to treat your eyes at night because if you wake up with dryness, you're battling that all day. We do want to treat both the day and the night.

[17:37] Punctal plugs. Punctal plugs are something that we use to preserve tears on the surface.

If you think you don't make enough tears, we either give you medications that help you make tears. We supplement your tears with tears, or we prevent the tears from draining out.

I usually think of this, or I describe it like plugging up the sink, right? A sink, you turn on the water, goes down the drain, you put a plug in the drain, water's going to stay in that sink.

Your eyes make tears in those little lacrimal glands on the upper outer part of your eyes. They coat your eye, and then they go down the tear drainage system near your nose.

[18:18] But if we plug up that little drainage system, the tears you add, the tears you make, we're going to keep those on the eyes to keep them wet.

We do have openings on both the lower and the upper part of the eyelids. I usually talk about lower getting more bang for your buck in terms of 80% of tears drain through the bottom.

Puncta, if you think about gravity, right, they're going to go through the bottom. It's harder for tears to kind of go up than to go down.

Typically we start with a lower plug. If that's not enough, we add the upper. Sometimes people have too many tears from these and they're not a good plan for them to have both plugged or even one.

Some people feel them. We make internal ones and external ones. So there's ways around that as well.

Then much of what we do in this, what I call the second category, that category that has sort of that long list you saw on a slide, a couple slides back.

We have so many medications for a long time. You know, we just had cyclosporine 0.05%, what we call Restasis. It was approved in the early 2000s.

But in this day and age, we have so many different ones. The hard thing I think for us and for you is that we don't know what's going to work for you. You know, it's a little bit of trial and error. What is going to work to make your eyes feel better? What's going to be tolerated? What's covered by insurance?

[19:45] And these medicines take time to reach full effectiveness. I could give you something today.  We don't know if it works until we reach its full effect at three months. So there's a little bit of this trial and error that we do till we find the regimen that works for you.

And what these drops are doing is actually helping you produce better tears and more tears and decreasing inflammation.

[20:10] Serum tears; these are a type of tear that is generated from your own blood.  And so there's different models out there. Sometimes you can go somewhere in your neighborhood where they will make these for you.

They even have more national ones where you can get your blood drawn locally, send it off, and then they send you the serum tears.

[20:31] The rationale behind this is that the clear part of our blood, what we call serum, is chock full of amazing things like vitamins and nerve factors and growth factors and all these things that an artificial tear you buy over the counter is not going to have.

These are more similar to our natural tears that you may be lacking than an over-the-counter tear. So this is one thing. They draw your blood. Typically, we make a three-month supply for patients.

The hard thing about these is that they have to be kept under certain conditions. So the ones that are not being used are kept in a freezer. The ones that are being used need to be refrigerated.

So if you're traveling, if you're out and about, you do have to keep these with a cool pack. That can be one of the difficulties with serum tears.

[21:23] Scleral lenses are another way to bring tears back to your eye.

There are many different versions of scleral lenses, but essentially, it's a hard lens. It sits on the white part of the eye. That's the sclera, the white part.

Instead of the cornea where a traditional, you know, soft contact, hard contact that you may use for vision reasons sits. This actually vaults over your cornea. The cornea is where your eye is dry. So that's really important. So we're not rubbing on the eye.

What's great about it, as you see in the top picture, is we're putting fluid in it. You put these tears in and then you put it on. And essentially, you're bathing your eye in an artificial tear all day long.

[22:03] And so what this does is reestablishes a healthy environment for your eye, allows it time to heal, and obviously makes you feel better.

So less pain, less light sensitivity. You can see they are big and there's a learning process to learning how to put them in and take them out.

And coverage can also be a problem with these. They're sometimes covered by insurance, but not always. And we fight with that a lot. But they are a wonderful addition if other things have not worked.

[22:35] What about controlling the evaporation? As you think back to that image, I had in a previous slide where we talked about tears and oil.

[This is the oil. That's the part that is going to control evaporation. And I always like to tell my patients, think about this as you do to telling a teenager about oily skin, right? Adults get oily eyelids. That's called blepharitis. Teenagers get oily skin, you know, and get acne. And usually we're telling them, wash your face every day with hot water and soap. 

And so, for blepharitis patients, we need to wash our eyelids with hot water and soap. Obviously not just any hot water, not just any soap, but a warm compress is really just sort of like a washcloth, warm water, and you place it on there. Some people get frustrated with this. You have to sit in front of the sink and rewarm it.

Some people take it in the shower to do this. We even have heat masks that you can put in the microwave, plug in to get the heat to be sort of steady state for a period of time. Usually, five minutes is what we ask of patients. Eyelid hygiene, like a baby shampoo formulation, or there's a lot of these over the counter now, or they're almost pre-made. They look like little makeup remover wipes that you can use to do this. For blepharitis, we also have topical antibiotics and oral antibiotics.

You've probably seen these commercials nowadays that have the little mites on them. And blepharitis is thought in some cases to be related to something we call demodex or these little mites. And we now have a medication that treats that and in turn treats the blepharitis. And so, we have a lot of new ways that we can treat the evaporative component of dry eye in what we call blepharitis.

[24:21] And a lot of people with graft-versus-host have blepharitis more than the average patient.

 What about eyelid procedures? There are a lot of them out there, and these are just two as representative photos, but essentially a lot of them give you sort of a deep cleaning or it's a machine that does that melting of the oil and then expression of the oil to try to get the unhealthy oil out and the healthy oil re-established in your eyelid so the oil that you produce in your tears is more normal appearing and helps keep that evaporative component and an appropriate amount.

[25:04] What about inflammation? We know dry eye is inflammatory, and topical corticosteroids are, you know, are the mainstay of treatment. You probably all know that steroids are a double-edged sword, right? We love steroids. They make people feel great, at least in their eyes, but they're not a great long-term option for most patients. The main things we worry about as ophthalmologists are cataracts and glaucoma. I always tell all my patients; we're all going to get cataracts, regardless of what medications you use. It is a natural aging of the lens, but I don't want to give a patient a cataract at 40 if they should be 60 or 70 or older before they get cataracts. And so, we use steroids when we need to, but we try not to use them long-term.

Some patients get glaucoma from steroids, not all. And so, it's just important if you're on steroids for dry eye or for graft-versus-host that you're being monitored in terms of your pressure.

If you do develop pressure from the steroids, it can be treated, right? Or the steroids can be stopped, and the pressure can go back to normal. So it's not something that's not treatable. It's just something that needs monitoring.

[26:14] And in some of my most severe cases, I will keep them on a topical corticosteroid chronically. Sometimes this looks like once a week, once a month. It's not an everyday thing typically.

But sometimes when everything else has failed, a little steroid is the only thing that works.

[26:31] We will go there. But if you think back to that original, what I call the do's, the dry eye algorithm, it's step four.  It's the last thing I do when everything else has been inadequate.

[26:44] What about surgical options?

 You know, luckily, these are pretty rare in the graft-versus-host community.

It's really when conventional medical therapy fails that we think about surgical interventions.

And again, the goal is to get you some more lubrication. Let's help the surface of the cornea heal. If you have scratches that aren't healing, we need to help those heal.

Sometimes you get scarring from having chronic scratches and we need to remove the cloudiness from the cornea and essentially restore vision. Tarsorrhaphy is a term that means close the eyelid.

Closing the eyelid is almost as if you're keeping it closed, but we do it with either a stitch or tape. And this can often help an eye heal. Again, not used commonly, but is a nice treatment if we need it. It is usually temporary.

[27:37] Amniotic membrane. Amniotic membrane, as you probably know, comes from the amniotic sac when someone is pregnant.

This is commercially available, and it is a membrane that's known to have many interesting properties, particularly on the eye.

It helps scratches heal. So that epithelialization means the scratch surface grows back.

[28:00] So when you have a scratch that won't heal, often will turn to our membranes. You can put this on a contact and put it in the eye. Sometimes we'll go and sew it in the operating room, but that, again, is less common.

They reduce inflammation. They help decrease scarring. They serve as like a band-aid, a biologic band-aid.

[28:20] Corneal transplantation, even more rare, right? Often we're trying to do everything else before we need to go to a corneal transplant. If we do need to go to a corneal transplant, we've tried to do everything first, right?

We've optimized that ocular surface before we go to transplant. Get your tears, get your eyelids working, closing correctly.

Sometimes we have to do other things with the transplant in order for it to not go the way that the original eye went.

If it was fraught with scratches, maybe we need to do membranes on it or contact lenses or that closing of the eyelid.

[29:01] I want to just spend a couple minutes here talking about timing of treatment because I think this is really important.

A lot of us don't know the right answer as to when treatment should start. We're still doing studies and trying to figure this out. But there was an interesting study done almost 15 years ago where they gave topical medicines.

In this case, it was Restasis, an older medication, topical cyclosporine, before a patient had a transplant. Then they looked at the patients afterwards.

They had about 80 patients that got the medication a month before their transplant and followed them out.

Then about 25 patients that didn't get it right away got it about six months after the transplant when they came in. And so they looked back, and they saw that dry eye was a lot more severe in the people that got it afterwards versus before at three months, one year, two years.

Of course, this is one study, and it can't be something that we extrapolate to everybody, right?

[30:08] We don't know if this is something we need to be doing or not, and we're studying this in more detail. But one of the things I try to do, if possible, is see patients ahead of time.

Because one of the hardest things to do is when a patient comes in and they're like, well, I had dry eye to begin with. Have we made the dry eye worse?

[30:28] When is it graft-versus-host disease just a little bit worsening of your underlying dry eye?

And how much does it matter? You know, a lot of times the treatments are essentially the same.

I think to figure out who needs to be pretreated, establish care with an ophthalmologist, even if you're asymptomatic, because I've seen that when patients come in, it can progress quite rapidly.

[30:52] And so I always think it's nice to have somebody that's familiar with graft-versus-host, even if they see you once every six months. It's really nice if you can go before your transplant, six months after, 12 months after.

And then if you're good after a couple of years, maybe you just transition back to your regular ophthalmologist. I think it bears repeating that ocular graft-versus-host is a really important disease. This is quality of life.

[31:19] You know, you go through a bone marrow transplant, you have, you know, gotten rid of the cancer, but you're left many times with disabling pain and in some cases blindness or at least, you know, decreased vision and pain. And this can be a big quality-of-life issue. I see so many patients that come in and they're like, I can deal with everything else, but the eyes, you know, I can't do my work.

[31:42] I can't read. I can't do the things that make me happy. And so, I think putting emphasis on this and making sure that we treat you well and early is so important. Early detection, early diagnosis, and early treatment. They're really the keys to preventing long-term complications. Of course, if you didn't get a chance to do the early detection diagnosis treatment, we can treat these patients, but it's much easier to prevent than to treat after the fact.

[32:09] I would obviously love to see all patients as early as possible if it's feasible before the transplant. This isn't always possible. Many people travel for these appointments, but I think getting some baseline testing and then figuring out when things change is such an important part of this. And so, I want to leave you with, and we're going to have question and answer, of course, but from a lecture standpoint, I want to leave you with, this is a really important disease and problem that many patients face after a bone marrow transplant. We are constantly studying this, refining what we want to do to both teach our colleagues and our patients and get medications and management into and treatments into your hands as quickly as possible.

I think that will be where I end and turn it over for questions. Thank you so much for listening.

[33:14] Moderator: Thank you, Dr. Ciralsky. That was an excellent presentation.  We will take questions now.

If you do have a question for Dr. Ciralsky, please type it in the question box on the lower left side of the screen. I see a lot of you have already, so we're going to try to answer as many as possible in the time that we have remaining.

[33:27] First question is, do you think Prokera is a good option for cornea damage from graft-versus-hosts?

Dr. Ciralsky: I think it's a great question.Prokera is amniotic membrane. Just maybe I can pull it up while we're talking. Bear with me one quick second.

Prokera is a type of amniotic membrane.It is actually on a ring that then gets placed into the eye, and the amniotic membrane is sort of sandwiched in between the ring.

So amniotic membrane is wonderful, like we talked about, for helping heal sort of some of the dry spots, a scratch on the eye.

I think of it as a temporary fix, right? I use it to get a patient through something acute.

It's not going to typically change sort of your overall long-term prognosis, meaning I'm still going to keep them on medications. If they're wearing scleral lenses, we're still going back to that.

But I do think it has a role in treatment. It's just not sort of a cure-all. It is a tool that I use for a specific purpose, and then I go back to treating with my other medications.

[34:45 ]Moderator: Our next question is, do any medications such as antihistamines cause further dry eye disease? If so, what options do stem cell transplant survivors with allergies have?

Dr. Ciralsky: Such a good question, and one I struggle with on a daily basis. Absolutely. I put that, I think, or that was in step one of the do's, that dry eye treatment algorithm that we talked about is removing offending agents.

Oral antihistamines are one of the worst. Some of the heart medications and mood stabilizing medications are up there. I think antihistamines are the worst.

What I try to tell patients is, if we can, I try to go to nasal sprays.

And if the main symptoms are nasal congestion and eye itching, a topical medication like over-the-counter olopatadine or azelastine and a nasal spray are much better than giving a systemic antihistamine.

So treat it locally if you can. If this is something that is not easy to treat with sort of local medications like the nasal sprays and the topical eye drops, I often will pair with an allergist because we run into this all the time.

Sometimes we'll even go back to allergy shots and things like that when you're able to get them because eyes are just a manifestation of everything else.

We want to limit how many offending agents you use. Sometimes I'll get you back into your allergist to work as a team.

[36:20] Moderator: Are there any surgical solutions on the horizon?

Dr. Ciralsky: Other than what I did, talk about a couple.

We talked about sort of tarsorrhaphies and corneal transplants, but nothing that I can think of that would be sort of a cure-all.

A lot more thought processes going into medications and new medications that are coming on the horizon. One that I didn't mention here that may fit into the surgical regimen is punctal cautery.

We talked about those little plugs that go into the tear ducts. Many times the plugs fall out.

You lose them or people don't like coming in every three or six months to do them, and we can close those off.

[37:05] But other than what I've talked about, not to my knowledge that there's a surgical fix coming down the road.

[37:11] Moderator: And if someone has dry eyes and they see an eye doctor once a year, should they use the special dye?

Dr. Ciralsky: The special doctor? Is that what you asked?

[37:20] Moderator: The special dye is what they say.

Dr. Ciralsky: Oh, the special dye. I'm sorry. Absolutely. Fluorescein is something that every eye doctor that you have, usually it's the one that's yellow, not the one that's green.

I would say that usually it's the dry eye doctors that have the green one we call lissamine green. The yellow one is pretty universal in every ophthalmologist toolbox. I would say yes, because many times dry eye can be subtle. We can look at you and not see it without the dye and the blue lights. So absolutely.

[37:55] Moderator: What is your opinion on the product ProOcular Gel for ocular GVHD?Does the foam work well? And this person says they don't do well with eye drops.

Dr. Ciralsky: Not sure. I know pro-ocular gel. I'm just going to see if there's a different name. Are we just talking any ocular or pro-ocular specifically? I think it's pro-ocular specifically.

[38:19] Moderator: They specifically use pro-ocular, but I think they're just kind of looking for alternatives to eye drops.

Dr. Ciralsky: Fair enough. I do know what this is. Okay. It's the one that goes on the forehead. There has been some data on this that it works.

I am not privy to knowing sort of all of the details of it, although I've spoken with the people that came up with it. A lot of our treatments nowadays are trying to look for sort of workarounds, right?

If you've already have dry eye, can we sort of use your central nervous system or the nerves in the eyes to produce tears differently?

There's a new medication on the market that does that. It sort of triggers these different nerves. It's an eye drop to get the eyes. It's called Tyrvaya.

And this one is in a similar vein. I think it goes to the trigeminal or the fifth nerve to try to stimulate tears. I don't have any personal experience using it in my patients, so I can't really comment on it.

Interesting, if you're not good at drops, there's also a nasal spray that we use for some people. It's called Tyrvaya that some people do when they don't like doing drops.

[39:40] Moderator:  Is there any safer or recommended way to decrease inflammation? Or do you have any suggestions of probiotics that might increase T-reg cells to drive down inflammation?

Dr. Ciralsky: That's a great question. You know, I don't know how probiotics weigh in on the ocular T-cells. I think that using steroids topically, eye drops, in short bursts has been proven to be safe.

 And so long-term, agree with you, and we don't want to use it. I don't think it's a good idea to use long-term steroids unless we have to. And we have evidence of other diseases where I use steroids every single day after someone gets a corneal transplant for the rest of their life. We have experience with this.

But thinking about other ways to do it, the eye almost has its own immune system. It's somewhat segregated from the systemic system. I don't know how probiotics will play a role. We used to recommend a lot of fish oil and flaxseed oil. The studies that have come out after the fact are mixed. Some people still do this to help with dry eye and tear film stability.

I'm not against it, but I don't think that the evidence really points us one way or the other.

[41:04] Moderator: Can Restasis cause a film on the eye which interferes with clear vision outside of the 30 minutes after applying it?

Dr. Ciralsky: Not typically. And so, some of the other ones do have more of a gel-like film, but Restasis is usually more of a teardrop. What I always tell my patients is after five minutes, your body has absorbed that medication. And so, if you don't feel good, if there's stinging, if there's filminess, anything like that, put an artificial tear in five minutes later, wash anything out that's still residual on your eye. You're not washing out the medication as long as you've waited five minutes.

 Moderator: Can you speak to the use of intense pulse light therapy to assist with persistent dry eyes after stem cell transplant?

Dr. Ciralsky: IPL goes into, when I talk about reducing evaporation or working on the evaporative part, there are procedures. I didn't show it in the picture, but it's one of the procedures that uses a light in sort of four different, three to four different sessions, and it helps stimulate those oil glands to be better, to produce better oil. So, I think if blepharitis or oily eyelid is one of the main components, IPL is something that has been shown to work. We know our graft-versus-host patients do get blepharitis, so I do think it has a role. It's not for everybody, but it's definitely shown some improvement in the right patient population. This person says that two years after transplant,

[42:41] Moderator: This person says that two years after transplant, they got ocular GVHD. One eye cleared up for them in one year. They use serum tears constantly and eyelash wipes about every 30 minutes. Do you have any advice?  They do use scleral lens for a few hours at a time.

Dr. Ciralsky: The eyelash wipes, I would probably limit to one to two times a day. I think you know, too much can be too much. But there's so many other things, you know, I would have to see them to be, to give a true, you know, assessment of their individual case. But I would say, you know, if you're not able to tolerate a scleral lens for long periods of time, often it means your eye is still inflamed, or the scleral lens doesn't fit well. In my hand, scleral lenses work in the majority of patients. We're talking over 95%. And when they don't, it's usually a fit problem, or the eye is still inflamed.

And so it's either that you need a new scleral lens fitting or that you need some medications that are anti-inflammatory, like a steroid or like a cyclosporine or something else to decrease some of that inflammation to make some of the other treatments work.

[43:49] Moderator: This person said that at the time of their BMT, they told their doctor that their eyes felt like sandpaper when they blinked.  And their doctor told them that they'd probably need eye drops for the rest of their life. Do you think this is pretty common or a reasonable expectation?

Dr. Ciralsky: I think that sandpaper feeling is a very common thing that we hear when someone has dry eye. Again, without seeing the patient, I don't know what the level of dry eye is.

Again, in the presentation, what we talk about is the earlier we catch this, the earlier we treat it, the better chance that we limit sort of the long-term side effects, sequelae of what's going on.

If you've made it to the eye doctor and you're already sort of in the moderate to severe, you probably are going to need some form of eye drop for the rest of your life. Could that be once or twice a day, or is it going to be five or six times a day? I don't know that, but if this is your first symptom and it's mild, many times we can give medications and, you know, limit eye drops on a daily basis. But again, I would have to see the patient to know exactly where they fall in that regimen.

[45:01] Moderator: Do you have any thoughts on lacrimal and meibomian? Sorry if I butchered that, gland transplants?

Dr. Ciralsky: Oh, wow. I don't know. Meibomian glands would be very hard to transplant. I don't know if there's any research on that. I know lacrimal glands people have looked into, but to my knowledge, I don't know anybody doing that successfully as of yet. And that might just be, I'm not familiar with it. 

[45:41] Moderator: This person is considering a cautery of lower ducts but is concerned about the lidocaine shot causing inflammation. Do you have any advice?

Dr. Ciralsky: Yeah, that's great. I would say no. The lidocaine is so minimal that they give, and cautery in and of itself can be inflammatory. Many times they'll put you on a little steroid drop afterwards, but I'm not concerned about the lidocaine portion of it.

[46:04] Moderator: Do you have an opinion on an eyedrop called DMAPS made by regenerative ocular immunologics? Are you familiar with its efficacy and would it produce better or more tears?

Dr. Ciralsky: I saw that question when we first sat down. It was one of the early ones.  I know they've done a pilot study, and that is sort of the extent of my knowledge.

I think it's in a phase one trial at the current time. And the main thing they were studying was dry eye. I don't know specifically if they're going to study graft-versus-host. Again, it's promising, but I don't have any more data than that.

[46:41] Moderator: We have to manage multiple things like heat compresses, lid cleaning, glaucoma medicines, dry eye medicines, eye drops. In what order should you do everything in?

Dr. Ciralsky: Such a good question. We don't want you spending your life just worried about your eyes and doing eye treatments all day long. So many times, you know, my patients are busy. You have a lot of things. You have a lot of medicines.

Glaucoma drops are probably the most important to do on a regular basis. Many of them need to be 12 hours apart, and that's how they work.

I think sticking with a regimen morning and night on your glaucoma drops is really important, or whichever regimen you need for your specific glaucoma drop. Many times I tell patients, why don't you take the warm compress to the shower and do it in there, or take the baby shampoo with you and make it part of your shower routine.

Most people go to the shower daily and can make that part of that routine, so it doesn't add more than a couple minutes to what you're already doing.

Take the compress, lay it on there while you do your hair, make it part of the routine. Glaucoma drops do make your eyes more dry.

And so when we're talking about offending agents, you do have to look at your glaucoma drops to see if they're part of the problem. They often are.

They make preservative-free ones. But in terms of efficacy or which is effective, which order goes first, I don't think there's a right or a wrong. I try to make it easy for my patients.

Glaucoma needs to be scheduled, fit in the dry eye treatments based on what works for you.

[48:12] Moderator: Do you have a trick to help squeeze the artificial tears tube?

This person says they don't have enough strength in their fingers or hands to do it by themselves, and they need their husband's help to insist.

Dr. Ciralsky: Such a hard one.

I hear you on that, and they are all made differently, and sometimes the vials are easier, and sometimes the bottles are easier, and I think that I don't know if it's one of those, but many times you can find a preservative-free bottle, artificial tear that's easier to squeeze than a preservative-free vial.

So sometimes that works. But I don't have too much advice. I know people are working on gadgets to help with that, but I don't know if there's anything out there right now that works great.

I will say that I often tell my patients, your body's only going to absorb one drop at a time. You spill out four drops because you squeezed too hard or something like that, you may waste your money, you may waste the drops, you're not going to hurt your eye.

If it's hard, but you can manage, even if you get three out instead of one, you're not going to do yourself any harm.

[49:23] Moderator: Could you please explain the significance of timing an immunogenic event to prevent the onset of ocular symptoms, specifically vaccinations?

This person's concerned about timing their vaccination bundles, and they don't want to boost and activate their immune system unnecessarily.

Dr. Ciralsky: I think the question is, am I going to get a worse dry eye event because of my vaccines? I think that's what it's asking.

Moderator: Yeah, possibly just the impact of any timing with it.

Dr. Ciralsky: You know, there's been a lot of work in this part of the field, not with graft-versus-host per se, but with other things.

We have corneal transplants that we deal with, and people get vaccines and then they reject their transplant. I don't see a significant amount of activation of dry eye from vaccines typically. I don't really tell people they need to do much.

If you're really concerned or you had a problem, we could treat it as we do our transplant patients, our corneal transplant patients, which is to say I give them a little topical steroid around the time of vaccines. I give it, you know, start a day before, do it for a week after, or something like that. But I haven't really had to do that in my population.

[50:39] Moderator:  This person would like to find out their mother has had two retinal detachments in her left eye. This happened two to three years ago, post-allogeneic transplant, and now the vision is hardly any in that eye. Did this happen due to her cGVHD or anti-rejection medicines?

Dr. Ciralsky:  I've never heard of that happening. I would say it is unlikely related, but not to my knowledge. I don't have any experience where I've seen that post-transplant.

[51:21] Moderator: They started having ocular migraines about five months ago. They haven't seen an eye doc yet. And general practitioner doesn't seem concerned. Made no recommendations other than referring to an eye doctor. Is there any possibility of late graft-versus disease or something else potentially related to the stem cell transplant?

Dr. Ciralsky: Making sure that ocular migraine diagnosis is correct, I think it's the first thing.  Typically, what I tell my patients is it happens in both eyes.

There's all different manifestations, but you see sort of lights or circles that grow or blind spots. But one important thing is that it's coming from both eyes.  And so it's actually not coming from the eyes. Ocular migraines are coming from the brain. That's why both eyes are involved because the eyes cross in the brain.

So if you're having an ocular migraine, it's more a variant of migraine affecting the eye centers of the brain and not something from the eyes.

So from an ophthalmologist standpoint, I'm not worried about it. Again, I want to make sure it truly is ocular migraine. So see an ophthalmologist and confirm that. It usually is sort of triggering.

Sometimes some of the medications or other parts of bone marrow transplant recovery can trigger migraines. So sometimes we send you to a neurologist or a headache doctor. But I'm not really worried about the eyes.

[52:42] Moderator: How do you know if you're a candidate for IPL or LipiFlow or manual expression of the meibomian glands?

Dr. Ciralsky: Yeah, typically what an eye doctor does in their office is very basic. And we have, maybe I can show it.

In this picture, dry eye testing, the bottom right, we do have some tests where you can actually look at the different oil glands and see if they're shortened or not at all producing oil.

But many people will just take a manual Q-tip, manually push and look at the quality of the oil. And many times what we're looking for is, does it look like toothpaste, or does it look like olive oil?

It should look like olive oil. It should not look like toothpaste. And so we're trying to figure out what the quality of the oil is. Based on that, then we determine if you're a candidate. They can use something like this picture, LipiView, we call it in some cases.

[53:49] Moderator: Do people with dry eyes prior to transplant have a higher risk of CGVHD of the eyes after the transplant? And should this be part of pre-transplant questions asked to patients?

Dr. Ciralsky: We don't know. I think that's sort of one of that study I showed in 2010 is sort of asking that question, right? Is it, you know; the question is, do all patients after graft-versus-host get a little bit drier?

And if you already start with dry eye, are we pushing you over the edge into like true dry eye or worsening dry eye, severe dry eye? Whereas people that just get a little bit worse that didn't have any to begin with don't notice it.

They're still in that mild category. I think that ideally, if it was up to me, everybody should be looked at pre and post.

But yes, I think it's something that we should be talking about ahead of transplant. I think we should get some baseline tests and then figure out if that answer is true. That's something that I'm interested in learning as well.

[54:47] Moderator: Our last question will be from a person who has mild, moderate, dry eyes. They like to ski and cycle. They wear glasses under their goggles while skiing and cycling.

About five years after their BMT, they still really struggle with pain, especially during these activities. Is there anything else you recommend that they could do to help them continue to engage with these activities?

Dr. Ciralsky: This is a hard one too. I think that there's two routes to get around this. You could get scleral lenses or some sort of contact lens made for dry eye that you wear and then wear the goggles over it. Sometimes they can get sort of a, almost like a little moisture glasses with your glasses and then wear the goggles over it so that there's some sort of moisture chamber there, either with a contact or with a glass and then wear the goggle over it. It's called moisture goggle glasses, but they can be made as true glasses with a prescription.

[55:49] Moderator: Well, thank you so much, Dr. Ciralsky. This was fantastic. And thank you for answering so many of the questions on behalf of BMT InfoNet and our partners. I'd like to thank you for your very helpful remarks and thank you to everyone in attendance for your excellent questions.