Graft-versus-Host Disease: Eyes

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Graft-versus-Host Disease: Eyes    

Presenter: Todd Margolis MD, PhD, Professor and Chair of Department of Ophthalmology and Visual Sciences, Washington University School of Medicine

April 30, 2024

This video includes 36 minutes of presentation, followed by 24 minutes of Q&A.

Many thanks to Incyte whose support helped make this workshop possible.

Summary:  Ocular graft-versus-host disease (GVHD) can cause tear loss, dry eyes, irritation, pain and vision problems and can impact quality of life after transplant.  This presentation will discuss symptoms of ocular GVHD and effective treatments. 

Highlights: 

• Topical therapies for ocular GVHD, such as artificial tears, treat only the symptoms, not the GVHD that is causing the symptoms. Systemic GVHD must be controlled in order for topical therapies to be effective.
• If you use tear drops throughout the day, be sure to avoid touching parts of your eyes to avoid irritation or an infection. Avoid “get the red out” eye drops, which can be toxic.
• A variety of therapies are available to treat the symptoms of ocular GVHD, some of which are costly and have unproven effectiveness. Consult an ophthalmologist who is a corneal specialist with GVHD experience to help you properly manage your ocular GVHD. You can consult BMT InfoNet's GVHD Directory to locate a physician who has experience treating ocular GVHD.

Key Points:

(04:38):  Parts of the eye often affected by GVHD include the lacrimal glands, cornea, conjunctiva and meibomian glands.

(06:43):  Primary ocular GVHD is an attack by donor immune cells on the lacrimal gland and conjunctiva causing inflammation. Systemic immunosuppression is required to treat it.

(08:18):  Secondary ocular GVHD are the symptoms that remain after primary GVHD has subsided, They most often treated by topical medications such as artificial tears and steroids.  

(11:11):  Lack of tears due to ocular GVHD can cause strands of mucous called corneal filaments on the cornea which can be painful.

(11:53):  Tear loss can cause keratinization – drying of the membrane that covers the cornea. This can cause irritation, thinning of the cornea and infection.

(21:27):  It’s important to insert an eye lubricant properly, without touching the eye, to avoid irritation and infection.   

(23:13):  Another strategy to treat tear loss is to block tear drainage with temporary punctal plugs, or by surgically closing the openings that pump out tears (the puncta).

(24:06)  Eye evaporation can be reduce by wearing goggles, taping the eye closed at night or sewing portions of the eyelids together.

(26:25):  Scleral contact lenses, which reduce discomfort and improve vision, can be a real game-changer for some patients.

(29:50):  There are a lot of costly therapies that are of questionable value including serum eye drops, amniotic membranes, topical cyclosporine, Xiidra, meibomian gland therapies, and omega-three supplements.

Transcript of Presentation:

(00:02): [Susan Stewart]:   Introduction.  Hello. My name is Sue Stewart and I will be your moderator for this workshop today. The workshop is titled Graft-Versus-Host Disease: Your Eyes. And before we begin, I'd like to thank Incyte, whose support helped make this workshop possible.

(00:19):  It's now my pleasure to introduce to you our speaker, Dr. Todd Margolis . Dr. Margolis is the Albert and Edith Wolff Distinguished Professor and Chair of the Department of Ophthalmology and Visual Sciences at Washington University in St. Louis, Missouri. His areas of specialty include infectious and inflammatory eye diseases, corneal disease and uveitis. To support care of patients with severe ocular inflammatory disease, he helped create a combined rheumatology-ocular inflammatory disease clinic and an ocular Graft-Versus-Host Disease (GVHD) clinic at Washington University School of Medicine. Please join me in welcoming Dr. Margolis.

(01:08):  [Dr. Todd Margolis]:  Overview of Talk. Thank you very much for that introduction and thank you everybody for the opportunity to talk today. I'm just going to go ahead and move forward. I am going to talk about Ocular GVHD and it's not just another dry eye and even the definition of dry eye gets complicated, but it's Ocular GVHD and the consequences. And I'm going to try to take a very practical guide to understanding and management of this disease.

(01:39):  What is ocular GVHD? The first is what is Ocular GVHD? It's immune-mediated disease of ocular structures following a bone marrow transplant. And you all know that basically if you get donor white blood cells, they're given to you in order to repopulate your body with healthy immune cells, but that these can also attack organs in your body. And oftentimes when you hear about this, you hear about major organ systems and you don't hear about the eyes being involved. But the same way that other major organ systems can be attacked as foreign, so can the eyes and the biggest problem with the eyes ends up being the front of the eye.

(02:20):  Primary ocular GVHD is GVHD that is currently active and causing eye inflammation. So things that I'll talk about. I'll talk about what I call primary Ocular GVHD. And this is active inflammation caused by active graft versus host disease. And I want to differentiate that from secondary Ocular GVHD.

(02:37):  Secondary Ocular GVHD are the problems you're left with after the inflammation has subsided. So even if you have secondary ocular disease, that can be dry eyes even though the graft versus host disease is not active. That can be scarring that has occurred even though the primary Ocular GVHD isn't active.

(03:00):  And then I'm going to talk about how to manage primary and secondary issues and who should be doing it and we can touch on some patient expectations as well. And once you understand primary disease versus secondary, I think that the expectations become a little more clear. And I'll try to leave plenty of time for questions.

(03:20):  What I WON’T Talk About.  I'll not talk about certain things intentionally. I'm not going to talk about the epidemiology of Ocular GVHD because it's constantly changing and with new treatments it's constantly changing.

(03:31):  I'm not going to talk about the pathogenesis of Ocular GVHD because actually very little is known about the pathogenesis of Ocular GVHD in humans and it's constantly changing. So anything I tell you now is probably not going to hold up a couple of years from now.

(03:45):  I'm not going to talk about Ocular GVHD involving the insides of the eyes because it's relatively rare and we're not going to have the time to get into it. I'm not going to talk about staging and grading of Ocular GVHD. That's really necessary only if you're doing studies.

(04:01):  I'm not going to talk about lid and lash issues in terms of lashes getting turned in because of the scarring.

(04:07):  And I'm not really going to talk about meibomian gland dysfunction, although I'm sure there's going to be a lot of questions about this. And the reason is that there's a lot of data that meibomian gland dysfunction, our understanding of it's poor and that the lipids that are in the meibomian glands actually don't make up the majority of the lipids of the tear film layer. And a lot of emphasis though is placed on we've got to treat the meibomian glands whereas we have no data that we have any effective therapies or that it really forms a significant part of the tear film.

(04:38):  Portions of the eye that can be affected by GVHD include th lacrimal glands, cornea, conjunctiva and meibomian glands. So let’s talk about anatomy. It's important to understand when we're looking at the eye, the location of the lids, the location of the lacrimal gland. And as you can see in the upper left-hand corner as you look at it, the lacrimal gland is underneath the skin above the eye. So when we talk about active lacrimal gland destruction due to primary ocular GVHD, we can't see that going on. We have no way of directly assessing the lacrimal gland.

(05:06):  We talked about the cornea, which is the clear part of the eye. And we have a magnified view of that in a minute over the iris. And we talk about the conjunctiva, which is the mucus membrane that wraps around the inside of the eye. It's on the inner side of the lids, it's on the outer side of the white part of the globe. And that is also where we have glands that produce mucin called goblet cells that also contribute to the tear film.

(05:35):  On the lower left, you see where the meibomian glands are. This is more just to locate these. They're not inside the eye, they're on the lid margin.

(05:43):  And we also on the bottom right-hand side, see what the conjunctiva looks like on the inside of the upper lid. And this is a normal-looking conjunctiva with normal blood vessels. And this is important because as we talk about the disease of the conjunctiva, I'll show you some pictures of what abnormal looks like.

(06:02):  The cornea consists of layers. It has an outer layer which is composed of cells of epithelium that replace themselves pretty rapidly. 90% of it is the stroma. If the stroma gets involved, you end up with scarring and distortion of vision. And the very bottom layer, which we're not going to talk about, the endothelium.

(06:21):  So when we talk about this clear piece of tissue over the iris or the colored part of the eye, it's made up of these pieces. When we talk about punctate epithelial erosions, it's in the epithelium and these are easily fixed and replaced. When we talk about stromal involvement, that ends up with scarring and major changes.

(06:43):  Primary ocular GVHD is an attack by donor immune cells on the lacrimal gland and conjunctiva that causes inflammation.  So what is primary Ocular GVHD? Primary Ocular GVHD is involvement of inflammation. It's an attack by your donor immune cells on the lacrimal gland, represented here by this lightning bolt to the lacrimal gland. And it is also caused by a lightning bolt or attack on the conjunctiva that wraps around the inside of the lids in the outer part of the globe and causing inflammation there. We can see conjunctival inflammation. We can't see lacrimal gland inflammation.

(07:28):  So why is it important to recognize primary Ocular GVHD? I'm making this distinction. A lot of doctors don't. Because that implies there's active inflammation of the lacrimal gland. That implies that there's active inflammation of the conjunctiva, not just damage done by that inflammation. And the reason that's important is because it requires systemic immune modulatory therapy. We cannot treat that locally with any of the drops that we have. We need to treat that systemically and be in communication with the bone marrow transplant team. The bone marrow transplant team wants to know is the GVHD active? Because if it's active, that's going to require more involvement of systemic medications.

(08:18):  Secondary ocular GVHD – the symptoms that remain after primary GVHD has subsided – are usually treated by topical medications such as artificial tears and steroids.  How Do We Treat Secondary GVHD?  Topical medications largely treat secondary GVHD and that includes artificial tears, steroids, and the like.

(08:25):  If you look at this on the bottom of this four slides, you'll see the conjunctiva. I've got a lightning bolt at it showing you that there could be activity there. And I'm going to show you in a minute what happens when there's activity.

(08:40):  Over here, secondary issues on the upper right-hand side, you see fluorescein staining of the cornea, punctate epithelial erosions of the cornea, which are secondary issues from the GVHD.

(08:52):  So in this next slide, what you'll see now in the bottom left is active inflammation of the conjunctiva. You see that it doesn't look like normal conjunctiva, which we showed just a moment ago. It looks inflamed. That's active GVHD. GVHD has caused scarring of the conjunctiva but isn't active as illustrated on the bottom right. So we have primary disease on the left, secondary disease on the right. You don't need active primary disease to have secondary disease going and need management, but it won't require systemic immunosuppression.

(09:31):  Whether the patient is able to make tears is one way to test whether GVHD has affected the lacrimal gland. Since we can't see active inflammation in the lacrimal gland, how do we take care of that? How do we understand that it's occurring? Well, one of the ways that we do this is look to see if the patient can make tears.

(09:45): The gold standard for measuring tear production is the Schirmer Test. Little pieces of paper with markings on them are placed in the outer portion of the eye. The patient can keep their eyes closed and we measure the production of tears and how many millimeters of wetting that we see on the Schirmer strips over time.

This is done without topical anesthesia if you're doing it according to the gold standard and the methods that are used in studies of dry eye disease where you want accurate measurements. So that's how we measure tear production. It's not a great test, but it's a test that we can perform. We can also ask patients can they cry. Patients who can't cry are not producing tears at all.

(10:31):  We also stain the ocular surface. We stain it with Fluorescein and that's here on the upper left, strips or liquid. And you can see the staining pattern with Fluorescein greenish look with the blue light on the ocular surface. Lissamine Green or Rose Bengal can also be used to look at the surface, especially on the conjunctiva or white part of the eye. But when we use Fluorescein, we're looking for damage that goes all the way through the epithelium or we're using Lissamine Green or Rose Bengal. We're looking for any ocular surface damage to the epithelium. So a little more sensitive than Fluorescein.

(11:11):  Lack of tears due to ocular GVHD can cause strands of mucous called corneal filaments on the cornea, which can be painful. All right. So now let's move on. What else can we see on the ocular surface because of the dryness? And one of the things that's common is corneal filaments. When we see corneal filaments, this represents mucus, which is very common in eyes that have Ocular GVHD combined with strands of corneal epithelial cells. And these string out every time the lid opens and closes. It tugs on the epithelium and it can be painful. Over on the left, you see these loose on the surface of the cornea, these linear areas. And on the right you actually see flattened filaments in a very dry eye.

(11:53):  Another consequence of tear loss is keratinization – drying of the membrane that covers the cornea that can cause irritation, thinning of the cornea and infection. You can have other severe complications of tear loss, not just having filaments. You can get keratinization of the conjunctiva illustrated by this white patch that I've got a dotted outline around.

(12:07):  Keratinization refers to the fact that instead of having a nice mucus-based membrane, a nice soft epithelial membrane, that areas of the membrane because they've been so dried out that they're protecting themselves and producing a skin-like substance of keratin to cover up the surface. And this can be very irritating and very tough and that can be rough on the cornea as well. You can develop thinning of the cornea if you have a breakdown of the epithelium and severe dryness. And we try to obviously prevent this.

(12:41):  And you can get corneal ulceration, which usually refers to an infection of the cornea because of breakdown of the epithelium as well as the fact that many patients who have this disease are being compromised, it makes it a little harder on them to fight infection. So all three of these are more severe complications of tear loss.

(13:04):  The goal of treatment is to improve quality of life. What about managing these problems? We talked about the corneal problems, the dryness, the conjunctival problems, the scarring. The real goal is to improve the quality of everybody's life. And so yeah, we want to improve vision. And a lot of patients are concerned about their vision, but they're even more concerned about comfort. They want to feel comfortable as they go about their daily lives.

(13:26):  And so as we talk about what we're going to do, a lot of it comes down to what is making the patient comfortable? And since they can understand also their visual needs, what improves their vision according to them? I can measure vision in the room, I can measure vision very accurately, high resolution targets, but I don't know what vision's like for practical vision, for day-to-day vision. And so we need to have responses from the patients in terms of how they're doing comfort-wise and vision-wise.

(13:56):  We also want to treat to prevent more secondary disease. So basically we don't want the dryness to cause damage to the cornea. We don't want the inflammation to cause more problems and so we manage to prevent secondary disease.

(14:15):  Cost can be an issue when considering treatment.  The other thing that is a main goal of management is to pay attention to the costs. There are a lot of treatments out there with very little data to support them and they can be very expensive. And so the bottom line is ‘Is there good data to support this’? Does it make the patient comfortable? Does it improve their vision? And if it doesn't make them comfortable and improve their vision, then why are we paying all this extra money?

(14:38):  And finally, GVHD patients in general have a lot of doctor visits. They have hospitalizations. They're embedded in the medical system. And what we want to do as ophthalmologists is minimize doctor visits. We're happy to see the patients as often as possible, but we don't want patients coming in all the time when they can be managed without having to come in all the time and just have another doctor visit. So those are my goals when it comes to management.

(15:05):  So how do we manage it? Well, first of all, there is no one magic bullet and no matter what you see on the internet on advertisements or anything else, there's no simple answer. It's a combination of things and understanding what's going on and trying to manage those problems.

(15:19):  The first line of treatment for ocular GVHD is systemic therapy.  The first is systemic therapy. If a patient has active primary Ocular GVHD, it needs to be managed with systemic medications. Local drugs are just simply not going to get it under control. And so that's why it's so important for whoever the treating physician is, who's the ophthalmologist, in order to understand whether or not there's active primary disease or this is all secondary.

(15:46):  Managing tear deficiency with tear substitutes or a scleral contact lens.  Then we can manage the secondary problems including tear deficiency. There's a bunch of tear substitutes, we're going to talk about them in a bit. But those work temporarily and what we really want is to be able to keep tears around even longer so we can block the drainage of tears and we can block tear evaporation and there are multiple ways of doing both of these.

(16:08): And finally, there's something called a scleral contact lens, which many of you have heard about and we're going to talk about the use of a scleral contact lens for tear deficiency as well.

(16:18):  Breaking up corneal filaments.  The other thing we can do is we can manage the complications of tear deficiency. We talked about corneal filaments and mucus. We can break that up with a topical drop of acetylcysteine. These have to be made up in pharmacies, specially prepared. They're not commercially available, but certainly in some patients we find this can be very helpful for breaking up mucus and breaking up corneal filaments.

(16:41):  We sometimes use the antibiotics to both prevent infection when we see breakdown of the surface of the cornea. In addition, I think antibiotics sometimes change the local microbiome and in doing basically quiet down the eye even though you don't pick up any infectious agents.

(16:57):  All-trans retinoic acid can reverse keratinization.  Another thing that's sometimes used is a topical agent called All-trans retinoic acid, which is a vitamin A type drug. We find that this can be used to reverse the keratinization that can occur on the epithelial surface. And finally we have a number of different ways of controlling inflammation.

(17:16):  Tear substitutes are used to provide comfort and protect the eye.  They do not treat the underlying GVHD.  So with that, let's talk about tear substitutes. And usually this is the big area of discussion. There's about a zillion tear substitutes out there. And the main thing I'm going to tell you is they're used for comfort and to protect the eye. They are not therapeutic. In other words, they're not going to treat any disease that you have. What they're going to do is protect the eye and allow it to heal on its own and to make you more comfortable. And because of that, you have to understand that the key to using tear substitutes is to use them before the eyes start to get irritated.

(17:53):  If somebody has dry eyes and they are fine when they wake up in the morning, they get worse as the day goes on the trick is to get them in before they get worse. Some people are so severe that it's bad first thing in the morning, that's fine. You want to be ahead as much as possible though with your use of tear substitutes.

(18:10):  Which tear substitute to use depends on which one works best for you – not necessarily the most expensive one or the one that heavily advertised.   And the question always comes up as to which ones. And the bottom line is whichever ocular lubricant works best for you, makes you feel best, improves your vision the best is the one you should be using. Not the most expensive one, not necessarily the one that somebody recommended to you or that you heard about in an advertisement. It's whatever works for you. And that goes for, are we talking about a drop, a gel or an ointment? It's whatever works for you and your needs is what's going to help you the best.

(18:41):  The other question that comes up is what about non-preserved tears? There's a lot of talk about if you're using drops more than four times a day, you should be on a non-preserved tear. There's actually no data for that. That's more of a campaign slogan from the drug industry than supported by any actual data. But basically if you're reacting to a preservative and your eyes are getting red because of the drops, you're putting in it, it could be you're reacting to the preservative. You need to stop it and try going to non-preserved. But if you're tolerating it and it's keeping you comfortable, it's protecting your eye, you can be using it 10, 12 times a day and it can be preserved as long as it's not irritating to you and causing a problem.

(19:20):  Some patient are allergic to agents in eye drops and lid cleaners.  Eye drops and lid cleaners are pushed a lot in this disease and other dry eye diseases and you got to understand that all these drops, even though they're over the counter, have potential toxicity. And this even goes for the non-preserved ones.

(19:36):  And I'm just going to show you a few examples here of patients I've had. The one on the left has inflammation around the eye. You can see all that redness. It turns out inside the eye is inflamed, too and they have a contact dermatitis or a contact allergic reaction to what was ever in the drop they were using, which was a drop called Tobradex, which contains Tobromycin, Dexamethasone, and a preservative. You stop the drop and all that improves. So you can react to drops and you can get skin involvement. As you can see here, it's a contact dermatitis, a contact allergic reaction. The corneal surface can get really beat up from some of these as well.

(20:18):  The middle one just happens to be a drop called Clear Eyes that I happened to see not too long ago in a patient. Some of these have vasoconstrictors in them, which are not made to be used on an ongoing basis. This particular patient was using Clear Eyes, something like 20 times a day. And you can see this opacity and it's actually keratinized on the surface in part due to the fact that it was a dry eye, but in part due to the use of the clear eye so frequently.

(20:47):  And then over on the right you see a red eye and if you look carefully, you can see some inflammation in the cornea. This was a patient of mine who was using Retain MGD something like 20 times a day and basically developed this infiltrate in the cornea because of the Retain MGD. So it doesn't matter which drop or lid cleaner you're using, they are potentially toxic and you have to be aware of that as well. So yes, use them as much as you need to as long as they're not causing a problem. But if they're causing a problem, stop, get some help. Any drop can do this even if it's preservative free or a lid cleaner.

(21:27):  It’s important to insert a lubricant properly, without touching the eye which can cause and infection.   Other concerns with using drops and lubricants. One is proper installation. I find that patients very frequently will touch their eye when they're using a dropper bottle, and that's especially a problem with non-preserved drops. There have been studies of glaucoma patients who put in drops all the time and found that up to 80% of them hit their eye or around their eye with the tip of the bottle when they're instilling their drops. So one way to do it without hitting your eye is to lay down flat, put the bottle across your nose, look up at the tip and just squeeze and it'll come right down in your eye. Less chance of being irritating to the eye. Less chance of hitting the eye, contaminating the eye.

(22:08):  The same thing goes for the use of facial tissue when you blot afterwards, make sure the eye is fully closed. Facial tissue can be irritating. I have plenty of patients who react to it. Think about using toilet paper to clean yourself off 20 times a day. If you're doing that around the eye, the same kind of irritation can occur. So you want to be cautious. If you're reacting to the Kleenex facial tissue, whatever it is, you can always go to just a clean white handkerchief and use that, but make sure your eye is fully closed.

(22:36):  If you hear there has been a recall of the tear substitute you are using, immediately throw it out.  The other thing we hear about is all these are recalled contaminated products. Most of these have been off-brand or generics, knockoffs, made in other countries, and so you have to be cautious about these. They're not without potential problems. So if you hear about a recall immediately stop that. Throw it out. The recalls have largely been in, as I said, the generic brands that sometimes the big pharmacies carry and label it under their own name or some name that you're not familiar with. So be cautious about your drops that you're using. They can be a problem.

(23:13):  Another strategy to reduce tear loss is blocking tear drainage.  So besides drops, what can we do? We can block tear drainage, we can use punctal plugs. You can see that in this diagram in the illustration. You can see these little nubbins that are in the corners on the lids and all the way over on the right, you can see little inserted silicone plugs as well. By putting plugs in, you prevent the drainage of the tears down into the nasal lacrimal system and this keeps the fluid around.

(23:40):  The other way we can do this is with surgical occlusion of the openings, the puncta. This can be done usually with cautery. It's a simple outpatient procedure. People talk about this being permanent. Sometimes it is, sometimes it isn't. If it needs to be opened up, it can be. But either way, I usually start with plugs. If people are finding it to be ineffective, we go to permanent occlusion using cautery.

(24:06)  You can also reduce evaporation of the eye with goggles, taping the eye closed at night or sewing portions of the eyelids together. Basically classically, we can sew portions of the eyelids together. That's called tarsorrhaphy, that's the upper left. There's various ways to use medical tape or even Breathe Right strips that are used for nasal dilation to keep the eye closed.

(24:25):  Sometimes people's eyes are open at night or you need to have it taped closed. Rather than a bulky bandage and tape and such, we find that Breathe Right strips or medical tape alone is sometimes very effective. But various patients have come in with things like onion goggles and pugs goggles, which is just a branding for a type of inexpensive goggle that you can wear. And you can see the onion goggles on a patient. You can see the pugs goggles on a patient. These can be very helpful during the day to block evaporation. They can be very helpful at night to block evaporation if an eye is open.

(25:00):  Finally, if we have acute reasons to close the eye rather than doing a tarsorrhaphy and surgically doing it, we use Glad Press and Seal Wrap. And one of my patients with bad ocular surface disease came in and taught me about this and we found it to be quite effective. So you just tear off a small piece, put it over the upper lid, pull it down and pull it on the other bottom lid. So the bottom right diagram here illustrates how you can use Press and Seal to keep that eye closed for healing purposes or in really severe dry eyes if you're trying to take care of things acutely.

(25:36):  And it turns out that sometimes just doing this patching, simple patching will work for corneal healing even after you fail everything. And people talk about coming in and saying, well, they used the amniotic membrane and they used contact lenses and we used all kinds of expensive stuff and it didn't heal. And then I stop everything and all I do is start patching and the eye starts to heal.

(26:02):  Now this eye may not look very pretty right now, but it was very red, very inflamed, very engaged, and it was very thin. And all we did was patch this on an ongoing basis with Glad Press ‘N Seal and within a couple of weeks we had the surface healed and the patient was doing a lot better and was off all that medication. So simple patching can be a simple way of dealing with the problems.

(26:25):  Scleral contact lenses can be a real savior and game-changer for some patients.  Scleral contact lenses. Many of you have heard about this. They can be a real, real savior and game changer for patients. They both improve vision and trap a layer of fluid underneath the contact lens between the contact lens and the cornea. And you can see this on the bottom right here. They reduce discomfort, improve vision. The cornea is protected from further damage. You can resolve corneal damage, but it takes a lot of work to learn how to put one of these in. They're not cheap. And so you've got a couple of hurdles here. The cost and the learning curve.

(27:02):  Some patients cannot wear these lenses, but I would say about 70 to 80% of my Ocular GVHD patients who I felt that this would be valuable for, found that they could wear it and that it was an improvement. They're not perfect. They tend to fog up. Sometimes wearing time is short, you have to take them out at night. So there's lots of reasons to understand that this isn't a simple fix, but it can really change quality of life for the hours that people are wearing them.

(27:32):  Eye inflammation can be reduced with steroid eye drops.  All right. Next step is reducing inflammation with steroid eye drops. And steroid eye drops include a number of different kinds that are available. Basically the drug names are Prednisolone, which is usually Pred Forte. Fluorometholone which is FML. Loteprednol which is Lodamax, and Dexamethasone. And any of these can be effective and helpful. The advantage of Dexamethasone is it's not a suspension so you don't have to shake it up.

(28:03):  Now people get really strange about the use of topical steroids. They go, well, I'm really scared about the side effects. But it all boils down to this. You're looking at how much benefit you're going to gain versus potential risks. I've been dealing for four decades with ocular inflammatory disease. I use topical steroids all the time. We minimize the risk, we watch for any potential problems, and if they are any, then we reduce it.

(28:28):  The major risk is a rise in eye pressure. And if the pressure goes up high enough and blasts long enough, it can do damage to the optic nerve that's called glaucoma. That's the major risk. It's much more common than cataract and it's a bigger problem than cataract, but it takes many years of elevated pressure to really cause a problem. And when I put people on steroids, I'm having them come back and I'm watching them and I'm following the pressure. Rarely, do you have a risk of infection. If you coach your patients properly, it shouldn't be a problem.

(29:01):  In my practice with the way I use topical steroids ... And I use a lot of them, about 75% of patients will not develop a pressure rise. Everybody's different. Not everybody gets every side effect. So that means that 75% of patients, I can use these without having to worry about the major side effect, which is the pressure problem. And they can get tremendous relief from the use of an anti-inflammatory. It makes them more comfortable and it helps the surface heal.

(29:28):  If you're going to get a pressure rise, we usually see it within the first two months and then we can always stop or reduce the steroid and the pressure can come back down. Yeah, we have to be concerned about it, but like any other drug and any other side effect. And for anybody who's had a bone marrow transplant, you've been through this a lot with other drugs as well.

(29:50):  There are a lot of costly therapies that I'm going to say are of questionable value. And many of you may have tried these or people may have told you that you should use them.

(29:58):  Serum Eye Drops.  Serum eye drops. I have a rare patient who finds that serum eye drops are helpful. It's not a major therapeutic advance by having serum eye drops. I've been using them for three decades. Occasionally I find a patient who finds that they're comfortable and we go with it. But basically in summaries of all the studies, not much. And there's no really good studies on the use of them in dry eye, due to graft-versus-host disease.

(30:26):  Amniotic Membrane.  Amniotic membrane. That's not why amniotic membrane was approved by the FDA. And in fact, it's not going to treat a chronic problem. You can use it for acute issues, but you've put it in, you get a one-time heal and then it comes off and you no longer get any therapeutic benefit and it's expensive.

(30:44):  Topical Cyclosporine, Restasis, Cequa.  Topical cyclosporine, Restasis and Cequa. There's no data that it does much even in regular dry eye, it does very little. But it's been touted as a tremendous help. If people find it makes them comfortable, great. But if you're on topical steroids, the amount of extra anti-inflammatory that you get from the Restasis or the Cequa is minimal.

(31:03):  Xiidra.  Xiidra also wasn't approved for severe dry eye, which most of you're going to be living with if you have Ocular GVHD and I found very little help from topical cyclosporine or Lifitegrast which is Xiidra.

(31:16):  Meibomian Gland Therapies.  The meibomian gland therapies. There's little or no evidence that they do anything for meibomian gland disease. They certainly don't prevent meibomian gland dropout over the long term. It's not even clear that the meibomian glands actually contribute to the lipid layer of the tear film.

(31:32):  Omega-three Supplements:  And then there's other things that are on this list like omega-three fatty acids and stuff. Very costly. A lot of these, questionable value. If they help you, great, but don't think that this is going to be the wonder cure from any of these things.

(31:50):  Bacterial conjunctivitis can be an issue for patients with active ocular GVHD.  Other common issues that we see. Patients oftentimes with Ocular GVHD are immunocompromised. They've had a bone marrow transplant, they maybe have immunosuppressive drugs, so we have to watch out for bacterial conjunctivitis. The key here is that you could have a bacterial conjunctivitis and you don't get a lot of inflammation because you have a suppressed immune system. So sometimes someone comes in, they're a little bit irritated, we'll treat with an antibiotic to see if it clears up or we'll culture them just because. And it turns out a lot of the time patients will get better just with the use of a topical antibiotic. They don't look like a classic bacterial conjunctivitis.

(32:29):  Avoid digging mucus out of your eye. It can cause irritation and injury. Mucus. The key is don't go digging for it because if you go digging for it, you start irritating your eye. And in fact, just below the mucus slide is the self-injury slide. This from an individual who was using brown paper towels to scoop inside the lower fornix in order to get the mucus out of there because it was bothering them.

(32:47):  Superior limbic keratoconjunctivitis (SLK) sometimes occur in patients with ocular GVHD.  And finally, there's something called SLK or superior limbic keratoconjunctivitis, which is an inflammatory disease of the conjunctiva up above. And in order to treat that, we use topical steroids, but we have to teach patients how to instill the drop so it gets up under the upper lid. If you don't do that, it really doesn't get under the upper lid very well.

(33:08):  Summary:  So what are some pearls we can talk about now that we've talked about how to approach this? One, local therapy is effective only if systemic GVHD is controlled. In other words, you've got to control the systemic GVHD before the local therapy is going to do anything. It's secondary. Local therapy is targeted mainly at symptoms.  If you're really bothered, we want you to feel better. We'll do what we can with lubrication and such to make you feel better. Don't fear topical steroids. Just be appropriately followed to ensure that the problems and side effects of topical steroids don't become a problem for you.

(33:46):  And then beware of self-injury. If you're putting lots of drops in the course of the day, odds are you're going to hit your eye. So do everything possible to avoid hitting the eye.   Avoid using tissue to clear things out of the eye. Make sure your eyes are closed if you dab around the eye. Beware of preservatives. And even the medications themselves can be toxic. So that's the first pearl slide.

(34:08):   The second is leave the lids alone. I see more problems because people start trying to do things to the lids to make them better. Very little you're going to do to the lids that is aggressive is going to cause the inflammation to calm down. It's inflamed. If you start doing vigorous scrubs, it's going to become more inflamed. So be careful about that.

(34:29):  Avoid the get the red out drops. There are a number of drops out there that are basically marketed to get the red out. That's going to be toxic, and you want to avoid that. Avoid any surgery while things are active unless it's absolutely necessary. This is ocular surgery. And talk about trying to get yourself into an experienced eye care provider because this really can matter.

(34:51):  Optometrists vs. Ophthalmologists. There are optometrists out there that are very good. There's ophthalmologists who are very good. What's the difference between an optometrist and ophthalmologist? The optometrist is not a physician. The optometrist went to optometry school. An ophthalmologist is a physician who's also trained to take care of surgical and medical problems of the eye. And they're going to know better in general than an optometrist, but there's some good optometrists out there.

(35:17):  Corneal Specialist.  Next, line of specialization. You probably want to see a corneal specialist. You will probably want to see a corneal specialist with Ocular GVHD experience. Otherwise, people are just going to throw things at you. There's going to be no rhyme or reason. It's just going to be try this, try that, rather than actually making sense out of what's going on.

(35:37):  All right, so I've gone on here for 35, 40 minutes. I'm just going to, before going on to questions, say that, what should your expectations be?

(35:48):  Understand that Ocular GVHD damages and or destroys the lacrimal gland, and there's very little ability for the lacrimal gland to recover from this. Sometimes it does a little bit. Once that lacrimal gland is knocked out, you may have dry eyes for the rest of your life. You may learn how to manage them properly. With time you may have some regeneration of the lacrimal gland, but in general, it's going to be a rough haul.  And so the question is how can you simplify your life and regimen so that you're relatively comfortable, your vision's relatively good and you get through it without constantly having issues. With that, I want to thank you for your attention and I'm more than happy to open this up at this point for questions and see what the moderators have for me.

Question and Answer Session

(36:43): [Susan Stewart]:   Thank you so much, Dr. Margolis. That was a wonderful presentation. And yes, we do have a lot of questions. Just as a reminder, if you have a question for Dr. Margolis, use the chat box on the left to type your question in and we'll try to answer as many of those as we can.

 So we'll start off with the first one, a little lengthy. "This is the first I heard anything about eyelashes growing into the eye, and it's a constant problem for me. Did I hear correctly that this is a result of scarring? And does that mean I have GVHD? I've seen a normal eye doctor who does the staining of the eye, et cetera, diagnose me with dry eye, but I have not seen someone specialized in eye GVHD."

(37:29): [Dr. Todd Margolis]:  All right, so the question is what's going on with eyelashes that are turned in? Eyelashes that are turned in can be the result of any number of conditions that cause scarring of the conjunctiva and lid margins, not just GVHD. But GVHD is one of those things that will do it. And when the lashes are turned in, if that's what's causing the irritation and the damage to the surface, you may not have dry eye. You may just have what are called trichiatic or distichiatic lashes. Lashes that are turned in rather than out. I think if there's any question in your mind about whether this is being managed properly and these can be surgically managed, if the eye is otherwise quiet, seek out another provider if your current provider isn't giving you the answers that you'd like.

(38:23): [Susan Stewart]:   Thank you. This person wants to know, is there any thought given to doing a baseline eye test at the time of transplant and more testing 60 to 100 days later to mitigate Ocular GVHD?

(38:39): [Dr. Todd Margolis]:  I don't think that there's any need for a baseline exam unless you're doing clinical trial studies so that you know what everything looks like. And I'm not sure that a standardized exam at 60 or 90 days is necessary either. Usually people will know whether their eyes are inflamed, whether they're irritated after having a bone marrow transplant. If they do, then it's time to come in and see a specialist who understands what the findings of active Ocular GVHD. The only way you're going to prevent things from getting worse is if you have primary disease and we talk to the bone marrow transplant docs and they increase your use of drugs that are going to immunosuppress you and protect you from systemic GVHD.

(39:29): [Susan Stewart]:   How do you determine whether a GVHD patient still has Ocular GVHD of the meibomian glands versus aging dry eyes once the GVHD in the other organs is resolved?

(39:44): [Dr. Todd Margolis]:   Yeah. That's a great question and this is one of the reasons I didn't talk about meibomian glands. Because they will remain inflamed, whether due to GVHD or not, once the conjunctiva has scarred. We actually have very little data that there's active attack on the meibomian glands during active GVHD. We know that any cicatrizing conjunctivitis, which includes GVHD, can cause damage to the meibomian glands.

And so I don't look at the meibomian glands when I'm trying to figure out whether someone has active Ocular GVHD. I'm looking at the conjunctiva. I showed pictures earlier of what an active primary GVHD looks like at the conjunctiva, and that's what I rely on. And generally that fits really well with what the bone marrow docs are thinking about the systemic situation as well. If I got into thinking that everyone who had chronic meibomian gland disease had active GVHD, we'd be treating way, way too many patients with systemic drugs that they really don't need. So, I would stay away from thinking about the meibomian glands. I know it's talked about a lot, but the reality is we can't really use that to determine whether you have active GVHD and we don't have any very effective treatments for it either.

(41:06): [Susan Stewart]:   This patient had an allogeneic transplant two and a half years ago with TBI and chemotherapy. She's now been diagnosed with cataracts and wants to know how she could locate a doctor who is familiar with stem cell transplantation as it relates to the cataract procedure. What question should I ask him or her and what information should I relay to him?

(41:31): [Dr. Todd Margolis]:  The question really surrounds the fact that both high dose prednisone and irradiation can cause cataracts to come on at an earlier age than you'd normally develop on that. There are no stem cell therapies right now for cataracts. And anybody who's trying to pitch this to you doesn't have good evidence to support the fact that it's an effective treatment for cataracts. We have very effective means of surgical intervention for cataracts, but stem cell therapy is still quite a ways away and I would stay away from anybody who's reporting to do a stem cell transplant on your eye for cataract surgery.

(42:11): [Susan Stewart]:  And the next question is, what suggestion do you have for frequent tearing?

(42:18): [Dr. Todd Margolis]:  If you have frequent tearing, there's usually two causes. The first is you don't have a dry eye. And I want to make that very clear. There's confusion about this. A lot of people say you're tearing because your eyes are dry. That's just simply not true. You tear either because your eyes are irritated, in which case you've got to understand what's causing the irritation and treat it. Is it an infection? Is it an allergy? Is it active inflammation? And you treat it. And that's one way to deal with tearing.

The other reason people tear is because they can't adequately pump the tears from their ocular surface down their puncta and into their nasal lacrimal system. And so when you go to see somebody and you're tearing excessively, oftentimes they'll try to treat things locally on the surface to quiet down any active disease. But then if that's not successful, they will probe the nasal lacrimal system to ensure that the tears are actually effectively being pumped into the nasal lacrimal system and down into the nasopharynx. And so I think those are the two reasons people tear. But you do not tear because your eyes are dry. And I just want to make sure everyone understands that.

(43:26): [Susan Stewart]:   This woman is asking a question about ... I believe it's pronounced niloto. Niloto. Wants to know whether it can cause retinal damage and what she should do about it.

(43:47): [Dr. Todd Margolis]:  I'm not familiar enough with that to tell you whether it can cause retinal damage.

(43:52): [Susan Stewart]:   This person is five years post transplant and has been getting constant tearing in her left eye, and this probably is the same answer you just gave. Is there a treatment for that?

(44:05): [Dr. Todd Margolis]:  Yeah. It's the same question, the same basic answer. The other thing that can happen is when you get scarring of the conjunctiva, sometimes the puncta will scar over as well, and so you can't drain the tears, but it's basically the same thing. Someone has to address is it an underlying infection or inflammation or is it a drainage problem? And the drainage problems can be fixed surgically.

(44:31): [Susan Stewart]:   Okay. This person wants to know if tear glands are damaged from GVHD, will they ever heal? I haven't produced tears in five years.

(44:41): [Dr. Todd Margolis]:  Yeah. So that's a great question and I'll refer to it as the lacrimal gland because that's the terminology that we tend to use, but that's the gland that makes the tears. It's interesting. We see damage and then sometimes after somebody's systemic GVHD has quieted down, we see the return of a little bit of tear function.

So we don't know this for sure, but I'm guessing that when you have involvement of the lacrimal gland, you have two things going on. You have active inflammation and then you have damage to the gland. And I suspect once an area of gland is damaged, there's very little repair that goes on. But if there's areas that are inflamed and then the inflammation goes away, sometimes we'll see return of some tear function. So unfortunately, most patients don't get normal function back, but some of them certainly get some function from the lacrimal gland back over time.

(45:37): [Susan Stewart]:   This patient said, "I have ocular GVHD and my eyes produce no tears. Also, I wear scleral lenses, which are lifesavers. Is their research going on for lacrimal gland transplants?"

(45:50): [Dr. Todd Margolis]:  Yeah. That's a great question. The real question is do we have data on anything we can use to regenerate the lacrimal gland versus lacrimal gland transplants? The data on lacrimal gland transplants is pretty poor. We really don't have much, although there are some people working on this where they're trying to use stem cells, inject them into the lacrimal glands and get activity back. But the data is pretty poor on either stem cells or lacrimal transplants. There's nothing that is officially approved for that at this time. That being said, we just hired a basic scientist in our department who's going to work on exactly that problem.

(46:31): [Susan Stewart]:   Interesting. Okay. We just got a response from the person who had asked about the drug we weren't familiar with. And it's Nilotinib. N-I-L-O-T-O-N-I-B.

(47:06): [Susan Stewart]:   This person wants to know whether the scarring of the conjuctiva resolves completely.

(47:13): [Dr. Todd Margolis]:  No. The scarring doesn't resolve. The inflammation resolves and you're left with the scarring that was created. Usually there's very little improvement of the scarring over time.

(47:24): [Susan Stewart]:   And this gentleman said, "I've had eyelashes turned in and then removed by a doctor. Later electrolysis was performed, which was helpful, but I still have a degree of comfort ..." Discomfort, excuse me. "Going to try scleral lenses. Now I've tried dozens of lotions, potions, drops, and other treatments. Have I missed anything?"

(47:45): [Dr. Todd Margolis]:  It's a great question. What do you do about these lashes? They get pulled. You do electrolysis. Scleral lenses can help. They're not going to really take care of the problem. They're just going to make you feel better. But that's okay.

Sometimes we just use soft contact lenses to keep the lashes off the ocular surface. But there are surgical procedures that involve splitting the lid and damaging the areas where the lashes grow out from to permanently get rid of them. So there are more invasive surgical answers than what you've been through.

Usually the doctors will want to make sure your eyes are as quiet as possible in regards to the systemic GVHD effect in the eye if they proceed with this. But I certainly have a partner in my practice who I work very closely with who's an ocular plastic specialist, and I basically hand these patients over to them and I say, here's my findings. This is what I'm thinking. What are you thinking? And if need be, we move on to more elaborate surgical procedures to eliminate the lashes.

(48:50): [Susan Stewart]:   Next question is, "I had dry eye before BMT and now GVHD. I'm scrubbing gently my lids twice a day with Avenova using Q-tips. Is that a bad idea?"

(49:06): [Dr. Todd Margolis]:  The first question is really, did you really have dry eye? And it gets over-diagnosed. Any ocular surface irritation or problem these days is called dry eye, even if the Schirmer is normal and there's no ocular surface staining. So that's the first part of this. We have to be really careful what we call dry eye.

And the second is you can gently scrub your lids if you find it's helpful. If it's not helping you, don't do it. There's no data that lid scrubs are going to prevent any permanent damage to the lid margins over time. If it gives you acute relief of symptoms, great, do it and be gentle with it. But there's no really good data.

Avenova is another one of these things that it's never really approved by the FDA. It's like any of the artificial tears or other things. It fits under a different category. There's no proof that it works in humans. But if it makes you feel more comfortable, go ahead and use it.

(50:05): [Susan Stewart]:   This person wants to know with regard to Press ‘N Seal on, how long do you keep the Press ‘N Seal on?

(50:12): [Dr. Todd Margolis]:  That's a great question. What I do is I tell patients to keep ... If I'm having a problem and we need to really close the eye because the surface is broken down and I just did this yesterday with a patient and we need to get it to heal because we've lost substance of the cornea or there's major league issues going on, I'll have them do it as often as they can and then I'll see them back and see how well it's healed up. If we have to use Press ‘N Seal on an ongoing basis because the eyes are so dry that patients just can't tolerate things, what I do is I say, "Look, use the Press ‘N Seal when you're at home and can tolerate using Press ‘N Seal, but that doesn't mean you shouldn't go out and have a social life, in which case take the Press ‘N Seal off and go out and do your normal life." Quality of life is really important with this disease.

(51:03): [Susan Stewart]:   And is this something you can get at the drugstore or is it something that gets prescribed?

(51:09): [Dr. Todd Margolis]:  Oh, you buy this at the supermarket. It's in your plastic wrap aisle right next to the other plastic wraps. And one roll, which is about three and a half dollars, will last you a really long time. It'll be the least expensive thing you buy for your dry eyes.

(51:28): [Susan Stewart]:   Who knew? All right. This person wants to know if you have any thoughts on the use of progesterone on the forehead for ocular GVHD.

(51:39): [Dr. Todd Margolis]:  Wow. That's a great question. And the reason is I've heard through back channels that there's some data that the use of progesterone and other drops and other medications on the forehead actually help ocular disease. I have yet to see any of the data, so I don't know the answer to that. We do know that there are some hormone therapies for dry eye. In general, the hormone therapies don't work for people who have really dry eyes, as in K-sicca, which is keratoconjunctivitis that occurs in graft versus host disease. But look, if it works for you, it makes you feel better, great. Go ahead and use it.

(52:16): [Susan Stewart]:   All right. This person says that she understands that steroid eye drops cause increased cataract formation and wants to know how to avoid it.

(52:28): [Dr. Todd Margolis]:  It isn't that they cause cataracts, it's just you're more likely to get cataract if you use steroids than if you don't. Everyone gets cataracts as they get older. And the real question is, some patients are steroid responders and they have pressure rises and they get cataracts. Pressure rise is much more important than cataract and a lot of patients do it and never have a problem.

So what you do is you monitor. And I generally monitor pressure because pressure rises almost always occur before any development of cataract occurs. So if you're not developing a pressure rise, odds that the topical steroids are going to cause a cataract are low. You're much more likely to get cataracts from those big doses of prednisone that you're on for various reasons because of your bone marrow transplant.

(53:21): [Susan Stewart]:   . This person wants to know whether there are interventions for conjunctiva scarring inside of upper eyelid.

(53:31): [Dr. Todd Margolis]:  Wow. Not very effective. And I would say we only do them if there end up being lash problems. Basically, you can get reconstructions and surgeries that will change the shape of your lid and get the lashes to point out. But otherwise we don't have therapies and surgical therapies where you just go in there and just strip out that scarring. That's just not something we have at this time.

(54:00): [Susan Stewart]:   Another question about scarring. Does 5 Fluorouracil injection help stop scarring in the conjunctiva?

(54:09): [Dr. Todd Margolis]:  Yeah. Another great question. We've had scarring diseases for decades, even before we saw a lot of bone marrow transplants. So we have a lot of experience on the use of things like 5 Fluorouracil and other drugs that are supposed to help with prevention of scarring.

There was never any good data that they really did for this kind of scarring. This is a chronic disease, chronic inflammation, which means you would need chronic drug like 5 FU, which can be quite toxic in order to prevent it. I wouldn't recommend it. I don't think it's a great idea. I think we have other ways to manage these issues.

(54:52): [Susan Stewart]:   All right. This gentleman said he's just over two years post-transplant and although he has GVHD issues, he's not had eye issues. However, in the last six months he's had what seems to be bouts of excessive tearing, not dryness. Is it safe to assume this tearing is not a GVHD issue, but something else?

(55:16): [Dr. Todd Margolis]:  Good question. Odds are it's not GVHD. That doesn't mean he shouldn't be checked out. It'd be great for someone to examine him. And one of the things I'll point out is you'll know that if you have at least a decent provider who's really looking out for you, if they're examining you for ocular GVHD, if they look at your conjunctiva by pulling down the lower lid, having you look up, having you look down, having you look right and left, and then flipping your upper lid and looking under that. If they don't flip your upper lid, you probably don't belong in that practice. You should be finding someone who knows what they're looking for.

(55:53): [Susan Stewart]:   All right. This person wants to know whether there's a correlation between having received vincristine in their induction chemotherapy and worsening cataracts.

(56:05): [Dr. Todd Margolis]:  I haven't heard that vincristine makes cataracts worse or it causes cataract development. But now that you ask the question, I'm going to see if I can search the literature and find out anything. But I haven't heard of anything about that.

(56:21): [Susan Stewart]:   All right. This person wants to know how good autologous serum drops are for eyes that are irritated by scars caused by GVHD.

(56:31): [Dr. Todd Margolis]:  Yeah. It's usually not the scarring that causes the irritation. The reason is the scars are covered up by mucous membrane. It's the secondary changes to the lid and lashes and the dryness that causes it.

 In terms of autologous serum drops, it's like I mentioned before, they're not a miracle and some patients find that they're a bit more comfortable than regular artificial tears. They're not preserved so there's an advantage there, but they're more expensive and you have to go and have blood drawn and have this done. But they're not a miracle for any of this by any means. If you find you use them and you like them because it makes you feel better, great. They're not going to reverse disease and that's really important for you to know.

(57:14): [Susan Stewart]:   And this gentleman would like some clarification. He knows you already addressed it, but wants to be clear, are preservative free drops better than non-preservative free drops?

(57:24): [Dr. Todd Margolis]:  Yeah. The question we always get. I would just say if you're finding that your preserved drops are causing irritation, go to preservative free. And in theory, the preservative free ones might be better for you, but they're also a lot more expensive. So you start weighing costs versus potential advantages. And it really depends on whether you find that the use of these drops is causing problems or if you continue ... Let's say you're lubricating all day long, but you're still having ocular surface problems in your eye is red. Maybe that's because it's reacting to the drops and you have to go to preservative free. But you don't have to go right to preservative free initially.

(58:06): [Susan Stewart]:   And this will have to be our last question. Is there a directory of doctors who provide ocular treatment for Ocular GVHD patients?

(58:27): [Dr. Todd Margolis]:  Gosh, I don't know. I'm going to ask that question to our moderator. Do you know if there's a-

(58:34): [Susan Stewart]:   Well, as a matter of fact, I do know. On the BMT InfoNet website, there is a Directory of GVHD clinics and specialists and subspecialists at bmtinfonet.org/gvhd-directory and those who treat ocular GVHD are in that directory.

And with that, I need to thank Dr. Margolis for a really great presentation., and also to thank you, the audience, for the terrific set of questions that were sent in. Please contact BMT InfoNet if we can help you in any other way.