Your Eyes and Graft-versus-Host Disease

Presenter: Zhonghui Katie Luo MD, PhD, Instructor in Ophthalmology, Massachusetts Eye and Ear

July 11, 2020 Part of the Virtual Celebrating a Second Chance at Life Survivorship Symposium 2020

Presentation is 48 minutes with 10 minutes of Q&A.            Download Speaker Slides  

Summary: Graft-versus-host (GVHD) disease often affects the eyes. Early detection is essential for effective treatment.

Highlights:

• Ocular GVHD is common after allogenic transplant, affecting 40-60% of patients.
• Ocular GVHD can occur just after transplant and/or many years out, recurrence is also possible.
• Symptoms of Ocular GVHD vary and any discomfort, change in appearance or light sensitivity.
• Patients should prioritize discussing their eyes with their oncologist after transplant and seek out a specialist in Ocular GVHD.
• Early and regular evaluation by a specialist is key to prevent permanent damage which can happen quickly.

Key Points:

08:22 Common symptoms of Ocular GVHD: dry/gritty feeling, light sensitivity, excessive eye crust, foamy discharge and cornea or lid inflammation.

25:44 Ocular GVHD is typically a lifelong condition that is managed through preventive care and repair.

25:44 Regular contact lenses can hide and worsen ocular GVHD and should not be used.

25:44 Rubbing or digging in your eyes causes trauma and increases crusting and discomfort.

29:24 The majority of over-the-counter eye drops are not appropriate for ocular GVHD and lead to more damage. Only use preservative free artificial tears. One drop every hour is best for prevention of symptoms.

29:54 Limiting use of screens, keeping your home above 40% humidity as well as daily warm compresses are all proven treatments.

36:13 Punctal plugs can be implanted to keep the eye from draining away moisture.

37:40 Steroids and other immunosuppression drugs can be helpful but must be monitored closely due to serious side effects.

39:09 Other treatments include blood serum tears and scleral lenses for more severe cases.

41:07 Avoid all cosmetic surgery near eyes. Cataract surgery should only be performed by an ocular GVHD specialist.

Transcript of Presentaton

00:00  [Moderator] Welcome to the workshop, Your Eyes and Graft-versus-Host Disease. My name is Mary Clare and I'll be your moderator for today. It is my pleasure to introduce you to today's speaker, Dr. Katie Luo. Dr. Luo's a physician scientist at Massachusetts Eye and Ear Harvard Medical School. Her specialty is ocular surface disease and cataract surgery. For the past six years, Dr. Luo has worked closely with Dana-Farber Cancer Institute providing medical and surgical care to a large population of patients with ocular graft-versus-host disease.

She is the principal investigator on a recently completed phase two randomized clinical trial on a novel treatment for ocular GvHD. Please join me in welcoming Dr. Luo.

00:55  [Dr. Luo] Hi everybody, I'm so excited to be here to talk with you today. I know some of you are my patients, so hi there. I know who you are and for everybody else, I'm so excited to have the opportunity to talk to you from my personal experience treating hundreds of the ocular GvHD patients over the years and a lot of things I heard and learned from them, their experiences going through the journey with me. So today I want to talk about what is ocular GvHD, what are the clinical findings, what's the etiology behind those findings and how do we manage those symptoms and pathology.

01:49  What is graft-versus-host disease (GVHD) So graft-versus-host disease coming from the graft, right? So, after the chemotherapy wiping out the disease and the immune system of you or your loved one, they get the cells from a donor. So, the donor is labeled as pink, those pink cells are going to the blue recipient and then these little pink cells, they start repopulating themselves. They basically re-establish the whole immune system in the recipient, therefore, to form a little army to defend you.

But what happens is that because this army is not 100% yours, despite some people telling me I'm a 10/10 match, I'm a complete match, that match is not 100%. You might be 99.99% matched but there is still a teeny little bit that's not matched and that caused this army, sometimes, recognizing you as foreigners and they think they're defending you but they're actually hurting you by attacking the host organs. So this is really the ultimate reason why there's graft-versus-host disease. We needed this army to protect from infectious disease, from tumor, from leukemia itself, but it can also do some harm.

03:26     Basics of Ocular GvHD So among all the GvHDs, ocular GvHD is a very common complication that happens and in fact, 40-60% of patients after the allogeneic - if you get the cells from a donor that is not yourself, that's called allogeneic stem cell transplant. So basically, there is a 50/50 chance after that transplant the eyes might get affected.

I want to clarify that sometimes not all clinicians, including the general clinicians, even some eye doctors, realize one can have ocular GvHD as one single item that's affecting you as a GvHD. If say, you don't have skin or lung or liver, it doesn't mean you cannot just have the eyes affected alone. It is possible. So it's not a requirement that you must have been diagnosed with GvHD already, then you say something is going on with my eyes, then that might be GvHD, okay? So just to put in there, the eye can be affected very early on, it can be affected alone and it can be affected say 15 years after transplant. Everything else going great, but the eyes starting to act up, this could still be GvHD.

04:57     How acute GvHD affect the Eyes: So we roughly divide the GvHD into two big categories, acute versus chronic, but the line is not a very sharp line. There's definitely overlapping. So if we want to talk about the most commonly seen acute GvHD, it usually happens within the first three months after transplant. Usually comes along with a skin rash, elevated liver enzyme, digestive system dysfunction and the eyes can have a sudden onset of problems.

This is actually a patient of mine who is having acute attack after already going into chronic GvHD, that's what I'm talking about, this can be overlap. But when acute GvHD attacks, it often does affect the skin and then one can see the eyes are really, really all of a sudden getting red and miserable. You see these pictures, there's that yellow line of material that's coating over the pink part, that's called conjunctiva, that's the inside lining of your eye. That thick material it is called pseudo-membrane, it is not even pus that one can wipe off. This is a representation of severe inflammation that happens all of sudden attacking the eyes.

And then this is a picture of the cornea. Cornea is the clear part in the eye. And then when you look at the cornea, you can actually see the iris. This patient has brown iris, you can see through it but the cornea itself is clear and it has multiple layers. This picture is showing that the top layer of the cornea, it's almost like the skin of the cornea, is sloughing off. You see in the middle there's that ridge there? It's like a burn patient, the skin having blistered, the cornea top is having a blister and peeling off.

So those with GvHD, a lot of them will be hospitalized because of a severe systemic issues as well. This is not usually something one deals with at home.

07:19  Chronic GVHD in the eyes And then we talk about if one gets through the first three months, the ones who go into that more stable part of their post-transplant course, and chronic GvHD can happen. Acute and chronic they are not completely tied together. One who has acute GvHD can then become completely well, asymptomatic going on for x number of months, x number of years and then start having chronic GvHD. Or someone who never had acute ocular GvHD can go on to have chronic ocular GvHD. So these two need to be dealt with separately.

So chronic GvHD in the eyes usually starts to happen around five months to 24 months, but I've certainly seen earlier. I've seen four months, I've seen three months. It can happen even a few weeks after the transplant. So it can also happen decades after transplant.

08:22  Manifestations of Chronic GVHD in the Eyes These patients, they tend to look like, this is one of my patients too. If you see them in a waiting room they're squinting all the time. You really cannot see their eye, you can't really see their eye color, you can't really see the white part of their eyes at all. They're squinting all the time or they're wearing sunglasses indoor. If they put their hand over their brows as if there's strong light coming at them, it's because of severe light sensitivity even in a very dimly lit room.

And there's very poor functional vision. At the doctor's office, when the numbing drop is put on, they might read 20/30. This is great vision but in reality, the functional vision to allow them to navigate outside the house in the bright lighting is extremely poor.

So let's break down to look at some images I can see with my microscope in the clinic room. So one frequently affected part of your eye by GvHD is actually the lid. So some patients telling me I'm fine but there's just this crusting. The morning when I wake up, I can't even open my eyes. I have to pry open my eyes or I have to go to the sink, I have to wash my face, otherwise my lids are shut together and this is why.

On the right side of the screen, you can see that yellow crusting lining on the roots of the lashes and on the left side you can also see that yellow color crusting on the pink colored lid margin. The lid margin is usually swollen and red. It's hard sometimes for you to tell, you might just say oh my eyes are red. But take one more look, sometimes even the eyeballs are okay, the lids are very red and irritated. That's because GvHD is attacking the lid skin and it can attack the pink part of the eyes too.

On the left side, the blue arrow is pointing to an ulcerated part of the eyelid. So it's almost like the skin on top of the eyelid was scraped off. It was not scraped off, it was actually eroded by the disease activity.

On the right side of the picture within that blue circle, you see there's a pile of foam. The foam is probably white. I dye the eyes with a yellow dye in clinic so it looks yellow on this picture, but there's this foamy discharge. That's also a hallmark of blepharitis. And if this happens a few months after the transplant, you've got to watch out, that is a sign of GvHD.

And then, this name is a mouthful, it's keratoconjunctivitis. Kerato means cornea, conjunctival meaning conjunctiva. So that means this is inflammation of the cornea and the conjunctiva. The conjunctival is just the lining of clear cells everywhere inside your eye. Over your cornea, over the pink part of the lid, over the white part of the eyeball, that's all covered by the cells called conjunctiva.

So look at this eye, this eye looks like people are going to say what happened to you? Did you get pink eye? It looks just like a viral conjunctivitis but it is not. It is not an infection and it is certainly not a bacterial conjunctivitis in this setting. Therefore, erythromycin ointment does not work. If it works, it's just a lubricant because oily. It really doesn't treat ocular GvHD and please do not try at home to use Visine or Clear Eyes or those line of over-the-counter medications to try to get rid of the redness because they won't ,because the redness is GvHD. If Visine gets rid of the redness for two minutes, it'll be back shortly after and it actually is pretty toxic to the eye which I will talk more later in the management part.

12:34  Diagnosis of Ocular GVHD: So I have my tools, I have special dyes in my clinic so I can stain a conjunctiva and the cornea and look at them. So you can see that the diffuse green dots everywhere, right? They're green when I use a special cobalt blue light to look at them. So these green dots are damages on the surface. These are like the Boston roads after harsh Winter. This is potholes everywhere on the otherwise - that's supposed to be a beautifully, nice, frozen pond surface. It's slippery, it's smooth, but no, they're full of potholes and these are damages and I will tell you why shortly.

These are tiny little damages, there's just tens of thousands of them. When they cannot be properly healed over by you, by the body with normal repairing function, what happens is the cells can go a little bit out of control. Instead of sealing the potholes we just talked about, they grow into strings. So this picture, you can see with the yellow arrows pointing to globs of little balls. So they're actually not balls, if I stretch them out they are very long strings of the cells on the cornea and on the conjunctiva. These are called a filament. These are the result of improper healing. It's like if you get a cut on your thumb and then the skin heals over not loosely, instead growing a skin tag off that.

That's as close as I can think of to explain to you. However, these tags they are hurting a lot. The light sensitivity, the putting your hand over the brow thing, a lot of them coming from these tags. And every time one blinks, it pull these tags on the cornea, not only causing a lot of pain, it can lead to cornea abrasion just by ripping the piece of tissue right underneath that string.

15:15  Function of tear and oil glands in eyes: And then let's say we are looking at the lids with a different modality, with a different machine. On the gray scale pictures, you see those white lines. Squiggly like wormish lines. So those lines are actually your oil glands on the lid. They are essential to maintain a good function of the tears.

So the ocular GvHD attacks those glands as well. When you see on the top one that's fairly normal, you have lots of glands on the lid margin. And the middle picture is the yellow arrow pointing to one that's killed, that's no longer there. And you look at the bottom, so there's barely any left. When the GvHD attacks those oil glands, they take away the function of normal oil secretion into your tear film. And on the right side with the colored photos, you see the pink part, that's the pink part inside your eyelid. So the conjunctiva is the clear cells lining on top of the pink tissue that we talked earlier, but you see the tissue doesn't look smooth, they're scarred.

16:09  Permanent scaring in eyes: And the bottom one you have the biggest scar, they look almost white. So that is evidence of GvHD attacking those cells and killing them, and then the scar tissue will fill in. And that is not only the evidence of previous graft-versus-host disease attacks but also the scar surface is not so smooth. So when you have that lining covering your cornea, sometimes those can lead to cornea damage from the scars as well. And then we talked about all these possible earlier damages, that can coalesce into much more problematic damages. Fortunately, not a lot of you will have to get to this part but it is good to understand how things can evolve. How long one can step on the path of no return from here.

17:11  So this is a picture also with a special stain. This particular patient unfortunately, - look at that big yellowish green map in the middle of the cornea. That is where the tissue is missing. So the top layer, the skin layer of the cornea is completely gone over there, that's why it stains green. And not only the cornea, but also a little bit before at 5 o'clock on the conjunctiva there's also parts missing tissue. So that is what can do when you have thousands of potholes. They cannot heal and the potholes merge just became a crater. And this is another patient of mine who unfortunately quickly developed a hole, so that purple circle is my surgical marking.

18:00  Inside that purple circle there's actually a crater that's so deep, that's gone through the cornea. So a piece of iris was plugging the hole, temporarily stopping the leakage of fluid from coming out and that dragged the pupil over there. So that's why the pupil is not round. So this is a medical emergency. This is basically an open globe because there is a hole, a real hole happening on the cornea. So I took the patient to the operating room, I got a piece of donor tissue that is showing on the forceps. A little tiny 3mm donor tissue, I put that on, I sew it up to patch the hole up. That's how this is treated urgently.

18:44  And this is a closeup. It looks great, right? You would think "oh, okay, I don't worry about it. If I got a hole, my doctor will patch me and end of the story." No, that is not the end of the story. So this looks beautiful. Patient was very good, very diligent with the care and everything. However, GvHD is relentless. It just wouldn't stop attacking him. So here, this is a couple months after. You see the left side, the first picture, the graft is still there but the area above the graft started melting and that melt is showing in that middle picture with the green melted part on top of the blue background. So that area is melted.

So I had to take him back to the operating room. I had to take off my previous graft and put a bigger graft over there. He is doing fine right now. I just want to show you that a surgical procedure not only is not a good result of any ocular complication, it is really the beginning of much bigger further problem in the future. So I want to put these pictures up here to let you know that we want to control the disease at a much, much earlier stage to prevent it eventually coming to this stage because the outcome is not always good. All right, so I don't want to scare you but I do want to give you a view of what I'm seeing, so what I need to deal with. Some eyeballs I can save and some eyeballs I cannot save.

20:29  Dry eye caused by ocular GVHD All right, so now I talk about what can we do about it? Well first, I want to understand the problem. I hope my earlier slides have given you an introduction and I'm going down to even more mechanism later on. And then we want to avoid preventable damage, we want to not do harm to our own eyes if we can control it, right? And the third, we want to invest your commitment in management. So the problem is really in the imbalance between damage and repair.

The ocular GvHD what happen is the immune cells, the pink cells, remember the pink cells going to a blue body and the pink cells started attacking the eyes and it has a lot of different tissue in the eye. On the left side of the picture, below the dryness marking, you see I put the little orange egg-ish thing above the eye. That is I'm showing you the lacrimal gland. That is supposed to be secreting tears, secreting fluid constantly at a very slow pace. Constantly secreting little tears to keep the eye surface moist. That's what we have when we're born and that's what usually goes pretty well without knowing. You don't have to cry, tears will just come out at a small amount, auto-regulated to keep the eye moist.

And then the tears would go across the cornea and going to the two little circles I put in the nasal corner of the picture. So you have excessive tears and collecting all the dust, unwanted material, wash over the surface and it drains that into the back of your throat through your nose. That's where those orange lines are going. So normally we have a situation where there's tear production balanced with tear drainage so you are not flooded all the time, but you are not dry all the time either.

What happens in ocular GvHD is that the lacrimal gland, that orange egg, gets attacked. It stops or have a severely decreased production of tears, that's why you are dry. You're not making tears as you used to. And then supposedly you still keep the normal amount of tear drainage, that's too much drainage relative to production. And again, we lose moisture to the dry air, to the environment all the time when the eyes are open.

Now on the left side of the picture of the inflammation, so what happens? GvHD causes inflammation, right? The immune cells attacking the tissue causes redness everywhere. I'm using the pink marks to show that the lids are red, the conjunctiva, the white part of the eyes are red, and those green dots you remember from the earlier pictures? Those green dots, those potholes, they are direct damage caused by inflammation.

So in normal eyes, let's review, in a normal eye we have normal wear and tear, daily living, but we also have the good amount of moist produced by lacrimal glands at a baseline. Keep the surface moist. With the functional stem cells in the moist environment, the stem cells are able to reproduce and fill in the potholes and fill them flat so next day, the eyes are better than new. You don't feel any pain or irritation on a regular basis. In GvHD, the tear production is severely decreased and there's more damage caused to the ocular surface than your regular circumstance. However, the stem cells cannot proliferate at a normal base because 1) they're under attack by the GvHD as well. 2) They live in such a dry environment, they don't work very well when they're dry.

Therefore we have an imbalance between damage and repair. Therefore we have persistent more and more potholes instead of getting a timely repair. Therefore, the eye surface is not able to heal and depending on how bad the balance is, one will end up either mild irritation or to some moderate damage, to the point of those horrible pictures I showed you, that severe damage that cannot even be brought back.

25:23  Treatment and prevention of dry eyes caused by ocular GVHD: All right, so let's talk about treatment now. The number one question I get in clinic is will this goes away? When will I be done with it? Will I ever get rid of it? Do I have this forever? So a garden variety, but the same question, will this go away?

25:44  I want to put out for everyone to hear that as long as the stem cells are living in your body, as long as the pink cells are living in the blue body and keeping you alive, defending you, there's always a risk of chronic GvHD. There's always a risk of flare ups, meaning you're doing well most of the time but occasionally you're not doing well, or persistently there's mild irritation all throughout. It is rare for someone to say completely GvHD would never come back to my system ever again. It is rare. So I want to set that expectation. We are thinking about managing the condition. We're managing you and your eyes and you are managing you and your eyes to live through ocular GvHD rather than thinking there is a cure to get rid of it.

All right? So we talk about how to avoid harm. So number one harmful behavior is actually putting contact lens in. Some people are contact lens dependent prior to transplant and contact lens is very easy to use. However, when one has

Number two, rub your eyes. Do not rub your eyes because I showed you how vulnerable the surface is. The lids, the conjunctiva, the cornea, they're already in very poor situation, very delicate situation. If you rub, this is direct damage that is caused by yourself. I tell my patients you sit on your hands. Seriously, you sit on your hands so that you do not rub your eyes. And you do the treatment that we're going to talk about in the future. We will be able to help protect the eyes because rubbing does not solve any problem. You all know rubbing them maybe give you ten seconds of relief and you're going to feel worse afterwards, okay?

And do not dig for mucous. Nobody else sees your crusting. Nobody else sees the corner there's some white stuff piling up except me looking at you with a 10x magnification. Nobody cares. Do not scratch it because every time you dig into that corner of your eye, that's creating trauma, big trauma, and the eye responds to trauma by abnormal healing or abnormal production of mucous. So the more you dig, the more mucous you're going to get, the more mucous you're going to get the next morning so that it's a vicious cycle. You want to stop it today. After this talk you want to stop scratching.

So you ask me what do I do with those? Okay, you take a facial cloth in the morning when you get up. Get warm water, fairly warm and wet, not dripping, and cover your eyes for a good ten minutes. That's going to soften everything and then you gently wipe with that cloth, get something off the surface. If there are a few stubborn ones left behind, leave it be. Once you stop rubbing, you're going to have decreased production.

29:24  Eye Drops for Ocular GVHD: Next, do not use redness reliever such as Visine, Opcon A, Naphcon A, because the chemicals are just very damaging to the surface in your circumstance. Try to not use over the counter allergy eye drops such as Alaway, Zaditor because those also make the surface more dry. A lot of you, from experience, your itchiness is a result of GvHD. It's not seasonal allergy. If you have seasonal allergy, take Claritin, take Zyrtec, control it systemically. Try to avoid eye drops. You're going to use a lot of artificial tears which I'll talk about shortly after. So no Clear Eye, no Alaway.

29:54  Screen Breaks, Makeup and Dry Air: And you also want to take breaks from your screen time. I know in this day and age if we cannot go out, what else can you do? You are on your screen. You can be on your screen, you're going to need to take breaks. You need to be 15 minutes on the screen, five minutes away. 15 minutes on the computer or iPhone, five minutes away. During that time you're going to do your artificial tears to wet your eyeballs.

Be easy on makeup and makeup removal because harsh chemicals can irritate the eyes. And you'll control the environment. In the Summer, it's the air conditioning. In the Winter, it's heat. So you want to keep your humidifier on. A lot of fancy humidifiers have indicator, you want your room to be 50%, not below 40% otherwise too dry, it's sucking the water out of your eyes. And you do want to wear sunglasses when you're outside. And there are actually sports googles you can order online, those are designed for motorcyclists so they have very good seal around your brow so it can create a little bit of a moisture chamber to keep the surrounding of your eyeballs wet.

31:13  Warm Compress and Lid Scrubs And you want to do warm compresses but try not to do lid scrubs. I know a lot of people getting instructions to do lid scrubs but that's a little bit harsh. I would say only use a facial cloth gently, very gently on your eyes. And you can buy those heating pads, they are filled with micro beads or I forget the name right now, but you can order on Amazon some mask you can heat up, blepharitis mask you can heat up in the microwave and do warm compress now and then and that's very soothing too.

31:52  How to Use Artificial Tears Okay, now you really want to be paying attention to this slide. We talked about how important it is to keep the eyes wet, right? So you want to do lubrication very frequently.

I'll give you examples of what drops to use in the next slide. You want to put the tears in every hour when you're awake. Again, every single hour when you're awake. That means if you get up at 7:00, 7:00 you put a drop in, 8:00 you put another drop in. 9:00 you put another drop, okay? So I want to emphasize that so if you tell me you're doing once or twice a day, it's as good as not doing anything. You are not making tears, that's why you need to give the eye the artificial tears to keep them wet. And every time you only need one drop, okay?

Next you want to control the humidity, we talked about and in the doctor's office, such as my office, I put plugs in those little two orange circles over there to stop the tears from draining into your nose. Okay, so the key on the lubricant is preservative free. So I use annoying pink to circle that so you remember. You have to look at that phrase, preservative free, and this is just a Google image. Most of them come in little single plastic tubes but please buy preservative free lubricant because the eyes are so delicate, they may not like the preservative. It's not worth trying. You don't want to get your eyes worse by putting preservatives in them.

And the ones you do every hour, if you are pretty happy, then you want to adjust the frequency. The correct frequency is to keep the symptoms from happening in between the drops. You want to get the next drop in before the eyes started telling you "oh I'm dry, I'm hurting, I want another drop". You want to stop that. That is the correct frequency. So do not wait until you are symptomatic before doing it. Remember, every time you put a drop in, that mimics your own tear production. I suggest if you're home, you put the opened artificial tears on the clean plate and put a clear glass on top of it. So no dog hair, no dust, no oil or accidentally contaminated tip and finish that tube in the next four to five hours will be good.

34:39  Tear Ointment At night you can use tear ointment. So again, look for that preservative free writing, okay? Look for that writing there. If you can find that, that's the best. If you only use it once at night, if you can't find the preservative free one, you have a little bit of preservative it might be okay. But lubricate with a thicker tear ointment or thicker tear gel might do you some benefit overnight because you can't do it every hour.

35:10  And then how do we make more tears? So frequently people are prescribed a Restasis or Xiidra, I will say that's a toss up. In some early diseases they might work, they might help despite a little bit of stinging, but if one has got significant graft-versus-host disease, if you're not making tears, they are, in my experience, they rarely work and if they burn you so bad, you might want to consult a GvHD specialist about using them or not. They are not proven to me to be effective in people with severe GvHD in the eyes. Some oral medications, such as Salagen and Evoxac, that usually you get prescribed to wet the mouth, actually, they can work for your eyes too. So when you are prescribed this medication by your transplant doctor or oral medicine doctor, pay attention to your eyes too. See if you can create a little more tears, it's worth a try.

36:13  Punctal Plugs  All right, so punctal plugs are things that the eye doctors can put in often. So it can be either dissolvable on the first panel - dissolvable that goes into the drainage tube so you don't see them from the outside, to a silicone one that you see a little cap that's sitting on top of the drainage duct, to the cautery, which is a little harsh, is really to burn that duct closed.

So I typically prefer the middle one because it is something that one can remove, one can put it back in, I can see it, do you still have it, do you not have it. The dissolvables don't work as well as the permanent silicone one because when they're dissolving, when they get skinnier, it just doesn't work and also you don't really know when they dissolve, when they are gone completely to replace them. And the cautery is with someone who either had a weird shape of their punctual and they cannot put a regular plug in, or for someone repeatedly losing plugs and just cannot deal with regular plugs. But this is the idea, if you remember my previous pictures, this is the idea to control less drainage. You have more tears put in there and you have less drainage, that is equivalent to having more tears at all times in your eyes.

37:40  Immunosuppressive Medications And the information I talked about, that's disease activity causing surface damage and the redness. So it is controlled by systemic immunosuppression such as tacrolimus, oral steroids, sirolimus and the garden variety of new treatments such as ECP, such as Jakafi. There's a lot of new treatment coming out. So something treating systemically, the eyeballs sometimes get a benefit too.

Popular treatment with topical steroids is very effective, especially in controlling the acute onset inflammation. You just want to remember, steroids are effective but it also have side effects. So if any eye doctor give you a prescription of steroid eye medication, a follow up visit is a must. You cannot go home with a steroid ointment or drop without a follow up appointment date in your hands, and that follow up appointment should not be a year, should not be six months, it should be maybe a month to two or even three depending on what kind of medication you're given. But if you get that, you want to say "doc, when am I coming back to see you?" Because your eye pressure should be checked and the effect of the treatment should be checked. Relatively I would say probably no more than two months.

39:09  Serum Tears and Scleral Lenses And then serum tears can be prescribed by your eye doctor which is cumbersome, takes your own blood to make tears, but it's very effective in many situations. There's another very effective treatment to manage your symptoms, the therapeutical scleral lenses. So these are not your daily, regular lenses. They do help with your vision but helping with the vision is not the primary goal. The primary goal is to protect your surface, putting a hard shell in front of your surface that allows, I'm going to give you the next slide, that allows keeping some fluid between your cornea.

See, that light blue is fluid and the dark is the lens on the left side picture. There's a constant layer of fluid bathing the cornea, that's held by the scleral lens. That's how it makes you comfortable. On the right handed picture, you can see there are two white lines. The left side white line is the lens. The inside white line is the cornea and that dark space in between is the fluid, therefore this is not a contact lens because there is no contact of your cornea with the lens. It's really the fluid bathing the cornea making it comfortable. Some popular places one can get them, one is BostonSight. I work with them a lot, they are in Needham [MA] but they have over 10 satellite locations all around the country. There's GP Lens Institute, there's EyePrint Pro, so your transplant doctor should be able to refer you to get the therapeutic lens fitting if needed.

41:07  Avoid Surgery Okay, so again, surgical treatment what's our take home point? Take home point is avoid it, right? It is not curative, it causes a lot more trouble, it is something we have to do when there's a hole or there's melting on your cornea but we don't want to go there if we don't have to. Amniotic membrane sometimes can help with the healing, the best surgery is to put something on, let it heal without cutting.

Cosmetic surgery, no, the answer is a clear no. Do not get cosmetic eyelid surgery, do not worry about the bags, do not worry about the sagging lids, we want the eyes to be more likely to be close than to be constantly open the whole time.

Do not get eyeliner tattoo, lash extensions, do not get LASIK. All those treatments, any cutting is going to promote inflammation and it can cause anatomical changes that can become a problem in the future. Cataract surgery is an exception because it helps with your vision. However, it needs to be done with extreme care. The post operative healing process is slightly different in patients with GvHD, than without GvHD. Ideally you want to go to a surgeon who's got previous experience with ocular GvHD, knows what to look out for, knows what to do when something happens either inter-operatively or post-operatively. The pre and post care are very different.

42:34  Clinical Trials Okay, so I want to remind everybody to support the research efforts because so far there's no FDA approved treatment for ocular GvHD. Other trials have been started but not all of them can even be finished. It is hard to trial in this group of people. Next time if there's a trial going on, please think about every trial you participate in as a potential cure for you or better management for you and for many, many people coming after you.

43:10  Advocate for Your Eyes So what you can and should do, I get it, you're very busy, you're very tired and you are hurt and you are fed up. You have so many things to deal with but how did I not know there are like 100 problems could happen after transplant? I get you, however nobody knows how your eyes feel. Before and after, there's subtle things. Very subtle things. You might be feeling great before but then for the last couple of weeks wait, I feel like I'm blinking too much. I feel like I don't want to keep my eyes open. So nobody knows that but yourself. You have to be the one to voice your concerns and remember, early diagnosis and treatment, they do make a difference. You don't want to get to the point with no return. What you and your family can do, you can advocate for your diagnosis and treatment. Always ask "is it my eyes are not feeling well"? Don't say "oh my liver enzyme is really high so I'm not going to bring it up because my liver's more important". Yes, your liver's important but your eyes are very important too.

Just say by the way doc, I really like Ms. Gordon's recommendation, you bring a notepad, you jot down your symptoms and put eyes somewhere there. By the way, I'm not sure what's going on but my eye's been feeling like this and this. The sooner you volunteer that information, the sooner your transplant doctor can hook you up with an eye doctor. So right after transplant in acute period, if there's anything wrong request inpatient consult service. Usually in the transplant center there is eye consult, they can take a look at you to treat acute GvHD. You want to volunteer information to your transplant doctor and if you have a regular doctor, you want to volunteer that information to your regular doctor as well.

This doctor may not be experienced with GvHD. I want to remind everybody, we want to make every doctor your friend, your ally, not your enemy. You don't want to say "oh you've never seen a GvHD ever in your life, why am I talking to you?" No, you need your local eye doctor to be your ally. You need them to refer you to a doctor experienced with GvHD and sometimes co management is necessary so you don't have to drive three hours every time you need some eye care.

You want to discuss any eye treatment or procedure or systemic treatment and change with a specialist. What do I mean? For example, when you see your eye doctor you want to tell them "oh, I was on 40mg of prednisone because my breathing was difficult and now I'm getting down to 20mg and my doc says next week it's going to go down to 16". So you want to give this information to your eye doctor because immunosuppression taper does affect how the eyes feel.

Vice versa if you've got a cataract, the eye doctor says we need to do cataract surgery you want your transplant doctor to know that because I frequently tell my Dana-Farber doctor "Mrs. So and so, I'm doing surgery on him next week, can you please hold off the taper? Let's keep the prednisone stable at 20 until he's properly healed, then we can review taper." So these are important. Sometimes the doctors are not really over the 100 notes you've had in the past three months, so you want to be your own advocate to connect the specialists around you. So your local eye doctor or the GvHD specialist can look for signs of ocular GvHD and other eye problems.

For example, you're having cataracts. Is that a problem with GvHD? It's a yes or no question. The steroid treatment might have promoted the progression of your cataract, but it might be pre-existing. But it is important to deal with it anyway.

Do you have glaucoma? Is there a family history of glaucoma? Are you having a pressure rise because of the systemic high dose steroid treatment? These are all the things the local doctors can do, too, to check the pressure, to manage if the pressure is high. You might need glaucoma treatment, you might need to see a special glaucoma doctor who also understands GvHD.

And at least one can take a look at you. Let's say if you live in A and you're five hours away from me, what the local doctor can do is tell me what the pressure is, tell me if there's a big cornea abrasion that you need to drive down here today to see me versus say oh actually there's a lash trapped. I removed the lash, patient feels much better, right? So we can work together to avoid some needless travel and we want to initiate treatment as early as possible. The more aggressive you treat, the earlier you treat, the wetter the eyes are, the better outcome is going to be.

All right, so I think I already talked about that. Communicate between different services. And then just remember it is we and us working together. We need to do this together. Just by prescribing you drugs and ointments and surgeries is not going to do 100% and we need you to be fully committed in the management and the talk. And thank you very much, I am done. I know I went a little over time.

Q&A

48:38     [Moderator] Thank you so much, Dr. Luo. That was a wonderful presentation. I know all of us learned a lot. We have quite a few questions, we're only going to have time to get to a few but I wanted to start with a question from Laurie. Have you heard of anyone having peripheral vision loss after transplant? This particular person is 17 years out from transplant and has lost some peripheral vision. Could this be ocular GvHD? Thank you.

49:10     [Dr. Luo] Okay, yeah it's a great question. It's a very difficult to answer the specific cause and effect but I can make up a story. Let's say one has a transplant and with high dose steroids for a long time and during that time the pressure in the eyes could be elevated without knowing for x number of months or even years and that's basically glaucoma and glaucoma can take away peripheral vision. That's definitely a scenario that could happen. Is it a scenario that you, Laurie, did have? I do not know.

49:48     [Dr. Luo] We do not have strong evidence that ocular GvHD directly attacks the optic nerve. That's what the peripheral vision loss is, is damage on the optic nerve directly. We don't really see that. I can't say it never happens, it could happen but more likely it's via the pressure caused. Sometimes if it happens, you no longer have increased interocular pressure, you will never be able to go back to say oh, this was what happened. So yeah, that's the best I can answer the question.

50:24     [Moderator] Okay, thank you. All right, so we have a question from Cathy, she asks are there foods like salmon, berries or even ocular vitamins that can be helpful to prevent inflammation?

50:38     [Dr. Luo] That's a good question. So there's a debate right now on whether omega 3 oil can help with dry eyes. By the way, ocular GvHD does have dry eyes but that doesn't mean ocular GvHD is dry eyes. Ocular GvHD is much more than dry eyes. Mild dry eyes is one form of ocular GvHD. So coming back to the omega 3 oil, some clinical trials showed it has significant benefit for dry eyes. Some say it doesn't. My personal opinion, because it has proven benefits to cardiovascular health, go ahead and take it anyway. It wouldn't harm your eyes. Maybe it wouldn't do much of a benefit but it wouldn't harm.

51:20     [Dr. Luo] The ocular vitamins, most commonly we're talking about those Ocuvite, studies for macular degeneration, lutine supplements, those are proven to be maybe mildly effective in macular degeneration which is a retina problem. Ocular GvHD rarely, if any, will attack the retina directly so there is no clear evidence those type of supplement for macular degeneration would do any benefit for ocular GvHD. Okay? Thank you, Cathy.

51:52     [Moderator] Okay. I've got another question from Roman and this is "Can blocked tear ducts from GvHD be reversed?"

52:14     [Dr. Luo] Ah, got it. Okay, depending on how it was blocked. There are two mechanism of blockage. One is natural, like your body scarred the tear ducts which happens especially after chemotherapy. It might not even be GvHD. The tear ducts can be, I'm talking about the tear drainage ducts, the two little orange circles. The drainage ducts can be scarred by itself and then one might actually have a tearing problem. If that's the case, I would say don't even reverse it because I want your eyes to be wet. You'd rather be wet than being dry. So don't fix it. It can be surgically opened up but anybody who's been through that surgery usually end up eyes will be too dry.

52:57     [Dr. Luo] So that is not a great thing for ocular GvHD. Two, if you had punctal plugs causing an arbitrary blockage of the tear drainage ducts, yes that should be able to be removed to reopen it. If you're talking about the tear ducts that secreting tears from the orange egg, the lacrimal glands, that's not making tears anymore, those are really not procedures one can do to open up the tear production ducts. So there are treatment we are working on to try to wake up the glands, to have them start secreting tears again but it's not a surgical procedure. That's why you need to have a supplement of artificial tears. I hope one of these things answer your question. Go ahead.

53:52     [Moderator] Okay, great. All right, we have one question from Gerry. When you mention that we should put in eye drops every hour even if it's a thicker style eye drop like Refresh Optive mega 3, is that also once an hour?

54:11     [Dr. Luo] Okay, that's a great question. So first of all, I will use this opportunity to explain furthermore. So there are different thickness of the drops. The thickest would be the ointment or the gel, so I recommend doing that at night because during the day it makes your vision much more blurry. If you can accept that, you can use it during the day too if it's preservative free. Two, there's some more milky colored drops than clear colored drops. Usually those milky colored drops they have more fat content, oil content in it. So it's a little thicker, stays around a little longer, it might work a little better such as the Refresh mega 3.

54:50     [Dr. Luo] So those can definitely be used every hour and the thinner tears too. When I say every hour, I mean you want to start with every hour. If your eyes are uncomfortable, you start with one drop every hour when you're awake and if that makes that hour in between the two drops you're absolutely happy, then you can stretch it out. You try it every two hours. If two hours you're happy, you stretch it to three hours. Quickly you're going to figure out that frequency and you will know when I stretch to three hours, oh boy, that last half hour I want it. Then it means three hours is too long. Then you go back to every two hours.

55:31     [Dr. Luo] So you're going to titrate to a frequency, that interval between the two drops comfortable. That's how you titrate the frequency. Okay, thank you. Next please.

55:44     [Moderator] Wonderful. Okay, so this is going to be our last question, and this is from Deanna. She says I am a nine and a half year post allo stem cell transplant recipient and my eyes are becoming worse. Her doctor just prescribed Imbruvica, if I'm saying that correctly, and she would like to know what the success rate is of this and what other therapies are available. She's concerned because it's affecting her driving regardless of sunny or overcast days, her eyes are suffering.

56:19     [Dr. Luo] Okay, yeah I hear you. Okay. Think that's a great question. So Imbruvica is ibrutinib, I think. Right? Imbruvica is ibrutinib which is a systemic GvHD treatment. I am not aware of that treating ocular GvHD. I've heard a lot of good things about it, systemic GvHD, but I don't have direct evidence whether it works on the eyes or not. I have not seen that personally. So if you are having eye issues, you need an evaluation really because your symptoms sound it could be a complex problem. For example, I'm just going to grab one of my patients as an example with what your complaint is.

So this particular patient got severe ocular GvHD with all those 10,000 little green dots on the surface everywhere. That alone causes blurry vision. That alone causes light sensitivity. That causes trouble driving. And that patient also has cataracts and the cataracts actually rapidly progressing and the specific type of cataract that can be induced by steroids sometimes it hits you overnight and in weeks, definitely. It can just catch on quickly, so that particular patient there are two different things going on. Both causing difficult driving, poor vision, discomfort.

Cataracts themselves don't cause discomfort but it certainly can mess up your vision. Surface damage is like those thousand potholes, they can cause severe discomfort as well as causing a symptom of poor vision. Usually that is fluctuating. If it's ocular surface caused, you might have good moments. In a blink I see pretty well but then it's gone in the next blink. So that's more likely ocular surface. If it's a continuous haze and it's getting worse and worse, darker and hazy vision, you could even have components of cataracts in there. So you really need someone to have a full evaluation of your eyes to give you a dissection of the problem. Okay, does that answer your question?

58:42   [Moderator] I think it does. Thank you so much. We're going to have to wrap up for now, but on behalf of BMT InfoNet and all of our partners, I would really like to thank Dr. Luo for your very helpful remarks and wonderful presentation.