Tackling dry eye disease: a clinical approach to treatment

Mark Dlugoss:

Dry eye disease is highly prevalent in the United States. It’s estimated that dry eye effects more than 22 million Americans and the number of new patients are expected to increase as the population ages. Hello, this is Mark Dlugoss, senior contributing editor of Ophthalmology 360. In recognition of July being National Dry Eye Awareness Month, Ophthalmology 360 wants to outline some clinical points associated with this growing medical problem. Joining me to offer his expertise in a subject of dry eye is Darryl White, MD, founder of Sky Vision Center is located in Westlake, Ohio, in suburban Cleveland. Welcome Dr. White and thank you for providing some time with us.

Darrell White, MD:

Hey Mark, thanks so much for inviting me. This is certainly a topic that’s near and dear to my heart. It’s something I’ve been doing a ton with for the last, oh gosh, 20 plus years, and how cool that we get our own month, that we get to talk about something which is so important, so critical to so many lives in the United States, and frankly to so many eye doctors.

Mark Dlugoss:

Okay, let’s start. The year 2023 could have been an exciting year for dry eye clinicians as new medications have already have received FDA approval, and there are some newer therapies on the horizon. But let’s start our discussion with a review of the current landscape and dry eye medications and let’s begin with the early medications.

Darrell White, MD:

Sure. The official start of pharmaceutical interventions for dry eye would have to be the approval of Restasis in 2003. Restasis is Cyclosporine 0.05% in a lipid moiety. It’s actually the Endura artificial tear made by Allergan, but you can actually go back a little bit further. In the late 1990s, both Bausch & Lomb and Alcon had steroids that had enormously helpful labeling from the FDA, and those medications really could have launched the pharmaceutical revolution, Flarex from Alcon and Lotemax from Bausch & Lomb. And for lots of complex reasons, neither company really added those medications officially to our armamentarium. And so the earliest kind of the Mac daddy, if you will, of dry eye medications would be Restasis. It’s been around for an awfully long time. It took a while for us to figure out how best to use it. It took us a while to realize that it wasn’t just for severe dry eye, which was where it was studied in the FDA trials.

And then it wasn’t just to increase a patient Schirmer test and it wasn’t the kind of medicine that was like a Tylenol. You have a headache, you take a Tylenol, you feel better, and whoever told you to take the Tylenol is a genius. Restasis was a medicine that took some patients, but if you applied your patients both on the patient’s side and the doctor’s side, gosh, it made an enormous difference and was revolutionary. It was a slow cooking revolution. We had to figure out how best to use it, but everything really started with Allergan making the big push to get Restasis into our hands.

Mark Dlugoss:

Over the last few years, several new medications have been added to the dry eye toolbox, so to speak. Can you outline some of these recent medications and what have they brought to the table compared to past medications?

Darrell White, MD:

Sure. I think the two biggest medications that have come onto the market in terms of access to dryness medications is one more cyclosporine, Cequa from Sun Pharmaceuticals, which is Cyclosporine 0.09% in a totally different vehicle. It’s a vehicle where the cyclosporine is encapsulated in micelles that allow the hydrophobic cyclosporine to penetrate the hydrophilic ocular surface. And Xiidra lifitegrast, that’s another immunomodulator and works on a similar, has a similar effect on white blood cells. And those were the big ones because those are ones that we can use on an ongoing basis. And those are medications that, again, if you have patients really, really are super effective in the hands of doctors who were taking care of dry eye. There’ve also been some new steroids which have come on the market, so whereas back in the ’90s, both Alcon and Bausch & Lomb really didn’t go for it when it came to dry eye.

We do have some steroids which are on the market now, which are really geared toward dryness. Eysuvis is the one that is really specifically designed to be used in dry eye, originally brought to the market by Kala and was recently purchased by Alcon. Eysuvis is a formulation of Loteprednol that was shown to be highly effective in treating flareups of dry eye and also incredibly safe. There was minimal elevation and intraocular pressure over the course of the FDA trials with vis, and it was dramatically successful at reducing the flares.

Dry eye can be characterized as a chronic disease, which can be controlled and you can largely have asymptomatic patients with long periods of time, but those periods of no symptoms are interspersed with flareups where for whatever reason, people will have everything that goes along with their dry eye. One of the things that Kala did beautifully and that Alcon has really picked up the ball and run with very nicely is to raise our awareness as ophthalmologists that these flareups are not super uncommon and they don’t mean that your base treatment is no longer effective. You can treat them in a pulse fashion with medications like Eysuvis. So I think Eysuvis was also a really, really nice addition to our armamentarium.

Mark Dlugoss:

In the last couple months Bausch & Lomb received approval from Miebo and also Novaliq received for Vevye. They’re both received FDA approval. How do these two medications add to the options now available and how different are they?

Darrell White, MD:

Well, the Novaliq cyclosporine Vevye I think it’s a super interesting version of cyclosporine. The data was very impressive. We now have a pretty crowded landscape when it comes to cyclosporine medications. This medication is 0.1%, so it is the strongest cyclosporine that’s on the marketplace with an FDA approval to treat the signs and symptoms of dry eye. It’s another option for us. No one really has very much experience with it, and so we don’t know if it stands apart from the other cyclosporine medications. It’s great to have more options. We also have to remember that in the marketplace now as I’m speaking to you, there are four generic versions of Cyclosporine. There are all generic versions of Cyclosporine, 0.05%. By and large, they’ve been pretty well accepted and pretty well utilized in the marketplace. It’ll be super interesting to see what happens when Vevye is out there and we have an opportunity to have it go head to head against the other cyclosporins.

Miebo the other hand is potentially a transformative medication, a revolution in the dry eye space. This is the first medication that we have to treat evaporative dry eye. It’s the first medication that we have to treat the dry eye that comes from meibomian gland disease, posterior blepharitis. Miebo directly treats the signs and symptoms of evaporative dry eye. This is killer. We’ve been, all of us have been waiting for something like this for two decades. I think that Miebo is certainly the most exciting thing that’s come on the market in at least 8, 9, 10 years, and I think it’s going to take the dry eye space by storm.

Mark Dlugoss:

Really it was [inaudible 00:09:33] I guess. And in the coming months, several medications are expected to receive FDA approval. What new medications do you see on the horizons and what outcomes can clinicians expect from these therapies?

Darrell White, MD:

There are a couple of medications which I think are really interesting that are coming up. I think TP-03 from Tarsus is going to be super helpful. One of the big underlying causes of meibomian gland disease is demodex infestation and TP-03, if it’s approved, I think the PDUFA date is July something. So if it’s approved, we will again have something that we haven’t had before. We’re going to have a direct effective treatment from one of the underlying causes of meibomian gland disease. And then Reproxalap from Aldeyra is a medication which kind of sits atop all of the inflammatory cascades as a dry eye medication and potentially as an anti-allergy medication. It has lots of promise. It’s really hard to know how Reproxalap will fit in to all of our basic protocols. Will it be used as a rescue drug?

Will it be used before we use some of the anti-inflammatory drugs? Nobody really knows. I can’t really see the brand new medications in the areas that we know have inflammation as the basic pathophysiology are going to change the environment. I think that we’re still going to see battles in the cyclosporine arena where the lipid emulsion based medications are going to be competing against the micelline capsulation strategy to get the medication to the ocular surface. There’s some really impressive data for Cequa in that part of our world that shows that that micelline encapsulation increases the penetration of the cyclosporine into the Oculus surface tissues two and a half or three times greater than the lipid emulsions. I think that that’s very impressive, and I think that Cequa with the micelle encapsulation, but also the other cyclosporines are going to continue to be the backbone of what we’re doing and everything else is really going to evolve over time. It’s super exciting though. We’ve gone so long without something which was different and it’s a super exciting time to be a dry eye doctor.

Mark Dlugoss:

I think the landscape now is growing to such a point now that we actually, doctors have something to work with before, which they didn’t have 20 years ago.

Darrell White, MD:

Oh, for sure. There’s no question about it. When I first started doing this in the late 1990s, my now retired associates, Scott Schlegel, who’s an optometrist, would work with me. And Scott, if you’re watching this, I’m still angry that you retired. I’m not sure I’m ever going to forgive you for that. But Scott and I really did a huge deep dive into dry eye in the late 1990s. We were doing great LASIK, just technically superb LASIK, and in a small subset of our patients, we were just getting mediocre results. And it turned out that it was from dry eye disease. And when we first started talking about this, Scott and the optometric community, myself and the ophthalmic community, people kind of nodded their head at us and “Yeah, whatever.” I used to call us the red-haired stepchildren of eyecare, we were sitting in the corner saying, “No, no, no, this is real.”

And Mark Milner was doing the same thing in his neck of the world. And it wasn’t until some of the real giants of ophthalmology kind of started to pay attention to this. The Dick Lindstrom, the Eric Donnenfeld, some of the really the Old War horses, Hank Perry, Ken Kenyon, people like this, Marguerite McDonald. Marguerite McDonald was totally instrumental in backing people like Mark and myself in telling folks that this was the real deal. And I totally agree with you, Mark. The fact that we’ve had these medications over the years, we’ve learned how to use them, and all of a sudden we’re sitting here and we’re getting an avalanche of new treatment modalities, all of which are incredibly impressive. To add to that wave that we just got. A new steroid directly on label for the treatment of dry eye, a new way to deliver cyclosporine that we got recently to treat dry eye and now these other modalities, the science is epic.

And as you stated, when you introduce the segment, I think the numbers of people with diagnosable dry eye are really incredibly high. I don’t think it’s 22 million, I think it’s more like 52 million. And if you look at the number of people who are now getting diagnosed, I think it’s up in the 50 or 60 million mark, and there are still only somewhere between 1.2 and 1.5 million people who were being actively treated for dry eye. I think that number’s going to go up because not only do we have these new medicines coming on board, but we also have medicines that we’re really, really familiar with now, and we’re just getting better at using them.

Mark Dlugoss:

In recent years, several studies have explored the side effects of dry eye medications. They found that they lead to noncompliance at sometimes, and even a large number of patients discontinue their medications because of the side effects. You authored a study in which one of the talking points of that paper was drop off rates among dry eye patients. Can you elaborate more about what you’ve discovered in that study?

Darrell White, MD:

Sure, sure. That was a cool paper. We may have done the first machine learning paper in all of eyecare, we collaborated with the IBM Watson team and applied their technology to billing records looking at the number of prescriptions that were made, the number of prescriptions that were refilled, and it was really astonishing. We compared specifically Restasis, the established cyclosporine at the time in Xiidra, the new kid on the block, and what we found was that the drop off rate for Restasis was quite high. 90% of people stopped using Restasis, I think it was 4.5 months after the initial prescription. Although Xiidra was better, nine months to have that kind of drop off. I think it was 78%, and I don’t have those numbers off the top of my head, but they were in those ranges. It’s still nine months that you don’t have people continuing on.

We didn’t get a chance to interview the patients, but from my experience in the clinic, Paul Karpecki was one of the co-authors. From Paul’s experience in the clinic, what we’ve learned is that the medications have some side effects that are troublesome. They can sting, they can burn, they can cause blurry vision, but the bigger deal thing is they don’t work right away. And as I said right at the outset of our program, if you have patients with these medications, people will stay on it. This was a huge population of prescribers, not all of whom were experienced dry eye prescribers. The medications can be hard to use because they do have some side effects. Medications are expensive. Remember that this was an insurance claims based protocol, and again, we all know that these medications can be expensive, that they can come with challenges for third party compensation to cover them.

I think that subsequent to that study my bet is that the numbers would be much, much better for a couple of reasons. Number one, we’re all getting better at it. We’re just frankly getting better at talking to our patients and explaining to them why it is that they’re having the side effects and why it is that it’s taking a while for them to get the relief that we expect they will get. And then on the other side, we’re all frankly getting much better at understanding how the insurance companies are paying for these, and we’re getting much better at playing by their rules, staying strictly within the rules of the game.

But I think if you talk to dry eye practices, ophthalmologists who concentrate on dry eye as one of their specialties, they’ll say that their patients have gotten better because we’ve gotten better at helping the patients be able to afford their medications. I would love to do a follow up, right? Gosh, there were about a dozen studies that I wanted to do with the IBM Watson folks. They’ve changed their emphasis, which is a bummer because I thought it was killer cool stuff, and it was fun for Paul Karpecki, for me to be the docs who were the ones who did those, probably the first quasi AI machine learning stuff and ophthalmology. That was cool stuff.

Mark Dlugoss:

Yeah. Several years ago, the Dry Eye Assessment Management study explored the association of dry eye with visual acuity and contrast sensitivity. And as you know, dry eye not only affects visual function, but it also affects patient’s quality of life. What more can we learn about the effects of dry eye on a visual acuity and the patient’s quality of life?

Darrell White, MD:

Boy, there was a study a long time ago that showed that people with dry eye had the same degree of life effects as people with chronic angina. It was mind-blowing, especially given the fact that during the time when this study was published, there were an awful lot of really, really influential ophthalmologists and physicians outside of eyecare who were poo-pooing dry eye as just a lifestyle disease. Yeah, it’s not a lifestyle disease unless you’re talking about how it’s crushing people’s lifestyles.

I think that’s now a given, the fact that people who have moderate and severe dry eye have really terrible, terrible consequences from their dry eye. If you listen to patients carefully, what you hear is that almost all of them actually have visual symptoms. They have fluctuation in vision. Their vision gets worse as the day goes on. We live in a society where if you don’t look at a computer, you’re unemployable. You and I are chatting through a computer, and that makes people’s dryness worse, and it makes it harder for them to use their computers. So the impact on patients’ lives is only getting greater as we have more and more people who have dry eye.

Mark Dlugoss:

Another issue associated with dry eye disease is effect on refractive and cataract surgery. Recent clinical literature has emphasized the importance of addressing dry eyes disease before and after surgery. What more surgeons and clinicians learn from optimizing the ocular surface to achieve better outcomes in these surgeries?

Darrell White, MD:

Again, I’ve been a shameless name-dropper during this whole interview and I’ll keep doing it. Eric Donnenfeld is famous for saying that if you diagnose dry eye preoperatively, it’s the patient’s problem. If you diagnose the patient postoperatively, it’s your problem. One of the things that I’m known for is, and I love the name, it’s White’s rule of dry eye. You can’t make an asymptomatic patient feel better. It’s challenging if you diagnose dry eye preoperatively, but the patient doesn’t have any symptoms. We’ve all had the situation where a patient comes into the office, they’re corneas as dry as a potato chip, and you ask them, “How’s your eye feel?” And their answer is, “I feel fine. Why do you ask?” It can be a challenge, but what we’re learning, and I think what we’ve learned over the last certainly five years is that if you don’t take care of the ocular surface, it’s going to be uncomfortable postoperatively.

Every anterior segment surgery makes the ocular surface more dry. It doesn’t always make it symptomatically dry, but we can show through tear osmolarity, through Schirmer testing, through topography, that the eye does indeed get drier. If you do cataract surgery, if you do LASIK surgery, SMILE, PRK, it gets drier. It doesn’t matter what you do. If you operate in the front of the eye, the eye’s going to get drier sometimes. What you’re trying to do is keep that asymptomatic dry eye situation from becoming symptomatic postoperatively.

We’ve all become better at that. Chris Star headed up a working group with ascaris, and they got all the information together from those people who’ve been treating dry eye, and they’ve basically said that this is something that needs to be part of the workup for anterior segment surgeries. This should be part of the workup for cataract surgery. Even if you’re doing cataract surgery with a basic or standard intraocular lens, this should be part of the workup. If you’re doing laser refractive surgery, doesn’t matter what type of laser refractive surgery you’re doing LASIK, doing PRK, doing SMILE, any of those, this should be part of the workup because it’s going to have a measurable effect on your outcome. It’s going to have a measurable effect on how well the patient does.

Is there more for us to learn? I think the lesson is really just to try hard. Every year we get better medicines as we’ve talked about. Every year we get more and better treatments, and there are newer diagnostic modalities, but you don’t need the fancy stuff. And the fanciest thing that we do for dry eye testing preoperatively is we do topography. Okay. Any cataract surgeon who’s doing advanced cataract surgery has a topographer, any laser refractive surgery surgeon has a topographer. The one thing that maybe we have that other folks don’t have is we do tear osmolarity on every single pre-op patient.

If we know they have a dry eye, we can bill for it. So it’s not like we’re being totally altruistic about this, but in defense of the ocular surface on our behalf as surgeons, but also on the patient’s behalf, we do it regularly just to make sure we don’t miss dry eye. So I think the lessons are, it’s important to work hard and try hard and do everything you can to find it preoperatively. And then the secondary lesson, I think that the ASCRS report, I call it the star chamber. The star chamber was quite clear. You don’t need fancy stuff. You just need to look, and if you find it, you need to treat it and you need to treat it seriously like the disease that it is

Mark Dlugoss:

With dry eye affecting more and more Americans, and there’s still quite a bit to learn about this disease and ways to treat our patients. From our discussion today, Dr. White, what is the take home message for dry eye clinicians in regard to both medications and the discussing points we outline Today?

Darrell White, MD:

I’m going to go back to my days as one of the red-haired stepchildren and say that the learning point has never changed. Dry eye is a real life, honest to goodness disease. It has immeasurable impacts on our patients. It impacts their ability to do their job. It impacts their ability to enjoy their lives. In response to that, some really, really smart, basic science researchers have been working for decades to bring us technologies both on the pharmaceutical side and the device side to make people feel better. It’s important to take it seriously as the serious disease that it is. Everybody can diagnose it. If you don’t care to treat it fine, send your patient to somebody like me or Laura Perman or Rolando Toyos or Ken Beckman or Alice Epitropoulos or Mark Milner, somebody who is really interested in treating them because there are more and more of us out there.

Everything that we have today, all of the developments that we have today are built on the foundation of those pioneers. Those folks who really stood up and stood with those of us who were kind of young at the time, the Marguerite McDonald’s, the Ken Kenyons, the Hank Perrys who said, yes, we’ve been telling you this for years. We’re all still riding their coattails, but the important message is still the same message. It’s a real disease. It deserves the same kind of effort that we give to every other thing that we treat, because it’s just as important and the patients who have it are no less important than the patient that we’re putting a fancy implant in.

Mark Dlugoss:

Okay. Thank you, Dr. White for spending some time with me today discussing situations involving dry eye and the issues involving not only for the doc clinicians, but for the patients. Appreciate your time.

Darrell White, MD:

Mark, I really enjoyed it. Thanks for having me.