® Viewpoint, “Advancement in the Management of Dry Eye.”

I’m Marguerite McDonald, an ophthalmologist from Manhasset, NY. Joining me in this discussion are my colleagues 

, an ophthalmologist from Garden City, NY; 

, an optometrist from Huntsville, AL; and 

Today we’re going to discuss a number of topics pertaining to dry eye

 including the diagnosis and clinical manifestations, traditional treatment options, and the potential new agents on the horizon. Let’s get started on our first topic.

First, we’ll talk about an overview of dry eye disease. Eric, if you could start, how is dry eye disease defined?

 Dry eye disease has many definitions, but essentially it’s an abnormality of the tear film that affects the quality of the tears, and it’s been associated with hyperosmolarity as well as a change in the consistency of the tears, and it can affect any of the layers of the tear film. It can be the mucin layer, the aqueous layer, or the lipid layer. All 3 components of the tear film are commonly involved in dry eye disease.

How common is it? Do we have any good numbers on this?

 Dry eye disease is extremely common. As a matter of fact, it’s arguably the single most common reason why patients come into an optometrist or an ophthalmologist office. Medicare numbers have proven that. But the studies that have looked at that are studies like the Salisbury Eye Evaluation study, the Melbourne, Australia Study, the Beaver Dam Offspring Study, all show between 14% and 15% incidence of dry eye.

It’s probably underdiagnosed, but it’s been suggested that maybe 1 in 7 people in the United States suffers from dry eye disease. It’s more common in women, but it affects men as well. It’s more common in older patients, but it affects young people as well. It’s associated with several systemic diseases. We know it’s very common in collagen vascular disease, and that includes thyroid disease, lupus, and rheumatoid arthritis. It’s also very common in patients who have diabetes. It’s seen after surgery very commonly. It’s almost ubiquitous.

The problem with dry eye is that it’s an epidemic in the United States, and there are a variety of reasons. Notably, it’s nutritional. We’ve changed our nutritional status: We’re eating less omega-3s and more saturated fats. It’s also associated with screen time. People don’t blink as much because they’re looking at screens. The lack of blinking doesn’t allow the meibum to flow through to the tear film.

I won’t belabor it anymore, but dry eye is a public health concern. It’s extremely common, it affects quality of vision and quality of life, and it’s 1 of the most underserved areas in eyecare professional disease.

Introduction and overview

 Crystal, can you tell us why it’s important to recognize and treat 

 Absolutely. What I have seen in my practice is exactly what Eric just said: The prevalence is growing. Basically, if you’re looking for it, it’s practically every patient, so much that I have ended up doing just dry eye. At that point I recognized how much of an impact the rest of the world and their lifestyle has on dry eye and vice versa. This correlation between depression, anxiety, and sleep quality and dry eye, and then…the diet: inflammatory foods, anti-inflammatory foods.

I saw not only all the things that contribute to the negative outcome but also how much the negative outcome affected patients. I was seeing more severe patients to the point where I had 5 patients say they wanted to commit suicide, which is a big deal. If we’re taking on the full responsibility that we should, we’ve got to realize how big of an impact it has. It affects every aspect of their lives. When they feel it every time they blink, there is no forgetting about it during the day.

Patients who are much earlier in that journey don’t realize how progressive it can be, and that’s also our responsibility to help them understand that you may be able to tolerate it and deal with it the way it is, but this is not the end. If you do nothing, it’s going to get worse and it’s going to look and feel a lot different from how it does now.

 Tracy, what are the consequences of untreated dry eye. In other words, what’s the risk of progression?

 Dry eye starts with the hyperosmolarity, and then you get the damage to the ocular surface, the goblet cells, and the epithelial cells, which increase inflammation, and then you develop tear film instability. Then the reduced tear film break-up time exacerbates the hyperosmolarity, and then you get an increase in physical symptoms with inflammation and patient discomfort. The patient just gets caught in that cycle.

The problem is we’re going to throw in problems like ocular allergy and ocular surface disease. For contact lens wearers, topical drops may contain preservatives. Plus, eye makeup and skin creams—we don’t want wrinkles, so women are using skin creams to reduce the wrinkles. We’re wearing masks that are going to further reduce that tear break-up time. This cycle is not going to get broken unless eyecare practitioners do something to stop it.

We need to address ocular surface disease in middle age, identify a peak increase in dry eye disease in the 40s and 50s. Left untreated, these eyes are going to become inflamed. They are going to become red and itchy, and the patients are going to have trouble with debris in their lashes and conjunctivochalasis causing a foreign-body sensation. They will have more trouble with debris in the lashes. Chronic inflammation can result in trichiasis and madarosis. We can develop things like lid wiper epitheliopathy, causing a foreign-body sensation, entropion, margin thickening, and scarring of the meibomian gland. Corneal diseases might include severe keratopathy with reduced best-corrected visual acuity, neovascularization, ulcers, and corneal melts.

We have been saying this for years, but a lot of dry eye goes untreated, so I thought that I might take a slightly different direction. What if we consider the way dry eye is directly affecting us, the eyecare practitioners? Consider contact lens dropout and increased emergencies in your office because of contact lens complications, or persistent blurry vision affecting spectacle prescriptions resulting in redos, which affect your bottom line.

Patients who might feel their symptoms were ignored are going to go somewhere else. They are going to go to a different office. We have to consider that noncandidacy due to dry eye can reduce the number of patients pursuing laser 

 keratomileusis (LASIK), and we might have increased LASIK enhancement if we are having refractive shift due to dry eye after surgery. Errors in intraocular lens (IOL) measurement can lead to refractive errors after surgery and make your patients unhappy, and we are going to make more patients unhappy if we increase their dry eye disease.

Consequences and epidemiology of untreated dry eye

 What is the diagnostic process for identifying 

 disease? What is your approach to screening for it?

 That’s a great question. A lot of things are involved, and a lot of tests are available. I like to take a pragmatic approach to dry eye, and it starts by listening to patients and hearing what they have to say. Sometimes just listening to their symptoms will give you a lot of information.

It speaks volumes about my personality, but I have a favorite symptom, and my favorite symptom is fluctuating vision. When a patient’s vision fluctuates, it’s almost always because of ocular surface disease. It could be vision changing between blinks. It could be vision on the computer getting blurry after half an hour. It could be that my vision is good in the morning but gets bad in the afternoon. It starts there.

Then the next part is the actual physical exam. It is really important to look at the eyelids. A lot of times eyecare professionals just don’t look at the lids. They go right to the eye and look at the eye itself. They [need to] look at the lid margin for meibomian gland disease. At least 75% of dry eye is due to meibomian gland disease.

Then we can start with the actual tear film diagnostics. The tests I like to do are predicated on patients walking into the office with a questionnaire that’s done. The questionnaire is administered by my staff to every patient who comes into the practice, and that questionnaire asks very specific questions about dry eye disease. If they answer positively, then it empowers my technicians to do the appropriate testing. I like to do osmolarity, sometimes we do matrix metallopeptidase (MMP) 9. I like topography as well because it gives me a lot of information about the quality of the tear film.

Then the patient comes to see me. My partner Hank Perry made me a convert—I like lissamine green staining. It’s very helpful to look at conjunctival staining. I like tear break-up time. I don’t really look at osmolarity as much anymore unless I am thinking someone has rheumatoid-related dry eye disease and their Schirmer’s test is 0 or 1. I want to know about that. But for routine patients, I don’t really do it any longer.

Then I basically put it all together and speak to the patient about what I’m finding. New tests like meibography play a significant role. But if I had to say to my staff what we should be doing, it is very simply to look at the lids and listen to the patient. Lissamine green staining and tear break-up time is really very helpful.

 Eric, why do you think dry eye is being underdiagnosed? What are the obstacles to its recognition?

 There is a misconception that diagnosing dry eye is an easy diagnosis, but that could not be further from the truth. Diagnosing dry eye requires a trained eye. It requires doing the correct testing. You need to be concerned about dry eye and take it very seriously.

Dry eye is underdiagnosed because a lot of symptoms will correlate with dry eye, that are common with other diseases—allergies and foreign body sensation can be misdiagnosed as dry eye. Some physical conditions like floppy eyelid syndrome, lid imbrication syndrome, and conjunctivochalasis will often be misdiagnosed as dry eye.

Number 1, you have to look for dry eye. You have to care about the diagnosis of dry eye. Then you have to have a treatment plan to treat dry eye and make this a very strong priority in your practice. This has been brought up by some of the ODs today on our panel, Tracy and Crystal, and that is that the most important lesson that I learned in my fellowship from Peter Laibson, who taught me everything I know about corneal external disease.

People don’t come to an ophthalmologist or an optometrist office for the difficult problems. They come in to be diagnosed with diseases that are common. If you can diagnose a common disease accurately and create a treatment plan that other people haven’t been able to do, that’s how you build a busy practice. For me, dry eye is 1 of the great unmet needs that we have in eyecare professionals, and if you can diagnose the dry eye and treat it effectively, you will be an extremely busy clinician.

 Do you think there is a lack of understanding about the discordance between signs and symptoms? In other words, do you think asymptomatic patients are being overlooked?

 Yes. Dry eye is underdiagnosed for many reasons, and a lot of it has to do with the fact that dry eye can be subclinical. If you don’t diagnose it in the early stage, it is going to progress most commonly to a more significant stage. As a surgeon, I take dry eye very seriously.

Diagnosis and overlooking asymptomatic patients with DED

 Crystal, what dry eye testing and assessments should be included as standard? What is your standard approach?

 I would answer those as 2 different questions: What should be included as standard, and then what’s my standard. I have to say, I agree with everything Eric just said, especially the part about the masqueraders and setting expectations. It is important that we walk in the door—for me personally, I say, “OK, today is about finding out underlying contributors.” Is there enough water and oil? Are there allergy, inflammation, bacteria, lid dysfunction, systemic environmental issues? We are going to test and whatever is positive, we are going to tailor a treatment targeted for that issue.

First, deciphering the difference between these masqueraders or these contributors. It is the bare essential, that you walk into the exam room and look at that patient—not behind the slit lamp but across the room. Are they sickly? Do they have thick, droopy, discolored lids as if there’s a big allergic problem? How is their gait? Do they have rosacea on the face? Are there significant lid issues that you can already tell? I pull out my penlight and look for that lagophthalmos. I’m watching for partial blinks as I do my slit lamp exam.

In my slit lamp exam, just as Eric said, I start at the lids. Many times, we talk about rushing and getting to the back of the eye. But we are going to miss so much even if we just jump to the cornea. We have to look at the adnexa and then look at those lids, the lashes, the follicles, the lid margin—if it is scalloped or thickened, if there is telangiectasia or there is scurf—and then go to the tear film. How much debris is in that tear film? Is there allergic mucous? Then there is conjunctivochalasis and lissamine green staining on the lid margin. Then get to the cornea.

This doesn’t take long, but that’s the bare minimum in the diagnostic process. The problem is, that’s not good enough to explain it to the patient. You might know exactly what you need to know and what you need to pair it with for treatment, but you don’t have the buy-in from the patient because you haven’t given them an adequate cause. That’s where you have to have the photos. You need to have some way of showing them what you see. I believe that is the bare minimum.

What I add to it is things like meibography, of course, and also more aggressive tear film analysis tools like tear meniscus height. I’ll do that on every patient—every time, honestly—and I look at the tear film dynamic so I can videotape what is going on in the tear film and how much contamination is there. I do interferometry for every patient, every time, so we can get a glimpse of how much oil is getting to the tear film, and I do a redness score on every patient. In my mind, it’s giving me a glimpse of water and oil, and that’s my bare minimum to which I hold myself accountable, to show that patient every time.

 You’re absolutely correct: A picture is worth a thousand words with these patients.

Standard testing and assessment for DED

 Tracy, outline for us the general principles of treatment, and do you do a stepwise, ladder-type approach based on severity?

 I look at the clinical signs, but I take a little bit more into account the patient’s symptoms, because when I choose my treatment, a lot of times I’m trying to address what their primary symptom is. But having said that, whenever people ask me about how I decide what to do, I basically refer to the 2 algorithms, the DEWS II and the CEDARS treatment. The DEWS II looks at the subtyping and then the disease severity. You figure out which type of dry eye disease the patient might suffer more from, and you look at the severity, and then you determine what to start with.

Mild eye disease is going to start with patient education, supplemental omega-3 fatty acids, maybe over-the-counter lubricants, lid treatments like a hot compress or a mask at home. Moderate is going to step it up to a prescription topical immunomodulator, maybe targeted lid treatments like hypochlorous acid or tea tree oil; in-office treatments like the LipiFlow, the BlephEx, or the intense pulsed light; punctal occlusion once you have resolved the inflammation; and then prescription medications like the doxycycline. I’m also a pretty frequent doxycycline user because it’s a little bit less expensive. But I do love topical azithromycin. I have found that to be invaluable when you combine topical azithromycin with compresses. The patient does the hot compress, and then follows it immediately with the topical azithromycin rubbed into the eye lids. I actually had one of my favorite Medicare patients who was flat broke, and he figured that out for me, and I’ve been using it ever since. I always share that with my patients, that one of my favorite patients with dry eye figured this out for me.

The more severe disease, we might look at autologous serum, oral secretagogues like cevimeline, especially if the patients are talking about having a dry eye in addition to having dry eyes, and use of contact lenses like scleral lens. I don’t actually do scleral fitting, and I don’t have a LipiFlow, but I live in kind of a small town, it has a small-town feel. So I have a doctor who has LipiFlow, and I have several doctors who do my scleral lens fittings for me, and we share patients all the time. That’s worked out really well because I don’t have a strictly dry eye practice. I do a ton of glaucoma and I have a lot of general ophthalmology, general optometry care. I don’t do glasses or contact lenses. I don’t have the capital, so I love sharing with my area colleagues. I have found that to be beneficial for the patients as well as myself because we get to talk. So even during COVID-19 [coronavirus disease 2019], I’m still talking, which is important.

 That is so wonderful that you have that relationship with your colleagues. That’s terrific.

General Principles of Treatment of DED

 Eric, it’s back to you. What do MDs [physicians] want from referring optometrists?

 That’s a great question, and I want to preface those remarks, Marguerite, by saying that if there’s one area where optometry and ophthalmology can work well together, it’s probably dry eye disease. I want to congratulate 

® for bringing this webinar together and bringing 2 excellent optometrists to join you, Marguerite, and myself here today. It’s really a pleasure listening to their expertise and to learn from them as well.

To answer your question, I think that this is a place where we can really work together to benefit the patient. If you’re treating dry eye in your office, it’s very good to work with ODs [optometrists] in your office to manage dry eye. If you’re not managing dry eye in your office, and there are a lot of ophthalmologists who just don’t have an interest in managing dry eye, I think it is a tremendous service to bring in a dedicated OD whose desire is to manage dry eye, because by not treating dry eye, you’re really not serving your patient population well. There are many practices like Marguerite’s and mine where we work with optometry, and there are many practices where the ophthalmologist will say, “I don’t have any interest in managing dry eye, but I want to refer to someone in the practice and capture those patients and treat them.” It’s great for patient care, it’s also good for the bottom line of the practice as well.

When I comanage patients in my practice, what I’m looking for in my referring optometrist is, did they do a thorough dry eye screening before the patient comes to see me for, commonly, LASIK or for cataract or for corneal surgery? There’s nothing more frustrating to a patient or to the doctor for that matter, than seeing a patient who comes in, and I find that they have significant dry eye that requires intervention and therapy that’s going to require a second visit back to me before I can do the appropriate testing for cataract or for refractive surgery. What I want from my screening referring ODs is for them to do a thorough dry eye exam. I want them to do staining of the cornea and conjunctiva, I want them to look at the tear film break-up time, and I want them to treat. I want them to treat aggressively, I want them to optimize the ocular surface. And there are a variety of therapies that I call rapid rehabilitation therapies that can bring patients back to a pristine ocular surface in a matter of days to weeks rather than weeks to months. I’m looking for the ODs that I work with to incorporate these ideas into their practice, to manage dry eye before they refer them to me, so that we can work together to give the patient the optimal experience and the best visual rehabilitation.

 Eric, among nonsurgical patients, what are the findings that should trigger referral from an OD to an MD?

 Well, I think that ODs who are dedicated to dry eye, like my colleagues here tonight, can manage most dry eye disease fairly effectively. I think the time that a referral might be indicated is when you have actual ulceration or breakdown of the ocular surface, when you have a loss of visual acuity, when you start seeing neovascularization coming into the visual axis due to chronic ocular surface disease, where it’s good to get a second opinion and to think of other therapies that might be needed. Patients who have had previous corneal transplants have greater risk of dry eye disease, and there are many syndromes that are associated with dry eye disease, that I think it’s good for optometry and ophthalmology to work together. But for the great variety of mild to moderate dry eye, I think this is something that optometry does a great job of managing better, and in some ways, they manage them better than ophthalmology does.

 Thank you, Eric. Crystal, what do ODs want from MDs?

 I personally want open communication and support, and I want validation to the patient. I have to give a shout out, I’m so thankful for the ophthalmologists we have in our town. Five of my biggest referral sources are ophthalmologists, and it’s just what you said, Eric, they can do it. But I’ve got more equipment, and they don’t want to do it. There are other things they want to spend their time on. But I’m so proud of them and appreciative because they realize that someone has to do more, and the reality is I’m not that patient’s primary OD. Someone else is. Yet they’re still sending to me, and it’s mainly out of the trust that I’m not going to take advantage of that. I’m not going to try to steal that patient from the original OD who sent them to the ophthalmologist. We have such a great system of open communication. I’m going to do my thing, I’m going to treat the dry eye, do it aggressively, and I’m going to make sure they’re going back to that original optometrist. I do that out of respect for the optometrist, but also the ophthalmologist who sent them to me, because if I didn’t do that, that would ruin everything. I’m very adamant about that.

I think one thing I really appreciate is when it comes to cataract surgery, they recognize, alright, they need more dry eye treatment, and then it’s a little bit hands off, “just send them back to me when they’re ready.” Or if there’s a need to cancel a cataract surgery because the cornea is not ready, there are no questions asked, there are no issues. It’s a complete trust of each other of saying, “OK, we’ve got the patient’s best interest at heart, and we’re going to do whatever it takes to get them there as quickly as possible, but with the best outcome as possible.”

OD and MD communication for optimal care

 Tracy, a little change of subject here. Do you make specific recommendations to your patients on artificial tears, preservative-free, lipid-based?

 I do. I will take a look at what their lids look like, what the cornea looks like, what the tear film is doing, look at topography, take a look at the Inflammatory. But I think it’s important, first of all, sometimes you have to start with the artificial tears because if a patient comes to you, and it always amazes me when this happens, but they come to you with this long list of complaints, and I say,“OK, what are you doing?” and they respond, “Nothing." In that situation, because you have to do the prior authorization for so many of these medications now, you have to do a trial of artificial tears. In those instances, I will tell them, “I need you to get this tear.” I don’t say go use artificial tears. I say “I want you to use a specific one.” I do that based on the different types of ingredients that a lot of the over-the-counter tears now have.

There are demulcents and then there’s emollients. The demulcents are sort of the older stuff a little bit, and they provide lubrication in the form of a mucoprotective film. They alleviate discomfort, they allow the product to stay along the ocular surface. The most common one is the carboxymethylcellulose, or CMC. Depending on the concentration of the CMC, that determines the viscosity. That lowers the concentration, like maybe 0.2, that can be used during the day. But something that’s approximately 1%, is going to be a little thicker, the patient is going to complain that you making them use that during the day is going to cause blurry vision, it’s going to cause debris or maybe sticky stuff on the eyelids, and they’re going to want to use that at night.

Emollients, because I do tend to lean towards everyone has evaporative tear disorders, I’m kind of a fan of the emollients. I do like those that have the fats or the oils to increase the lipid layer thickness of the tear film. Stabilize the tear film so it stabilizes their vision and reduces evaporation, allows them to read a little bit longer or to use the computer a little bit longer. Those typically use a combination of mineral oil, light mineral oil, or the white petrolatum. I like to supplement the lipid layer if there is a component of lid disease, which I kind of feel like a lot of times there is.

A few quick notes. TheraTears is a hypo-osmolar drop, which if you have someone with really high osmolarity, it may or may not be beneficial, and FreshKote is the opposite, that’s a hyperosmolar drop, which I really like to use that over-the-counter prep if I have EDMD [Emery-Dreifuss muscular dystrophy] or maybe arecurrent corneal erosion. I really like sodium hyaluronate with the CMC. That’s the newest product from Refresh. I really like that to increase lubrication. I find that it acts like a thicker, viscous drop, but it doesn’t blur the vision and it doesn’t leave that sticky stuff all over the patient’s eyelids. I’ve had a lot of success with that.

For those that have moderate to severe keratitis, contact lens wearers, those that might take glaucoma medications, I will use single-use vials to reduce the amount of preservatives, because that’s going to increase the hyperosmolarity and I don’t want to do that.

Typically what I do is I’ll tell a patient I want you to use this drop, and I will either give them a sample or I’ll give them a coupon with a picture of the drop that I want them to use, and I will write the directions on the coupon and I tell them maybe this is cheaper at Kroger than it is as Walmart or whatever. I try to give them as best directions to really be specific and I’ll start with the artificial tear. I do use artificial tears, and then I have them back in a month because then I’m looking to see what progress we made in that month. I want to know did they use the tears 4 times a day, because so many times they don’t, and that tells me how adherent that patient is going to be, which is going to drive my treatment plan. Maybe I’m going to be more likely to do things in the office if I told them to do something 4 times a day and they did it once a week. I want to know how quickly their symptoms resolved, and I want to know how they felt things are going, and I want them to make sure that they know that I’m listening to their complaints. I’ll revisit the main complaint, and then at that 1-month visit, I’ll continue to talk about what we think we need to do for a treatment plan.

Review of artificial tears for DED

 Eric, back to you, we’re going to talk about the role of treatment options for dry eye management. Let’s start with anti-inflammatory agents. When do you prescribe them, and do you have a preference for a particular agent?

 Anti-inflammatory agents are very important in the management of dry eye, and that’s really been the change in therapy that’s really revolutionized dry eye. Twenty years ago, dry eye was the back pain of eye care. Patients complained about it and you really couldn’t do much about it. The revolution occurred almost 20 years ago with the use of Restasis and the idea that cyclosporine could play a significant role in treating dry eye. We’ve now had other immunomodulators that have come forward. We have lifitegrast, which is a very potent immunomodulator, we have different concentrations of cyclosporine coming, and now for the first time we also have FDA-approved corticosteroids for the treatment of dry eye disease. We know that steroids and immunomodulators play a very significant role in dry eye, and they are very effective. They’re very safe if you’re talking about lifitegrast and cyclosporine, and very effective if you’re talking about corticosteroids.

I like to initiate therapy early on. When I talk to patients who come in with dry eye, I tell them you have a disease and you have 2 treatment options. We can treat your symptoms, or we can treat the disease itself. Lubricants treat the symptoms. Immunomodulators treat the disease process. If I was a patient and I was given the option of actually treating the disease, I’d want my disease treated rather than my symptoms. I think immunomodulators play a very significant role and continue to be significantly underutilized. I think there’s a lot of role for combining immunomodulation with a corticosteroid and a cyclosporine or lifitegrast, and I think using both of them together is a very effective way of initiating therapy.

 Terrific. Do you ever initiate the immunomodulatory agent with a short run in of a topical corticosteroid?

 Marguerite, that’s become my go-to therapy. This is done in all of medicine, you start on a steroid and you use the immunomodulation, and we in ophthalmology and optometry are doing exactly the same thing. The steroids work more rapidly, they reduce the secondary adverse effects of burning and irritation and foreign body sensation. I think there’s a synergy working together with them. Then we run in the steroids for maybe a month or so, and then are able to taper off and maintain the patient very commonly on just the nonsteroid immunomodulator.

Now, patients also get flare-ups, and that’s the nature of dry eye. It’s not a stagnant disease. You don’t get dry eye and it doesn’t stay off a plateau the entire year. We have these flares where it goes up and down. I think that the approval of loteprednol 0.25% for dry eye flares is a really significant advance in the management of dry eye, because it allows us to do a short-term therapy to really treat those patients who really have intermittent dry eye, where they become very symptomatic over time. I know for me, when I go out west and I go skiing at 10,000 feet, my dry eye becomes very significant. Most of the day at home, at sea level, it doesn’t really bother me. So to answer your question, I think the use of steroids and immunomodulators like cyclosporine or lifitegrast are really crucial to the management of dry eye.

Corticosteroids and Immunomodulators for the treatment of dry eye

 Eric, what do you think the role is of nutritional supplements for dry eye management?

 Marguerite, you’ve brought up a really controversial topic here, and that is the role of nutrition. There have been studies that have gone both ways, that have shown that it’s effective and that it’s not effective. The classic study that showed that it was ineffective with the DREAM study [NCT02128763], but there were several problems with that study. They used an active comparator, and the patients who got the omega-3s actually benefitted very greatly from it, just not more than the patients who got the oil therapies. I happen to believe in omega-3s. I think omega-3s are extremely helpful. I’ve had significant experience with it, I’ve written papers on the use of omega-3s, and we’ve found it to be extremely helpful. We like to use a high concentration of omega-3s, we like to see the patient get 2 g a day, and it takes about a month to start working. I think that a holistic approach to a chronic disease just to me makes sense. I have become a big believer in the use of omega-3s and it’s a linchpin in the therapy that I use in patients who are coming into my practice with dry eye.

Now, Marguerite, I’m going to turn it on you. What do you think about using omega-3s in patients who have dry eye?

 I’m a huge believer. I put virtually every patient with dry eye on it unless they have a contraindication. If they’re getting chemotherapy and radiation for cancer, of course I get the sign-off from the oncologist, and anybody taking a blood-thinning agent such as Coumadin, Eliquis, Persantine, I usually don’t put them on it unless I clear it with their internist. But everybody else gets put on omega-3s for sure. There’s so much compelling evidence.

Now, what do you think, Eric, is the role of antibiotics, topical and oral, in the treatment of dry eye?

 Antibiotics do play a significant role. They’re really directed mostly towards meibomian gland disease and lipid-deficiency dry eye. I don’t think there’s been any proof to show that antibiotics play a role in aqueous-deficiency dry eye, so I wouldn’t be using it in Sjögren syndrome, for example. But for a patient who has meibomian gland disease, I think the classic case is the rosacea case. A patient comes in with blocked oil glands and inflammation, we know that there’s a significant anti-collagenolytic effect with the use of the tetracycline family of antibiotics.

I’m a huge believer in using these medications. I used to go very early on with the use of a tetracycline family antibiotic. I don’t use tetracycline because it has side effects and it has a lot of gastrointestinal [GI] adverse effects, but I’ve gone to almost always using oral doxycycline. Doxycycline is generally used at 100 mg twice a day if you’re treating infections. Very low-dose doxycycline is very effective. It’s a sub-antibiotic threshold, it’s an anti-inflammatory threshold, so I use as low as 50 mg a day or you can actually go down to 40 mg a day. There are some concentrations of doxycycline at 40 mg that work very effectively.

For patients who don’t want to have the side effects of an oral antibiotic, pregnant women, women who have problems with yeast infections, people who have GI intolerance, there is a significant role for using a topical antibiotic, and the macrolide family of antibiotics has a significant effect on treating dry eye disease as well. I’ve been a big believer in using topical azithromycin. We apply it to the lid margin, it works very effectively, it has an anti-inflammatory effect just like doxycycline that’s separate from the antibiotic effect, and I like it very much. Erythromycin has a similar effect and that can be used very well also. I think that for meibomian gland disease, I think the use of antibiotics is underutilized and very effective.

The role of nutritional supplements and antibiotics in DED

 Crystal, let’s talk about your preferred methods for treating meibomian gland dysfunction, and let’s start with what do you think of at-home lid hygiene? Does it work?

 It has limitations. Depends on if we’re talking about cleaning or ….., they both have limitations. The lid was made to ….. away from the cornea to protect it. So here we are trying to put a mask on and ….. go through the lid. What I’ve found is, my overall theme when it comes to MGD [meibomian gland dysfunction] is thin it out and keep it moving. It’s a 2-fold treatment. It’s not just about cleaning the lid or the heat therapy. It’s really about, like what Eric has been talking about, nutrition and nutraceuticals, things like that, and anti-inflammatories, on thinning out what we’re making. Then as far as keeping it moving, then we talk about the heat. I believe there’s a big difference in nutraceuticals, I believe there’s a big difference in heat therapy.

As far as my preferred treatments, I’m a big fan of the Eye Eco ….., which has the foam outer ring, so it traps the heat in there and it penetrates better, but the patient needs to commit to 20 minutes. Now, most of my patients are severe, so they will. If they won’t, then I’m going to lead them towards the new lid device, because not only is it going to clean the lid exponentially better than a scrub would, it’s going to also help with the circulation—blood circulation, distribution of fluid, but also help motivate those meibomian glands to move and to work better. They can do that in a minute versus the 20 minutes on a warm compress. I think they’re both very effective and it depends how much intervention I need for the patient and how willing they are to do the at-home treatments.

 Crystal, you mentioned that you think there’s a big difference in nutraceuticals. Can you expand on that? I’d like to hear what you have to think, because I agree with you. What do you think is important about omega-3s?

 Omega-3 specifically, I believe honestly, it’s got to be triglyceride form. We need the alcohol out of there so that we can get better absorption and better tolerability, because if I want them to do more than 2,000 milligrams a day, I need them not to have fish burps and GI [gastrointestinal] issues with it. I need the absorption, but also, I believe there’s a little bit of magic to the 3:1 ratio of EPA [eicosapentaenoic acid] to DHA [docosahexaenoic acid]. I’ve trialed a lot of different formulations and that seems to be a very effective portion. Even in the same brand where it was not a three-to-one, it wasn’t effective among my patients.

Now, in addition ….., I appreciate the benefit of science-based ….. with their omega-6. I think they work very, very well together. So a lot of times I’m looking at the patient going, OK, how much systemic inflammation of disease do they have? How good is their diet? ….. deficient do I think they are in omega-3s, and a lot of ….. pull out the omega-6 as my first defense. But, no matter what I’ve started them on, every single visit, I’m going to ….. do just an ….. expression to see what’s coming out, and they know it. They’re expecting it. It’s kind of like wanting to know what their pressure is or what their osmolarity is. They want to know, alright, what have we got. So that’s going to determine is our dosing right. Am I going to ask you to do more pills a day or to combine 2 different mechanisms of action, or am I going to finally tell you it looks awesome and you can back off now?

How to treat meibomian gland dysfunction

 Tell me a little about the in-office treatments that you offer.

 I offer thermal expression, of course, and LipiFlow is my go-to because I’ve had it since the beginning. There’s been some other treatments come to market, but when you already have LipiFlow, it is, in my mind, a standard of care when it comes to thermal expression, primarily because it’s heating underneath the lid. Now, with that being said, it’s a line in the sand and ….. evacuate those glands, but it’s up to the patient to change what got you here. Not only that, if it’s the only thing you do, it’s not going to be enough, because their only problem is not MGD [Meibomian gland dysfunction]. My workhorse is the IPL [intense pulsed light], primarily because, I call it my stabilizer, but it works on multiple mechanisms of action. It does so much to reduce the inflammation, that as a secondary benefit, I’m getting cleaner meibum and I’m getting better flow in my meibomian glands, but I’ve also got the incredible benefit of reducing the inflammation. I can see it in the tear film, I can see it in the lid, I can see it in the face. But it’s not immediate, by any means. I’ll do a series of 4 about 3 or 4 weeks apart. But then when they come back for that 6-month visit ….. and they come back again, these people, I can’t drag a complaint out of them and they’re doing almost nothing at home. I have not found anything else that can create that kind of stability in my office and into my patients.

 What do you think of things like lid debridement with a spatula, a little hockey stick, or BlephEx, microblepharoexfoliation?

 As a diagnostic measure, I debride with the Karpecki Debrider every single visit, just to see what’s there, so that I know do we need to do something to treat the lid margin, do we need hypochlorous acid on there or some other measure. Now, I’ve had BlephEx in the office for years, and I was using it quite a bit as an in-office treatment. I got discouraged. I’m not downing it, it’s a wonderful asset to ….. But I got discouraged because they would come back looking the same. I believe there is a tremendous difference in the patient’s overall outcome and being able to do it at home on a daily basis versus coming in the office and having me do it. I’m a huge fan of NuLids, because it does that same exfoliation, but on a daily basis. What I’ve found is this. When they come back, not only are their lashes clean, but that lid margin is clean. Where they had the strong line of mark staining and the scurf that I was debriding every time, it’s gone. It’s dry and pristine. But what that also means is that their tear film is now cleaner, which means the eye is not as red and the patient is not as bothered. I see this cascade event happening when they’re able to do it at home on a daily basis.

 Crystal, how do you encounter patient resistance to these out-of-pocket procedures? How do you deal with that?

 I used to like it to death and I felt like I was selling something. The more confidence I gained in my outcomes and my treatments that I offered, I quit doing that. I put all my emphasis on the patient education. I use the Oculus 5M, so I have my collage of pictures up there. It’s nine pictures, I just tell them the story. I tell them their status on the ….. oil ….. inflammation, all these things, and I consider myself a messenger. Once I do that, they’re asking me what we can do. First of all, ….. when it comes to out-of-pocket expenses, but I tell them we’re going to make this decision together. I’m going to tell you the problem, and then I’m going to tell you the good, better, best option, and we’ll make our initial decision based on your best ….. you’re going to be a part of that. When I do that, they know my honest intentions and they know that there’s no pressure to do something that costs out-of-pocket immediately. But I’ve made them aware of it and they know that it’s part of the process, and if what we start at doesn’t work, that’s where we’re headed.

In-office procedures and patient resistance for DED treatments

 Tracy, let’s talk about aqueous dry eye. What are your preferred methods for treating that? Do you ever think an in-office procedure is indicated?

 If I have a patient who I decide has dry eye, subclinical, moderate to severe, I don’t think an in-office treatment isn’t indicated. I’ll talk about all the options that we might have. I tend to give them options at first, and I will discuss things that we might do down the line. I also do the IPL [intense pulsed light]. I get very excited when I talk about IPL, and I will bring that up at the first visit. I’ll say this is something we can consider. But I think if you have a lot of faith in one of the treatments that you’re offering in office, like I do the IPL, I do the microexfoliation. But I like the IPL better, and I’m quite sure that shows on my face when I talk about it. I have a lot of patients who willjust leap, and be like, “I don’t want to do the artificial tears, I don’t want to do that, I want to do IPL first.” It’s like the first thing out of the gate; they get excited because I’m getting excited about what I’m able to offer, because I genuinely enjoy making patients better with that technology, and I love to do it.

But I do a lot of autologous serum, too. That has been something that we set up years and years ago in Huntsville, [Alabama], and I have a whole 3-page brochure and we give it to the patients, and it makes it really easy for my technicians and for the staff. If I have a patient who, where so many things are no longer covered, if cyclosporine is not covered and the loteprednol is not covered, and the only thing that maybe I can get them is going to be topical pred [prednisolone], but it’s going to be $75? No, let’s just do autologous serum 4 times a day, and I’ve had a lot of success with that as well.

A lot of times I will present things that might be covered by insurance, and then if we run into issues with their insurance, I keep going back to, “Well, we can try this, we can try this,” and I try to keep that conversation open. A lot of times, I agree with Crystal, if you try a bunch of things and it doesn’t work, then their acceptance of something that initially they said, “Oh, I can’t do that, there’s no way,” they come right around and they’ll do it.

 In aqueous-deficient dry eye, I’m definitely a fan of punctal plugs. I do use the InflammaDry test in my office. I don’t want that InflammaDry to be positive before I put the plugs in. I want to make sure that there’s no inflammation before I plug them, because otherwise I feel like there’s nowhere for that inflammation to drain, and you’re just going to make it worse, and then they’re going to come back and ask you to pull out their plugs.

 We don’t want to trap nasty tears against the ocular surface. Tracy, how do you deal with patient resistance to these out-of-pocket procedures? Do you have any tips?

 Sometimes, like let’s say I have a patient who’s maybe taking a topical NSAID [nonsteroidal anti-inflammatory drug] and a cyclosporine and maybe using loteprednol. That’s a lot. Sometimes I’m like, “How much are you spending every month on all of this stuff, and you’re still not totally controlled? I don’t feel like you’re totally comfortable with this treatment plan, I think we need to look at something else.” Sometimes we’ll write down how much the stuff is, sometimes I’ll even have them bring in their receipts for the last 3 months, and if you go over those numbers, sometimes what they think isn’t affordable actually is.

 Can I bring up a point? It’s been brought up about IPL; I have a lot of respect for a lot of different therapies that are around, but I have not really found it to be that helpful. I still like heating, and I think the iLUX device, the TearCare device, and the Johnson & Johnson device LipiFlow are all excellent. But the device that’s really been a game changer for me has been microblepharoexfoliation with BlephEx. I think for a variety of reasons, that’s become my go-to, because, No. 1, it works quickly. It makes intuitive sense that the lid margin is covered by biofilm, which coats the lid and prevents the bacteria from being treated, it prevents the oils from escaping, and a blepharoexfoliation opens up those oil glands. Now, that’s the perfect scenario for adding IPL, for adding a heating device as well. But for me, what I like about it also is the price point is reasonable. This is something that every patient can afford, it’s much less expensive than the other things we’ve talked about. What’s also very nice about microblepharoexfoliation is that, again, it partners with everything else. It makes everything else we do better. For me, that’s been the biggest advance that I’ve seen in meibomian gland disease, is use of microblepharoexfoliation. I respect everyone’s opinions here, and I like hearing different points of view from different places. I just want to add my perspective as well.

 I agree with you, Eric. I have to say, if somebody presses me, I’ll offer these things separately, but I don’t present them that way to a new patient. I say it’s BlephEx/iLUX, BlephEx/LipiFlow, BlephEx/TearCare, because 1 plus 1 equals 3, they

Treatments for aqueous dry eye

 Eric, what do you think the biggest challenge is that eye care providers face in identifying dry eye disease? How can we streamline the diagnosis, and what role do your technicians play in identifying the patients with dry eye?

 If I had to say, the greatest challenge for eye care providers for dry eye is apathy. It’s not caring enough about a serious condition and you need to get more invested in it. But to do that, we’ve really taken the responsibility of diagnosing dry eye in many ways out of the hands of the eye doctor and put it in the hands of our staff and technicians, who listen to the patients, and we have them do the testing that is deemed appropriate for these patients. So the patient comes in with all the tests necessary to make a very rapid diagnosis. Streamlining the diagnosis, I think is key, and I’m looking forward to new biomarkers that are coming out in the near future that will make diagnosis of dry eye easier and more reproducible. I think that will allow us to treat more effectively as well.

It’s been brought up by several of my colleagues here tonight, but again, I think the key to diagnosing dry eye is to differentiate between aqueous deficiency and meibomian gland disease, and very commonly patients have both. But you need to treat the appropriate form of dry eye. For 10 years, when all we had was Restasis, it was like all we had was a hammer and everything looked like a nail. You need to treat the appropriate disease. Treating meibomian gland disease when the patient has aqueous-deficiency dry eye isn’t that effective. So you need to diagnose the dry eye effectively, do the proper testing, let your technicians play a role, get the testing done, facilitate the movement of the patients through the office, make it a faster visit, and then spend more time caring for the patient. I think this is the place where optometry and ophthalmology need to work better together. In a busy ophthalmic practice where there may not be the time that’s necessary for counseling patients or for following them as closely as they should, you need to have a colleague who you can hand the patient off to, who will spend the time and effort that’s needed to make these patients happy, and to make sure that they follow up with their disease management.

 Great. Crystal, what do you think are the biggest challenges that eye care professionals face in managing dry eye disease, and how big of a problem do you think is patient adherence and compliance?

 That is one of the biggest challenges we face. I think the other one is cost and continually balancing those two. When it comes to the compliance issue, I preach all the time that everything stems from that. You could have the best treatment in the world, but if you don’t have compliance, you’re not going to get the outcome. The way I managed to get the compliance was through an effective patient communication and patient education piece. It used to be much harder for me to get that compliance, and now I feel like it’s not work because, again, I’m the messenger. I’m using effective patient communication and being able to show them and tell them that story, and that creates the compliance because they understand the why. No. 1, patient education and setting expectations; No. 2, keeping it simple, keeping the plan simple; and No. 3, really encouraging and adapting when they come back. When they come back, show them the things that are better, get excited, because they may not feel it yet. But I need them to know that I can see it, so that they keep holding on to the treatment plan because it’s working. I think those 3 things together have done wonders for patient compliance in my office. I know everybody has their own recipe.

The other thing that I’ve done recently, I wrote a book that was 120 pages. I use the term book loosely, but it is bound, and it’s all about the lifestyle, and here’s how lack of sleep affects your outcomes, here are 31 ways to get better sleep. Here’s how stress affects it, here are 16 ways to reduce stress. Here are supplements to help with that, here are inflammatory foods, all these things. Then it has a section on categories: for an oil problem, the better/best solution. Water, better/best. Inflammation, good/better/best. All the brochures that I would normally run around the office and give, they’re in the back of the book. This has really helped because they see me as a partner with them. They know that my heart is in it and that I’m bringing everything to the table, and I expect the same from them. It’s really about accountability on each side.

Challenges in the management of DED

 Do you use technicians in patient counseling?

 I do. I used to do it myself more, but the better that my technicians and my assistants have gotten, the easier it’s been for me to let go of that and know that they’re going to do an amazing job. The way that I got them to that point was doing it myself but having them continually listen and hear it from me over and over, and I had a lot of tools. I’ve got the Dry Eye Institute, so I’ve got 400 pages worth of resources. In my office, they have written out scripts of what every product does and what to say about it. In the examination room, when I’m face to face, I may be able to explain to a patient why they use this omega-3 instead of something over the counter, but I need them [staff members] to explain it exactly the same way, so that message is carried through over and over. That’s helped my staff get better at it, more confident, more comfortable, which has then made me more comfortable turning it over to them. So I can advise them about what I want them to do, and then leave the room and let them take over.

 Do you find that the cost of medication or maybe formulary issues are affecting your patients’ ability to get the medicines you prescribe?

 Yes, and I commiserate with them, but we work so hard. Here are some tips that I can share with you. No. 1, prior authorizations [PAs], we do them over the phone and we get a much better success rate. No. 2, when I have them fill out my dry eye questionnaire before they ever come for their evaluation, I ask them to write everything, everything, they have ever tried in their 20 years of misery, and then circle it if they’re still using it. I do extensive testing with my Keratograph 5M and other things during the evaluation. We take these little chunks of information, and that’s what we give on the PA. When it talks about what they’ve used in the past, we basically...we write everything they’ve ever tried, here’s all the negative testing, all the data we collected, and it was not adequate... and here’s why this patient needs this. That has helped us tremendously, especially when we do it over the phone.

 I’ll say one more thing. There are also pharmacies you can work with, where if you have a few different drugs on the market and that insurance company wants you to use No. 1 first, but you want No. 3 to be given, you tell the pharmacy what your tier choice is and they can help you do that 30-day trial. They correspond with the patient, communicate with them, “is it working, are you having adverse effects,” and go ahead and change it to my preferred prescription. We’re just now trialing that and so far, it’s working really well.

Counseling and formulary concerns for DED therapies

Overlapping diseases and COVID-19's impact

 We’re going to talk about some of the agents that are in phase 3 clinical trials. There’s quite a lineup of amazing things coming our way. Let’s start with Crystal. Do you want to run through BRM421 and RGN-259?

 Yes, it rolls off the tip if your tongue, doesn’t it? The BRM421, this is a synthetic peptide that’s derived from pigment epithelium factor.

It’s going to aid in corneal repair, but it’s also going to stimulate...production. With the RGN-259, there is a long list of its potential benefits. I don’t want to miss any of them, so I’m reading them to you. It promotes corneal healing by reducing inflammation, promotes cell migration, angiogenesis, and stem cell recruitment, protecting cells from cytotoxicity, reducing apoptosis, accelerating collagen and upregulation production of laminin-5, and reduces scar formation. We’re especially excited about that one.

 Absolutely. Eric, why don’t you tell us about the next 2 in the pipeline?

 Varenicline is a highly selective nicotinic acetylcholine receptor agonist being developed as a preservative-free nasal spray. It basically is sprayed into the nose, and it creates a reflex that produces tear production in a very significant way. It activates the lacrimal glands to produce tears, and it reduces the signs and symptoms of dry eye. The FDA trials are extremely promising for this new drug that activates the trigeminal parasympathetic pathway to stimulate natural tear production.

And then SkQ1 is a cardiolipin peroxidation inhibitor that acts on the mitochondria to reduce oxidative stress and neutralizes mitochondrial reactive oxygen species. This again is going through the FDA pipeline at the present time.

Agents in the pipeline for DED

 Tracy, tell us about 3 more agents in the pipeline.

 The first one I’m going to talk about is tanfanercept. This is a tumor necrosis factor receptor 1 fragment that targets pro-inflammatory cytokines to reduce inflammation. This is a new biomedicine that inhibits the tumor necrosis factor activity, so that’s going to modulate the inflammation in the body and hopefully prevent corneal damage. In September 2019, they finished their phase 2 clinical trial in China, and then they proceeded with the phase 2 and now phase 3. According to the manufacturer, they’re going to be presenting data at the ophthalmology meeting in November.

 I will be presenting that paper, and it’s very exciting. What’s really exciting about this is they found a biomarker in looking at these patients, and if a patient is positive for the biomarker, there’s an exponential increase in activity. For the first time, you have a patient who can be given a biomarker test, and if the biomarker comes back positive, you’re fairly certain that the patient is going to have a positive response to therapy. If the patient is not positive for the biomarker, then you shouldn’t prescribe the medicine. It’s going to be selective therapy based on patients who have the DNA profile to manage this disease.

 The second one I’m going to talk about is reproxalap. That is a new inflammatory mediator that inhibits reactive aldehyde species [RASP]. Reactive aldehyde species, or RASP, are reactive molecules that covalently bind to cellular biomolecules, disrupting their function and activating pro-inflammatory mediators, which increase inflammation. If we bind the free aldehydes, we can diminish the RASP levels, which would then improve ocular inflammation. That’s the mechanism of action. These are also in phase 2 clinical trials, primarily in allergy with allergic conjunctivitis, and they also are saying that they’re going to present data at the coming academy meeting. The typical concentrations initially were 0.25% and 0.5%, but they both had about the same improvement. So now they’re just going to go with the 0.25% in a phase 3 INVIGORATE trial. We’re hoping that they will get results in the first half of 2021 from that phase 3 trial.

Then the last one I’m going to talk about is the one that I’m most excited about. NOVO3 is 100% perfluorohexyloctane, which stabilizes the lipid layer to protect the tear film for extended periods and has the ability to penetrate the meibomian glands. This is the first drug that uses a water-free technology, which is designed to prevent excessive tear evaporation and restore the tear film balance. The reason I’m so excited is this has the potential to penetrate the meibomian glands and dissolve the thickened meibum, which can directly improve meibomian gland function. In the SEECASE-1 trial, they had both subjective and objective improvements in dry eye disease associated with meibomian gland dysfunction, so now they’ve proceeded with the SEECASE-2 trial, and we’re hoping for an NDA [new drug application] submission in 2021. I think one thing that’s interesting about this as well is the carrier, which is called EyeSol, is a water-free technology that is used as a carrier for ophthalmic products. This is a carrier that increases the residual time that that medication is available on the ocular surface, and they’re reporting excellent tolerability and safety. What’s interesting is the drop size is small. It’s 10 μL, which I think would be great for toxicity. I’m a little worried, though, can’t you guys see your patients asking you if the drop got in, if it’s so small?

 Absolutely. This is tremendous that we have 7 compounds in development, and some of them quite near FDA approval, that will attack the problem from some very new directions.

Thank you, Eric, Tracy, and Crystal, and thank you to our viewing audience. We hope you found this Viewpoint program to be rich and informative.

Novel agents in the pipeline for DED

Advancements in dry eye managment

Marguerite McDonald, MD, Eric Donnenfeld, MD, Tracy Swartz, OD, MS, FAAO, and Crystal Brimer, OD, FAAO, discuss a number of topics pertaining to dry eye, including the diagnosis and clinical manifestations, traditional, treatment options, and the potential new agents in the horizon.