Picture this scene: A dusty, leather-faced cowboy hitches his horse to the post on a dirt street, throws open the double doors of the saloon, ambles, bow-legged, to a bar stool, and orders a bourbon, neat. He throws it back quickly, grits his teeth, and rubs his sore, dry eyes with the heels of his palms. He’s been roping young steers all day and the dust they’ve kicked up, combined with hours of squinting from the sun, has left his eyes red and raw.
Now, swap out that cowboy for a modern office worker, the horse for a Toyota, the saloon for a café, the cows for numbers in a spreadsheet, and the dust in the air for smog. The result of these occupational concoctions is the same: a marked increase for the risk of developing dry eye.
The itchiness and irritation that come with dry eye disease (DED) are all too familiar to many, and the prevalence of the condition is spreading like a prairie fire. Roughly 10% of the American population and around 350 million people worldwide suffer from the disease in one form or another, and ophthalmologists are well aware that DED is one of the most common reasons for clinic visits.
Why DED Remains an Unconquered Territory
Amazingly enough, for a problem that’s plagued mankind since the beginning of time, DED represents a frontier yet to be conquered by ophthalmic science. It’s only been in the last few decades that DED was even recognized as a condition in its own right. Indeed, the first definition of it was as recent as 1995, when, we should note, the second “D” stood for “disorder.”
So, why did it take so long to get recognized by the medical community? It’s a valid question, so we asked Dr. Laura Periman to help us better understand it. For reference, she’s a board-certified, cornea-trained ophthalmologist based in Seattle at her own clinic that specifically focuses on dry eye. To say she’s made DED her life’s work would be right on the money.
“We didn’t have the right language to diagnose it and talk about it until not too long ago,” Dr. Periman said. “We didn’t have the right tools to treat it. Scientific growth needed to happen first.”
“There’s a medical awareness layer that needed to come in,” she continued. “There’s an innovation layer that needed to come in. We needed all the wheels on the wagon before we could really get anywhere.”
One of the major problems in treating DED is it’s a multifactorial condition. Diagnosing the actual cause of a person’s DED is often a challenge. That’s why Dr. Periman had to change the structure of her clinic.
“Dry eye is a busy, noisy and messy disease state,” she said. “It’s a big umbrella diagnosis with a bunch of different diagnoses and you can’t solve it in just six minutes. You need more time. The traditional medical care model doesn’t serve the dry eye patient, and it can be an exercise in frustration for both doctor and patient.”
A deeper dive into a proper DED diagnosis often requires a bit of sleuthing on an ophthalmologist’s part. When the cause of the condition could be anything from allergies leading to meibomian gland dysfunction (MGD), to autoimmune disorders like Sjogren’s syndrome — or even environmental, dietary, cosmetic or hygienic factors — ophthalmologists may need to connect the dots between the differing medical specialties.
There’s good news, though. There have recently been significant developments for DED treatment, and more are on the way. The condition is finally getting the medical recognition it deserves — because it’s a true quality of life issue, and not simply a minor inconvenience to be brushed off and ignored.
Dr. Periman noted that in the ophthalmic community, there’s been a significant uptick in DED recognition in just the last four or five years. And the pharmaceutical industry has been making significant strides in treatment options as well — which we’ll discuss just now.
Novel Dry Eye Treatments: The Sheriff’s New Posse
Samuel Colt’s revolver changed the nature of the American “Wild West” because it was the first gun that could fire multiple shots before being reloaded. New treatments for DED effectively give doctors multiple shots to target DED’s numerous causes, which at least gives them a fighting chance.
Demodex blepharitis: Mighty overlooked mites
Demodex folliculorum infestations may well be a seriously overlooked problem. Demodex blepharitis is caused by an infestation of pesky, eight-legged mites. These little varmints just love to make eyelashes their home, which can lead to eyelid inflammation, meibomian gland dysfunction, chalazia and severe dry eye, especially in older patients.
A 2010 study¹ showed that 84% of 60-year-olds and 100% of those older than 70 hosted demodex infestations. As aging is a known predisposing factor for dry eye, there may be something to really chew on here. The mites can cause mechanical damage via collarettes — their waste — and can also carry bacteria that leads to other problems, including rosacea. Almost half (45%) of blepharitis cases are caused by demodex mites, so they’ve got to go.
One such treatment that may soon be available is from Tarsus Pharmaceutical (Irvine, California, USA). The company is currently developing the first treatment specifically for demodex blepharitis, and things look promising. Their eye drop, currently named TP-03, has undergone multiple successful trials and is currently in phase 2b/3. Dr. Periman told us that TP-03 can kill the mites for up to six months after a twice daily, four-week treatment regimen.
Interestingly, TP-03 is a lotilaner .25% solution — and was borrowed from the veterinary world, where it’s used to kill ticks and fleas on dogs. In this case, what’s good for Fido may also be good for Fred.
Another potential treatment for demodex infestations is intense pulsed light (IPL). The in-vitro study2 published by Dr. Periman and her collaborators, Harvey Fishman MD and Ami Shah MD, showed that IPL can lead to “complete destruction of the organism.” In other words, it kills them dead.
TearClear: More than a lick and a promise
Interestingly, the way topical ophthalmic medications are delivered may soon change — and this can have a significant benefit for dry eye patients. Dr. William Trattler brought our attention to a company called TearClear (Boston, Massachusetts, USA) that’s working to produce a special filter that removes preservatives in eye drops.
Benzalkonium chloride (BAK) is a common eye drop preservative. In the past, it was viewed as potentially beneficial — it appeared to help drugs penetrate the ocular surface and allow for better drug delivery.
However, BAK has come under scrutiny, with many arguing against its use — and it’s been strongly implicated to worsen dry eye. A 2017 study3 pointed out that BAK reduces mitochondrial function in corneal epithelial cells, which could be what causes adverse reactions.
TearClear is currently focusing their efforts on glaucoma medication, but dry eye is in their sights as well. Keep an eye on this startup: A functional preservative filter would be a game-changer indeed.
DED treatments: Keep ‘em comin’
Another up-and-coming dry eye treatment is Eysuvis (Kala Pharmaceuticals, Watertown, Massachusetts, USA). It’s a topical corticosteroid that was approved by the FDA as recently as October 2020, and is the first prescription medication specifically indicated as a short-term dry eye treatment. Because it’s tailor-made for dry eye, it’ll likely be one of the most popular choices for ophthalmologists going forward.
Then there are antihistamine treatments for dry eye, which can often be a result of allergies. Rather than take a systemic antihistamine, doctors can recommend Zerviate (Eyevance, Fort Worth, Texas, USA) as a topical antihistamine. It relies on cetirizine, and was approved by the FDA just a few years ago in 2017.
Biologics may have an interesting role to play as well. Lubricin (Lubris Biopoharma, Framingham, Massachusetts, USA) naturally found in the ocular surface, may be a valuable addition to a dry eye regimen. The “lubri-” part of the word is a good clue as to what it does: It prevents friction between the cornea and the conjunctiva during blinking. Studies4 have shown it’s extremely effective at reducing this friction, thus reducing mechanical wear and tear on the ocular surface. It feels good to blink smoothly, doesn’t it?
Reimagining human nerve growth factor drugs has also led to potential success in treating DED. Cenegermin in the form of Oxervate (Dompé, Boston, Massachusetts, USA) was originally developed and approved to treat neurotrophic keratitis, but it has also shown promise as a DED regimen. A recent British study5 showed the drug was safe and effective. It’s very good news for a product that’s already on the market to have multiple uses.
Even Botox has been shown to be useful in the fight against DED, as Dr. Periman pointed out. “You can use Botox right above the lacrimal sac to decrease the tear clearance pump function in order to create tear conservation without punctal plugs,” she said.
The true grit of Azura’s AZR-MD-001
Meibomian gland dysfunction (MGD) is becoming better understood as one of the chief causes of dry eye disease, but there are currently no approved treatments for it. Azura (Tel Aviv, Israel) is looking to treat that, and in early March 2021, they released compellingly positive phase 2 results for their drug, unpoetically named AZR-MD-001. Interestingly, the company brands itself as taking a dermatological approach to ocular surface diseases.
The drug’s goal? To reduce the hyperkeratinization of meibomian glands, which blocks the release of sebum. Essentially, a blocked meibomian gland means there’s not a thick enough meibum protecting the top layer of tears from evaporation and lubricating the eyes.
Azura argues that MGD is significantly underdiagnosed, and they may be right. If the treatment proves to be a big of a hit as the company seems to expect, someone could stand to make significant money. We’ll be keen to keep up for further developments.
Hold your horses! Neurostimulators are on the way
Two interesting treatments rely on neurostimulation to induce tear production — a novel, non-eye drop approach. One is Olympic Ophthalmics’ (Issaquah, Washington, USA) iTear100, a device that relies on external vibrations. It was approved by the FDA specifically for this purpose in May 2020. Dr. Periman participated in the phase 3 FDA trials and was a co-author on the paper6 published late 2020.
The iTear100 is pocket-sized and delivers vibrations to the side of the nose for about 30 seconds — which then stimulates tear production. One study demonstrated a 22mm change in the Schirmer score, and another long-term study showed significant Schirmer score improvements over 30 days. Overall, the iTear100 is a neat, reliable buzzy device that produces a complete tear and improves tear production, corneal staining and meibomian gland secretion scores. Simple solutions can be very refreshing sometimes.
Another neurostimulation treatment is a preservative-free nose spray relying on varenicline, a drug often used to treat nicotine addiction. Oyster Point Pharma (Princeton, New Jersey, USA) submitted a new drug application to the FDA as recently as December 2020, for their spray, dubbed OC-01. The spray stimulates the trigeminal nerve via the nose, which stimulates tear production.
Good ole at-home treatments
It wouldn’t be 2021 if we weren’t discussing at-home treatments, as doing everything at home has been all the (necessary) rage. But patients suffering from DED will likely continue to appreciate these home treatments, even if they can now return to their favorite ophthalmologist.
One notable at-home treatment Dr. Periman is very keen on is called NuLids (NuSight Medical; Rancho Santa Fe, California, USA). It looks like an electric toothbrush and, in fact, has a similar purpose. Its soft tip gently cleans the eyelids while stimulating the meibomian glands.
There’s an additional bonus: The device also helps remove any potential mites in your eyelids by simply sweeping them away. Cool, right?
Giddy-up! Make DED Dead
It’s taken a lot of work to get where we are now with DED treatments, and a lot more are on the way. Any civilian would probably be shocked to learn just how complicated DED can be, and just how many factors are at play.
The eye’s tears are its natural defense mechanism, and not having enough of them is ironically something to cry about.
We’re very pleased to see the progress occuring in the DED world, and the next few years should turn up further significant improvements. Shining the medical world’s flashlight on DED has proven to be enlightening in more ways than many even in the industry would have anticipated not long ago.
So, let’s conquer this frontier of medicine and get DED corralled for good. If it can be done, it should. Just like any good sheriff protecting his town, it’s the doctors’ job to make sure the townspeople are taken care of.
REFERENCES:
1: Liu J, et al. Pathogenic role of Demodex mites in blepharitis. Curr Opin Allergy Clin Immunol. 2010;10(5):505-510.
2. Fishman HA, Periman LM, Shah AA. Real-Time Video Microscopy of In Vitro Demodex Death by Intense Pulsed Light. Photobiomodul Photomed Laser Surg. 2020;38(8):472-476.
3: Datta S, Baudouin C, Brignole-Baudouin F, et al. The Eye Drop Preservative Benzalkonium Chloride Potently Induces Mitochondrial Dysfunction and Preferentially Affects LHON Mutant Cells. Invest Ophthalmol Vis Sci. 2017;58(4):2406-2412.
4: Schmidt TA, Sullivan DA, Truitt ER, et al. Lubricin Functions as an Ocular Surface Boundary Lubricant. Invest Ophthalmol Vis Sci. 2010;51(13):3399.
5: Sacchetti M, Lambiase A, Schmidl D, et al. Effect of recombinant human nerve growth factor eye drops in patients with dry eye: a phase IIa, open label, multiple-dose study. Br J Ophthalmol. 2020;104(1):127-135.
6. Ji MH, Moshfeghi DM, Periman L, et al. Novel Extranasal Tear Stimulation: Pivotal Study Results. Transl Vis Sci Technol. 2020;9(12):23.
