It was not long ago that dry eye therapies were primarily limited to relatively rudimentary treatments such as saline-based rewetting drops, warm compresses made from rice-filled socks, punctal plugs, and baby shampoo for lid hygiene.
However, thanks to an ever-increasing understanding of the nature of dry eye, the therapeutic options available to treat the condition have increased exponentially since these early days.
The evolution of dry eye treatments
Dry eye management is now one of the most rapidly growing areas of eyecare, and due to intense interest from clinicians, researchers, and industry, advancements in dry eye treatment can only be expected to grow further.
Two major milestones in dry eye treatment were the development of Restasis, the first FDA-approved pharmaceutical treatment for dry eye disease in 2003, and the FDA clearance of LipiFlow in 2011, which was the first widely implemented device-based in-office treatment for meibomian gland dsyfunction (MGD) and dry eye.
These therapies moved dry eye from the realm of almost exclusively over-the-counter treatments to a disease with a prescription medication option and a dedicated in-office procedure as well.
These changes kickstarted a dry eye treatment revolution that we are still experiencing today. We now have numerous treatment options at our disposal, including several prescription medications, multiple in-office treatments, and many new therapeutics that are on the horizon.
Anti-inflammatory treatments for dry eye
While Restasis (cyclosporine ophthalmic emulsion 0.05%, Allergan) was the first immunomodulator, we now also have a second generation of immunomodulators with Xiidra (lifitegrast ophthalmic solution 5%, Novartis), and Cequa (cyclosporine ophthalmic solution 0.09%, Sun Pharmaceuticals) as options to manage the chronic inflammatory component of dry eye.
Comparing Restasis, Xiidra, and Cequa as dry eye treatments
Both lifitegrast and cyclosporine reduce inflammation through the inhibition of T-cell activity but differ in their mechanism of action. Cyclosporine is a calcineurin inhibitor that blocks T-cell activation,1 while lifitegrast blocks the binding of LFA-1 and ICAM-1, which is thought to inhibit the adhesion and activation of T-cells on the ocular surface.2,3
What makes Cequa unique amongst the two forms of cyclosporine is its increased concentration and unique vehicle that incorporates NCELL technology that utilizes nanomicelles comprised of a hydrophilic exterior and hydrophobic core, which allows for enhanced penetration of the ocular surface tissue.4-7
Eysuvis to treat dry eye
While Xiidra, Cequa, and Restasis are helpful for long-term inflammation management, we also have a new option for the management of acute dry eye flares with the FDA approval of Eysuvis (loteprednol etabonate ophthalmic suspension 0.25%, Alcon).
Eysuvis is the first FDA-approved steroid for dry eye and is indicated for the short-term management of dry eye flares.8 Eysuvis is also unique in its concentration and vehicle, as it is formulated with AMPPLIFY technology that makes use of nanoparticles that allow the drug to better penetrate the mucin barrier and the ocular surface.9,10
This enhanced penetration and subsequent absorption allow for the use of a lower concentration of loteprednol,11 which enhances the safety profile by reducing the risk of side effects, such as increases in intraocular pressure (IOP) and cataract development, typically associated with topical corticosteroid use.
“This also makes Eysuvis an excellent choice as a ‘rescue’ drop.”
Similar to a rescue inhaler used for asthma attacks, patients can keep Eysuvis on hand to use on those “bad eye days,” when symptoms are especially disruptive. When used in this semi-as-needed manner, it is crucial to educate patients on proper use thoroughly and to reiterate the risks associated with consistent overuse of a topical steroid.
However, when used properly, Eysuvis can be an incredibly beneficial treatment option that helps patients manage even the most difficult days with their dry eye.
Oral doxycycline to treat dry eye
Oral doxycycline is another long-standing treatment option used to manage both meibomian gland dysfunction (MGD) and ocular rosacea, as it retains anti-inflammatory effects even at low doses (i.e., 40 to 50mg or less). However, doxycycline should not be used in people who are pregnant or nursing or children 12 years old or younger.12-15
Oral azithromycin, a macrolide antibiotic, has also been shown to be beneficial in the treatment of MGD due to its anti-inflammatory effects.16 Additionally, topical AzaSite (azithromycin ophthalmic solution 1%, Théa), when used off-label, can also improve MGD when dosed twice daily for 2 days and then once daily for maintenance.17-19
In-office treatments for dry eye
The number of in-office treatment options has also grown tremendously since the development of LipiFlow. The use of warm compresses and manual gland expression have been mainstays since the early days of dry eye treatment.
While the use of at-home heat masks can be beneficial, especially from a comfort standpoint, dedicated thermal pulsation procedures such as LipiFlow (Johnson & Johnson), iLux (Alcon), and TearCare (Sight Sciences) are more efficacious treatment options as these devices can more effectively heat meibum to the 42.5°C required for melting to occur.20-22
How are different thermal pulsation procedures performed?
- LipiFlow is fully automated, where activators are applied to the eyes, and a preset program of warming and mechanical expression is performed over a course of 12 minutes.23
- iLux involves the use of a single handpiece where heat is applied via LED light with manual expression performed directly after heating with the same device head, which allows for individualized treatment that typically takes 8 to 12 minutes.24 The iLux2 (Alcon) was recently released, which adds infrared meibomian gland imaging and HD video capabilities to the device.25
- TearCare can be similarly individualized, as the devices utilize external SmartLids adhesive warming applicators that apply heat for 15 minutes, followed by manual gland expression within 3 minutes using the specialized Clearance Assistant expression tool.26
While a recent study has shown that outcomes with TearCare were superior to LipiFlow,27 each of these treatments is a viable option for the management of meibomian gland dysfunction, as previous studies have demonstrated similar efficacy amongst them.28,29 Additionally, due to the differences in performing these procedures, one may be better suited for an individual practice’s workflow than another.
Factoring in intense pulsed light therapy to treat dry eye
While in-office treatments for dry eye were for years primarily limited to thermal pulsation procedures, this has largely changed due to the advent of intense pulsed light (IPL) therapy. IPL is a particularly powerful treatment option, as it addresses several contributory conditions of dry eye in a single treatment modality.
Treatment with IPL has been shown to improve the following:
- Meibomian gland structure and function30-36
- Decrease ocular surface inflammation37-46
- Destroy proinflammatory telangiectatic vessels, which are commonly associated with ocular rosacea41,47-49
- Reduce bacterial and Demodex populations37,47,50,51
- It may improve blinking mechanics through enhanced collagen synthesis resulting in increased tone and rigidity of eyelids skin, which may improve lid position and lid margin scarring37,52-56
Lumenis’ IPL is the first and only FDA-approved for the management of dry eye due to MGD. OptiLight, with the patented OPT technology, is specifically indicated for this use.35 Additionally, intense pulsed light is a “dropless” treatment option, as it does not require that the patient add another treatment to their daily routine, which can be a major benefit for patients who are often already on rather involved treatment regimens.
All these potential benefits make IPL well-suited for the multifactorial nature of dry eye, and therefore represent a major advancement in the management of the disease.
Treatments for maintaining eyelid hygiene
Eyelid hygiene has also come a long way since the days of baby shampoo, which, while helpful at removing lid and lash debris, can actually have detrimental effects on the tear film.57 The use of hypochlorous acid has become widespread, as it is particularly effective at reducing bacterial populations on the lids and lashes.58 This is because the leukocytes of the immune system use hypochlorous acid as an antiseptic agent.59
Hypochlorous acid is available in several spray formulations, including HyClear (hypochlorous acid 0.01%, Contamac), Optase Protect (hypochlorous acid 0.015%, SCOPE), and Avenova (hypochlorous acid 0.01%, NovaBay Pharmaceuticals), but is also available as a lid wipe with NeutraWipe (hypochlorous acid 0.0125%, TearRestore).
Cleansers for removing lid and lash debris
Tea tree oil (TTO), which is broadly antimicrobial and antiseptic, is commonly used for its ability to kill Demodex.60-64 When using TTO, I prefer foaming cleansers, such as Advanced Formula 2% Tea Tree Eyelid & Facial Cleanser (EyeEco), as it more easily reaches the base of the lashes and eyelid margin where Demodex mites reside.65
While it can be an effective cleanser, the main issue with TTO is it is a relatively harsh treatment that can cause significant irritation.66
Additional cleansing options include the following:
- OcuSoft Lid Scrubs (OCuSOFT)
- OPTASE TTO Eyelid Cleansing Gel (SCOPE)
- ZocuFoam Eyelid Cleanser and Moisturizer and ZocuWipes (Zocular)
- This okra-based treatment can also decrease bacteria and Demodex67
Tools for lid margin debridement
Microblepharoexfoliation devices have also become mainstays of dry eye treatment. While manual lid margin debridement has long been performed, BlephEx (BlephEx) was one of the first dedicated devices to be used in-office to manually remove lid and lash debris, including proinflammatory Demodex-associated lash collarettes and bacterial biofilm.68-70
The NuLids (NuSight Medical) device offers an at-home option for patients to perform maintenance debridement, and recently NuLids PRO (NuSight Medical) was also released as another office-based treatment option.
What makes NuLids PRO unique is the oscillating motion of the device tip, which delivers a deep cleansing of the lids and lashes, and provides another viable tool for lid margin hygiene.
Biologic and regenerative treatments for dry eye
The use of biologics and regenerative treatments for dry eye have their origin in autologous serum tears (AST). AST have long been used as a dry eye therapy because they more closely mimic a patient’s natural tears as they are created from their own blood. Consequently, AST contains growth and anti-inflammatory factors that promote healing and encourage a healthy ocular surface.71,72
A similar therapy, platelet-rich plasma (PRP), has also been utilized for dry eye treatment. Like AST, PRP is derived from the patient’s blood, contains growth factors, is anti-inflammatory, and promotes healing.73,74 However, as its name implies, PRP retains platelets, which may make it an even more effective treatment option when compared to AST.75-79
Amniotic membranes to treat ocular surface disease
The goals of regenerative treatments are to encourage healing and restore function at a fundamental level, and this is where the use of amniotic membranes excels. Amniotic membranes as treatments for dry eye have been especially useful in cases of severe ocular surface disease where the cornea is significantly disrupted, as amniotic membranes contain numerous growth factors and have anti-inflammatory, anti-angiogenic, and anti-fibrotic properties.80-84
Amniotic membranes are available in cryopreserved forms, like Prokera (BioTissue), dehydrated forms, such as AcellFX (acellular amniotic membrane, Théa Pharma), and Aril (acellular amniotic membrane, Seed Biotech), or lyophilized forms, like XcellerEYES (lyophilized amniotic membrane, Oculus Biologics).
“Each can be used effectively to improve the ocular surface, however there are conflicting studies as to the efficacy of each form.”
Some studies suggest cryopreserved forms are superior as important factors are lost during the dehydration process,85 although other studies suggest lyophilized amniotic membranes may have similar efficacy to cryopreserved forms.86,87 Additionally, the regenerative properties of cryopreserved amniotic membranes make them a beneficial treatment for neurotrophic keratitis, especially in the early stages of the disease.88
Oxervate to treat neurotrophic keratitis
A notable advancement in the area of biologic treatments for ocular surface disease is Oxervate (cenegermin-bkbj ophthalmic solution 0.002% (20 mcg/mL), Dompé), which is indicated for the treatment of neurotrophic keratitis (NK). Oxervate is a recombinant form of human nerve growth factor, which allows it to repair the corneal nerves which are damaged in NK, thereby treating the root cause of the disease and restoring function.89,90
Not only is Oxervate the first FDA-approved treatment for NK, but it is also the first approved topical biologic medication for ophthalmic use and the first use of human nerve growth factor as a therapeutic agent.91,92
Neurostimulation treatments for dry eye
We have also seen a new class of treatment emerge in the form of neurostimulation treatments, such as Tyrvaya (varenicline solution nasal spray 0.03mg, Viatris) and the iTEAR100 device (Olympic Ophthalmics).
This category of treatment originated with the FDA approval of the now-defunct TrueTear device in 2017.93 The goal of these treatments is to promote natural tear production through neural stimulation that targets the parasympathetic pathway via the trigeminal nerve.94-96
How do neurostimulation treatments work?
- Tyrvaya is a nasal spray that promotes tearing by binding to nicotinic acetylcholine receptors found on the anterior ethmoidal nerve, which is a terminal branch of the trigeminal nerve in the nasal cavity. This binding stimulates parasympathetic innervation of the lacrimal gland, which is innervated by the trigeminal nerve and results in enhanced tear production.94,95
- The iTEAR100 device functions through a similar mechanism of action, but initial activation occurs through physical stimulation of the external nasal nerve when the oscillating head of the device is placed against the skin of the nose between the nasal cartilage and the nasal bone.96
Both treatments promote natural tear production while being “dropless” therapies, making them unique treatment options. This can be incredibly beneficial, especially for patients with a highly sensitive ocular surface or already on several topical medications, such as glaucoma patients. Neurostimulation treatments allow these patients to use a treatment option that will avoid potentially irritating the ocular surface by introducing another drop.
Additionally, because the tears produced through treatment are the patient’s natural tears, they will contain anti-inflammatory and growth factors not found in artificial tears,95,97 which aim to mimic our physiologic tears but cannot fully replicate this complex composition.
Treatments for exposure
Lagophthalmos can be particularly problematic in dry eye, especially in regard to nocturnal exposure. There are several approaches to management of incomplete lid closure ranging from the use of nocturnal lubrication to sleep goggles. HYLO Night ointment (SCOPE) is an excellent topical option, as it is preservative-free and contains vitamin A, which may encourage corneal healing, although higher concentrations of vitamin A are likely necessary to receive this benefit.98,99
For those who find ointments too thick or blurring, I recommend Siccasan gel (AGEPHA Pharma) for nighttime use. If a patient requires even more protection, Eyeseals 4.0 (EyeEco) moisture goggles create a barrier that seals the eyes from the external environment.
If a patient is unable to wear goggles due to sleeping position (i.e., patients who sleep on their stomachs), SleepTite/SleepRite (Ophthalmic Resources Partners) adhesive eye patches are an alternative option that can also provide a tight seal throughout the night.
In cases where patients struggle with daytime exposure, such as cases of significant ectropion or excessive lid laxity, scleral lenses or soft bandage contact lenses can also be utilized.
Dietary supplements to treat dry eye
It has long been understood that omega-3 fatty acids can be beneficial in the management of dry eye.100-102 However, not all omega-3 supplements are of the same quality or formulation.
Put simply, for an omega-3 supplement to be beneficial when used for the treatment of dry eye and MGD, the supplement should include a high quality, re-esterified, triglyceride-based omega-3 supplement with a 3:1 eicosapentaenoic acid (EPA) to docosahexaenoic acid (DHA) ratio and at least 2 grams of combined EPA and DHA, as this is the formulation that has been shown to improve MGD effectively.102
While there are many high-quality omega-3 supplements, I use De3 Omega Benefits (PRN Physician Recommended Nutriceuticals) as it meets these criteria.
Cosmetic treatments for dry eye
Although it may not be the first thing that comes to mind when discussing dry eye treatment, cosmetic concerns over redness related to dry eye are often a significant issue for patients.
This makes Lumify (brimonidine tartrate ophthalmic solution 0.025%, Bausch + Lomb) a major advancement in the management of dry eye-related injection. While it may not seem like a significant advancement on the surface, prior to Lumify we had to warn patients against the use of Visine (0.05% tetrahydrozoline hydrochloride, Johnson & Johnson) and ClearEyes (0.012% naphazoline hydrochloride, Prestige Consumer Healthcare) due to the risk of inducing rebound redness.103,104
With Lumify, those concerns are alleviated as both rebound redness and tachyphylaxis are rare with brimonidine use.105 So, while the use of Lumify in no way takes the place of foundational dry eye therapies aimed at addressing the root cause of the ocular injection, it does provide a quick, safe, and effective way to alleviate cosmetic redness.
Additionally, brimonidine may also have anti-inflammatory and anti-angiogenic properties as well,106-110 making Lumify an excellent adjunct therapy for managing dry eye-associated redness.
Dry eye pharmaceutical pipeline
Even though these current therapeutics provide effective treatment options for our dry eye patients, the near future offers even further innovation.
Potentially game-changing treatments in the dry eye pipeline include:
- TP-03 (topical ophthalmic lotilaner solution, Tarsus Pharmaceuticals) treats Demodex blepharitis.111
- NOV03 (topical perfluorohexyloctane, Bausch + Lomb) stabilizes the lipid layer of the tear film and improves MGD.112
- Reproxalap (Aldeyra Therapeutics) inhibits pro-inflammatory reactive aldehyde species (RASP) and has shown the ability to improve symptoms of dry eye in minutes.113
- CyclASol (Novaliq) is a unique water-free formulation of cyclosporine that may enhance penetrance and bioavailability by increasing the time the drug resides on the ocular surface.114
- AR-15512 (Aerie/Alcon) is a TRPM8 agonist that acts on thermoreceptors of the nerves of the cornea and eyelid, resulting in a cooling sensation that can decrease dry eye symptoms.115
Each of these therapeutics represents a significant leap forward in our ability to treat dry eye and its many contributing factors, and with target dates within 2023 to 2024 for each treatment, they may be available very soon.
Other potential treatments further down the pipeline include:
- AZR-MD-001 (Azura Ophthalmics)116
- OTX-CSI (Ocular Therapeutix)117
- SURF-100 and SURF-200 (Surface Ophthalmics)118
- RGN-259 (RegeneRx Biopharmaceuticals)119
- CBT-008 (Cloudbreak Therapeutics)120
- ALY688 (Allysta Pharmaceuticals)121
- INV102 (Invirsa)122
- Lacripep (TearSolutions)123
Conclusion
We have come a long way from the early days of managing dry eye with simple rewetting drops and warm compresses made from rice-filled socks, but with numerous recent innovations, and those likely to be available in the near future, it truly feels as though we are entering into a Golden Age of dry eye treatment.
