AN INTRODUCTION TO DRY EYE DISEASE
Understanding the mechanism of action behind dry eye development.
Dry eye disease (DED) is a multifactorial condition, affecting at least 34 million adults in the United States and more than 340 million people worldwide.1 Although it affects all ages and demographic groups, it is most common in patients age 65 and older.2 Approximately 15 million people in the United States have been diagnosed with DED, but fewer than 2 million are currently on pharmacologic treatment. DED continues to be underdiagnosed and undertreated because clinicians may be unfamiliar with what they need to assess and/or how to align patient symptoms and clinical signs of disease. DED is often described as a vicious circle, but the actual mechanism of action is not well understood (Figure).
Figure. The core mechanisms of DED are tear film instability, hyperosmolarlty, inflammation, and ocular surface damage. All core mechanisms can be further impacted by the other elements. MGD and evaporation, as well as low aqueous tear production are entry points into the vicious circle.3
No single set of diagnostics can make a diagnosis, and the etiology of DED is multifactorial, including aging, hormonal influence, the environment, contact lenses, systemic conditions (diabetes, autoimmune disorders, etc.) and ocular surgery.
Meibomian gland dysfunction (MGD), in particular, has been firmly established in the literature as a major contributor to DED.3 “The inability to create and secrete meibum that’s of appropriate quality and quantity is probably the most common cause of dry eye,” said Kelly K. Nichols, OD, MPH, PhD, FAAO. “If the lipid layer is irregular, that results in that vicious circle of hyperosmolarity, increased evaporation and alterations to tear film stability, which leads to the upregulation of inflammatory mediators on the ocular surface and ocular surface damage.”
There are other components of the ocular surface functional unit including the lacrimal gland, which secretes the aqueous component. While techniques used to measure lipids in the tear film and meibum vary, there may be hundreds of unique lipid molecules in the tear film. The Tear Film and Ocular Surface Society International Dry Eye Workshop II (TFOS DEWS II) reports more than 1,800 proteins in the tear film.4
For Damon Dierker, OD, FAAO, the hallmarks of DED are loss of homeostasis and tear film hyperosmolarity, which damage the ocular surface and lead to the inflammatory cascade. When evaluating the signs and symptoms of DED to create a treatment plan, clinicians must find the source of the stressor that is causing tear film hyperosmolarity to determine the specific type of DED.
TFOS DEWS II4,5 recognizes two primary DED subtypes which can occur alone or together—evaporative and aqueous deficient—each of which has a different pathophysiology. Evaporative dry eye is typically caused by MGD or tear film instability due to the evaporation of tears and hyperosmolarity. Aqueous deficient dry eye can be caused by chronic autoimmune disorders (Sjögren syndrome), systemic conditions such as lymphoma or viral infections, lacrimal gland ablation, and ocular surface aging, among others.
Although TFOS DEWS II categorizes DED into two subtypes, patients may suffer from a combination rather than falling into a single category. Lemp et al found that patients are 3 times more like to have evaporative than aqueous deficient dry eye, but that 30% of patients have a mixture of both types.6 The prevalence of mixed etiology DED may be as high as 70%.7
“Dry eye is complex,” said Damon Dierker, OD, FAAO. “The good news is we understand more than we did 10 years ago as to how dry eye develops. This help us in trying to understand treatments that may be effective on the horizon.”
DRY EYE SIGNS AND SYMPTOMS MAY NOT ALIGN
One of the biggest challenges for clinicians when diagnosing DED is the variability in patient-reported symptoms and the misalignment between symptoms and clinical signs.
“Many of my patients report that their eyes are extremely dry but they’ll have minimal corneal staining,” Dr. Vollmer said. “Then you have the other side where a patient reports their eyes feel fine but they have confluent superficial punctate keratopathy throughout the cornea and decreased vision. Their cornea has come neurotrophic, and the normal levels of discomfort are replaced with minimal to no symptoms at all.”
Lienert et al studied the natural history of DED over a year and found that patients reported symptom fluctuations.8 In 2020, Tsubota et al published a clinical consensus on the definition of DED, proposing an updated definition that clarified the instability of DED symptoms:
“Dry eye is a multifactorial disease characterized by a persistently unstable and/or deficient tear film causing discomfort and/or visual impairment, accompanied by variable degrees of ocular surface epitheliopathy, inflammation and neurosensory abnormalities.”9
The symptom variability may be due to dry eye episodes caused by any number of triggers. Environmental factors, such as reduced humidity and exposure to increased heat, wind, air conditioning, smoke or smoking, and allergens may aggravate dry eye symptoms such as ocular irritation, redness, excessive tearing, itching, and soreness.1,3,7,10
“Patients have anywhere from four to six dry eye flares throughout the year, whether it’s due to changes in the weather, allergies, or indoor environmental factors,” explained Walter O. Whitley, OD, MBA, FAAO. “Whether we’re treating a patient for an acute or chronic condition, patients will experience symptom fluctuations or dry eye flares throughout the day, week, or year.”
The lack of association between signs and symptoms of DED presents another significant challenge for clinicians. Nichols et al studied 75 patients with DED to examine the relationship between signs and symptoms of dry eye and found that symptoms were generally not associated with clinical signs regardless of patient age or artificial tear use.11
“Publishing that paper was actually quite a challenge because it was a negative finding; people wanted the symptoms to correlate to the test,” Dr. Nichols explained. “Many patients are in an emerging dry eye state during which they sometimes have symptoms and sometimes they do not. You need to listen to these patients carefully because the clinical signs may be inconsistent. They’ll often describe events during the year that wax and wane.”
Dr. Vollmer sees many patients in his clinic, especially patients with MGD, who are asymptomatic. These patients are particularly difficult to treat because they need to be convinced to use eye drops when their perception is that nothing is wrong. Tests used to diagnose DED are listed in the Table.
“We need to look at the ocular surface regardless of whether the patient is complaining,” Dr. Whitley said. “We must evaluate their tear film break-up time, check for corneal staining, and express their meibomian glands. If we don’t, we’re going to miss dry eye cases. We must be proactive in our approach to identify these patients whether or not they’re symptomatic.”
Dr. Dierker agreed: “I think everyone has ocular surface disease until proven otherwise.”
REFERENCES
1. Akpek EK, Amescua G, Farid M, et al. Dry eye syndrome preferred practice pattern. Ophthalmology. 2019;126(1):286-334.
2. Craig JP, Nichols KK, Akpek EK, et al. TFOS DEWS II definition and classification report. Ocul Surf. 2017;15(3):276-283.
3. Bron AJ, de Paiva CS, Chauhan SK, et al. TFOS DEWS II pathophysiology report. Ocul Surf. 2017;15(3):438-510.
4. Willcox MDP, Argueso P, Georgiev GA, et al. TFOS DEWS II tear film report. Ocul Surf. 2017;15(3):366-403.
5. Craig JP, Nelson JD, Azar DT, et al. TFOS DEWS II Report Executive Summary. Ocul Surf. 2017;15(4):802-812.
6. Lemp MA, Crews LA, Bron AJ, Foulks GN, Sullivan BD. Distribution of aqueous-deficient and evaporative dry eye in a clinic-based patient cohort: a retrospective study. Cornea. 2012;31(5):472-478.
7. Jones L, Downie LE, Korb D, et al. TFOS DEWS II management and therapy report. Ocul Surf. 2017;15(3):575-628.
8. Lienert JP, Tarko L, Uchino M, et al. Long-term natural history of dry eye disease from the patient’s perspective. Ophthalmology. 2016;123(2):425-433.
9. Tsubota K, Pflugfelder SC, Liu Z, et al. Defining dry eye from a clinical perspective. Int J Mol Sci. 2020;21(23):9271.
10. Lopez-Miguel A, Teson M, Martin-Montanez V, et al. Dry eye exacerbation in patients exposed to desiccating stress under controlled environmental conditions. Am J Ophthalmol. 2014;157(4):788-798.e2.
11. Nichols KK, Nichols JJ, Mitchell GL. The lack of association between signs and symptoms in patients with dry eye disease. Cornea. 2004;23(8):762-770.
UNDERSTANDING THE INFLAMMATORY COMPONENT OF OCULAR SURFACE DISEASE
Tear film homeostasis and its effect on dry eye disease.
The parasympathetic nervous system controls tear film homeostasis by innervating the lacrimal functional unit through the trigeminal parasympathetic pathway. Tear secretion is regulated by the lacrimal functional unit, which consists of the ocular surface (cornea, conjunctiva, accessory lacrimal glands, and meibomian glands), the main lacrimal gland, and the interconnecting nerves.1
The lacrimal functional unit2 unifies the complex reflex network connecting the sensory tissues and secretory glands that provide homeostasis on the ocular surface and is composed of the ocular surface tissues (cornea, corneal limbus, conjunctiva, conjunctival blood vessels, and eyelids), the tear secreting machinery (main and accessory lacrimal glands, meibomian glands, conjunctival goblet, and epithelial cells), and their neural connections. The lacrimal functional unit is tightly controlled by neural input from the ocular surface tissues. Subconscious stimulation of the corneal nerve endings triggers afferent impulses through the ophthalmic branch of the trigeminal nerve, which integrate in the central nervous system and the paraspinal sympathetic tract, in turn generating efferent secretomotor impulses that stimulate secretion of the healthy tear film. Any one of several sensory stimuli, eg, pain, microbial/environmental insult, and emotion can stimulate the tear secreting reflex.
Most dry eye symptoms are caused by inflammation within the lacrimal functional unit, which causes tear film instability and creates the feedback loop of DED. The tear film has three main layers: aqueous, lipid, and mucin.3 Tears are secreted through the trigeminal nerve—brainstem—facial nerve—lacrimal gland reflex arc. The trigeminal nerve is the largest cranial nerve and is important, not just for homeostasis, but for the many symptoms that occur with trigeminal nerve hyperstimulation.
“Trigeminal nerve stimulation is thought to impact all the glands on the ocular surface,” Kelly K. Nichols, OD, MPH, PhD, FAAO, said. “If you were to stimulate the trigeminal nerve, you would produce all the components of the tear film, probably simultaneously. That would be a fantastic move in creating more components of the natural tear film, which could lead to homeostasis, because you’re enhancing of the tear components on the ocular surface.”
Homeostasis is the balance of the beneficial proteins, antiinflammatory cytokines, immunoglobulins, and electrolytes in the tear film. If there’s a disruption in the balance, you’re going to lose tear film homeostasis and develop tear film instability.
“In the early stages of the inflammatory cycle, ocular surface damage leads to reflex stimulation of the lacrimal gland,” said Patrick Vollmer, OD, FAAO. “When that happens, you get an inflammatory cytokine response within the gland that dumps even more inflammatory markers into the tear film. The vicious circle perpetuates if you look at the neuronal feedback loop diagram.”
From a treatment perspective, the goal is to use the trigeminal nerve parasympathetic pathway as a therapeutic target and use the body’s system with a natural on/off switch to produce healthy tears.
“There’s no substitute for a natural tear film because of its complexities. Therefore, it’s not surprising that things like artificial tears don’t treat the disease. They can give some short-term relief of some symptoms, but the disease itself is unchecked because of the inability to replicate what a natural tear film actually does for the surface of the eye,” said Damon Dierker, OD, FAAO.
CURRENT PHARMACOLOGIC ANTIINFLAMMATORY TREATMENTS
During the past 2 decades, DED treatment has been primarily with antiinflammatory therapies like steroids. Pharmacologic treatments such as cyclosporine, now available from two different manufacturers and dosages (0.05% [Restasis]; 0.09% [Cequa]), lifitegrast, and loteprednol 0.25% are indicated for DED treatment and specifically address the inflammatory component of DED.4-7
Clinical trials have indicated that cyclosporine may be disease modifying, with a systematic review showing that Restasis dosed twice daily significantly improved both objective and subjective outcomes in patients with DED.8 Cequa is also a cyclosporine, but dosed at a higher level than Restasis and includes a nanomicellar formulation that better penetrates the aqueous layer, thereby improving drug absorption.9 The pivotal phase 3 trial showed clinically significant improvements in tear production and ocular surface integrity with Cequa, although the long-term efficacy is unknown. The longterm efficacy of lifitegrast is also unknown, but studies show the agent improves both signs and symptoms of DED.10
With topical steroid therapy, although these agents are very effective in treating inflammation, long-term use causes several serious side effects such as increased intraocular pressure, glaucoma, and cataract formation. Patients who are successfully managed on anti-inflammatory DED treatments can still have dry eye episodes.
“If a patient has an episode or dry eye flare, we may need to add another type of treatment that addresses the inflammation and/or the hyperosmolarity,” Dr. Whitley said. “It’s going back to the proactive versus reactive approach.”
Antiinflammatories are a critical part of DED management but are not the whole picture and don’t address MGD, for example. Proactive treatment is especially important when for MGD, Dr. Whitley said, as prompt treatment will prevent additional inflammation, perhaps disrupting that vicious circle.
In addition to prescription antiinflammatory drops, Dr. Vollmer has also seen patients improve with omega 3s and will frequently suggest patients adopt a Mediterranean diet.11-13 There are conflicting data in the literature regarding omega 3s, with the DREAM study finding no improvement in DED symptoms with omega 3 use compared with placebo.14 However, a recent meta-analysis of 17 clinical trials found that omega 3 supplementation did improve the symptoms of dry eye, indicating it may be an effective treatment.15
“It’s important to set expectations for the patient no matter what therapeutic we choose and let them know that we don’t have a cure for their disease. It’s about finding the best personalized management strategy for that patient,” Dr. Dierker said, which may involve mixing and matching multiple approaches. For example, a patient on long-term antiinflammatory treatment may need something additional in the short term to manage an episode.
“Patients who have more advanced disease often need a multifaceted approach and several antiinflammatory therapies to get them under control,” Dr. Dierker said. “But if you’re proactive in screening for signs and symptoms, and treating inflammation as early as possible, then you’ve got a better chance with our current therapies for monotherapy to be successful. But that’s not nearly as common in people who have more well-established complex ocular surface disease.”
Topical and oral antibiotics such as doxycycline 100 mg may also be helpful, depending on the patient. Oral azithromycin is an option as well and, in addition to being less expensive, may be more effective than doxycycline.16
REFERENCES
1. Stern ME, Gao J, Siemasko KF, et al. The role of the lacrimal functional unit in the pathophysiology of dry eye. Exp Eye Res. 2004;78(3):409-416.
2. Stern ME, Schaumburg CS, Pflugfelder SC. Dry eye as a mucosal autoimmune disease. Int Rev Immunol. 2013;32(1):19-41.
3. Willcox MDP, Argueso P, Georgiev GA, et al. TFOS DEWS II tear film report. Ocul Surf. 2017;15(3):366-403.
4. Beckman K, Katz J, Majmudar P, et al. Loteprednol etabonate for the treatment of dry eye disease. J Ocul Pharmacol Ther. 2020;36(7):497-511.
5. Mandal A, Gote V, Pal D, et al. Ocular pharmacokinetics of a topical ophthalmic nanomicellar solution of cyclosporine (Cequa) for dry eye disease. Pharm Res. 2019;36(2):36.
6. Schultz C. Safety and efficacy of cyclosporine in the treatment of chronic dry eye. Ophthalmol Eye Dis. 2014;6:37-42.
7. Chan CC, Prokopich CL. Lifitegrast ophthalmic solution 5.0% for treatment of dry eye disease: overview of clinical trial program. J Pharm Pharm Sci. 2019;22(1):49-56.
8. Akpek EK, Amescua G, Farid M, et al. Dry eye syndrome preferred practice pattern. Ophthalmology. 2019;126(1):286-334.
9. Goldberg DF, Malhotra RP, Schechter BA, et al. A phase 3, randomized, double-masked study of OTX-101 ophthalmic solution 0.09% in the treatment of dry eye disease. Ophthalmology. 2019;126(9):1230-1237.
10. Holland EJ, Luchs J, Karpecki PM, et al. Lifitegrast for the treatment of dry eye disease: results of a phase III, randomized, doublemasked, placebo-controlled trial (OPUS-3). Ophthalmology. 2017;124(1):53-60.
11. Epitropoulos AT, Donnenfeld ED, Shah ZA, et al. Effect of Oral re-esterified omega-3 nutritional supplementation on dry eyes. Cornea. 2016;35(9):1185-1191.
12. Chew EY, Clemons TE, Agron E, et al. Effect of omega-3 fatty acids, lutein/zeaxanthin, or other nutrient supplementation on cognitive function: the AREDS2 randomized clinical trial. JAMA. 2015;314(8):791-801.
13. Liu A, Ji J. Omega-3 essential fatty acids therapy for dry eye syndrome: a meta-analysis of randomized controlled studies. Med Sci Monit. 2014;20:1583-1539.
14. Asbell PA, Maguire MG, Pistilli M, et al. n-3 fatty acid supplementation for the treatment of dry eye disease. N Engl J Med. 2018;378(18):1681-1690.
15. Giannaccare G, Pellegrini M, Sebastiani S, et al. Efficacy of omega-3 fatty acid supplementation for treatment of dry eye disease: a metaanalysis of randomized clinical trials. Cornea. 2019;38(5):565-573.
16. Kashkouli MB, Fazel AJ, Kiavash V, et al. Oral azithromycin versus doxycycline in meibomian gland dysfunction: a randomised doublemasked open-label clinical trial. Br J Ophthalmol. 2015;99(2):199-204.
OBSTACLES TO SUCCESSFUL LONG-TERM TREATMENT
Incorporating dry eye algorithms in the clinic.
Several treatment algorithms have been developed over the last few years to help guide clinicians in assessing for, diagnosing, and treating DED. The three primary algorithms are TFOS DEWS II, CEDARS, and the American Society of Cataract and Refractive Surgery (ASCRS) Preoperative Ocular Surface Disease Algorithm.1-3
“They are all different in their own respective ways,” Walter O. Whitley, OD, MBA, FAAO, said. “TFOS DEWS II is more severity based and includes different treatment recommendations. It’s truly an evidence-based algorithm.”
TFOS DEWS II takes a stepwise approach based on questioning and diagnostic testing (Figure), recommending different treatments based on disease severity. It is more of an organizational tool than a rigid algorithm.
Figure. Diagrammatic representation of the process associated with the management of DED recommended by TFOS DEWS II.1,18
“CEDARS is interesting because it’s more diagnosis-based and divides DED into several categories, which helps clinicians differentiate and classify the various DED conditions including dry eye co-conspirators such as SLK, conjunctivochalasis, etc.,” Dr. Whitley said. “As for treatments, it provides recommendations for first, second- and third-line treatments based on the diagnosis and not solely on severity.”
CEDARS divides DED into four categories designed to help clinicians make a differential diagnosis: aqueous deficiency, blepharitis/MGD (evaporative and nonevaporative), goblet cell deficiency/mucin deficiency, and exposure related dysfunctional tear syndrome.2
ASCRS has an extensive algorithm to test for ocular surface disease before cataract surgery, including the SPEED questionnaire, tear osmolarity analysis, corneal topography, staining, and tear break-up time and Schirmer testing.3
Importantly, the expert panel noted that one algorithm isn’t any better than the other, and no single algorithm should be used exclusively. Instead, they recommend viewing each algorithm as a reference point, pulling a little bit from each to create a unique algorithm based on patient needs.
“These treatment guidelines are based on group expert opinions, backed up with clinical data should it exist,” said Kelly K. Nichols, OD, MPH, PhD, FAAO. “In some cases, there is evidence to support those opinions. All the treatment algorithms, including TFOS DEWS II, are a great start for someone who hasn’t thought of all treatments in order, from a stepwise approach. But if patients fail at any place in the steps, you have to move on to the next level.”
Although they shouldn’t be followed exactly, each algorithm is helpful. For example, Dr. Whitley finds the patient questionnaires and LLPP—“look, lift, pull, push”—aspects of ASCRS particularly useful. On the other hand, Patrick Vollmer, OD, FAAO, and Damon Dierker, OD, FAAO, don’t find the stepwise approach of TFOS DEWS II that practical in the real world and prefer to treat patients aggressively immediately.
“A step-up therapy for me in my practice doesn’t always make sense,” Dr. Dierker said. “Why have a patient fail something before I move on to the next step? I have a step-down approach, where I’m treating aggressively at the start and try to get them back into that state of homeostasis. Then I start backing down after that to maintain it.”
CHALLENGES WITH INSURANCE AND PATIENT COMPLIANCE
Insurance preauthorization and patient compliance remain the biggest obstacles to treating DED. That’s one justification for the stepwise approach to DED management; you’re building a case to establish medical necessity of prescription drops for insurance coverage. Because DED is a chronic condition, cost must be factored into the treatment paradigm. There’s often a discrepancy between what clinicians want to prescribe and what patients can afford.
“If you prescribe a treatment that a patient won’t be able to pay for or will not have access to, that should be considered,” Dr. Nichols said, “but never underestimate what a patient can afford or is willing to pay for quality care and treatments.”
If patients can afford the medication out-of-pocket or it’s covered by insurance, the next barrier is getting them to adhere to therapy long term—and correctly. Studies have shown that many patients will refill a medication once and then drop off shortly thereafter.4 White et al found that 60% of DED patients discontinued treatment within 12 months of initiation.
Patient education is a critical part of compliance as patients don’t understand that dry eye is a chronic, recurring, progressive disease and won’t be resolved in a few weeks. Patients must also understand the potential side effects of DED treatment, such as stinging and burning. With Restasis, for example, 17% of patients have ocular burning upon instillation. Lifitegrast also causes stinging and burning, but at a lesser rate.
“I take an A, B, A approach with patient education,” Dr. Dierker said. “I tell the patient A, what we’re doing, why we’re doing it, and give my recommendation. Then I move on to B and tell them about the potential downsides and things to expect. I then go back to A, framing it as what I’m hoping to see the next time they come in and discuss their long-term prognosis. A lot of this is about having that conversation with your patient and individualizing your approach.”
THE RISE OF IATROGENIC DRY EYE
Iatrogenic dry eye, or dry eye caused by topical or systemic drugs, contact lens wear, and ophthalmic surgical and nonsurgical procedures, is a growing concern. In 2009, 22 of the bestselling 100 systemic drugs in the United States caused dry eye. Of the nine systemic drugs known to secrete into the tear film, eight are associated with DED.5 Glaucoma treatment, in particular, can cause DED due to the inclusion of preservatives such as benzalkonium chloride (BAK).6
It’s estimated that 15% of the general population has a BAK sensitivity. Clinical studies have shown that BAK is linked to worsening ocular surface disease and damages the meibomian glands, as patients on preserved drops have more signs and symptoms of dry eye.7,8 Leung et al found that each additional BAK-containing eye drop per day was associated with 2 times higher odds of abnormal lissamine green staining results.9 This is especially important patients with glaucoma, as many are on multiple mediations containing BAK, resulting in a significant overlap between patients with glaucoma and dry eye. A study by Katz et al found that out of 630 patients with glaucoma on medications, 48% had an abnormal Ocular Surface Disease Index score.10
“That’s why it’s so important to look at the meibography in our glaucoma patients,” Dr. Whitley said. “We must also look at the tear osmolarity and ask them questions. If they have ocular surface issues, we need to explore BAK-free medications or consider selective laser trabeculoplasty. If you have a glaucoma practice, you have a dry eye practice.”
In addition to medications, overuse of contact lenses can cause of DED; up to 50% of contact lens wears drop out within 3 years of use due to discomfort.11
“The COVID-19 pandemic has had an interest impacting on contact lens use because of masking,” Dr. Vollmer said. “I’ve had more patients try contact lenses because their glasses fog up when they are wearing a mask.”
Increased screen time is another factor. Patients who spend more time reading and using the computer or smartphones have more DED symptoms.12 Dr. Vollmer expects the COVID-19 pandemic to impact this as well, as people are staying home and spending more time on their computers.
“These factors underscore the point that I go into an exam needing to rule out dry eye in a patient. I assume they have it because they have a lot of risk factors or things in their environment that makes it more likely they have DED,” Dr. Dierker said. “Dry eye may not be their primary diagnosis or their chief complaint, but we need to screen for signs and symptoms of dry eye because it’s so common.”
Finally, cataract and refractive surgery are known to exacerbate dry eye symptoms, especially in the 3-month postoperative period.13,14 This could be due to the health of the ocular surface preoperatively, the incision during the surgery itself, or the eye drops containing preservatives patients use postoperatively. To reduce surgical-induced dry eye, clinicians must ensure the ocular surface is healthy enough for surgery. The American Academy of Ophthalmology recommends that all patients considering cataract and refractive surgery undergo a full dry eye examination, including tear film and ocular surface evaluation, and that any ocular surface issues are addressed preoperatively.15
“It’s important to identify dry eye before any type of ocular surgery,” Dr. Whitley said. “If you find the dry eye after surgery it becomes the gift that keeps on giving because the patient believes they never had it before.”
Undiagnosed dry eye is prevalent in the cataract surgery population. The PHACO study found that of 136 patients scheduled for cataract extraction, the majority (62%) had a tear break-up time of 5 seconds or less, 77% had positive corneal staining, and 50% had positive central corneal staining. Yet nearly 60% never complained of a foreign body sensation, a common DED symptom.16 Trattler et al estimated that 20% of the study population would never have received a DED diagnosis had they not presented for a cataract surgery evaluation. Gupta et al further confirmed this, estimating that 80% of patients having a cataract surgery evaluation have ocular surface dysfunction, which is largely undiagnosed.17
“When these patients come in, they tend to be thinking about their glaucoma or their cataracts; they aren’t going to tell you how their eyes feel unless you ask them. They could have dry eye symptoms and don’t know it. Then they go on to surgery and think you’ve caused their dry eyes,” Dr. Nichols said. “The reality is they’ve had it all along and didn’t say anything. It’s very important that patients are evaluated for dry eye before they go into surgery.”
REFERENCES
1. Jones L, Downie LE, Korb D, et al. TFOS DEWS II management and therapy report. Ocul Surf. 2017;15(3):575-628.
2. Milner MS, Beckman KA, Luchs JI, et al. Dysfunctional tear syndrome: dry eye disease and associated tear film disorders - new strategies for diagnosis and treatment. Curr Opin Ophthalmol. 2017;27 Suppl 1:3-47.
3. Starr CE, Gupta PK, Farid M, et al. An algorithm for the preoperative diagnosis and treatment of ocular surface disorders. J Cataract Refract Surg. 2019;45(5):669-684.
4. White DE, Zhao Y, Ogundele A, et al. Real-World treatment patterns of cyclosporine ophthalmic emulsion and lifitegrast ophthalmic solution among patients with dry eye. Clin Ophthalmol. 2019;13:2285-2292.
5. Fraunfelder FT, Sciubba JJ, Mathers WD. The role of medications in causing dry eye. J Ophthalmol. 2012;2012:285851-285851. doi:10.1155/2012/285851
6. Baudouin C, Labbe A, Liang H, Pauly A, Brignole-Baudouin F. Preservatives in eyedrops: the good, the bad and the ugly. Prog Retin Eye Res. 2010;29(4):312-334.
7. Fechtner RD, Godfrey DG, Budenz D, et al. Prevalence of ocular surface complaints in patients with glaucoma using topical intraocular pressure-lowering medications. Cornea. 2010;29(6):618-621.
8. Ha JY, Sung MS, Park SW. Effects of Preservative on the meibomian gland in glaucoma patients treated with prostaglandin analogues. Chonnam Med J. 2019;55(3):156-162.
9. Leung EW, Medeiros FA, Weinreb RN. Prevalence of ocular surface disease in glaucoma patients. J Glaucoma. 2008;17(5):350-355.
10. Katz G, Springs CL, Craven ER, Montecchi-Palmer M. Ocular surface disease in patients with glaucoma or ocular hypertension treated with either BAK-preserved latanoprost or BAK-free travoprost. Clin Ophthalmol. 2010;4:1253-1261.
11. Markoulli M, Kolanu S. Contact lens wear and dry eyes: challenges and solutions. Clin Optom. 2017;9:41-48.
12. Karakus S, Mathews PM, Agrawal D, et al. Impact of dry eye on prolonged reading. Optom Vis Sci. 2018;95(12):1105-1113.
13. Woodward MA, Randleman JB, Stulting RD. Dissatisfaction after multifocal intraocular lens implantation. J Cataract Refract Surg. 2009;35(6):992-997.
14. Iglesias E, Sajnani R, Levitt RC, et al. Epidemiology of persistent dry eye-like symptoms after cataract surgery. Cornea. 2018;37(7):893-898.
15. Akpek EK, Amescua G, Farid M, et al. Dry Eye Syndrome Preferred Practice Pattern. Ophthalmology. 2019;126(1):286-334.
16. Trattler WB, Majmudar PA, Donnenfeld ED, et al. The Prospective Health Assessment of Cataract Patients’ Ocular Surface (PHACO) study: the effect of dry eye. poster. Clin Ophthalmol. 2017;11:1423-1430.
17. Gupta PK, Drinkwater OJ, VanDusen KW, et al. Prevalence of ocular surface dysfunction in patients presenting for cataract surgery evaluation. J Cataract Refract Surg. 2018;44(9):1090-1096.
18. Wolffsohn JS, Arita R, Chalmers R, et al. TFOS DEWS II diagnostic methodology report. Ocul Surf. 2017; 15: 539-574.
FUTURE TREATMENT OPTIONS FOR DRY EYE DISEASE
Reactive aldehyde species as an endpoint.
There is currently no single diagnostic or point-of-care test in the clinic to diagnose dry eye. That may be changing, as the FDA recently approved reactive aldehyde species (RASP) as an objective sign of DED.1 RASP is a precytokine proinflammatory mediator that is upregulated in the tears of patients with DED and correlate with DED signs and symptoms.2 A phase 2a trial by Aldeyra Therapeutics investigating reproxalap, a first-inclass RASP inhibitor for DED, found that reproxalap reduced RASP levels 28 days after treatment.3
“I’m enthusiastically in favor of finding biomarkers for measurement because right now we’re doing a collection of dry eye tests and symptoms to come up with a diagnosis. We don’t have one test,” said Kelly K. Nichols, OD, MPH, PhD, FAAO. “While we’ve used these clinical measures, which are really surrogate measures, for the disease state, this would actually be a bit closer to the actual disease. If you see RASP, you measure it. If you treat the patient and RASP improves, then that ultimately would be what we’d all be looking for; something you can measure quickly in a point-of-care test in the clinic.”
MOVING BEYOND ANTI-INFLAMMATORY TREATMENT
In the near future, dry eye therapy will go beyond anti-inflammatory treatment. There are several novel treatments in the pipeline including neurostimulating nasal sprays and devices and disease-modifying regenerative treatments that treat the root cause of DED.
TrueTear (Allergan) was a device that temporarily increased tear production in adult patients with dry eye through neurostimulation. Small studies have found that intranasal neurostimulation increases tear volume and reduces ocular pain and dryness. 4 Approved by the US FDA in 2017, TrueTear stimulated the anterior ethmoidal nerve to cause tearing through two silicone prongs inside the nose. Patients could use the device up to four times a day for 30 total minutes in a 24-hour period. Although TrueTear was effective, Allergan recently discontinued its manufacturing, likely due to cost.5
“One of the reasons I don’t think TrueTear was successful was because it was almost too novel. It may have worked, but the barrier was it was too new; the technology wasn’t accepted,” said Patrick Vollmer, OD, FAAO.
The iTear100 (Olympic Ophthalmic) is another FDA-cleared neurostimulator device. iTear100 is applied to the skin of the external nasal region and stimulates the trigeminal nerve in less than 30 seconds. FDA clearance was based on two pivotal trials: TEAR1 and TEAR2. In both trials, the iTear100 demonstrated a 22-mm change in Schirmer score versus sham with no device-related adverse events. iTear100 also demonstrated the ability to increase tear production continuously over 30 days with an increase in Schirmer score from 6 mm retreatment to 9.4 mm at 30 days of treatment.6 Although new to the market, Damon Dierker, OD, FAAO, thinks it will be an easier transition for patients than TrueTear because the electromechanical device works externally rather than internally.
Oyster Point is developing a varenicline nasal spray that, if proven safe and effective, will also likely have more success than TrueTear because patients are familiar with the drug delivery method. The varenicline nasal spray is selective cholinergic agonist that demonstrated statistically significant improvements in Schirmer score compared with control in the phase 3 ONSET-2 trial.7
“We use nasal sprays all the time for allergies and nasal congestion,” Dr. Vollmer said. “To use it for dry eye makes perfect sense. It has a great place in the market.”
Other new DED agents are regenerative, including autologous serum and platelet-rich plasma. Autologous serum tears are more effective than regular tears at improving tear film stability in patients with severe dry eye because they are customizable to each patient and contain the core components of human tears (growth factors, proteins, antioxidants, and lipids) starting at a concentration of 20 to 30%.8,9 Platelet-rich plasma may be even more effective than autologous serum for patients with severe DED because they are richer in growth factors, antiinflammatory cytokines, and other platelet derivatives.10,11
The expert panel agreed that these approaches, although effective, are not yet widely adopted by patients because they are too new and should only be reserved for patients with very severe dry eye.
“The nasal spray will have broad application because it’s something that’s already out there as far as an actual device, not the indication,” Dr. Vollmer said. “I think because it’s been accepted by society for years it will be well-received for FDA approval to treat the signs and symptoms of dry eye.”
Other agents in the pipeline include RGN-259 (RegeneRx), a Tß4-based sterile and preservative-free eye drop under development for DED and neurotrophic keratitis. RGN-259 reduces corneal apoptosis and inflammation through cell migration and increasing laminin-5 production. It’s currently being investigated in the phase 3 ARISE-3 study (NCT03937882).
Although Dr. Vollmer acknowledges there is some excitement with these therapies in the pipeline, he does not think dry eye will be alleviated with a drop. Specifically, Dr. Vollmer thinks MGD thermal lasers and intense pulsed light devices will be major players.
“There are some really good drops coming down the pipeline, but I think future dry eye therapy will be device-oriented,” he said. “The drops will be like palliative care along the way.”
That said, the panel doesn’t necessarily think these treatments will be more effective as no single treatment will work for every patient. Instead, the expert panel agreed these approaches, although effective, are not yet widely adopted due to lack of patient access, limited physician experience, and cost.
“Patients need to want to use these drops because they feel good upon instillation,” Dr. Vollmer said. “Once or twice daily dosing and less burning upon instillation are keys to success.”
REFERENCES
1. Aldeyra Therapeutics reaches agreement with the us food and drug administration for the use of RASP as an objective sign for the treatment of dry eye disease. June 4, 2020, Accessed April 11, 2021.
2. Augustin AJ, Spitznas M, Kaviani N, et al. Oxidative reactions in the tear fluid of patients suffering from dry eyes. Graefes Arch Clin Exp Ophthalmol. 1995;233(11):694-698.
3. Clark D, Sheppard J, Brady TC. A randomized double-masked phase 2a trial to evaluate activity and safety of topical ocular reproxalap, a
novel RASP inhibitor, in dry eye disease. J Ocul Pharmacol Ther. Jan 15 2021.
4. Farhangi M, Cheng AM, Baksh B, et al. Effect of non-invasive intranasal neurostimulation on tear volume, dryness and ocular pain. Br J Ophthalmol. 2020;104(9):1310-1316.
5. Darrell White. RIP TrueTear: Allergan pulls the plug on electrical stimulation. Ocular Surgery News. Accessed April 11, 2021.
6. Olympic Ophthalmics presents clinical evidence for iTEAR100. Available at: https://www.prnewswire.com/news-releases/olympic-ophthalmicspresents-clinical-evidence-for-itear100-301064095.html. Accessed March 31, 2021.
7. Oyster Point Pharma announces positive results in ONSET-2 phase 3 Trial of OC-01 nasal spray for the treatment of the signs and symptoms of dry eye disease. Available at: www.globenewswire.com/news-release/2020/05/11/2030882/0/en/Oyster-Point-Pharma-Announces-Positive-Results-in-ONSET-2-Phase-3-Trial-of-OC-01-Nasal-Spray-for-the-Treatment-of-the-Signs-and-Symptoms-of-Dry-Eye-Disease.html. Accessed April 11, 2021.
8. Celebi AR, Ulusoy C, Mirza GE. The efficacy of autologous serum eye drops for severe dry eye syndrome: a randomized double-blind crossover study. Graefes Arch Clin Exp Ophthalmol. 2014;252(4):619-626.
9. Jirsova K, Brejchova K, Krabcova I, et al. The application of autologous serum eye drops in severe dry eye patients; subjective and objective parameters before and after treatment. Curr Eye Res. 2014;39(1):21-30.
10. Alio JL, Colecha JR, Pastor S, et al. Symptomatic dry eye treatment with autologous platelet-rich plasma. Ophthalmic Res. 2007;39(3):124-129.
11. López-Plandolit S, Morales MC, Freire V, et al. Efficacy of plasma rich in growth factors for the treatment of dry eye. Cornea. 2011;30(12):1312-1317.
