DRY EYE DISEASE What We Know About It Today and Its Importance for Optometry

dry eye disease 1

Arthur B. Epstein, OD, FAAO Paul M. Karpecki, OD, FAAO Katherine M. Mastrota, MS, OD, FAAO Walter O. Whitley, OD

Sponsored by

UUntitled-2ntitled-2 1 44/25/16/25/16 11:3711:37 AMAM 2 dry eye disease

INTRODUCTION Although critically important to the practice of optometry, a sophisticated understanding of dry eye disease (DED) is a relatively recent development. Just 20 years ago, DED was a poorly understood entity for which there was a signiﬁcant

controversy with respect to diagnosis.1 This picture began to change with the publication of the “Report of the National

Eye Institute/Industry Workshop on Clinical Trials in Dry Eyes.”1 Like the subsequent DEWS Report, the NEI/Industry Workshop brought together and gave structure to our then-current knowledge of DED and laid the groundwork for future research and understanding. Thanks to signiﬁcant interest—including commercial interest—the ﬁeld has grown rapidly. So much has happened that a second DEWS Report (DEWS II) is now being undertaken.

TOWARDS A NEW Dry eye is a multifactorial UNDERSTANDING disease of the tears and Arthur B. Epstein, OD, So how far have we come? And ocular surface that results FAAO, FABCO, FBCLA, what does a new understanding DPNAP, is co-founder of in symptoms of discomfort, Phoenix Eye Care, PLLC, mean for optometric practice? visual disturbance, and where he heads the Ocular We can start by looking back. Surface Disease Center tear film instability with and serves as the Center’s In 1995, the NEI/Industry potential damage to director of clinical research. Workshop defined dry eye as the ocular surface. It is “a disorder of the tear film due accompanied by increased Paul M. Karpecki, OD, to tear deficiency or excessive FAAO, heads the Advanced osmolarity of the tear film Ocular Surface Disease evaporation, which causes damage and inflammation of the Center and is director to the interpalpebral ocular surface 2 of clinical research at ocular surface. the Kofﬂer Vision Group, and is associated with symptoms Lexington, KY. of ocular discomfort.”1 This definition recognized two primary etiologies (aqueous deficiency Katherine M. Mastrota, MS, OD, FAAO, is Regional and excessive evaporation), a sign Practice Ambassador/ (ocular surface “damage,” primarily Director, Omni Eye Surgery New York Dry Eye/Ocular detectable by staining [Figure 1]), Wellness Center. and a symptom (discomfort) but was otherwise silent with respect to causes, effects, or corollaries of the 1 Walter O. Whitley, OD, condition. is Director, Optometric Twelve years after the NEI/ Services at Virginia Eye FIGURE 1 Fluorescein stain Consultants, Norfolk, VA. Industry Workshop, the DEWS shows inferior corneal staining Report was able to offer a more suggestive of DED tissue damage. robust definition: (Photo courtesy Dr. Karpecki.)

Untitled-2 1 4/25/16 11:38 AM dry eye disease 3

This definition makes clear that 30 inflammation and hyperosmolarity Women are hallmarks of the condition and that visual disturbance, tear 25 Men film instability, and ocular surface Overall damage are characteristic clinical 20 findings of DED. The inclusion of visual disturbance and the 15 emphasis on tear film instability

brings the definition closer to our (%) Prevalence 10 current understanding. While much has been learned since its 5 publication, the DEWS Report gave us a useful platform for 0 thinking about the diagnosis of 21-34 35-44 45-54 55-64 65-84 DED. The DEWS Report has Age in years been enormously influential in shaping both research and clinical FIGURE 2 Prevalence of dry eye symptoms found in the Beaver Dam practice. Offspring Study 2005–2008. (Adapted from Paulsen Reference 4.) In the following pages, we’ll look at advances in understanding DED since the DEWS Report was published, and its impact on for estimating the level of DED When stratified by sex, the diagnosis and day-in, day-out in the general population of US effect of age on dry eye differed optometric practice. While still adults.4 between men and women in incomplete, our knowledge has In that study, baseline data BOSS. In men, the estimated significantly expanded. were collected between 2005 and prevalence was similar among 2008 from BOSS participants aged all age groups and there was no PREVALENCE 21 to 84 years via a questionnaire observed effect of age P( = 0.91); We have said that DED is on health history, medication critically important to optometry, use, risk factors, and quality of and part of what makes DED so life. Whether a BOSS subject “As we have learned from the important is the sheer number had DED was determined by of people affected. To put DED self-report of symptom frequency BOSS data and from experience prevalence in perspective, we and intensity or reported use of in our own clinics, a DED normally think of glaucoma as a artificial tears. highly prevalent eye disease. In In an initial publication of diagnosis should not be ruled quantitative terms, the prevalence these baseline data, Paulsen and out simply because a patient is of open-angle glaucoma in the US coworkers reported an overall is approximately 3 million (almost prevalence of DED symptoms young—particularly if the patient 2% of the US population).3 of 14.5%—or nearly 30 million How prevalent is DED? people—with rates significantly is a contact lens wearer.” Although studies vary based higher in women than men —PAUL M. KARPECKI, OD, FAAO on the definition of DED (17.9% vs. 10.5%, P < 0.0001) and a population studied, the (Figure 2).4 Interestingly, although recently published report on DED has traditionally been DED prevalence among 3257 associated with aging, in the while in women, prevalence participants in the long-term, overall BOSS group, symptoms increased with age (P = 0.02), ongoing Beaver Dam Offspring were also prevalent among younger although this interaction was Study (BOSS) provided a baseline subjects.4 not significant (Figure 2).4 Using

UUntitled-2ntitled-2 1 44/25/16/25/16 11:3811:38 AMAM 4 dry eye disease

different criteria, Schaumberg and Perimenopausal women weren’t medical aspect of DED. Patients coworkers’ important work found the only patients, but if you asked come to us with DED because an age-adjusted prevalence of dry a fellow clinician to describe the they are uncomfortable and/ eye syndrome of 7.8% in women typical DED patient, that was or unable to achieve clear, stable 50 and older in a study population what you were likely to hear. vision, impacting productivity between 49 and 89 years of age.5 The BOSS data also aligns well and some visual-related activities In a separate study, Schaumberg with our clinical impression that, of daily living (e.g., reading and and colleagues also reported that although perimenopausal women driving). dry eye was common in men still make up a significant fraction It’s also important to recall (aged 50 to 99 years), with an age of DED sufferers, younger women that DED can be a side effect adjusted prevalence of 4.34% in and men of all ages are increasingly of ocular surgery or topical men 50 and older.6 susceptible (Figure 2). medications. It no longer So, clearly, DED prevalence Although the evidence is still surprises an eye care physician rates vary depending on the largely anecdotal, it is no longer when DED crops up following study population and criteria, considered unusual to encounter ocular surgery10 or in medically but our clinical experience 20-somethings with DED. treated glaucoma patients, where (which admittedly is skewed by Whether this is because there is Baudouin and others have shown our status as clinicians with an more DED at younger ages or that preservatives—particularly because we are more conscious benzalkonium chloride (BAK)— of DED and therefore more used in intraocular pressure- “The impact of dry eye on an willing to diagnose it in younger lowering medications can produce patients is an open question. But significant damage to the ocular individual’s perception of their there is precedent for large scale surface.11 And diabetes, a growing social/environmental changes threat to global health, can health is substantial and of to impact vision. Consider, for produce ocular surface changes as importance as a public health example, the enormous increase well as the better known retinal in myopia in young people that complications.12 problem.” we have witnessed over the last 2 Whether the patient initially generations.7 presented for spectacles, contact —JA PAULSEN AND COLLEAGUES, 2014 lenses, surgery, a glaucoma check, DED AND OPTOMETRIC or any other medical condition, PRACTICE what matters in the end is how well interest in DED) is that the 14.5% DED can produce a range of the patient can see—and vision prevalence rate in the BOSS is a negative impacts on the patients starts with the ocular surface. reasonable estimate and possibly whom optometrists see every day. Because it impacts both vision even an underestimate of the The typical optometric practice and comfort, DED can be the number of Americans affected. is likely to offer contact lenses, enemy of patient satisfaction and The BOSS data also conform and for many practices, contact optometric success—or it can be an to another aspect of our clinical lenses are central to their success. opportunity for practice growth. experience: that a DED diagnosis Changes to the tears, ocular should not be ruled out simply surface, and lid margin can reduce BURDEN OF DISEASE because a patient is young— wearing time—and may even lead Leaving aside its potential particularly if the patient is a to contact lens drop out.8 effects on contact lens wear and contact lens wearer. For optometrists who either surgical outcomes, DED itself can work in a surgical practice or be a very unpleasant condition. IS THE DED POPULATION comanage surgical patients, The BOSS looked closely at DED’s CHANGING? DED can compromise critical impact on some visual-related DED was once commonly preoperative measurements and activities of daily living and found talked about as largely a disease affect postoperative outcomes.9 that while ocular pain was the of perimenopausal women. And of course, there is the most serious impact of DED, dry

UUntitled-2ntitled-2 1 44/25/16/25/16 11:3811:38 AMAM dry eye disease 5

eye could also be associated with As Nichols has pointed out, According to Bron and disruptions in daily function, and patients may have signs of DED coworkers, basing DED diagnosis the effects of DED were similar with few symptoms, or vice versa; on symptoms alone could result across all age groups—it is not just and Sullivan has shown us that in missing as many as 40% of older adults who are impacted by standard tests for dry eye often patients with DED—imagine DED.4 In the words of the current produce contradictory results. As an optometric practice that got report on the BOSS: “The impact clinicians, we want information 40% of its spectacles prescriptions of dry eye on an individual’s to be straightforward—we want wrong! The other side of the coin perception of their health is tests to tell us unambiguously is that among patients who report substantial and of importance as a whether to monitor or dismiss typical dry eye symptoms— public health problem.” the patient. That said, one of the burning and a dry, gritty feeling This impact on patients was great understandings that has with ocular fatigue and irritation often overlooked in the past. Since been achieved in DED is that it especially late in the day or after DED may be chronic and patients is a condition where that level of intense visual tasks—not all of often have been to multiple certainty can’t be expected from them will have DED. Some may doctors, an optometrist who takes any single test (except, perhaps, turn out to have other conditions, their complaints seriously earns with results that are clearly normal the symptoms of which overlap their gratitude and respect. Often or markedly abnormal).14 In fact, with DED. these patients are vocal about it is the very variability of the this with their friends, which can results that often points to dry eye provide word of mouth to grow disease.14 Whether the patient initially the practice. One approach to the problem presented for spectacles, contact As we continue to better of poor correlation between signs understand DED, changes in and symptoms has been to make a lenses, surgery, a glaucoma practice may be called for. For diagnosis solely on symptoms. Yet check, or any other medical example, when a contact lens in a major review for The Ocular patient complains of end-of- Surface, Bron and coworkers make condition, what matters in the day discomfort, our reflex has the following assertion: been to change the lens and/or end is how well the patient can While symptoms solution. Similarly, we have all see—and vision starts with the encountered patients who present are thought to be with complaints of blurred vision, characteristic of DED, ocular surface. thinking they need new glasses recent studies have when the problem may be DED. shown that less than 60% of subjects with other NEW TECHNOLOGY AND DIAGNOSTIC objective evidence of DIAGNOSTIC STRATEGY CHALLENGES DED are symptomatic. We now have a spate of Despite enormous progress Thus the use of symptoms new diagnostic and therapeutic in DED diagnostic technology, alone in diagnosis will technologies that can help us challenges in DED diagnosis likely result in missing help our patients. Major advances remain. One challenge derives a significant percentage include easy-to-use point-of-care from the well-known but still of DED patients, tests for osmolarity and detection frustrating lack of concordance particularly with early/ of the inflammatory marker matrix between DED signs and mild disease. This could metalloproteinase-9 (MMP-9). symptoms13 and the overlap of have considerable impact Other devices enable practitioners DED signs and symptoms with in patients undergoing to visualize meibomian glands signs and symptoms of other cataract or refractive or use topography to measure ocular surface inflammatory surgery, as patients with tear film indices, while still other disorders, including allergic DED have less than instruments measure blink and 14 conjunctivitis and blepharitis. optimal visual results. lipid layer thickness. We have also

UUntitled-2ntitled-2 1 44/25/16/25/16 11:3911:39 AMAM 6 dry eye disease

come to appreciate how much accurate diagnosis can be made Following this logic, much can be learned from something as without unnecessary expenditure attention has been given to simple and low tech as meibomian of time or dollars. the diagnosis of obstructed gland expression. Not all of these meibomian glands. That is entirely testing modalities are equally THE LID MARGIN AND A appropriate, but is it the end of the valuable, but all add to our CHANGE IN THINKING story? It shouldn’t be. First, even knowledge. Over the last decade, an if the majority of DED has an The best strategy is not to enormous amount of information MGD component, there remains depend on any single test or has come to the fore detailing a subset of DED patients with marker. As in glaucoma diagnosis, the role of the lid margin and minimal or no meibomian gland no single test tells us everything the meibomian glands in the involvement—and a much larger we need to know. To continue pathogenesis of DED; in parallel set of patients with meibomian the analogy, although elevated with this, a number of therapeutic gland involvement that also have IOP is often a sign of glaucoma, measures aimed at MGD have inflammation, biofilm formation, it is not diagnostic when taken been developed. This has given rise and tear film instability. More in isolation. Now we have to a broad rethinking about DED. important is to ask: what is the quantifiable biochemical and To give an idea of how far the symptom driver in DED? anatomical markers to break the pendulum has swung, in the 1995 complex conundrum of DED into NEI/Industry Workshop report, DED: A TEAR FILM manageable entities. It’s very useful the expert panel, led by Michael ABNORMALITY to look at multiple markers. Lemp, stated without qualification: DED has been described as “Tear-deficient dry eye is the a tear film abnormality in which largest category of dry eye.”1 tears no longer provide adequate 16 When a contact lens patient Fast forward to 2011 and we support to the ocular surface. find the following statement in Tear dysfunction occurs when the complains of end-of-day an article by Lemp and coworkers lacrimal functional unit (consisting describing a multicenter study of of the lacrimal glands, conjunctival discomfort, our reﬂex has aqueous deficiency vs meibomian goblet cells, meibomian glands, been to change the lens and/ gland dysfunction (MGD) in 224 and their neural and hormonal patients diagnosed with DED: support structures) is unable to or solution. Similarly, we have all “159 [of the 224 DED patients maintain a stable tear layer. A could be] classified into 1 of 3 broad range of environmental encountered patients who present categories: 79 were classified and endogenous factors can with complaints of blurred vision, with only MGD, whereas only trigger dysfunction of the lacrimal 23 were classified as purely functional unit, but in all cases, thinking they need new glasses aqueous deficient, and 57 showed once triggered, there is a chronic when the problem may be DED. evidence of both MGD and inflammatory reaction that sets aqueous deficiency. Overall, 86% in motion an immune reaction of these qualified DED patients that produces the condition we demonstrated signs of MGD.”15 recognize as DED.16 But one need not go to the The conclusion: in a typical patient Once triggered, ocular surface other extreme and use every population, the great bulk of DED inflammation can contribute available test. The key is to have is either the result of MGD or has to sustained dysfunction of the a panel of tests (that may be used a demonstrable MGD component. lacrimal functional unit. The result serially) that will provide adequate Evolving science led by top is a lacrimal functional unit that information about tear production, researchers in the field continues cannot produce tears of adequate degree of ocular surface damage, to shape our understanding of this quantity or quality. Without an and meibomian gland status. disease, and it is imperative that we adequately protective tear film, The goal is to balance diagnostic keep pace with new knowledge to there is continued stress on the efficacy with efficiency, so that an best serve our patients. ocular surface, leading to a cycle

UUntitled-2ntitled-2 1 44/25/16/25/16 11:3911:39 AMAM dry eye disease 7

early 1980s, T cell target recognition was shown to occur through a complex reaction in which a T cell surface receptor called lymphocyte function-associated antigen-1 (LFA-1) FIGURE 4 LFA-1/ICAM-1 adhesion, was able to bind to a an important event in the inflammatory ligand on the target cycle of DED. ICAM-1 is a protein cell (Figure 4). This found on ocular epithelial and ligand is intercellular endothelial tissues. ICAM-1 mediates the inflammatory response by binding adhesion molecule-1 to the LFA-1 receptor on the T cell (ICAM-1), which surface. FIGURE 3 T cells infiltrating the ocular plays an important 18 surface. role in inflammation. As evidence of DED.18 When ICAM-1 binds to of DED in which inflammation this role, ICAM-1 is normally LFA-1, it sets in motion three key produces tissue damage, which expressed in low levels on components of the inflammatory in turn causes cytokine release. epithelial and endothelial response: T cell activation, Resultant inflammation then leads cells of ocular tissues as well recruitment and cytokine release to further cytokine release—an as on antigen presenting cells. (Figure 5).18-20 ongoing cycle that, in some ICAM-1 is overexpressed in Let us look at this cycle of patients at least, can continue, with patients with DED, and this mediator release, inflammation, the DED becoming progressively ICAM-1 overexpression can be and mediator release. In the first worse.2 Even if the inciting cause demonstrated in DED patients’ phase of the cycle, expression, a was meibomian gland obstruction ocular surface and lacrimal triggering event leads to increased that led to evaporative dry eye, tissues.18 expression of ICAM-1 on an inflammatory cycle has been The binding of ICAM-1 to epithelial and endothelial cells initiated. LFA-1 integrin on the surface of in ocular tissues as well as on T cells plays an important role antigen-presenting cells (APCs), THE ROLE OF T CELLS in the inflammatory process of with eventual overexpression of AND MEDIATORS In this process, T cells play an important role by contributing to ocular inflammation through production and release of proinflammatory cytokines.17 This can be shown in histopathology studies, where DED is characterized by T cell infiltration of the lacrimal gland and conjunctiva (Figure 3).18 To make the process comprehensible and clinically meaningful, let us drill down a bit and look at some of the specific mediators, how they are produced, FIGURE 5 ICAM-1 binding initiates a self-perpetuating inflammatory and how they function. In the cycle.16,18-21

Untitled-2 1 4/25/16 11:39 AM 8 dry eye disease

ICAM-1 on the ocular surface.18,21 that perpetuates the cycle—is MAKING CLINICAL SENSE In the next phase, activation, cytokine release: ICAM-1 binding OF DED ICAM-1 binding to LFA-1 on T stimulates cytokine release The pathogenesis of DED is cells contributes to their activation. that further increases ICAM- complex. One can’t simply treat Continuing the cascade, in the 1 expression, leading to tissue the lid margin and leave it at that. third phase, recruitment, ICAM-1 damage and another round of the Today, we know a considerable binding to T cell LFA-1 facilitates cycle.19 (These numbered steps are amount about the processes that recruitment of additional immune included for educational purposes. can cause the lacrimal functional cells to the ocular surface from Due to the multifactorial nature unit to produce too few and the tear film and blood vessels.21 of DED and the complexity of poor quality tears. We know The ICAM-1/LFA-1 interaction inflammation, there are many too that there is much more to becomes a key component of the different entry points to the cycle be learned, and that while our continued migration of T cells to and simultaneous processes; tools for diagnosing DED are target tissues.18 therefore, the cycle may not follow good, there are still gaps in our The final step—and the step these linear steps in exact order.) understanding.

REFERENCES and 1999-2004. Arch Ophthalmol. Distribution of aqueous-deficient and 1. Lemp MA. Report of the National Eye 2009;127(12):1632-39. evaporative dry eye in a clinic-based Institute/Industry workshop on Clinical 8. Nichols JJ, Sinnott LT. Tear film, contact patient cohort: a retrospective study. Trials in Dry Eyes. CLAO J. 1995 lens, and patient-related factors associated Cornea. 2012 May;31(5):472-8. Oct;21(4):221-32. with contact lens-related dry eye. Invest 16. Stern ME, Schaumburg CS, 2. The Definition and Classification of Ophthalmol Vis Sci. 2006;47:1319-28. Pflugfelder SC. Dry eye as a mucosal Dry Eye disease: report of the Definition 9. Epitropoulos AT, Matossian C, Berdy autoimmune disease. Int Rev and Classification Subcommittee of the GJ, et al. Effect of tear osmolarity on Immunol. 2013 Feb;32(1):19-41. doi: International Dry Eye Workshop (2007). repeatability of keratometry for cataract 10.3109/08830185.2012.748052. Ocul Surf. 2007;5(2):75-92. surgery planning. J Cataract Refract Surg. 17. Pflugfelder SC, Corrales RM, Paiva CS. T 3. The Eye Diseases Prevalence Research 2015 Aug;41(8):1672-7. helper cytokines in dry eye disease. Exp Eye Group. Prevalence of Open-Angle 10. Raoof D, Pineda R. Dry eye after laser Res. 2013 December;117. Glaucoma Among Adults in the in-situ keratomileusis. Semin Ophthalmol. 18. Gao J, Morgan G, Tieu D, et al. ICAM-1 United States. Arch Ophthalmol. 2004 2014 Sep-Nov;29(5-6):358-62. expression predisposes ocular tissues to Apr;122(4):532-8. 11. Baudouin C. Detrimental effect of immune-based inflammation in dry eye 4. Paulsen AJ, Cruickshanks KJ, Fischer ME, preservatives in eyedrops: implications patients and Sjögrens syndrome-like MRL/lpr et al. Dry eye in the beaver dam offspring for the treatment of glaucoma. Acta mice. Exp Eye Res. 2004 Apr;78(4):823-35. study: prevalence, risk factors, and health- Ophthalmol. 2008 Nov;86(7):716-26. 19. Pavilack MA, Elner VM, Elner SG, et al. related quality of life. Am J Ophthalmol. 12. Manaviat MR, Rashidi M, Afkhami- Differential expression of human corneal 2014 Apr;157(4):799-806. Ardekani M. Prevalence of dry eye and perilimbal ICAM-1 by inflammatory 5. Schaumberg DA, Sullivan DA, Buring syndrome and diabetic retinopathy in type cytokines. Invest Ophthalmol Vis Sci. 1992 JE, et al. Prevalence of dry eye syndrome 2 diabetic patients. BMC Ophthalmol. Mar;33(3):564-73. among US women. Am J Ophthalmol. 2008 Jun 2;8:10. 20. Anderson ME, Siahaan TJ. Targeting 2003 Aug;136(2):318-26. 13. Nichols KK, Nichols JJ, Mitchell GL. ICAM-1/LFA-1 interaction for controlling 6. Schaumberg DA, Dana R, Buring JE, et The lack of association between signs and autoimmune diseases: designing peptide al. Prevalence of Dry Eye Disease among symptoms in patients with dry eye disease. and small molecule inhibitors. Peptides. US Men: Estimates from the Physicians’ Cornea. 2004 Nov;23(8):762-70. 2003 Mar;24(3):487-501. Health Studies. Arch Ophthalmol. 2009 14. Bron AJ, Tomlinson A, Foulks GN, et al. 21. Stern ME, Gao J, Schwalb TA, et al. Jun;127(6): 763-8. Rethinking dry eye disease: a perspective Conjunctival T-Cell Subpopulations 7. Vitale S, Sperduto RD, , Ferris FL III. on clinical implications. Ocul Surf. 2014 in Sjogren’s and Non-Sjogren’s Patients Increased Prevalence of Myopia in the Apr;12(2 Suppl):S1-31. with Dry Eye. Invest Ophthalmol Vis Sci. United States Between 1971-1972 15. Lemp MA, Crews LA, Bron AJ, et al. 2002;43:2609-14.

This educational program was developed in conjunction with and sponsored by Shire, based on interviews with Arthur B. Epstein, OD, FAAO, Paul M. Karpecki, OD, FAAO, Katherine M. Mastrota, MS, OD, FAAO, and Walter O. Whitley, OD. Dr Epstein, Dr Karpecki, Dr Mastrota, and Dr Whitley each received a fee for participation in this program.

UUntitled-2ntitled-2 1 44/25/16/25/16 11:3911:39 AMAM