CONTINUING EDUCATION

The New Dry Eye — A Global Perspective

A review of how dry eye has changed in the two years since the International Dry Eye Workshop report.

BY KELLY K. NICHOLS, OD, PHD, & GARY N. FOULKS, MD, FACS

The last decade in ocular surface disease has been remarkable in that over this period of time, the general public has come to recognize and embrace the term "dry eye." Typing the term "dry eye" into the Google search engine on the Internet results in "about 13,600,000" hits ranging from comprehensive overviews of symptoms, diagnosis, and management to chat groups, support groups, and blogs. Companies manufacturing pharmaceuticals, over-the-counter artificial tear preparations, and other treatment devices have Web sites dedicated to dry eye. In addition, non-profit groups such as the Sjögren's Syndrome Foundation and the Red Hot Mamas, a menopause education Web site, also provide information on dry eye to interested patients, consumers, and practitioners.

Organizations specific to dry eye disease and the ocular surface continue to flourish. The Tear Film and Ocular Surface Society (TFOS) continues to grow in membership, and the international meeting held every three years remains the premier meeting in this topical area. New organizations, such as the Ocular Surface Society of Optometry (OSSO), are being established to meet the needs of clinicians, thereby providing a resource to both practitioners and patients.

Finally, research funding through the National Eye Institute (NEI) in the topical area of ocular surface disease has increased significantly over the last decade. In this time period, a journal dedicated to the topic, special issues dedicated to ocular surface disease, and countless publications have become available to clinicians and researchers alike. This is also supported by the number of newly chronicled projects on dry eye and ocular surface disease that are listed on clinicaltrials.gov. Indeed, this is a perfect time to be seeing patients or doing clinical, translational, and/or basic research in the area of ocular surface disease.

International Dry Eye, Reinvented

There has been a culmination of effort by a growing group of passionate and steadfast individuals in the clinical and research dry eye community over the last decade. Some of the more recent fruits of these efforts are reflected in the published report(s) of the International Dry Eye WorkShop (DEWS, 2007).

We can assess the recent growth of our knowledge in the field of dry eye by comparing the DEWS reports to what is arguably the most read and cited paper in the field of dry eye research, the 1995 NEI/Industry report on clinical trials in dry eye. The NEI/Industry report is 12 pages in length, including references. At the time it was published, it represented the most significant effort put forth by researchers in defining the disease, classifying the condition, and defining future research directions. The current DEWS report (an entire journal issue, more than 125 pages excluding references in length) demonstrates the significant advances in the field over time and, like its predecessor, provides a dry eye research road map for the next generation of tear film and ocular surface clinicians and researchers.

This report appeared in 2007; now two years later, how has the research and clinical care landscape changed because of the report? Has dry eye been reinvented?

Defining Dry Eye

It is exciting to see new research addressing the cutting-edge areas mentioned within the DEWS report that will provide new information to fill gaps in our knowledge of the condition. In 1995, we had minimal knowledge of the prevalence, incidence, or risk factors associated with dry eye disease. Since that time, numerous prevalence studies as well as a study reporting the 10-year incidence of dry eye in an older U.S. population (Moss et al, 2008) have been published. In the latter study, the 10-year incidence of dry eye was 21.6 percent, while reported prevalence of dry eye ranges from 10-to-15 percent, depending on the methods used to classify dry eye. Aging patients are very likely to be seen in clinical practice, and this segment of the population will continue to grow in the upcoming decades, increasing the likelihood of significant dry eye appearing in all types of practices.

While we have greatly increased our knowledge of the patient characteristics in dry eye, our understanding of the natural history of the condition is limited. In some regards, this challenges researchers in defining dry eye patients consistently in clinical trials and also creates an environment of cat-and-mouse in drug development for new therapeutics for the condition. It is likely that we will see natural history epidemiology studies developed to address this issue, which will aid in clinical care.

Core Mechanisms The DEWS definition and classification report highlights four "core mechanisms" in the etiology of this multifactorial condition: tear instability, tear hyperosmolarity, association with inflammatory pathways, and ocular surface damage. It is unclear how the core mechanisms result in the symptoms reported by patients; a better understanding of the interrelationship of these mechanisms is needed.

For example, the role of inflammation in dry eye is a very hotly debated topic at the forefront of the field. Unfortunately, translational research in this area has been limited in the past, partially due to a lack of technology in assessing small-volume tear samples. Several researchers are making significant contributions in this area. A recent study (Li et al, 2008) profiling tears of Sjögren's Syndrome patients highlights the evaluation of biochemical tear components including inflammatory mediators such as cytokines. This type of research is a challenge in that tear samples, especially those collected from dry eye patients, may be insufficient in volume for many of the commonly utilized techniques for protein analysis, thereby requiring sensitive instrumentation that is not widely available.

This article also demonstrated that methodological steps need to be taken to understand the complex nature of tear proteins in the evaluation of biomarkers. Even without dry eye disease, the tear film proteome is complex. One recent study (Green-Church et al, 2008) reported up to 100 unique proteins observed in tear samples collected via microcapillary tube or Schirmer strip in normal patients. We expect more cutting edge research like this over the next few years as these techniques become more widely accepted and available.

Diagnosis

At present, there is no single "gold standard" test for developing a clinical diagnosis of dry eye; therefore, a battery of tests is generally employed in clinical practice as well as for research purposes to define "dry eye." Additionally, patients' self-reported symptoms are a primary element in diagnosis, although symptoms of ocular discomfort are common in many ocular surface conditions other than dry eye.

Despite the subjective nature of symptom reporting, symptom reports are more repeatable and reliable than are the objective tests commonly used in evaluating dry eye. Several studies over the years have shown that symptom evaluations have moderate-to-high repeatability, while repeatability was generally poor-to-moderate for objective tests and best for the tear breakup time (TBUT) test. Utilizing a symptom survey or standard interview, whether designed for the practice or for clinical research, can help patients provide more consistent answers. Using the same technique and order of clinical tests (e.g. TBUT and Schirmer) can also improve the outcome of testing.

Dry Eye as a Symptom-Based Disease Because of the general repeatability of symptoms compared to that of diagnostic tests, dry eye has often been considered a symptom-based disease. A recent international panel that used Delphi methods (in which a panel of experts anonymously answers questions and may later revise their answers upon hearing other experts' responses) to develop consensus recommendations considered symptoms and signs to be of primary importance in diagnostic and treatment decisions, with diagnostic tests taking a secondary role. This was further validated by the DEWS report, which created a "global" consensus for dry eye diagnosis. This grid, however, represents a snapshot in time — a starting point, if you will. As clinicians use the grid and interpret the findings, changes will likely be made to the grid. Table 1 represents an interpretation of the grid and the likely order of tests commonly assessed in a dry eye examination.

Assessing Symptoms The relatively good reliability of symptom assessments extends to many of the symptom questionnaires in common use: The Ocular Surface Disease Index (OSDI) has good-to-excellent test-retest reliability. The OSDI has been widely accepted for use in dry eye clinical trials, yet standard cutpoints for graded severity of dry eye are not widely published. It is generally considered that an OSDI score of 13 or more is indicative of level 2 dry eye on the DEWS diagnosis grid.

The DEWS grid does not specify how we should routinely ask patients about symptoms, but does indicate several important components to symptom assessment: frequency (how often a symptom is expressed), severity (how bad or disabling the symptom is), and impact of the environment. It is thought that in the early stages of disease, symptoms are not present all of the time but rather are episodic in nature and could be influenced by environmental factors such as airplane travel or contact lens wear. In addition, how disabling a symptom may be is likely very dependent on the individual. Some patients have a higher tolerance for ocular irritation compared to others. Other patients may stop or avoid certain activities but may not consider this to be related to how their eyes feel. Asking patients questions about how eye irritation or discomfort can prevent them from performing activities that they want to do, such as reading or using a computer, can help in determining impact of symptoms. Specific questions about length of comfortable lens wearing time or comfortable computer use in hours can help track changes over time with or without treatment.

Visual symptoms were added to the definition of dry eye for the first time in the 2007 DEWS report. Many practitioners have noted visual symptoms in dry eye patients for years, yet some of the eyecare community has been slow to embrace visual symptoms in part because of their subjective nature and because of the difficulty confirming visual symptoms with standard visual acuity testing.

Unfortunately, the grid does not specifically recommend testing beyond patient-reported blur or "transient vision." There is some indication that contrast sensitivity or low-contrast visual acuity may be affected by significant dry eye, yet there is no current recommendation regarding testing procedures. It is likely that an immediate assessment (without blinking) may have a different (poorer) response in a patient who has poor tear film stability, although more research in this area is needed.

Dye Testing More clinicians are actively using both fluorescein and lissamine green in assessing dry eye patients. Strips wetted with saline represent the most commonly used clinical method, although a number of practices are purchasing liquid dyes compounded by pharmacies such as 2% fluorescein, 15mL and 1% lissamine green, 10mL, both nonpreserved. Clinicians are also beginning to use the DEWS-recommended NEI grid to assess staining on a 0-to-3 scale in five corneal regions (superior, inferior, nasal, temporal, and central; Figure 1) and in six conjunctival regions (far nasal, nasal-superior, nasal-inferior, far temporal, temporal-superior, and temporal-inferior; Figure 2). TBUT is performed prior to the fluorescein staining assessment, and generally three readings are taken and averaged. Clinicians should make an effort to instill an equal amount of dye to each eye, which they can achieve by using one strip per eye, or 5 microliters of liquid fluorescein or 10 microliters of liquid lissamine green. Approximately two minutes should pass between dye instillation and the staining assessment.

Figure 1. The NEI-recommended corneal regions for assessing fluorescein staining. Note that the central region is approximately 4mm (one-third the corneal diameter). Clinical pearl: Staining is best viewed with a yellow Wratten filter.

Figure 2. The NEI-recommended conjunctival regions for assessing lissamine green staining. Clinical pearl: add enough dye and wait two minutes to assess staining. Pooling of dye must dissipate prior to viewing staining.

Meibomian Gland Dysfunction

Of notable interest in the DEWS report is the inclusion of meibomian gland dysfunction (Figure 3) in the evaporative category of dry eye. There is considerable controversy in this area. The "Delphi report" (Behrens et al, 2006) considered lid disease (anterior and posterior blepharitis) separate from dry eye, but still under the umbrella of "dysfunctional tear syndrome." In contrast, the DEWS report includes "meibomian oil deficiency" as a subcategory of evaporative dry eye, and the recommended management of this condition is part of the overall DEWS dry eye management scheme.

Figure 3. Posterior lid margin redness found in patients who have meibomian gland dysfunction.

Because of this controversy and significant grass-roots interest in managing the condition, a new DEWS-like International Meibomian Gland Workshop has been developed. This effort is sponsored by industry and supported by TFOS, with details on the workshop available at http://www.tearfilm.org/mgdworkshop/. The report of the workshop (expected in early 2010) will delineate the current level of knowledge and provide research and clinical care insight, much like the 1995 dry eye report did. The report will discuss the definition, classification, diagnosis, etiology, and management of meibomian gland-related conditions, which many believe to be the new "dry eye." It is possible that a significant majority of mild dry eye patients may also have low-grade lid disease, warranting future clinical and basic science research in this area.

Contact Lens Dry Eye

While contact lenses are considered a contributing factor in dry eye disease, many believe the diagnosis and management scheme should be different for contact lens-related dry eye. Of specific interest in the contact lens research community is the impact of materials and care solutions on dryness symptoms, tear component changes, and ocular surface damage as well as improvement in the condition with changes in any of these parameters.

In evaluating factors associated with contact lens dropout, patient-reported dryness drives contact lens discontinuation (Richdale et al, 2007); therefore, a better understanding of the role of these factors in lens-related dry eye is a step toward preventing dropout.

Impact of the DEWS Report

As discussed, the DEWS Report is very important for current and future dry eye diagnosis, treatment, and research. In this regard, we asked four prominent clinician/researchers the question: "In your opinion, what has been the global impact of the DEWS report?" Following are their responses.

MICHAEL LEMP, MD, Clinical Professor of Ophthalmology, Georgetown University, George Washington University; Chief Medical Officer, Tearlab Corp. The DEWS report stands as a landmark resource for clinicians and researchers seeking to understand contemporary thinking on virtually all aspects of dry eye disease. In one document you can find the world literature summarized, the consensus of the world's experts presented, and practical guidelines for evaluating and treating patients. I regard it as an essential part of the library for anyone interested in understanding and applying current concepts in the diagnosis and management of dry eye disease.

DAVID SULLIVAN, PhD, President, Tear Film and Ocular Surface Society; Senior Scientist, Schepens Eye Research Institute; Associate Professor, Harvard Medical School The Dry Eye Workshop (DEWS), which was sponsored by the Tear Film & Ocular Surface Society (TFOS), was created to provide an evidence-based critical review of the definition, classification, epidemiology, diagnosis, management, and research techniques of dry eye disease. The findings have been presented in major symposia in North America, Europe, and Asia.

In addition, the DEWS report, which has been translated into Chinese, English, French, German, Italian, Japanese, Spanish, and Portuguese, is available in its entirety on the TFOS Web site (www.tearfilm.org). The online DEWS report has been opened more than 11,000 times by people from around the world. This report has changed the approach of global pharmaceutical companies in their development of new dry eye treatments. I believe the impact of the DEWS report will be long-lasting.

GARY N. FOULKS, MD, Arthur and Virginia Keeney Professor of Ophthalmology, University of Louisville School of Medicine When the NEI/Industry Dry Eye Workshop was convened in the mid 1990s, the goal was to improve terminology and methodology in conducting clinical trials in dry eye disease. The guidelines of that workshop served well for 10 years to harmonize the approach to clinical trials in treating dry eye.

But the advances in research into dry eye as well as the expanding international interest in the disease prompted a more ambitious attempt to collect, collate, and evaluate current information regarding dry eye. The International Dry Eye Workshop employed an expanded number of participants from a truly international group of clinicians and researchers to evaluate the current understanding of dry eye disease through an evidence-based review of the literature. The final product of the workshop was a compendium of recommendations with regard to definition and classification, epidemiology, diagnostic methodology, design and conduct of clinical trials, management and therapy, and research accomplishments and needs for dry eye disease. In addition to a comprehensive written report, online resources with an extensive library of diagnostic techniques was created.

During the two years since the published report, it is apparent that the goals of the DEWS project have been achieved, and the clinical and research communities have increasingly adopted communication regarding dry eye disease as well as progress toward the research challenges that were identified in the report. Major examples of such implementation include:

• Recognition of the multifactorial nature of dry eye and the appreciation that symptoms of the disease include alteration of visual function as well as ocular discomfort. The recognition that functional visual acuity is a better index of visual impairment compared to simple Snellen acuity and that determination of quality-of-life measures must include assessment of visual performance is now standard in evaluating dry eye.

• Recognition of the importance of increased tear film osmolarity and the role of inflammation in the pathogenesis of dry eye disease. The central role of these two aspects of dry eye has allowed for a more global view of altered tear function whether the disease presents as an evaporative or aqueous-deficient phenotype. Understanding the mechanisms of inflammation that are operative in dry eye disease has increased options for therapeutic intervention.

• Management decision based upon disease severity. Although the mechanisms contributing to dry eye disease are still identified as evaporative or aqueous-deficient processes, recognizing the concurrence and interdependence of the disease process has allowed formulation of guidelines based upon disease severity rather than mechanism alone.

• Clinical trial research methodology has changed. Although the regulatory guidelines have not appreciably changed, clinical trial research has incorporated methods to validate biomarkers of disease as potential outcome measures for therapy. Despite the fact that the regulatory guidelines are slow to reflect it, the potential role of measurable biomarkers could help resolve the dilemma of poor correlation of clinical symptoms and signs, which is a vagary of dry eye disease study.

The DEWS process and project, although arduous, has succeeded in organizing discussion and both clinical and basic science investigation of dry eye disease. The resources and stimulus provided to the field assures more progress in future years.

PAUL KARPECKI, OD, Corneal Services and Ocular Surface Disease Director, Koffler Vision Group, Lexington, KY I view the DEWS report as significant for many reasons:

1. It validated much of what we were doing in clinical practice.
2. It added new insights into therapies such as doxycycline use and the role of osmolarity and inflammation.
3. It gave us a structure or recipe for dysfunctional tear syndrome (DTS)/dry eye management and helped to demonstrate that dry eye is a significant disease that warrants physician attention as opposed to a nuisance condition — in other words, it supports what our patients have been saying for years.

Regarding my first point, the DEWS provided sound scientific and research support around the therapies we've included in managing patients who have DTS. It showed that medications such as loteprednol and doxycycline have clinical research behind them; it supported the use of Restasis (Allergan) via research and references as a pivotal drop in the management of DTS.

Regarding my second point, it made us think about our approaches by adding insightful scientific support to many therapeutic options — low dose doxycycline comes to mind as well as managing lid disease.

My third point may be the most important. Many practitioners dismiss dry eye as a nuisance condition, but dry eye is significant and debilitating and may lead to serious sequalae if not managed. Patients have been saying for years how much this condition affects them, but without a comprehensive guide such as the DEWS report, many clinicians did not respect them as they should have. This workshop and the level of scientific support clearly shows the impact of ocular surface disease, the effect on patients, the various scientifically based treatment options, and that it is indeed a significant pathology that warrants this level of publication.

The Future is Bright

With a wave of new clinicians and researchers interested in dry eye and new technology to support these efforts, it is clear that the field of dry eye is moving forward with innovation and creativity. The DEWS report provided a 10+ year follow up to the 1995 NEI/Industry Report, and dry eye has already changed even in the short time since publication of the DEWS report. Clinicians seeing dry eye patients every day are leading the charge to determine whether the current diagnosis and management recommendations are accurate for clinical care. New therapeutic agents are in development to address elements of the four aspects of the core sequence in dry eye disease. With diligence and perseverance, in 10 year's time the "new" dry eye will have been reinvented many times over. CLS

Dr. Nichols is an associate professor at The Ohio State University College of Optometry. She has current NIH funding to study dry eye in postmenopausal women in addition to funding through the pharmaceutical and contact lens industries, including Alcon, Inspire Pharmaceuticals, Ocusense, and Pfizer, to support related research projects.

Dr. Foulks is the Arthur and Virginia Keeney Professor of Ophthalmology in the Department of Ophthalmology and is the director of the Cornea and External Disease Institution at the University of Louisville School of Medicine. He is also the assistant dean for Clinical Trial Research at the University of Louisville School of Medicine. He is a consultant or advisor to Acucela, Alcon, Aton Pharma, Bausch & Lomb, Inspire Pharmaceuticals, Pfizer, Santen, and Tearlab and has received research funding from Alcon, Inspire Pharmaceuticals, and Tearlab.

For references, please visit www.clspectrum.com/references.asp and click on document #162.