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Dry Eye Disease

Dry Eye Disease

the current understanding of DRY DISEASE

The Role of Clinicians in Educating the Public Insights from a Roundtable Discussion

program chair Anthony J. Bron, FRCOphth, FMedSci, FARVO: Oxford, UK participants Penny Asbell, MD, FACS, MBA: New York New York, USA Stefano Barabino, MD, PhD: Genoa, Italy Christophe Baudouin, MD, PhD, FARVO: Paris, France Eric D. Donnenfeld, MD: New York, New York, USA Gerd Geerling, MD, PhD: Düsseldorf , Germany Debra A. Schaumberg, ScD, OD, MPH: Boston, Massachusetts, USA

This medical education activity was supported by Pfizer Inc.

A supplement to

This medical education activity was developed by MedEdicus LLC

JULY/AUGUST 2011 the current understanding of DRY

The Role of Clinicians in Educating the Public Insights from a Roundtable Discussion program chair Anthony J. Bron, FRCOphth, FMedSci, FARVO Professor Emeritus Nuffield Laboratory of University of Oxford, UK participants Penny Asbell, MD, FACS, MBA Professor of Ophthalmology Director of and Refractive Services Department of Ophthalmology Mount Sinai School of Medicine New York, New York, USA Stefano Barabino, MD, PhD Associate Professor Clinica Oculistica Department of Neurosciences, Ophthalmology, and Genetics University of Genoa Genoa, Italy Christophe Baudouin, MD, PhD, FARVO Professor of Ophthalmology Quinze-Vingts National Ophthalmology Hospital Vision Institute, University of Paris 6 Paris, France Eric D. Donnenfeld, MD Clinical Professor of Ophthalmology New York University New York, New York, USA Trustee of Dartmouth Medical School Hanover, New Hampshire, USA Chair of Cornea for the American Society of and Refractive (ASCRS) Gerd Geerling, MD, PhD Department of Ophthalmology Heinrich-Heine-University Düsseldorf, Germany Debra A. Schaumberg, ScD, OD, MPH Associate Professor of Medicine and Ophthalmology Director of Ophthalmic Epidemiology Brigham and Women's Hospital Harvard Medical School Boston, Massachusetts, USA

Proprietary or commercial disclosures may be found after the references.

2 The International Dry Eye Workshop (DEWS) was held in PROF ASBELL: There remains an underappreciation of dry eye 2007 and was published in Ocular Surface .1 The report is an disease by both European and US professionals. In the last decade, evidence-based review of the present state of knowledge of however, clinicians have had an increased understanding of the dry eye disease (DED) and the methods used to evaluate, prevalence of DED and a growing acceptance of the concept that diagnose, and manage the disorder. In addition, the DED can negatively affect patient quality of vision as well as International Dysfunction Workshop was comfort. 3-5 This may be less well understood in Europe. There is also completed in 2010 and was published on March 2011. 2 These an economic impact of DED that varies from country to country, 2 workshops summarize the findings of current research and which is hard to calculate since many patients are self-diagnosed and identify future needs for a better understanding of the self-treated with over-the-counter remedies. A limited survey has etiology, pathogenesis, and potential therapy of DED. It is been reported in Europe. 6 Therefore, there is clearly an opportunity therefore an excellent opportunity to assess the outcomes of in Europe and in the , as well as in other parts of the these workshops, to obtain a global perspective and, at the world, to raise awareness of the prevalence of DED. same time, to consider the implications for ophthalmologists in Europe. EVOLVING CONCEPT OF DRY EYE DISEASE A group of renowned experts in anterior segment disease convened to share their insights into the current understanding PROF BRON: The DEWS report defines dry eye disease as a of the disease and to think about the implications for their multifactorial disease of the and ocular surface that results in patients. The highlights of this discussion are presented here. symptoms of discomfort, visual disturbance, tear film instability, and potential damage to the ocular surface. 1 Dry eye disease is NEEDS OF CLINICIANS TO accompanied by increased osmolarity of the tear film and UNDERSTAND DRY EYE DISEASE inflammation of the ocular surface. Hyperosmolarity plays a causal role and is regarded as a gold standard in the diagnosis of DED. How PROF GEERLING: There are 2 primary needs to better understand has this concept evolved? dry eye disease: First, a need to be aware of the differential diagnosis of DED, as has been reviewed in the Dry Eye Workshop (DEWS) PROF SCHAUMBERG: Unlike the previous definition, the new and Meibomian Gland Dysfunction Workshop (MGD) . Second, there definition of dry eye disease recognizes that the symptoms of the is a need for diagnostic tools to differentiate between DED and MGD. disease could cause both discomfort and visual problems and, thus, Additionally, in Germany, ophthalmologists are looking for specific the new definition eliminates the disconnect that often exists therapeutic approaches to DED, such as the use of anti-inflammatory between the symptoms and the appearance of the ocular surface. agents to supplement the use of tear substitutes, which are used currently to restore tear volume. PROF ASBELL: The 2007 DEWS report also expanded our understanding of the mechanism of dry eye disease. PROF BRON: Yes, I agree. Tear substitutes can ameliorate symptoms and have some important therapeutic effects, but newer therapies can specifically target the disease process. “We have not yet convinced the entire ophthalmology community that inflammation PROF BAUDOUIN: In France, the situation is similar to that in is present in dry eye disease.” — PROF BAUDOUIN Germany. There is typically limited knowledge about the pathophysiology of dry eye. This limited knowledge frustrates many ophthalmologists because they believe that their patients are not PROF BRON: We must remember that patients are focused getting symptomatic relief from tear substitutes despite the primarily on the resolution of their symptoms and not on ocular availability of a large variety of these agents on the market. Since surface signs. Ophthalmologists recognize the prime importance of the availability of cyclosporine 5 years ago (not approved in France, symptoms, but they care about signs too, because these signs reflect but obtainable through hospital pharmacies), there has been an eye pathology, which may predict later outcomes. increasing recognition that inflammation is involved in DED. PROF DONNENFELD: In the past, dry eye disease was considered PROF BRON: Cyclosporine, incidentally, is not approved in most an irreversible, inevitable change due to age. Now we know that countries in Europe, although it is available in Turkey. inflammation plays a major role in many cases of DED and that anti- inflammatory therapy can both improve the ocular surface and PROF BARABINO: The situation is very similar in Italy. One of the prevent disease progression. major problems in my country is that dry eye patients are not referred to an ocular surface specialist. Instead, they consult their PROF BRON: Initially, there was much resistance to the idea of pharmacist, who gives them artificial tears on nonspecific grounds. inflammation of the ocular surface in dry eye disease because Next, they see a general practitioner, who also may not recognize clinicians did not see a bright . Instead, they saw subtle dry eye as a disease. Even when patients do consult a general hyperemic changes. However, Paiva and Pflugfelder convinced the ophthalmologist, that physician often prescribes artificial tears medical community that treating inflammation could reverse both without making a diagnosis of DED or distinguishing it from patient symptoms and ocular surface signs. 7 meibomian gland dysfunction . Therefore, it is imperative that both ophthalmologists and general practitioners become well informed PROF BAUDOUIN: I believe that we have not yet convinced the about both diseases. Moreover, we need to educate patients about entire ophthalmology community that inflammation is present in dry DED because they do not really understand the nature of the disease. eye disease.

3 PROF BARABINO: Understanding inflammation is undoubtedly a measured easily; hyperosmolarity, however, can be measured quite step forward in our comprehension of the pathogenesis of dry eye easily. Sullivan and colleagues have shown that hyperosmolarity is a disease, but the problem of diagnosing inflammation on the ocular better indicator of severity than the Schirmer test, tear breakup time, surface remains. There is a great need for simple approaches or staining with dyes. 12 that can be used by the general ophthalmologist to quantify inflammation. PROF BRON: Prof Baudouin, please describe your “vicious circle” concept that is important for the understanding of the self- PROF BAUDOUIN: Measuring inflammation remains a difficult perpetuation of this disease. task in clinical practice. Biopsies are invasive and difficult to propose to patients. Impression cytology appears to be a more appropriate PROF BAUDOUIN: Tear hyperosmolarity increases the disorders way to assess the ocular surface because it allows for the of corneal and conjunctival epithelial cells and goblet cells because quantification of squamous metaplasia, counts, and it causes apoptosis. Most likely, the destruction of goblet cells, which identification of inflammatory cells. Flow cytometry is a biological is a hallmark of dry eye disease, is a major contributor to the disease. technique that quantifies inflammatory markers expressed by At the level of the cornea, activation of reflex arcs probably conjunctival cells. It has been used in the clinical setting and in stimulates the ocular surface, further augmenting the neurogenic multicenter trials to quantify and monitor inflammation in dry eye inflammation. This, in turn, leads to the release of inflammatory disease. 8 Human leucocyte antigen DR (HLA-DR) expression is a cytokines and the subsequent stimulation of inflammatory cells and reliable marker for measuring inflammation in DED. Other lymphocytes. All those inflammatory or degenerative phenomena are techniques such as RT-PCR or tear cytokine measurements may also additional events that cause further goblet cell destruction and tear be used. ELISA (enzyme-linked immunosorbent assay) or multiplex film instability, resulting in a vicious circle (Figure 1) . bead analysis have been used successfully for assessing the presence of inflammatory cytokines or chemokines in the tears in DED. 9,10 However, tear collection in DED patients remains difficult and the risk of protein dilution by reflex tearing cannot be ruled out. DRY EYE DISEASE TERMINOLOGY PROF BRON: The Delphi report 11 provided a consensus approach to symptomatic ocular surface disease and generated a treatment algorithm based on the severity of symptoms and signs. The panelists were justifiably critical of the term “dry eye disease” because it contradicts the fact that patients may not always experience actual ‘dryness’ and, in fact, may have increased tearing as one of their symptoms as is the case in evaporative dry eye. Because of these conceptual difficulties, the panel created the term “dysfunctional tear syndrome”. This is a nice general term for symptomatic ocular surface disease, but it is not an appropriate term to replace “dry eye disease” itself, which is a subset characterized by tear hyperosmolarity. MAPK=mitogen-activated protein kinase; MGD=meibomian gland dysfunction; PROF BARABINO: I agree. The term “dry eye disease” is MMP=matrix metalloproteinase proteolytic [enzymes]; NSSDE=non-Sjögren incomplete, and yet “dysfunctional tear syndrome” is too complex and syndrome-associated dry eye; SSDE=Sjögren syndrome-associated dry eye; is difficult for patients to understand. A term in between the 2 would TNF=tumor necrosis factor be of , perhaps a term that includes the words “ocular surface”. Figure 1: Pathophysiology of dry eye disease. 1 Reprinted with permission from Ethis Communications, Inc. PROF SCHAUMBERG: My issue with the term “dysfunctional tear syndrome”, apart from its complexity, is that it points the finger at PROF ASBELL: Laboratory research has shown that conjunctival and the tears, while the ocular surface is what is really affected. corneal epithelial cells can be stimulated by abnormalities in the tear film, making them active participants in the inflammatory process, and PROF GEERLING: Events in the tears are important, but it is true, not just bystander tissues that are injured during the course of the as you say, that it is problematic when a terminology is chosen for disease. The corneal and conjunctival cells actually produce cytokines dry eye disease that relates to the tear film only, rather than to a and inflammatory mediators that amplify the process. 13-18 specific anatomic structure such as the ocular surface. PROF BARABINO: Mouse models of dry eye disease have clearly PROF BRON: There is still some work to be done to arrive at a shown that DED is not simply an inflammatory disease, but that it simple language that locks together the concept of dryness with involves the activation of immune cells, especially the antigen- increased saltiness of the tears—thus, incorporating both the presenting cells of the cornea. The DED mouse model that was aqueous-deficient and the evaporative forms of the disease. developed in Massachusetts Eye and Ear Infirmary (Boston, PATHOPHYSIOLOGY OF Massachusetts, USA) has shown the invasion of the cornea by lymphatic vessels, the migration of antigen-presenting cells to the DRY EYE DISEASE lymph nodes, and the activation of lymphocytes. 19 The activation of PROF BAUDOUIN: Two major mechanisms have been suggested the lymphocytes is probably the reason DED is a chronic disease for the pathophysiology of dry eye disease—inflammation and and it explains the reason behind the effectiveness of cyclosporine, hyperosmolarity. Inflammation can be treated, but cannot be which has activity against lymphocytes, in the treatment of DED. 19

4 ENVIRONMENTAL FACTORS CLASSIFICATION OF THAT AFFECT DRY EYE DISEASE DRY EYE DISEASE PROF SCHAUMBERG: The effect of environmental stimuli on dry PROF BRON: I think we are comfortable with the 2 established eye disease poses a complex issue. Recently, several important major categories of dry eye disease classification. 1 First is aqueous- research articles have added significantly to our knowledge of the deficient DED. This can be subdivided into Sjögren Syndrome role of environmental stimuli. Patients often complain that reading (primary or secondary) and non-Sjögren DED, which includes age- and computer use exacerbate their DED symptoms. Himebaugh and related DED. In this case, lacrimal function is impaired by invasion colleagues have shown decreased blink rates and more central of the with inflammatory cells. Lacrimal flow can also breakup of the tear film during computer use in people with DED be reduced by cicatricial obstruction to the lacrimal ducts. compared with normal subjects. 20 The second major category is evaporative DED. The DEWS There is also the role of low humidity and its effects on patients report 1 recognized an intrinsic form of DED that was lid-related, with dry eye disease. For example, a study from Taiwan examined including not only meibomian gland dysfunction , but also poor lid more than 3000 people, 21 with approximately half the people congruity or lid dynamics, a low blink rate, and the toxicity of investigated working in an indoor environment with moderate systemic retinoids used in the treatment of acne vulgaris. Another humidity. The study showed that working in this environment was form of evaporative DED is that caused by damage to the ocular significantly associated with a higher prevalence of DED. surface, due to deficiency, topical preservatives, contact wear, and allergy (Figure 2) . Other studies have examined the issue of air travel. One study surveying 1246 Australian pilots showed a marked association between DED and the flight environment, with 72% of respondents reporting DED during flight, but only 5% reporting such symptoms at other times. 22

Lastly, studies from —specifically Tibet, 23 Mongolia, 24 and India 25 —suggest that people living at high altitudes (ie, low humidity), have a very high prevalence (approximately 50%) of DED symptoms.

PROF BARABINO: A significant decrease in tear secretion from the lacrimal gland was observed 3 days after placing mice in a low- humidity chamber with a constant airflow, suggesting that low humidity stimulates a negative feedback loop. 26 One of the possible reasons for this is that chronic stress of the ocular surface could induce irreversible changes in the lacrimal gland, thereby decreasing its tear production.

PROF SCHAUMBERG: Sometimes dry eye disease can be affected by low humidity alone, but the culprit may also be the actual movement of air over the ocular surface. VTU=video monitor Figure 2: Classification of dry eye disease. 1 Reprinted with permission from PROF BRON: Certainly, both low humidity and air movement Ethis Communications, Inc. increase evaporation. It seems that environmental factors such as humidity, high altitude, and extended viewing of computer monitors, among others, affect people in all professions and in all parts of the “It is important to acknowledge that aqueous- world. It is evident that both the clinicians and the public require deficient and evaporative DRY EYE DISEASE more education about these aspects of dry eye disease. are not mutually exclusive. They can and do EFFECT OF ON occur in combination; therefore, they can DRY EYE DISEASE produce complex hybrid states.” — PROF BRON PROF BRON: What is the effect on dry eye disease of the internal environment created, for instance, by certain medications? Another mechanism that may trigger dry eye disease is the feedback from the ocular surface through the lacrimal functional PROF SCHAUMBERG: Medications play a very important role in unit. When corneal sensation is impaired, a loss of sensory drive to dry eye disease. The Physicians’ Health Study 27 and the Beaver Dam the lacrimal gland occurs, that may reduce the secretory function of Eye Study 28 showed that the use of is associated with the lacrimal gland. 29,30 It is important to acknowledge that aqueous- an increased risk of DED. Other commonly used medicines, such as deficient and evaporative DED are not mutually exclusive. They can , beta-blockers, and anything with an anticholinergic and do occur in combination; therefore, they can produce complex effect, are also associated with increased DED symptoms. hybrid states.

5 PROF SCHAUMBERG: A pure aqueous-deficient dry eye disease ETIOLOGIES OF DRY EYE DISEASE state with no evaporative component is probably uncommon. PROF DONNENFELD: Aqueous-deficient dry eye disease begins Conversely, meibomian gland dysfunction is very common, with with abnormalities of the lacrimal gland, which not only reduce the perhaps 45% to 60% or more of people with DED having some such amount of aqueous, but also reduce the associated defense proteins abnormality. 31,32 Most people likely experience a mixed mechanism, found in the tear film. Inflammatory events in the gland can have at least, in the long term. Dry eye disease may start with lacrimal this result. Furthermore, low androgen levels can negatively gland disease and aqueous deficiency, but certainly, in Sjögren influence aqueous production. Meibomian gland dysfunction, which patients, there is MGD as well. is also associated with androgen dysfunction, is responsible for PROF BRON: As you say, it has been demonstrated in the literature evaporative DED. As discussed earlier, medications such as diuretics that both of these disorders occur in patients with severe Sjögren and topical ocular medications with preservatives, particularly syndrome. In my opinion, however, there is less evidence for this in artificial tears, can play a very significant role. the population as a whole. However, there is a move toward PROF BAUDOUIN: Preservatives can be detrimental to the ocular emphasizing the contribution of evaporative dry eye. surface. Benzalkonium chloride (BAK) may cause or aggravate dry DIAGNOSIS OF DRY EYE DISEASE eye disease. Short exposure to BAK has been shown to decrease goblet cell density in humans. 34 Long-term exposure to antiglaucoma PROF DONNENFELD: To diagnose dry eye disease, the clinician drugs with preservatives also cause decreased goblet cell density. 35 needs to start with symptoms of DED and the patient’s history. Many experimental reports have been published showing the overall toxicity of BAK to the ocular surface, even at low concentrations, Aqueous-deficient DED, in general, tends to worsen throughout and possible direct proinflammatory properties have been the day as the aqueous component of the tears evaporates from the suggested. 36 In addition, as a surface-active detergent, BAK also ocular surface, and causes a general irritation and foreign body destabilizes the lipid layer of the tear film, increasing evaporative sensations. Patients who have or who are taking loss. The result of both mechanisms, namely the mucus and lipid certain medications, as discussed earlier, are most likely to have layer alterations, is a globally impaired tear film with tear instability aqueous-deficient DED. and excessive evaporation. Evaporative DED tends to be worse in the morning, perhaps PROF DONNENFELD: An important etiology for dry eye disease because of the abnormal lipids that have accumulated overnight, that is overlooked often is ocular surgery. A meta-analysis study causing patients to experience burning. Patients with evaporative DED examining the incidence of DED after LASIK (laser-assisted in situ often have systemic skin disorders, such as acne vulgaris or . keratomileusis) surgery, found that 20% of LASIK patients On clinical examination, diagnosis can sometimes be made very experienced dryness symptoms that were significantly worse than easily by looking at the lids, because of telangiectasia, erythema, those experienced preoperatively. This indicates that DED symptoms meibomian gland dysfunction with meibomian oil turbidity, and are common complications of ocular surgery. 37 occluded meibomian glands. Aqueous-deficient DED tends to have a PROF BRON: Prof Donnenfeld, does that worsen the risk of less plentiful tear film. Schirmer scores may be lower than normal regression after surgery? and there tends to be interpalpebral staining of the and cornea with lissamine green or in the classical DED PROF DONNENFELD: Yes, there are articles by several authors, distribution. including Marguerite McDonald 38 and John Hovanesian, 39 that have shown that dry eye disease can affect postoperative results. Patients who have evaporative DED often have clearly defined De Paiva 40 and Ursea 41 showed that DED was associated with MGD, meibomian foam, and an increase in staphylococcal regression, suboptimal outcomes, and low patient satisfaction. The commensals on the lid margin. In addition to interpalpebral staining, etiology of this relationship stems from the negative effect of surgical some inferior conjunctival staining may be present and is consistent trauma, specifically because of the damage to the corneal nerves with the presence of pathogenic staphylococci. caused by the incision and photoablation. Damage to these nerves, PROF BRON: If a symptomatic patient has a normal Schirmer which are responsible for innervating the cornea, can disrupt the score, extensive MGD, and ocular surface staining, he or she can be normal feedback loop from the cornea, which normally drives lacrimal reasonably diagnosed as having evaporative dry eye disease. It is tear production. Recent evidence suggests that topical cyclosporine when the Schirmer score is low and there is evidence of decreased may reduce the risk of DED after implantation and aqueous production that clinicians must make a value judgment as LASIK by having a direct effect on corneal nerve repair. 42,43 to whether aqueous-deficient and evaporative dry eye are both PROF BRON: Prof Donnenfeld, do you think neuropathic input can present. As we have said, lacrimal deficiency and MGD can occur also cause pain independent of a dry eye disease mechanism? together in the same patient and result in a combined mechanism for dry eye. However, it is also possible that this hybrid state could PROF DONNENFELD: Yes, I do. In my opinion, it is an etiology come about in another way. For instance, if we suppose that there is that is sometimes overlooked. Some patients have significant an evaporative dry eye due to MGD, then, as the severity of the neurogenic pain following surgery without associated corneal condition increases and the corneal surface is damaged, we can staining. Wilson and colleagues have made a very strong case that postulate that a loss of sensory drive to the lacrimal gland could what is classified as dry eye disease following LASIK may actually be reduce the compensatory lacrimal flow and result in an additional, a neurological disease, which they have termed LASIK-induced functional aqueous deficiency. 33 neuroepitheliopathy, or LINE. 43,44

6 PROF BARABINO: Dry eye disease is also a of PREVALENCE OF DRY EYE cataract surgery. A study presented at the European Association for DISEASE Vision and Eye Research (EVER) showed significant, prolonged tear instability after cataract surgery. Changes in tear film breakup time PROF SCHAUMBERG: There are a large number of studies of the were evident 1 month after surgery and changes in the lipid part of prevalence of dry eye disease across the , including the United 27,48 49 50 51 52 the tear film were still seen 2 months after surgery. 45 States, , Canada, Europe, and Asia. We have learned from the prevalence studies that DED symptoms are very PROF BRON: Do you think this patient population was already at common, with DED ranging from 3% to 15% in patients aged 50 risk for dry eye disease and was tipped into it by destabilization of years and older, which is the age of populations examined in most of the ocular surface? these studies. 51 The study in Spain reported a prevalence of 11% or 12%. Asian studies generally show a higher prevalence, approximately double that reported in either the United States, “Dry eye should be viewed as an expected Australia, or Europe. complication of any surgery that disturbs the ocular surface.” — PROF GEERLING “We have learned from the prevalence studies that DRY EYE DISEASE symptoms are very common, PROF BARABINO: Yes, I do. With these patients, the surgery goes with DED ranging from 3% to 15% in patients perfectly well and they have excellent postoperative vision, but they aged 50 years and older.” — PROF SCHAUMBERG complain of burning and foreign body sensation. The possible causes for these postoperative symptoms were attributed to tear film instability. PROF BRON: How does the prevalence of meibomian gland PROF DONNENFELD: Cyclosporine has been shown to dysfunction relate to the prevalence of dry eye disease? significantly improve the quality of vision after cataract surgery. Limbal relaxing incisions probably caused the most significant dry PROF SCHAUMBERG: There have been fewer studies looking at eye disease of all other incisions. 42 meibomian gland dysfunction, but in my opinion, the trends are similar, with higher levels of MGD in the Asian populations compared PROF GEERLING: Dry eye should be viewed as an expected with the Caucasian populations. complication of any surgery that disturbs the ocular surface. Heimann and colleagues showed that approximately two-thirds of EMERGING DIAGNOSTIC patients who underwent vitreoretinal surgery suffered from DED TECHNIQUES symptoms postoperatively. 46 PROF ASBELL: Minimally invasive diagnostic methods are the PROF ASBELL: One way to think about dry eye disease and ocular future of dry eye disease diagnosis. First, we need to be able to surgery is in terms of the DEWS classification of severity, 1 with a diagnose DED, differentiate it from other types of external diseases, scale ranging from 1 to 4. If a patient has a score of 1 preoperatively, and then to classify the DED subtypes. Second, we would like to he or she is going to have a score of 2 or 3 postoperatively. better classify disease severity because the current severity grading is difficult to put into practice. Third, we need tests that can quantify PROF BRON: Clinicians generally treat patients based on the severity of dry eye disease that was judged intuitively. But as you say, changes on the ocular surface and tear film that result from both the DEWS and the meibomian gland dysfunction workshops treatment. have attempted to classify the severity of disease. Sullivan and Some of the interesting new diagnostic areas include the colleagues studied a large number of subjects, both DED and normal evaluation of tear osmolarity, 12 examining tears with optical individuals, looking at the typical tests for DED diagnosis—Ocular coherence tomography (OCT), measuring tear height and tear Surface Disease Index (OSDI), osmolarity, tear breakup time, volume, and looking at the contents of the tears both by proteomics Schirmer test, corneal and conjunctival stain. The authors obtained and by measuring inflammatory cytokines. a consensus severity assessment of each of those tests and then normalized the data, mapping those gradings to a single scale, to produce a composite score for each patient. 12 “Minimally invasive diagnostic methods are the future of dry eye disease diagnosis.” PROF SCHAUMBERG: Dr. Sullivan used a weighted average of multiple tests to arrive at an overall score. A difficulty with such an — PROF ASBELL approach is that some patients have very severe symptoms, but minimal ocular surface signs. Using this method, clinicians would Another exciting possibility is the use of impression cytology probably underestimate the severity of the symptoms. combined with flow cytometry, to examine specific inflammatory biomarkers. This approach was pioneered by Prof Baudouin. 8 Before we leave the topic of etiology, I would like to point out that contact can be another exacerbating factor for dry eye I think the next diagnostic area that has gained momentum lately disease. Patients may be fairly well compensated in terms of ocular is the improved evaluation of the and meibomian gland surface homeostasis without contact lenses, but putting a contact dysfunction and, specifically, the recognition of how lid disease and lens on the eye disrupts the system enough to cause the DED meibum alterations contribute to changes in the tear film and the symptoms. More than 50% of people who discontinue contact lenses ocular surface. There is certainly a high level of interest among do so because of DED symptoms. 47 ophthalmologists in obtaining better biomarkers and more objective

7 metrics to help in the diagnosis of DED. Currently, scientists from low-humidity environments, and specific head positions during Europe and are collaborating to explore such techniques computer use. 54 However, these nonpharmacologic treatments have in other human disease models. Their work may lead to poor compliance among patients. Other measures, such as anti- breakthroughs and a better understanding of DED. inflammatory , are generally more accepted by patients.

PROF BRON: I was especially interested in the study by Beuerman Surgical measures, such as punctal plugging in aqueous-deficient and colleagues in which it was found that the level of 2 tear proteins, dry eye and systemic tetracycline derivatives, which are thought to calgranulin A and B, correlated with the severity of meibomian gland be effective in patients with MGD, are limited to the severe form of dysfunction and a range of ocular surface symptoms. 53 the disease. These treatments, even if available, are frequently underused. PROF BARABINO: With respect to the use of lissamine green or as a diagnostic tool for dry eye disease, it has to be PROF BRON: Some experts have suggested using a short course of pointed out that both vital stains are available in Europe, but their topical prior to inserting punctal plugs in patients with use is limited to some ocular surface specialists. In fact, there is moderate or severe aqueous-deficient dry eye disease. 55 The evidence that ophthalmologists in Italy use lissamine green less than rationale is that punctal plugs may not only conserve the tears, but 10% of the time. Lissamine green is very important because, as does may also conserve inflammatory mediators. Thus, the steroids can rose bengal, it can quantify both corneal and conjunctival damage, be useful initially to damp down the inflammation, and possibly but without the discomfort induced by rose bengal’s intrinsic toxicity increase the effectiveness of the plugs. or the phototoxicity induced by ultra-violet exposure. Prof Asbell, do you use a severity-specific protocol for management PROF BRON: This is an important point because lissamine green of DED? is hardly used in the , and rose bengal is unavailable. In the past, clinicians used rose bengal routinely, but when it was PROF ASBELL: I often direct my treatment according to the withdrawn from the market and lissamine green became available, patient's symptoms because that is the key reason for the patient clinicians did not switch to lissamine green; and so, a real diagnostic seeking treatment. If the patient is satisfied with what is being done, opportunity has been lost. It seems that residents in training hesitate I continue using that treatment. If the patient is not satisfied, I before using lissamine green because it is unfamiliar to them or explore other treatments. because it might stain the lids if not used properly. As a result, these With respect to the various artificial tear preparations, I look at clinicians are failing to examine the ocular surface directly. the differences among them. I do not think all of them work well for PROF DONNENFELD: A study by Sullivan and colleagues on tear everybody. For mild disease, I generally start out with a multiuse osmolarity and dry eye disease severity showed that the second bottle, since it is cost-effective and convenient. I tend to choose highest correlation with DED severity was conjunctival staining, preparations that are available without BAK because that preservative followed by corneal staining. 12 Therefore, if a tear osmolarity sensor is particularly toxic to the ocular surface. If the response is not is not available, in my opinion, conjunctival staining is the second satisfactory, I move to unit-dose artificial tears. I reserve topical most useful way to diagnose DED. cyclosporine for those patients who have severe findings. Recently, I have also been prescribing a low-dose nonpreserved PROF ASBELL: The other point to emphasize is that when examining the eye, clinicians often ignore the lid, the meibomian gland orifices, (dexamethasone, 0.01%), which is available in the United and the quality of expressed meibum, thereby missing an important States only through a compounding pharmacy—a pharmacy that will part of the examination in patients with ocular surface disease. prepare, on request, specific eye drop formulations that are not commercially available. This very-low-dose steroid medication does MANAGEMENT OF not appear to induce elevated intraocular pressure, a side effect we DRY EYE DISEASE often find with higher-dose steroids. Yet, it can be effective for many patients with inflammatory ocular surface disease. PROF GEERLING: There is extensive variation across nations in the management of dry eye disease, in no small part due to Another treatment option approved by the US Food and Drug differences in the availability of certain drugs. The majority of Administration is a ophthalmic insert, which patients, regardless of disease subtype, are treated first with is a tear pellet that is placed in the lower lid cul-de-sac. The pellet lubricants because these are widely available. melts with the patient's own tears, providing lubrication over a period of time. These lubricants can be a little thick and sometimes interfere with vision. Therefore, I suggest placing the pellet at night “There is extensive variation across nations in to provide lubrication overnight and possibly even provide some the management of dry eye disease, in no small early morning comfort. part due to differences in the availability of PROF BAUDOUIN: We also have the tear pellets in France. Mainly — PROF GEERLING certain drugs.” Sjögren syndrome patients, who instill many, many eye drops each day, use these pellets.

There is a huge need in the early stages, however, for additional PROF BRON: When do you offer conserving spectacles? nonpharmacologic management. This includes instructing patients about etiologies; use of lid hygiene and lid warming (eg, in PROF ASBELL: The idea of using conserving spectacles to meibomian gland dysfunction -associated dry eye); and avoidance of decrease evaporation is appealing. However, these spectacles are risk factors or exacerbating conditions such as certain medications, not easy to get for my patients in New York.

8 PROF BRON: In the United Kingdom, one can get commercial conserving spectacles, or the departments will make them. “In our practice, we are strong believers They are very helpful if the patient can accept them cosmetically. of the use of combination immunomodulation. PROF BAUDOUIN: Conserving spectacles are not available in By adding a to cyclosporine, you France. With respect to management, ophthalmologists are obtain a more rapid effect and alleviate the convinced that preservatives are toxic for the ocular surface, burning and irritation that is sometimes especially in dry eye disease, so they worry about preservatives in associated with cyclosporine therapy.” artificial tears. Ocular surface specialists will frequently use anti- — PROF DONNENFELD inflammatory eye drops. Additionally, in France, there is preservative-free steroid and topical cyclosporine. Hospital pharmacists can prepare cyclosporine, or commercial cyclosporine PROF BARABINO: Inflammation certainly plays a pivotal role in can be imported with a specific authorization. We also use systemic dry eye disease pathogenesis and, therefore, we need to focus doxycycline, which is particularly prescribed in meibomian gland simultaneously on tear replacement and anti-inflammatory therapy. dysfunction and rosacea patients. In such patients, topical I do not think we need to eliminate inflammation, but we need to azithromycin, recently introduced in France, is under investigation. modulate it by using soft steroids or using other commercial in diluted formulations or at reduced dosage. We PROF BRON: As mentioned earlier, commercial topical need to be dynamic in our approach and adjust anti-inflammatory cyclosporine is not available in the European Union, but people do formulate it for treatment of dry eye disease. Erythromycin and therapy according to changes in ocular surface conditions with time. azithromycin have been of interest as systemic or topical treatments For example, in some of my patients I control inflammation by using of meibomian gland dysfunction in younger patients. steroids twice a week, which has a positive effect on ocular surface inflammation and may help tear substitutes to adhere to ocular PROF GEERLING: Metronidazole topical gel, 0.75%, is available surface epithelia. At the same time, at this dosage, the well-known for topical treatment of inflammatory changes associated with negative effects of steroids can be limited. Most Italian rosacea in Germany, the United Kingdom, and the United States . It ophthalmologists do not feel comfortable prescribing chronic has been used successfully for evaporative dry eye disease, corticosteroid therapy, but if it is used cautiously, it may be meibomian gland dysfunction, and . 56 We often initiate beneficial. 60,61 Regarding the use of systemic omega-3 fatty acids, I treatments simultaneously simply because patients have been totally agree with Prof Donnenfeld, that in most cases they are very suffering for so long and want rapid relief. Punctal plugging is helpful in improving patients’ symptoms, as my group had effective in patients with a zero Schirmer score. I choose not to use demonstrated some years ago. 62 a topical steroid unless there is obvious inflammation, because my expectation is that the frequent instillation of artificial tears may PROF BRON: Steroids are potentially risky in dry eye disease dilute any inflammatory markers on the surface. In addition, patients because the ocular surface is already damaged, possibly enhancing prefer not to apply too many eye drops. their entry into the eye. Newer steroidal agents, such as soft steroids and glucocorticoid receptor agonists, are becoming commercially PROF DONNENFELD: In our practice, we are strong believers of available. They are interesting agents because of their favorable the use of combination immunomodulation. By adding a safety profiles. However, if patients are prescribed steroid therapy, corticosteroid to cyclosporine, you obtain a more rapid effect and how can a clinician make sure that patients do not use them alleviate the burning and irritation that is sometimes associated with indiscriminately? cyclosporine therapy. 57 However, we recognize the possibility of long- term side effects with topical corticosteroids and limit their use to 1 PROF GEERLING: I prescribe only 1 bottle, which ensures that the month, during acute exacerbations of dry eye disease. With respect patient runs out of supply within a month. Furthermore, I reexamine to tear preparations, we start with 1, which is transiently preserved, and reevaluate my patients at 6 weeks, including assessment of that is to say, a preservative that inactivates on exposure to light or intraocular pressure. to the tear film. We also believe that patients who have hyperosmolar tear films benefit from a hypo-osmotic tear formulation. There are many other modalities for the off-label medical treatment of dry eye disease, including systemic tetracyclines, To bring up a new topic, we also advocate oral nutritional acetylcysteine, and even retinoic acid for secondary surface changes supplements. Wojtowicz and colleagues reported a dramatic such as keratinisation, but some of these agents are difficult to improvement in Schirmer scores in patients taking omega-3 obtain. Another medication that is even more challenging to obtain supplementation. 58 is a form of nutrient tear substitute. We produce these autologous PROF ASBELL: There has been great interest by both clinicians serum drops to add nutrients to the tear film. Patients often benefit and patients in the use of nutritional supplements to treat dry eye immensely, but supplying this blood-derived medication on a disease. Most suggest an increase in dietary intake of omega-3 fatty permanent basis requires the distributor to have a specific license for acids to reduce inflammation associated with DED. Though there is the product. Currently, only 4 universities in Germany have this some experimental data supporting the use of essential fatty acids license, so it is nearly always unavailable unless a patient happens to for heart disease and rheumatoid arthritis, the evidence for treatment live near one of these institutions. I believe that this is the same of DED is limited at this time, and even contradictory. 59 situation throughout the continent.

9 PROF BAUDOUIN: I treat severe dry eye disease the same way, PROF BARABINO: Ophthalmologists are increasingly interested including the occasional use of autologous serum. in the treatment of dry eye disease. This year we have launched an online course on ocular surface disease with the intention of PROF BARABINO: We also use autologous serum in very specific reaching more than 1000 ophthalmologists in Italy each year. We cases in Italy, but in my opinion, in the more severe cases, the use of strongly believe that education is the most important way to improve a combination of steroids and cyclosporine is the best approach. our knowledge of DED treatment. We are hoping that in the future, PROF BRON: Autologous serum is also used in the United our course can be translated to make it available to other European Kingdom, to a limited extent. countries and to encourage the participation of other European ocular surface experts. We are also producing a document for the PHYSICIANS’ UNDERSTANDING Italian government to increase the understanding of DED as an OF DRY EYE DISEASE important chronic disease. We could possibly collaborate with other countries to do this throughout Europe. PROF GEERLING: General physicians misunderstand the concept of dry eye disease, and think that it is primarily an aqueous deficiency. “We strongly believe that education is the most PROF BRON: Also, some physicians trivialize dry eye disease. Even important way to improve our knowledge of dry ophthalmologists often do not always give it enough weight, perhaps eye disease treatment.” — PROF BARABINO because detailed information about DED has not been emphasized in our education and early practice. 63 PROF BRON: In summary, dry eye disease is prevalent all over the PROF GEERLING: Education is needed to emphasize the effect of world and has many causes. It adversely affects ocular comfort, the severe form of the disease on individual patients. Buchholz and vision, and quality of life. The DEWS report broadened the definition colleagues showed that the quality of life of patients with severe dry of DED and confirmed its major forms as aqueous-deficient and eye disease was similar to that for patients with severe angina, renal evaporative dry eye. The recently published meibomian gland dialysis, or disabling hip fracture. 64 dysfunction workshop report emphasized the importance of PROF SCHAUMBERG: In the United States, multiple events took evaporative dry eye, of which the most common cause is MGD. place to convince physicians of the seriousness of dry eye disease. The presence of MGD is sometimes overlooked, but it can be First, large epidemiological studies demonstrated that DED is indeed very prevalent. Additionally, awareness of the inflammatory readily diagnosed by routine lid inspection and meibum expression. mechanism has helped patients and clinicians to understand DED as Our discussion highlighted the causal role of tear hyperosmolarity in a disease and not just a normal part of aging. DED and the importance of ocular surface inflammation. Inflammation is an important therapeutic target. There is a need to With only one prevalence study conducted and published in Europe, identify inflammatory biomarkers to aid diagnosis, and to monitor it might be helpful if there were some additional European data that severity and the response to treatment. One of the consequences of could be covered in the popular press and used to educate patients. surface inflammation is epithelial damage and increased tear film instability, causing a vicious circle that amplifies and perpetuates the PROF BRON: I think that is an important message. I do not really know why Europe is lagging behind in this area. It may be related to disease. An avoidable contributor to this vicious circle is the frequent lack of funding for such studies. use of preserved eye drops.

PROF BAUDOUIN: I have organized many meetings in France. All Many other aspects of dry eye disease were discussed, more the meetings that dealt with ocular surface disease, dry eye disease, than can be summarized here, but an important conclusion or allergic disease were well attended because ophthalmologists of the roundtable was that ophthalmologists can do a better want to better understand these conditions so they can better treat job to promote a clearer understanding of dry eye disease, their patients. There is undoubtedly a great desire within the among themselves, other physicians, and members of the ophthalmological community to improve their knowledge and public. It is our hope that this report will provide some efficiency in the management of ocular surface diseases. impetus to this intent.

financial disclosures financial relationships as follows: board membership–Alcon, Allergan, Bausch + Lomb, The authors have made the following disclosures: Prof Asbell received an honorarium from Pfizer; expert testimony–Santen, Voisin Consult; speakers bureau– Bausch + Lomb; Pfizer for participation in this project; she has other relevant financial relationships as manuscript preparation– Alcon. Prof Schaumberg received an honorarium from Pfizer for follows: consultancy–Addition, Alcon, Aton Pharma, Bausch + Lomb, Candeo Clinical/ participation in this project; she has other relevant financial relationships as follows: board Science Communications, Inspire, Johnson & Johnson, Merck, Otsuka, Pfizer, Santen, membership–SARcode, Mimetogen; consultancy–Alcon, Allergan, Bausch + Lomb, Celtic Vindico Medical Education, Vistakon; grant/research funding to institution– Alcon, Aton Pharma, Eleven Biotherapeutics, Inspire/Merck; grants to institution–Pfizer; development Pharma, Bausch + Lomb, Inspire, Martin and Toni Sosnoff New Works Fund, National of educational presentations–Allergan; stock–Tearlab, Mimetogen. Institutes of Health, Pfizer, Research to Prevent Blindness. Prof Barabino received an correspondence honorarium from Pfizer for participation in this project; he has no other disclosures to Anthony J Bron, FRCOphth, c/o MedEdicus, 73 Redding Road, PO Box 839, Georgetown, make. Prof Baudouin received an honorarium from Pfizer for participation in this project; CT 06829, USA. email: [email protected]. he has other relevant financial relationships as follows: consultancy–Alcon, Allergan, MSD, Pfizer, Santen Pharmaceutical. Prof Bron received an honorarium from Pfizer for grant support participation in this project; he has other relevant financial relationships as follows: This medical education activity is supported through an educational grant from Pfizer Inc. consultancy–Acucela, Actelion Pharmaceuticals, Alcon, Alto Pharma, AOPharma, Bausch + The views and opinions expressed in this educational activity are those of the authors Lomb, Clinact, F2G Discovery, Novagali Pharma, Novaliq, Otsuka, Pfizer, Takeda, and do not necessarily represent the views of MedEdicus LLC, Pfizer Inc, or EuroTimes . OcuSense/TearLab; stock– OcuSense/TearLab. Prof Donnenfeld received an honorarium Please refer to the official prescribing information for each product for discussion of from Pfizer for participation in this project; he has other relevant financial relationships as approved indications, contraindications, and warnings. follows: consultancy–Alcon, Allergan, Bausch + Lomb, Inspire/Merck, Pfizer. Prof Geerling received an honorarium from Pfizer for participation in this project; he has other relevant ©2011 MedEdicus LLC. All rights reserved.

10 references 33. Bron AJ, Yokoi N, Gafney E, Tiffany J. Predicted phenotypes of dry eye: proposed 1. DEWS Report: A Mission Completed. Ocul Surf. 2007;5(2):65-204. consequences of its natural history. Ocul Surf. 2009;7(2):78-92. 2. The International Workshop on Meibomian Gland Dysfunction. Invest Ophthalmol 34. Herreras JM, Pastor JC, Calonge M, Asensio VM. Ocular surface alteration after Vis Sci. 2011;52(4):1917-2085. long-term treatment with an antiglaucomatous drug. Ophthalmology. 1992;99(7): 3. Introduction to the report of the International Dry Eye WorkShop (2007). Ocul Surf. 1082-1088. 2007;5(2):69-70. 35. Pisella PJ, Debbasch C, Hamard P, et al. Conjunctival proinflammatory and 4. Smith JA. The epidemiology of dry eye disease: report of the Epidemiology proapoptotic effects of latanoprost and preserved and unpreserved timolol: an ex Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf. vivo and in vitro study. Invest Ophthalmol Vis Sci. 2004;45(5):1360-1368. 2007;5(2):93-107. 36. Baudouin C, Labbé A, Liang H, Pauly A, Brignole-Baudouin F. Preservatives in 5. Asbell P, Lemp M. Treatment and diagnosis. In: Asbell P, Lemp M, eds. Dry Eye eyedrops: the good, the bad and the ugly. Prog Retin Eye Res. 2010;29(4):312-314. Disease: The Clinician's Guide to Diagnosis and Treatment. New York, NY: 37. Bailey MD, Zadnik K. Outcomes of LASIK for with FDA-approved lasers. Thieme Medical Publishers, Inc; 2006. Cornea. 2007;26(3):246-254. 6. Clegg JP, Guest JF, Lehman A, Smith AF. The annual cost of in 38. Salib GM, McDonald MB, Smolek M. Safety and efficacy of cyclosporine 0.05% drops France, Germany, Italy, Spain, Sweden and the United Kingdom among patients versus unpreserved artificial tears in dry-eye patients having laser in situ managed by ophthalmologists. Ophthalmic Epidemiol. 2006;13(4):263-274. keratomileusis. J Cataract Refract Surg. 2006;32(5):772-778. 7. Paiva CS, Pflugfelder SC. Rationale for anti-inflammatory therapy in dry eye 39. Hovanesian JA, Shah SS, Maloney RK. Symptoms of dry eye and recurrent erosion syndrome. Arq Bras Oftalmol. 2008;71(6 suppl):89-95. syndrome after . J Cataract Refract Surg. 2001;27(4):577-584. 8. Brignole-Baudouin F, Ott AC, Warnet JM, Baudouin C. Flow cytometry in conjunctival 40. De Paiva CS, Chen Z, Koch DD, et al. The incidence and risk factors for developing impression cytology: a new tool for exploring ocular surface pathologies. Exp Eye dry eye after myopic LASIK. Am J Ophthalmol. 2006;141(3):438-445. Res. 2004;78(3):473-481. 41. Ursea R, Purcell T, Tan B, et al. The effect of cyclosporine A (Restasis) on recovery of 9. Wakamatsu TH, Dogru M, Ayako I, et al. Evaluation of lipid oxidative stress status following LASIK. J Refract Surg. 2008;24(5):473-476. and inflammation in atopic ocular surface disease. Mol Vis. 2010;16:2465-2475. 42. Donnenfeld ED, Solomon R, Roberts CW, Wittpenn JR, McDonald MB, Perry HD. 10. Enríquez-de-Salamanca A, Castellanos E, Stern ME, et al. Tear cytokine and Cyclosporine 0.05% to improve visual outcomes after multifocal intraocular lens chemokine analysis and clinical correlations in evaporative-type dry eye disease. implantation. J Cataract Refract Surg. 2010;36(7):1095-1100. Mol Vis. 2010;16:862-873. 43. Ambrósio R Jr, Tervo T, Wilson SE. LASIK-associated dry eye and neurotrophic 11. Behrens A, Doyle JJ, Stern L, et al; Dysfunctional tear syndrome study group. epitheliopathy: pathophysiology and strategies for prevention and treatment. Dysfunctional tear syndrome: a Delphi approach to treatment recommendations. J Refract Surg. 2008;24(4):396-407. Cornea . 2006;25(8):900-907. 44. Wilson SE, Ambrósio R. Laser in situ keratomileusis-induced neurotrophic 12. Sullivan BD, Whitmer D, Nichols KK, et al. An objective approach to dry eye disease epitheliopathy. Am J Ophthalmol. 2001;132(3):405-406. severity. Invest Ophthalmol Vis Sci. 2010;51(12):6125-6130. 45. Barabino S, Solignani F, Rolando M. Dry eye-like symptoms and signs after cataract 13. Li DQ, Chen Z, Song XJ, Luo L, Pflugfelder SC. Stimulation of matrix surgery. Invest Ophthalmol Vis Sci. 2010;51:E-Abstract 6254–D882. metalloproteinases by hyperosmolarity via a JNK pathway in human corneal 46. Heimann H, Gochman R, Hellmich M, Bechrakis NE, Foerster MH. Dry eye epithelial cells. Invest Ophthalmol Vis Sci. 2004;45(12):4302-4311. symptoms following retinal surgery and ocular tumour therapy [in German]. 14. Luo J, Li DQ, Corrales RM, Pflugfelder SC. Hyperosmolar is a proinflammatory Ophthalmologe. 2004;101(11):1098-1104. stress on the mouse ocular surface. Eye . 2005;31(5):186-193. 47. Richdale K, Sinnott LT, Skadahl E, Nichols JJ. Frequency of and factors associated 15. Lam H, Bleiden L, de Paiva CS, Farley W, Stern ME, Pflugfelder SC. Tear cytokine with contact lens dissatisfaction and discontinuation. Cornea. 2007;26(2):168-174. profiles in dysfunctional tear syndrome. Am J Ophthalmol. 2009;147(2):198-205. e1. 48. Schaumberg DA, Sullivan DA, Buring JE, Dana MR. Prevalence of dry eye syndrome 16. De Paiva CS, Corrales RM, Villarreal AL, et al. Corticosteroid and doxycycline among US women. Am J Ophthalmol. 2003;136(2):318-326. suppress MMP-9 and inflammatory cytokine expression, MAPK activation in the 49. McCarty CA, Bansal AK, Livingston PM, Stanislavsky YL, Taylor HR. The corneal in experimental dry eye. Exp Eye Res. 2006;83(3):526-535. epidemiology of dry eye in Melbourne, Australia. Ophthalmology. 17. Epstein SP, Chen D, Asbell PA. Evaluation of biomarkers of inflammation in response 1998;105(6):1114-1119. to benzalkonium chloride on corneal and conjunctival epithelial cells. J Ocul 50. Caffery BE, Richter D, Simpson T, Fonn D, Doughty M, Gordon K. CANDEES. The Pharmacol Ther. 2009;25(5):415-424. Canadian Dry Eye Epidemiology Study. Adv Exp Med Biol. 1998;438:805-806. 18. Chen D, Wei Y, Li X, Epstein S, Wolosin JM, Asbell PA. sPLA2-IIa is an inflammatory 51. Viso E, Rodriguez-Ares M, Gude F. Prevalence of and associated factors for dry eye in mediator when the ocular surface is compromised. Exp Eye Res. 2009;88(5): a Spanish adult population (the Salnes Eye Study). Ophthalmic Epidemiol. 880-888. 2009;16(1):15-21. 19. Barabino S, Dana M. Dry eye syndromes. Chem Immunol Allergy. 2007;92:176-184. 52. Jie Y, Xu L, Wu YY, Jonas JB. Prevalence of dry eye among adult Chinese in the 20. Himebaugh NL, Begley CG, Bradley A, Wilkinson JA. Blinking and tear break-up Beijing Eye Study. Eye (Lond) . 2009;23(3):688-693. during four visual tasks. Optom Vis Sci. 2009;86(2):E106-E114. 53. Tong L, Zhou L, Beuerman RW, Zhao SZ, Li XR. Association of tear proteins with 21. Su SB, Wang BJ, Tai C, Chang HF, Guo HR. Higher prevalence of dry symptoms in Meibomian gland disease and dry eye symptoms. Br J Ophthalmol. 2010 Oct 28. skin, , nose and throat among workers in clean rooms with moderate humidity. [Epub ahead of print] J Occup Health. 2009;51(4):364-369. 54. Wolkoff P. “Healthy” eye in office-like environments. Environ Int. 2008;34(8): 22. McCarty DJ, McCarty CA. Survey of dry eye symptoms in Australian pilots. 1204-1214. Clin Experiment Ophthalmol. 2000;28(3):169-171. 55. Sainz De La Maza Serra M, Simón Castellvi C, Kabbani O. Nonpreserved topical 23. Lu P, Chen X, Liu X, et al. Dry eye syndrome in elderly Tibetans at high altitude: a steroids and lacrimal punctal occlusion for severe sicca population-based study in . Cornea . 2008;27(5):545-551. [in Spanish]. Arch Soc Esp Oftalmol . 2000;75(11):751-756. 24. Guo B, Lu P, Chen X, Zhang W, Chen R. Prevalence of dry eye disease in Mongolians 56. Junk AK, Lukacs A, Kampik A. Topical administration of metronidazole gel as at high altitude in China: the Henan eye study. Ophthalmic Epidemiol. an effective therapy alternative in chronic Demodex blepharitis—a case report 2010;17(4):234-241. [in German]. Klin Monbl Augenheilkd. 1998;213(1):48-50. 25. Gupta N, Prasad I, Himashree G, D'Souza P. Prevalence of dry eye at high altitude: 57. Sheppard JD, Scoper SV, Samudre S. Topical loteprednol pretreatment reduces a case controlled comparative study. High Alt Med Biol. 2008;9(4):327-334. cyclosporine stinging in chronic dry eye disease. J Ocul Pharmacol Ther. 2010 26. Barabino S, Shen L, Chen L, Rashid S, Rolando M, Dana MR. The controlled- Dec 6. [Epub ahead of print] environment chamber: a new mouse model of dry eye. Invest Ophthalmol Vis Sci. 58. Wojtowicz JC, Butovich I, Uchiyama E, Aronowicz J, Agee S, McCulley JP. Pilot, 2005;46(8):2766-2771. prospective, randomized, double-masked, placebo-controlled clinical trial of an 27. Schaumberg DA, Dana R, Buring JE, Sullivan DA. Prevalence of dry eye disease omega-3 supplement for dry eye. Cornea. 2011;30(3):308-314. among US men: estimates from the Physicians’ Health Studies. Arch Ophthalmol. 59. Rosenberg E, Asbell P. Essential fatty acids in the treatment of dry eye. Ocul Surf. 2009;127(6):763-768. 2010;8(1):18-28. 28. Moss SE, Klein R, Klein BE. Long-term incidence of dry eye in an older population. 60. Mataftsi A, Narang A, Moore W, Nischal KK. Do reducing regimens of Optom Vis Sci. 2008;85(8):668-674. fluorometholone for paediatric ocular surface disease cause ? Br J 29. Stern ME, Gao J, Siemasko KF, Beuerman RW, Pflugfelder SC. The role of the Ophthalmol. 2011 Feb 4. [Epub ahead of print] lacrimal functional unit in the pathophysiology of dry eye. Exp Eye Res. 61. Marsh P, Pflugfelder SC. Topical nonpreserved methylprednisolone therapy for 2004;78(3):409-416. keratoconjunctivitis sicca in Sjögren syndrome. Ophthalmology. 1999;106(4): 30. Stern ME, Beuerman RW, Fox RI, Gao J, Mircheff AK, Pflugfelder SC. The pathology 811-816. of dry eye: the interaction between the ocular surface and lacrimal glands. Cornea. 62. Barabino S, Rolando M, Camicione P, et al. Systemic linoleic and gamma-linolenic 1998;17(6):584-589. acid therapy in dry eye syndrome with an inflammatory component. Cornea. 31. Lin PY, Tsai SY, Cheng CY, Liu JH, Chou P, Hsu WM. Prevalence of dry eye among an 2003;22(2):97-101. elderly Chinese population in Taiwan: the Shihpai Eye Study. Ophthalmology. 63. Wilson SE, Stulting RD. Agreement of physician treatment practices with the 2003;110(6):1096-1101. international task force guidelines for diagnosis and treatment of dry eye disease. 32. Viso E, Gude F, Rodriguez-Ares MT. The association of meibomian gland dysfunction Cornea. 2007;26(3):284-289. and other common ocular diseases with dry eye: a population-based study in Spain. 64. Buchholz P, Steeds C, Stern LS, et al. Utility assessment to measure the impact of dry Cornea . 2011;30(1):1-6. eye disease. Ocul Surf. 2006;4(3):155-161.

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