OCULAR SURFACE DISEASE

Transcription

1 CME ACTIVITY OCULAR SURFACE DISEASE in the Presence of Glaucoma The effect of topical IOP-lowering therapy on the ocular surface and considerations in the management of these comorbidities. Supplement to February/March 2011 Jointly sponsored by the Dulaney Foundation, Glaucoma Today,and Advanced Ocular Care.

2 Ocular Surface Disease in the Presence of Glaucoma The effect of topical IOP-lowering therapy on the ocular surface and considerations in the management of these comorbidities. Jointly sponsored by the Dulaney Foundation, Glaucoma Today, and Advanced Ocular Care. Release date: February Expiration date: February This continuing medical education activity is supported by an unrestricted educational grant from Alcon Laboratories, Inc. STATEMENT OF NEED Glaucoma is a serious, chronic neurodegenerative disease that affects more than 2 million people in the United States. 1 According to a summary of population-based epidemiologic studies of dry eye by the International Dry Eye WorkShop, 14.6% of the individuals enrolled in the Salisbury Eye Study (N = 2,420; age range, 65 years) often experienced dry eye disease. 2 The incidence of glaucoma and of ocular surface disease rises with increasing age. For this reason, physicians who treat patients with glaucoma must recognize the high likelihood that these individuals will also suffer from ocular surface disease. By diagnosing and managing ocular surface disease and minimizing the negative effects of long-term glaucoma therapy on conjunctival and corneal health, clinicians can improve the health of the ocular surface and thus patients quality of life. TARGET AUDIENCE This certified continuing medical education (CME) activity is designed for glaucoma specialists, general ophthalmologists, and clinical optometrists involved in the management of patients with glaucoma. LEARNING OBJECTIVES Upon completion of this activity, the participant should be able to Recognize that ocular surface disease is prevalent in the glaucoma population Discuss the effect of preservatives and topical glaucoma therapy, both branded and generic, on the health of the ocular surface Identify which glaucoma patients are at increased risk of ocular surface disease and adjust topical hypotensive therapy as appropriate for these individuals Develop a stepwise approach to the diagnosis and management of mild and moderate ocular surface disease in glaucoma patients METHOD OF INSTRUCTION Participants should read the learning objectives and CME activity in their entirety. After reviewing the material, please complete the self-assessment test, which consists of a series of multiple choice questions. To answer these questions online and receive real-time results, please visit and click Online Courses. Upon completing the activity and achieving a passing score of over 70% on the self-assessment test, you may print out a CME credit letter awarding 1.5 AMA PRA Category 1 Credits. The estimated time to complete this activity is 1.5 hours. 2 SUPPLEMENT TO GLAUCOMA TODAY AND ADVANCED OCULAR CARE FEBRUARY/MARCH 2011

3 ACCREDITATION/DESIGNATION STATEMENT This activity has been planned and implemented in accordance with the essential areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Dulaney Foundation, Glaucoma Today, and Advanced Ocular Care. The Dulaney Foundation is accredited by the ACCME to provide continuing education for physicians. The Dulaney Foundation designates this medical education activity for a maximum of 1.5 AMA PRA Category 1 Credits. Physicians should only claim credit commensurate with the extent of their participation in the activity. DISCLOSURE In accordance with the disclosure policies of the Dulaney Foundation and to conform with ACCME and FDA guidelines, anyone in a position to affect the content of the CME activity is required to disclose to the activity participants: (1) the existence of any financial interest or other relationships with the manufacturers of any commercial products/devices or providers of commercial services, and (2) identification of a commercial product/device that is unlabeled for use or an investigational use of a product/device not yet approved. FACULTY DISCLOSURE DECLARATIONS Dr. Asbell discloses that she has received grant/research support from Alcon Laboratories, Inc., and is a consultant to Alcon Laboratories, Inc., Bausch + Lomb, and Pfizer Inc. She is on the speakers bureaus of Alcon Laboratories, Inc.; Allergan, Inc.; Bausch + Lomb; and Vistakon Pharmaceuticals Inc. Dr. Fechtner discloses that he is a consultant to Alcon Laboratories, Inc., and Allergan, Inc., and he is on the speakers bureau of Merck & Co., Inc. Dr. Kahook discloses that he has received grant/research support from Actelion Pharmaceuticals US, Inc.; Alcon Laboratories, Inc.; Allergan, Inc.; Genentech, Inc.; Merck & Co., Inc.; and the State of Colorado. He is a consultant to Alcon Laboratories, Inc.; Allergan, Inc; Ivantis Inc.; Merck & Co., Inc.; QLT Ophthalmics, Inc.; and the US Food & Drug Administration. All others involved in the planning, editing, and peer review of this educational activity report no financial relationships to disclose. FACULTY CREDENTIALS Robert D. Fechtner, MD (moderator), is the director of the Glaucoma Division and a professor of ophthalmology at New Jersey Medical School/UMDNJ in Newark. Dr. Fechtner may be reached at (908) ; fechtner@umdnj.edu. Penny A. Asbell, MD, MBA, is a professor of ophthalmology at Mount Sinai School of Medicine and director of the Cornea and Refractive Surgery Services in the Department of Ophthalmology at Mount Sinai Medical Center in New York. Dr. Asbell may be reached at (212) ; penny.asbell@mssm.edu. Malik Y. Kahook, MD, is an associate professor of ophthalmology and the director of clinical research, Department of Ophthalmology, The University of Colorado at Denver & Health Sciences Center. Dr. Kahook may be reached at (720) ; malik.kahook@ucdenver.edu. CONTENTS Comorbidity The Effect of Preservatives and Topical Glaucoma Therapy on the Ocular Surface Managing Ocular Surface Disease in Glaucoma Patients Signs and Symptoms Practical Considerations CME Questions FEBRUARY/MARCH 2011 SUPPLEMENT TO GLAUCOMA TODAY AND ADVANCED OCULAR CARE 3

4 COMORBIDITY Fechtner: The medical treatment of glaucoma has a long history, and in recent years, large, prospective, randomized clinical trials have supported the beneficial effect of lowering IOP on delaying the progression of glaucoma. 3,4 The initial therapy for glaucoma is usually topical medication. Physicians must consider the benefits and risks of all treatments, including these drugs. One of the comorbidities in glaucoma is ocular surface disease (OSD), and we will explore its relationship with glaucoma and medical topical therapies that lower IOP. What is the prevalence of OSD in the population? Asbell: When considering patients with glaucoma, we all focus on IOP, because most of the data suggest that it is a key modifiable risk factor for the disease. We perhaps forget to consider the whole patient and how he or she views his or her disease. For example, continuously red eyes, ocular irritation, and foreign body sensation are problems for the patient, even if his or her IOP is on target. One issue that has become clear is the commonality of OSD. The exact prevalence varies by study from the teens to as high as 60%. 2,5 Regardless, the problem is clearly present in all populations, and its prevalence grows with increasing age. As the world s population ages, we are going to see more patients with dry eye disease and OSD. The incidence of glaucoma also rises with increasing age, which explains why physicians treating patients with glaucoma need to be concerned about OSD as well (Figure 1). Kahook: Intrinsic and external factors lead to OSD. The glaucoma population has two strikes against it. From an intrinsic standpoint, these patients are elderly, and as Dr. Asbell just described, the incidence of dry eyes increases as patients age. From an external standpoint, in addition to exposure to different pollutants and allergens in the air, our patients are placing a glaucoma therapeutic on the ocular surface. The active ingredient, along with the preservatives, likely causes some changes that exacerbate the intrinsic factors that are already present in these patients (Table 1). Asbell: Glaucoma, by definition, is a chronic problem. Once you start treating a patient, you are unlikely to discontinue therapy, although surgical intervention may reduce the patient s need for drops. In general, however, medical therapy continues for a long time. It is difficult to isolate the effects of long-term therapy with glaucoma drops from other causes of OSD such as dry eye disease and meibomian gland dysfunction. Figure 1. Physicians treating patients with glaucoma must be prepared to diagnose and manage dry eye disease as well. THE EFFECT OF PRESERVATIVES AND TOPICAL GLAUCOMA THERAPY ON THE OCULAR SURFACE Fechtner: Dr. Kahook pointed out the external factor of ophthalmic medications. There has been concern about the interaction of these agents with the ocular surface and the preservatives in particular. Why are preservatives necessary in ophthalmic solutions? Kahook: I think the history of benzalkonium chloride (BAK) is important to mention here. BAK was introduced into ophthalmology in the 1930s and 1940s, first with wetting solutions and contact lens solutions. BAK had already been used in urology and dentistry long before ophthalmic applications. Many early approvals of topical ophthalmic drops by the FDA had BAK as the major preserving component. As a result, the FDA became familiar with BAK, and manufacturers tried to incorporate this preservative into every multidose bottle in the belief that its presence would help clear the way to the product s approval. BAK serves a very practical purpose. It is important to keep a multidose bottle as sterile as possible. The detergent preservatives, specifically BAK, are very effective at keeping the bottles free of bacterial and fungal contaminants. During the past 3 decades, other preservatives have been introduced. The next family of preservatives that has a strong hold in glaucoma is oxidizing agents, including Purite (Allergan, Inc.) and SofZia (Alcon Laboratories, Inc.). Their introduction started a debate over what is toxic to the ocular surface: is it the active ingredient or the preservative? In order to answer that question, a few researchers, including Dr. Asbell and Dr. Baudouin as well as our group at the University of Colorado, started in vitro studies specifically looking at oxidizing versus detergent preservatives and com- (Courtesy of Penny A. Asbell, MD, MBA.) 4 SUPPLEMENT TO GLAUCOMA TODAY AND ADVANCED OCULAR CARE FEBRUARY/MARCH 2011

5 paring different active ingredients. What we found is pretty clear-cut. BAK has a deleterious effect on the metabolism of ocular surface cells in vitro that is dose and time dependent. Oxidizing preservatives like Purite and SofZia have a lesser effect on the metabolism of the ocular surface cells In these studies, it appeared that, for most glaucoma medications, the active ingredients offer a protective effect on the conjunctival and corneal cells. The exact reason for this is currently unknown. Asbell: Interestingly, the take-home message of those groups studying OSD and dry eye disease was simple: (1) preservative-free artificial tears are probably a better choice if you are concerned about the ocular surface and (2) preservatives are the number-one cause of worsening dry eye disease and OSD as well as of perpetuating patients pain syndrome. That is true whether we are just treating dry eye disease and OSD or in the context of toxicity and the chronic use of medications, such as in our glaucoma patients. Getting away from a preservative is a take-home message from the past decade: if we can, let s not drop anything that is toxic onto the ocular surface. Concern about toxicity led to the information that maybe BAK is not the best preservative in terms of the ocular surface. Maybe there are alternatives that would be effective at keeping the bottle sterile while not injuring the ocular surface. One of the ways to try to tease that out is looking at other models of these drops effect on the ocular surface. Specifically, the models that people have used are typically a tissue culture. You can take conjunctival and corneal cells; grow them in a tissue culture; in a controlled manner, put different solutions on top; and analyze whether or not those cells are healthy. Several techniques and methodologies are used. As Dr. Kahook mentioned, more than one peerreviewed publication in this area has confirmed that preservatives, particularly BAK, are toxic to the ocular surface. Not only are they toxic in terms of the viability of the cells, but they actually induce the epithelial cells to make inflammatory markers. All of this increases inflammation of the ocular surface. 6,7 Fechtner: Dr. Asbell, you have published your findings on the comparative toxicity of preservatives on corneal and conjunctival epithelial cells. Can you tell us about your observations? Asbell: We looked at tissue cultures in conjunctival cells and corneal epithelial cells, the cells of a normal ocular surface. Once the cells grow to cover the bottom of the tissue culture plates, then test solutions are placed to cover the cells. After 1 hour, the solution is removed and replaced with MTT solution, which normal cells metabolize, and there is a color change. You can then measure the amount of color change, determine the healthiness of the cells, and use this reaction (the color) as a guide of cellular viability. Typically, the positive control is the medium itself, which maintains healthy cells. Formalin is the ultimate preservative; it kills all the cells and thus serves as a negative control. We looked at a few of the glaucoma products, in particular the prostaglandin group (travoprost [Travatan; Alcon Laboratories, Inc.], bimatoprost [Lumigan; Allergan, Inc.], and latanoprost [Xalatan; Pfizer, Inc.]), and compared their effects on conjunctival epithelial cells and corneal epithelial cells. Regardless of how we did this study, it came out the TABLE 1. FACTORS IN DRY EYE DISEASE AMONG GLAUCOMA PATIENTS INTRINSIC Age Hormonal changes Blepharitis Auto-immune disease Courtesy of Robert D. Fechtner, MD. EXTERNAL Dry environment Contact lens wear LASIK Alcohol use Pollution Computer use Systemic medications (eg, antidepressants) Topical ocular medications (eg, those with quaternary ammonium preservatives such as benzalkonium chloride) FEBRUARY/MARCH 2011 SUPPLEMENT TO GLAUCOMA TODAY AND ADVANCED OCULAR CARE 5

6 same each time. Lumigan and Xalatan were quite similar in that they were clearly associated with a significant loss of cellular viability. If the medium is 100%, that is how we do the calculations. Lumigan and Xalatan are down under 20% viability, which is a very significant drop. Travatan Z remains high at about 60% viability. It is the diluents, not the active ingredients, that are causing this change in cellular viability. 11 Similar experiments show the leading driver to be the preservative rather than the active ingredients. 11 As a group, prostaglandins seem to be okay in terms of their effect on epithelial cells, but the preservatives, specifically BAK, clearly interfere with cellular viability. Kahook: I have a question on the comparison made in your study between BAK and hydrogen peroxide, an agent known to induce metabolic stress in vitro in conjunctival cells as well in corneal cells. 6 I am struck by the differences between equivalent concentrations of BAK and hydrogen peroxide. Did they surprise you? Asbell: What surprised us is that we did a study looking at lower concentrations of BAK far lower than in commercial ophthalmic drops and no matter how low we got, we still saw very significant toxicity and the production of inflammatory mediators. When we looked at 0.001% BAK, which is far lower than in any commercial preparation, it produced almost the same level of toxicity as the concentrations used in commercial bottles. Any amount of BAK is going to be toxic in the eye. Fechtner: Other researchers have investigated the impact of topical ophthalmic medications and their preservatives on patients. For example, my colleagues and I published a multicenter (10 sites) study of the prevalence of ocular surface complaints in patients with glaucoma using IOP-lowering medications. 12 The study was conducted over the course of almost 1 year and enrolled 630 glaucoma patients who were treated with one or more IOP-lowering medications. The Ocular Surface Disease Index (OSDI) was graded, and we looked at prevalence-ranking OSD as normal, mild, moderate, or severe. We found that 48.4% of treated glaucoma patients reported OSD on the survey; more than 27% had moderate or severe symptoms. These numbers correspond to studies by other groups using the OSDI 13,14 and are much higher than the prevalence of OSD seen in the general population in other reports. 15,16 Rossi et al studied symptoms by surveys and signs by fluorescein staining and tear breakup time; they reported that increasing the number of drops led to increasing symptoms. 13 There is a relationship between glaucoma topical therapy and OSD symptoms. What do we know about that interaction? [In vitro], there is a clear effect from BAK on both conjunctival and corneal cells with a dose-response curve that stands up to rigorous scientific review. Malik Y. Kahook, MD Kahook: The work of Leung and colleagues raised some clinical questions that we have had difficulty answering. Their research showed a correlation between being on glaucoma therapy and having certain signs and symptoms of OSD. 14 What we have struggled with in this and other studies is finding consistency in a dose-response curve (ie, number of glaucoma drops used) with OSD and a consistency between signs and symptoms in the same patient. The question that we often ask ourselves in the clinic is, do we have a metric that may better portray the clinical picture in a way that can be reproducibly measured and included in a study that would give a valid comparison between groups? Fechtner: We struggle with those metrics. Researchers and clinicians alike have observed that signs and symptoms do not always correlate in patients with dry eye. It is easier to study the interaction between preservatives and cells using in vitro models. What have we learned from these models? Kahook: What can we learn from the in vitro data involving corneal and conjunctival cells that might relate to clinical practice? It is easy to compare active ingredients or preservatives in a controlled environment in the laboratory using tissue cultures. As a clinician, what I can say from the in vitro data is that there is a clear effect from BAK on both conjunctival and corneal cells with a dose-response curve that stands up to rigorous scientific review. Multiple researchers around the world have replicated these data In order to test for a correlation of these findings in the clinic, we need to choose which metrics might be surrogates for the metabolic information we are getting in the in vitro studies. Several articles from the past 3 or 4 years help here, including one that Michael Horsley, MD, and I published. 17 We looked at patients who were on a prostaglandin analogue preserved with BAK and then switched those patients to a prostaglandin analogue preserved with an oxidative preservative (SofZia). Briefly, 20 patients (40 eyes) had been on their medications for an extended period of time. All patients were switched from latanoprost with 0.02% BAK to travoprost with SofZia and 6 SUPPLEMENT TO GLAUCOMA TODAY AND ADVANCED OCULAR CARE FEBRUARY/MARCH 2011

7 examined 8 weeks later. The same endpoints were collected at baseline and at the 8-week follow-up. We observed a significant increase in tear breakup time in this patient population, from an average of 2 seconds to an average of 6 seconds. I think it is important to point out that these patients were in the severe category as far as the baseline tear breakup time is concerned. They started with a tear breakup time of around 2 seconds, and it is very plausible that we are more likely to see an effect in these patients, as they were selected for the study due to existing issues with their topical drops. At the 8-week time point, these patients also experienced an improvement in symptoms, as measured by the OSDI. In addition, punctate epithelial erosions decreased, and the IOP did not change significantly after the switch in medication. Ours was a very basic study with clear findings, but it was conducted in a geographical area that is very dry (Denver) and included a patient population from a single investigator. We also used a very controlled environment in our clinic, and all measurements were photographed and videotaped for masked evaluation. Certain conclusions need to be validated in a multicenter way, matching the controlled environment of the study. It would also be useful to choose some other metrics that would be more easily reproducible among centers, and I think that is the major limiting factor with OSD studies. In a similar vein, the goal of a recent study by Whitson et al was to determine whether switching from latanoprost with 0.02% BAK would lead to any measurable change. 18 One-third of patients were randomized to receive bimatoprost preserved with 0.005% BAK, one-third were randomized to travoprost with SofZia, and one-third remained on latanoprost. The investigators found no statistically significant differences between the groups in terms of the medications ocular surface tolerability. It is important to mention that these patients were quite different from those in the study that we reported in our clinic. 17 Whitson and colleagues selected patients who had been on latanoprost monotherapy for at least 4 weeks. At enrollment, these patients tear breakup time was nearly normal. I am not surprised that patients who were not having difficulty with their latanoprost therapy did not experience any measurable change when they either stayed on that medication or switched to another prostaglandin analogue. This study is fairly strong, in that the investigators randomized the patients into three different groups and observed them for 12 weeks. A limitation was the number of patients in each group. Fechtner: Patient selection will affect a study s outcomes, and the results can only be generalized to a population that is similar to that of the study. You point out that, if you Patient selection will affect a study s outcomes, and the results can only be generalized to a population that is similar to that of the study. Robert D. Fechtner, MD select patients with a healthy tear film who are tolerating latanoprost, it is unlikely that you will see abnormalities after switching them to a medication with less BAK or with an alternative preservative system. Yet, as we mentioned earlier, nearly 50% of treated glaucoma patients reported symptoms using the OSDI. Other techniques using markers that may be more sensitive reveal different results. Kahook: As in the studies by Horsley and me 17 and by Whitson et al, 18 Uusitalo and colleagues selected a group of patients who were on latanoprost monotherapy, preserved with BAK, and switched them to a preservative-free prostaglandin analogue in this case, tafluprost. In addition to using many of the same clinical metrics that we have discussed (eg, staining, tear breakup time), the investigators performed impression cytology and measured inflammatory markers within the conjunctiva. The study period was 12 weeks. The investigators found no significant difference in IOP, but most of the other metrics underwent statistically significant changes in favor of tafluprost rather than the BAK-preserved latanoprost. In addition, the conjunctival impression cytology inflammatory markers significantly improved after patients switched to tafluprost. 19 The addition of inflammatory markers with objective data that have been validated in several laboratories I think is a strong point of the study by Uusitalo et al. It shows that the ocular surface changes after switching from a medication with BAK to one without preservatives. Fechtner: Dr. Kahook, you pointed out earlier how patient selection influences the observations. The study by Uusitalo et al selected a very different population than the study by Whitson et al. In this study, where the patients had to exhibit at least two ocular symptoms or one symptom and one sign of ocular surface irritation or inflammation to be enrolled, there appeared to be a benefit from switching from a medication preserved with BAK. Kahook: Correct. There are two ways to think about this requirement, and it applies to the study by Horsley and me as well. You could think of it as selecting patients in order FEBRUARY/MARCH 2011 SUPPLEMENT TO GLAUCOMA TODAY AND ADVANCED OCULAR CARE 7

8 to best address the question at hand. If you select patients with ocular symptoms and signs, you would expect them to have some sort of measurable change at the end of the study after switching the medication that they are using. On the other hand, if you are starting off with normal patients who are tolerating the medication that they are on, the likelihood of these patients becoming abnormal within a 12-week stretch is very low. Obviously, more studies are needed in this area. Asbell: When treating patients, understanding the effect of the disease on their quality of life has become an increasingly recognized area of importance. The effects of dry eye disease on patients reading, work, computer use, TV viewing, and driving during the day and night can be considerable. 20 Sometimes, we overlook these issues during brief discussions with our patients. They may have symptoms that are not easily recorded or even elicited during the examination, but there is plenty of evidence suggesting that, when the surface is not normal, patients are symptomatic: it affects the activities of daily living. A key aspect of the International Dry Eye WorkShop (DEWS) report was that inflammation is a part of OSD. 21 OSD is not just affecting cellular health; it is bringing in inflammatory mediators, which can affect the ocular surface and other aspects of ocular function. SIGNS AND SYMPTOMS Asbell: A hot topic in all of medicine these days is biomarkers. In ophthalmology, it may be that the only truly acceptable biomarker is IOP for gauging the severity of glaucoma and the effectiveness of its treatment. We recognize OSD and dry eye disease upon presentation, but we do not always have the best objective, minimally invasive metrics with which to define the severity of the disease, make the classification, and measure the efficacy of treatment. One approach is to ask patients how they feel. They often use terms like chronic pain, irritation, and foreign body sensation. They will also talk about variable vision. Patients with OSD may complain about their vision but have excellent visual acuity (eg, 20/20) in the examination lane, because they blink frequently. Outside, they blink less often, and their quality of vision can be far less. Several studies document that visual acuity can drop from 20/20 to 20/50, which is not even appropriate for driving and normal activities. We should take patients complaints seriously and realize that what they are saying is probably a more real finding in terms of their normal activities. Schirmer testing is not highly specific or sensitive, but it is easy to do in the office setting. Assessing tear breakup time is easy to do at the slit lamp, and a normal measure is around 7 to 10 seconds. Less is considered abnormal. A Listen to what patients are saying about their treatment, and give them the opportunity to express themselves. Penny Asbell, MD, MBA third measure is punctate staining. I also like to evaluate the conjunctiva with lissamine green. Sometimes, we forget that the conjunctiva is a big part of the ocular surface and may be a key factor in the symptoms that the patient is describing. Lissamine staining can be easier to use sometimes than fluorescein, and the strips are inexpensive (see Managing Ocular Surface Disease in Glaucoma Patients). Fechtner: The DEWS showed the sensitivity and specificity of a number of tests. 22 Among those that are accessible to the clinician were tear breakup time and surveys. Dr. Asbell, you pointed out the importance of eliciting the symptoms from patients. Would you please talk about the possible disconnection between science and symptoms? Asbell: The issue of signs and symptoms not matching is a popular topic. There are really two aspects to this issue: patients with severe OSD may in fact have less sensitivity, whereas patients with significant symptoms may have subtle changes to the ocular surface that are not apparent during a standard slit-lamp examination. Often, the ability of patients with severe OSD to notice its symptoms decreases. 23 They may in fact have less innervation of the ocular surface and experience less pain, despite the obviousness of their disease at the slit lamp. In contrast, we may not see much evidence at the slit lamp of mildto-moderate OSD, but these patients may complain loudly. The typical in-office examination is not sensitive, which is why researchers such as myself have looked for more precise measurements of OSD. Tear osmolarity and corneal permeability measurements, for example, may provide information that better correlates with patients symptoms. 22,24 PRACTICAL CONSIDERATIONS Fechtner: I want to highlight some practical points. It is clear that some glaucoma patients do just fine tolerating a single drop. Many of my patients have been using medications containing BAK throughout my practicing career. Who is at risk? When might we want to start thinking about whether preservatives are a consideration in a patient s long-term glaucoma therapy? 8 SUPPLEMENT TO GLAUCOMA TODAY AND ADVANCED OCULAR CARE FEBRUARY/MARCH 2011

9 MANAGING OCULAR SURFACE DISEASE IN GLAUCOMA PATIENTS By Penny A. Asbell, MD, MBA There is ample evidence that the topical agents used to treat glaucoma are associated with an increased prevalence of ocular surface disease (OSD) and the associated typical signs and symptoms of dry eye disease. 1-6 In addition, because glaucoma and dry eye disease are both associated with increasing age, it is highly likely that patients with glaucoma coincidentally also have dry eye disease. This discussion reviews the basics of diagnosing and managing OSD. DIAGNOSIS To diagnose and manage OSD in your glaucoma patients, start by being suspicious. Inquire about symptoms. Ask patients if they have any ocular irritation or consider using a dry eye questionnaire such as the Ocular Surface Disease Index that they can complete in the waiting room before their eye examination. During the slit-lamp examination, look for signs of OSD. One approach is corneal staining with fluorescein. It is important to use more than the typical amount for application measurements. Wet the strip and then apply it to the sclera. A second, readily available diagnostic test is to perform lissamine green staining of the conjunctiva. You can also assess the quantity of the tear film along the lower lid margin and measure tear breakup time. Do not forget to evaluate the patient s eyelids! Meibomian gland dysfunction can cause the tear film to break up due to changes in the lipid layer. Check for neovascularization of the eyelids and abnormal meibum. Applying gentle pressure on the lid with your finger or a cotton swab will reveal whether the gland expression is clear, thick and opaque, or absent. Also consider lid function the blink and possible lagophthalmos. TREATMENT Treatment starts with acknowledging patients symptoms. Let them know that you understand that their chronic irritation or pain and fluctuating vision are real problems and that you can treat the OSD to help decrease these difficulties. Consider which eye drops the patient is using. Can you eliminate or decrease his or her exposure to benzalkonium chloride? Can you decrease the number of drops he or she needs? Be sure to ask the patient about over-the-counter drops he or she may be using, since they can contribute to OSD, especially if they are preserved with benzalkonium chloride. You may want to prescribe artificial tears for regular use. If so, select brands that have soft preservatives or unit dose preparations without preservatives. Suggest the patient use artificial tears every day to keep the ocular surface healthy rather than wait for the symptoms of OSD to occur. Bear in mind that not all artificial tears are alike; in addition to the preservative used, they differ in their composition, viscosity, and mechanism of action. If the patient has significant lid disease, warm soaks and lid scrubs can help. You may also wish to consider artificial tears. If you think there is an element of exposure, instruct the patient to apply before sleep a lubricating gel or ointment or to use Lacrisert (Aton Pharma, Inc.). The last is a tear pellet that melts once placed in the inferior cul de sac of the lower eye lid. Another option is Restasis (cyclosporin ophthalmic emulsion) 0.05% (Allergan, Inc.), which may improve tear production, but inform the patient that several months may elapse before he or she will notice an improvement. Most ophthalmologists try several modalities to treat OSD; for the more severe findings, doctors reported trying five different treatments per year on average. 7 CONCLUSION Treating OSD is challenging, so plan to try a few approaches to see what works best for each patient. 7 He or she will appreciate your concern for the whole patient versus a focus solely on the IOP reading or visual field results. Moreover, when the patient begins to feel better, it may be more likely that he or she will take his or her glaucoma medications as prescribed. 1. Asbell PA, Potapova N. Effects of topical antiglaucoma medications on the ocular surface. Ocul Surf. 2005;3(1): Fechtner RD, Godfrey DG, Budenz D, et al. Prevalence of ocular surface complaints in patients with glaucoma using topical intraocular pressure-lowering medications. Cornea. 2010;29(6): Ghosh S, Crowston J, Lamoureux E, et al. Assessment of prevalence of ocular toxicity in glaucomatous patients. Paper presented at: AAO Annual Meeting; November 20, 2008; Atlanta, GA. 4. Leung EW, Medeiros FA, Weinreb RN. Prevalence of ocular surface disease in glaucoma patients. J Glaucoma. 2008;17: Rossi GC, Tinelli C, Pasinetti GM, et al. Dry eye syndrome-related quality of life in glaucoma patients. Eur J Ophthalmol. 2009;19: Schmier JK, Covert DW. Characteristics of respondents with glaucoma and dry eye in a national panel survey. Clin Ophthalmol. 2009;3: Asbell PA, Spiegel S. Ophthalmologist perceptions regarding treatment of moderateto-severe dry eye: results of a physician survey. Eye Contact Lens. 2010;36(1): FEBRUARY/MARCH 2011 SUPPLEMENT TO GLAUCOMA TODAY AND ADVANCED OCULAR CARE 9

10 Asbell: Who is at risk? Patients who are older have more OSD. We should be concerned about patients who come in with dry eye disease independent of their glaucoma. Also, patients may have increased environmental exposure such as extensive travel on airplanes. Clearly, if someone is on multiple drops, he or she is going to be at increased risk. All things being equal, I am going to pick the least toxic medication. I think it would be very difficult to argue that a BAK preservative is a better option than not using BAK. If we have a choice, we want the least toxic agent and the most infrequent dosing schedule to improve compliance and decrease potential side effects and complications. That is how I look at drugs regardless of the disease process. Fechtner: Currently in the United States, however, generic glaucoma medications are becoming predominant, and a generic prostaglandin is expected in March There are great cost incentives to patients to use generic agents, which are almost all preserved with BAK. What should we be looking for in our patients to recognize when they might be having a problem with one of these medications? The reality is they are going to use them. Asbell: A key factor is for the clinician to be thinking about OSD. Also, listen to what patients are saying about their treatment, and give them the opportunity to express themselves. If they voice concerns related to the ocular surface, chronic pain, chronic irritation, or variable vision throughout the day, consider that the problem may not just be their glaucoma medication but also dry eye disease. Fechtner: How do we identify which patients on a medication preserved with BAK might benefit from a switch to a medication without BAK? Kahook: Again, thinking about the problem is half the battle. Most of the time when we are in clinic, we are focused on IOP. I have a large group of patients on BAKpreserved prostaglandin analogues, and they do well with these medications. A subgroup of patients, however, benefits from a switch to BAK-free medications. You might notice certain aspects of their clinical examination like tear breakup time, lissamine green staining, or punctate erosions in the cornea. The presence of these signs should prompt us to consider switching the patient to a BAK-free agent. By measuring those particular metrics in the same reproducible way in the clinic each time you see your patients, you are likely to identify patients who might benefit from the switch. As Dr. Asbell said, we must consider the whole patient. OSD may be affecting patients activities of daily living. Fechtner: Glaucoma and OSD are both conditions that rise in prevalence with increasing age. Although early glaucoma may be without symptoms, OSD can range from a minor annoyance to a major disabling condition. We recognize that glaucoma is a potentially blinding disease and have asked our patients to tolerate medications and preservative systems that we now realize can contribute to OSD. In fact, nearly 50% of our treated glaucoma patients may be experiencing symptoms of OSD. 12 We must be vigilant to detect subtle signs of OSD such as early tear breakup. We must ask our patients about the comfort of their eyes. We must recognize the possibility that topical medications, particularly those preserved with BAK, may be contributing to OSD. For our patients with glaucoma and OSD, we need to take the holistic approach Dr. Asbell described. A step forward is recognizing the effect of topical IOP-lowering therapy on the ocular surface when managing these comorbidities. 1. Friedman DS, Wolfs RC, O Colmain BJ, et al. Eye Diseases Prevalence Research Group. Prevalence of open-angle glaucoma among adults in the United States. Arch Ophthalmol. 2004;122(4): The epidemiology of dry eye disease: report of the Epidemiology Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf. 2007;5(2): Kass MA, Heuer DK, Higginbotham EJ, et al. The Ocular Hypertension Treatment Study: a randomized trial determines that ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol. 2004;122(4): Leske MC, Heijl A, Hussein M, et al; Early Manifest Glaucoma Trial. Factors for glaucoma progression and the effect of treatment: the Early Manifest Glaucoma Trial. Arch Ophthalmol. 2003;121(1): Asbell PA, Lemp M, eds. Current Treatment and Diagnosis in Dry Eye Disease. New York, NY: Thieme Medical Publishers, Inc.; Epstein SP, Chen D, Asbell PA. Evaluation of biomarkers of inflammation in response to benzalkonium chloride on corneal and conjunctival epithelial cells. J Ocul Pharmacol Ther. 2009;25(5): Epstein SP, Ahdoot M, Marcus E, Asbell PA. Comparative toxicity of preservatives on immortalized corneal and conjunctival epithelial cells. J Ocul Pharmacol Ther. 2009;25(2): Baudouin C, Labbé A, Liang H, et al. Preservatives in eyedrops: the good, the bad and the ugly [published online ahead of print March 17, 2009]. Prog Retin Eye Res. 2010;29(4): Kahook MY, Ammar DA. In vitro toxicity of topical ocular prostaglandin analogs and preservatives on corneal epithelial cells. J Ocul Pharmacol Ther. 2010;26(3): Ammar DA, Noecker RJ, Kahook MY. Effects of benzalkonium chloride-preserved, polyquadpreserved, and SofZia-preserved topical glaucoma medications on human ocular epithelial cells [published online ahead of print October 7, 2010]. Adv Ther. 2010;27(11): Epstein SP, Chen D, Asbell PA. Inflammatory response by ocular surface epithelia upon exposure to prostaglandin analogs. Invest Ophthalmol Vis Sci. 2008;49(4 suppl):s Fechtner RD, Godfrey DG, Budenz D, et al. Prevalence of ocular surface complaints in patients with glaucoma using topical intraocular pressure-lowering medications. Cornea. 2010;29(6): Rossi GC, Tinelli C, Pasinetti GM, et al. Dry eye syndrome-related quality of life in glaucoma patients. Eur J Ophthalmol. 2009;19: Leung EW, Medeiros FA, Weinreb RN. Prevalence of ocular surface disease in glaucoma patients. J Glaucoma. 2008;17: Schaumberg DA, Sullivan DA, Buring JE, Dana MR. Prevalence of dry eye syndrome among US women. Am J Ophthalmol. 2003;136(2): Schaumberg DA, Dana R, Buring JE, Sullivan DA. Prevalence of dry eye disease among US men: estimates from the Physicians Health Studies. Arch Ophthalmol. 2009;127(6): Horsley MB, Kahook MY. Effects of prostaglandin analog therapy on the ocular surface of glaucoma patients. Clin Ophthalmol. 2009:3: Whitson JT, Trattler WB, Matossian C, et al. Ocular surface tolerability of prostaglandin analogs in patients with glaucoma or ocular hypertension. J Ocul Pharmacol Ther. 2010;26(3): Uusitalo H, Chen E, Pfeiffer N, et al. Switching from a preserved to a preservative-free prostaglandin preparation in topical glaucoma medication. Acta Ophthalmolgica. 2010;88: Miljanovic B, Dana R, Sullivan DA, Schaumberg DA. Impact of dry eye syndrome on visionrelated quality of life. Am J Ophthalmol. 2007;143(3): Research in dry eye: report of the Research Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf. 2007;5(2): Methodologies to diagnose and monitor dry eye disease: report of the Diagnostic Methodology Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf. 2007;5(2): Johnson ME. The association between symptoms of discomfort and signs in dry eye. Ocul Surf. 2009;7(4): Fahim MM, Haji S, Koonapareddy CV, et al. Fluorophotometry as a diagnostic tool for the evaluation of dry eye disease. BMC Ophthalmol. 2006;6: SUPPLEMENT TO GLAUCOMA TODAY AND ADVANCED OCULAR CARE FEBRUARY/MARCH 2011

11 INSTRUCTIONS FOR CME CREDIT 1.5 AMA PRA Category 1 Credits Expires February 2012 CME credit is available electronically via To answer these questions online and receive real-time results, please visit and click Online Courses. If you are experiencing problems with the online test, please us at support@dulaneyfoundation.org or call Alternatively, you may fax your exam to us at Certificates are issued electronically, so supply your address below. Please type or print clearly, or we will be unable to issue your certificate. Name MD participant non-md participant Phone (required) (required) City State CME QUESTIONS 1. In a study by Fechtner and colleagues of more than 600 patients with glaucoma, what percentage reported having ocular surface disease? a. Greater than 27% b. Greater than 48% c. Greater than 60% 2. Possible factors in ocular surface disease include a. Contact lens wear and alcohol consumption b. Systemic and topical ophthalmic medications c. Age and hormonal changes d. All of the above e. B and C 3. Which of the following statements is true? a. Benzalkonium chloride negatively affects the metabolism of ocular surface cells in vitro. b. Oxidizing preservatives exert a protective effect on the corneal and conjunctival cells in vitro. c. The active ingredients in prostaglandin analogues are the leading cause of changes in cellular viability d. All of the above e. A and B 4. Whitson and colleagues found no statistically significant differences between three prostaglandin analogues in terms of ocular surface tolerability. a. True b. False 5. Based on a report from the International Dry Eye WorkShop, a. Ocular surface disease may be associated with poor epithelial cellular health b. Ocular surface disease may be associated with an increase in inflammatory cytokines c. A and B 6. Which of the following statements is true? a. Patients with severe ocular surface disease may experience less pain than patients with milder forms of the disease b. Patients who have ocular surface disease may have a poorer quality of vision outside the office than in the examination lane c. Typical in-office examinations for ocular surface disease are not sensitive d. All of the above e. A and B f. B and C 7. A valid approach to diagnosing ocular surface disease is to ask patients if they are experiencing ocular irritation. a. True b. False 8. In a study by Asbell and Spiegel, how many modalities on average did ophthalmologists try per year to treat ocular surface disease? a. Two b. Three c. Four d. Five e. Six 9. Which of the following should prompt clinicians to consider the preservative load of a glaucoma patient? a. Older age b. Increased exposure to dry environments c. Complaints about chronic pain or irritation of the eye d. Complaints about variable vision e. Use of multiple topical drops f. All of the above g. A, C, D, and E 10. Some options for treating ocular surface disease in the glaucoma population are a. Reducing their use of glaucoma medications preserved with benzalkonium chloride b. Asking about over-the-counter medications patients are using c. Recommending the use of artificial tears that have a soft or no preservative d. Treating significant lid disease e. All of the above f. A, C, and D Sponsored by the Dulaney Foundation. Supported by an unrestricted educational grant from Alcon Laboratories, Inc. FEBRUARY/MARCH 2011 SUPPLEMENT TO GLAUCOMA TODAY AND ADVANCED OCULAR CARE 11

12 ACTIVITY EVALUATION Your responses to the questions below will help us evaluate this CME activity. They will provide us with evidence that improvements were made in patient care as a result of this activity as required by the Accreditation Council for Continuing Medical Education (ACCME). Please complete the following course evaluation and send it back to the Dulaney Foundation via fax at Name and Do you feel the program was educationally sound and commercially balanced? Yes No Comments regarding commercial bias: Rate your knowledge/skill level prior to participating in this course: 5 = High, 1 = Low Rate your knowledge/skill level after participating in this course: 5 = High, 1 = Low Would you recommend this program to a colleague? Yes No Do you feel the information presented will change your patient care? Yes No If yes, please specify. We will contact you by in 1 to 2 months to see if you have made this change. If no, please identify the barriers to change. Please list any additional topics you would like to have covered in future Dulaney Foundation CME activities or other suggestions or comments. 12 SUPPLEMENT TO GLAUCOMA TODAY AND ADVANCED OCULAR CARE FEBRUARY/MARCH 2011 Sponsored by the Dulaney Foundation.