Dry Eye Syndrome

P&T DIGEST A PEER-REVIEWED COMPENDIUM OF FORMULARY CONSIDERATIONS

DRY EYE SYNDROME

• Historical perspectives

• Prevalence and economic implications

• Etiology of disease

• 2003 AAO guidelines for treatment

• Drug-therapy review

• Pharmacoeconomic data Continuing education credit for physicians and pharmacists sponsored by The Chatham Institute • Proper medication use

This program is supported by an educational grant SUPPLEMENT TO from Allergan CareM A N A G E D Vol.12,No.12 December 2003 ABOUT THIS PUBLICATION

P&T DIGEST A PEER-REVIEWED COMPENDIUM OF FORMULARY CONSIDERATIONS

Chief Medical Editor A Tool for Formulary Decision Makers John D.Sheppard, MD, MMSc he understanding of keratoconjunctivitis sicca (KCS), also Faculty known as dry eye syndrome, has changed in the past 5 years. Eric D.Donnenfeld, MD Until recently, it was thought to have been due to aqueous in- Richard G. Fiscella, RPh, MPH T Jan D.Hirsch, PhD sufficiency. Today, it is understood that KCS is a multifactorial dis- Henry D.Perry, MD ease that also involves inflammation of the ocular surface and Steven E.Wilson, MD lacrimal gland, neurotrophic deficiency, and meibomian dysfunction. This change in understanding, reflected in the 2003 AAO Dry Editor Michael D.Dalzell Eye Syndrome Preferred Practice Pattern that is summarized herein, has led to the development of new and effective medications. Consulting Editor This peer-reviewed publication gives physicians and pharmacists John A.Marcille who serve on pharmacy and therapeutics committees up-to-date Contributing Editors information about the most efficacious and cost-effective medical Tony Berberabe treatments available. Relatively little published data exist in a cen- Bob Carlson tralized format about medical therapies for dry eye syndrome, Frank Diamond compared with information about other chronic conditions. This William W.Edelman publication, a digest of existing knowledge and best practices, serves Linda Felcone as a valuable tool for formulary decision makers and is an impor- Maxine Losseff Jack McCain tant contribution to the medical literature. Paula Sirois Editorial Advisory Board Design Director Philip Denlinger John D. Sheppard, MD, MMSc Chairman, Editorial Advisory Board and Chief Medical Editor Group Publisher P&T Digest | Dry Eye Syndrome Timothy P.Search, RPh Program Director, Department of Ophthalmology Director, New Product Development Eastern Virginia Medical School Timothy J.Stezzi Norfolk, Va. Eastern Sales Manager Scott MacDonald Richard G. Fiscella, RPh, MPH Assistant Director, Clinical Services/Ambulatory Care Senior Account Manager University of Illinois at Chicago (UIC) Hospital Blake Rebisz Department of Pharmacy Midwest Sales Manager Clinical Associate Professor Terry Hicks UIC Department of Pharmacy Practice Director, Production Services Clinical Coordinator Waneta Peart UIC Eye and Ear Infirmary Chicago MANAGED CARE (ISSN 1062-3388) is published monthly by MediMedia USA Inc., at 780 Township Line Road,Yardley, PA 19067.This is Volume 12, Issue 12.Periodical postage paid at This publication is made possible by an educational grant from Morrisville, Pa., and at additional mailing offices.POSTMAS- Allergan. TER: Send address changes to MANAGED CARE, 780 Township Line Road,Yardley, PA 19067.Prices: $10 per copy, $93 per year in the USA; $120 per year elsewhere.Send letters to the editor c/o Frank Diamond, MANAGED CARE, 780 Township Line Road,Yardley, PA 19067.Letters may be edited for length and clarity.E-mail: [email protected]: (267) 685-2788; fax (267) 685-2966; circulation inquiries (267) 685-2782.Copyright ©2003 MediMedia USA Inc. P&T DIGEST A PEER-REVIEWED COMPENDIUM OF FORMULARY CONSIDERATIONS

John D.Sheppard, MD, MMSc Chief Medical Editor P&T DIGEST A PEER-REVIEWED COMPENDIUM OF FORMULARY CONSIDERATIONS

DRY EYE SYNDROME

Continuing education objectives and accreditation statements...... 4

INTRODUCTION Dry Eye Moves Beyond Palliative Therapy ...... 6 Keratoconjunctivitis sicca, or dry eye syndrome, is a complex condition characterized by inflammation of the ocular surface and tear-producing glands. When dry eye is controlled, there is significant potential for improved quality of life and cost savings. JOHN D. SHEPPARD,MD,MMSC

OVERVIEW Dry Eye: Prevalence, Utilization, and Economic Implications ...... 9 Epidemiological reports worldwide vary, but about one in seven American adults may experience frequent symptoms of dry eye syndrome. Untreated disease drives unnecessary resource utilization and poses risks for expensive complications. MICHAEL D. DALZELL

ETIOLOGY Inflammation: A Unifying Theory for the Origin of Dry Eye Syndrome ...... 14 Dry eye syndrome has been difficult to diagnose and treat, due to its heterogeneity. These difficulties are being overcome, however, as evidence of a common etiology emerges. An inflammatory mechanism appears to underlie the condition. STEVEN E. WILSON,MD DETECTION AND TREATMENT Guidelines for the Treatment of Chronic Dry Eye Disease...20 Recently released guidelines from the American Academy of Ophthalmology provide a framework for managing this chronic disorder. With the treatment approaches outlined in this article, symptoms and signs can be alleviated and the potential for ocular surface damage and impaired vision can be minimized. JOHN D. SHEPPARD,MD,MMSC

Cover art: Paul Klee,1914,217 PHARMACOTHERAPEUTIC OPTIONS St.Germain near Tunis (Inland) Medications for Dry Eye Syndrome: 21.8 x 31.5 cm A Drug-Therapy Review...... 26 Watercolor on paper Musée national d'art Early interventions attempted to replace water lost from the tear film. Emerging thera- moderne,Centre Georges pies are directed at underlying inflammation. This new focus uses pharmacologic agents Pompidou,Paris © 2003 Artists Rights to manage dry eye disease and to control or reverse corneal damage. Society (ARS),New York / HENRY D. PERRY,MD VG Bild-Kunst,Bonn ERIC D. DONNENFELD,MD

COST-EFFECTIVENESS Considerations in the Pharmacoeconomics of Dry Eye...... 33 Until recently, all treatments for dry eye have been palliative. A new treatment, cyclosporine A ophthalmic emulsion, addresses the disease’s underlying causes. It warrants pharmacoeconomic analysis to determine its place in managed care. JAN D. HIRSCH,PHD

CHRONIC THERAPY Issues in the Use of Preservative-Free Topicals ...... 39 Preservative-free ophthalmologic agents can be easily contaminated once the patient opens the container. Clinicians must acknowledge this and protect patients from using contaminated medication and to assure optimal clinical outcomes. HENRY D. PERRY,MD ERIC D. DONNENFELD,MD

CONTINUING EDUCATION Post-test ...... 42 Physician CME answer sheet/evaluation form ...... 43 Pharmacist CPE answer sheet/evaluation form...... 44 SELF-STUDY CONTINUING EDUCATION ACTIVITY P&T DIGEST Dry Eye Syndrome

GENERAL INFORMATION CONTINUING EDUCATION

Continuing education credit is offered to physicians Medical accreditation and pharmacists who read pages 6 through 41 of this The Chatham Institute is accredited by the Accredita- publication, complete the post-test on pages 42 and 45, tion Council for Continuing Medical Education (ACCME) and fill out the appropriate evaluation form on either to provide continuing medical education for physicians. page 43 (physicians) or 44 (pharmacists). The Chatham Institute designates this educational activity for a maximum of 3.0 category 1 credits toward PURPOSE AND OVERVIEW the AMA Physician’s Recognition Award.Each physician should claim only those credits that he/she actually This activity is designed to educate health care practi- spent in the activity. tioners and managed care professionals about current This activity has been planned and implemented in and emerging treatments for dry eye syndrome.Recent accordance with the ACCME Essential Areas, Elements, developments in the etiology of dry eye have triggered and Policies. the development of new pharmacotherapeutic treatment strategies, prompting physicians, patients, and Pharmacy accreditation payers to request information about the status and The Chatham Institute is approved by the effectiveness of current and emerging therapies.The American Council on Pharmaceutical Educa- content of this program was developed on the basis of ® tion (ACPE) as a provider of continuing faculty perceptions of significant trends or issues. pharmaceutical education. This activity provides 3.0 contact hours (0.3 CEU) of Educational objectives continuing education for pharmacists.Credit will be After reading this publication, the participant should awarded upon successful completion of the post-test be able to: and the activity evaluation. ACPE Universal Program Number (UPN): 1. Describe the etiology of dry eye syndrome, or kera- 812-000-03-016-H01. toconjunctivitis sicca (KCS), and risks of untreated disease. Release date: Dec. 15, 2003. 2. Outline the prevalence of KCS and the economic Expiration date: Dec. 15, 2004. implications thereof. Medium: Journal supplement. 3. Review the American Academy of Ophthalmology guidelines for treatment of KCS and design appro- Planning committee members priate treatment for patient care. John D.Sheppard, MD, MMSc, professor of ophthal- 4. Explain the mechanisms of action of pharma- mology, microbiology, and immunology, Eastern Virginia cotherapies for KCS. Medical School;Timothy P.Search, RPh, group publisher, 5. Summarize pharmacoeconomic data of emerging MANAGED CARE, published by MediMedia USA; Michael D. anti-inflammatory agents for KCS. Dalzell, editor, custom publications, Managed Markets 6. Identify considerations in proper handling and Publishing Group, MediMedia USA. administration of preservative-free topical agents for KCS.

Target audiences Managed care organization medical directors and pharmacy directors; practicing primary care physicians, ophthalmologists, and pharmacists; members of pharmacy and therapeutics committees.

Continuing education credit sponsored by The Chatham Institute.

4 P&T DIGEST SELF-STUDY CONTINUING EDUCATION ACTIVITY

PRIMARY FACULTY John D.Sheppard, MD, MMSc, acknowledges grant and research support from Alcon, Allergan, Bausch & Eric D. Donnenfeld, MD Lomb, Ciba Vision, GlaxoSmithKline, Insite Pharma- Founding Partner ceuticals, Isis Pharmaceuticals, Ista Pharmaceuticals, Ophthalmic Consultants of Long Island Lumenis, Novartis, Santen, and Science-Based Health. Lynbrook, N.Y. He has consulting relationships with Allergan, Bausch & Lomb, Ciba Vision, Insite Pharmaceuticals, Isis Pharma- Jan D. Hirsch, PhD ceuticals, Ista Pharmaceuticals, Novartis, Santen, and Director, Clinical Research Science-Based Health.He is on speaker’s bureaus for Prescription Solutions Alcon, Allergan, Bausch & Lomb, Ciba Vision, Glaxo- Costa Mesa, Calif. SmithKline, Lumenis, Novartis, Santen, and Science- Based Health. Henry D. Perry, MD Steven E.Wilson, MD, acknowledges a consulting Senior Founding Partner relationship with Allergan.He is on the speaker’s Ophthalmic Consultants of Long Island bureau for Allergan. Lynbrook, N.Y. PUBLISHER’S STATEMENT John D. Sheppard, MD, MMSc Professor of Ophthalmology, Microbiology, The opinions expressed herein are those of the sym- and Immunology posium faculty, and do not necessarily reflect the views Eastern Virginia Medical School of Allergan Inc.,The Chatham Institute, or the publisher, Norfolk,Va. editor, or the editorial boards of this publication or those of the journals MANAGED CARE and P&T. Steven E.Wilson, MD Clinical judgment must guide each clinician in Professor and Chairman, weighing the benefits of treatment against the risk of Department of Ophthalmology toxicity.Dosages, indications, and methods of use for Grace E.Hill Professor in Vision Research products referred to in this special supplement may University of Washington reflect the clinical experience of the authors or may Seattle reflect the professional literature or other clinical sources, and may not necessarily be the same as indi- Conflict-of-interest policy and disclosures cated on the approved package insert.Please consult of significant relationships the complete prescribing information on any products As an accredited provider, The Chatham Institute mentioned in this special supplement before adminis- requires that its faculty comply with ACCME Standards for tering. Commercial Support of Continuing Medical Education and disclose the existence of any significant financial interest or any other relationship a faculty member may have with the manufacturer(s) of any commercial product(s) or device(s). It also requires the faculty to disclose discussion of off-label uses in their presentations.

Eric D.Donnenfeld, MD acknowledges grant and research support from Allergan.He also has a consulting relationship with Allergan. Richard G. Fiscella, RPh, MPH acknowledges grant and research support from Allergan, Merck, and Phar- macia.He has consulting relationships with Allergan, Merck, and Pharmacia. Jan D.Hirsch, PhD, acknowledges stock ownership in Allergan. Henry D.Perry, MD, acknowledges grant and research support from Allergan.He also has a consulting relationship with Allergan.

DRY EYE SYNDROME 5 INTRODUCTION INTRODUCTION Dry Eye Moves Beyond Palliative Therapy

JOHN D. SHEPPARD, MD, MMSC1 Eastern Virginia Medical School

SUMMARY patient satisfaction. When it comes to formulary con- Keratoconjunctivitis sicca, or dry eye syn- siderations, health plans drome, is a complex condition characterized seek data that demonstrate by inflammation of the ocular surface and each drug’s therapeutic ef- tear-producing glands.Emerging awareness fectiveness and potential for of the etiology of dry eye has led to the de- cost offset. The information velopment of highly effective therapy.When herein is intended to help pharmacy and therapeutic dry eye is controlled, there is significant po- committees with this task. tential for cost savings. ETIOLOGY AND ry eye syndrome, also known as keratocon- PREVALENCE junctivitis sicca, is a common condition re- The theory and epidemi- John D.Sheppard, MD, MMSc ported by patients who seek ophthalmologic ology of dry eye and thera- Dcare. Knowledge of the pathophysiology of peutic considerations are discussed at length elsewhere dry eye has made significant strides in recent years; today, in this volume of P&T Digest. In general, dry eye com- what was once thought to be a simple matter of the eye prises a heterogeneous assortment of conditions involv- not producing sufficient tear flow is understood within ing aqueous insufficiency, inflammation of the ocular the ophthalmologic community to be a multifactorial disease. Many family physicians and payers, however, 1 John D. Sheppard, MD, MMSc, received a Masters in may still perceive dry eye to be little more than an irri- Medical Science and his MD from Brown University on a tation and thus may not be aware of emerging specific full Armed Forces Health Professions Scholarship. He spent potent therapies. four years with the U.S. Navy as 6th Fleet medical officer Research has shown that dry eye is a complex condi- and chief of Family Practice. He completed his Ophthal- tion, the hallmark of which is inflammation of the ocu- mology residency at the University of Pittsburgh Eye and lar surface and tear-producing glands (Stern 1998). This Ear Institute and a 30-month fellowship in corneal diseases, awareness has fostered the development of highly effec- uveitis, third-world blindness, and ocular immunology at tive anti-inflammatory therapies. These treatments boast the Proctor Research Foundation at the University of the potential for dramatic advances in quality of life for California–San Francisco. In 1989, Sheppard joined Vir- millions of people whose condition interferes with ac- ginia Eye Consultants and the ophthalmology, microbiology, tivities of everyday living. and immunology faculty of Eastern Virginia Medical School, Improved patient satisfaction and clinical outcomes where he now serves as Ophthalmology program director alone should be the raison d’être for this volume of P&T and as clinical director of the Thomas R. Lee Center for Ocu- Digest, which seeks to promote awareness of dry eye and lar Pharmacology. Sheppard has served as an associate ex- innovative treatment strategies. The reality of medical aminer for the American Board of Ophthalmology for seven practice in a managed care environment, however, is that years and is now a mentor examiner. He has participated therapy must not only be effective, but cost efficient. as principal investigator in more than 45 clinical research Anti-inflammatory therapy carries prospects for favor- trials. Sheppard has authored more than 100 peer-reviewed able pharmacoeconomics, in terms of reduced office vis- abstracts, articles, and chapters. He received the American its and avoidance of complications, let alone enhanced Academy of Ophthalmology Honor Award in 1995.

6 P&T DIGEST INTRODUCTION surface and lacrimal glands, neurotrophic deficiency, cialty — making it difficult to diagnose and treat ocular and meibomian gland dysfunction. Iatrogenic disease, in conditions adequately in a family physician’s office, clinic, which topical prescription medications create hyper- or emergency room. sensitivity or toxicity in the eye and oral medications create lacrimal hyposecretion, also can induce symptoms of NEW TREATMENT,COST-SAVING POTENTIAL dry eye. Before medical research transformed our under- Estimates of the prevalence of dry eye syndrome vary standing of dry eye, treatment had been limited to the use widely (see the following chapter, beginning on page 9), of artificial tears, ointments, and such nonpharmacologic but as many as 40 million Americans may either have therapies as punctal occlusion, environmental control, symptoms of dry eye or remain at risk for it. Post- moisture-retaining eyewear, and surgery. Each had lim- menopausal women may be the largest risk group, due to ited effectiveness, and few produced lasting improve- decreases in hormonal levels that can lead to loss of anti- ment in patients’ quality of life. inflammatory protection and decreased lacrimal function. Today, dry eye can be treated successfully with anti- Individuals with concomitant inflammatory conditions, inflammatory agents, the most beneficial of which is particularly allergies, asthma, and collagen vascular dis- topical cyclosporine. In four multicenter, randomized, ease, are also at risk. Patients who have had eye surgery controlled clinical studies of approximately 1,200 pa- that could compromise the neurogenic support of the tients with moderate to severe keratoconjunctivitis sicca,

HUMAN FACTORS — QUALITY OF LIFE AND PATIENT SAFETY — SHOULD MERIT CONSIDERATION WHEN DECISIONS ABOUT ACCESS TO NEW MEDICATIONS ARE MADE. ocular-surface epithelium — LASIK, transplants, or older cyclosporine ophthalmic emulsion (0.05 percent) extracapsular cataract procedures, for instance — could demonstrated statistically significant increases in have moderate to severe dry eye, but this condition is Schirmer wetting at 6 months (Allergan 2003). This is the frequently unrecognized. This suggests at least some de- first prescription product for dry eye targeting well be- gree of undiagnosed disease that belies published esti- yond palliative therapy, addressing the root inflammation mates of prevalence; more importantly, these groups, of dry eye. Thus, demand for cyclosporine within this pa- taken together, make up a sizeable universe of dry eye can- tient population may well prove to be high. didates, with an equally impressive price tag. If so, this product will get the attention of managed This impressive demographic emphasizes the impor- care pharmacy directors and, one hopes, that of medical tance of early detection and effective treatment, not only directors as well. Managed care organizations are rou- from the perspective of function or comfort, but also in tinely criticized for looking at expenditures in silo fash- terms of recognition of what may be a systemic disease ion, yet new systemic agents increasingly demonstrate a with potentially devastating effects on the individual. marked potential for offsetting nonpharmacy costs. Patients with dry eye are at direct risk for potentially When dry eye is controlled, there is significant potential blinding infections, including bacterial keratitis (Lemp for cost savings in a number of areas: complication costs, 1997), and they present with higher risks for routine overutilization costs, opportunity costs, and intangibles. procedures, such as LASIK. Indirectly, dry eye can be a Some complication costs are derived from sequelae of marker for secondary conditions. The cornea has more untreated dry eye and can be significant. For instance, nociceptors or pain receptors per square millimeter than bacterial keratitis, mentioned earlier, is costly and can any other place in the body, making it one of the most lead to corneal transplantation — a $20,000 procedure. painful targets of diffuse autoimmune conditions. The Other complication costs can result from elective surgery. ophthalmologist or primary care physician, then, must There are 1.5 million laser procedures and another 1.5 be attuned to the likelihood that a systemic disease is be- million cataract surgeries annually in the United States hind the patient’s complaints of dry eye. (Moretti 2000, Desai 2001), and dry eye is a potential Family physicians should always refer complaints of complication of both procedures.When surgical patients dry eye to an ophthalmologist. Ocular problems are take longer to heal and require more follow-up visits, unique — unfamiliar to many other physicians, in part there is added expenditure to the system. because the instrumentation is foreign to every other spe- Overutilization cost offsets represent another group

DRY EYE SYNDROME 7 INTRODUCTION

of potential savings. Some of these are easily identified, must apply artificial tears several times each hour, with such as decreased use of artificial tears or reduced office- little lasting relief exacerbated by protracted blurred vi- visit utilization that stems from poor patient satisfaction sion. Health plans can improve the satisfaction of mil- and compromised lifestyle due to dry eye symptoms. lions of members who have moderate to severe dry eye Until very recently, practitioners have been able to offer disease by imparting appropriate access to newer treat- patients only palliative therapy; many of these individ- ments. Further gains might also be achieved through uals jump from physician to physician in search of relief tasteful and intellectually sound marketing of newly from their progressively debilitating condition. In their available technology to selected existing patients, physi- modest way, these patients chronically and unnecessar- cians, and potential clients. Rightly, such publicity should ily tax the health care system. be limited through concerns regarding creation of ex- Other overutilization costs are more subtle. The more cessive unnecessary demand. than 3 million elective eye procedures each year in the Safety is a primary ingredient in the success of out- United States often involve patients who are predisposed comes-driven medical practice.With the knowledge that to dry eye; cataract patients, for instance, tend to be has been obtained through study of the pathogenesis of older, while some LASIK patients dislike their contact dry eye, our approach to treatment has changed accord- lenses — often because their dry eyes make wearing ingly; over the past few years, ophthalmologists have contacts irritating or unbearable. Some of these elective begun to prescribe custom formulations of cyclosporine procedures can, in fact, be avoided altogether by con- for dry eye patients.While these formulations have been trolling the dry eye. reasonably efficacious in treating disease, they can be Yet another group of potential savings is in opportu- uncomfortable, difficult for patients to obtain, and — as nity costs outside the health care system. These include off-formulary compounds — expensive for patients indirect costs, such as loss of productivity attributed to (Wilson 2001). Moreover, these compounds inherently morbidity, and reduced comfort and convenience to pa- possess a more threatening side-effect profile than do tients. Bacterial keratitis may result in permanent scar- products that have or will eventually receive approval ring.Without a corneal transplant, these patients can suf- from the U.S. Food and Drug Administration. fer loss of effectiveness relative to areas such as work We have learned that dry eye is a systemic disease and performance, night driving, caring for family members, that it responds well to cyclosporine anti-inflammatory or engaging in a favorite activity. The projections can play therapy. Agents coming to market and in development out in various ways — a prospective fiscal analysis of this have altered the paradigm of treatment radically. This is nature would hinge on the variables selected for study. an exciting time for medical professionals and for pa- Nevertheless, when opportunity costs are factored in, the tients, who undoubtedly will clamor for access to these overall costs to the health care system and to society are therapies.As new therapeutic options become available, logarithmically accelerated. an opportunity exists to create standards for their uti- Finally, intangibles include a satisfied patient popula- lization that balances everyone’s interests while making tion being offered a first-in-class drug therapy that rep- them accessible to people who will benefit the most from resents a new paradigm in dry eye treatment. Contented them. patient clients reflect well on any health care organization, creating goodwill, an open dialog, new patient re- REFERENCES ferrals, less confrontation, and more personable and ap- Allergan, Irvine, Calif. 2003. Restasis prescribing information. Available at: «http://www.restasis.com/RestasisPI.pdf». propriate access patterns. Accessed March 27, 2003. Desai M, Pratt LA, Lentzner H, Robinson KN. Trends in vision NONECONOMIC CONSIDERATIONS and hearing among older Americans. U.S. Centers for Dis- Opportunity costs could never be reflected in a health ease Control and Prevention, National Center for Health Statistics. 2001:3. Available at: plan’s bottom line or in a P&T committee analysis. Yet, «http://www.cdc.gov/nchs/data/agingtrends/02vision.pdf». human factors — members’ quality of life, client satis- Accessed March 27, 2003. faction, and patient safety — merit consideration when Lemp MA, Chacko B. Diagnosis and treatment of tear deficien- decisions about access to new medications are made. cies. In: Tasman W, Jaeger E, eds. Duane’s Clinical Ophthal- mology. Philadelphia: Harper and Row. 1997. Dry eye is the most prevalent chronic ocular surface Moretti M. U.S. laser vision correction market explodes. Eye disease. Ophthalmologists share the frustration experi- World. 2000;12:29–31. enced by patients for whom artificial tears and punctal Stern ME, Beuerman RW, Fox RI, et al. The pathology of dry eye: occlusion are ineffective. These treatments also are in- the interaction between the ocular surface and lacrimal glands. Cornea. 1998;17(6):584–589. convenient; in such environments as airplanes, dry cli- Wilson SE. Dry Eye Disease: New Paradigm, New Treatment? mates, or heated or air conditioned rooms, some patients Research to Prevent Blindness, New York. 2001.

8 P&T DIGEST OVERVIEW OVERVIEW Dry Eye: Prevalence, Utilization, and Economic Implications

MICHAEL D. DALZELL1

ry eye syndrome is believed to affect more This would suggest that health plans and practi- than 4 million Americans (Schein 1997). tioners that place an emphasis on detection and The nature of the condition, however, treatment of dry eye syndrome — sometimes dis- Dsuggests that the universe of individuals missed as a trivial complaint — will benefit from with untreated disease — whether the symptoms improved clinical and financial outcomes. Beyond are ocular or otherwise in origin — may be larger. considerations of systemic illness, untreated dry Dry eye is a common disorder, characterized by in- eye itself can lead to corneal damage and visual im- flammation of the ocular surface and lacrimal pairment (Lemp 1987). glands. Often, dry eye symptoms serve as a marker The next several pages provide a statistical snap- for systemic illness. shot of dry eye syndrome: its prevalence, populations at risk, potential complications, associated 1 Michael D. Dalzell is editor of P&T DIGEST and is man- conditions, the demands dry eye places on health aging editor of MANAGED CARE, a peer-reviewed journal. care utilization, and the ramifications for payers.

EPIDEMIOLOGY The most commonly cited estimate of prevalence in the United States is derived from a population-based study of 2,482 elderly people in Maryland.About 1 in 7 subjects age 65 to 84 reported symptoms of dry eye often or all of the time.Extrapolated to the general population, Schein (1997) estimated that 4.3 million Ameri- cans in this age cohort suffer from ocular irritation and that 1 million have diagnosable disease.Moss (2000) reported similar overall prevalence (14.4 percent) in a larger cohort (3,722 subjects between ages 48 and 91). While Schein found no correlation of disease with age or sex, other researchers have made such associations. Moss noted that after age 59, prevalence more than doubled.A separate Australian study of 926 subjects age 40 and older found generally higher prevalence of dry eye in women (Figure 1). FIGURE 1 Prevalence by age and sex % 35 31.8 31.3 Clinical signs of dry eye (%)* 30 Symptoms of dry eye (%)† 25

20.0 20

15 13.6 12.6 10.0 10 5.9 6.0 6.3 6.9 6.3 4.7 4.4 4.7 5 4.1 3.2 3.9 2.5 2.5 2.4

0 Sex: F M FMFMFMFM Age: 40–49 50–59 60–69 70–79 80–89 * As diagnosed by one or more tests. † Self-reported symptoms, not including subjects with hay fever. SOURCE: MCCARTY 1998

DRY EYE SYNDROME 9 OVERVIEW

EPIDEMIOLOGY, continued

Claims-based studies ology of dry eye.As such, definitions of dry eye Claims-based prevalence estimates provide a syndrome have differed from study to study, mak- different perspective from population-based ing results incomparable (Brewitt 2001).This is studies.Claims studies measure the impact of complicated by the lack of a standardized clinical symptoms that require medical attention — testing protocol to diagnose the condition. a perspective that is valuable to payers. The effect of this diagnostic void is illustrated in In one study of claims data in a managed care Figure 3.In one study,four diagnostic tests yielded environment covering 12 million lives, researchers wide differences in results among patients who noted a strong connection between dry eye and complained of one or more severe dry eye symp- both advancing age and sex (Figure 2).Females toms; the tests also varied greatly in their ability to were more likely to have a dry eye-related diagno- discriminate between signs and symptoms.Rela- sis or procedure.Women experienced a sharp in- tively few patients received diagnoses compatible crease in prevalence earlier than men — around with their symptoms. age 45, or roughly the onset of menopause. FIGURE 3 Test used to detect clinical signs FIGURE 2 Rates of diagnoses and Percentages are of patients reporting ≥1 severe symptom procedures, by age and sex Test result (%) Rate per 100,000 33 1997 Abnormal (diagnosis) 1998 1653.4 Normal (no diagnosis) 1427.8 20 18

12 9 8 9 9 689.6 567.7 385.9 319.6 Fluorescein Rose bengal Schirmer Tear-film breakup 273.0 221.8 Figures are rounded to nearest whole percentage point. SOURCE: MCCARTY 1998

Female Male Age <65 Age ≥65 Each of these diagnostic tests has limited useful- SOURCE:YAZDANI 2001 ness when performed alone, yet performing multiple tests is rarely feasible or cost-effective.Pflugfelder Explaining variability in prevalence (1998) has proposed an algorithm for determining Epidemiological studies of dry eye syndrome in the diagnostic utility of tests.Meanwhile, the emerg- the United States and other countries suggest ing recognition of dry eye as a multifactorial inflam- wide differences in prevalence.The difficulty in matory condition may lead to consensus on diagnos- pinpointing the extent of disease stems, in part, tic testing, as well as a more thorough understanding from a previous lack of understanding of the eti- of iatrogenic contributions to dry eye syndrome.

HIGH-RISK POPULATIONS FOR DRY EYE SYNDROME • Inflammatory disease (vascular, allergy, asthma) • Extracapsular or intracapsular large-incision cataract • Autoimmune diseases (RA, lupus, colitis) surgery • Peri- and postmenopausal women and HRT patients • Laser in situ keratomileusis (LASIK) • Diabetes mellitus • Systemic medications (diuretics, antihistamines, • Thyroid disease psychotropics, cholesterol-lowering agents • Sjögren’s syndrome • Contact lens wear • Corneal transplantation • Environmental conditions (allergens, cigarette smoke, • Previous keratitis or corneal scarring wind, dry climate, air travel, chemicals, some perfumes)

ADAPTED FROM: AAO 2003, BREIL 2002, MCCARTY 2000, MOSS 2000, SCHAUMBERG 2001

10 P&T DIGEST OVERVIEW

UTILIZATION TRENDS

Low patient satisfaction has been documented Forty-two percent of these patients had undergone among individuals with moderate to severe dry eye punctal occlusion at least once in the past. syndrome (Lubniewski 1990).The chronic symptoma- Surveys of subpopulations have identified higher tology of dry eye, as well as relatively ineffective tra- office utilization and frequent visits; Hirsch (1998), for ditionally available treatment modalities, spawns instance, reported that 89 percent of Sjögren’s dry frustration and high health-resource utilization eye patients visited an ophthalmologist an average among patients seeking relief from the condition. of 3.1 times per year for their symptoms, and more than one fourth of all subjects had visited other Office visits physicians at least once in the past year for their con- In the Schein (1997) study, 73 percent of subjects dition. who reported frequent dry eye symptoms visited an eye care professional in the past year.A smaller sur- Pharmaceutical interventions vey, conducted among patients participating in A recent study of resource utilization among non- phase 2 trials of a cyclosporine A topical preparation Sjögren’s dry eye patients found high utilization of for dry eye syndrome, found that 60 percent of dry medical therapies — among products specifically eye patients visited a physician more than twice in designed to treat dry eye symptoms as well as other the past year for their symptoms (Nelson 2000). drugs (Figures 4 and 5).

FIGURE 4 Medications used by dry eye patients In the past 3 months Used at all Used regularly or always (subset of “used at all”) Not used

Lubricant drops Lubricant ointments

13% 16% Used Used Used at all: at all: 40% at all: 44% 40% 87% 61% 56% 60%

FIGURE 5 Additional medications used to treat dry eye symptoms In the past 3 months

Analgesics 12.8%

Antibiotics 5.7%

Anti-inflammatory agents 5.7%

Any additional medications 27.0%

SOURCE: NELSON 2000

Future trends With the advent of medical therapy that addresses the underlying inflammatory nature of dry eye syndrome, there is potential for increased patient satisfaction — and, thus, fewer office visits and reduced utilization of tear substitutes and other pharmaceutical therapies.Studies that document this potential are reported in the chapter on pharmacoeconomics that begins on page 33.

DRY EYE SYNDROME 11 OVERVIEW

ECONOMIC IMPLICATIONS Moss also examined lifestyle factors, finding a sur- prise protective effect of caffeine and a contributing Relatively few data exist on direct and indirect factor in multivitamin use (Figure 7).This research costs of dry eye and its sequelae.Likely, this is due to also identified an opportunity for physicians to the fact that until recently, when the etiology of this counsel patients who smoke or drink heavily. common disease became more fully understood, dry eye was viewed largely as an irritant and not neces- FIGURE 7 Lifestyle factors* sarily a serious condition worthy of medical atten- Behavior Odds ratio2 tion.Nelson (2000) challenged this view from an economic standpoint, arguing that older treatment Current smoker 1.82 modalities can lead to unacceptable costs and progressive use of health care resources.Emerging sci- Multivitamin use 1.41 entific knowledge about dry eye may prompt payers or the government to conduct comprehensive data analyses of the economic impact of dry eye. History of heavy alcohol use 1.31

Direct medical costs and complications Small-scale models have been developed to esti- Caffeine 0.75 mate the cost of office visits, drugs, and procedures attributed specifically to dry eye.In one study, the * Adjusted for age and sex. 95-percent confidence interval. cost of managing and treating dry eye patients with SOURCE: MOSS 2000 palliative medications, punctal plugs, and surgery, over the course of 1 year, was $357,050 for an organi- Dry eye is a direct complication of large-incision zation covering 500,000 lives (Lee 2000).The authors cataract procedures, corneal transplantation, and speculated that a more effective dry eye interven- LASIK.Moss reported a 1.39 odds ratio in patients tion could improve cost effectiveness by decreasing who had undergone any sort of lens surgery, while patient demand for physician visits and procedures. Breil (2002) found that dry eye is one of the most The multifactorial nature of dry eye makes a full common postoperative complications of LASIK. accounting of direct medical costs complex.Because dry eye can be a marker for systemic illnesses, costs Indirect costs of treating dry eye symptoms are often figured Dry eye syndrome has the potential to reduce under other diagnoses.Moss (2000) used a logistic employee productivity significantly.In one study, model to calculate factors associated with dry eye, dry eye patients experienced an average of 184 work including arthritis and diabetes.This research also days of reduced productivity, at an estimated annual discovered a protective effect in total-to-HDL (high- cost of $5,362 per individual (Kozma 2000). density lipoprotein) cholesterol ratio (Figure 6). Another study — this of a subset of dry eye patients, those with Sjögren’s syndrome — indicated FIGURE 6 Prevalence of comorbidities* that symptoms interfered with the activities of daily living in all but 29 days of the year (Figure 8). Condition Odds ratio2

Arthritis 1.91 FIGURE 8 Interference with activities Days per year among Sjögren’s patients

History of gout 1.42 Days lost from work: 5 Leisure days with symptom interference: 123

History of thyroid disease 1.41

Diabetes 1.38 Days worked with symptoms: 208 Total-to-HDL No reported effects: 29 -to-HDL cholesterol ratio† 0.93 SOURCE: HIRSCH 1998 2 An odds ratio is calculated by dividing the odds in the * Adjusted for age and sex. 95-percent confidence interval. † Per increment of 1 unit. treated group by the odds in the control group. Factors that cause harm have an odds ratio >1.0.An odds ratio SOURCE: MOSS 2000 of 2.0 represents a 100-percent increased risk.

12 P&T DIGEST OVERVIEW

Lee JT,Teale CW.Development of an economic model to as- SUMMARY sess costs and outcomes associated with dry eye disease. Poster presented at the 2000 Spring Practice and Re- Dry eye syndrome is far more prevalent than previ- search Forum of the American College of Clinical Phar- ously considered.There are significant comorbidities, macy, April 2–5, 2000, Monterey, Calif. Lemp MA.Recent developments in dry eye management. associated diseases,and behavioral and environ- Ophthalmology. 1987;94:1299–1304. mental factors that may contribute to the severity of Lubniewski AJ, Nelson JD.Diagnosis and management of dry dry eye.Dry eye syndrome has significant economic eye and ocular surface disorders. Ophthalmol Clin North implications,including costs associated with in- Am. 1990;3:575–594. creased health care utilization,missed school and McCarty CA, Bansal AK, Livingston PM, et al.The epidemiology work,and leisure and quality-of-life issues.Dry eye of dry eye in Melbourne, Australia.Ophthalmology. 1998;105:1114–1119. presents important economic challenges to patients, McCarty DJ, McCarty CA.Survey of dry eye symptoms in Aus- physicians,and health care delivery organizations. tralian pilots.Clin Experiment Ophthalmol. 2000;28:169–171. Moss SE, Klein R, Klein BE.Prevalence and risk factors for dry REFERENCES eye syndrome.Arch Ophthalmol.2000;118:1264–1268. AAO (American Academy of Ophthalmology). Preferred Prac- Nelson JD, Helms H, Fiscella R, Southwell Y,Hirsch JD.A new tice Pattern: Dry Eye Syndrome.San Francisco: AAO, 2003. look at dry eye disease and its treatment.Adv Ther. Breil P,Frisch L, Dick HB.Diagnosis and therapy of LASIK- 2000;17:84–93. induced neurotrophic epitheliopathy.Ophthalmologe. Pflugfelder SC,Tseng SC, Sanabria O, et al.Evaluation of subjec- 2002;99:53–57. tive assessments and objective diagnostic tests for diag- Brewitt H, Sistani F.Dry eye disease: the scale of the problem. nosing tear-film disorders known to cause ocular irrita- Surv Ophthalmol.2001;45(suppl2):S199–S202. tion.Cornea.1998;17:38–56. Hirsch JD, Kozma CM,Wojcik AR, Reis B.Economic and quality Schaumberg DA, Buring JE, Sullivan DA, Dana MR.Hormone re- of life impact of dry eye symptoms: a Sjögren’s patient placement therapy and dry eye syndrome.JAMA. survey.Invest Ophthalmol Vis Sci.1998;39:S65. Abstract. 2001;286:2114–2119. Kozma CM, Hirsch JD,Wojcik AR.Economic and quality of life Schein OD, Munoz B,Tielsch JM, et al.Prevalence of dry eye impact of dry eye symptoms.Poster presented at the among the elderly.Am J Ophthalmol.1997;124:723–728. Annual Meeting of the Association for Research in Vision Yazdani C, McLaughlin T, Smeeding JE,Walt JG.Prevalence of and Ophthalmology, April 30–May 5, 2000, Ft.Lauderdale, treated dry eye disease in a managed care population. Fla. Clin Ther. 2001;23:1672–1682.

DRY EYE SYNDROME 13 ETIOLOGY ETIOLOGY Inflammation: A Unifying Theory For the Origin of Dry Eye Syndrome

STEVEN E. WILSON, MD1 Cole Eye Institute, Cleveland Clinic Foundation

SUMMARY damaged, or killed by activated T-cell lymphocytes. Dry eye syndrome has been difficult to diag- A variety of factors can nose and treat, due to its heterogeneity. exacerbate KCS (Table 2). These difficulties are being overcome, how- New evidence has shown ever, as evidence becomes available about a that regardless of the pre- disposing factor(s), most common etiology.An inflammatory mecha- KCS results from a localized nism apparently underlies the condition. immune-mediated inflam- This theory has been proven by use of mation affecting both the immunomodulators that show efficacy in lacrimal glands and the oc- treating patients with dry eye syndrome. ular surface (Stern 2002). Historically, KCS has eratoconjunctivitis sicca (KCS), or dry eye syn- been frustrating to study drome, is a common ophthalmologic abnor- and treat, in part due to its Steven E.Wilson, MD mality involving bilateral disruption of the diverse symptoms and dis- Kprecorneal tear film. It is caused either by in- ease variables. The heterogeneity of dry eye creates chal- adequate tears or an inability to maintain an effective tear lenges in the diagnosis and treatment of individual cases. film. In KCS, the tear film is disrupted, causing a variety The high degree of variability in patient populations of symptoms (Table 1). Dry eye syndrome can occur in makes data analysis extremely difficult. Thus, the ability any age group, but is especially prevalent in people over to postulate and prove a unifying etiology has been hin- age 65. It estimated that 10 to 15 percent of Americans dered by the multifactorial nature of KCS and the clini- in this age group have one or more symptoms of this dis- cal conundrum of matching patients’symptoms and di- ease (Schein 1997). In serious cases, dry eye syndrome agnostic test results with patients’actual disease severity. can lead to photophobia and vision loss. 1 It is evident from its name that KCS is a drying in- Steven E. Wilson, MD, is director of corneal research at flammation: kerato (corneal) conjunctivitis (conjuncti- the Cole Eye Institute of the Cleveland Clinic Foundation. val inflammation) sicca (from the Latin sicco, meaning “to A board-certified ophthalmologist, Wilson recently came dry”). KCS can occur sporadically or as a chronic condi- to Cleveland from the University of Washington in Seattle, where he directed an NEI-supported laboratory that in- tion that becomes a self-perpetuating syndrome. This ar- vestigates the function of growth factors and cytokines ticle will explore current trends in KCS etiology research. in controlling corneal wound healing. He has authored Destruction of corneal and bulbar conjunctival epi- more than 300 papers, abstracts, and book chapters. After thelium from KCS can arise from many diverse causes earning his medical degree from the University of (AAO 1998); it is often secondary to Sjögren’s syndrome, California–San Diego, Wilson completed an ophthalmol- an autoimmune disease that results in dry eyes and ogy residency at the Mayo Clinic and a fellowship in mouth. Sjögren’s syndrome can occur with or without cornea, external disease, and refractive surgery at the rheumatoid arthritis, lupus, or scleroderma. In Sjögren’s Louisiana State University Eye Center in New Orleans. KCS, the exocrine glands secreting tears, saliva, and gas- Wilson, who holds memberships in numerous professional tric excretions are inadequate. KCS — either Sjögren’s or societies, serves on the board of trustees of the Association non-Sjögren’s — is now believed to be an autoimmune of Research in Vision and Ophthalmology and on the ex- state in which the epithelial cells of the lacrimal glands are ecutive board of the ISRS-RSIG for the American Academy detected as antigens by the immune system and attacked, of Ophthalmology.

14 P&T DIGEST ETIOLOGY

A COMMON UNDERLYING ETIOLOGY of secretions from primary and secondary glands lo- The pathophysiology of KCS has long been known to cated under the eyelids and from sebaceous glands on the involve a disruption of the layer of tears that protects and flat rims of the eyelids that secrete an antievaporation nourishes the delicate eye tissues. The goal of therapy has lipid layer (Figure 2, page 16). been to normalize tear volume and composition, so that The tear drainage system is also important in normal- the eye tissues are properly lubricated, nourished, and izing hydration of the eye. Inflammation-induced dys- protected. This has been accomplished to some extent by function in this drainage system can precipitate KCS. The increasing tear secretion, reducing tear turnover, and/or system includes the punctal opening (the tiny hole in the promoting epithelial healing on the ocular surface using upper and lower eyelids). Blinking causes tears to enter the lubricants and emollients. If the KCS results from a sys- punctae, where they are drained through canaliculi into temic disorder, the systemic disease can be treated and the the lacrimal sac and the nasolacrimal duct into the nose. symptoms thereby decreased. Part of the function of tears is to protect the eye from Local treatment strategies for the eye (aside from treat- microbial invasion. In a normally functioning adult eye, ing infections) have been essentially palliative, however, an anti-inflammatory component keeps the disruptive and do not address the inflammatory response. The treat- effect of irritation to a minimum.When this component ment goal of this new approach to disease is to suppress is lacking, however, or when irritation is not controlled, the inflammation that underlies symptoms and signs. the body’s immune system activates its inflammatory T- The recent discovery of a neurological-inflammatory lymphocytes. component has provided an explanation for the patho- Cytokines are hormone-like proteins that regulate the physiology of KCS. If inflammation in KCS is considered immune response. They also damage tissue when over- not a symptom but a cause, then suppressing the abundant (Table 3,page 17). Cytokines and other proin- cytokine-mediated inflammatory response that occurs at flammatory mediators lead to activation of more T-cells, a histological level can be applied to KCS regardless of production of more inflammatory substances, and tissue disease-state association.An emerging strategy for treat- damage. ment of KCS is therapy with immunomodulators that address the local inflammation caused by cytokines that TABLE 1 Symptoms of keratoconjunctivitis sicca circulate in the lacrimal glands and con- Dry sensation Foreign body or “gritty”sensation junctiva, regardless of whether any asso- Dry sensation Blurred vision ciated disease state is local or systemic. Irritation/redness Contact lens intolerance According to this new theory of KCS Redness Increased frequency of blinking etiology, a cyclical syndrome causes the Tearing Mucous discharge Burning/stinging SOURCE: PFLUGFELDER 2000a lacrimal glands to suffer from neurogenic inflammation, T-cell activation, and cytokine secretion into tears. The cytokine- laden tears inflame the ocular surface, dis- TABLE 2 Variables in keratoconjunctivitis sicca rupting sensory signals from the surface of the eye, so the normal stimulus for tear se- Precipitating factors cretion is curtailed. In addition, the Medication (e.g., anticholinergics) Environmental conditions (e.g., wind) lacrimal glands, both primary and sec- Trauma (e.g., chemical burns) or corneal dystrophies ondary, may be damaged or destroyed. Reading for lengthy periods (especially from a computer screen) This leads to a virtual shutdown of the lacrimal system and to a self-perpetuating Severity potential inflammation that cannot be ameliorated Annoyance only Acute increase in severity (e.g., photophobia and blepharospasm) by the eye’s normal defense system. The Loss of normal configuration of conjunctival fornices immune system itself is the problem Ulceration, vascularization, and scarring of cornea (Figure 1, page 16). This localized inflam- Severe visual disability mation cycle can be demonstrated in both Sjögren’s and non-Sjögren’s patients. Duration Sporadic, reversible Chronic nonreversible deficiency of tear production The normal lacrimal system • Waxing or waning Normally, the integrity of the lacrimal • Constant condition SOURCE: STERN 2002 system is maintained by a precise interplay

DRY EYE SYNDROME 15 ETIOLOGY

from dogs with dry eye syndrome FIGURE 1 Dry eye: an immune-mediated inflammatory disorder demonstrate such lymphocytes (Fig- ure 3). Total T-cells that are abnor- mally increased in dry eye syndrome Lacrimal glands: Interrupted secretometer can be seen by fluorescing T-cells in • Neurogenic nerve impulses the conjunctiva of Sjögren’s and non- inflammation Sjögren’s patients. • T-cell activation • Cytokine The main and accessory lacrimal secretion glands may be susceptible to inflam- into tears Tears inflame ocular surface mation due to an age- and hormone- related degenerative process. The change in tear secretions leads to the Cytokines pathophysiology described above as a disrupt neural arc neurological inflammatory disease that becomes a constant cycle (Figure FIGURE 2 The three major components of normal tear film 4, page 18). As sensory input to the lacrimal glands decreases, the quantity and quality of tears is reduced, Lipid layer causing further irritation of the ocu- Soluble lar surface. proteins Cyclosporine as an anti- inflammatory agent in dry eye Aqueous/ Soluble mucin gel mucins Marsh (1999) showed that corticosteroids could be used for treating severe dry eye in humans. Never- Membrane theless, use of corticosteroids was mucins limited by the known side effects of cataract formation, glaucoma, and Epithelium infection. Cyclosporine A (CsA) was tested and found efficacious by oph- Layer Function Origin thalmologists experimenting with it Anterior Lipid layer, which acts as vapor barrier Meibomian glands in severe, treatment-resistant KCS patients. Now, it is available as a topical Middle Aqueous electrolytes and proteins that consti- Lacrimal glands tute 98 percent of the total tear film.This layer anti-inflammatory for dry eye syn- contains nutrients, enzymes, cytokines, and drome, formulated at doses thou- antimicrobials. sands of times smaller than those Posterior Heavily glycosylated proteins, mucins Goblet cells in con- used to avoid graft-versus-host dis- (adjacent to • Immunoglobulins junctiva and corneal ease in tissue transplantation. epithelium) • Antimicrobial proteins and conjunctival Cyclosporine is an immunomodu- • Growth factors (e.g., transforming growth epithelial cells lator that primarily is used systemi- factor-alpha or epidermal growth factor) cally in transplant, psoriasis, and SOURCE: PFLUGFELDER 2000b rheumatoid arthritis patients. This agent’s anti-inflammatory effects arise Ordinarily, when any kind of an invasion or disrup- primarily from its ability to prevent the activation of T- tion is detected, more tears are produced to flush out the cells and resulting production of cytokines and other in- entire lacrimal system. In autoimmune diseases, however, flammatory agents. Until recently, there was no commer- the inflammatory response in the eye can attack healthy cially available preparation of CsA for topical use in the epithelial cells with enzymes that are meant to lyse inva- eye. The preparation had to be custom formulated in ir- ders, damaging the matrix of tears and the conjunctiva. ritating oils by pharmacists for ophthalmologists. Despite Evidence from canine research shows that the origin the fact that this use of CsA had not been systematically of KCS is associated with lymphocytic infiltrations in tested in humans, many ophthalmologists reported good both the conjunctiva and the lacrimal glands. Biopsies results with few complications other than stinging.

16 P&T DIGEST ETIOLOGY

CsA was approved in the United States in 1995 to treat chronic dry TABLE 3 The role of cytokines and T-cells in adaptive immunity eye disease in dogs. Now that CsA has been tested in humans at a Immunomodulator Description and function dose of 0.05 percent in a special vehicle, it can be used to increase Cytokines These are proteins released by various types of cells tear production in patients whose (Examples: including lymphocytes and corneal epithelial cells. production levels are presumed to interferon, Cytokines regulate the process of T-cell prolifera- be suppressed due to ocular in- interleukin, tion and differentiation, and serve an antiviral and lymphokines) anti-tumor function in the immune system.They flammation associated with KCS. promote allergic reactions, boost T-cell functions, The effect of CsA ophthalmic and thus are used to evaluate immune activity. emulsion on inflammation arises from its ability to inhibit activa- T-cells These are lymphocytes with antigen-receptor tion of T-cells by blocking their complexes on their surfaces.They are produced by intracellular signal transduction the thymus and have the ability to lyse foreign or virus-infected cells.They reside primarily in the cascade responsible for upregula- lymphatic system and secrete hormone-like pep- tion of NF-AT and NF-kB regu- tides that mediate the immune response; they also lated genes, including genes for regulate erythroid cell maturation in bone marrow. many cytokines (Table 4). CD3 cells These are a subset of leukocytes involved in signal transduction in the cell membrane. Phase 2 and 3 clinical studies of cyclosporine for KCS A phase 2 study of CsA among FIGURE 3 Evidence of inflammation in dry eye syndrome 162 patients was undertaken using doses ranging from 0.05 percent to 0.40 percent twice a day. The results determined that doses of 0.05 percent to 0.10 percent were effective and well tolerated (Stevenson 2000). At the small doses used in the phase 3 study, there was no evidence of the increased risk of infections and tumors observed Conjunctiva Lacrimal gland with large doses of cyclosporine T- cell infiltrations used for transplantation.With the (Dark-stained cells; canine biopsy) fractional dose used for KCS SOURCE: STERN 1998 (2,500 times smaller), there were no ocular infections related to CsA, nor was the drug detected TABLE 4 Anti-inflammatory activity of cyclosporine A in the blood of patients who were administered a 0.05 percent dose. • Binds to an intracellular protein • Inhibits an activation enzyme (calcineurin) The 1-year results of phase 3 • Inhibits expression of numerous genes essential for T-cell activation study of CsA (both Sjögren’s and and proliferation non-Sjögren’s) are briefly de- • Prevents replication of T-cells by blocking a transcription factor scribed in Tables 5–7 on page 19, • Keeps T-cells from expressing some cytokines or “homing”to and then in more detail in the inflammation site chapter “Medications for Dry Eye • Promotes a gene (transforming growth factor) that inhibits the Syndrome: A Drug-Therapy inflammatory response Review,”which begins on page 26. Use of cyclosporine resulted in both clinical improve- was evident especially during the first arm of the study ments and a decrease in markers of immunity and in- (Sall 2000). flammation in conjunctival biopsies. This improvement The efficacy of the vehicle used for a comparison in the

DRY EYE SYNDROME 17 ETIOLOGY

lymphocyte cell marker CD3 in FIGURE 4 Steps in the cycle of inflammation in KCS Sjögren’s and non-Sjögren’s dry eye patients showed a reduction 1. When the ocular surface and Chronic in T-lymphocyte infiltration lacrimal glands are chronically irritation after treatment with CsA. irritated,T-cells become acti- Comparing baseline stains with vated. those after 6 months of CsA 2. These activated T-cells recruit treatment, there was a 3- to 5- additional T-cells and cause an immune-based local inflamma- fold decrease in the number of Symptoms tion. CD3-positive cells in the con- develop Immune 3. Cytokines are released in tears; junctiva of Sjögren’s and non- activation this further irritates the ocular Sjögren’s patients. These similar surface and blocks messages to results in Sjögren’s and non- the lacrimal gland. Sjögren’s patients are consistent 4. As a result, normal tear secretion with a similar pathophysiology is reduced, and chronic dry eye for both conditions (Figure 5). syndrome symptoms develop. Inflammation Disruption of the tear film

SOURCE: STERN 1998 overlying the cornea generates variable irregular astigmatism. This results in blurred vision, FIGURE 5 Decreased inflammation in Sjögren’s an important efficacy measure and non-Sjögren’s patients of treatment. Blurred vision and reliance on artificial tears were CD3-stained T-lymphocytes in conjunctival biopsies included as endpoints in the Sjögren’s Non-Sjögren’s phase 3 study (Table 7). Patients in all groups were allowed to instill preservative-free artificial tears between doses of Baseline 3965 2291 cells/mm2 cells/mm2 study medication throughout the trial. Reduced utilization of artificial tears was a gauge of symptom relief. It should be noted that in clinical studies, CsA did not in- CsA 0.05% 819 762 crease tear production in pa- 2 2 6 months cells/mm cells/mm tients already taking topical anti-inflammatory drugs. This evidence served to confirm the unifying hypothesis of inflam- SOURCE: KUNERT 2000 mation as the etiology of dry eye syndrome. phase 3 study unexpectedly proved to be palliative for Although the anti-inflammatory theory has been cor- symptoms in and of itself, and it was later developed as roborated by clinical efficacy of CsA in KCS, the dry eye a separate artificial tear product. This was apparently a induced by LASIK surgery is not expected to be eligible result of the emulsion that contained both aqueous and for anti-inflammatory treatment, as it has a different oil components, thus maintaining the multilayer tear neurotrophic origin. LASIK patients who had preexist- film rather than comprising an aqueous solution alone. ing dry eye may, however, benefit from CsA treatment. It was partially due to the positive effect of the emulsion vehicle itself that the second arm of the CsA study CONCLUSION showed less dramatic results than the first.Also, the sec- Traditionally, KCS was difficult to diagnose and treat, ond 6-month extension of the phase 3 study included pa- due to its heterogeneity. An inflammatory mechanism tients with less severe disease. apparently underlies the condition. This unifying theory Staining of conjunctival tissue for immune T- has been proven by use of imunomodulators that showed

18 P&T DIGEST ETIOLOGY

efficacy in treating patients with KCS. The TABLE 5 Phase 3 study topical CsA phase 2 and phase 3 studies provided evidence of inflammation re- Subjects 235 subjects with KCS (moderate to severe, with or duction after treatment. These findings without Sjögren’s syndrome), were accompanied by subjective and ob- Design Multicenter, double-blind, randomized parallel trial jective symptom improvements. that lasted for 6 months with most patients remaining Difficulties in studying and treating this through another treatment period of 6 months (total: 1 disease are being overcome as more evi- year) dence becomes available about a common Doses • Cyclosporine 0.05 percent twice daily etiology. For patients, this will mean less ir- • Cyclosporine 0.10 percent twice daily ritation and inflammation. It also should • Vehicle alone twice daily translate to a reduced reliance on artificial tears and ointments and fewer office visits. Results Significant benefit found in both Sjögren’s and non-Sjögren’s patients relative to: REFERENCES • Signs and symptoms AAO (American Academy of Ophthalmology). • Objective measures of tear system and eye function Preferred Practice Pattern: Dry Eye • Safety Syndrome. San Francisco: AAO, 1998. Kunert KS, Tisdale AS, Stern ME, et al. Analysis Not all arms equally successful; of topical cyclosporine treatment of pa- variability in tients with dry eye syndrome: effect on • Signs/symptoms conjunctival lymphocytes. Arch • No correlation between signs and symptoms Ophthalmol. 2000;18:1489–1496. • Variations in severity in second arm of study Marsh P,Pflugfelder SC. Topical nonpreserved methylprednisolone therapy for keratoconjunctivitis sicca in Sjögren’s syndrome. Ophthalmology. 1999;106:811–816. TABLE 6 Summary of objective primary efficacy results Pflugfelder SC, Solomon A, Stern ME. The diagnosis and management of dry eye: a 25- year review. Cornea. 2000a;19:644–649. A total of 59 percent of CsA users achieved a 1–10 mm or more im- Pflugfelder SC, Liu Z, Monroy D, et al. Detection provement in tear production from baseline in Schirmer scores at of sialomucin complex (MUC4) in human 6 months (n=238).Of these, 44 percent had a 1–9 mm increase and ocular surface epithelium and tear fluid. 15 percent had ≥10 mm increase (all patients had ≤5 mm prior to Invest Ophthalmol Vis Sci. 2000b;41: treatment). 1316–1326. Sall K, Stevenson OD, Mundorf TK, Reis BL and the CsA phase 3 study group. Two multi- With CsA 0.05 percent emulsion, patients showed statistically and center, randomized studies of the efficacy clinically significant mean reductions of more than 30 percent vs. and safety of cyclosporine ophthalmic baseline in corneal staining at all time points. emulsion in moderate to severe dry eye disease. Ophthalmology. 2000;107:631–639. Schein OD, Tielsch JM, Munoz B, et al. Relation between signs and symptoms of dry eye in the elderly: a population-based perspective. TABLE 7 Summary of subjective efficacy results Ophthalmology. 1997;104:1395–1401. Stern ME, Beuerman RW, Fox RI, et al. The Endpoints Results pathology of dry eye: the interaction between the ocular surface and lacrimal • Blurred vision 0.05 percent cyclosporine-treated patients glands. Cornea. 1998;17:584–589. exhibited statistically and clinically significant Stern ME, Gao J, Schwalb TA, et al. Conjunctival reductions. T-cell subpopulations in Sjögren’s and non- Sjögren’s patients with dry eye. Invest • Artificial tear Overall use of artificial tears fell by a third Ophthalmol Vis Sci. 2002;43:2609–2614. reliance at month 6. Stevenson D, Tauber J, Reis BL. Efficacy and safety of cyclosporine A ophthalmic emul- • Increase in Mucopolysaccharide secretory cells in the sion in the treatment of moderate to severe the number epithelium increased by 191 percent in the dry eye disease: a dose-ranging, random- of goblet cells treated group vs.13 percent in the vehicle- ized trial. The Cyclosporine A Phase 2 treated controls (p=.013). Study Group. Ophthalmology. 2000;107:967–974. SOURCE FOR TABLES 5–7: SALL 2000

DRY EYE SYNDROME 19 DETECTION AND TREATMENT Guidelines for the Treatment Of Chronic Dry Eye Disease

JOHN D. SHEPPARD, MD, MMSC

SUMMARY or set of tests to confirm or rule out dry eye definitively have limited the comparability of epidemiological data for Keratoconjunctivitis sicca (KCS),also known as this condition. dry eye syndrome,dry eye disease,chronic One clinic-based study found that 17 percent of 2,127 dry eye disease,or keratitis sicca,refers to dis- consecutive new outpatients were diagnosed with dry eye orders of the tear film caused by reduced tear following a comprehensive examination (Hikichi 1995). production,poor tear quality,or excessive tear In a population-based study in Australia, 16.3 percent evaporation.These disorders are associated and 10.8 percent of 926 participants, ages 40 to 97, tested positively for dry eye, based on a low Schirmer test or a with such symptoms of ocular discomfort as high rose bengal score, respectively (McCarty 1998). An irritation,foreign body sensation,or redness, evaluation of claims data for nearly 10 million enrollees and may cause disease of the ocular surface. in managed care plans found that dry eye was diagnosed or treated in 0.5 percent of enrollees (Yazdani 2001). hronic dry eye disease (CDED) is highly het- Risk factors for dry eye include advanced age and fe- erogeneous, and patients present in many dif- male gender (McCarty 1998, Moss 2000, Yazdani 2001), ferent ways. For example, patients with severe arthritis (McCarty 1998, Moss 2000), smoking, multi- Csymptoms may reveal minimal signs upon ex- vitamin use (Moss 2000), and hormone replacement amination, while patients with a multitude of seemingly therapy (Schaumberg 2001). significant findings at the slit lamp may have few complaints. The American Academy of Ophthalmology’s Pathogenesis of dry eye newly released guidelines for diagnosis, treatment, and The ocular surface and tear-secreting glands function management reflect a universal acceptance by clinicians as an integrated unit to refresh the tear supply and to clear of dry eye — alone or in combination with other condi- used tears (Stern 1998). Disease or dysfunction of this tions — as an inflammatory ocular surface disorder that unit results in ocular irritation and dry eye syndrome. can be a cause of visual morbidity and may compromise Decreased tear secretion and clearance initiate an in- the results of corneal surgery, cataract surgery, or other flammatory response on the ocular surface, and research ocular surface procedures. Dry eye symptoms often im- suggests that this inflammation plays a role in the patho- prove with treatment, but the disease usually is not cur- genesis of dry eye (Pflugfelder 2000). able. Many of the ocular surface changes associated with Dysfunction may develop from aging, a decrease in KCS can be reversed with specific treatment. supportive factors (such as androgen hormones), sys- To preserve or improve vision, prevent or minimize temic inflammatory diseases (such as rheumatoid arthri- structural damage to the ocular surface, and alleviate pa- tis), ocular surface diseases (e.g., herpes zoster ophthal- tient discomfort, clinicians must be aggressive both in di- micus), surgery that disrupts the trigeminal afferent agnosing possible underlying systemic inflammatory dis- sensory nerves (including laser in situ keratomileusis ease and in making ocular surface anti-inflammatory [LASIK], extracapsular cataract extraction, or penetrat- therapy a key component of their treatment approach. En- ing keratoplasty), and systemic diseases or medications vironmental control, as well as a careful evaluation of sys- that disrupt the efferent cholinergic nerves that stimu- temic medications, also may yield clinical improvement. late tear secretion (Bacman 2001).

Epidemiology of dry eye Associated conditions The heterogeneity of dry eye, the lack of uniformity in Symptoms caused by dry eye may be exacerbated by sys- its definition, and the inability of any single diagnostic test temic medications such as diuretics, antihistamines, anti-

20 P&T DIGEST DETECTION AND TREATMENT cholinergics, antidepressants, HMG co-A reductase in- to inflammation, scarring, and destruction of the con- hibitors, systemic retinoids, and isotretinoin (Moss 2000). junctival goblet cells. Atopy may produce dry eye due to Dry eye also may be made worse by environmental factors, systemic antihistamine use or blepharitis and eczema. including exogenous irritants and allergens, wind, drafts, air conditioning, heating, and reduced humidity. Natural history In a study of Maryland residents age 65 or older, sub- CDED varies in severity, duration, and etiology (Lemp jects with blepharitis associated with meibomitis were 1995). In most patients, it does not threaten sight but is twice as likely to have dry eye symptoms as those with- characterized by troublesome symptoms of irritation. out signs of meibomitis (Schein 1997). When dry eye is caused by an irreversible deficiency of tear Systemic diseases associated with dry eye include Sjö- production or a chronic condition such as blepharitis gren’s syndrome, rosacea, viral infections such as ac- that leads to increased tear evaporation, symptom sever- quired immune deficiency syndrome (Lucca 1990), hepa- ity may wax and wane, or gradually increase over time. titis C (Abe 1999, Siagris 2002), primary and persistent Reversible conjunctival squamous metaplasia and Epstein-Barr virus infections (Pflugfelder 1987, Merayo- punctate epithelial erosions of the conjunctiva and cornea Lloves 2001, Pflugfelder 1993), and graft-versus-host develop in many patients who have moderate to severe dry disease in recipients of allogenic bone marrow or stem eye. Rarely, patients with severe dry eye will develop com- cell transplants (Ogawa 1999). plications such as ocular surface keratinization; corneal ul- In Sjögren’s syndrome, an inflammatory cellular in- ceration, scarring, thinning (ectasia), or neovasculariza- filtration of the lacrimal gland leads to deficient tear tion; microbial keratitis; and sterile corneal keratolysis, production. Rosacea is associated with posterior ble- with possible perforation and severe visual loss. pharitis, poor tear quality, accelerated tear film breakup time (TBUT), and increased tear evaporation. Aqueous DIAGNOSIS,TREATMENT,AND MANAGEMENT tear deficiency may develop in conditions such as lym- According to guidelines established in the AAO’s 2003 phoma, sarcoidosis (Drosos 1989), hemochromatosis, Preferred Practice Pattern, the goals of diagnosing, treat- and amyloidosis (Fox 1994). ing, and managing patients with dry eye are: to establish Diseases such as ocular cicatricial pemphigoid and the diagnosis of dry eye, differentiating it from other Stevens-Johnson syndrome produce tear deficiency due causes of irritation and redness; to identify the causes of

FIGURE 1 Modified diagnostic classification scheme for dry eye

1. Ocular irritation syndrome 2. Tear film instability DRY EYE 3. Ocular surface disease

Deficient aqueous Increased tear production evaporative loss

Sjögren’s Non-Sjögren’s

Blepharitis/ Exposure Other factors Meibomian gland 1.Contact lenses dysfunction 2.Blink abnormality SOURCE: LEMP 1995 3. Environmental

DRY EYE SYNDROME 21 DETECTION AND TREATMENT

dry eye; to establish appropriate therapy; to relieve dis- burning, stinging, foreign-body sensation, photophobia, comfort; to prevent complications, including visual loss, blurred vision, contact lens intolerance, redness, mucous infection, and structural damage; and to educate pa- discharge, increased frequency of blinking, itching, and di- tients and involve them in managing their disease. urnal fluctuation; exacerbating conditions, such as wind, In moderate to severe cases that are unresponsive to air travel, or low humidity; prolonged visual effort that is treatment or when systemic disease is suspected, timely associated with a decreased rate of blinking; duration of referral to an ophthalmologist with experience in man- symptoms; and any topical medications that have been aging this condition is recommended. Referral to an in- used, as well as their effects on symptoms. ternist or rheumatologist can be considered for patients The patient’s ocular and medical histories should in- with systemic immune dysfunction or for individuals re- clude the factors listed in Table 1. In addition, the medi- quiring immunosuppressive therapy (AAO 2003). cal history should describe use of systemic medications, The most important aspects of caring for patients with including antihistamines, diuretics, hormones and hor- dry eye are to educate them about the chronic nature of monal antagonists, antidepressants, cardiac antiarrhyth- the disease process and to provide specific instructions for mic drugs, diphenoxylate/atropine, isotretinoin, beta therapeutic regimens. It is helpful to discuss realistic ex- blockers, chemotherapy agents, HMG co-A reductase pectations, in terms of therapeutic goals. It also is essen- inhibitors, and any drug with anticholinergic effects. tial to assess, periodically, the extent of their understanding of the disease and adherence to treatment. Physical examination The physical examination should include a visual acu- Diagnosis ity measurement, an external examination, and a slit- Many ocular surface diseases produce symptoms sim- lamp biomicroscopy. The external examination and the ilar to those associated with dry eye, such as foreign- biomicroscopy serve to document signs of dry eye, assess body sensation, mild itching, burning, blurred vision, ir- the presence and severity of deficient aqueous tear pro- ritation, and soreness. The initial evaluation of a patient duction and/or increased evaporative loss, and exclude presenting with symptoms that are suggestive of dry eye other causes of ocular irritation. should include those features of the comprehensive adult The examination and biomicroscopy should focus on eye evaluation relevant to dry eye (AAO 2003). factors listed in Table 2. Additionally, at the slit lamp, the It is often difficult to diagnose patients with mild dry clinician should direct attention toward the four punc- eye syndrome because of the inconsistent correlation be- tums, noting patency or closure, juxtaposition to the bul- tween reported symptoms and clinical signs (Schein bar conjunctiva, and the size of the opening when patent. 1997) and the relatively poor sensitivity and/or specificity of existing diagnostic tests (AAO 2003). When environ- Diagnostic tests mental factors and other potential causes of ocular irri- The poor correlation between reported symptoms tation (see page 10) have been eliminated from consid- and clinical signs, coupled with the aforementioned eration, patients with suggestive symptoms who do not limitations of clinical tests, make it difficult to diagnose have overt signs of disease should be placed on trial treat- dry eye in its mild form. For patients with mild irritation ments, such as artificial tears or, where appropriate, trial symptoms, a rapid TBUT may detect an unstable tear discontinuation of systemic antihistamines (AAO 2003). film with normal aqueous tear production, and ocular Because most dry eye conditions are chronic, repeat surface dye staining may detect a minimal pattern or no observation and the reporting of symptoms over time pattern. For patients with moderate to severe aqueous will allow a more accurate clinical diagnosis of dry eye. tear deficiency, the diagnosis can be made with one or A diagnostic classification scheme, adapted from a Na- more of the following tests: TBUT, ocular surface dye- tional Eye Institute Workshop, is shown in Figure 1 on staining pattern (rose bengal, fluorescein, or lissamine page 21 (Lemp 1995). Participants in this workshop green), or Schirmer wetting test. agreed that two major factors — deficient aqueous tear These tests should be performed in the above se- production and increased evaporative loss — may cause quence, because the Schirmer test can disrupt tear film dry eyes independently but also may contribute con- stability and cause false-positive ocular surface dye stain- currently to dry eye symptoms and signs. ing. Other tests may be helpful in evaluating selected patients, but some have limited availability. These tests Patient history include tear osmolarity, fluorescein clearance, impression According to the AAO 2003 guidelines, the history of cytology, tear function index, and tear protein analysis the patient’s illness should include symptoms and signs re- (including lactoferrin, lysozyme, immunoglobulin, and lating to the eyes such as dry sensation, irritation, tearing, albumin) (AAO 2003).

22 P&T DIGEST DETECTION AND TREATMENT

Corneal sensation should be assessed when trigeminal nerve TABLE 1 AAO guidelines: patient history dysfunction is suspected (Hei- Ocular history should describe: gle 1996).A laboratory and clin- • Contact lens use,lens material,solutions,wearing schedule,lens care ical evaluation for autoimmune • Allergic conjunctivitis disorders should be considered • Corneal history (prior keratoplasty, LASIK, photorefractive keratectomy, radial for patients with significant dry keratotomy, or extracapsular cataract extraction) eyes, other signs and symptoms • Punctal plugs or surgery of an autoimmune disorder • Eyelid surgery (prior ptosis repair, blepharoplasty, entropion/ectropion repair) (e.g., dry mouth, rash, arthritis, • Chronic ocular surface inflammation (acid or alkaline burns, ocular cicatricial colitis, or renal dysfunction), or pemphigoid, or Stevens-Johnson syndrome) a family history of autoimmune Medical history should include: disorders. • Smoking, menopause, and atopy • Dermatological diseases (including seborrhea, eczema, rosacea) Treatment • Trauma (including exposure to chemicals,ultraviolet light,dust,sawdust,fumes) • Systemic inflammatory diseases (Sjögren’s syndrome, rheumatoid arthritis, Patients with a clinical diag- systemic lupus erythematosus, scleroderma, graft-versus-host disease) nosis of mild dry eye may ben- • Chronic viral infections, such as chronic hepatitis C or human immuno- efit from behavioral and envi- deficiency virus ronmental modification, such • Surgery (bone marrow transplant, head and neck surgery) as learning to take breaks while • Radiation of orbit reading, lowering the computer • Neurological conditions (including Parkinson’s disease, Bell’s palsy, and Riley- monitor to decrease lid aper- Day syndrome) ture, and humidification of the • Xerostomia (dry mouth), dental cavities, and oral ulcers environment (Nordstrom 1995). SOURCE: AAO 2003 Because dry eye can be iatrogenic, elimination of exogenous medical factors, such as prescription regimens that include ocular topical preser- TABLE 2 AAO guidelines: physical exam vatives or systemic antihistamines or diuretics, may help. External examination should focus on: For patients with mild disease, use of tear substitutes is • Skin (scleroderma,facial changes indicating rosacea) indicated. As the severity of dry eye increases, nonpre- • Eyelids (incomplete closure/malposition,erythema served tear substitutes or emulsions, gels, and ointments of eyelid margins,incomplete/infrequent blinking, may be used instead of conventional preserved tear sub- abnormal deposits/secretions,entropion,ectropion) stitutes. Noninvasive therapies such as spectacle side • Adnexa (enlargement of the lacrimal glands) shields, moisture inserts, and moisture chambers are ap- • Proptosis propriate for more severe disease, but these tend to be un- • Cranial nerve function (including cranial nerve V,VII) popular among patients for cosmetic reasons (AAO 2003). • Disorders affecting the hand (joint deformities char- acteristic of rheumatoid arthritis,gout,or psoriasis) Medications Slit-lamp biomicroscopy should include attention to: • Tear film (height of meniscus, debris, foam) Pilocarpine and cevimeline, two cholinergic agonists, • Eyelashes (trichiasis,distichiasis,madarosis,deposits) have been approved by the U.S. Food and Drug Admin- • Anterior/posterior eyelid margins and character istration to treat the symptoms of dry mouth in patients of meibomian gland secretions with Sjögren’s syndrome (Vivino 1999, Fox 2001). These • Vascularization crossing the mucocutaneous oral medications stimulate secretion of the salivary and junction, keratinization, and scarring sweat glands and appear to improve tear production, but • Puncta (patency and position) most clinical studies demonstrate greater improvement • Conjunctiva (inferior fornix and tarsal conjunctiva, in dry mouth than dry eye (Vivino 1999, Nelson 1998). and bulbar conjunctiva) Patients treated with pilocarpine at a dosage of 5 mg • Cornea (localized interpalpebral drying, punctate epithelial erosions, filaments, macroepithelial de- orally, 4 times daily, experienced a significantly greater fects, punctate staining with rose bengal or fluo- overall improvement in the ability to focus their eyes dur- rescein dyes, mucous plaques, keratinization, pan- ing reading, as well as improvements in symptoms of nus formation, thinning, infiltrates, ulceration, blurred vision, compared to placebo-treated patients. neovascularization, and scarring) (AAO 2003,Vivino 1999). The most common side effect SOURCE: AAO 2003 from this medication class is excessive sweating, which

DRY EYE SYNDROME 23 DETECTION AND TREATMENT

occurred in more than 40 percent of patients. whom medical treatment has been inadequate or im- Cevimeline also has been found to improve ocular ir- practical (AAO 2003). ritation symptoms and aqueous tear production (Pet- Aqueous enhancement by means of punctal occlu- rone 2002) and may have fewer adverse systemic side ef- sion can be accomplished surgically with semipermanent fects than oral pilocarpine (AAO 2003). plugs (silicone or thermal labile polymer) that are lodged Anti-inflammatory therapies may be considered in at the punctal orifice (AAO 1997,AAO 1998,AAO 2003), addition to aqueous enhancement therapies. In clinical or by permanent occlusion with thermal or laser cautery. trials, topical cyclosporine has been reported to increase Prior to permanent or semipermanent punctal occlusion, aqueous tear production and decrease ocular irritation temporary slow-dissolving collagen punctal plugs can be symptoms in dry eye treatment (Gunduz 1994, Sall 2000). placed in most patients’ lower punctum. Because an oc- Clinically significant improvements in Schirmer wetting, cluded punctum can trap inflammatory mediators, in- punctuate keratopathy, quality-of-life measures, and ar- flammation, logically, should be controlled prior to punc- tificial tear use proved sufficient for FDA approval of the tal occlusion. Nevertheless, many patients with successful first prescription medication for dry eye disease on Dec. or partially helpful punctal occlusion procedures obtain 24, 2002 — a topical, preservative-free 0.05 percent cy- additional benefit from subsequent initiation of topical closporine emulsion. The proprietary emulsion prepa- anti-inflammatory therapy. ration is ideally formulated to distribute the relatively in- Eyelid abnormality as a result of blepharitis, trichia- soluble cyclosporine molecule to the ocular surface with sis, or lid malposition (e.g., entropion/ectropion, lago- maximal bioavailability. Previous formulations by com- phthalmos) should be corrected prior to permanent pounding pharmacies utilizing much higher concentra- punctal occlusion (AAO 2003). tions — as high as 4 percent — do not achieve tissue lev- Semipermanent plugs are reversible if the patient de- els equivalent to the approved emulsion. velops symptoms of epiphora, while cautery is not read- Cyclosporine is an 11-amino-acid cyclopeptide, pro- ily reversible. Therefore, a trial occlusion with collagen duced as a metabolite by the fungus species Beauveria plugs should be performed first. To minimize the possi- nivea. Cyclosporine prevents activation and nuclear bility of epiphora, no more than one punctum should be translocation of cytoplasmic transcription factors that are cauterized in each eye. The lower punctum is preferable required for T-cell activation and inflammatory cytokine for occlusion, as it is usually larger and more accessible. production. It also inhibits mitochondrial pathways of It is important to inspect the upper punctum first for apoptosis and has been reported to heal paracentral ster- both patency and integrity, before occluding the lower ile corneal ulcers associated with Sjögren’s syndrome and punctum. In general, laser cautery is not as effective as rheumatoid corneal ulceration (Kervick 1992). Cyclo- thermal cautery in achieving permanent, complete oc- sporine therapy appears to address all three tear film clusion and is more expensive. components (aqueous, oil, and mucin), and therefore Tarsorrhaphy can be performed to decrease tear evap- the three types of tear deficiency that may occur in vari- oration in patients with severely dry eyes, and for whom ous combinations in dry eye disease. all other medical and surgical therapies have been ex- Nonpreserved topical corticosteroids have been re- hausted. ported to decrease ocular irritation symptoms, reduce corneal fluorescein staining, and improve filamentary Management keratitis (Marsh 1999, Prabhasawat 1998). Low-dose The purpose of the follow-up evaluation, as outlined corticosteroid therapy can be used at infrequent inter- in the AAO 2003 guidelines, is to assess the patient’s re- vals for short-term (2-week) suppression of irritation sponse to therapy and the need to adjust treatment, to secondary to inflammation. monitor for structural ocular damage, and to provide re- Patients with systemic disease such as primary Sjö- assurance to the patient. The follow-up evaluation’s fre- gren’s syndrome, or with connective tissue disease such quency and composition is determined by disease sever- as rheumatoid arthritis, should be managed in con- ity, the therapeutic approach, a patient’s personality and junction with the appropriate medical specialist. Anti- adherence to therapy, and the response to therapy. inflammatory/immunosuppressive therapy may be ap- Patients with mild dry eyes can be seen once or twice propriate for patients with a systemic disease such as per year for follow-up if symptoms are controlled by rheumatoid arthritis (AAO 2003). therapy. Patients with sterile corneal ulceration associated with dry eye require careful, sometimes daily, monitor- Surgical treatment ing. Patients with existing dry eye, on the other hand, Surgical treatment is generally reserved for patients should be cautioned that LASIK or photorefractive kera- with symptomatic, moderate, or severe disease, and for tectomy may worsen their condition.

24 P&T DIGEST DETECTION AND TREATMENT

CONCLUSIONS Heigle TJ, Pflugfelder SC. Aqueous tear production in patients with neurotrophic keratitis. Cornea. 1996;15:135–138. The AAO Preferred Practice Pattern for dry eye syn- Hikichi T, Yoshida A, Fukui Y, et al. Prevalence of dry eye in Japanese drome was developed as practitioners of ophthalmology eye centers. Graefes Arch Clin Exp Ophthalmol. 1995;233: 555–558. and optometry have come to understand the inflamma- Kervick GN, Pflugfelder SC, Haimovici R, et al. Paracentral rheumatoid corneal ulceration. Clinical features and cyclosporine ther- tory nature of the condition. Since then, discoveries apy. Ophthalmology. 1992;99:80–88. about the etiology of dry eye disease and the subsequent Lemp MA. Report of the National Eye Institute/Industry Workshop on development of new therapies to treat — rather than pal- Clinical Trials in Dry Eyes. Clao J. 1995;21:221–232. Lucca JA, Farris RL, Bielory L, Caputo AR. Keratoconjunctivitis sicca liate — have effectively launched a new era for millions in male patients infected with human immunodeficiency virus of people who suffer from the sometimes devastating type 1. Ophthalmology.1990;97:1008–1010. consequences of dry eye. Marsh P, Pflugfelder SC. Topical nonpreserved methylprednisolone therapy for keratoconjunctivitis sicca in Sjögren syndrome. Oph- Eye care professionals are engaged in discussions re- thalmology. 1999;106:811–816. garding the appropriate use of these emerging therapies McCarty CA, Bansal AK, Livingston PM, et al. The epidemiology of dry as first-line treatments. Certainly, high-risk individuals, eye in Melbourne, Australia. Ophthalmology. 1998;105: 1114–1119. postmenopausal females, patients requiring 4 or more Merayo-Lloves J, Baltatzis S, Foster CS. Epstein-Barr virus dacryo- drops of artificial tears per day, and patients with rheu- adenitis resulting in keratoconjunctivitis sicca in a child. Am J matologic conditions should strongly be considered can- Ophthalmol. 2001;132:922–923. Moss SE, Klein R, Klein BE. Prevalence of and risk factors for dry eye didates for anti-inflammatory therapy. Clinicians are well syndrome. Arch Ophthalmol. 2000;118:1264–1268. aware that the severely dry patient of today, with com- Nelson JD, Friedlaender M,Yeatts RP,et al. Oral pilocarpine for symp- promised vision due to central corneal ulceration, was the tomatic relief of keratoconjunctivitis sicca in patients with Sjo- gren’s syndrome. The MGI PHARMA Sjögren’s Syndrome Study mildly dry eye patient of yesterday. CDED is progressive Group. Adv Exp Med Biol. 1998;438:979–983. and intimately associated with the aging process, akin to Nordstrom K, Norback D, Akselsson R. Influence of indoor air qual- glaucoma, hypertension, and hypercholesterolemia. Per- ity and personal factors on the sick building syndrome (SBS) in Swedish geriatric hospitals. Occup Environ Med. 1995;52:170–176. haps early intervention and preventive strategies will not Ogawa Y,Okamoto S,Wakui M,et al. Dry eye after haematopoietic stem only avoid significant morbidity and discomfort, but en- cell transplantation. Br J Ophthalmol. 1999;83: 1125–1130. able overall cost savings through proactive selective inter- Petrone D, Condemi JJ, Fife R, et al. A double-blind, randomized, placebo-controlled study of cevimeline in Sjögren’s syndrome pa- vention. Ultimately, decisions will be made on the basis tients with xerostomia and keratoconjunctivitis sicca. Arthritis of everyday clinical evidence, just as the FDA has ruled on Rheum. 2002;46:748–754. the precision of prospective clinical trial data analysis. Pa- Pflugfelder SC, Roussel TJ, Culbertson WW. Primary Sjögren’s syndrome after infectious mononucleosis. JAMA. 1987; tients and payers, meanwhile, are watching. 257:1049–1050. The potential for improved quality of life, decreased Pflugfelder SC, Crouse CA, Monroy D, et al. Epstein-Barr virus and the routine and emergent visits to the ophthalmologist, and lacrimal gland pathology of Sjögren’s syndrome. Am J Pathol. 1993;143:49–64. the implications for reducing costs and complications of Pflugfelder SC, Solomon A, Stern ME. The diagnosis and manage- treatment are enormous. These considerations, discussed ment of dry eye: a twenty-five-year review. Cornea. 2000; throughout this publication, represent state-of-the-art, 19:644–649. Prabhasawat P,Tseng SC. Frequent association of delayed tear clearance patient-oriented, quality-conscious eye care. in ocular irritation. Br J Ophthalmol. 1998;82: 666–675. Sall K, Stevenson OD, Mundorf TK, Reis BL. Two multicenter, ran- REFERENCES domized studies of the efficacy and safety of cyclosporine oph- AAO (American Academy of Ophthalmology). Punctal occlusion for thalmic emulsion in moderate to severe dry eye disease. CsA the dry eye: ophthalmic procedure assessment. Ophthalmology. Phase 3 Study Group. Ophthalmology. 2000;107:631–639. 1997;104:1521–1524. Schaumberg DA, Buring JE, Sullivan DA, Dana MR. Hormone re- AAO. Preferred Practice Pattern: Dry Eye Syndrome. San Francisco: placement therapy and dry eye syndrome. JAMA. 2001;286: AAO, 1998. 2114–2119. AAO. Preferred Practice Pattern: Dry Eye Syndrome. San Francisco: Schein OD, Munoz B, Tielsch JM, et al. Prevalence of dry eye among AAO, 2003. the elderly. Am J Ophthalmol. 1997;124:723–728. Abe T, Nakajima A, Matsunaga M, et al. Decreased tear lactoferrin Siagris D, Pharmakakis N, Christofidou M, et al. Keratoconjunctivitis concentration in patients with chronic hepatitis C. Br J Ophthal- sicca and chronic HCV infection. Infection. 2002;30: 229–233. mol. 1999;83:684–687. Stern ME, Beuerman RW, Fox RI, et al. The pathology of dry eye: the Bacman S, Berra A, Sterin-Borda L, Borda E. 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DRY EYE SYNDROME 25 PHARMACOTHERAPEUTIC OPTIONSPHARMACOTHERAPEUTIC OPTIONS Medications for Dry Eye Syndrome: A Drug-Therapy Review

HENRY D. PERRY, MD1 ERIC D. DONNENFELD, MD2 Ophthalmic Consultants of Long Island

SUMMARY treatments are in the pipeline as well, and these could contribute to this evolving paradigm. Early interventions were palliative,attempt- ing to replace water lost from the tear film. TREATMENT APPROACHES: AN OVERVIEW Today,therapy is directed at the underlying Traditionally, the approach to the treatment of dry eye inflammation,a recognized component of syndrome has been palliative, relying predominantly on replacement of tears to curb symptoms without ad- dry eye syndrome,and at the resulting pro- dressing the underlying disease process. Over the years, gressive changes to the ocular surface.This improvements were made in the formulation of artificial approach offers promise of lasting relief to tears and lubricants — including the addition of demul- patients with moderate to severe symptoms. cents to improve viscosity and lubricant properties, and the development of preservative-free solutions to avoid esearch into dry eye syndrome (keratocon- causing corneal toxicity. Yet, despite their widespread junctivitis sicca) has advanced dramatically in 1 the last decade, providing a better understand- Henry D. Perry, MD, is clinical associate professor of Oph- ing of the pathophysiology, underlying mech- thalmology at the Weill School of Medicine, Cornell Uni- R versity, and the senior founding partner of Ophthalmic anisms, and natural history of the disease. This advance in knowledge has been accompanied by a more focused Consultants of Long Island. He graduated from the Uni- versity of Cincinnati College of Medicine and completed his therapeutic approach, with new treatments targeted at internship and residency at Nassau County Medical Cen- underlying pathophysiologic processes. Whereas early ter and the University of Pennsylvania Scheie Eye Institute. interventions for dry eye syndrome attempted to simply He went on to complete fellowships in ophthalmic pathol- replace water lost from the tear film, today there exists a ogy at the Armed Forces Institute of Pathology in Wash- new therapy directed at the underlying inflammation, ington and in cornea and external disease at the Massa- now a recognized component of dry eye syndrome, and chusetts Eye and Ear Infirmary, Harvard University. He at the progressive changes in the ocular surface that occur reviews for and serves on the editorial board for several jour- over time with the disease (Table 1, page 28). nals, and has authored over 150 peer review articles on dis- More than 4 million people in the United States are eases and surgery of the cornea and ophthalmic pathology. thought to suffer from dry eye syndrome (Schein 1997), 2 and as much as 25 percent of patients visiting eye care Eric D. Donnenfeld, MD, is a founding partner of Oph- clinics describe dry eye symptoms (Hikichi 1995; thalmic Consultants of Long Island. A board-certified ophthalmologist, he is experienced in laser vision correction, in- Doughty 1997). The United States Food and Drug Ad- cluding LASIK and PRK. Donnenfeld graduated magna ministration’s recent approval of cyclosporine oph- cum laude with a bachelor’s degree from Dartmouth Col- thalmic emulsion 0.05 percent as the first prescription lege. He received his medical degree from Dartmouth Medi- medication to treat keratoconjunctivitis sicca may her- cal School, graduating in the top 5 percent of his class. After ald the start of a new therapeutic era. This new thera- completing his ophthalmology residency at Manhattan peutic focus corrects underlying pathologies that lead to Eye, Ear, and Throat Hospital, Donnenfeld completed a fel- dry eye and uses pharmacologic agents with anti- lowship in disease, treatment, and surgery of the cornea at inflammatory/immunomodulatory mechanisms to Wills Eye Hospital in Philadelphia. He has been president manage the signs and symptoms of disease and to con- of numerous professional societies and has written more than trol or reverse corneal damage. Other novel and exciting 100 papers and books on refractive and corneal surgery.

26 P&T DIGEST PHARMACOTHERAPEUTIC OPTIONS use and proven activity relative to improving ocular lu- thereby prevents T-cells from releasing cytokines (pri- brication, increasing humidity at the ocular surface, and marily interleukin-6) that incite the inflammatory com- even contributing to improved vision, these products ponent of dry eye. Early studies suggesting its utility in dry generally failed to accurately reproduce natural tears, eye syndrome came from dog studies in which topical ap- could not acceptably substitute for the continuous flow plication of cyclosporine ophthalmic emulsion twice daily of natural tears, and did not correct underlying pathol- reduced lymphocyte infiltration in the lacrimal glands ogy or tissue damage that can occur over time with dry and conjunctiva (Kaswan 1989, Gao 1998, Tsubota 1998). eye syndrome (Calonge 2001, Lemp 1994, Murube 1998a, Cyclosporine A also was associated with reduced apop- Murube 1998b, Pflugfelder 1998, Liu 1999). tosis of lacrimal glands and conjunctival epithelial cells in Alternative therapeutic interventions were aimed at dogs, effects that contribute to reduced inflammation tear preservation or stimulation of natural tears. Canalic- and clinical improvement of dry eye (Gao 1998). ular or punctal tamponade occlusion is a popular non- The earliest human studies in keratoconjunctivitis pharmacologic approach to improving aqueous tear film sicca revealed that topical eye treatment with cyclo- content (both quantity and quality), with the result of sporine A relieved the signs and symptoms of the disease improving signs and symptoms of dry eye (Lemp 1994, (Power 1993, Gunduz 1994, Laibovitz 1993). More recent Murube 1996, Willis 1987). While this technique can be data from two United States phase 3 randomized, multi- helpful for relieving dry eye symp- center, double-blind, 6-month toms, it carries a risk of decreased protocols establish the efficacy, tear production, clearance, and safety, and anti-inflammatory ac- ocular surface sensation (Yen 1999) tivity of cyclosporine A ophthal- and exacerbates the already delayed mic emulsion compared with tear clearance and turnover rate castor oil-based topical emulsion (Macri 2000), ultimately resulting vehicle alone in patients with in desensitization of the corneal moderate to severe dry eye syn- surface and possible inflammation. drome (Sall 2000). In the com- Overall, these palliative thera- Henry D.Perry, MD Eric D.Donnenfeld, MD bined results from these studies pies have been recognized as having limited value for (N=877), both objective (corneal staining, Schirmer test) long-term control or cure of progressive dry eye syn- and subjective (blurred vision, need for concomitant ar- drome. In the last quarter century, however, research tificial tears, physician evaluation of global response to began to focus more aggressively on the pathophysiology treatment) measures of treatment efficacy were signifi- of dry eye syndrome, yielding several important findings cantly better with cyclosporine 0.05 percent emulsion that suggest an inflammatory etiology. than with vehicle (p<.05). Especially notable is the im- It is now recognized that dry eye syndrome results provement in corneal staining (Figure 1, page 29), which from an underlying cytokine and receptor-mediated in- indicates that cyclosporine ophthalmic emulsion sup- flammatory process affecting the lacrimal glands (Mirch- presses the inflammatory processes underlying dry eye eff 1994, Pflugfelder 1986, Pflugfelder 1999, Stern 1998, syndrome in these patients, and by doing so, improves the Williamson 1973). The observed inflammation, in turn, integrity of the ocular surface. This pathophysiologic can either decrease tear production or alter the contents benefit contributes to enhanced vision and normalized of the tear film and disrupt homeostasis at the ocular sur- lacrimal gland response to blinking and other stimuli — face, ultimately leading to keratoconjunctivitis sicca. and hence to the Schirmer value improvements in this These findings have redirected treatment efforts toward study (Figure 2, page 30). more targeted therapies aimed at resolving the underly- The first (and currently only) cyclosporine ophthal- ing inflammation. Anti-inflammatory/immunomodu- mic emulsion 0.05 percent was recently approved by the latory treatments — most notably cyclosporine A — are FDA for the safe and effective treatment of underlying in- now becoming standard therapy for moderate to severe flammation in dry eye syndrome. This is the only treat- dry eye syndrome. ment available that addresses the immunogenic and inflammatory causes of dry eye syndrome and is not solely Review of drug therapy options3 palliative. It is a sterile, preservative-free emulsion that Newer agents appears white opaque to slightly translucent. It has a fa- Cyclosporine A. Cyclosporine A is a well-known vorable safety profile, the most common adverse event immunomodulator, most commonly used to prevent re- being mild ocular burning and stinging — effects that jection after organ/tissue transplantation. It also confers anti-inflammatory activity and, in dry eye syndrome, 3 Table 2,page 29, lists the trade names of generic agents.

DRY EYE SYNDROME 27 PHARMACOTHERAPEUTIC OPTIONS

also were common with the vehicle alone. Changes were methylprednisolone or lotaprednol etabonate — has not detected in intraocular pressure, vision, or the cornea been shown to reduce early inflammation in dry eye as assessed by biomicroscopy (Sall 2000). syndrome (Marsh 1999, Prabhasawat 1998). This effect Topical corticosteroids. Immunomodulation with has been linked to reduced levels of the chemotactic topical nonpreserved corticosteroid therapy — such as cytokine IL-8 in the conjunctival epithelium (Pflugfelder

TABLE 1 Options for dry eye syndrome

List is not inclusive Product How supplied Dosing Targeted therapies Immunomodulators: Cyclosporine A unit dose vials (0.4 mL) 1 drop 2x daily Mucolytic agents: N-acetylcysteine 10–20% drops 1–2 drops up to 4x daily Antibiotics: Topical: various, e.g.: loading dose, then bacitracin, chlortetracycline 1–2 drops 2x daily Systemic: doxycycline 100 mg 2x daily Palliative therapies Artificial tears: Low viscosity (carboxymethylcellulose based): various, e.g.: GenTeal multi dose 1–2 drops as needed Refresh Plus unit dose Refresh Tears multi dose TheraTears unit and multi dose Moderate viscosity (hydroxymethyl- cellulose based): various, e.g.: Bion Tears unit dose, preservative free Ocucoat unit dose, preservative free High viscosity: various, e.g.: Refresh Celluvisc best for nocturnal instillation Refresh Liquigel AquaSite Murocel Gel formulations: various, e.g.: GenTeal Gel tube delivery system fingertip application into cul de sac Tears Again tube delivery Lubricating ointments: HypoTears fingertip application Refresh PM (1/4 inch) into cul de sac Tears Naturale PM Therapeutic plug Hydroxypropyl cellulose insert 5 mg water-soluble rod 1–2 rods per eye daily Secretagogues: Eledoisin Pilocarpine 5 mg tablets 1 daily Corticosteroids: Loteprednol etabonate 1–2 drops 4x daily Prednisolone acetate 2 drops 4x daily

ADAPTED FROM PACKAGE INSERTS

28 P&T DIGEST PHARMACOTHERAPEUTIC OPTIONS

ful in mild dry eye syndrome for the simple re- TABLE 2 Generic/trade-name pharmaceutical lief of dry eye symptoms, including scratchiness conversion chart and dryness. These over-the-counter products are formulated from one of a variety of linear Generic Trade name polymers that simulate the cell-surface glyco- Bacitracin/polymyxin B Polysporin proteins that maintain ocular hydration. Over the Cyclosporine ophthalmic emulsion Restasis years, manufacturers have attempted to closely Hydroxypropyl cellulose Lacrisert mimic natural tears, which contain lipid (surface N-acetylcysteine Mucomyst layer that retards evaporation), substantial Loteprednol etabonate Lotemax amounts of water with dissolved salt and proteins Pilocarpine Salagen (aqueous layer), and mucin (the film that coats Prednisolone acetate Pred Forte the corneal surface). Despite these attempts to Sodium carboxymethylcellulose TheraTears (0.25 percent) improve composition, however, these products have inherent limitations; natural tears have a complex composition that artificial tears cannot 1999). Symptomatic relief has been reported to extend for fully substitute, while the mucus layer of the tear film has months after the steroid application has been stopped not been satisfactorily reproduced (Calonge 2001). (Marsh 1999). Long-term use of this class, however, is as- Artificial tear products currently are available in sociated with severe side effects, including ocular hy- various formulations, including solutions, gels, and oint- pertension, cataract formation, glaucoma, and infection. ments. The key differences in these products are viscos- For this reason, these drugs should be reserved for symp- ity, composition, and preservative vs. preservative-free toms that are severe and recalcitrant to aggressive appli- formulation.Viscosity describes the relative density of the cation of artificial tears, and used only for acute treatment formulation — which reflects its mucoadhesive proper- (<2 weeks) of dry eye exacerbations. ties and therefore the degree of contact time with the ocular surface — and generally ranges from 1.5 mL pas Older agents (Pascal seconds, a standard of measurement for viscos- Tear substitutes. Until the recent identification of in- ity) to 15 mL pas, with an average of 5.0 mL pas. Agents flammation as an important etiology in dry eye syn- added to artificial tears to increase viscosity include car- drome, the most commonly used treatment for dry eyes boxymethylcellulose, dextran 70, gelatin, glycerin, hy- was topically applied artificial tears and lubricants. Al- droxymethylcellulose, hydroxypropyl methylcellulose, though solely a palliative therapy, artificial tears are use- methylcellulose, PEG, poloxamer 407, polysorbate 80, propylene glycol, polyvinyl alcohol, FIGURE 1 Changes from baseline (mean + standard error) and polyvinylpyrrolidone. Products in corneal staining with low viscosity commonly are Related to application of cyclosporine ophthalmic solution used early in the progression of dry 0.05 percent, 0.1 percent, and vehicle alone eye syndrome, as they are less likely to Month 1 Month 3 Month 4 Month 6 disrupt vision. As dry eye syndrome 0 progresses, more viscous tear products are needed to achieve symptomatic control, but these are associated –0.2 with progressive blurring of vision. Lubricant ointments are reserved pri- –0.4 marily for overnight treatment. Compounds included to repli- cate the lipid occlusive layer are white –0.6 petrolatum, mineral oil, lanolin, or lanolin alcohols. The mucin layer,

Change in staining score which allows the solution to spread –0.8 CsA 0.05% * over the ocular surfaces, is simulated ≤ * CsA 0.10% * p .05 vs.vehicle by use of polysorbate 20 and 80, ≤ Vehicle † p .62 vs.vehicle † poloxamer 282, or tyloxapol. In ad- –1.0 * dition, many tear supplements con- SOURCE: SALL 2000 tain preservatives to stabilize the pro-

DRY EYE SYNDROME 29 PHARMACOTHERAPEUTIC OPTIONS

As a rule, these agents are infre- FIGURE 2 Schirmer value changes from baseline quently prescribed due to the limited (mean + standard error) data, absence of compelling evidence Cyclosporine ophthalmic emulsion 0.05 percent, 0.1 percent, of improvement, and the associated vs.vehicle alone (testing performed under anesthesia) adverse effects, including generalized nausea, sweating, and rashes. Fur- * p ≤ .05 vs.vehicle 0.6 CsA 0.05% thermore, some authors have sug- CsA 0.10% * gested that generating tears from in- Vehicle 0.4 flamed lacrimal glands may worsen * dry eye by distributing proinflamma- tory cytokines to the ocular surface; 0.2 * when the glands are substantially damaged, this approach may fail to produce tears at all (Calonge 2001). 0.0 Therapeutic ocular inserts.An artificial tear insert that provides long- Change in Schirmer score –0.2 term slow release of artificial tear polymers is an alternative, if rarely used, therapy for moderate-to-severe –0.4 Month 3 Month 6 dry eye. This approach is most beneficial for those patients with moder- Categorized Schirmer values graded on 5-point scale: 1=<3mm/5 min; ate dry eye for whom artificial tear lu- 2=3-6mm/5min; 3=7-10mm/5 min; 4=11-14mm/5min; 5=>14mm/5min. brication does not resolve symptoms or is required at increasingly frequent SOURCE: SALL 2000 intervals. There is currently only one duct for longer periods. Benzalkonium chloride (BAK), therapeutic insert manufactured, which contains hy- benzethonium chloride, cetylpyridinium chloride, droxypropyl cellulose in a sterile, translucent, water-sol- chlorobutanol, EDTA, phenylmercuric nitrate, phenyl- uble rod. Each insert, applied once or twice daily inside mercuric acetate, methyl/propylparaben, thimerosal, the inferior cul de sac of the eyelid, dissolves over 14 to phenylethyl alcohol, sodium benzoate, sodium propi- 18 hours. The slow release of the tear substance stabilizes onate, and sorbic acid are the most commonly used ad- and thickens the precorneal tear film and prolongs tear ditives. Preservatives — extensive data have been re- film breakup time. It also lubricates the eye and, in some ported on BAK — can induce corneal desquamation or patients, may halt or reverse progressive visual damage. cause irritation or allergic reactions, particularly as daily The system, however, is difficult to handle, and many pa- use increases due to worsening dry eye (Becquet 1998, tients find it uncomfortable. Burstein 1980, Lopez Bernal 1991, Tripathi 1989); the de- Mucolytics. Patients with keratoconjunctivitis sicca velopment of preservative-free products has relieved are prone to development of corneal mucous plaques, some of the burden of this potential complication (Deb- which are composed of mucus, epithelial cells, and pro- basch 2001). While preservative-free solutions do not teinaceous and lipoidal material that cling to the corneal worsen corneal barrier function, however, they have not surface (Lemp 1994, Thermes 1991). These plaques may been found to normalize it either. collect external dust and bacteria and cause vision diffi- Secretagogues. There are a number of drugs that culties, foreign body sensation, and substantial pain. have been used with some success to stimulate the Topical mucolytic agents, such as N-acetylcysteine 20 lacrimal glands to produce tears. Pilocarpine in partic- percent (Mucomyst) diluted to a 10-percent solution ular has been shown to increase tear volume and flow and with artificial tears, can be used to break down mucin improve dry eye symptoms in patients with Sjögren’s molecules, dissolve corneal filaments, and release the syndrome (Mathers 2000, Vivino 1999). Eledoisin, an mucoid plaque in patients with this condition. This so- endekapeptide, has yielded improved tear production lution may smell like rotten eggs, requires refrigeration, and flow (Gobbels 1991), although clinical improve- and, if formulated without preservatives, must be dis- ment of dry eye signs and symptoms has never been carded after 30 days. It is not commercially available as formally documented. Bromhexine and ambroxol have a topical agent, though it can be readily compounded but met with equivocal results in clinical trials (Ichikawa at high expense for a relatively small amount. 1988, Avisar 1988). Antibiotics. Some patients who experience poor con-

30 P&T DIGEST PHARMACOTHERAPEUTIC OPTIONS trol of moderate dry eye symptoms with artificial tears of IL-1 as part of the inflammatory process. Tetracy- will benefit from antibiotic therapy. Antibiotics con- clines are potent inhibitors of this enzyme and are being tribute to reduced inflammation and improved lipid investigated for a role in the management of inflamma- production in dry eye syndrome. Topical bacitracin tion in the genesis of dry eye syndrome (Solomon 2001). polymyxin B or tetracycline-based ointments can be Retinoic acid. Retinol is present in tears and deficient used to supplement hot compresses and lid scrubs to in dry eye syndrome, leading some investigators to sug- some benefit. Systemic administration of low doses of gest a role for retinol replacement therapy. Results with doxycycline, which decreases the viscosity of naturally se- topical administration of retinoic acid have been variable, creted oils, may also yield positive results in patients however, with evidence that its particular value is to re- with meibomian gland dysfunction over a 6- to 8-week verse keratinization, which occurs only in extremely se- course of therapy (Gilbard 1999). vere cases of dry-eye related disease (Calonge 2001).

Treatments under investigation CONCLUSION Hormones. Sexual hormones have been reputed to The treatment of dry eye syndrome has relied pre- contribute to an anti-inflammatory state at the ocular dominantly on artificial tears and lubricants. This pal- surface (Stern 1998, Sullivan 1999a), leading investiga- liative approach generally has been successful at reliev- tors to consider their potential role in the therapy of dry ing the signs and symptoms of mild to moderate disease eye syndrome. Topical application of an estradiol oint- and, in rare cases, has slowed the progressive damage to ment to 22 postmenopausal women was shown in one the cornea and conjunctiva that occur over time with dry study to confer modest improvement in Schirmer tests eye. Nevertheless, these products do not address the un- and rose Bengal staining (Akramian 1998).Additionally, derlying disease process and, in some cases (particularly the presence of androgen receptors on the ocular surface with artificial tears containing BAK or certain other may indicate a potential therapeutic role in dry eye syn- preservatives), can be toxic and allergenic, worsening drome that warrants further study (Smith 1999). In ani- the clinical markers of the disease. mal models, systemic administration of androgens has Increasing research and advancing knowledge has reduced lymphocytic infiltration at the lacrimal gland identified an inflammatory component to dry eye syn- and improved lacrimal gland function (Sullivan 1997, drome and has focused treatment efforts at addressing this Sullivan 1999b). Currently, an androgen ointment prod- newly identified etiology. Topical cyclosporine emulsion uct is in phase 3 trials. 0.05 percent is the first and currently only FDA-approved P2Y2 receptor agonists. The P2Y2 receptor in the eye targeted immunomodulatory/anti-inflammatory product stimulates ocular hydration and lubrication by mediating to combat the underlying source of disease. Other simi- mucosal secretion of mucin as well as salt, water, mucus, larly targeted agents are under investigation and, if ap- and other tear components from conjunctival goblet cells. proved, will likely contribute to the start of an entirely new Mucin is the component of the tear film that maintains management standard — one based on control of in- tear stability and protects against damage to the ocular flammatory sources and immunologic mechanisms — for surface. Stimulation of the P2Y2 receptor can be accom- the treatment of dry eye syndrome. plished by administration of adenine analogues in both rabbits and humans (Jumblatt 1998), suggesting a novel REFERENCES pathway for therapeutic modulation of tear film.A phase Akramian J, Wedrich A, Nepp J, Sator M. Estrogen therapy in keratoconjunctivitis sicca. Adv Exp Med Biol. 2 study of a novel P2Y2 receptor agonist has been com- 1998;438:1005–1009. pleted at 12 ophthalmology centers in the United States. Avisar R, Savir H. Our further experience with bromhexine in Dequafosol, a P2Y2 agonist in topical eye drop form, keratoconjunctivitis sicca. Ann Ophthalmol. 1988;20:382. provided both objective and subjective improvements in Becquet F, Goldschild M, Moldovan MS, et al. Histopathological effects of topical ophthalmic preservatives on rat corneo- ocular parameters when compared with placebo in the conjunctival surface. Curr Eye Res. 1998;17:19-25;410–425. treatment of moderate to severe dry eye syndrome (Li Burstein NL. Corneal cytotoxicity of topically applied drugs, ve- 2001). Phase 3 studies will determine the precise role of hicles and preservatives. Surv Ophthalmol. 1980;25:15–30. these agents in the treatment of dry eye syndrome. Calonge M. The treatment of dry eye. Surv Ophthalmol. 2001;45 (suppl 2): S227–S239. Tetracyclines.A collagenase enzyme — MMP9 — has Debbasch C, Brignole F, Pisella PJ, et al. Quaternary ammoni- been found to be elevated in the ocular fluid of patients ums and other preservatives’ contribution in oxidative with aqueous tear deficiency (related to Sjögren’s syn- stress and apoptosis on Chang conjunctival cells. Invest drome) compared with normal controls. This elevated Ophthalmol Vis Sci. 2001;42:642–652. Doughty MJ, Fonn D, Richter D, et al. A patient questionnaire enzyme level might reflect a mechanism by which pro- approach to estimating the prevalence of dry eye symptoms inflammatory molecules are cleaved to achieve activation

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in patients presenting to optometric practices across Pflugfelder SC. Advances in the diagnosis and management of Canada. Optom Vis Sci. 1997;74:624–631. keratoconjunctivitis sicca. Curr Opin Ophthalmol. Gao J, Schwalb TA, Addeo JV. The role of apoptosis in the patho- 1998;9:50–53. genesis of canine keratoconjunctivitis sicca: the effect of Pflugfelder SC, Jones D, Ji Z, et al. Altered cytokine balance in topical cyclosporine A therapy. Cornea. 1998;17:654–663. the tear fluid and conjunctiva of patients with Sjögren’s Gilbard JP.Dry eye, blepharitis and chronic eye irritation: divide syndrome keratoconjunctivitis sicca. Curr Eye Res. and conquer. J Ophthalmic Nurs Technol. 1999;18(3): 1999;19:201–211. 109–115. Power WJ, Mullaney P,Farrell M, Collum LM. Effect of topical Gobbels M, Selback J, Spitznas M. Effect of eledoisin on tear vol- cyclosporine A on conjunctival T-cells in patients with sec- ume and tear flow in humans as assessed by fluorophoto- ondary Sjögren’s syndrome. Cornea. 1993;12;507–511. metry. Graefes Arch Clin Exp Ophthalmol. 1991;229: Prabhasawat P,Tseng SCG. The frequent association of tear 549–552. clearance in ocular irritation. Br J Ophthalmol. Gunduz K, Ozdemir O. Topical cyclosporine treatment of 1998;82:666–675. keratoconjunctivitis sicca in secondary Sjögren’s syndrome. Sall K, Stevenson OD, Mundorf TK, Reis BL and the CsA phase 3 Acta Ophthalmol. 1994;72:438–442. study group. Two multicenter, randomized studies of the Hikichi T,Yoshida A, Fukui Y, et al. Prevalence of dry eye in efficacy and safety of cyclosporine ophthalmic emulsion in Japanese eye centers. Graefe’s Arch Clin Exp Ophthalmol. moderate to severe dry eye disease. Ophthalmology. 1995;233:555–558. 2000;107:631–639. Ichikawa Y, Tokunaga M, Shimizu H. Clinical trial of ambroxol Schein OD, Munoz B, Tielsch JM, et al. Prevalence of dry eye (Mucosolvan) in Sjögren’s syndrome. Tokai J Exp Clin Med. among the elderly. Am J Ophthalmol. 1997;124:723–728. 1988;13:165–169. Smith RE, Taylor CR, Rao NA, et al. Immunohistochemical iden- Jumblatt JE, Jumblatt MM. Regulation of ocular mucin secre- tification of androgen receptors in human lacrimal glands. tion by P2Y2 nucleotide receptors in rabbit and human Curr Eye Res. 1999;18:300–309. conjunctiva. Exp Eye Res. 1998;67(3):341–346. Solomon A, Dursun D, Liu Z, et al. Pro- and anti-inflammatory Kaswan RL, Salisbury MA, Ward DA. Spontaneous canine forms of interleukin-1 in the tear fluid and conjunctiva of keratoconjunctivitis sicca. A useful model for human patients with dry-eye disease. Invest Ophthalmol Vis Sci. keratoconjunctivitis sicca: treatment with cyclosporine eye 2001;42(10):2283–2292. drops. Arch Ophthalmol. 1989;107:1210–1216. Stern ME, Beuerman RW, Fox RI, et al. The pathology of dry eye: Laibovitz RA, Solch S, Andriano K, et al. Pilot trial of cyclo- the interaction between the ocular surface and lacrimal sporine 1 percent ophthalmic ointment in the treatment of glands. Cornea. 1998;17:584–589. keratoconjunctivitis sicca. Cornea. 1993;124:311–323. Sullivan DA, Edwards JA. Androgen stimulation of lacrimal Lemp MA. Management of the dry-eye patient. Int Ophthalmol gland function in mouse models of Sjögren’s syndrome. J Clin. 1994;34:101–113. Steroid Biochem Mol Biol. 1997;60:237–245. Li Y, Kuang K, Yerxa B, et al. Rabbit conjunctival epithelium Sullivan DA, Krenzer KL, Sullivan BD, et al. Does androgen in- transports fluid, and P2Y2(2) receptor agonists stimulate sufficiency cause lacrimal gland inflammation and aqueous Cl(-) and fluid secretion. Am J Physiol Cell Physiol. tear deficiency? Invest Ophthalmol Vis Sci. 2001;281:C595–602. 1999a;40:1261–1265. Liu Z, Pflugfelder SC. Corneal surface regularity and the effect Sullivan DA, Wickham LA, Rocha EM, et al. Androgens and dry of artificial tears in aqueous tear deficiency. eye in Sjögren’s syndrome. Ann NY Acad Sci. Ophthalmology. 1999;106:939–943. 1999b;876:312–324. Lopez Bernal D, Ubels J. Quantitative evaluation of the corneal Thermes F, Molon-Noblot S, Grove J. Effects of acetylcysteine on epithelial barrier: effect of artificial tears and preservatives. rabbit conjunctival and corneal surfaces. A scanning elec- Curr Eye Res. 1991;10:645–656. tron microscopy study. Invest Ophthalmol Vis Sci. Macri A, Rolando M, Pflugfelder S. A standardized visual scale 1991;32:2958–2963. for evaluation of tear fluorescein clearance. Ophthalmology. Tripathi BJ, Tripathi RC. Cytotoxic effects of benzalkonium 2000;107:1338–1343. chloride and chlorobutanol on human corneal epithelial Marsh P,Pflugfelder SC. Topical nonpreserved methylpred- cells in vitro. Lens Eye Toxic Res. 1989;6:395–403. nisolone therapy for keratoconjunctivitis sicca in Sjögren’s Tsubota K, Saito I, Ishimaru N, Hayashi Y. Use of topical cyclo- syndrome. Ophthalmology. 1999;106:811–816. sporine A in a primary Sjögren’s syndrome mouse model. Mathers WE, Dolney AM. Objective demonstration of tear stim- Invest Ophthalmol Vis Sci. 1998;39:1551–1559. ulation with oral pilocarpine in dry eye patients. Invest Vivino FB, Al-Hashimi I, Khan Z, et al. Pilocarpine tablets for Ophthalmol Vis Sci. 2000;41:S60. the treatment of dry mouth and dry eye symptoms in pa- Mircheff AK, Gierow JP,Wood RL. Traffic of major histocom- tients with Sjögren’s syndrome: a randomized, placebo- patibility complex class II molecules in rabbit lacrimal controlled, fixed-dose, multi-center trial. P92-01 study gland acinar cells. Invest Ophthalmol Vis Sci. group. Arch Intern Med. 1999;159:174–181. 1994;35:3943–3951. Williamson J, Gibson AA, Wilson T, et al. Histology of the Murube J, Paterson A, Murube E. Classification of artificial lacrimal gland in keratoconjunctivitis sicca. Br J Ophthal- tears. I: Composition and properties. Adv Exp Med Biol. mol. 1973;57:852–858. 1998a;438:693–704. Willis RM, Folberg R, Krachmer JH, Holland EJ. The treatment Murube J, Murube A, Zhuo C. Classification of artificial tears. II: of aqueous-deficient dry eye with removable punctal plus. Additives and commercial formulas. Adv Exp Med Biol. A clinical and impression-cytologic study. Ophthalmology. 1998b;438:705–715. 1987;94:514–518. Murube J, Murube E. Treatment of dry eye by blocking the Yen MT, Monroy D, Pflugfelder SC. Punctal occlusion decreases lacrimal canaliculi. Surv Ophthalmol. 1996;40:463–480. tear production, clearance, and ocular surface sensation Pflugfelder SC, Wilhelmus KR, Osato MS, et al. The autoim- (abstract). Invest Ophthalmol Vis Sci. 1999;40(suppl):S980. mune nature of aqueous tear deficiency. Ophthalmology. 1986;93:1513–1517.

32 P&T DIGEST COST EFFECTIVENESS COST EFFECTIVENESS ISSUES Considerations in the Pharmacoeconomics of Dry Eye

JAN D. HIRSCH, PHD1 Prescription Solutions

SUMMARY creased productivity; and intangible costs related to Dry eye disease diminishes the quality of pain and suffering. Clinical patients’lives and drives utilization of health outcomes include efficacy, care resources.Until recently, all treatments onset of action, percentage for dry eye have been palliative.A new treat- of patients who become ment, cyclosporine A ophthalmic emulsion, free of symptoms, symp- addresses the disease’s underlying causes. tom recurrence, and adverse effects. Humanistic It warrants pharmacoeconomic analysis to outcomes include health- determine its place in managed care. related quality of life, return to normal functioning, and harmacoeconomic (PE) research identifies, patient satisfaction with measures, and compares the costs and conse- therapy. Some variables quences of pharmaceutical product and service may relate not only to pa- Jan D.Hirsch, PhD Putilization. In this definition, costs refers to re- tients but also to caregivers sources consumed; the consequences of using pharma- and significant others. ceutical products and services are considered to be the This chapter considers the economic and quality-of- outcomes derived.A system for classifying the full range life burden of moderate to severe chronic dry eye syn- of outcomes is the ECHO (Economic, Clinical, and drome, then introduces PE analysis techniques that can Humanistic Outcomes) model, proposed by Kozma be used to evaluate treatments for chronic disease. (1993). Economic outcomes in the ECHO model include direct medical costs, such as the costs of the drug, BURDEN OF DRY EYE administration, and treatment of adverse effects; direct Dry eye syndrome is common, but its prevalence is nonmedical costs, such as patient transportation; indi- somewhat difficult to pinpoint, primarily because the rect costs, such as lost work days, lost earnings, and de- disease is multifactorial, definitions differ, and research is sparse. Furthermore, diagnostic techniques lack stan- 1 Jan D. Hirsch, PhD, is the director for post-launch clini- dardization and are inconclusive in milder cases. Clinical cal research at Prescription Solutions, a Costa Mesa, Calif.- signs do not always correlate with symptoms, except in based pharmacy benefit management company. Hirsch moderate to severe cases and in association with auto- leads the clinical research group’s Real World Prospective immune diseases, such as Sjögren’s syndrome (Nichols Outcomes Research program, which evaluates the value, 1999). safety, and effectiveness of FDA-approved medications and In a German study, 22.8 percent of women and 9.9 devices in actual patient care settings and focuses specifi- percent of men age 55 to 59 reported often experiencing cally on such managed care environments as HMOs, IPAs, a sandy sensation in the eyes. In the Canadian Dry Eye medical groups, and integrated health systems. A phar- Epidemiology Study, optometrists surveyed all patients macist by initial training, Hirsch earned her PhD in using a standard questionnaire; researchers reported pharmacy administration from the University of South that, across all age groups, 28.7 percent reported dry eye Carolina. She has authored book chapters in multiple symptoms, 7.6 percent indicated constant but moderate pharmacoeconomic texts and has written numerous jour- symptoms, and 1.6 percent complained of severe symp- nal articles on the value of specific pharmaceutical agents. toms (Brewitt 2001). In the United States, researchers at

DRY EYE SYNDROME 33 COST EFFECTIVENESS

the Schepens Eye Research Institute — using a broad de- vere, and 22 percent indicated their symptoms were mod- finition of dry eye syndrome — estimate that 10 million erate. Half of the patients who revealed their ages were at Americans suffer from its symptoms (Schepens 2001). least 65. Of the 70 respondents, only two reported using Other estimates of prevalence are reported elsewhere in no topical treatments, such as artificial tears and lubri- this publication. cants; at least 61 percent reported using them always or Because this chapter focuses on treatment of moder- regularly. More than 40 percent had received punctal oc- ate to severe dry eye syndrome, it is useful to consider the clusion; 27 percent reported using other medications — prevalence of the disease in terms of the percentage of pa- analgesics, antibiotics, anti-inflammatory agents — to tients with symptoms severe enough to seek health care treat their dry eye; 60 percent said they visited a physician services. In a survey of third-party payers, Nelson and at least twice in the past year because of dry eye, and 84 colleagues (2000) reported the prevalence of dry eye syn- percent sought the aid of an ophthalmologist. drome to be 0.19 percent among managed care plan par- These researchers also noted that about 73 percent of ticipants, 0.21 percent among persons covered by com- respondents indicated that, despite all the treatments mercial payers, 0.35 percent among Medicaid recipients, they were using, dry eye interfered with the activities of and 1.30 percent among Medicare recipients. daily life; 76 percent (53 of 70) indicated that their symp- Many factors — ranging from autoimmune diseases toms had not improved or had worsened over the course such as Sjögren’s syndrome to age-related changes (e.g., of the previous year. This team’s findings of the impact menopause) to environmental conditions (e.g., contact- of the symptoms of dry eye on quality of life are sum- lens wear) — can cause dry eye syndrome (Albietz 2001). marized in Table 1. Annually, these patients lost 2 work Persistent uncontrolled dry eye can lead to superficial days because of their dry eye symptoms, and went to punctate staining, epithelial erosions, corneal filaments, work despite the interference on 191 days, presumably re- and persistent epithelial defects. In the most severe cases, ducing their efficiency and effectiveness. corneal ulcers occur. Clearly, moderate to severe dry eye Reviewing cases from a managed care database, reis painful and debilitating, and the burden of dry eye can searchers showed that patients with dry eye syndrome ex- be substantial in terms of both economic and humanistic perienced a significantly greater increase in total costs outcomes. after diagnosis than a matched control group (Smeeding 2001). These researchers suggested a link between dry eye Economic impact and several other costly ophthalmic conditions, such as Until the recent market availability of cyclosporine A glaucoma. After dry eye syndrome diagnosis, total (CsA) ophthalmic emulsion, then-available treatments charges increased significantly more in the dry eye group not only failed to provide adequate relief of symptoms (22 percent) as compared to the control group (15 per- but also failed to stop progression of the disease. Dry eye cent, p<0.001). The higher management costs associ- is a chronic progressive inflammatory condition and is ated with dry eye syndrome were primarily from more by no means self-limited. In turn, as dry eye severity infrequent visits to physicians. In addition, dry eye pa- creased, both individual and societal treatment costs in- tients were also more likely than controls to receive arti- creased. ficial tears, ophthalmic antibiotics, and corticosteroids. A survey of Sjögren’s syndrome patients indicated that Although artificial tear preparations are sold over the sufferers used drops and ointments, on average, more counter, topical antibiotics and corticosteroids are both than 7 times daily, and nearly 1 in 3 had received punc- costly and fraught with potential side effects that in- tal occlusion. Despite these measures, 89 percent visited crease the need for clinical evaluation — thereby in- their ophthalmologist an average of 3.1 times a year for creasing utilization costs. relief from their symptoms, and 28 percent consulted other physicians for help with their dry eye problems. On Humanistic impact average, these patients went to work despite their symp- Recognizing that the impact of moderate to severe toms on 208 days annually and missed 5 work days due dry eye is symptom-driven, several research groups have to their dry eye symptoms or treatment. Patients also re- developed patient questionnaires to quantify the impact ported that dry eye symptoms interfered with leisure of dry eye in terms of clinical outcomes (e.g., pain) and activities on 123 days of the past year (Hirsch 1998). functional activities (e.g., daily activity impairment). In a survey of patients without Sjögren’s syndrome, Studies evaluating the validity and reliability of these Nelson (2000) confirmed that dry eye can be chronic instruments also provide insight into the effect of dry eye and devastating; on average, patients responding to the symptoms on patients’ daily lives. study had been diagnosed 9.23 +/– 7.19 years previously, In a study testing the performance and repeatability of 52 percent described their symptoms as severe or very se- the National Eye Institute Visual Function Question-

34 P&T DIGEST COST EFFECTIVENESS naire, researchers confirmed that the 25-question VFQ- 25 is a reliable tool for quantifying dry eye pain and TABLE 1 Impact of dry eye symptoms concluded that low-vision patients with diagnostically on daily life confirmed dry eye experience more ocular pain than do Patients who said dry eye symptoms interfered other low-vision persons. Further, the VFQ-25 can be with activities most or all of the time (%) used to stage dry eye (Nichols 2002). Table 2, on page 36, lists sample questions from the VFQ-25; the entire ques- Quality-of-life factors tionnaire can be viewed online at «www.nei.nih.gov/ Loss of confidence 38.6 Decrease of leisure time 35.7 resources/visionfunction/vfq_ia.pdf». Frustration with daily activities 34.3 Citing poor correlation between dry eye symptom as- Change of activities 25.7 sessment and objective test results, another team of re- Depression, unhappiness 25.7 searchers evaluated the Dry Eye Questionnaire (DEQ) in Need for assistance 14.3 an assessment of confirmed dry eye patients (with and Missed outings 12.9 without Sjögren’s syndrome) and controls. Concen- Decrease of work time 11.4 trating on frequency and intensity of symptoms, they Change of work 7.1 found that 10 percent of controls, 30 percent of dry eye Other 22.9 patients without Sjögren’s syndrome, and 60 percent of None of the above 27.1 dry eye patients with Sjögren’s syndrome had so much Vision-related activities eye pain and trouble that they frequently halted their Nighttime driving 32.3 Reading 27.5 daily activities and closed their eyes to gain relief. The re- Working at electronic monitor 25.7 searchers also determined that symptom intensity in- Watching television 17.9 creases as the day progresses, and they suggested that further testing of the DEQ is needed (Begley 2002). SOURCE: NELSON 2000 Using another set of patient questionnaires, the Dry Eye Disease Impact Questionnaire (DEDIQ), the Ocular III/IV angina (see Figure, page 36). They suggested that Surface Disease Index (OSDI, a valid and reliable tool for an effective dry eye treatment could be expected to restore measuring disease severity, which has the psychometric patient benefits of a magnitude comparable to those as- properties necessary to be used as a clinical-trial end sociated with treating severe angina. This study also in- point [Schiffman 2000]), the Facial Expression Subjective dicated that dry eye utilities vary in a manner consistent Scale, and the SF-12 Health Survey, researchers deter- with disease severity. mined that 53 percent of dry eye patients rated their symptoms as severe to very severe; their average OSDI TREATMENT OPTIONS AND RELATIVE COSTS score was 0.41 (Kozma 2000). In the OSDI system, a As the above research suggests, dry eye symptoms per- score of 0 indicates no disability and a score of 1 means sist or worsen despite standard therapies. Typically, as complete disability due to dry eye symptoms. Their SF- with mild dry eye, patients with moderate to severe dry 12 physical and mental summary scores were 42.3 and eye rely on artificial tears. The mainstay of therapy for dry 50.2, respectively, compared to a United States norm of eye syndrome, artificial tears are palliative, applied sev- 50.0. Only 25 percent of these patients reported symp- eral times daily, to substitute for natural tears that are de- tom improvement after 1 year of treatment, while the ficient in quality or quantity. Other treatment options for other 75 percent complained that their symptoms failed more severe dry eye syndrome include punctal occlusion to improve or worsened. with temporary or permanent plugs, electrocautery Although researchers have used several validated in- surgery, and, for patients with Sjögren’s syndrome, hor- struments to assess dry eye, each of the available method- mone replacement therapy. ologies constructs a multidimensional profile of the pa- Recently approved by the United States Food and Drug tient’s health status. In a landmark study, researchers Administration, topical CsA is intended to address the applied, for the first time, several standard methodolo- underlying inflammatory causes of dry eye syndrome gies for assessing an indexed type of humanistic outcome and provide far more than palliative therapy for many dry called utilities (Walt 2001). Health utilities are funda- eye patients (Allergan 2002). Although the exact mech- mental values that represent a subject’s preferences for anism of action of this product is not fully understood, specific outcomes, relative to states of health or treat- it is thought to act as a partial immunomodulator and ments, and can be used to compare the relative impact anti-inflammatory, arresting T-cell activation, thereby of different diseases. In the OSDI study, patients with the preventing T-cells from releasing cytokines that begin the severe dry eye rated its impact as comparable to Class inflammatory cycle of dry eye. As CsA is utilized and its

DRY EYE SYNDROME 35 COST EFFECTIVENESS

TABLE 2 NEI VFQ-25: sample questions FIGURE Comparing utilities among dry eye, other conditions

From version 2000.Weighted kappa values (Kw) are used to determine the repeatability of individual VFQ-25 Utilities are used to develop a cost-utility analysis questions.2 (see page 37).A utility of 1.00 equates to perfect health, while 0.00 equals death. Question 4 (Kw = 0.42). How much pain or discomfort have you had in and around your eyes (e.g., burning, itching, or aching)? Would you say it is: Mild psoriasis 0.89 (Choose one) Mild dry eye 0.81 None Mild Asymptomatic dry eye 0.78 Moderate Severe Moderate dry eye 0.78 Very severe Moderate angina 0.75

Question 16 (Kw = 0.85). How much difficulty do you have driving at night: Severe dry eye 0.72 No difficulty at all Class III/IV angina 0.71 A little difficulty Moderate difficulty Disabling hip fracture 0.65 Extreme difficulty Have stopped doing this because of eyesight Severe dry eye with tarsorrhaphy 0.62 Have stopped doing this for other reasons Moderate stroke 0.39

Question 19 (Kw = 0.42).How much does pain or discomfort in or around your eyes keep you Complete blindness 0.33 from doing what you’d like to do: AIDS 0.21 All of the time

Most of the time SOURCE:WALT 2001 Some of the time A little of the time None of the time have focused mainly on safety and efficacy factors. A comprehensive evaluation of these treatments should Question 20 (K = 0.90). I stay home most of the w also include investigation of their broader impact, fo- time because of my eyesight: cusing on their ability to relieve the economic and hu- Definitely true manistic burdens of dry eye syndrome on both individ- Mostly true ual patients and society. Only a few studies have included Not sure economic or humanistic assessments of any kind, notably Mostly false Definitely false studies for punctal occlusion and the newly approved ophthalmic cyclosporine formulation. 2 In Cohen’s kappa statistic, >0.80 has been described as close to perfect (good reliability) and 1.00 is considered unlikely.In terms of repeatability, ≥0.67 allows for tentative conclusions to be drawn, Punctal occlusion while ≥0.40 indicates to researchers that moderate agreement can Although punctal occlusion has been used to treat be expected. dry eye patients for 40 years, few clinical studies have ade- ADAPTED FROM NEI 2000, NICHOLS 2002 quately characterized the benefits of this procedure. In a controlled, double-masked, prospective study, replace in practice becomes clearer, the role of traditional searchers in Mexico recently determined that patients palliative agents may change significantly. who received bilateral collagen and silicone lacrimal occlusion implants in both the superior and inferior canali- Pharmacoeconomic analysis of dry eye culi experienced progressive clinical improvement over The burden of dry eye syndrome has been assessed time (Nava-Castaneda 2003). At 8 weeks, suffering had across the full range of outcomes. However, in the rou- been relieved by more than 90 percent, compared with tine assessment of its therapies, researchers customarily baseline readings.At 6 months, 86 percent of treated pa-

36 P&T DIGEST COST EFFECTIVENESS tients remained free of symptoms. In contrast, symptoms remained unchanged among patients in the sham procedure Basic principles of group. In addition, the researchers also re- pharmacoeconomic research ported a change in resource utilization; 76 E evaluations estimate the value of the economic, clinical, and percent of patients had stopped the daily humanistic outcomes resulting from different treatments, use of eye lubricants, thus relieving a portion P which are compared to help decision makers determine optimal of the patient’s economic burden. therapeutic approaches for their patient populations.Several Retrospectively, researchers at Wills Eye types of analyses are available, including cost-minimization,cost- Hospital, Philadelphia, established that punc- effectiveness,cost-benefit, and cost-utility analyses.Each type of tal plug insertion is a simple method that is analysis expresses resources consumed in terms of monetary safe and effective in the treatment of a wide units, but uses a different unit to express the outcome. range of diseases of the ocular surface and Cost minimization is the simplest of these analyses,because it aqueous tear deficiency, including toxic ep- assumes that the outcomes of the therapies being compared have itheliopathy that cannot be controlled by ar- been proven equivalent among treatment groups.This reduces tificial tears (Ming-Chen 2002). In addition, the analysis to a monetary comparison of resources consumed. they focused on a common event that has an A cost-effectiveness comparison of two or more treatments an- economic impact — spontaneous plug ex- alyzes the dollars spent in consumed resources and the clinical trusion, which requires repeated medical vis- outcomes derived from this expenditure.Because it uses natural its and procedures. Of 312 plugs inserted, 14 units of medical outcomes (e.g., life-years gained, percentage of were removed — 11 because of epiphora and successfully treated patients) to compare medical treatments, this type of PE analysis — more than any — parallels the medical three due to conjunctival erosions. Overall thought process and is intuitively accepted within the medical success was about 77 percent, but would have community.That is why, in medical-decision making, cost effec- been about 10 percentage points higher if tiveness is the most commonly performed of the four analyses.A only patients with dry eye had been included cost-effectiveness evaluation, however, cannot be used to com- in the study. One reason for suboptimal clin- pare treatments with dissimilar outcomes. ical results was undiagnosed blepharitis, In a cost-benefit analysis, the outcomes of two dissimilar treat- which often coexists with dry eye. The au- ment groups, inherently expressed in dissimilar natural units, can thors also noted that clinicians should care- be estimated in terms of monetary units.This conversion allows fully choose plug size and monitor patients; the investigator to compare dollars with dollars: dollars spent in these could have added economic benefits. consumed resources with the dollar value gained in clinical out- Using data from the literature and expert comes.Thus, a cost-benefit analysis allows the investigator to opinion, Lee and colleagues developed a compare costs and outcomes of unrelated health care interven- Markov economic model to assess the med- tions, such as the treatment of glaucoma and dry eye syndrome. ical costs and outcomes of dry eye syndrome A cost-utility analysis evaluates the effect of treatment on soci- (Lee 2000). They reported that, over the etal outcomes, typically expressing results in terms of health util- course of 1 year, the cost of managing and ities or quality-adjusted life years.A cost-utility evaluation allows treating a population of dry eye patients the investigator to include the humanistic outcomes of patient preferences or quality of life when comparing products or pro- with palliative medications, punctal plugs, grams with dissimilar outcomes measures.This analysis tech- and surgery is estimated to be $357,050 for nique, in effect, expands cost-benefit analyses beyond express- an organization covering 500,000 lives. ing outcomes as monetary units. These researchers suggest their model could The clinical characteristics of a disease and the resulting bur- be used to quantitatively assess the impact of den determine the relevance of each type of outcome for a PE new treatments on health-system budgets analysis.For example, lost work days are relevant in the evalua- and speculated that a more effective dry eye tion of asthma or migraine, in which symptoms can temporarily intervention could improve cost effective- debilitate sufferers.More relevant to a symptom-silent disease ness by decreasing patient demand for physi- (such as early-stage glaucoma) would be, for example, the cost of cian visits and procedures. noncompliance, which generates greater downstream expenditures associated with more invasive therapies.In the case of Cyclosporine A ophthalmic emulsion moderate to severe dry eye syndrome, the burden of disease With the recent approval of CsA oph- data indicates that both economic and humanistic outcomes are thalmic emulsion, investigators have re- important to consider. newed reason to apply PE assessment to dry

DRY EYE SYNDROME 37 COST EFFECTIVENESS

eye treatments. So far, studies have included analyses Hirsch JD, Kozma CM, Wojcik AR, Reis B. Economic and quality from the economic perspective regarding reduction in ar- of life impact of dry eye symptoms: a Sjögren’s patient survey [abstract]. Invest Ophthalmol Vis Sci. 1998;39:S65. tificial tear and medication use after CsA treatment. Kozma CM, Reeder CE, Schulz RM. Economical, clinical, and In a double-masked phase 2 study of CsA, the use of humanistic outcomes: a planning model for pharmacoeco- artificial tears generally decreased at weeks 4, 8, and 12 nomic research. Clin Ther. 1993;15:1121–1132. during therapy, and at weeks 2 and 4 after it (Stevenson Kozma CM, Hirsch JD, Wojcik AR. Economic and quality of life impact of dry eye symptoms. Poster presented at the 2000). Annual Meeting of the Association for Research in Vision In a phase 3 trial of 0.05 percent and 0.1 percent CsA and Ophthalmology, April 30–May 5, 2000, Ft. Lauderdale, emulsions, patients instilled 1 drop of the study medi- Fla. cation in each eye twice daily and were allowed to use ar- Lee JT, Teale CW. Development of an economic model to assess costs and outcomes associated with dry eye disease. Poster tificial tears as adjunctive medication at will. Over the presented at the 2000 Spring Practice and Research Forum course of the study, patients applying the CsA formula- of the American College of Clinical Pharmacy, April 2–5, tion decreased their reliance on artificial tears (Sall 2000). 2000, Monterey, Calif. Ming-Chen T, Banu Cosar C, Cohen EJ, et al. The clinical effi- A 1-year observational study using the DEDIQ deter- cacy of silicone punctal plug therapy. Cornea. mined that CsA 0.05 percent is highly efficacious in treat- 2002;21:135–139. ing dry eye syndrome. Of 181 enrolled subjects in a pri- Nava-Castaneda A, Tovilla-Canales JL, Rodriguez L, et al. Effects vate ophthalmology practice, more than 60 percent of lacrimal occlusion with collagen and silicone plugs on patients with conjunctivitis associated dry eye. Cornea. reported symptom improvement. From an economic 2003;22(1):10–14. perspective, total medication orders, including those NEI (National Eye Institute). National Eye Institute Visual used for dry eye (nonsteroidal anti-inflammatory drugs, Functioning Questionnaire–25. Version 2000. Bethesda, antihistamines, artificial tears, ophthalmic antibiotics, Md: NEI, 2000. Nelson JD, Helms H, Fiscella R, Southwell Y, Hirsch JD. A new and ophthalmic/antibiotic steroid combinations) fell 55 look at dry eye disease and its treatment. Adv Ther. percent in the post-CsA treatment period (Cross 2002). 2000;17(2):84–93. Nichols KK, Begley CG, Caffrey B, Jones LA. Symptoms of ocu- CONCLUSION lar irritation in patients diagnosed with dry eye. Optom Vis Sci. 1999;76(12):838–844. Providing optimal medical care of dry eye syndrome Nichols KK, Mitchell GL, Zadnik K. Performance and repeatabil- requires planning that is based not only on drug safety ity of the NEI-VFQ-25 in patients with dry eye. Cornea. and efficacy, but also on data relating the full value of 2002;21(6):578–583. medical treatments, that is, changes in economic and Sall K, Stevenson OD, Mundorf TK, Reis BL, and the CsA Phase 3 Study Group. Two multicenter, randomized studies of the humanistic outcomes that are achieved due to the treat- efficacy and safety of cyclosporine ophthalmic emulsion in ment effect. Applying PE methods to assess the value of severe to moderate dry eye disease. Ophthalmology. treatments systematically can improve both the overall 2000;107(4):631–639. Schepens Eye Research Institute. Dry eye syndromes: your ques- quality and efficacy of dry eye medical care. tions answered. 2001. Available at «http://www.eri.har- Although full-range PE studies of dry eye syndrome re- vard.edu/ main to be conducted, the course of such analyses is clear. text/dryeye.text.html». Accessed March 10, 2003. Researchers must determine which therapies or regimens Schiffman RM, Christianson MD, Jacobsen G, Hirsch JD, Reis BL. Reliability and validity of the Ocular Surface Disease provide the greatest effect in terms of relieving the clini- Index. Arch Ophthalmol. 2000;118:615–621. cal, economic, and humanistic burden of dry eye syn- Smeeding JE, McLaughlin C, Walt JG. Dry-eye increases in drome, for specific patient groups at the most effective cost. health care and utilization and expenditures. Poster presented at the sixth annual international meeting of the REFERENCES International Society for Pharmacoeconomics and Outcomes Research, May 20–23, 2001, Arlington, Va. Albietz JM. Dry eye: an update on clinical diagnosis, manage- Stevenson D, Tauber J, Reis BL, the Cyclosporine A Phase 2 ment and promising new treatments. Clin Exp Optom. Study Group. Efficacy and safety of cyclosporine A oph- 2001;84:4–18. thalmic emulsion in the treatment of severe to moderate Allergan Inc. Allergan’s Restasis approved by the FDA [news re- dry eye disease: a dose-ranging, randomized trial. lease]. Dec. 26, 2002. Available online at «http:// Ophthalmology. 2000;107:967–974. www.restasis.com/press.html». Accessed April 6, 2003. Walt JG, Schiffman RM, Jacobsen G, et al. Utility assessment Begley CG, Caffery B, Chalmers RL, Mitchell GL. Use of the dry among patients with dry eye disease. Poster presentation, eye questionnaire to measure symptoms of ocular irritation exhibited at the Annual Meeting of the International in patients with aqueous tear deficient dry eye. Cornea. Society for Quality of Life Research, Nov. 8, 2001, 2002;21:664–670. Amsterdam. Brewitt H, Sistani F. Dry eye disease: the scale of the problem. Surv Ophthalmol. 2001;45(suppl2):S199–S202. Cross WD, Lay LF, Walt JG, Kozma CM. Clinical and economic implications of topical cyclosporine A for the treatment of dry eye. Manag Care Interface. 2002;15:44–49.

38 P&T DIGEST CHRONIC THERAPY «PRODUCT HED» Issues in the Use Of Preservative-Free Topicals

HENRY D. PERRY, MD ERIC D. DONNENFELD, MD Ophthalmic Consultants of Long Island

SUMMARY tears provide temporary, albeit strictly palliative, relief from the effects of dry eye. In a perfect world, patients would use medi- Common artificial tear ingredients include tonicity, cations as prescribed.In reality, patients may buffering, viscosity, wetting, and lubricating agents; anti- cut corners, especially if they may save oxidants; and preservatives (Power Graphics 1999). money by doing so.Clinicians and pharma- Tonicity agents adjust the preparation’s osmolality. Buffering agents adjust its pH level to between 6 and 8. cists must acknowledge this tendency, yet at Viscosity agents slow the flow of the solution through the the same time protect patients from using eye’s drainage ducts, to extend its usefulness. Wetting contaminated ophthalmologic agents and agents facilitate the spread of the material over the ocu- strive to achieve optimal clinical outcomes. lar surfaces, and lubricating agents supplement the lipid occlusive layer.Antioxidants prevent deterioration of the n treating dry eye syndrome, appropriate product product when it is exposed to oxygen. Preservatives re- administration is an important but often neglected tard the growth of bacteria, increasing the shelf life of ar- issue. At present, concerns about product adminis- tificial tear formulations in multiple-use vials. Itration apply only to topical artificial tear preparations, but in the future physicians will have the option of Why use preservatives? treating the underlying cause of the disease, rather than Today, both preserved and preservative-free artificial its effects, in many patients. This is because the Food and tear formulations are available. Preserved products, Drug Administration recently approved a new dry eye which on a per-use basis generally tend to cost less than medication, a 0.05 percent cyclosporine A (CsA) oph- nonpreserved formulations, are packaged in multiple- thalmic formulation, marketed by Allergan as Restasis dose bottles. Preservative-free formulations are sold in (Allergan 2002). CsA is contraindicated in patients with single-dose vials. The FDA and the U.S. Pharmacopoeia active ocular infection or suspected or known hyper- mandate the inclusion of preservatives for all multidose sensitivity to any of its components, and therefore is not topical ophthalmic medications (Abelson 2002). Over the appropriate for a subset of patients. years, pharmaceutical companies have replaced harsher In brief, CsA restores tear function. Unlike artificial tear preservatives in artificial tear preparations with gentler medications, which dry eye sufferers may apply four or ingredients. more times daily, CsA is applied twice daily. Because its Preservatives have benefits when used in ophthalmic clinical benefits become apparent after about 3 months topical medications, but experts caution against pro- of therapy, it is reasonable to suspect that patients put on longed use of artificial tears containing preservatives, a CsA regimen will continue to use artificial tear formu- especially benzalkonium chloride (BAK) and chloro- lations during the initial months of therapy. They also may butanol, which have been shown to irritate users (Abel- continue to use artificial tears adjunctively thereafter, but son 2002). They further advise that, in contrast to BAK, probably at a lower daily dosage and with an end in sight. sorbic acid infrequently causes adverse reactions, poly- Until CsA gains broad utilization, the artificial tear quaternium-1 causes only superficial epithelial damage, preparations — liquids, gels, and ointments — will con- and sodium perborate converts to hydrogen peroxide tinue to represent the mainstay of dry eye treatment. By on exposure to air and then breaks down into oxygen and increasing humidity at the ocular surface, improving lu- water. Stabilized oxychloro complex has been found to brication, and smoothing the corneal surface, artificial be safe and well tolerated, even with frequent use.

DRY EYE SYNDROME 39 CHRONIC THERAPY

Although preservative-free artificial tear solutions after opening and that unpreserved drops be discarded were developed for patients who demonstrate sensitiv- 1 week after opening. Neither of these products need re- ity to preservatives, the general avoidance of preservatives frigeration. may be wise. In a rat model, researchers demonstrated that, especially over the long term, most preservatives PRODUCT USE ISSUES used in ophthalmic eyedrops have the potential to dam- For patients who need to instill artificial tears several age human conjunctival and corneal epithelial cells (Bec- times daily, larger containers of medication are desirable. quet 1998). Although preservatives interfere with the British researchers observed that patients who frequently growth, multiplication, and metabolism of microbes, apply eye drops may need to carry multiple single-dose they have a similar effect on eukaryotic cells, which ex- containers, which are cumbersome (Oldham 1996). They plains their cytotoxicity and inflammatory cell response. also recognized that purchasing single-dose containers Even at lower concentrations, and after a single instilla- can be more than 1,000 percent as expensive. tion, BAK was toxic to the corneoconjunctival surface. It can be expected, then, that patients who purchase These researchers warn that prolonged exposure to unpreserved medications in single-dose vials will try to preservatives is likely to produce subclinical inflamma- derive the most benefit from their dollars. A single-dose tion, which might lead to chronic irritation and fibrosis vial can provide 10 or more drops, all of which may be that can worsen dry eye syndrome. used to relieve symptoms in one eye; a patient who uses Several researchers indicate that the negative effects of the entire vial in a day does not risk contamination. Yet preservative-free artificial tears on the eye are minor, if a patient requiring 4 drops daily may be tempted to save not negligible (Albietz 2001a,Albietz 2001b, Berdy 1992, the remaining medication for use beyond the first day. Pisella 2002, Schein 1992). The primary concern relating In our practice, we therefore advise patients that to the use of preservative-free artificial tear formula- preservative-free artificial tears are free of contamination tions is contamination of the contents once the patient the day they are opened, are probably not contaminated opens the container and applies the medication. The on the second day, but are likely contaminated on the contamination typically is due to contact with the pa- third day and must be discarded. Our goal is to make sure tient’s cornea, conjunctiva, eyelashes, or hands. Even that the patient at least reduces the risk of infection to a bacteria that are not pathologic may alter the pH value level with which we are relatively comfortable. Consid- of the medication and interfere with efficacy. ering that the dry eye medications we prescribe have A decade ago, researchers determined that patients been tested and remained uncontaminated when ex- using ocular-surface medications can trigger a cycle of posed to room air for as long as 28 days, we are confident microbial contamination between their conjunctivae that our warning suffices to prevent patients from in- and the container (Schein 1992). This team studied 220 stilling contaminated medications. in-use medications obtained from 101 patients with nonmicrobial ocular-surface disease. They cultured the Compliance bottle caps, a drop from each bottle obtained by inver- Patients with dry eye may become noncompliant with sion, and the contents of the bottle. They also obtained an established regimen for different reasons. Some will conjunctival cultures from the patients using the med- use too much medication because their artificial tears ications and 50 age-matched controls. They harvested provide insufficient relief. Some may be unable to apply pathological organisms from the conjunctivae of 34 per- the medication correctly. cent (34/101) of patients but only 10 percent (5/50) of the In a study of noncompliance in 200 patients using controls. eyedrops (mean age, 26 years; range, 9 to 92 years), the To test the susceptibility of unpreserved eye drops to main reasons that emerged for noncompliance were poor contamination, British researchers inoculated 21 differ- motivation (stemming from inadequate understanding ent unpreserved eye drop formulations with a known of the function of the medication) and inability to use eye quantity of four different microorganisms and stored the drops properly (Winfield 1990). Sixty-two percent con- containers at different temperatures for as long as 28 sistently self-administered their drops, 17 percent self- days (Oldham 1996). They recommend that unpreserved medicated when no help was available, 21 percent always eye drops be stored at between 2 degrees and 8 degrees obtained help, and 8 percent never tried to administer Celsius (35.6 to 46.4 degrees Fahrenheit) after opening, their medication. Approximately half the patients had and confirmed that, in general, drops containing alky- difficulty aiming the drop. Other problems included in- loids or antibiotics should be discarded after 7 days. The ability to squeeze the container well enough, blinking, Lothian Joint Formulary (NHS 2002) recommends that and inability to see the tip of the container. In particu- eye drops in multiple-use containers be discarded 4 weeks lar, arthritic patients experienced physical difficulties

40 P&T DIGEST CHRONIC THERAPY

Product administration TABLE Discussion points To help patients achieve optimal benefit from oph- for optimizing benefit thalmic medications, clinicians and pharmacists need from ophthalmic medications to discuss the benefits of the chosen therapy with patients and their at-home care providers, and the correct way to General instructions apply the medication (see Table). • If using two different types of eye drops, instill the first, wait 5 minutes, then instill the second. CONCLUSION • If using drops and ointment,instill the drop first, Although new ophthalmic drug-delivery systems al- wait 5 minutes,then apply ointment. leviate dry eye somewhat, and a new CsA ophthalmic • When using products in single-use vials, emulsion may alleviate the syndrome in many patients, agitate the container so that the color and/or proper administration of dry eye medications remains opaqueness of its contents are uniform. vital to successful treatment. The trend toward preserv- Preventing contamination ative-free medications means patients and their care- • Wash hands before opening container. givers must exercise care during administration to pre- • Prevent container tip from touching the eye. vent contamination of the remaining contents in the • When finished, tighten container cap. vial. Patients should be cautioned not to instill more • Single-use vials should be used immediately after opening and discarded after use. than one drop of medication at a time, to prevent wast- Eye drops ing the medication. Eye care clinicians can help patients • Lean head back. achieve optimal relief by providing a combination of the • Instill eye drops by gently sliding skin below most appropriate medication with the education on eyelid over prominent point of cheekbone to proper self-medication. form pocket. • Put one drop into pocket. REFERENCES • Close eye and refrain from blinking for about 1 Abelson MB, Washburn S. The downside of tear preservatives. Rev Ophthalmol. 2002;9(5). minute. Albietz JM. Dry eye: an update on clinical diagnosis, manage- • Press tightly (but not tightly enough to cause ment and promising new treatments. Clin Exp Optom. injury) with one finger on inside corner of eye 2001a;84:4–18. for about 30 seconds after instilling drop. Albietz JM, Bruce AS. The conjunctival epithelium in dry eye • Use only 1 drop at a time. subtypes: effect of preserved and non-preserved topical treatments. Curr Eye Res. 2001b;22:8–18. • The eye’s conjunctival fornix can accommo- Allergan, Inc. Allergan’s Restasis approved by the FDA [press re- date only 1 drop at a time. Any fluid beyond 1 lease]. December 26, 2002. drop will overflow. Becquet F, Goldschild M, Moldovan MS, et al. Histopathological Ointment effects of topical ophthalmic preservatives on rat corneo- • Start at inside corner of eye. conjunctival surface. Curr Eye Res. 1998;17:419–425. Berdy GJ, Abelson MB, Smith LM, George MA. Preservative-free • Squeeze thin line (about 0.5 cm) of medication artificial tear preparations: assessment of corneal epithelial along inside of lower lid. toxic effects. Arch Ophthalmol. 1992;110:528–532. • Blink. NHS Lothian. Lothian Joint Formulary. Available at: «http://www.nhslothian.scot.nhs.uk/ lothianformulary/11/11_8.html.» Accessed April 7, 2003. with administration. These researchers also reported Oldham GB, Andrews V. Control of microbial contamination in that most patients were reluctant to admit they were ex- unpreserved eyedrops. Br J Ophthalmol. 1996;80:588–591. Pisella PJ, Pouliquen P,Baudouin C. Prevalence of ocular symp- periencing problems with the process. toms and signs with preserved and preservative free glau- In a separate survey of patients by telephone, 50 per- coma medication. Br J Ophthalmol. 2002;86:418–423. cent (114/229) of patients with dry eye said they con- Power Graphics. Common ingredients in artificial tears. 1999;3(1):1–2. Available at: tinued to use the artificial tear solutions they had been «http://www.powerpak.com/PowerGraphics/1999/January/ prescribed, while 53 percent (47 of 89) reported dis- CommonIngredients.cfm». Accessed March 15, 2003. continued use of prescribed ointments (Swanson 1998). Schein OD, Hibberd PL, Starck T, et al. Microbial contamination This research detected “extreme” variability in the of in-use ocular medication. Arch Ophthalmol. 1992;110:82–85. amount of artificial tear medication used, from patient Swanson M. Compliance with and typical usage of artificial tears to patient, and day to day. Patients appeared to titrate in dry eye conditions. J Am Optom Assoc. 1998;69:649–655. their artificial tear dosage to their symptoms on a daily Winfield AJ, Jessiman AJ, Williams A, Esakowitz L. A study of the basis; this researcher recommends patient education to causes of non-compliance by patients prescribed eyedrops. Br J Ophthalmol. 1990;74:477–480. foster compliance.

DRY EYE SYNDROME 41 CONTINUING EDUCATION POST-TEST P&T Digest Dry Eye Syndrome Please tear out the combined answer sheet/evaluation form on page 43 (physicians) or page 44 (pharmacists). On the answer sheet, place an X through the box of the letter corresponding with the correct response for each question.There is only one correct answer to each question.

1. Symptoms of dry eye syndrome, or kerato- 7. Dry eye can occur sporadically or as a chronic conjunctivitis sicca, include all but which of condition that becomes a self-perpetuating the following? syndrome. a. Gritty sensation under eyelids. a. True. b. Numbness. b. False. c. Mucous discharge. d. Increased frequency of blinking. 8. Topical corticosteroids should: e. Redness. a. Be reserved for patients who experience severe and recalcitrant symptoms. 2. Despite improving ocular lubrication and in- b. Be considered as front-line therapy for creasing humidity at the ocular surface, artifi- patients on antihistamine therapy. cial tears and lubricants fail to: c. Be used for 2 weeks or less for severe exacer- a. Accurately reproduce natural tears. bations of dry eye syndrome. b. Improve vision. d. Answers a and c. c. Correct the underlying pathology that can e. All the above. occur with dry eye. d. Answers “a”and “c.” 9. For patients with severe dry eye, a diagnosis usually is supported by the following: 3. The AAO 2003 guidelines include all but a. Schirmer wetting test. which of the following goals for managing b. Ocular surface dye-staining pattern. patients with dry eye? c. Tear break-up time test. a. To establish appropriate therapy. d. All the above. b. To educate the patient. c. To prevent complications. 10. Dry eye syndrome has numerous risk factors. d. To reduce the use of concurrent therapies. Which of the following are risk factors for dry e. To identify the causes of the condition. eye syndrome? a. Vitamin A deficiency. 4. In a population-based study, Schein (1997) b. Hormone replacement therapy. estimated that dry eye symptoms are present c. Arthritis. in: d. Answers b and c. a. 1 million elderly Americans. e. All the above. b. 1 in 7 elderly Americans. c. 1.30 percent of Medicare managed care 11. Preservative-free artificial tears were devel- covered lives. oped: d. 0.21 percent of commercial managed care a. For patients who demonstrate sensitivity to covered lives. preservatives. b. Because preservatives are known carcinogens. 5. Contamination of preservative-free artificial c. To reduce the cost of the medication. tear products typically is due to: d. To encourage the use of more medication. a. Improper manufacturing practices. b. Contact with the patient’s cornea,conjunctiva, 12. In a survey of third-party payers, prevalence eyelashes, or hands. of dry eye syndrome among persons covered c. Airborne microbes. by commercial plans was determined to be: d. The patient’s sneezing or coughing. a. 0.21 percent. b. 0.35 percent. 6. Artificial tears are best described as: c. 1.30 percent. a. Preventive therapy. d. 10.00 percent. b. Curative therapy. c. Palliative therapy. d. Counterintuitive therapy. continued on page 45

42 P&T DIGEST CONTINUING EDUCATION ANSWER SHEET/CERTIFICATE REQUEST P&T Digest Dry Eye Syndrome EXAMINATION: Place an X through the box of the letter that represents the best answer to each question on pages CME CREDIT FOR PHYSICIANS 42 and 45.There is only ONE answer per question.Place all Sponsored by The Chatham Institute answers on this answer form: ABCDE ABCDE See page 44 for answer sheet for pharmacists 1. 11. 2. 12. I certify that I have completed this educational activity 3. 13. and post-test and claim ______credits. 4. 14. 5. 15. Signature: ______6. 16. 7. 17. 8. 18. First name, MI ______9. 19. 10. 20. Last name, degree ______PROGRAM EVALUATION Title ______So that we may assess the value of this self-study program, we ask that you please fill out this evaluation form. Affiliation ______Have the activity’s objectives been met? Yes No 1. Describe the etiology of dry eye syndrome, Specialty ______or keratoconjunctivitis sicca (KCS), and risks of untreated disease. 2. Outline the prevalence of KCS and the Address ______economic implications thereof. 3. Review the American Academy of Ophthal- City ______State _____ ZIP ______mology guidelines for treatment of KCS. 4. Explain the mechanisms of action of Daytime telephone (______) ______pharmacotherapies for KCS. 5. Summarize pharmacoeconomic data of emerging anti-inflammatory agents for KCS. Fax (______) ______6. Identify considerations in proper handling and administration of preservative-free topical E-mail ______agents for KCS.

Was this publication fair, balanced, and free of Physician — Maximum of 3.0 category 1 credits toward commercial bias? Yes _____ No _____ AMA Physician’s Recognition Award. If no,please explain: ______To receive CME credit, complete answer sheet/evaluation form and mail or fax to: Did this educational activity meet my needs,contribute to my personal effectiveness,and improve my ability to: Office of Continuing Education Strongly Strongly The Chatham Institute agree disagree 26 Main Street, 3rd Floor Treat/manage patients? 54321n/a Chatham, NJ 07928 Communicate with patients? 54321n/a Fax: (973) 701-2515 Manage my medical practice? 54321n/a Other ______54321n/a Credit will be awarded upon successful completion of assessment questions (70 percent or better) and completion Effectiveness of this method of presentation: Very of program evaluation. If a score of 70 percent or better is Excellent good Good Fair Poor not achieved, no credit will be awarded and the registrant 54321 will be notified. Time spent reading this publication: H ____ M ______Please allow up to 6 weeks for processing. What other topics would you like to see addressed? ______The cost of this activity is provided at no charge to the par- ______ticipant through an educational grant from Allergan. Comments: ______CMC3000 ______

DRY EYE SYNDROME 43 CONTINUING EDUCATION ANSWER SHEET/REQUEST FOR STATEMENT OF CREDIT P&T Digest Dry Eye Syndrome EXAMINATION: Place an X through the box of the letter CPE CREDIT FOR PHARMACISTS that represents the best answer to each question on pages Sponsored by The Chatham Institute 42 and 45.There is only ONE answer per question.Place all answers on this answer form: See page 43 for answer sheet for physicians ABCDE 1. I certify that I have completed this educational activity 2. and post-test and claim ______credits. 3. 4. Signature: ______5. 6. First name, MI ______7. 8. 9. Last name, degree ______10. 11. Title ______12. 13. Affiliation ______14. 15. Specialty ______16. 17. 18. Address ______19. 20. City ______State _____ ZIP ______PROGRAM EVALUATION Daytime telephone (______) ______To receive continuing education credit, please answer all information requested below.This assures prompt and ac- Fax (______) ______curate issuance of your continuing education certificate. Please rate this program as follows: E-mail ______Very Excellent good Good Fair Poor Pharmacist — This program is approved for 3.0 contact Overall quality of program 54321 hours (0.3 CEU). Content 54321 Relevance to objectives 54321 ACPE program number: 812-000-03-016-H01. Effectiveness of Release date: Dec.15, 2003. this format for learning 54321 Expiration date: Dec.15, 2004. Value to me in my ® daily responsibilities 54321 Complete answer sheet/evaluation form and mail to: How long did it take you to complete this continuing Office of Continuing Education education activity? The Chatham Institute Hours ______Minutes ______26 Main Street, 3rd Floor Chatham, NJ 07928 Requested topics/skills to address in future programs: ______Fax: (973) 701-2515 ______Credit will be awarded upon successful completion of the post-test (a score of 70 percent or better) and activity eval- Did you detect any bias in this presentation? uation. If a score of 70 percent or better is not achieved, no Yes ______No ______credit will be awarded and the registrant will be notified. If yes,please explain: ______Please allow up to 6 weeks for processing. Comments : ______The cost of this activity is provided at no charge to the participant through an educational grant from Allergan. ______CMC3000

44 P&T DIGEST CONTINUING EDUCATION SELF-TEST, continued P&T Digest Dry Eye Syndrome

13. If inflammation is considered to be a cause 18. In a survey of patients with dry eye disease, of dry eye syndrome, then suppressing the which quality-of-life factor was most often cytokine-mediated inflammation response mentioned as being affected by the disease? that occurs at a histological level can apply a. Decrease of leisure time. to dry eye regardless of the disease-state b. Decrease of work time. association. c. Depression, unhappiness. a. True. d. Loss of confidence. b. False. 19. Which of the following statements is true? 14. In tears, lipid is: a. Cytokines are hormone-like proteins that reg- a. A mixture of water, salt, and proteins. ulate the immune response. b. A surface layer that retards evaporation. b. Cytokines are a subset of leukocytes involved c. The film that coats the corneal surface. in signal transduction in the cell membrane. d. A secretion that degrades the quality of the c. Cytokines have antigen-receptor complexes tears. on their surfaces. d. The underproduction of cytokines can dam- 15. The use of tear substitutes is indicated for pa- age tissue. tients with mild dry eye syndrome. For patients with more severe disease, which of the 20. In dry eye syndrome, cyclosporine A: following is not necessarily indicated? a. Mediates mucosal secretions. a. Spectacle side shields. b. Promotes cytokine release to reduce inflam- b. Nonpreserved tear substitutes or ointments, mation. gels, and emulsions. c. Prevents release of cytokines that incite in- c. Laser surgery. flammation. d. Moisture inserts. d. Inhibits release of a collagenous enzyme that e. None of the above. incites inflammation.

16. A 1998 study of individuals with Sjögren’s syndrome found that, on average, this subset of dry eye patients experiences ocular irritation that interferes with activities of daily living on all but 29 days each year. a. True b. False.

17. Overutilization costs in dry eye syndrome frequently arise from: a. Corneal transplantation. b. Low patient satisfaction with palliative therapy. c. A loss of productivity. d. None of the above.

DRY EYE SYNDROME 45