A PEER-REVIEWED COMPENDIUM OF FORMULARY …€¦ · A PEER-REVIEWED COMPENDIUM OF FORMULARY...

Continuing education credit for physicians and pharmacists sponsored by The Chatham Institute

DRY EYE SYNDROME

P&T DIGESTA PEER-REVIEWED COMPENDIUM OF FORMULARY CONSIDERATIONS

• Historicalperspectives

• Prevalence and economicimplications

• Etiology of disease

• 2003 AAO guidelines for treatment

• Drug-therapy review

• Pharmacoeconomicdata

• Proper medication use

This program is supported by an educational grant from Allergan

Vol. 12, No. 12December 2003

S U P P L E M E N T T O

M A N A G E D

CareCare

A Tool for Formulary Decision Makers

The understanding of keratoconjunctivitis sicca (KCS), alsoknown as dry eye syndrome, has changed in the past 5 years.Until recently, it was thought to have been due to aqueous in-

sufficiency. Today, it is understood that KCS is a multifactorial dis-ease that also involves inflammation of the ocular surface andlacrimal gland, neurotrophic deficiency, and meibomian dysfunc-tion. This change in understanding, reflected in the 2003 AAO DryEye Syndrome Preferred Practice Pattern that is summarized herein,has led to the development of new and effective medications.

This peer-reviewed publication gives physicians and pharmacistswho serve on pharmacy and therapeutics committees up-to-dateinformation about the most efficacious and cost-effective medicaltreatments available. Relatively little published data exist in a cen-tralized format about medical therapies for dry eye syndrome,compared with information about other chronic conditions. Thispublication, a digest of existing knowledge and best practices, servesas a valuable tool for formulary decision makers and is an impor-tant contribution to the medical literature.

Editorial Advisory Board

John D. Sheppard, MD, MMScChairman, Editorial Advisory Board and Chief Medical EditorP&T Digest | Dry Eye SyndromeProgram Director, Department of OphthalmologyEastern Virginia Medical SchoolNorfolk, Va.

Richard G. Fiscella, RPh, MPHAssistant Director, Clinical Services/Ambulatory CareUniversity of Illinois at Chicago (UIC) Hospital Department of PharmacyClinical Associate ProfessorUIC Department of Pharmacy PracticeClinical CoordinatorUIC Eye and Ear InfirmaryChicago

This publication is made possible by an educational grant from Allergan.

Chief Medical EditorJohn D. Sheppard, MD, MMSc

FacultyEric D. Donnenfeld, MDRichard G. Fiscella, RPh, MPHJan D. Hirsch, PhDHenry D. Perry, MDSteven E.Wilson, MD

EditorMichael D. Dalzell

Consulting EditorJohn A. Marcille

Contributing EditorsTony BerberabeBob CarlsonFrank DiamondWilliam W. EdelmanLinda FelconeMaxine LosseffJack McCainPaula Sirois

Design DirectorPhilip Denlinger

Group PublisherTimothy P. Search, RPh

Director, New Product DevelopmentTimothy J. Stezzi

Eastern Sales ManagerScott MacDonald

Senior Account ManagerBlake Rebisz

Midwest Sales ManagerTerry Hicks

Director, Production ServicesWaneta Peart

MANAGED CARE (ISSN 1062-3388) is published monthly byMediMedia USA Inc., at 780 Township Line Road,Yardley, PA19067.This is Volume 12, Issue 12. Periodical postage paid atMorrisville, Pa., and at additional mailing offices. POSTMAS-TER: Send address changes to MANAGED CARE, 780 TownshipLine Road,Yardley, PA 19067. Prices: $10 per copy, $93 peryear in the USA; $120 per year elsewhere. Send letters to theeditor c/o Frank Diamond, MANAGED CARE, 780 TownshipLine Road,Yardley, PA 19067. Letters may be edited for lengthand clarity. E-mail: [email protected]. Phone:(267) 685-2788; fax (267) 685-2966; circulation inquiries (267)685-2782. Copyright ©2003 MediMedia USA Inc.

A B O U T T H I S P U B L I C AT I O N

A PEER-REVIEWED COMPENDIUM OF FORMULARY CONSIDERATIONS

P&T DIGEST

John D. Sheppard, MD, MMSc

Chief Medical Editor

DRY EYESYNDROME


P&T DIGEST

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

INTRODUCTION

Dry Eye Moves Beyond Palliative Therapy ................................6Keratoconjunctivitis sicca, or dry eye syndrome, is a complex condition characterized byinflammation of the ocular surface and tear-producing glands. When dry eye is con-trolled, 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 .........................................................9Epidemiological reports worldwide vary, but about one in seven American adults mayexperience frequent symptoms of dry eye syndrome. Untreated disease drives unneces-sary resource utilization and poses risks for expensive complications.MICHAEL D. DALZELL

ETIOLOGY

Inflammation: A Unifying Theory for the Origin of Dry Eye Syndrome ..................................................................14Dry eye syndrome has been difficult to diagnose and treat, due to its heterogeneity. Thesedifficulties are being overcome, however, as evidence of a common etiology emerges. Aninflammatory mechanism appears to underlie the condition.STEVEN E. WILSON, MD

DRY EYE SYNDROME


P&T DIGEST

Cover art:Paul Klee, 1914, 217St. Germain near Tunis(Inland)21.8 x 31.5 cmWatercolor on paperMusée national d'artmoderne, Centre GeorgesPompidou, Paris© 2003 Artists Rights Society (ARS), New York /VG Bild-Kunst, Bonn

DETECTION AND TREATMENT

Guidelines for the Treatment of Chronic Dry Eye Disease...20Recently released guidelines from the American Academy of Ophthalmology provide aframework for managing this chronic disorder. With the treatment approaches outlinedin this article, symptoms and signs can be alleviated and the potential for ocular surfacedamage and impaired vision can be minimized.JOHN D. SHEPPARD, MD, MMSC

PHARMACOTHERAPEUTIC OPTIONS

Medications for Dry Eye Syndrome:A Drug-Therapy Review .............................................................26Early interventions attempted to replace water lost from the tear film. Emerging thera-pies are directed at underlying inflammation. This new focus uses pharmacologic agentsto manage dry eye disease and to control or reverse corneal damage.HENRY D. PERRY, MDERIC D. DONNENFELD, MD

COST-EFFECTIVENESS

Considerations in the Pharmacoeconomics of Dry Eye..........33Until 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 ........................39Preservative-free ophthalmologic agents can be easily contaminated once the patientopens the container. Clinicians must acknowledge this and protect patients from usingcontaminated medication and to assure optimal clinical outcomes.HENRY D. PERRY, MDERIC D. DONNENFELD, MD

CONTINUING EDUCATION

Post-test .......................................................................................42

Physician CME answer sheet/evaluation form ........................43

Pharmacist CPE answer sheet/evaluation form.......................44

4 P&T DIGEST

P&T DIGEST

Dry Eye Syndrome

S E L F - S T U DY CO N T I N U I N G E D U C AT I O N AC T I V I T Y

GENERAL INFORMATION

Continuing education credit is offered to physiciansand pharmacists who read pages 6 through 41 of thispublication, complete the post-test on pages 42 and 45,and fill out the appropriate evaluation form on eitherpage 43 (physicians) or 44 (pharmacists).

PURPOSE AND OVERVIEW

This activity is designed to educate health care practi-tioners and managed care professionals about currentand emerging treatments for dry eye syndrome. Recentdevelopments in the etiology of dry eye have triggeredthe development of new pharmacotherapeutic treat-ment strategies, prompting physicians, patients, andpayers to request information about the status andeffectiveness of current and emerging therapies.Thecontent of this program was developed on the basis offaculty perceptions of significant trends or issues.

Educational objectivesAfter reading this publication, the participant should

be able to:

1. Describe the etiology of dry eye syndrome, or kera-toconjunctivitis sicca (KCS), and risks of untreateddisease.

2. Outline the prevalence of KCS and the economicimplications thereof.

3. Review the American Academy of Ophthalmologyguidelines for treatment of KCS and design appro-priate treatment for patient care.

4. Explain the mechanisms of action of pharma-cotherapies for KCS.

5. Summarize pharmacoeconomic data of emerginganti-inflammatory agents for KCS.

6. Identify considerations in proper handling andadministration of preservative-free topical agentsfor KCS.

Target audiencesManaged care organization medical directors and

pharmacy directors; practicing primary care physicians,ophthalmologists, and pharmacists; members of phar-macy and therapeutics committees.

Continuing education credit sponsored by The Chatham Institute.

CONTINUING EDUCATION

Medical accreditationThe Chatham Institute is accredited by the Accredita-

tion Council for Continuing Medical Education (ACCME)to provide continuing medical education for physicians.

The Chatham Institute designates this educationalactivity for a maximum of 3.0 category 1 credits towardthe AMA Physician’s Recognition Award. Each physicianshould claim only those credits that he/she actuallyspent in the activity.

This activity has been planned and implemented inaccordance with the ACCME Essential Areas, Elements,and Policies.

Pharmacy accreditationThe Chatham Institute is approved by theAmerican Council on Pharmaceutical Educa-tion (ACPE) as a provider of continuing

pharmaceutical education.This activity provides 3.0 contact hours (0.3 CEU) of

continuing education for pharmacists. Credit will beawarded upon successful completion of the post-testand the activity evaluation.

ACPE Universal Program Number (UPN):812-000-03-016-H01.

Release date: Dec. 15, 2003.Expiration date: Dec. 15, 2004.Medium: Journal supplement.

Planning committee membersJohn D. Sheppard, MD, MMSc, professor of ophthal-

mology, microbiology, and immunology, Eastern VirginiaMedical School;Timothy P. Search, RPh, group publisher,MANAGED CARE, published by MediMedia USA; Michael D.Dalzell, editor, custom publications, Managed MarketsPublishing Group, MediMedia USA.

®

PRIMARY FACULTY

Eric D. Donnenfeld, MDFounding PartnerOphthalmic Consultants of Long IslandLynbrook, N.Y.

Jan D. Hirsch, PhDDirector, Clinical ResearchPrescription SolutionsCosta Mesa, Calif.

Henry D. Perry, MDSenior Founding PartnerOphthalmic Consultants of Long IslandLynbrook, N.Y.

John D. Sheppard, MD, MMScProfessor of Ophthalmology, Microbiology,

and ImmunologyEastern Virginia Medical SchoolNorfolk,Va.

Steven E.Wilson, MDProfessor and Chairman,

Department of OphthalmologyGrace E. Hill Professor in Vision ResearchUniversity of WashingtonSeattle

Conflict-of-interest policy and disclosures of significant relationships

As an accredited provider, The Chatham Instituterequires that its faculty comply with ACCME Standards forCommercial Support of Continuing Medical Educationand disclose the existence of any significant financialinterest or any other relationship a faculty member mayhave with the manufacturer(s) of any commercial prod-uct(s) or device(s). It also requires the faculty to disclosediscussion of off-label uses in their presentations.

Eric D. Donnenfeld, MD acknowledges grant andresearch support from Allergan. He also has a consult-ing relationship with Allergan.

Richard G. Fiscella, RPh, MPH acknowledges grantand research support from Allergan, Merck, and Phar-macia. He has consulting relationships with Allergan,Merck, and Pharmacia.

Jan D. Hirsch, PhD, acknowledges stock ownership inAllergan.

Henry D. Perry, MD, acknowledges grant and researchsupport from Allergan. He also has a consulting rela-tionship with Allergan.

John D. Sheppard, MD, MMSc, acknowledges grantand research support from Alcon, Allergan, Bausch &Lomb, Ciba Vision, GlaxoSmithKline, Insite Pharma-ceuticals, Isis Pharmaceuticals, Ista Pharmaceuticals,Lumenis, Novartis, Santen, and Science-Based Health.He has consulting relationships with Allergan, Bausch &Lomb, Ciba Vision, Insite Pharmaceuticals, Isis Pharma-ceuticals, Ista Pharmaceuticals, Novartis, Santen, andScience-Based Health. He is on speaker’s bureaus forAlcon, Allergan, Bausch & Lomb, Ciba Vision, Glaxo-SmithKline, Lumenis, Novartis, Santen, and Science-Based Health.

Steven E.Wilson, MD, acknowledges a consultingrelationship with Allergan. He is on the speaker’sbureau for Allergan.

PUBLISHER’S STATEMENT

The opinions expressed herein are those of the sym-posium faculty, and do not necessarily reflect the viewsof Allergan Inc.,The Chatham Institute, or the publisher,editor, or the editorial boards of this publication orthose of the journals MANAGED CARE and P&T.

Clinical judgment must guide each clinician inweighing the benefits of treatment against the risk oftoxicity. Dosages, indications, and methods of use forproducts referred to in this special supplement mayreflect the clinical experience of the authors or mayreflect the professional literature or other clinicalsources, and may not necessarily be the same as indi-cated on the approved package insert. Please consultthe complete prescribing information on any productsmentioned in this special supplement before adminis-tering.

DRY EYE SYNDROME 5

S E L F - S T U DY CO N T I N U I N G E D U C AT I O N AC T I V I T Y

6 P&T DIGEST

INTRODUCTION

patient satisfaction. Whenit comes to formulary con-siderations, health plansseek data that demonstrateeach drug’s therapeutic ef-fectiveness and potential forcost offset. The informationherein is intended to helppharmacy and therapeuticcommittees with this task.

ETIOLOGY ANDPREVALENCE

The theory and epidemi-ology of dry eye and thera-peutic considerations are discussed at length elsewherein this volume of P&T Digest. In general, dry eye com-prises a heterogeneous assortment of conditions involv-ing aqueous insufficiency, inflammation of the ocular

Dry Eye Moves Beyond Palliative TherapyJOHN D. SHEPPARD, MD, MMSC1

Eastern Virginia Medical School

Dry eye syndrome, also known as keratocon-junctivitis sicca, is a common condition re-ported by patients who seek ophthalmologiccare. Knowledge of the pathophysiology of

dry eye has made significant strides in recent years; today,what was once thought to be a simple matter of the eyenot producing sufficient tear flow is understood withinthe ophthalmologic community to be a multifactorialdisease. Many family physicians and payers, however,may still perceive dry eye to be little more than an irri-tation and thus may not be aware of emerging specificpotent therapies.

Research has shown that dry eye is a complex condi-tion, the hallmark of which is inflammation of the ocu-lar surface and tear-producing glands (Stern 1998). Thisawareness has fostered the development of highly effec-tive anti-inflammatory therapies. These treatments boastthe potential for dramatic advances in quality of life formillions of people whose condition interferes with ac-tivities of everyday living.

Improved patient satisfaction and clinical outcomesalone should be the raison d’être for this volume of P&TDigest, which seeks to promote awareness of dry eye andinnovative treatment strategies. The reality of medicalpractice in a managed care environment, however, is thattherapy must not only be effective, but cost efficient.Anti-inflammatory therapy carries prospects for favor-able pharmacoeconomics, in terms of reduced office vis-its and avoidance of complications, let alone enhanced

1 John D. Sheppard, MD, MMSc, received a Masters inMedical Science and his MD from Brown University on afull Armed Forces Health Professions Scholarship. He spentfour years with the U.S. Navy as 6th Fleet medical officerand chief of Family Practice. He completed his Ophthal-mology residency at the University of Pittsburgh Eye andEar Institute and a 30-month fellowship in corneal diseases,uveitis, third-world blindness, and ocular immunology atthe Proctor Research Foundation at the University ofCalifornia–San Francisco. In 1989, Sheppard joined Vir-ginia Eye Consultants and the ophthalmology, microbiology,and immunology faculty of Eastern Virginia Medical School,where he now serves as Ophthalmology program directorand as clinical director of the Thomas R. Lee Center for Ocu-lar Pharmacology. Sheppard has served as an associate ex-aminer for the American Board of Ophthalmology for sevenyears and is now a mentor examiner. He has participatedas principal investigator in more than 45 clinical researchtrials. Sheppard has authored more than 100 peer-reviewedabstracts, articles, and chapters. He received the AmericanAcademy of Ophthalmology Honor Award in 1995.

INTRODUCTION

John D. Sheppard, MD, MMSc

Keratoconjunctivitis sicca, or dry eye syn-drome, is a complex condition characterizedby inflammation of the ocular surface andtear-producing glands. Emerging awarenessof the etiology of dry eye has led to the de-velopment of highly effective therapy.Whendry eye is controlled, there is significant po-tential for cost savings.

SUMMARY

DRY EYE SYNDROME 7

INTRODUCTION

surface and lacrimal glands, neurotrophic deficiency,and meibomian gland dysfunction. Iatrogenic disease, inwhich topical prescription medications create hyper-sensitivity or toxicity in the eye and oral medications cre-ate lacrimal hyposecretion, also can induce symptoms ofdry eye.

Estimates of the prevalence of dry eye syndrome varywidely (see the following chapter, beginning on page 9),but as many as 40 million Americans may either havesymptoms of dry eye or remain at risk for it. Post-menopausal women may be the largest risk group, due todecreases in hormonal levels that can lead to loss of anti-inflammatory protection and decreased lacrimal function.Individuals with concomitant inflammatory conditions,particularly allergies, asthma, and collagen vascular dis-ease, are also at risk. Patients who have had eye surgerythat could compromise the neurogenic support of the

ocular-surface epithelium — LASIK, transplants, or olderextracapsular cataract procedures, for instance — couldhave moderate to severe dry eye, but this condition isfrequently unrecognized. This suggests at least some de-gree of undiagnosed disease that belies published esti-mates of prevalence; more importantly, these groups,taken together, make up a sizeable universe of dry eye can-didates, with an equally impressive price tag.

This impressive demographic emphasizes the impor-tance of early detection and effective treatment, not onlyfrom the perspective of function or comfort, but also interms of recognition of what may be a systemic diseasewith potentially devastating effects on the individual.Patients with dry eye are at direct risk for potentiallyblinding infections, including bacterial keratitis (Lemp1997), and they present with higher risks for routineprocedures, such as LASIK. Indirectly, dry eye can be amarker for secondary conditions. The cornea has morenociceptors or pain receptors per square millimeter thanany other place in the body, making it one of the mostpainful targets of diffuse autoimmune conditions. Theophthalmologist or primary care physician, then, mustbe attuned to the likelihood that a systemic disease is be-hind the patient’s complaints of dry eye.

Family physicians should always refer complaints ofdry eye to an ophthalmologist. Ocular problems areunique — unfamiliar to many other physicians, in partbecause the instrumentation is foreign to every other spe-

cialty — making it difficult to diagnose and treat ocularconditions adequately in a family physician’s office, clinic,or emergency room.

NEW TREATMENT, COST-SAVING POTENTIALBefore medical research transformed our under-

standing of dry eye, treatment had been limited to the useof artificial tears, ointments, and such nonpharmacologictherapies as punctal occlusion, environmental control,moisture-retaining eyewear, and surgery. Each had lim-ited effectiveness, and few produced lasting improve-ment in patients’ quality of life.

Today, dry eye can be treated successfully with anti-inflammatory agents, the most beneficial of which istopical cyclosporine. In four multicenter, randomized,controlled clinical studies of approximately 1,200 pa-tients with moderate to severe keratoconjunctivitis sicca,

cyclosporine ophthalmic emulsion (0.05 percent)demonstrated statistically significant increases inSchirmer wetting at 6 months (Allergan 2003). This is thefirst prescription product for dry eye targeting well be-yond palliative therapy, addressing the root inflammationof dry eye. Thus, demand for cyclosporine within this pa-tient population may well prove to be high.

If so, this product will get the attention of managedcare pharmacy directors and, one hopes, that of medicaldirectors as well. Managed care organizations are rou-tinely criticized for looking at expenditures in silo fash-ion, yet new systemic agents increasingly demonstrate amarked potential for offsetting nonpharmacy costs.When dry eye is controlled, there is significant potentialfor cost savings in a number of areas: complication costs,overutilization costs, opportunity costs, and intangibles.

Some complication costs are derived from sequelae ofuntreated dry eye and can be significant. For instance,bacterial keratitis, mentioned earlier, is costly and canlead to corneal transplantation — a $20,000 procedure.Other complication costs can result from elective surgery.There are 1.5 million laser procedures and another 1.5million cataract surgeries annually in the United States(Moretti 2000, Desai 2001), and dry eye is a potentialcomplication of both procedures.When surgical patientstake longer to heal and require more follow-up visits,there is added expenditure to the system.

Overutilization cost offsets represent another group

HUMAN FACTORS — QUALITY OF LIFE AND PATIENT SAFETY —

SHOULD MERIT CONSIDERATION WHEN DECISIONS ABOUT ACCESS

TO NEW MEDICATIONS ARE MADE.

must apply artificial tears several times each hour, withlittle lasting relief exacerbated by protracted blurred vi-sion. Health plans can improve the satisfaction of mil-lions of members who have moderate to severe dry eyedisease by imparting appropriate access to newer treat-ments. Further gains might also be achieved throughtasteful and intellectually sound marketing of newlyavailable technology to selected existing patients, physi-cians, and potential clients. Rightly, such publicity shouldbe limited through concerns regarding creation of ex-cessive unnecessary demand.

Safety is a primary ingredient in the success of out-comes-driven medical practice. With the knowledge thathas been obtained through study of the pathogenesis ofdry eye, our approach to treatment has changed accord-ingly; over the past few years, ophthalmologists havebegun to prescribe custom formulations of cyclosporinefor dry eye patients. While these formulations have beenreasonably efficacious in treating disease, they can beuncomfortable, difficult for patients to obtain, and — asoff-formulary compounds — expensive for patients(Wilson 2001). Moreover, these compounds inherentlypossess a more threatening side-effect profile than doproducts that have or will eventually receive approvalfrom the U.S. Food and Drug Administration.

We have learned that dry eye is a systemic disease andthat it responds well to cyclosporine anti-inflammatorytherapy. Agents coming to market and in developmenthave altered the paradigm of treatment radically. This isan exciting time for medical professionals and for pa-tients, who undoubtedly will clamor for access to thesetherapies. As new therapeutic options become available,an opportunity exists to create standards for their uti-lization that balances everyone’s interests while makingthem accessible to people who will benefit the most fromthem.

REFERENCESAllergan, Irvine, Calif. 2003. Restasis prescribing information.

Available at: «http://www.restasis.com/RestasisPI.pdf».Accessed March 27, 2003.

Desai M, Pratt LA, Lentzner H, Robinson KN. Trends in visionand hearing among older Americans. U.S. Centers for Dis-ease Control and Prevention, National Center for HealthStatistics. 2001:3. Available at:«http://www.cdc.gov/nchs/data/agingtrends/02vision.pdf».Accessed March 27, 2003.

Lemp MA, Chacko B. Diagnosis and treatment of tear deficien-cies. In: Tasman W, Jaeger E, eds. Duane’s Clinical Ophthal-mology. Philadelphia: Harper and Row. 1997.

Moretti M. U.S. laser vision correction market explodes. EyeWorld. 2000;12:29–31.

Stern ME, Beuerman RW, Fox RI, et al. The pathology of dry eye:the interaction between the ocular surface and lacrimalglands. Cornea. 1998;17(6):584–589.

Wilson SE. Dry Eye Disease: New Paradigm, New Treatment? Research to Prevent Blindness, New York. 2001.

8 P&T DIGEST

INTRODUCTION

of potential savings. Some of these are easily identified,such as decreased use of artificial tears or reduced office-visit utilization that stems from poor patient satisfactionand compromised lifestyle due to dry eye symptoms.Until very recently, practitioners have been able to offerpatients only palliative therapy; many of these individ-uals jump from physician to physician in search of relieffrom their progressively debilitating condition. In theirmodest way, these patients chronically and unnecessar-ily tax the health care system.

Other overutilization costs are more subtle. The morethan 3 million elective eye procedures each year in theUnited States often involve patients who are predisposedto dry eye; cataract patients, for instance, tend to beolder, while some LASIK patients dislike their contactlenses — often because their dry eyes make wearingcontacts irritating or unbearable. Some of these electiveprocedures can, in fact, be avoided altogether by con-trolling the dry eye.

Yet another group of potential savings is in opportu-nity costs outside the health care system. These includeindirect costs, such as loss of productivity attributed tomorbidity, and reduced comfort and convenience to pa-tients. Bacterial keratitis may result in permanent scar-ring.Without a corneal transplant, these patients can suf-fer loss of effectiveness relative to areas such as workperformance, night driving, caring for family members,or engaging in a favorite activity. The projections can playout in various ways — a prospective fiscal analysis of thisnature would hinge on the variables selected for study.Nevertheless, when opportunity costs are factored in, theoverall costs to the health care system and to society arelogarithmically accelerated.

Finally, intangibles include a satisfied patient popula-tion being offered a first-in-class drug therapy that rep-resents a new paradigm in dry eye treatment. Contentedpatient clients reflect well on any health care organiza-tion, creating goodwill, an open dialog, new patient re-ferrals, less confrontation, and more personable and ap-propriate access patterns.

NONECONOMIC CONSIDERATIONSOpportunity costs could never be reflected in a health

plan’s bottom line or in a P&T committee analysis. Yet,human factors — members’ quality of life, client satis-faction, and patient safety — merit consideration whendecisions about access to new medications are made.

Dry eye is the most prevalent chronic ocular surfacedisease. Ophthalmologists share the frustration experi-enced by patients for whom artificial tears and punctalocclusion are ineffective. These treatments also are in-convenient; in such environments as airplanes, dry cli-mates, or heated or air conditioned rooms, some patients

DRY EYE SYNDROME 9

OVERVIE W

Dry Eye: Prevalence, Utilization,and Economic ImplicationsMICHAEL D. DALZELL1

EPIDEMIOLOGYThe 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 eyeoften 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) re-ported 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 40and older found generally higher prevalence of dry eye in women (Figure 1).

Dry eye syndrome is believed to affect morethan 4 million Americans (Schein 1997).The nature of the condition, however,suggests that the universe of individuals

with untreated disease — whether the symptomsare ocular or otherwise in origin — may be larger.Dry eye is a common disorder, characterized by in-flammation of the ocular surface and lacrimalglands. Often, dry eye symptoms serve as a markerfor systemic illness.

This would suggest that health plans and practi-tioners that place an emphasis on detection andtreatment of dry eye syndrome — sometimes dis-missed as a trivial complaint — will benefit fromimproved clinical and financial outcomes. Beyondconsiderations of systemic illness, untreated dryeye itself can lead to corneal damage and visual im-pairment (Lemp 1987).

The next several pages provide a statistical snap-shot of dry eye syndrome: its prevalence, popula-tions at risk, potential complications, associatedconditions, the demands dry eye places on healthcare utilization, and the ramifications for payers.

OVERVIE W

FIGURE 1 Prevalence by age and sex

* As diagnosed by one or more tests.† Self-reported symptoms, not including subjects with hay fever.

SOURCE: MCCARTY 1998

1 Michael D. Dalzell is editor of P&T DIGEST and is man-aging editor of MANAGED CARE, a peer-reviewed journal.

4.15.9

2.5

6.0

12.6

4.76.3

3.2 4.4 3.92.5 2.4

10.0

13.6

6.94.7

31.8

20.0

31.3

6.3

FSex:

%

M

40–49

F M

50–59

F M

60–69

F M

70–79

F M

80–89

35

30

25

20

15

10

5

0

Age:

Clinical signs of dry eye (%)*

Symptoms of dry eye (%)†

10 P&T DIGEST

OVERVIE W

EPIDEMIOLOGY, continued

Explaining variability in prevalenceEpidemiological studies of dry eye syndrome in

the United States and other countries suggestwide differences in prevalence.The difficulty inpinpointing the extent of disease stems, in part,from a previous lack of understanding of the eti-

ology of dry eye. As such, definitions of dry eyesyndrome have differed from study to study, mak-ing results incomparable (Brewitt 2001).This iscomplicated by the lack of a standardized clinicaltesting protocol to diagnose the condition.

The effect of this diagnostic void is illustrated inFigure 3. In one study, four diagnostic tests yieldedwide differences in results among patients whocomplained of one or more severe dry eye symp-toms; the tests also varied greatly in their ability todiscriminate between signs and symptoms. Rela-tively few patients received diagnoses compatiblewith their symptoms.

Claims-based studiesClaims-based prevalence estimates provide a

different perspective from population-basedstudies. Claims studies measure the impact ofsymptoms that require medical attention — a perspective that is valuable to payers.

In one study of claims data in a managed careenvironment covering 12 million lives, researchersnoted a strong connection between dry eye andboth advancing age and sex (Figure 2). Femaleswere more likely to have a dry eye-related diagno-sis or procedure.Women experienced a sharp in-crease in prevalence earlier than men — aroundage 45, or roughly the onset of menopause.

Each of these diagnostic tests has limited useful-ness when performed alone, yet performing multipletests is rarely feasible or cost-effective. Pflugfelder(1998) has proposed an algorithm for determiningthe diagnostic utility of tests. Meanwhile, the emerg-ing recognition of dry eye as a multifactorial inflam-matory condition may lead to consensus on diagnos-tic testing, as well as a more thorough understandingof iatrogenic contributions to dry eye syndrome.

• Inflammatory disease (vascular, allergy, asthma)• Autoimmune diseases (RA, lupus, colitis)• Peri- and postmenopausal women and HRT patients• Diabetes mellitus• Thyroid disease• Sjögren’s syndrome• Corneal transplantation• Previous keratitis or corneal scarring

• Extracapsular or intracapsular large-incision cataractsurgery

• Laser in situ keratomileusis (LASIK)• Systemic medications (diuretics, antihistamines,

psychotropics, cholesterol-lowering agents• Contact lens wear• Environmental conditions (allergens, cigarette smoke,

wind, dry climate, air travel, chemicals, some perfumes)

HIGH-RISK POPULATIONS FOR DRY EYE SYNDROME

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

Female Male Age <65 Age ≥65

689.6567.7

273.0 221.8

385.9319.6

1653.4

1427.8

1997

1998

FIGURE 2 Rates of diagnoses and procedures, by age and sex

Rate per 100,000

SOURCE:YAZDANI 2001

Figures are rounded to nearest whole percentage point.SOURCE: MCCARTY 1998

Fluorescein Rose bengal Schirmer Tear-film breakup

33

9

20

8

129

18

9

Abnormal (diagnosis)

Normal (no diagnosis)

FIGURE 3 Test used to detect clinical signsPercentages are of patients reporting ≥1 severe symptom

Test result (%)

DRY EYE SYNDROME 11

OVERVIE W

Low patient satisfaction has been documentedamong individuals with moderate to severe dry eyesyndrome (Lubniewski 1990).The chronic symptoma-tology of dry eye, as well as relatively ineffective tra-ditionally available treatment modalities, spawnsfrustration and high health-resource utilizationamong patients seeking relief from the condition.

Office visitsIn the Schein (1997) study, 73 percent of subjects

who reported frequent dry eye symptoms visited aneye care professional in the past year. A smaller sur-vey, conducted among patients participating inphase 2 trials of a cyclosporine A topical preparationfor dry eye syndrome, found that 60 percent of dryeye patients visited a physician more than twice inthe past year for their symptoms (Nelson 2000).

Forty-two percent of these patients had undergonepunctal occlusion at least once in the past.

Surveys of subpopulations have identified higheroffice utilization and frequent visits; Hirsch (1998), forinstance, reported that 89 percent of Sjögren’s dryeye patients visited an ophthalmologist an averageof 3.1 times per year for their symptoms, and morethan one fourth of all subjects had visited otherphysicians at least once in the past year for their con-dition.

Pharmaceutical interventionsA recent study of resource utilization among non-

Sjögren’s dry eye patients found high utilization ofmedical therapies — among products specificallydesigned to treat dry eye symptoms as well as otherdrugs (Figures 4 and 5).

Future trendsWith 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 tearsubstitutes and other pharmaceutical therapies. Studies that document this potential are reported in the chap-ter on pharmacoeconomics that begins on page 33.

UTILIZATION TRENDS

61%

13% 16%

60%

Lubricant ointments

Used at all Used regularly or always Not used

40%44%

Lubricant drops

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

FIGURE 4 Medications used by dry eye patientsIn the past 3 months

Any additional medications

Anti-inflammatory agents

Antibiotics

Analgesics 12.8%

5.7%

5.7%

27.0%

SOURCE: NELSON 2000

Used at all:87%

Used at all:56%

Used at all:40%

(subset of “used at all”)

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OVERVIE W

ECONOMIC IMPLICATIONS

Relatively few data exist on direct and indirectcosts of dry eye and its sequelae. Likely, this is due tothe fact that until recently, when the etiology of thiscommon disease became more fully understood, dryeye was viewed largely as an irritant and not neces-sarily a serious condition worthy of medical atten-tion. Nelson (2000) challenged this view from an eco-nomic standpoint, arguing that older treatmentmodalities can lead to unacceptable costs and pro-gressive use of health care resources. Emerging sci-entific knowledge about dry eye may prompt payersor the government to conduct comprehensive dataanalyses of the economic impact of dry eye.

Direct medical costs and complicationsSmall-scale models have been developed to esti-

mate the cost of office visits, drugs, and proceduresattributed specifically to dry eye. In one study, thecost of managing and treating dry eye patients withpalliative medications, punctal plugs, and surgery,over the course of 1 year, was $357,050 for an organi-zation covering 500,000 lives (Lee 2000).The authorsspeculated that a more effective dry eye interven-tion could improve cost effectiveness by decreasingpatient demand for physician visits and procedures.

The multifactorial nature of dry eye makes a fullaccounting of direct medical costs complex. Becausedry eye can be a marker for systemic illnesses, costsof treating dry eye symptoms are often figuredunder other diagnoses. Moss (2000) used a logisticmodel to calculate factors associated with dry eye,including arthritis and diabetes.This research alsodiscovered a protective effect in total-to-HDL (high-density lipoprotein) cholesterol ratio (Figure 6).

FIGURE 6 Prevalence of comorbidities*

Dry eye is a direct complication of large-incisioncataract procedures, corneal transplantation, andLASIK. Moss reported a 1.39 odds ratio in patientswho had undergone any sort of lens surgery, whileBreil (2002) found that dry eye is one of the mostcommon postoperative complications of LASIK.

Indirect costsDry eye syndrome has the potential to reduce

employee productivity significantly. In one study,dry eye patients experienced an average of 184 workdays of reduced productivity, at an estimated annualcost of $5,362 per individual (Kozma 2000).

Another study — this of a subset of dry eye pa-tients, those with Sjögren’s syndrome — indicatedthat symptoms interfered with the activities of daily living in all but 29 days of the year (Figure 8).

FIGURE 8 Interference with activitiesDays per year among Sjögren’s patients

-to-HDL cholesterol ratio†

Diabetes

History of thyroid disease

History of gout

Arthritis 1.91

1.42

1.41

1.38

0.93

Caffeine

History of heavy alcohol use

Multivitamin use

Current smoker 1.82

1.41

1.31

0.75

* Adjusted for age and sex. 95-percent confidence interval.† Per increment of 1 unit.

SOURCE: MOSS 2000

SOURCE: HIRSCH 1998

2 An odds ratio is calculated by dividing the odds in thetreated group by the odds in the control group. Factorsthat cause harm have an odds ratio >1.0. An odds ratioof 2.0 represents a 100-percent increased risk.

* Adjusted for age and sex. 95-percent confidence interval.

SOURCE: MOSS 2000

Days lost from work: 5

Days worked with symptoms: 208

Leisure days with symptom interference: 123

No reported effects: 29

Moss also examined lifestyle factors, finding a sur-prise protective effect of caffeine and a contributingfactor in multivitamin use (Figure 7).This researchalso identified an opportunity for physicians tocounsel patients who smoke or drink heavily.

FIGURE 7 Lifestyle factors*

Total-to-HDL cholesterol ratio†

Odds ratio2Condition

Odds ratio2Behavior

Dry eye syndrome is far more prevalent than previ-ously considered.There are significant comorbidities,associated diseases, and behavioral and environ-mental factors that may contribute to the severity ofdry eye. Dry eye syndrome has significant economicimplications, including costs associated with in-creased health care utilization, missed school andwork, and leisure and quality-of-life issues. Dry eyepresents important economic challenges to patients,physicians, and health care delivery organizations.

REFERENCESAAO (American Academy of Ophthalmology). Preferred Prac-

tice Pattern: Dry Eye Syndrome. San Francisco: AAO, 2003.Breil P, Frisch L, Dick HB. Diagnosis and therapy of LASIK-

induced neurotrophic epitheliopathy. Ophthalmologe.2002;99:53–57.

Brewitt H, Sistani F. Dry eye disease: the scale of the problem.Surv Ophthalmol. 2001;45(suppl2):S199–S202.

Hirsch JD, Kozma CM,Wojcik AR, Reis B. Economic and qualityof life impact of dry eye symptoms: a Sjögren’s patientsurvey. Invest Ophthalmol Vis Sci. 1998;39:S65. Abstract.

Kozma CM, Hirsch JD,Wojcik AR. Economic and quality of lifeimpact of dry eye symptoms. Poster presented at the Annual Meeting of the Association for Research in Visionand Ophthalmology, April 30–May 5, 2000, Ft. Lauderdale,Fla.

Lee JT,Teale CW. Development of an economic model to as-sess costs and outcomes associated with dry eye disease.Poster presented at the 2000 Spring Practice and Re-search Forum of the American College of Clinical Phar-macy, April 2–5, 2000, Monterey, Calif.

Lemp MA. Recent developments in dry eye management.Ophthalmology. 1987;94:1299–1304.

Lubniewski AJ, Nelson JD. Diagnosis and management of dryeye and ocular surface disorders. Ophthalmol Clin NorthAm. 1990;3:575–594.

McCarty CA, Bansal AK, Livingston PM, et al.The epidemiologyof dry eye in Melbourne, Australia. Ophthalmology.1998;105:1114–1119.

McCarty DJ, McCarty CA. Survey of dry eye symptoms in Aus-tralian pilots. Clin Experiment Ophthalmol.2000;28:169–171.

Moss SE, Klein R, Klein BE. Prevalence and risk factors for dryeye syndrome. Arch Ophthalmol. 2000;118:1264–1268.

Nelson JD, Helms H, Fiscella R, Southwell Y, Hirsch JD. A newlook at dry eye disease and its treatment. Adv Ther.2000;17:84–93.

Pflugfelder SC,Tseng SC, Sanabria O, et al. Evaluation of subjec-tive assessments and objective diagnostic tests for diag-nosing tear-film disorders known to cause ocular irrita-tion. Cornea. 1998;17:38–56.

Schaumberg DA, Buring JE, Sullivan DA, Dana MR. Hormone re-placement therapy and dry eye syndrome. JAMA.2001;286:2114–2119.

Schein OD, Munoz B,Tielsch JM, et al. Prevalence of dry eyeamong the elderly. Am J Ophthalmol. 1997;124:723–728.

Yazdani C, McLaughlin T, Smeeding JE,Walt JG. Prevalence oftreated dry eye disease in a managed care population.Clin Ther. 2001;23:1672–1682.

DRY EYE SYNDROME 13

OVERVIE W

SUMMARY

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ETIOLOGY ETIOLOGY

damaged, or killed by acti-vated T-cell lymphocytes.

A variety of factors canexacerbate KCS (Table 2).New evidence has shownthat regardless of the pre-disposing factor(s), mostKCS results from a localizedimmune-mediated inflam-mation affecting both thelacrimal glands and the oc-ular surface (Stern 2002).

Historically, KCS hasbeen frustrating to studyand treat, in part due to itsdiverse symptoms and dis-ease variables. The heterogeneity of dry eye creates chal-lenges in the diagnosis and treatment of individual cases.The high degree of variability in patient populationsmakes data analysis extremely difficult. Thus, the abilityto postulate and prove a unifying etiology has been hin-dered by the multifactorial nature of KCS and the clini-cal conundrum of matching patients’ symptoms and di-agnostic test results with patients’ actual disease severity.

Inflammation: A Unifying TheoryFor the Origin of Dry Eye SyndromeSTEVEN E. WILSON, MD1

Cole Eye Institute, Cleveland Clinic Foundation

Keratoconjunctivitis sicca (KCS), or dry eye syn-drome, is a common ophthalmologic abnor-mality involving bilateral disruption of the precorneal tear film. It is caused either by in-

adequate tears or an inability to maintain an effective tearfilm. In KCS, the tear film is disrupted, causing a varietyof symptoms (Table 1). Dry eye syndrome can occur inany age group, but is especially prevalent in people overage 65. It estimated that 10 to 15 percent of Americansin this age group have one or more symptoms of this dis-ease (Schein 1997). In serious cases, dry eye syndromecan lead to photophobia and vision loss.

It is evident from its name that KCS is a drying in-flammation: kerato (corneal) conjunctivitis (conjuncti-val inflammation) sicca (from the Latin sicco, meaning “todry”). KCS can occur sporadically or as a chronic condi-tion that becomes a self-perpetuating syndrome. This ar-ticle will explore current trends in KCS etiology research.

Destruction of corneal and bulbar conjunctival epi-thelium from KCS can arise from many diverse causes(AAO 1998); it is often secondary to Sjögren’s syndrome,an autoimmune disease that results in dry eyes andmouth. Sjögren’s syndrome can occur with or withoutrheumatoid arthritis, lupus, or scleroderma. In Sjögren’sKCS, the exocrine glands secreting tears, saliva, and gas-tric excretions are inadequate. KCS — either Sjögren’s ornon-Sjögren’s — is now believed to be an autoimmunestate in which the epithelial cells of the lacrimal glands aredetected as antigens by the immune system and attacked,

Dry eye syndrome has been difficult to diag-nose and treat, due to its heterogeneity.These difficulties are being overcome, how-ever, as evidence becomes available about acommon etiology. An inflammatory mecha-nism apparently underlies the condition.This theory has been proven by use ofimmunomodulators that show efficacy intreating patients with dry eye syndrome.

SUMMARY

1 Steven E. Wilson, MD, is director of corneal research atthe Cole Eye Institute of the Cleveland Clinic Foundation.A board-certified ophthalmologist, Wilson recently cameto Cleveland from the University of Washington in Seattle,where he directed an NEI-supported laboratory that in-vestigates the function of growth factors and cytokines in controlling corneal wound healing. He has authoredmore than 300 papers, abstracts, and book chapters. Afterearning his medical degree from the University ofCalifornia–San Diego, Wilson completed an ophthalmol-ogy residency at the Mayo Clinic and a fellowship incornea, external disease, and refractive surgery at theLouisiana State University Eye Center in New Orleans.Wilson, who holds memberships in numerous professionalsocieties, serves on the board of trustees of the Associationof Research in Vision and Ophthalmology and on the ex-ecutive board of the ISRS-RSIG for the American Academyof Ophthalmology.

Steven E.Wilson, MD

ETIOLOGY

DRY EYE SYNDROME 15

A COMMON UNDERLYING ETIOLOGYThe pathophysiology of KCS has long been known to

involve a disruption of the layer of tears that protects andnourishes the delicate eye tissues. The goal of therapy hasbeen to normalize tear volume and composition, so thatthe eye tissues are properly lubricated, nourished, andprotected. This has been accomplished to some extent byincreasing tear secretion, reducing tear turnover, and/orpromoting epithelial healing on the ocular surface usinglubricants and emollients. If the KCS results from a sys-temic disorder, the systemic disease can be treated and thesymptoms thereby decreased.

Local treatment strategies for the eye (aside from treat-ing infections) have been essentially palliative, however,and do not address the inflammatory response. The treat-ment goal of this new approach to disease is to suppressthe inflammation that underlies symptoms and signs.

The recent discovery of a neurological-inflammatorycomponent has provided an explanation for the patho-physiology of KCS. If inflammation in KCS is considerednot a symptom but a cause, then suppressing thecytokine-mediated inflammatory response that occurs ata histological level can be applied to KCS regardless ofdisease-state association. An emerging strategy for treat-ment of KCS is therapy with immuno-modulators that address the local in-flammation caused by cytokines thatcirculate in the lacrimal glands and con-junctiva, regardless of whether any asso-ciated disease state is local or systemic.

According to this new theory of KCSetiology, a cyclical syndrome causes thelacrimal glands to suffer from neurogenicinflammation, T-cell activation, and cy-tokine secretion into tears. The cytokine-laden tears inflame the ocular surface, dis-rupting sensory signals from the surface ofthe eye, so the normal stimulus for tear se-cretion is curtailed. In addition, thelacrimal glands, both primary and sec-ondary, may be damaged or destroyed.This leads to a virtual shutdown of thelacrimal system and to a self-perpetuatinginflammation that cannot be amelioratedby the eye’s normal defense system. Theimmune system itself is the problem(Figure 1, page 16). This localized inflam-mation cycle can be demonstrated in bothSjögren’s and non-Sjögren’s patients.

The normal lacrimal systemNormally, the integrity of the lacrimal

system is maintained by a precise interplay

of secretions from primary and secondary glands lo-cated under the eyelids and from sebaceous glands on theflat rims of the eyelids that secrete an antievaporationlipid layer (Figure 2, page 16).

The tear drainage system is also important in normal-izing hydration of the eye. Inflammation-induced dys-function in this drainage system can precipitate KCS. Thesystem includes the punctal opening (the tiny hole in theupper and lower eyelids). Blinking causes tears to enter thepunctae, where they are drained through canaliculi intothe lacrimal sac and the nasolacrimal duct into the nose.

Part of the function of tears is to protect the eye frommicrobial invasion. In a normally functioning adult eye,an anti-inflammatory component keeps the disruptiveeffect of irritation to a minimum. When this componentis lacking, however, or when irritation is not controlled,the body’s immune system activates its inflammatory T-lymphocytes.

Cytokines are hormone-like proteins that regulate theimmune response. They also damage tissue when over-abundant (Table 3, page 17). Cytokines and other proin-flammatory mediators lead to activation of more T-cells,production of more inflammatory substances, and tissuedamage.

TABLE 1 Symptoms of keratoconjunctivitis sicca

Dry sensation Foreign body or “gritty”sensationDry sensation Blurred visionIrritation/redness Contact lens intoleranceRedness Increased frequency of blinkingTearing Mucous dischargeBurning/stinging SOURCE: PFLUGFELDER 2000a

TABLE 2 Variables in keratoconjunctivitis sicca

Precipitating factorsMedication (e.g., anticholinergics)Environmental conditions (e.g., wind)Trauma (e.g., chemical burns) or corneal dystrophiesReading for lengthy periods (especially from a computer screen)

Severity potentialAnnoyance onlyAcute increase in severity (e.g., photophobia and blepharospasm)Loss of normal configuration of conjunctival fornicesUlceration, vascularization, and scarring of corneaSevere visual disability

DurationSporadic, reversibleChronic nonreversible deficiency of tear production

• Waxing or waning• Constant condition SOURCE: STERN 2002

16 P&T DIGEST

ETIOLOGY

Ordinarily, when any kind of an invasion or disrup-tion is detected, more tears are produced to flush out theentire lacrimal system. In autoimmune diseases, however,the inflammatory response in the eye can attack healthyepithelial cells with enzymes that are meant to lyse inva-ders, damaging the matrix of tears and the conjunctiva.

Evidence from canine research shows that the originof KCS is associated with lymphocytic infiltrations inboth the conjunctiva and the lacrimal glands. Biopsies

from dogs with dry eye syndromedemonstrate such lymphocytes (Fig-ure 3). Total T-cells that are abnor-mally increased in dry eye syndromecan be seen by fluorescing T-cells inthe conjunctiva of Sjögren’s and non-Sjögren’s patients.

The main and accessory lacrimalglands may be susceptible to inflam-mation due to an age- and hormone-related degenerative process. Thechange in tear secretions leads to thepathophysiology described above as aneurological inflammatory diseasethat becomes a constant cycle (Figure4, page 18). As sensory input to thelacrimal glands decreases, the quan-tity and quality of tears is reduced,causing further irritation of the ocu-lar surface.

Cyclosporine as an anti-inflammatory agent in dry eye

Marsh (1999) showed that corti-costeroids could be used for treatingsevere dry eye in humans. Never-theless, use of corticosteroids waslimited by the known side effects ofcataract formation, glaucoma, andinfection. Cyclosporine A (CsA) wastested and found efficacious by oph-thalmologists experimenting with itin severe, treatment-resistant KCS pa-tients. Now, it is available as a topicalanti-inflammatory for dry eye syn-drome, formulated at doses thou-sands of times smaller than thoseused to avoid graft-versus-host dis-ease in tissue transplantation.

Cyclosporine is an immunomodu-lator that primarily is used systemi-cally in transplant, psoriasis, andrheumatoid arthritis patients. Thisagent’s anti-inflammatory effects arise

primarily from its ability to prevent the activation of T-cells and resulting production of cytokines and other in-flammatory agents. Until recently, there was no commer-cially available preparation of CsA for topical use in theeye. The preparation had to be custom formulated in ir-ritating oils by pharmacists for ophthalmologists. Despitethe fact that this use of CsA had not been systematicallytested in humans, many ophthalmologists reported goodresults with few complications other than stinging.

FIGURE 1 Dry eye: an immune-mediated inflammatory disorder

Interrupted secretometernerve impulses

Cytokinesdisrupt neural arc

Lacrimal glands:• Neurogenic

inflammation• T-cell activation• Cytokine

secretioninto tears Tears inflame ocular surface

FIGURE 2 The three major components of normal tear film

Soluble proteins

Soluble mucins

Membrane mucins

Epithelium

Layer

Anterior

Middle

Posterior(adjacent toepithelium)

Function

Lipid layer, which acts as vapor barrier

Aqueous electrolytes and proteins that consti-tute 98 percent of the total tear film.This layercontains nutrients, enzymes, cytokines, and antimicrobials.

Heavily glycosylated proteins, mucins• Immunoglobulins• Antimicrobial proteins• Growth factors (e.g., transforming growth

factor-alpha or epidermal growth factor)

Origin

Meibomian glands

Lacrimal glands

Goblet cells in con-junctiva and cornealand conjunctival epithelial cells

SOURCE: PFLUGFELDER 2000b

Lipid layer

Aqueous/mucin gel

ETIOLOGY

DRY EYE SYNDROME 17

CsA was approved in the UnitedStates in 1995 to treat chronic dryeye disease in dogs. Now that CsAhas been tested in humans at adose of 0.05 percent in a specialvehicle, it can be used to increasetear production in patients whoseproduction levels are presumed tobe suppressed due to ocular in-flammation associated with KCS.

The effect of CsA ophthalmicemulsion on inflammation arisesfrom its ability to inhibit activa-tion of T-cells by blocking theirintracellular signal transductioncascade responsible for upregula-tion of NF-AT and NF-kB regu-lated genes, including genes formany cytokines (Table 4).

Phase 2 and 3 clinical studies of cyclosporine for KCS

A phase 2 study of CsA among162 patients was undertakenusing doses ranging from 0.05percent to 0.40 percent twice aday. The results determined thatdoses of 0.05 percent to 0.10 per-cent were effective and well toler-ated (Stevenson 2000).

At the small doses used in thephase 3 study, there was no evi-dence of the increased risk of in-fections and tumors observedwith large doses of cyclosporineused for transplantation.With thefractional dose used for KCS(2,500 times smaller), there wereno ocular infections related toCsA, nor was the drug detectedin the blood of patients who wereadministered a 0.05 percent dose.

The 1-year results of phase 3study of CsA (both Sjögren’s andnon-Sjögren’s) are briefly de-scribed in Tables 5–7 on page 19,and then in more detail in thechapter “Medications for Dry EyeSyndrome: A Drug-TherapyReview,”which begins on page 26.Use of cyclosporine resulted in both clinical improve-ments and a decrease in markers of immunity and in-flammation in conjunctival biopsies. This improvement

was evident especially during the first arm of the study(Sall 2000).

The efficacy of the vehicle used for a comparison in the

TABLE 3 The role of cytokines and T-cells in adaptive immunity

Immunomodulator Description and function

These are proteins released by various types of cellsincluding lymphocytes and corneal epithelial cells.Cytokines regulate the process of T-cell prolifera-tion and differentiation, and serve an antiviral andanti-tumor function in the immune system.Theypromote allergic reactions, boost T-cell functions,and thus are used to evaluate immune activity.

These are lymphocytes with antigen-receptorcomplexes on their surfaces.They are produced bythe thymus and have the ability to lyse foreign orvirus-infected cells.They reside primarily in thelymphatic system and secrete hormone-like pep-tides that mediate the immune response; they alsoregulate erythroid cell maturation in bone marrow.

These are a subset of leukocytes involved in signal transduction in the cell membrane.

Cytokines(Examples:interferon,interleukin,lymphokines)

T-cells

CD3 cells

TABLE 4 Anti-inflammatory activity of cyclosporine A

• Binds to an intracellular protein• Inhibits an activation enzyme (calcineurin)• Inhibits expression of numerous genes essential for T-cell activation

and proliferation• Prevents replication of T-cells by blocking a transcription factor• Keeps T-cells from expressing some cytokines or “homing”to

inflammation site• Promotes a gene (transforming growth factor) that inhibits the

inflammatory response

FIGURE 3 Evidence of inflammation in dry eye syndrome

Lacrimal gland

T- cell infiltrations(Dark-stained cells; canine biopsy)

Conjunctiva

SOURCE: STERN 1998

lymphocyte cell marker CD3 inSjögren’s and non-Sjögren’s dryeye patients showed a reductionin T-lymphocyte infiltrationafter treatment with CsA.Comparing baseline stains withthose after 6 months of CsAtreatment, there was a 3- to 5-fold decrease in the number ofCD3-positive cells in the con-junctiva of Sjögren’s and non-Sjögren’s patients. These similarresults in Sjögren’s and non-Sjögren’s patients are consistentwith a similar pathophysiologyfor both conditions (Figure 5).

Disruption of the tear filmoverlying the cornea generatesvariable irregular astigmatism.This results in blurred vision,an important efficacy measureof treatment. Blurred vision andreliance on artificial tears wereincluded as endpoints in thephase 3 study (Table 7).

Patients in all groups were al-lowed to instill preservative-freeartificial tears between doses ofstudy medication throughoutthe trial. Reduced utilization ofartificial tears was a gauge ofsymptom relief.

It should be noted that inclinical studies, CsA did not in-crease tear production in pa-tients already taking topicalanti-inflammatory drugs. Thisevidence served to confirm theunifying hypothesis of inflam-mation as the etiology of dryeye syndrome.

Although the anti-inflammatory theory has been cor-roborated by clinical efficacy of CsA in KCS, the dry eyeinduced by LASIK surgery is not expected to be eligiblefor anti-inflammatory treatment, as it has a differentneurotrophic origin. LASIK patients who had preexist-ing dry eye may, however, benefit from CsA treatment.

CONCLUSIONTraditionally, KCS was difficult to diagnose and treat,

due to its heterogeneity. An inflammatory mechanismapparently underlies the condition. This unifying theoryhas been proven by use of imunomodulators that showed

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ETIOLOGY

phase 3 study unexpectedly proved to be palliative forsymptoms in and of itself, and it was later developed asa separate artificial tear product. This was apparently aresult of the emulsion that contained both aqueous andoil components, thus maintaining the multilayer tearfilm rather than comprising an aqueous solution alone.It was partially due to the positive effect of the emulsionvehicle itself that the second arm of the CsA studyshowed less dramatic results than the first. Also, the sec-ond 6-month extension of the phase 3 study included pa-tients with less severe disease.

Staining of conjunctival tissue for immune T-

1. When the ocular surface andlacrimal glands are chronically irritated,T-cells become acti-vated.

2. These activated T-cells recruit additional T-cells and cause an immune-based local inflamma-tion.

3. Cytokines are released in tears;this further irritates the ocularsurface and blocks messages tothe lacrimal gland.

4. As a result, normal tear secretionis reduced, and chronic dry eyesyndrome symptoms develop.

SOURCE: STERN 1998

SOURCE: KUNERT 2000

FIGURE 4 Steps in the cycle of inflammation in KCS

FIGURE 5 Decreased inflammation in Sjögren’s and non-Sjögren’s patients

Chronicirritation

Inflammation

Immuneactivation

Symptoms develop

CD3-stained T-lymphocytes in conjunctival biopsies

Sjögren’s Non-Sjögren’s

3965cells/mm2

2291cells/mm2

819cells/mm2

Baseline

CsA 0.05%6 months

762cells/mm2

ETIOLOGY

DRY EYE SYNDROME 19

efficacy in treating patients with KCS. Thetopical CsA phase 2 and phase 3 studiesprovided evidence of inflammation re-duction after treatment. These findingswere accompanied by subjective and ob-jective symptom improvements.

Difficulties in studying and treating thisdisease are being overcome as more evi-dence becomes available about a commonetiology. For patients, this will mean less ir-ritation and inflammation. It also shouldtranslate to a reduced reliance on artificialtears and ointments and fewer office visits.

REFERENCESAAO (American Academy of Ophthalmology).

Preferred Practice Pattern: Dry EyeSyndrome. San Francisco: AAO, 1998.

Kunert KS, Tisdale AS, Stern ME, et al. Analysisof topical cyclosporine treatment of pa-tients with dry eye syndrome: effect onconjunctival lymphocytes. ArchOphthalmol. 2000;18:1489–1496.

Marsh P, Pflugfelder SC. Topical nonpreservedmethylprednisolone therapy for kerato-conjunctivitis sicca in Sjögren’s syndrome.Ophthalmology. 1999;106:811–816.

Pflugfelder SC, Solomon A, Stern ME. The diag-nosis and management of dry eye: a 25-year review. Cornea. 2000a;19:644–649.

Pflugfelder SC, Liu Z, Monroy D, et al. Detectionof sialomucin complex (MUC4) in humanocular surface epithelium and tear fluid.Invest Ophthalmol Vis Sci. 2000b;41:1316–1326.

Sall K, Stevenson OD, Mundorf TK, Reis BL andthe CsA phase 3 study group. Two multi-center, randomized studies of the efficacyand safety of cyclosporine ophthalmicemulsion in moderate to severe dry eye dis-ease. Ophthalmology. 2000;107:631–639.

Schein OD, Tielsch JM, Munoz B, et al. Relationbetween signs and symptoms of dry eye inthe elderly: a population-based perspective.Ophthalmology. 1997;104:1395–1401.

Stern ME, Beuerman RW, Fox RI, et al. Thepathology of dry eye: the interaction be-tween the ocular surface and lacrimalglands. Cornea. 1998;17:584–589.

Stern ME, Gao J, Schwalb TA, et al. ConjunctivalT-cell subpopulations in Sjögren’s and non-Sjögren’s patients with dry eye. InvestOphthalmol Vis Sci. 2002;43:2609–2614.

Stevenson D, Tauber J, Reis BL. Efficacy andsafety of cyclosporine A ophthalmic emul-sion in the treatment of moderate to severedry eye disease: a dose-ranging, random-ized trial. The Cyclosporine A Phase 2Study Group. Ophthalmology.2000;107:967–974.

TABLE 5 Phase 3 study

Subjects 235 subjects with KCS (moderate to severe, with orwithout Sjögren’s syndrome),

Design Multicenter, double-blind, randomized parallel trialthat lasted for 6 months with most patients remainingthrough another treatment period of 6 months (total: 1year)

Doses • Cyclosporine 0.05 percent twice daily• Cyclosporine 0.10 percent twice daily• Vehicle alone twice daily

Results Significant benefit found in both Sjögren’s and non-Sjögren’s patients relative to:• Signs and symptoms• Objective measures of tear system and eye function• Safety

Not all arms equally successful;variability in• Signs/symptoms • No correlation between signs and symptoms• Variations in severity in second arm of study

TABLE 6 Summary of objective primary efficacy results

A total of 59 percent of CsA users achieved a 1–10 mm or more im-provement in tear production from baseline in Schirmer scores at 6 months (n=238). Of these, 44 percent had a 1–9 mm increase and15 percent had ≥10 mm increase (all patients had ≤5 mm prior totreatment).

With CsA 0.05 percent emulsion, patients showed statistically andclinically significant mean reductions of more than 30 percent vs.baseline in corneal staining at all time points.

TABLE 7 Summary of subjective efficacy results

Endpoints Results

• Blurred vision 0.05 percent cyclosporine-treated patients exhibited statistically and clinically significant reductions.

• Artificial tear Overall use of artificial tears fell by a third reliance at month 6.

• Increase in Mucopolysaccharide secretory cells in the the number epithelium increased by 191 percent in the of goblet cells treated group vs. 13 percent in the vehicle-

treated controls (p=.013).

SOURCE FOR TABLES 5–7:SALL 2000

20 P&T DIGEST

or set of tests to confirm or rule out dry eye definitivelyhave limited the comparability of epidemiological data forthis condition.

One clinic-based study found that 17 percent of 2,127consecutive new outpatients were diagnosed with dry eyefollowing a comprehensive examination (Hikichi 1995).In a population-based study in Australia, 16.3 percentand 10.8 percent of 926 participants, ages 40 to 97, testedpositively for dry eye, based on a low Schirmer test or ahigh rose bengal score, respectively (McCarty 1998). Anevaluation of claims data for nearly 10 million enrolleesin managed care plans found that dry eye was diagnosedor treated in 0.5 percent of enrollees (Yazdani 2001).

Risk factors for dry eye include advanced age and fe-male gender (McCarty 1998, Moss 2000, Yazdani 2001),arthritis (McCarty 1998, Moss 2000), smoking, multi-vitamin use (Moss 2000), and hormone replacementtherapy (Schaumberg 2001).

Pathogenesis of dry eyeThe ocular surface and tear-secreting glands function

as an integrated unit to refresh the tear supply and to clearused tears (Stern 1998). Disease or dysfunction of thisunit results in ocular irritation and dry eye syndrome.Decreased tear secretion and clearance initiate an in-flammatory response on the ocular surface, and researchsuggests that this inflammation plays a role in the patho-genesis of dry eye (Pflugfelder 2000).

Dysfunction may develop from aging, a decrease insupportive factors (such as androgen hormones), sys-temic inflammatory diseases (such as rheumatoid arthri-tis), ocular surface diseases (e.g., herpes zoster ophthal-micus), surgery that disrupts the trigeminal afferentsensory nerves (including laser in situ keratomileusis[LASIK], extracapsular cataract extraction, or penetrat-ing keratoplasty), and systemic diseases or medicationsthat disrupt the efferent cholinergic nerves that stimu-late tear secretion (Bacman 2001).

Associated conditionsSymptoms caused by dry eye may be exacerbated by sys-

temic medications such as diuretics, antihistamines, anti-

Guidelines for the Treatment Of Chronic Dry Eye DiseaseJOHN D. SHEPPARD, MD, MMSC

Chronic dry eye disease (CDED) is highly het-erogeneous, and patients present in many dif-ferent ways. For example, patients with severesymptoms may reveal minimal signs upon ex-

amination, while patients with a multitude of seeminglysignificant findings at the slit lamp may have few com-plaints. The American Academy of Ophthalmology’snewly released guidelines for diagnosis, treatment, andmanagement reflect a universal acceptance by cliniciansof dry eye — alone or in combination with other condi-tions — as an inflammatory ocular surface disorder thatcan be a cause of visual morbidity and may compromisethe results of corneal surgery, cataract surgery, or otherocular surface procedures. Dry eye symptoms often im-prove with treatment, but the disease usually is not cur-able. Many of the ocular surface changes associated withKCS can be reversed with specific treatment.

To preserve or improve vision, prevent or minimizestructural damage to the ocular surface, and alleviate pa-tient discomfort, clinicians must be aggressive both in di-agnosing possible underlying systemic inflammatory dis-ease and in making ocular surface anti-inflammatorytherapy a key component of their treatment approach. En-vironmental control, as well as a careful evaluation of sys-temic medications, also may yield clinical improvement.

Epidemiology of dry eyeThe heterogeneity of dry eye, the lack of uniformity in

its definition, and the inability of any single diagnostic test

D E T E C T I O N A N D T R E AT M E N T

Keratoconjunctivitis sicca (KCS), also known asdry eye syndrome,dry eye disease,chronicdry eye disease,or keratitis sicca, refers to dis-orders of the tear film caused by reduced tearproduction, poor tear quality,or excessive tearevaporation.These disorders are associatedwith such symptoms of ocular discomfort asirritation, foreign body sensation, or redness,and may cause disease of the ocular surface.

SUMMARY


DRY EYE SYNDROME 21

cholinergics, antidepressants, HMG co-A reductase in-hibitors, systemic retinoids, and isotretinoin (Moss 2000).Dry eye also may be made worse by environmental factors,including exogenous irritants and allergens, wind, drafts,air conditioning, heating, and reduced humidity.

In a study of Maryland residents age 65 or older, sub-jects with blepharitis associated with meibomitis weretwice as likely to have dry eye symptoms as those with-out signs of meibomitis (Schein 1997).

Systemic diseases associated with dry eye include Sjö-gren’s syndrome, rosacea, viral infections such as ac-quired immune deficiency syndrome (Lucca 1990), hepa-titis C (Abe 1999, Siagris 2002), primary and persistentEpstein-Barr virus infections (Pflugfelder 1987, Merayo-Lloves 2001, Pflugfelder 1993), and graft-versus-hostdisease in recipients of allogenic bone marrow or stemcell transplants (Ogawa 1999).

In Sjögren’s syndrome, an inflammatory cellular in-filtration of the lacrimal gland leads to deficient tearproduction. Rosacea is associated with posterior ble-pharitis, poor tear quality, accelerated tear film breakuptime (TBUT), and increased tear evaporation. Aqueoustear deficiency may develop in conditions such as lym-phoma, sarcoidosis (Drosos 1989), hemochromatosis,and amyloidosis (Fox 1994).

Diseases such as ocular cicatricial pemphigoid andStevens-Johnson syndrome produce tear deficiency due

to inflammation, scarring, and destruction of the con-junctival goblet cells. Atopy may produce dry eye due tosystemic antihistamine use or blepharitis and eczema.

Natural historyCDED varies in severity, duration, and etiology (Lemp

1995). In most patients, it does not threaten sight but ischaracterized by troublesome symptoms of irritation.When dry eye is caused by an irreversible deficiency of tearproduction or a chronic condition such as blepharitisthat leads to increased tear evaporation, symptom sever-ity may wax and wane, or gradually increase over time.

Reversible conjunctival squamous metaplasia andpunctate epithelial erosions of the conjunctiva and corneadevelop in many patients who have moderate to severe dryeye. Rarely, patients with severe dry eye will develop com-plications such as ocular surface keratinization; corneal ul-ceration, scarring, thinning (ectasia), or neovasculariza-tion; microbial keratitis; and sterile corneal keratolysis,with possible perforation and severe visual loss.

DIAGNOSIS,TREATMENT, AND MANAGEMENTAccording to guidelines established in the AAO’s 2003

Preferred Practice Pattern, the goals of diagnosing, treat-ing, and managing patients with dry eye are: to establishthe diagnosis of dry eye, differentiating it from othercauses of irritation and redness; to identify the causes of

SOURCE: LEMP 1995

FIGURE 1 Modified diagnostic classification scheme for dry eye

1. Ocular irritation syndrome

2. Tear film instability

3. Ocular surface diseaseDRY EYE

Deficient aqueoustear production

Increasedevaporative loss

Sjögren’s Non-Sjögren’s

Blepharitis/Meibomian gland

dysfunction

Exposure Other factors1. Contact lenses2. Blink abnormality3. Environmental


22 P&T DIGEST

dry eye; to establish appropriate therapy; to relieve dis-comfort; to prevent complications, including visual loss,infection, and structural damage; and to educate pa-tients and involve them in managing their disease.

In moderate to severe cases that are unresponsive totreatment or when systemic disease is suspected, timelyreferral to an ophthalmologist with experience in man-aging this condition is recommended. Referral to an in-ternist or rheumatologist can be considered for patientswith systemic immune dysfunction or for individuals re-quiring immunosuppressive therapy (AAO 2003).

The most important aspects of caring for patients withdry eye are to educate them about the chronic nature ofthe disease process and to provide specific instructions fortherapeutic regimens. It is helpful to discuss realistic ex-pectations, in terms of therapeutic goals. It also is essen-tial to assess, periodically, the extent of their under-standing of the disease and adherence to treatment.

DiagnosisMany ocular surface diseases produce symptoms sim-

ilar to those associated with dry eye, such as foreign-body sensation, mild itching, burning, blurred vision, ir-ritation, and soreness. The initial evaluation of a patientpresenting with symptoms that are suggestive of dry eyeshould include those features of the comprehensive adulteye evaluation relevant to dry eye (AAO 2003).

It is often difficult to diagnose patients with mild dryeye syndrome because of the inconsistent correlation be-tween reported symptoms and clinical signs (Schein1997) and the relatively poor sensitivity and/or specificityof existing diagnostic tests (AAO 2003). When environ-mental factors and other potential causes of ocular irri-tation (see page 10) have been eliminated from consid-eration, patients with suggestive symptoms who do nothave overt signs of disease should be placed on trial treat-ments, such as artificial tears or, where appropriate, trialdiscontinuation of systemic antihistamines (AAO 2003).

Because most dry eye conditions are chronic, repeatobservation and the reporting of symptoms over timewill allow a more accurate clinical diagnosis of dry eye.A diagnostic classification scheme, adapted from a Na-tional Eye Institute Workshop, is shown in Figure 1 onpage 21 (Lemp 1995). Participants in this workshopagreed that two major factors — deficient aqueous tearproduction and increased evaporative loss — may causedry eyes independently but also may contribute con-currently to dry eye symptoms and signs.

Patient historyAccording to the AAO 2003 guidelines, the history of

the patient’s illness should include symptoms and signs re-lating to the eyes such as dry sensation, irritation, tearing,

burning, stinging, foreign-body sensation, photophobia,blurred vision, contact lens intolerance, redness, mucousdischarge, increased frequency of blinking, itching,and di-urnal fluctuation; exacerbating conditions, such as wind,air travel, or low humidity; prolonged visual effort that isassociated with a decreased rate of blinking; duration ofsymptoms; and any topical medications that have beenused, as well as their effects on symptoms.

The patient’s ocular and medical histories should in-clude the factors listed in Table 1. In addition, the medi-cal history should describe use of systemic medications,including antihistamines, diuretics, hormones and hor-monal antagonists, antidepressants, cardiac antiarrhyth-mic drugs, diphenoxylate/atropine, isotretinoin, betablockers, chemotherapy agents, HMG co-A reductaseinhibitors, and any drug with anticholinergic effects.

Physical examinationThe physical examination should include a visual acu-

ity measurement, an external examination, and a slit-lamp biomicroscopy. The external examination and thebiomicroscopy serve to document signs of dry eye, assessthe presence and severity of deficient aqueous tear pro-duction and/or increased evaporative loss, and excludeother causes of ocular irritation.

The examination and biomicroscopy should focus onfactors listed in Table 2. Additionally, at the slit lamp, theclinician should direct attention toward the four punc-tums, noting patency or closure, juxtaposition to the bul-bar conjunctiva, and the size of the opening when patent.

Diagnostic testsThe poor correlation between reported symptoms

and clinical signs, coupled with the aforementionedlimitations of clinical tests, make it difficult to diagnosedry eye in its mild form. For patients with mild irritationsymptoms, a rapid TBUT may detect an unstable tearfilm with normal aqueous tear production, and ocularsurface dye staining may detect a minimal pattern or nopattern. For patients with moderate to severe aqueoustear deficiency, the diagnosis can be made with one ormore of the following tests: TBUT, ocular surface dye-staining pattern (rose bengal, fluorescein, or lissaminegreen), or Schirmer wetting test.

These tests should be performed in the above se-quence, because the Schirmer test can disrupt tear filmstability and cause false-positive ocular surface dye stain-ing. Other tests may be helpful in evaluating selectedpatients, but some have limited availability. These testsinclude tear osmolarity, fluorescein clearance, impressioncytology, tear function index, and tear protein analysis(including lactoferrin, lysozyme, immunoglobulin, andalbumin) (AAO 2003).


DRY EYE SYNDROME 23

Corneal sensation should beassessed when trigeminal nervedysfunction is suspected (Hei-gle 1996).A laboratory and clin-ical evaluation for autoimmunedisorders should be consideredfor patients with significant dryeyes, other signs and symptomsof an autoimmune disorder(e.g., dry mouth, rash, arthritis,colitis, or renal dysfunction), ora family history of autoimmunedisorders.

TreatmentPatients with a clinical diag-

nosis of mild dry eye may ben-efit from behavioral and envi-ronmental modification, suchas learning to take breaks whilereading, lowering the computermonitor to decrease lid aper-ture, and humidification of theenvironment (Nordstrom 1995).Because dry eye can be iatro-genic, elimination of exogenous medical factors, such asprescription regimens that include ocular topical preser-vatives or systemic antihistamines or diuretics, may help.

For patients with mild disease, use of tear substitutes isindicated. As the severity of dry eye increases, nonpre-served tear substitutes or emulsions, gels, and ointmentsmay be used instead of conventional preserved tear sub-stitutes. Noninvasive therapies such as spectacle sideshields, moisture inserts, and moisture chambers are ap-propriate for more severe disease, but these tend to be un-popular among patients for cosmetic reasons (AAO 2003).

MedicationsPilocarpine and cevimeline, two cholinergic agonists,

have been approved by the U.S. Food and Drug Admin-istration to treat the symptoms of dry mouth in patientswith Sjögren’s syndrome (Vivino 1999, Fox 2001). Theseoral medications stimulate secretion of the salivary andsweat glands and appear to improve tear production, butmost clinical studies demonstrate greater improvementin dry mouth than dry eye (Vivino 1999, Nelson 1998).

Patients treated with pilocarpine at a dosage of 5 mgorally, 4 times daily, experienced a significantly greateroverall improvement in the ability to focus their eyes dur-ing reading, as well as improvements in symptoms ofblurred vision, compared to placebo-treated patients.(AAO 2003,Vivino 1999). The most common side effectfrom this medication class is excessive sweating, which

TABLE 1 AAO guidelines: patient history

Ocular history should describe:• Contact lens use, lens material, solutions, wearing schedule, lens care• Allergic conjunctivitis• Corneal history (prior keratoplasty, LASIK, photorefractive keratectomy, radial

keratotomy, or extracapsular cataract extraction)• Punctal plugs or surgery• Eyelid surgery (prior ptosis repair, blepharoplasty, entropion/ectropion repair)• Chronic ocular surface inflammation (acid or alkaline burns, ocular cicatricial

pemphigoid, or Stevens-Johnson syndrome)Medical history should include:• Smoking, menopause, and atopy• Dermatological diseases (including seborrhea, eczema, rosacea)• Trauma (including exposure to chemicals, ultraviolet light, dust, sawdust, fumes)• Systemic inflammatory diseases (Sjögren’s syndrome, rheumatoid arthritis,

systemic lupus erythematosus, scleroderma, graft-versus-host disease)• Chronic viral infections, such as chronic hepatitis C or human immuno-

deficiency virus• Surgery (bone marrow transplant, head and neck surgery)• Radiation of orbit• Neurological conditions (including Parkinson’s disease, Bell’s palsy, and Riley-

Day syndrome)• Xerostomia (dry mouth), dental cavities, and oral ulcers

SOURCE: AAO 2003

TABLE 2 AAO guidelines: physical exam

External examination should focus on:• Skin (scleroderma,facial changes indicating rosacea)• Eyelids (incomplete closure/malposition,erythema

of eyelid margins, incomplete/infrequent blinking,abnormal deposits/secretions,entropion,ectropion)

• Adnexa (enlargement of the lacrimal glands)• Proptosis• Cranial nerve function (including cranial nerve V,VII)• Disorders affecting the hand (joint deformities char-

acteristic of rheumatoid arthritis,gout,or psoriasis)Slit-lamp biomicroscopy should include attention to:• Tear film (height of meniscus, debris, foam)• Eyelashes (trichiasis,distichiasis,madarosis,deposits)• Anterior/posterior eyelid margins and character

of meibomian gland secretions• Vascularization crossing the mucocutaneous

junction, keratinization, and scarring• Puncta (patency and position)• Conjunctiva (inferior fornix and tarsal conjunctiva,

and bulbar conjunctiva)• Cornea (localized interpalpebral drying, punctate

epithelial erosions, filaments, macroepithelial de-fects, punctate staining with rose bengal or fluo-rescein dyes, mucous plaques, keratinization, pan-nus formation, thinning, infiltrates, ulceration,neovascularization, and scarring)

SOURCE: AAO 2003


24 P&T DIGEST

occurred in more than 40 percent of patients.Cevimeline also has been found to improve ocular ir-

ritation symptoms and aqueous tear production (Pet-rone 2002) and may have fewer adverse systemic side ef-fects than oral pilocarpine (AAO 2003).

Anti-inflammatory therapies may be considered inaddition to aqueous enhancement therapies. In clinicaltrials, topical cyclosporine has been reported to increaseaqueous tear production and decrease ocular irritationsymptoms in dry eye treatment (Gunduz 1994, Sall 2000).Clinically significant improvements in Schirmer wetting,punctuate keratopathy, quality-of-life measures, and ar-tificial tear use proved sufficient for FDA approval of thefirst prescription medication for dry eye disease on Dec.24, 2002 — a topical, preservative-free 0.05 percent cy-closporine emulsion. The proprietary emulsion prepa-ration is ideally formulated to distribute the relatively in-soluble cyclosporine molecule to the ocular surface withmaximal bioavailability. Previous formulations by com-pounding pharmacies utilizing much higher concentra-tions — as high as 4 percent — do not achieve tissue lev-els equivalent to the approved emulsion.

Cyclosporine is an 11-amino-acid cyclopeptide, pro-duced as a metabolite by the fungus species Beauverianivea. Cyclosporine prevents activation and nucleartranslocation of cytoplasmic transcription factors that arerequired for T-cell activation and inflammatory cytokineproduction. It also inhibits mitochondrial pathways ofapoptosis and has been reported to heal paracentral ster-ile corneal ulcers associated with Sjögren’s syndrome andrheumatoid corneal ulceration (Kervick 1992). Cyclo-sporine therapy appears to address all three tear filmcomponents (aqueous, oil, and mucin), and thereforethe three types of tear deficiency that may occur in vari-ous combinations in dry eye disease.

Nonpreserved topical corticosteroids have been re-ported to decrease ocular irritation symptoms, reducecorneal fluorescein staining, and improve filamentarykeratitis (Marsh 1999, Prabhasawat 1998). Low-dosecorticosteroid therapy can be used at infrequent inter-vals for short-term (2-week) suppression of irritationsecondary to inflammation.

Patients with systemic disease such as primary Sjö-gren’s syndrome, or with connective tissue disease suchas rheumatoid arthritis, should be managed in con-junction with the appropriate medical specialist. Anti-inflammatory/immunosuppressive therapy may be ap-propriate for patients with a systemic disease such asrheumatoid arthritis (AAO 2003).

Surgical treatmentSurgical treatment is generally reserved for patients

with symptomatic, moderate, or severe disease, and for

whom medical treatment has been inadequate or im-practical (AAO 2003).

Aqueous enhancement by means of punctal occlu-sion can be accomplished surgically with semipermanentplugs (silicone or thermal labile polymer) that are lodgedat the punctal orifice (AAO 1997,AAO 1998,AAO 2003),or by permanent occlusion with thermal or laser cautery.Prior to permanent or semipermanent punctal occlusion,temporary slow-dissolving collagen punctal plugs can beplaced in most patients’ lower punctum. Because an oc-cluded punctum can trap inflammatory mediators, in-flammation, logically, should be controlled prior to punc-tal occlusion. Nevertheless, many patients with successfulor partially helpful punctal occlusion procedures obtainadditional benefit from subsequent initiation of topicalanti-inflammatory therapy.

Eyelid abnormality as a result of blepharitis, trichia-sis, or lid malposition (e.g., entropion/ectropion, lago-phthalmos) should be corrected prior to permanentpunctal occlusion (AAO 2003).

Semipermanent plugs are reversible if the patient de-velops symptoms of epiphora, while cautery is not read-ily reversible. Therefore, a trial occlusion with collagenplugs should be performed first. To minimize the possi-bility of epiphora, no more than one punctum should becauterized in each eye. The lower punctum is preferablefor occlusion, as it is usually larger and more accessible.It is important to inspect the upper punctum first forboth patency and integrity, before occluding the lowerpunctum. In general, laser cautery is not as effective asthermal cautery in achieving permanent, complete oc-clusion and is more expensive.

Tarsorrhaphy can be performed to decrease tear evap-oration in patients with severely dry eyes, and for whomall other medical and surgical therapies have been ex-hausted.

ManagementThe purpose of the follow-up evaluation, as outlined

in the AAO 2003 guidelines, is to assess the patient’s re-sponse to therapy and the need to adjust treatment, tomonitor for structural ocular damage, and to provide re-assurance to the patient. The follow-up evaluation’s fre-quency and composition is determined by disease sever-ity, the therapeutic approach, a patient’s personality andadherence to therapy, and the response to therapy.

Patients with mild dry eyes can be seen once or twiceper year for follow-up if symptoms are controlled bytherapy. Patients with sterile corneal ulceration associatedwith dry eye require careful, sometimes daily, monitor-ing. Patients with existing dry eye, on the other hand,should be cautioned that LASIK or photorefractive kera-tectomy may worsen their condition.

Heigle TJ, Pflugfelder SC. Aqueous tear production in patients withneurotrophic keratitis. Cornea. 1996;15:135–138.

Hikichi T, Yoshida A, Fukui Y, et al. Prevalence of dry eye in Japaneseeye centers. Graefes Arch Clin Exp Ophthalmol. 1995;233: 555–558.

Kervick GN, Pflugfelder SC, Haimovici R, et al. Paracentral rheuma-toid corneal ulceration. Clinical features and cyclosporine ther-apy. Ophthalmology. 1992;99:80–88.

Lemp MA. Report of the National Eye Institute/Industry Workshop onClinical Trials in Dry Eyes. Clao J. 1995;21:221–232.

Lucca JA, Farris RL, Bielory L, Caputo AR. Keratoconjunctivitis siccain male patients infected with human immunodeficiency virustype 1. Ophthalmology.1990;97:1008–1010.

Marsh P, Pflugfelder SC. Topical nonpreserved methylprednisolonetherapy for keratoconjunctivitis sicca in Sjögren syndrome. Oph-thalmology. 1999;106:811–816.

McCarty CA, Bansal AK, Livingston PM, et al. The epidemiology of dryeye in Melbourne, Australia. Ophthalmology. 1998;105:1114–1119.

Merayo-Lloves J, Baltatzis S, Foster CS. Epstein-Barr virus dacryo-adenitis resulting in keratoconjunctivitis sicca in a child. Am JOphthalmol. 2001;132:922–923.

Moss SE, Klein R, Klein BE. Prevalence of and risk factors for dry eyesyndrome. Arch Ophthalmol. 2000;118:1264–1268.

Nelson JD, Friedlaender M,Yeatts RP, et al. Oral pilocarpine for symp-tomatic relief of keratoconjunctivitis sicca in patients with Sjo-gren’s syndrome. The MGI PHARMA Sjögren’s Syndrome StudyGroup. Adv Exp Med Biol. 1998;438:979–983.

Nordstrom K, Norback D, Akselsson R. Influence of indoor air qual-ity and personal factors on the sick building syndrome (SBS) inSwedish geriatric hospitals. Occup Environ Med. 1995;52:170–176.

Ogawa Y, Okamoto S,Wakui M, et al. Dry eye after haematopoietic stemcell transplantation. Br J Ophthalmol. 1999;83: 1125–1130.

Petrone D, Condemi JJ, Fife R, et al. A double-blind, randomized,placebo-controlled study of cevimeline in Sjögren’s syndrome pa-tients with xerostomia and keratoconjunctivitis sicca. ArthritisRheum. 2002;46:748–754.

Pflugfelder SC, Roussel TJ, Culbertson WW. Primary Sjögren’s syn-drome after infectious mononucleosis. JAMA. 1987;257:1049–1050.

Pflugfelder SC, Crouse CA, Monroy D, et al. Epstein-Barr virus and thelacrimal gland pathology of Sjögren’s syndrome. Am J Pathol.1993;143:49–64.

Pflugfelder SC, Solomon A, Stern ME. The diagnosis and manage-ment of dry eye: a twenty-five-year review. Cornea. 2000;19:644–649.

Prabhasawat P, Tseng SC. Frequent association of delayed tear clearancein ocular irritation. Br J Ophthalmol. 1998;82: 666–675.

Sall K, Stevenson OD, Mundorf TK, Reis BL. Two multicenter, ran-domized studies of the efficacy and safety of cyclosporine oph-thalmic emulsion in moderate to severe dry eye disease. CsAPhase 3 Study Group. Ophthalmology. 2000;107:631–639.

Schaumberg DA, Buring JE, Sullivan DA, Dana MR. Hormone re-placement therapy and dry eye syndrome. JAMA. 2001;286:2114–2119.

Schein OD, Munoz B, Tielsch JM, et al. Prevalence of dry eye amongthe elderly. Am J Ophthalmol. 1997;124:723–728.

Siagris D, Pharmakakis N, Christofidou M, et al. Keratoconjunctivitissicca and chronic HCV infection. Infection. 2002;30: 229–233.

Stern ME, Beuerman RW, Fox RI, et al. The pathology of dry eye: theinteraction between the ocular surface and lacrimal glands.Cornea. 1998;17:584–589.

Vivino FB, Al-Hashimi I, Khan Z, et al. Pilocarpine tablets for thetreatment of dry mouth and dry eye symptoms in patients withSjögren syndrome: a randomized, placebo-controlled, fixed-dose,multicenter trial. P92-01 Study Group. Arch Intern Med.1999;159:174–181.

Yazdani C, McLaughlin T, Smeeding JE, Walt J. Prevalence of treateddry eye disease in a managed care population. Clin Ther.2001;23:1672–1682.

CONCLUSIONSThe AAO Preferred Practice Pattern for dry eye syn-

drome was developed as practitioners of ophthalmologyand optometry have come to understand the inflamma-tory nature of the condition. Since then, discoveriesabout the etiology of dry eye disease and the subsequentdevelopment of new therapies to treat — rather than pal-liate — have effectively launched a new era for millionsof people who suffer from the sometimes devastatingconsequences of dry eye.

Eye care professionals are engaged in discussions re-garding the appropriate use of these emerging therapiesas first-line treatments. Certainly, high-risk individuals,postmenopausal females, patients requiring 4 or moredrops of artificial tears per day, and patients with rheu-matologic conditions should strongly be considered can-didates for anti-inflammatory therapy. Clinicians are wellaware that the severely dry patient of today, with com-promised vision due to central corneal ulceration, was themildly dry eye patient of yesterday. CDED is progressiveand intimately associated with the aging process, akin toglaucoma, hypertension, and hypercholesterolemia. Per-haps early intervention and preventive strategies will notonly avoid significant morbidity and discomfort, but en-able overall cost savings through proactive selective inter-vention. Ultimately, decisions will be made on the basisof everyday clinical evidence, just as the FDA has ruled onthe precision of prospective clinical trial data analysis. Pa-tients and payers, meanwhile, are watching.

The potential for improved quality of life, decreasedroutine and emergent visits to the ophthalmologist, andthe implications for reducing costs and complications oftreatment are enormous. These considerations, discussedthroughout this publication, represent state-of-the-art,patient-oriented, quality-conscious eye care.

REFERENCESAAO (American Academy of Ophthalmology). Punctal occlusion for

the dry eye: ophthalmic procedure assessment. Ophthalmology.1997;104:1521–1524.

AAO. Preferred Practice Pattern: Dry Eye Syndrome. San Francisco:AAO, 1998.

AAO. Preferred Practice Pattern: Dry Eye Syndrome. San Francisco:AAO, 2003.

Abe T, Nakajima A, Matsunaga M, et al. Decreased tear lactoferrinconcentration in patients with chronic hepatitis C. Br J Ophthal-mol. 1999;83:684–687.

Bacman S, Berra A, Sterin-Borda L, Borda E. Muscarinic acetylcholinereceptor antibodies as a new marker of dry eye Sjögren syn-drome. Invest Ophthalmol Vis Sci. 2001;42:321–327.

Drosos AA, Constantopoulos SH, Psychos D, et al. The forgotten causeof sicca complex; sarcoidosis. J Rheumatol. 1989;16: 1548–1551.

Fox RI. Systemic diseases associated with dry eye. Int Ophthalmol Clin.1994;34:71–87.

Fox RI, Konttinen Y, Fisher A. Use of muscarinic agonists in the treat-ment of Sjögren’s syndrome. Clin Immunol. 2001;101: 249–263.

Gunduz K, Ozdemir O. Topical cyclosporin treatment of keratocon-junctivitis sicca in secondary Sjögren’s syndrome. Acta Ophthal-mol. (Copenh) 1994;72:438–442.


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PHARMACOTHER APEUTIC OPTIONS

treatments are in the pipeline as well, and these couldcontribute to this evolving paradigm.

TREATMENT APPROACHES: AN OVERVIEWTraditionally, the approach to the treatment of dry eye

syndrome has been palliative, relying predominantly onreplacement of tears to curb symptoms without ad-dressing the underlying disease process. Over the years,improvements were made in the formulation of artificialtears and lubricants — including the addition of demul-cents to improve viscosity and lubricant properties, andthe development of preservative-free solutions to avoidcausing corneal toxicity. Yet, despite their widespread

Research into dry eye syndrome (keratocon-junctivitis sicca) has advanced dramatically inthe last decade, providing a better understand-ing of the pathophysiology, underlying mech-

anisms, and natural history of the disease. This advancein knowledge has been accompanied by a more focusedtherapeutic approach, with new treatments targeted atunderlying pathophysiologic processes. Whereas earlyinterventions for dry eye syndrome attempted to simplyreplace water lost from the tear film, today there exists anew therapy directed at the underlying inflammation,now a recognized component of dry eye syndrome, andat the progressive changes in the ocular surface that occurover time with the disease (Table 1, page 28).

More than 4 million people in the United States arethought to suffer from dry eye syndrome (Schein 1997),and as much as 25 percent of patients visiting eye careclinics describe dry eye symptoms (Hikichi 1995;Doughty 1997). The United States Food and Drug Ad-ministration’s recent approval of cyclosporine oph-thalmic emulsion 0.05 percent as the first prescriptionmedication to treat keratoconjunctivitis sicca may her-ald the start of a new therapeutic era. This new thera-peutic focus corrects underlying pathologies that lead todry eye and uses pharmacologic agents with anti-inflammatory/immunomodulatory mechanisms tomanage the signs and symptoms of disease and to con-trol or reverse corneal damage. Other novel and exciting


Early interventions were palliative, attempt-ing to replace water lost from the tear film.Today, therapy is directed at the underlyinginflammation, a recognized component ofdry eye syndrome, and at the resulting pro-gressive changes to the ocular surface.Thisapproach offers promise of lasting relief topatients with moderate to severe symptoms.

SUMMARY

Medications for Dry Eye Syndrome: A Drug-Therapy ReviewHENRY D. PERRY, MD1

ERIC D. DONNENFELD, MD2

Ophthalmic Consultants of Long Island

1 Henry D. Perry, MD, is clinical associate professor of Oph-thalmology at the Weill School of Medicine, Cornell Uni-versity, and the senior founding partner of OphthalmicConsultants of Long Island. He graduated from the Uni-versity of Cincinnati College of Medicine and completed hisinternship and residency at Nassau County Medical Cen-ter and the University of Pennsylvania Scheie Eye Institute.He went on to complete fellowships in ophthalmic pathol-ogy at the Armed Forces Institute of Pathology in Wash-ington and in cornea and external disease at the Massa-chusetts Eye and Ear Infirmary, Harvard University. Hereviews for and serves on the editorial board for several jour-nals, and has authored over 150 peer review articles on dis-eases and surgery of the cornea and ophthalmic pathology.

2 Eric D. Donnenfeld, MD, is a founding partner of Oph-thalmic Consultants of Long Island. A board-certified oph-thalmologist, he is experienced in laser vision correction, in-cluding LASIK and PRK. Donnenfeld graduated magnacum laude with a bachelor’s degree from Dartmouth Col-lege. He received his medical degree from Dartmouth Medi-cal School, graduating in the top 5 percent of his class. Aftercompleting his ophthalmology residency at ManhattanEye, Ear, and Throat Hospital, Donnenfeld completed a fel-lowship in disease, treatment, and surgery of the cornea atWills Eye Hospital in Philadelphia. He has been presidentof numerous professional societies and has written more than100 papers and books on refractive and corneal surgery.

DRY EYE SYNDROME 27


thereby prevents T-cells from releasing cytokines (pri-marily interleukin-6) that incite the inflammatory com-ponent of dry eye. Early studies suggesting its utility in dryeye syndrome came from dog studies in which topical ap-plication of cyclosporine ophthalmic emulsion twice dailyreduced lymphocyte infiltration in the lacrimal glandsand conjunctiva (Kaswan 1989, Gao 1998, Tsubota 1998).Cyclosporine A also was associated with reduced apop-tosis of lacrimal glands and conjunctival epithelial cells indogs, effects that contribute to reduced inflammationand clinical improvement of dry eye (Gao 1998).

The earliest human studies in keratoconjunctivitissicca revealed that topical eye treatment with cyclo-sporine A relieved the signs and symptoms of the disease(Power 1993, Gunduz 1994, Laibovitz 1993). More recentdata from two United States phase 3 randomized, multi-

center, double-blind, 6-monthprotocols establish the efficacy,safety, and anti-inflammatory ac-tivity of cyclosporine A ophthal-mic emulsion compared withcastor oil-based topical emulsionvehicle alone in patients withmoderate to severe dry eye syn-drome (Sall 2000). In the com-bined results from these studies

(N=877), both objective (corneal staining, Schirmer test)and subjective (blurred vision, need for concomitant ar-tificial tears, physician evaluation of global response totreatment) measures of treatment efficacy were signifi-cantly better with cyclosporine 0.05 percent emulsionthan with vehicle (p<.05). Especially notable is the im-provement in corneal staining (Figure 1, page 29), whichindicates that cyclosporine ophthalmic emulsion sup-presses the inflammatory processes underlying dry eyesyndrome in these patients, and by doing so, improves theintegrity of the ocular surface. This pathophysiologicbenefit contributes to enhanced vision and normalizedlacrimal gland response to blinking and other stimuli —and hence to the Schirmer value improvements in thisstudy (Figure 2, page 30).

The first (and currently only) cyclosporine ophthal-mic emulsion 0.05 percent was recently approved by theFDA for the safe and effective treatment of underlying in-flammation in dry eye syndrome. This is the only treat-ment available that addresses the immunogenic and in-flammatory causes of dry eye syndrome and is not solelypalliative. It is a sterile, preservative-free emulsion thatappears white opaque to slightly translucent. It has a fa-vorable safety profile, the most common adverse eventbeing mild ocular burning and stinging — effects that

use and proven activity relative to improving ocular lu-brication, increasing humidity at the ocular surface, andeven contributing to improved vision, these productsgenerally failed to accurately reproduce natural tears,could not acceptably substitute for the continuous flowof natural tears, and did not correct underlying pathol-ogy or tissue damage that can occur over time with dryeye syndrome (Calonge 2001, Lemp 1994, Murube 1998a,Murube 1998b, Pflugfelder 1998, Liu 1999).

Alternative therapeutic interventions were aimed attear preservation or stimulation of natural tears. Canalic-ular or punctal tamponade occlusion is a popular non-pharmacologic approach to improving aqueous tear filmcontent (both quantity and quality), with the result ofimproving signs and symptoms of dry eye (Lemp 1994,Murube 1996, Willis 1987). While this technique can behelpful for relieving dry eye symp-toms, it carries a risk of decreasedtear production, clearance, andocular surface sensation (Yen 1999)and exacerbates the already delayedtear clearance and turnover rate(Macri 2000), ultimately resultingin desensitization of the cornealsurface and possible inflammation.

Overall, these palliative thera-pies have been recognized as having limited value forlong-term control or cure of progressive dry eye syn-drome. In the last quarter century, however, researchbegan to focus more aggressively on the pathophysiologyof dry eye syndrome, yielding several important findingsthat suggest an inflammatory etiology.

It is now recognized that dry eye syndrome resultsfrom an underlying cytokine and receptor-mediated in-flammatory process affecting the lacrimal glands (Mirch-eff 1994, Pflugfelder 1986, Pflugfelder 1999, Stern 1998,Williamson 1973). The observed inflammation, in turn,can either decrease tear production or alter the contentsof the tear film and disrupt homeostasis at the ocular sur-face, ultimately leading to keratoconjunctivitis sicca.These findings have redirected treatment efforts towardmore targeted therapies aimed at resolving the underly-ing inflammation. Anti-inflammatory/immunomodu-latory treatments — most notably cyclosporine A — arenow becoming standard therapy for moderate to severedry eye syndrome.

Review of drug therapy options3

Newer agentsCyclosporine A. Cyclosporine A is a well-known

immunomodulator, most commonly used to prevent re-jection after organ/tissue transplantation. It also confersanti-inflammatory activity and, in dry eye syndrome, 3 Table 2,page 29, lists the trade names of generic agents.

Henry D. Perry, MD Eric D. Donnenfeld, MD

methylprednisolone or lotaprednol etabonate — hasbeen shown to reduce early inflammation in dry eyesyndrome (Marsh 1999, Prabhasawat 1998). This effecthas been linked to reduced levels of the chemotacticcytokine IL-8 in the conjunctival epithelium (Pflugfelder

28 P&T DIGEST


also were common with the vehicle alone. Changes werenot detected in intraocular pressure, vision, or the corneaas assessed by biomicroscopy (Sall 2000).

Topical corticosteroids. Immunomodulation withtopical nonpreserved corticosteroid therapy — such as

TABLE 1 Options for dry eye syndrome

List is not inclusive

Product How supplied Dosing

Targeted therapiesImmunomodulators:Cyclosporine A unit dose vials (0.4 mL) 1 drop 2x dailyMucolytic agents:N-acetylcysteine 10–20% drops 1–2 drops up to 4x dailyAntibiotics:Topical: various, e.g.: loading dose, then

bacitracin, chlortetracycline 1–2 drops 2x dailySystemic: doxycycline 100 mg 2x daily

Palliative therapiesArtificial tears:Low viscosity (carboxymethylcellulose based): various, e.g.:

GenTeal multi dose 1–2 drops as neededRefresh Plus unit doseRefresh Tears multi doseTheraTears unit and multi dose

Moderate viscosity (hydroxymethyl-cellulose based): various, e.g.:

Bion Tears unit dose, preservative freeOcucoat unit dose, preservative free

High viscosity: various, e.g.:Refresh Celluvisc best for nocturnal instillationRefresh LiquigelAquaSiteMurocel

Gel formulations: various, e.g.:GenTeal Gel tube delivery system fingertip application into cul de sacTears Again tube delivery

Lubricating ointments:HypoTears fingertip applicationRefresh PM (1/4 inch) into cul de sacTears Naturale PM

Therapeutic plugHydroxypropyl cellulose insert 5 mg water-soluble rod 1–2 rods per eye daily

Secretagogues:EledoisinPilocarpine 5 mg tablets 1 daily

Corticosteroids:Loteprednol etabonate 1–2 drops 4x dailyPrednisolone acetate 2 drops 4x daily

ADAPTED FROM PACKAGE INSERTS

DRY EYE SYNDROME 29


1999). Symptomatic relief has been reported to extend formonths after the steroid application has been stopped(Marsh 1999). Long-term use of this class, however, is as-sociated with severe side effects, including ocular hy-pertension, cataract formation, glaucoma, and infection.For this reason, these drugs should be reserved for symp-toms that are severe and recalcitrant to aggressive appli-cation of artificial tears, and used only for acute treatment(<2 weeks) of dry eye exacerbations.

Older agentsTear substitutes. Until the recent identification of in-

flammation as an important etiology in dry eye syn-drome, the most commonly used treatment for dry eyeswas topically applied artificial tears and lubricants. Al-though solely a palliative therapy, artificial tears are use-

ful in mild dry eye syndrome for the simple re-lief of dry eye symptoms, including scratchinessand dryness. These over-the-counter productsare formulated from one of a variety of linearpolymers that simulate the cell-surface glyco-proteins that maintain ocular hydration. Over theyears, manufacturers have attempted to closelymimic natural tears, which contain lipid (surfacelayer that retards evaporation), substantialamounts of water with dissolved salt and proteins(aqueous layer), and mucin (the film that coatsthe corneal surface). Despite these attempts toimprove composition, however, these productshave inherent limitations; natural tears have acomplex composition that artificial tears cannot

fully substitute, while the mucus layer of the tear film hasnot been satisfactorily reproduced (Calonge 2001).

Artificial tear products currently are available invarious formulations, including solutions, gels, and oint-ments. The key differences in these products are viscos-ity, composition, and preservative vs. preservative-freeformulation.Viscosity describes the relative density of theformulation — which reflects its mucoadhesive proper-ties and therefore the degree of contact time with the oc-ular surface — and generally ranges from 1.5 mL pas(Pascal seconds, a standard of measurement for viscos-ity) to 15 mL pas, with an average of 5.0 mL pas. Agentsadded to artificial tears to increase viscosity include car-boxymethylcellulose, dextran 70, gelatin, glycerin, hy-droxymethylcellulose, hydroxypropyl methylcellulose,methylcellulose, PEG, poloxamer 407, polysorbate 80,

propylene glycol, polyvinyl alcohol,and polyvinylpyrrolidone. Productswith low viscosity commonly areused early in the progression of dryeye syndrome, as they are less likely todisrupt vision. As dry eye syndromeprogresses, more viscous tear prod-ucts are needed to achieve sympto-matic control, but these are associatedwith progressive blurring of vision.Lubricant ointments are reserved pri-marily for overnight treatment.

Compounds included to repli-cate the lipid occlusive layer are whitepetrolatum, mineral oil, lanolin, orlanolin alcohols. The mucin layer,which allows the solution to spreadover the ocular surfaces, is simulatedby use of polysorbate 20 and 80,poloxamer 282, or tyloxapol. In ad-dition, many tear supplements con-tain preservatives to stabilize the pro-

0

–0.2

–0.4

–0.6

–0.8

–1.0

Month 1 Month 3 Month 4 Month 6

Ch

ang

e in

sta

inin

g s

core

CsA 0.05%

CsA 0.10%

Vehicle

* p ≤ .05 vs. vehicle

† p ≤ .62 vs. vehicle

**

* †

SOURCE: SALL 2000

FIGURE 1 Changes from baseline (mean + standard error) in corneal staining

Related to application of cyclosporine ophthalmic solution 0.05 percent, 0.1 percent, and vehicle alone

TABLE 2 Generic/trade-name pharmaceutical conversion chart

Generic Trade name

Bacitracin/polymyxin B Polysporin Cyclosporine ophthalmic emulsion RestasisHydroxypropyl cellulose LacrisertN-acetylcysteine MucomystLoteprednol etabonate LotemaxPilocarpine SalagenPrednisolone acetate Pred ForteSodium carboxymethylcellulose TheraTears (0.25 percent)

30 P&T DIGEST


duct for longer periods. Benzalkonium chloride (BAK),benzethonium chloride, cetylpyridinium chloride,chlorobutanol, EDTA, phenylmercuric nitrate, phenyl-mercuric acetate, methyl/propylparaben, thimerosal,phenylethyl alcohol, sodium benzoate, sodium propi-onate, and sorbic acid are the most commonly used ad-ditives. Preservatives — extensive data have been re-ported on BAK — can induce corneal desquamation orcause irritation or allergic reactions, particularly as dailyuse increases due to worsening dry eye (Becquet 1998,Burstein 1980, Lopez Bernal 1991, Tripathi 1989); the de-velopment of preservative-free products has relievedsome of the burden of this potential complication (Deb-basch 2001). While preservative-free solutions do notworsen corneal barrier function, however, they have notbeen found to normalize it either.

Secretagogues. There are a number of drugs thathave been used with some success to stimulate thelacrimal glands to produce tears. Pilocarpine in partic-ular has been shown to increase tear volume and flow andimprove dry eye symptoms in patients with Sjögren’ssyndrome (Mathers 2000, Vivino 1999). Eledoisin, anendekapeptide, has yielded improved tear productionand flow (Gobbels 1991), although clinical improve-ment of dry eye signs and symptoms has never beenformally documented. Bromhexine and ambroxol havemet with equivocal results in clinical trials (Ichikawa1988, Avisar 1988).

As a rule, these agents are infre-quently prescribed due to the limiteddata, absence of compelling evidenceof improvement, and the associatedadverse effects, including generalizednausea, sweating, and rashes. Fur-thermore, some authors have sug-gested that generating tears from in-flamed lacrimal glands may worsendry eye by distributing proinflamma-tory cytokines to the ocular surface;when the glands are substantiallydamaged, this approach may fail toproduce tears at all (Calonge 2001).

Therapeutic ocular inserts. An ar-tificial tear insert that provides long-term slow release of artificial tearpolymers is an alternative, if rarelyused, therapy for moderate-to-severedry eye. This approach is most bene-ficial for those patients with moder-ate dry eye for whom artificial tear lu-brication does not resolve symptomsor is required at increasingly frequentintervals. There is currently only one

therapeutic insert manufactured, which contains hy-droxypropyl cellulose in a sterile, translucent, water-sol-uble rod. Each insert, applied once or twice daily insidethe inferior cul de sac of the eyelid, dissolves over 14 to18 hours. The slow release of the tear substance stabilizesand thickens the precorneal tear film and prolongs tearfilm breakup time. It also lubricates the eye and, in somepatients, may halt or reverse progressive visual damage.The system, however, is difficult to handle, and many pa-tients find it uncomfortable.

Mucolytics. Patients with keratoconjunctivitis siccaare prone to development of corneal mucous plaques,which are composed of mucus, epithelial cells, and pro-teinaceous and lipoidal material that cling to the cornealsurface (Lemp 1994, Thermes 1991). These plaques maycollect external dust and bacteria and cause vision diffi-culties, foreign body sensation, and substantial pain.Topical mucolytic agents, such as N-acetylcysteine 20percent (Mucomyst) diluted to a 10-percent solutionwith artificial tears, can be used to break down mucinmolecules, dissolve corneal filaments, and release themucoid plaque in patients with this condition. This so-lution may smell like rotten eggs, requires refrigeration,and, if formulated without preservatives, must be dis-carded after 30 days. It is not commercially available asa topical agent, though it can be readily compounded butat high expense for a relatively small amount.

Antibiotics. Some patients who experience poor con-

0.6

0.4

0.2

0.0

–0.2

–0.4 Month 3 Month 6

Ch

ang

e in

Sch

irm

er s

core

CsA 0.05%

CsA 0.10%

Vehicle

* p ≤ .05 vs. vehicle

*

*

SOURCE: SALL 2000

Categorized Schirmer values graded on 5-point scale: 1=<3mm/5 min;2=3-6mm/5min; 3=7-10mm/5 min; 4=11-14mm/5min; 5=>14mm/5min.

FIGURE 2 Schirmer value changes from baseline (mean + standard error)

Cyclosporine ophthalmic emulsion 0.05 percent, 0.1 percent,vs. vehicle alone (testing performed under anesthesia)

*

DRY EYE SYNDROME 31


trol of moderate dry eye symptoms with artificial tearswill benefit from antibiotic therapy. Antibiotics con-tribute to reduced inflammation and improved lipidproduction in dry eye syndrome. Topical bacitracinpolymyxin B or tetracycline-based ointments can beused to supplement hot compresses and lid scrubs tosome benefit. Systemic administration of low doses ofdoxycycline, which decreases the viscosity of naturally se-creted oils, may also yield positive results in patientswith meibomian gland dysfunction over a 6- to 8-weekcourse of therapy (Gilbard 1999).

Treatments under investigationHormones. Sexual hormones have been reputed to

contribute to an anti-inflammatory state at the ocularsurface (Stern 1998, Sullivan 1999a), leading investiga-tors to consider their potential role in the therapy of dryeye syndrome. Topical application of an estradiol oint-ment to 22 postmenopausal women was shown in onestudy to confer modest improvement in Schirmer testsand rose Bengal staining (Akramian 1998). Additionally,the presence of androgen receptors on the ocular surfacemay indicate a potential therapeutic role in dry eye syn-drome that warrants further study (Smith 1999). In ani-mal models, systemic administration of androgens hasreduced lymphocytic infiltration at the lacrimal glandand improved lacrimal gland function (Sullivan 1997,Sullivan 1999b). Currently, an androgen ointment prod-uct is in phase 3 trials.

P2Y2 receptor agonists. The P2Y2 receptor in the eyestimulates ocular hydration and lubrication by mediatingmucosal secretion of mucin as well as salt, water, mucus,and other tear components from conjunctival goblet cells.Mucin is the component of the tear film that maintainstear stability and protects against damage to the ocularsurface. Stimulation of the P2Y2 receptor can be accom-plished by administration of adenine analogues in bothrabbits and humans (Jumblatt 1998), suggesting a novelpathway for therapeutic modulation of tear film.A phase2 study of a novel P2Y2 receptor agonist has been com-pleted at 12 ophthalmology centers in the United States.Dequafosol, a P2Y2 agonist in topical eye drop form,provided both objective and subjective improvements inocular parameters when compared with placebo in thetreatment of moderate to severe dry eye syndrome (Li2001). Phase 3 studies will determine the precise role ofthese agents in the treatment of dry eye syndrome.

Tetracyclines.A collagenase enzyme — MMP9 — hasbeen found to be elevated in the ocular fluid of patientswith aqueous tear deficiency (related to Sjögren’s syn-drome) compared with normal controls. This elevatedenzyme level might reflect a mechanism by which pro-inflammatory molecules are cleaved to achieve activation

of IL-1 as part of the inflammatory process. Tetracy-clines are potent inhibitors of this enzyme and are beinginvestigated for a role in the management of inflamma-tion in the genesis of dry eye syndrome (Solomon 2001).

Retinoic acid. Retinol is present in tears and deficientin dry eye syndrome, leading some investigators to sug-gest a role for retinol replacement therapy. Results withtopical administration of retinoic acid have been variable,however, with evidence that its particular value is to re-verse keratinization, which occurs only in extremely se-vere cases of dry-eye related disease (Calonge 2001).

CONCLUSIONThe treatment of dry eye syndrome has relied pre-

dominantly on artificial tears and lubricants. This pal-liative approach generally has been successful at reliev-ing the signs and symptoms of mild to moderate diseaseand, in rare cases, has slowed the progressive damage tothe cornea and conjunctiva that occur over time with dryeye. Nevertheless, these products do not address the un-derlying disease process and, in some cases (particularlywith artificial tears containing BAK or certain otherpreservatives), can be toxic and allergenic, worseningthe clinical markers of the disease.

Increasing research and advancing knowledge hasidentified an inflammatory component to dry eye syn-drome and has focused treatment efforts at addressing thisnewly identified etiology. Topical cyclosporine emulsion0.05 percent is the first and currently only FDA-approvedtargeted immunomodulatory/anti-inflammatory productto combat the underlying source of disease. Other simi-larly targeted agents are under investigation and, if ap-proved, will likely contribute to the start of an entirely newmanagement standard — one based on control of in-flammatory sources and immunologic mechanisms — forthe treatment of dry eye syndrome.

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keratoconjunctivitis sicca. Adv Exp Med Biol.1998;438:1005–1009.

Avisar R, Savir H. Our further experience with bromhexine inkeratoconjunctivitis sicca. Ann Ophthalmol. 1988;20:382.

Becquet F, Goldschild M, Moldovan MS, et al. Histopathologicaleffects of topical ophthalmic preservatives on rat corneo-conjunctival surface. Curr Eye Res. 1998;17:19-25;410–425.

Burstein NL. Corneal cytotoxicity of topically applied drugs, ve-hicles and preservatives. Surv Ophthalmol. 1980;25:15–30.

Calonge M. The treatment of dry eye. Surv Ophthalmol. 2001;45(suppl 2): S227–S239.

Debbasch C, Brignole F, Pisella PJ, et al. Quaternary ammoni-ums and other preservatives’ contribution in oxidativestress and apoptosis on Chang conjunctival cells. InvestOphthalmol Vis Sci. 2001;42:642–652.

Doughty MJ, Fonn D, Richter D, et al. A patient questionnaireapproach to estimating the prevalence of dry eye symptoms

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Pflugfelder SC. Advances in the diagnosis and management ofkeratoconjunctivitis sicca. Curr Opin Ophthalmol.1998;9:50–53.

Pflugfelder SC, Jones D, Ji Z, et al. Altered cytokine balance inthe tear fluid and conjunctiva of patients with Sjögren’ssyndrome keratoconjunctivitis sicca. Curr Eye Res.1999;19:201–211.

Power WJ, Mullaney P, Farrell M, Collum LM. Effect of topicalcyclosporine A on conjunctival T-cells in patients with sec-ondary Sjögren’s syndrome. Cornea. 1993;12;507–511.

Prabhasawat P, Tseng SCG. The frequent association of tearclearance in ocular irritation. Br J Ophthalmol.1998;82:666–675.

Sall K, Stevenson OD, Mundorf TK, Reis BL and the CsA phase 3study group. Two multicenter, randomized studies of theefficacy and safety of cyclosporine ophthalmic emulsion inmoderate to severe dry eye disease. Ophthalmology.2000;107:631–639.

Schein OD, Munoz B, Tielsch JM, et al. Prevalence of dry eyeamong the elderly. Am J Ophthalmol. 1997;124:723–728.

Smith RE, Taylor CR, Rao NA, et al. Immunohistochemical iden-tification of androgen receptors in human lacrimal glands.Curr Eye Res. 1999;18:300–309.

Solomon A, Dursun D, Liu Z, et al. Pro- and anti-inflammatoryforms of interleukin-1 in the tear fluid and conjunctiva ofpatients with dry-eye disease. Invest Ophthalmol Vis Sci.2001;42(10):2283–2292.

Stern ME, Beuerman RW, Fox RI, et al. The pathology of dry eye:the interaction between the ocular surface and lacrimalglands. Cornea. 1998;17:584–589.

Sullivan DA, Edwards JA. Androgen stimulation of lacrimalgland function in mouse models of Sjögren’s syndrome. JSteroid Biochem Mol Biol. 1997;60:237–245.

Sullivan DA, Krenzer KL, Sullivan BD, et al. Does androgen in-sufficiency cause lacrimal gland inflammation and aqueoustear deficiency? Invest Ophthalmol Vis Sci.1999a;40:1261–1265.

Sullivan DA, Wickham LA, Rocha EM, et al. Androgens and dryeye in Sjögren’s syndrome. Ann NY Acad Sci.1999b;876:312–324.

Thermes F, Molon-Noblot S, Grove J. Effects of acetylcysteine onrabbit conjunctival and corneal surfaces. A scanning elec-tron microscopy study. Invest Ophthalmol Vis Sci.1991;32:2958–2963.

Tripathi BJ, Tripathi RC. Cytotoxic effects of benzalkoniumchloride and chlorobutanol on human corneal epithelialcells in vitro. Lens Eye Toxic Res. 1989;6:395–403.

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Vivino FB, Al-Hashimi I, Khan Z, et al. Pilocarpine tablets forthe treatment of dry mouth and dry eye symptoms in pa-tients with Sjögren’s syndrome: a randomized, placebo-controlled, fixed-dose, multi-center trial. P92-01 studygroup. Arch Intern Med. 1999;159:174–181.

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Hikichi T, Yoshida A, Fukui Y, et al. Prevalence of dry eye inJapanese eye centers. Graefe’s Arch Clin Exp Ophthalmol.1995;233:555–558.

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Laibovitz RA, Solch S, Andriano K, et al. Pilot trial of cyclo-sporine 1 percent ophthalmic ointment in the treatment ofkeratoconjunctivitis sicca. Cornea. 1993;124:311–323.

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Liu Z, Pflugfelder SC. Corneal surface regularity and the effectof artificial tears in aqueous tear deficiency.Ophthalmology. 1999;106:939–943.

Lopez Bernal D, Ubels J. Quantitative evaluation of the cornealepithelial barrier: effect of artificial tears and preservatives.Curr Eye Res. 1991;10:645–656.

Macri A, Rolando M, Pflugfelder S. A standardized visual scalefor evaluation of tear fluorescein clearance. Ophthalmology.2000;107:1338–1343.

Marsh P, Pflugfelder SC. Topical nonpreserved methylpred-nisolone therapy for keratoconjunctivitis sicca in Sjögren’ssyndrome. Ophthalmology. 1999;106:811–816.

Mathers WE, Dolney AM. Objective demonstration of tear stim-ulation with oral pilocarpine in dry eye patients. InvestOphthalmol Vis Sci. 2000;41:S60.

Mircheff AK, Gierow JP, Wood RL. Traffic of major histocom-patibility complex class II molecules in rabbit lacrimalgland acinar cells. Invest Ophthalmol Vis Sci.1994;35:3943–3951.

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Murube J, Murube A, Zhuo C. Classification of artificial tears. II:Additives and commercial formulas. Adv Exp Med Biol.1998b;438:705–715.

Murube J, Murube E. Treatment of dry eye by blocking thelacrimal canaliculi. Surv Ophthalmol. 1996;40:463–480.

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DRY EYE SYNDROME 33

CO S T E F F E C T I V E N E S S I S S U E S

creased productivity; andintangible costs related topain and suffering. Clinicaloutcomes include efficacy,onset of action, percentageof patients who becomefree of symptoms, symp-tom recurrence, and ad-verse effects. Humanisticoutcomes include health-related quality of life, returnto normal functioning, andpatient satisfaction withtherapy. Some variablesmay relate not only to pa-tients but also to caregiversand significant others.

This chapter considers the economic and quality-of-life burden of moderate to severe chronic dry eye syn-drome, then introduces PE analysis techniques that canbe used to evaluate treatments for chronic disease.

BURDEN OF DRY EYEDry eye syndrome is common, but its prevalence is

somewhat difficult to pinpoint, primarily because thedisease is multifactorial, definitions differ, and researchis sparse. Furthermore, diagnostic techniques lack stan-dardization and are inconclusive in milder cases. Clinicalsigns do not always correlate with symptoms, except inmoderate to severe cases and in association with auto-immune diseases, such as Sjögren’s syndrome (Nichols1999).

In a German study, 22.8 percent of women and 9.9percent of men age 55 to 59 reported often experiencinga sandy sensation in the eyes. In the Canadian Dry EyeEpidemiology Study, optometrists surveyed all patientsusing a standard questionnaire; researchers reportedthat, across all age groups, 28.7 percent reported dry eyesymptoms, 7.6 percent indicated constant but moderatesymptoms, and 1.6 percent complained of severe symp-toms (Brewitt 2001). In the United States, researchers at

Considerations in thePharmacoeconomics of Dry EyeJAN D. HIRSCH, PHD1

Prescription Solutions

Jan D. Hirsch, PhDPharmacoeconomic (PE) research identifies,measures, and compares the costs and conse-quences of pharmaceutical product and serviceutilization. In this definition, costs refers to re-

sources consumed; the consequences of using pharma-ceutical products and services are considered to be theoutcomes derived. A system for classifying the full rangeof outcomes is the ECHO (Economic, Clinical, andHumanistic Outcomes) model, proposed by Kozma(1993). Economic outcomes in the ECHO model in-clude direct medical costs, such as the costs of the drug,administration, and treatment of adverse effects; directnonmedical costs, such as patient transportation; indi-rect costs, such as lost work days, lost earnings, and de-

1 Jan D. Hirsch, PhD, is the director for post-launch clini-cal research at Prescription Solutions, a Costa Mesa, Calif.-based pharmacy benefit management company. Hirschleads the clinical research group’s Real World ProspectiveOutcomes Research program, which evaluates the value,safety, and effectiveness of FDA-approved medications anddevices in actual patient care settings and focuses specifi-cally on such managed care environments as HMOs, IPAs,medical groups, and integrated health systems. A phar-macist by initial training, Hirsch earned her PhD inpharmacy administration from the University of SouthCarolina. She has authored book chapters in multiplepharmacoeconomic texts and has written numerous jour-nal articles on the value of specific pharmaceutical agents.

Dry eye disease diminishes the quality of patients’ lives and drives utilization of healthcare resources. Until recently, all treatmentsfor dry eye have been palliative. A new treat-ment, cyclosporine A ophthalmic emulsion,addresses the disease’s underlying causes.It warrants pharmacoeconomic analysis todetermine its place in managed care.

SUMMARY

CO S T E F F E C T I V E N E S S

34 P&T DIGEST


the Schepens Eye Research Institute — using a broad de-finition of dry eye syndrome — estimate that 10 millionAmericans suffer from its symptoms (Schepens 2001).Other estimates of prevalence are reported elsewhere inthis publication.

Because this chapter focuses on treatment of moder-ate to severe dry eye syndrome, it is useful to consider theprevalence of the disease in terms of the percentage of pa-tients with symptoms severe enough to seek health careservices. In a survey of third-party payers, Nelson andcolleagues (2000) reported the prevalence of dry eye syn-drome to be 0.19 percent among managed care plan par-ticipants, 0.21 percent among persons covered by com-mercial payers, 0.35 percent among Medicaid recipients,and 1.30 percent among Medicare recipients.

Many factors — ranging from autoimmune diseasessuch as Sjögren’s syndrome to age-related changes (e.g.,menopause) to environmental conditions (e.g., contact-lens wear) — can cause dry eye syndrome (Albietz 2001).Persistent uncontrolled dry eye can lead to superficialpunctate staining, epithelial erosions, corneal filaments,and persistent epithelial defects. In the most severe cases,corneal ulcers occur. Clearly, moderate to severe dry eyeis painful and debilitating, and the burden of dry eye canbe substantial in terms of both economic and humanisticoutcomes.

Economic impactUntil the recent market availability of cyclosporine A

(CsA) ophthalmic emulsion, then-available treatmentsnot only failed to provide adequate relief of symptomsbut also failed to stop progression of the disease. Dry eyeis a chronic progressive inflammatory condition and isby no means self-limited. In turn, as dry eye severity in-creased, both individual and societal treatment costs in-creased.

A survey of Sjögren’s syndrome patients indicated thatsufferers used drops and ointments, on average, morethan 7 times daily, and nearly 1 in 3 had received punc-tal occlusion. Despite these measures, 89 percent visitedtheir ophthalmologist an average of 3.1 times a year forrelief from their symptoms, and 28 percent consultedother physicians for help with their dry eye problems. Onaverage, these patients went to work despite their symp-toms on 208 days annually and missed 5 work days dueto their dry eye symptoms or treatment. Patients also re-ported that dry eye symptoms interfered with leisureactivities on 123 days of the past year (Hirsch 1998).

In a survey of patients without Sjögren’s syndrome,Nelson (2000) confirmed that dry eye can be chronicand devastating; on average, patients responding to thestudy had been diagnosed 9.23 +/– 7.19 years previously,52 percent described their symptoms as severe or very se-

vere, and 22 percent indicated their symptoms were mod-erate. Half of the patients who revealed their ages were atleast 65. Of the 70 respondents, only two reported usingno topical treatments, such as artificial tears and lubri-cants; at least 61 percent reported using them always orregularly. More than 40 percent had received punctal oc-clusion; 27 percent reported using other medications —analgesics, antibiotics, anti-inflammatory agents — totreat their dry eye; 60 percent said they visited a physicianat least twice in the past year because of dry eye, and 84percent sought the aid of an ophthalmologist.

These researchers also noted that about 73 percent ofrespondents indicated that, despite all the treatmentsthey were using, dry eye interfered with the activities ofdaily life; 76 percent (53 of 70) indicated that their symp-toms had not improved or had worsened over the courseof the previous year. This team’s findings of the impactof the symptoms of dry eye on quality of life are sum-marized in Table 1. Annually, these patients lost 2 workdays because of their dry eye symptoms, and went towork despite the interference on 191 days, presumably re-ducing their efficiency and effectiveness.

Reviewing cases from a managed care database, re-searchers showed that patients with dry eye syndrome ex-perienced a significantly greater increase in total costsafter diagnosis than a matched control group (Smeeding2001). These researchers suggested a link between dry eyeand several other costly ophthalmic conditions, such asglaucoma. After dry eye syndrome diagnosis, totalcharges increased significantly more in the dry eye group(22 percent) as compared to the control group (15 per-cent, p<0.001). The higher management costs associ-ated with dry eye syndrome were primarily from morefrequent visits to physicians. In addition, dry eye pa-tients were also more likely than controls to receive arti-ficial tears, ophthalmic antibiotics, and corticosteroids.Although artificial tear preparations are sold over thecounter, topical antibiotics and corticosteroids are bothcostly and fraught with potential side effects that in-crease the need for clinical evaluation — thereby in-creasing utilization costs.

Humanistic impactRecognizing that the impact of moderate to severe

dry eye is symptom-driven, several research groups havedeveloped patient questionnaires to quantify the impactof dry eye in terms of clinical outcomes (e.g., pain) andfunctional activities (e.g., daily activity impairment).Studies evaluating the validity and reliability of theseinstruments also provide insight into the effect of dry eyesymptoms on patients’ daily lives.

In a study testing the performance and repeatability ofthe National Eye Institute Visual Function Question-

III/IV angina (see Figure, page 36). They suggested thatan effective dry eye treatment could be expected to restorepatient benefits of a magnitude comparable to those as-sociated with treating severe angina. This study also in-dicated that dry eye utilities vary in a manner consistentwith disease severity.

TREATMENT OPTIONS AND RELATIVE COSTSAs the above research suggests, dry eye symptoms per-

sist or worsen despite standard therapies. Typically, aswith mild dry eye, patients with moderate to severe dryeye rely on artificial tears. The mainstay of therapy for dryeye syndrome, artificial tears are palliative, applied sev-eral times daily, to substitute for natural tears that are de-ficient in quality or quantity. Other treatment options formore severe dry eye syndrome include punctal occlusionwith temporary or permanent plugs, electrocauterysurgery, and, for patients with Sjögren’s syndrome, hor-mone replacement therapy.

Recently approved by the United States Food and DrugAdministration, topical CsA is intended to address theunderlying inflammatory causes of dry eye syndromeand provide far more than palliative therapy for many dryeye patients (Allergan 2002). Although the exact mech-anism of action of this product is not fully understood,it is thought to act as a partial immunomodulator andanti-inflammatory, arresting T-cell activation, therebypreventing T-cells from releasing cytokines that begin theinflammatory cycle of dry eye. As CsA is utilized and its

DRY EYE SYNDROME 35


naire, researchers confirmed that the 25-question VFQ-25 is a reliable tool for quantifying dry eye pain andconcluded that low-vision patients with diagnosticallyconfirmed dry eye experience more ocular pain than doother low-vision persons. Further, the VFQ-25 can beused to stage dry eye (Nichols 2002). Table 2, on page 36,lists sample questions from the VFQ-25; the entire ques-tionnaire can be viewed online at «www.nei.nih.gov/resources/visionfunction/vfq_ia.pdf».

Citing poor correlation between dry eye symptom as-sessment and objective test results, another team of re-searchers evaluated the Dry Eye Questionnaire (DEQ) inan assessment of confirmed dry eye patients (with andwithout Sjögren’s syndrome) and controls. Concen-trating on frequency and intensity of symptoms, theyfound that 10 percent of controls, 30 percent of dry eyepatients without Sjögren’s syndrome, and 60 percent ofdry eye patients with Sjögren’s syndrome had so mucheye pain and trouble that they frequently halted theirdaily activities and closed their eyes to gain relief. The re-searchers also determined that symptom intensity in-creases as the day progresses, and they suggested that fur-ther testing of the DEQ is needed (Begley 2002).

Using another set of patient questionnaires, the DryEye Disease Impact Questionnaire (DEDIQ), the OcularSurface Disease Index (OSDI, a valid and reliable tool formeasuring disease severity, which has the psychometricproperties necessary to be used as a clinical-trial endpoint [Schiffman 2000]), the Facial Expression SubjectiveScale, and the SF-12 Health Survey, researchers deter-mined that 53 percent of dry eye patients rated theirsymptoms as severe to very severe; their average OSDIscore was 0.41 (Kozma 2000). In the OSDI system, ascore of 0 indicates no disability and a score of 1 meanscomplete disability due to dry eye symptoms. Their SF-12 physical and mental summary scores were 42.3 and50.2, respectively, compared to a United States norm of50.0. Only 25 percent of these patients reported symp-tom improvement after 1 year of treatment, while theother 75 percent complained that their symptoms failedto improve or worsened.

Although researchers have used several validated in-struments to assess dry eye, each of the available method-ologies constructs a multidimensional profile of the pa-tient’s health status. In a landmark study, researchersapplied, for the first time, several standard methodolo-gies for assessing an indexed type of humanistic outcomecalled utilities (Walt 2001). Health utilities are funda-mental values that represent a subject’s preferences forspecific outcomes, relative to states of health or treat-ments, and can be used to compare the relative impactof different diseases. In the OSDI study, patients with thesevere dry eye rated its impact as comparable to Class

TABLE 1 Impact of dry eye symptoms on daily life

Patients who said dry eye symptoms interferedwith activities most or all of the time (%)

Quality-of-life factorsLoss of confidence 38.6Decrease of leisure time 35.7Frustration with daily activities 34.3Change of activities 25.7Depression, unhappiness 25.7Need for assistance 14.3Missed outings 12.9Decrease of work time 11.4Change of work 7.1Other 22.9None of the above 27.1

Vision-related activitiesNighttime driving 32.3Reading 27.5Working at electronic monitor 25.7Watching television 17.9

SOURCE: NELSON 2000

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place in practice becomes clearer, the role of traditionalpalliative agents may change significantly.

Pharmacoeconomic analysis of dry eyeThe burden of dry eye syndrome has been assessed

across the full range of outcomes. However, in the rou-tine assessment of its therapies, researchers customarily

From version 2000.Weighted kappa values (Kw) are usedto determine the repeatability of individual VFQ-25 questions.2

Question 4 (Kw = 0.42). How much pain or discom-fort have you had in and around your eyes (e.g.,burning, itching, or aching)? Would you say it is:(Choose one)NoneMildModerateSevereVery severe

Question 16 (Kw = 0.85). How much difficulty do youhave driving at night:No difficulty at allA little difficultyModerate difficultyExtreme difficultyHave stopped doing this because of eyesightHave stopped doing this for other reasons

Question 19 (Kw = 0.42). How much does pain or discomfort in or around your eyes keep you from doing what you’d like to do:All of the timeMost of the timeSome of the timeA little of the timeNone of the time

Question 20 (Kw = 0.90). I stay home most of thetime because of my eyesight:Definitely trueMostly trueNot sureMostly falseDefinitely false

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,while ≥0.40 indicates to researchers that moderate agreement can be expected.

ADAPTED FROM NEI 2000, NICHOLS 2002

Utilities are used to develop a cost-utility analysis (see page 37). A utility of 1.00 equates to perfect health,while 0.00 equals death.

have focused mainly on safety and efficacy factors. Acomprehensive evaluation of these treatments shouldalso include investigation of their broader impact, fo-cusing on their ability to relieve the economic and hu-manistic burdens of dry eye syndrome on both individ-ual patients and society. Only a few studies have includedeconomic or humanistic assessments of any kind, notablystudies for punctal occlusion and the newly approvedophthalmic cyclosporine formulation.

Punctal occlusionAlthough punctal occlusion has been used to treat

dry eye patients for 40 years, few clinical studies have ade-quately characterized the benefits of this procedure.

In a controlled, double-masked, prospective study, re-searchers in Mexico recently determined that patientswho received bilateral collagen and silicone lacrimal oc-clusion implants in both the superior and inferior canali-culi experienced progressive clinical improvement overtime (Nava-Castaneda 2003). At 8 weeks, suffering hadbeen relieved by more than 90 percent, compared withbaseline readings. At 6 months, 86 percent of treated pa-

AIDS

Complete blindness

Moderate stroke

Severe dry eye with tarsorrhaphy

Disabling hip fracture

Class III/IV angina

Severe dry eye

Moderate angina

Moderate dry eye

Asymptomatic dry eye

Mild dry eye

Mild psoriasis 0.89

0.81

0.78

0.78

0.75

0.72

0.71

0.65

0.62

0.39

0.33

0.21

SOURCE:WALT 2001

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

DRY EYE SYNDROME 37


tients remained free of symptoms. In con-trast, symptoms remained unchangedamong patients in the sham proceduregroup. In addition, the researchers also re-ported a change in resource utilization; 76percent of patients had stopped the dailyuse of eye lubricants, thus relieving a portionof the patient’s economic burden.

Retrospectively, researchers at Wills EyeHospital, Philadelphia, established that punc-tal plug insertion is a simple method that issafe and effective in the treatment of a widerange of diseases of the ocular surface andaqueous tear deficiency, including toxic ep-itheliopathy that cannot be controlled by ar-tificial tears (Ming-Chen 2002). In addition,they focused on a common event that has aneconomic impact — spontaneous plug ex-trusion, which requires repeated medical vis-its and procedures. Of 312 plugs inserted, 14were removed — 11 because of epiphora andthree due to conjunctival erosions. Overallsuccess was about 77 percent, but would havebeen about 10 percentage points higher ifonly patients with dry eye had been includedin the study. One reason for suboptimal clin-ical results was undiagnosed blepharitis,which often coexists with dry eye. The au-thors also noted that clinicians should care-fully choose plug size and monitor patients;these could have added economic benefits.

Using data from the literature and expertopinion, Lee and colleagues developed aMarkov economic model to assess the med-ical costs and outcomes of dry eye syndrome(Lee 2000). They reported that, over thecourse of 1 year, the cost of managing andtreating a population of dry eye patientswith palliative medications, punctal plugs,and surgery is estimated to be $357,050 foran organization covering 500,000 lives.These researchers suggest their model couldbe used to quantitatively assess the impact ofnew treatments on health-system budgetsand speculated that a more effective dry eyeintervention could improve cost effective-ness by decreasing patient demand for physi-cian visits and procedures.

Cyclosporine A ophthalmic emulsionWith the recent approval of CsA oph-

thalmic emulsion, investigators have re-newed reason to apply PE assessment to dry

Basic principles of pharmacoeconomic research

PE evaluations estimate the value of the economic, clinical, andhumanistic outcomes resulting from different treatments,

which are compared to help decision makers determine optimaltherapeutic approaches for their patient populations. Severaltypes of analyses are available, including cost-minimization, cost-effectiveness, cost-benefit, and cost-utility analyses. Each type ofanalysis expresses resources consumed in terms of monetaryunits, but uses a different unit to express the outcome.

Cost minimization is the simplest of these analyses, because itassumes that the outcomes of the therapies being compared havebeen proven equivalent among treatment groups.This reducesthe analysis to a monetary comparison of resources consumed.

A cost-effectiveness comparison of two or more treatments an-alyzes the dollars spent in consumed resources and the clinicaloutcomes derived from this expenditure. Because it uses naturalunits of medical outcomes (e.g., life-years gained, percentage ofsuccessfully treated patients) to compare medical treatments, thistype of PE analysis — more than any — parallels the medicalthought process and is intuitively accepted within the medicalcommunity.That is why, in medical-decision making, cost effec-tiveness is the most commonly performed of the four analyses. Acost-effectiveness evaluation, however, cannot be used to com-pare treatments with dissimilar outcomes.

In a cost-benefit analysis, the outcomes of two dissimilar treat-ment groups, inherently expressed in dissimilar natural units, canbe estimated in terms of monetary units.This conversion allowsthe investigator to compare dollars with dollars: dollars spent inconsumed resources with the dollar value gained in clinical out-comes.Thus, a cost-benefit analysis allows the investigator tocompare costs and outcomes of unrelated health care interven-tions, such as the treatment of glaucoma and dry eye syndrome.

A cost-utility analysis evaluates the effect of treatment on soci-etal outcomes, typically expressing results in terms of health util-ities or quality-adjusted life years. A cost-utility evaluation allowsthe investigator to include the humanistic outcomes of patientpreferences or quality of life when comparing products or pro-grams with dissimilar outcomes measures.This analysis tech-nique, in effect, expands cost-benefit analyses beyond express-ing outcomes as monetary units.

The clinical characteristics of a disease and the resulting bur-den determine the relevance of each type of outcome for a PEanalysis. For example, lost work days are relevant in the evalua-tion of asthma or migraine, in which symptoms can temporarilydebilitate sufferers. More relevant to a symptom-silent disease(such as early-stage glaucoma) would be, for example, the cost ofnoncompliance, which generates greater downstream expendi-tures associated with more invasive therapies. In the case ofmoderate to severe dry eye syndrome, the burden of diseasedata indicates that both economic and humanistic outcomes areimportant to consider.

Hirsch JD, Kozma CM, Wojcik AR, Reis B. Economic and qualityof life impact of dry eye symptoms: a Sjögren’s patient sur-vey [abstract]. Invest Ophthalmol Vis Sci. 1998;39:S65.

Kozma CM, Reeder CE, Schulz RM. Economical, clinical, andhumanistic outcomes: a planning model for pharmacoeco-nomic research. Clin Ther. 1993;15:1121–1132.

Kozma CM, Hirsch JD, Wojcik AR. Economic and quality of lifeimpact of dry eye symptoms. Poster presented at theAnnual Meeting of the Association for Research in Visionand Ophthalmology, April 30–May 5, 2000, Ft. Lauderdale,Fla.

Lee JT, Teale CW. Development of an economic model to assesscosts and outcomes associated with dry eye disease. Posterpresented at the 2000 Spring Practice and Research Forumof the American College of Clinical Pharmacy, April 2–5,2000, Monterey, Calif.

Ming-Chen T, Banu Cosar C, Cohen EJ, et al. The clinical effi-cacy of silicone punctal plug therapy. Cornea.2002;21:135–139.

Nava-Castaneda A, Tovilla-Canales JL, Rodriguez L, et al. Effectsof lacrimal occlusion with collagen and silicone plugs onpatients with conjunctivitis associated dry eye. Cornea.2003;22(1):10–14.

NEI (National Eye Institute). National Eye Institute VisualFunctioning Questionnaire–25. Version 2000. Bethesda,Md: NEI, 2000.

Nelson JD, Helms H, Fiscella R, Southwell Y, Hirsch JD. A newlook at dry eye disease and its treatment. Adv Ther.2000;17(2):84–93.

Nichols KK, Begley CG, Caffrey B, Jones LA. Symptoms of ocu-lar irritation in patients diagnosed with dry eye. Optom VisSci. 1999;76(12):838–844.

Nichols KK, Mitchell GL, Zadnik K. Performance and repeatabil-ity of the NEI-VFQ-25 in patients with dry eye. Cornea.2002;21(6):578–583.

Sall K, Stevenson OD, Mundorf TK, Reis BL, and the CsA Phase3 Study Group. Two multicenter, randomized studies of theefficacy and safety of cyclosporine ophthalmic emulsion insevere to moderate dry eye disease. Ophthalmology.2000;107(4):631–639.

Schepens Eye Research Institute. Dry eye syndromes: your ques-tions answered. 2001. Available at «http://www.eri.har-vard.edu/text/dryeye.text.html». Accessed March 10, 2003.

Schiffman RM, Christianson MD, Jacobsen G, Hirsch JD, ReisBL. Reliability and validity of the Ocular Surface DiseaseIndex. Arch Ophthalmol. 2000;118:615–621.

Smeeding JE, McLaughlin C, Walt JG. Dry-eye increases inhealth care and utilization and expenditures. Poster pre-sented at the sixth annual international meeting of theInternational Society for Pharmacoeconomics andOutcomes Research, May 20–23, 2001, Arlington, Va.

Stevenson D, Tauber J, Reis BL, the Cyclosporine A Phase 2Study Group. Efficacy and safety of cyclosporine A oph-thalmic emulsion in the treatment of severe to moderatedry eye disease: a dose-ranging, randomized trial.Ophthalmology. 2000;107:967–974.

Walt JG, Schiffman RM, Jacobsen G, et al. Utility assessmentamong patients with dry eye disease. Poster presentation,exhibited at the Annual Meeting of the InternationalSociety for Quality of Life Research, Nov. 8, 2001,Amsterdam.

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eye treatments. So far, studies have included analysesfrom the economic perspective regarding reduction in ar-tificial tear and medication use after CsA treatment.

In a double-masked phase 2 study of CsA, the use ofartificial tears generally decreased at weeks 4, 8, and 12during therapy, and at weeks 2 and 4 after it (Stevenson2000).

In a phase 3 trial of 0.05 percent and 0.1 percent CsAemulsions, patients instilled 1 drop of the study medi-cation in each eye twice daily and were allowed to use ar-tificial tears as adjunctive medication at will. Over thecourse of the study, patients applying the CsA formula-tion decreased their reliance on artificial tears (Sall 2000).

A 1-year observational study using the DEDIQ deter-mined that CsA 0.05 percent is highly efficacious in treat-ing dry eye syndrome. Of 181 enrolled subjects in a pri-vate ophthalmology practice, more than 60 percentreported symptom improvement. From an economicperspective, total medication orders, including thoseused for dry eye (nonsteroidal anti-inflammatory drugs,antihistamines, artificial tears, ophthalmic antibiotics,and ophthalmic/antibiotic steroid combinations) fell 55percent in the post-CsA treatment period (Cross 2002).

CONCLUSIONProviding optimal medical care of dry eye syndrome

requires planning that is based not only on drug safetyand efficacy, but also on data relating the full value ofmedical treatments, that is, changes in economic andhumanistic outcomes that are achieved due to the treat-ment effect. Applying PE methods to assess the value oftreatments systematically can improve both the overallquality and efficacy of dry eye medical care.

Although full-range PE studies of dry eye syndrome re-main to be conducted, the course of such analyses is clear.Researchers must determine which therapies or regimensprovide the greatest effect in terms of relieving the clini-cal, economic, and humanistic burden of dry eye syn-drome, for specific patient groups at the most effective cost.

REFERENCESAlbietz JM. Dry eye: an update on clinical diagnosis, manage-

ment and promising new treatments. Clin Exp Optom.2001;84:4–18.

Allergan Inc. Allergan’s Restasis approved by the FDA [news re-lease]. Dec. 26, 2002. Available online at «http://www.restasis.com/press.html». Accessed April 6, 2003.

Begley CG, Caffery B, Chalmers RL, Mitchell GL. Use of the dryeye questionnaire to measure symptoms of ocular irritationin patients with aqueous tear deficient dry eye. Cornea.2002;21:664–670.

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 economicimplications of topical cyclosporine A for the treatment ofdry eye. Manag Care Interface. 2002;15:44–49.

DRY EYE SYNDROME 39

«PRODUCT HED»CHRONIC THER APY

tears provide temporary, albeit strictly palliative, relieffrom the effects of dry eye.

Common artificial tear ingredients include tonicity,buffering, viscosity, wetting, and lubricating agents; anti-oxidants; and preservatives (Power Graphics 1999).Tonicity agents adjust the preparation’s osmolality.Buffering agents adjust its pH level to between 6 and 8.Viscosity agents slow the flow of the solution through theeye’s drainage ducts, to extend its usefulness. Wettingagents facilitate the spread of the material over the ocu-lar surfaces, and lubricating agents supplement the lipidocclusive layer. Antioxidants prevent deterioration of theproduct when it is exposed to oxygen. Preservatives re-tard the growth of bacteria, increasing the shelf life of ar-tificial tear formulations in multiple-use vials.

Why use preservatives?Today, both preserved and preservative-free artificial

tear formulations are available. Preserved products,which on a per-use basis generally tend to cost less thannonpreserved formulations, are packaged in multiple-dose bottles. Preservative-free formulations are sold insingle-dose vials. The FDA and the U.S. Pharmacopoeiamandate the inclusion of preservatives for all multidosetopical ophthalmic medications (Abelson 2002). Over theyears, pharmaceutical companies have replaced harsherpreservatives in artificial tear preparations with gentleringredients.

Preservatives have benefits when used in ophthalmictopical medications, but experts caution against pro-longed use of artificial tears containing preservatives,especially benzalkonium chloride (BAK) and chloro-butanol, which have been shown to irritate users (Abel-son 2002). They further advise that, in contrast to BAK,sorbic acid infrequently causes adverse reactions, poly-quaternium-1 causes only superficial epithelial damage,and sodium perborate converts to hydrogen peroxideon exposure to air and then breaks down into oxygen andwater. Stabilized oxychloro complex has been found tobe safe and well tolerated, even with frequent use.

Issues in the UseOf Preservative-Free TopicalsHENRY D. PERRY, MD

ERIC D. DONNENFELD, MD

Ophthalmic Consultants of Long Island

In treating dry eye syndrome, appropriate productadministration is an important but often neglectedissue. At present, concerns about product adminis-tration apply only to topical artificial tear prepara-

tions, but in the future physicians will have the option oftreating the underlying cause of the disease, rather thanits effects, in many patients. This is because the Food andDrug Administration recently approved a new dry eyemedication, a 0.05 percent cyclosporine A (CsA) oph-thalmic formulation, marketed by Allergan as Restasis(Allergan 2002). CsA is contraindicated in patients withactive ocular infection or suspected or known hyper-sensitivity to any of its components, and therefore is notappropriate for a subset of patients.

In brief, CsA restores tear function. Unlike artificial tearmedications, which dry eye sufferers may apply four ormore times daily, CsA is applied twice daily. Because itsclinical benefits become apparent after about 3 monthsof therapy, it is reasonable to suspect that patients put ona CsA regimen will continue to use artificial tear formu-lations during the initial months of therapy. They also maycontinue to use artificial tears adjunctively thereafter, butprobably at a lower daily dosage and with an end in sight.

Until CsA gains broad utilization, the artificial tearpreparations — liquids, gels, and ointments — will con-tinue to represent the mainstay of dry eye treatment. Byincreasing humidity at the ocular surface, improving lu-brication, and smoothing the corneal surface, artificial

In a perfect world, patients would use medi-cations as prescribed. In reality, patients maycut corners, especially if they may savemoney by doing so. Clinicians and pharma-cists must acknowledge this tendency, yet atthe same time protect patients from usingcontaminated ophthalmologic agents andstrive to achieve optimal clinical outcomes.

SUMMARY

40 P&T DIGEST

CHRONIC THER APY

Although preservative-free artificial tear solutionswere developed for patients who demonstrate sensitiv-ity to preservatives, the general avoidance of preservativesmay be wise. In a rat model, researchers demonstratedthat, especially over the long term, most preservativesused in ophthalmic eyedrops have the potential to dam-age human conjunctival and corneal epithelial cells (Bec-quet 1998). Although preservatives interfere with thegrowth, multiplication, and metabolism of microbes,they have a similar effect on eukaryotic cells, which ex-plains their cytotoxicity and inflammatory cell response.Even at lower concentrations, and after a single instilla-tion, BAK was toxic to the corneoconjunctival surface.These researchers warn that prolonged exposure topreservatives is likely to produce subclinical inflamma-tion, which might lead to chronic irritation and fibrosisthat can worsen dry eye syndrome.

Several researchers indicate that the negative effects ofpreservative-free artificial tears on the eye are minor, ifnot negligible (Albietz 2001a, Albietz 2001b, Berdy 1992,Pisella 2002, Schein 1992). The primary concern relatingto the use of preservative-free artificial tear formula-tions is contamination of the contents once the patientopens the container and applies the medication. Thecontamination typically is due to contact with the pa-tient’s cornea, conjunctiva, eyelashes, or hands. Evenbacteria that are not pathologic may alter the pH valueof the medication and interfere with efficacy.

A decade ago, researchers determined that patientsusing ocular-surface medications can trigger a cycle ofmicrobial contamination between their conjunctivaeand the container (Schein 1992). This team studied 220in-use medications obtained from 101 patients withnonmicrobial ocular-surface disease. They cultured thebottle caps, a drop from each bottle obtained by inver-sion, and the contents of the bottle. They also obtainedconjunctival cultures from the patients using the med-ications and 50 age-matched controls. They harvestedpathological organisms from the conjunctivae of 34 per-cent (34/101) of patients but only 10 percent (5/50) of thecontrols.

To test the susceptibility of unpreserved eye drops tocontamination, British researchers inoculated 21 differ-ent unpreserved eye drop formulations with a knownquantity of four different microorganisms and stored thecontainers at different temperatures for as long as 28days (Oldham 1996). They recommend that unpreservedeye drops be stored at between 2 degrees and 8 degreesCelsius (35.6 to 46.4 degrees Fahrenheit) after opening,and confirmed that, in general, drops containing alky-loids or antibiotics should be discarded after 7 days. TheLothian Joint Formulary (NHS 2002) recommends thateye drops in multiple-use containers be discarded 4 weeks

after opening and that unpreserved drops be discarded1 week after opening. Neither of these products need re-frigeration.

PRODUCT USE ISSUESFor patients who need to instill artificial tears several

times daily, larger containers of medication are desirable.British researchers observed that patients who frequentlyapply eye drops may need to carry multiple single-dosecontainers, which are cumbersome (Oldham 1996). Theyalso recognized that purchasing single-dose containerscan be more than 1,000 percent as expensive.

It can be expected, then, that patients who purchaseunpreserved medications in single-dose vials will try toderive the most benefit from their dollars. A single-dosevial can provide 10 or more drops, all of which may beused to relieve symptoms in one eye; a patient who usesthe entire vial in a day does not risk contamination. Yeta patient requiring 4 drops daily may be tempted to savethe remaining medication for use beyond the first day.

In our practice, we therefore advise patients thatpreservative-free artificial tears are free of contaminationthe day they are opened, are probably not contaminatedon the second day, but are likely contaminated on thethird day and must be discarded. Our goal is to make surethat the patient at least reduces the risk of infection to alevel with which we are relatively comfortable. Consid-ering that the dry eye medications we prescribe havebeen tested and remained uncontaminated when ex-posed to room air for as long as 28 days, we are confidentthat our warning suffices to prevent patients from in-stilling contaminated medications.

CompliancePatients with dry eye may become noncompliant with

an established regimen for different reasons. Some willuse too much medication because their artificial tearsprovide insufficient relief. Some may be unable to applythe medication correctly.

In a study of noncompliance in 200 patients usingeyedrops (mean age, 26 years; range, 9 to 92 years), themain reasons that emerged for noncompliance were poormotivation (stemming from inadequate understandingof the function of the medication) and inability to use eyedrops properly (Winfield 1990). Sixty-two percent con-sistently self-administered their drops, 17 percent self-medicated when no help was available, 21 percent alwaysobtained help, and 8 percent never tried to administertheir medication. Approximately half the patients haddifficulty aiming the drop. Other problems included in-ability to squeeze the container well enough, blinking,and inability to see the tip of the container. In particu-lar, arthritic patients experienced physical difficulties

DRY EYE SYNDROME 41

CHRONIC THER APY

with administration. These researchers also reportedthat most patients were reluctant to admit they were ex-periencing problems with the process.

In a separate survey of patients by telephone, 50 per-cent (114/229) of patients with dry eye said they con-tinued to use the artificial tear solutions they had beenprescribed, while 53 percent (47 of 89) reported dis-continued use of prescribed ointments (Swanson 1998).This research detected “extreme” variability in theamount of artificial tear medication used, from patientto patient, and day to day. Patients appeared to titratetheir artificial tear dosage to their symptoms on a dailybasis; this researcher recommends patient education tofoster compliance.

TABLE Discussion points for optimizing benefit from ophthalmic medications

General instructions• If using two different types of eye drops, instill

the first, wait 5 minutes, then instill the second.• If using drops and ointment, instill the drop first,

wait 5 minutes, then apply ointment.• When using products in single-use vials,

agitate the container so that the color and/oropaqueness of its contents are uniform.

Preventing contamination• Wash hands before opening container.• Prevent container tip from touching the eye.• When finished, tighten container cap.• Single-use vials should be used immediately

after opening and discarded after use.Eye drops• Lean head back.• Instill eye drops by gently sliding skin below

eyelid over prominent point of cheekbone toform pocket.

• Put one drop into pocket.• Close eye and refrain from blinking for about 1

minute.• Press tightly (but not tightly enough to cause

injury) with one finger on inside corner of eyefor about 30 seconds after instilling drop.

• Use only 1 drop at a time.• The eye’s conjunctival fornix can accommo-

date only 1 drop at a time. Any fluid beyond 1drop will overflow.

Ointment• Start at inside corner of eye.• Squeeze thin line (about 0.5 cm) of medication

along inside of lower lid.• Blink.

Product administrationTo help patients achieve optimal benefit from oph-

thalmic medications, clinicians and pharmacists needto discuss the benefits of the chosen therapy with patientsand their at-home care providers, and the correct way toapply the medication (see Table).

CONCLUSIONAlthough new ophthalmic drug-delivery systems al-

leviate dry eye somewhat, and a new CsA ophthalmicemulsion may alleviate the syndrome in many patients,proper administration of dry eye medications remainsvital to successful treatment. The trend toward preserv-ative-free medications means patients and their care-givers must exercise care during administration to pre-vent contamination of the remaining contents in thevial. Patients should be cautioned not to instill morethan one drop of medication at a time, to prevent wast-ing the medication. Eye care clinicians can help patientsachieve optimal relief by providing a combination of themost appropriate medication with the education onproper self-medication.

REFERENCESAbelson MB, Washburn S. The downside of tear preservatives.

Rev Ophthalmol. 2002;9(5).Albietz JM. Dry eye: an update on clinical diagnosis, manage-

ment and promising new treatments. Clin Exp Optom.2001a;84:4–18.

Albietz JM, Bruce AS. The conjunctival epithelium in dry eyesubtypes: effect of preserved and non-preserved topicaltreatments. Curr Eye Res. 2001b;22:8–18.

Allergan, Inc. Allergan’s Restasis approved by the FDA [press re-lease]. December 26, 2002.

Becquet F, Goldschild M, Moldovan MS, et al. Histopathologicaleffects of topical ophthalmic preservatives on rat corneo-conjunctival surface. Curr Eye Res. 1998;17:419–425.

Berdy GJ, Abelson MB, Smith LM, George MA. Preservative-freeartificial tear preparations: assessment of corneal epithelialtoxic effects. Arch Ophthalmol. 1992;110:528–532.

NHS Lothian. Lothian Joint Formulary. Available at:«http://www.nhslothian.scot.nhs.uk/lothianformulary/11/11_8.html.» Accessed April 7, 2003.

Oldham GB, Andrews V. Control of microbial contamination inunpreserved eyedrops. Br J Ophthalmol. 1996;80:588–591.

Pisella PJ, Pouliquen P, Baudouin C. Prevalence of ocular symp-toms and signs with preserved and preservative free glau-coma medication. Br J Ophthalmol. 2002;86:418–423.

Power Graphics. Common ingredients in artificial tears.1999;3(1):1–2. Available at:«http://www.powerpak.com/PowerGraphics/1999/January/CommonIngredients.cfm». Accessed March 15, 2003.

Schein OD, Hibberd PL, Starck T, et al. Microbial contaminationof in-use ocular medication. Arch Ophthalmol.1992;110:82–85.

Swanson M. Compliance with and typical usage of artificial tearsin dry eye conditions. J Am Optom Assoc. 1998;69:649–655.

Winfield AJ, Jessiman AJ, Williams A, Esakowitz L. A study of thecauses of non-compliance by patients prescribed eyedrops.Br J Ophthalmol. 1990;74:477–480.

7. Dry eye can occur sporadically or as a chroniccondition that becomes a self-perpetuatingsyndrome.a. True.b. False.

8. Topical corticosteroids should:a. Be reserved for patients who experience

severe and recalcitrant symptoms.b. Be considered as front-line therapy for

patients on antihistamine therapy.c. Be used for 2 weeks or less for severe exacer-

bations of dry eye syndrome.d. Answers a and c.e. All the above.

9. For patients with severe dry eye, a diagnosisusually is supported by the following:a. Schirmer wetting test.b. Ocular surface dye-staining pattern.c. Tear break-up time test.d. All the above.

10. Dry eye syndrome has numerous risk factors.Which of the following are risk factors for dryeye syndrome?a. Vitamin A deficiency.b. Hormone replacement therapy.c. Arthritis.d. Answers b and c.e. All the above.

11. Preservative-free artificial tears were devel-oped:a. For patients who demonstrate sensitivity to

preservatives.b. Because preservatives are known carcinogens.c. To reduce the cost of the medication.d. To encourage the use of more medication.

12. In a survey of third-party payers, prevalenceof dry eye syndrome among persons coveredby commercial plans was determined to be:a. 0.21 percent.b. 0.35 percent.c. 1.30 percent.d. 10.00 percent.

1. Symptoms of dry eye syndrome, or kerato-conjunctivitis sicca, include all but which ofthe following?a. Gritty sensation under eyelids.b. Numbness.c. Mucous discharge.d. Increased frequency of blinking.e. Redness.

2. Despite improving ocular lubrication and in-creasing humidity at the ocular surface, artifi-cial tears and lubricants fail to:a. Accurately reproduce natural tears.b. Improve vision.c. Correct the underlying pathology that can

occur with dry eye.d. Answers “a”and “c.”

3. The AAO 2003 guidelines include all butwhich of the following goals for managingpatients with dry eye?a. To establish appropriate therapy.b. To educate the patient.c. To prevent complications.d. To reduce the use of concurrent therapies.e. To identify the causes of the condition.

4. In a population-based study, Schein (1997)estimated that dry eye symptoms are presentin:a. 1 million elderly Americans.b. 1 in 7 elderly Americans.c. 1.30 percent of Medicare managed care

covered lives.d. 0.21 percent of commercial managed care

covered lives.

5. Contamination of preservative-free artificialtear products typically is due to:a. Improper manufacturing practices.b. Contact with the patient’s cornea, conjunctiva,

eyelashes, or hands.c. Airborne microbes.d. The patient’s sneezing or coughing.

6. Artificial tears are best described as:a. Preventive therapy.b. Curative therapy.c. Palliative therapy.d. Counterintuitive therapy.

CONTINUING EDUCATION POST-TESTP&T DigestDry 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 eachquestion.There is only one correct answer to each question.

continued on page 45

42 P&T DIGEST

CME CREDIT FOR PHYSICIANSSponsored by The Chatham Institute

See page 44 for answer sheet for pharmacists

I certify that I have completed this educational activityand post-test and claim ______ credits.

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To receive CME credit, complete answer sheet/evaluationform and mail or fax to:

Office of Continuing EducationThe Chatham Institute26 Main Street, 3rd FloorChatham, NJ 07928Fax: (973) 701-2515

Credit will be awarded upon successful completion of as-sessment questions (70 percent or better) and completionof program evaluation. If a score of 70 percent or better isnot achieved, no credit will be awarded and the registrantwill be notified.

Please allow up to 6 weeks for processing.

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DRY EYE SYNDROME 43

EXAMINATION: Place an X through the box of the letterthat represents the best answer to each question on pages42 and 45.There is only ONE answer per question. Place allanswers on this answer form:

PROGRAM EVALUATIONSo that we may assess the value of this self-study program,we ask that you please fill out this evaluation form.

Have the activity’s objectives been met? 1. Describe the etiology of dry eye syndrome,

or keratoconjunctivitis sicca (KCS), and risks of untreated disease.

2. Outline the prevalence of KCS and the economic implications thereof.

3. Review the American Academy of Ophthal-mology guidelines for treatment of KCS.

4. Explain the mechanisms of action of pharmacotherapies for KCS.

5. Summarize pharmacoeconomic data ofemerging anti-inflammatory agents for KCS.

6. Identify considerations in proper handling andadministration of preservative-free topicalagents for KCS.

Was this publication fair, balanced, and free of commercial bias? Yes _____ No _____

If no, please explain: _______________________________________________________________________________

Did this educational activity meet my needs, contributeto my personal effectiveness, and improve my ability to:

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Treat/manage patients? 5 4 3 2 1 n/aCommunicate with patients? 5 4 3 2 1 n/aManage my medical practice? 5 4 3 2 1 n/aOther __________________ 5 4 3 2 1 n/a

Effectiveness of this method of presentation:Very

Excellent good Good Fair Poor

5 4 3 2 1

Time spent reading this publication: H ____ M _______

What other topics would you like to see addressed?________________________________________________________________________________________________Comments: ______________________________________________________________________________________________________________________________________

A B C D E1. �� 2. �� 3. �� 4. �� 5. �� 6. �� 7. �� 8. �� 9. �� 10. ��

A B C D E11. �� 12. �� 13. �� 14. �� 15. �� 16. �� 17. �� 18. �� 19. �� 20. ��

Yes No

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CPE CREDIT FOR PHARMACISTSSponsored by The Chatham Institute

See page 43 for answer sheet for physicians

I certify that I have completed this educational activityand post-test and claim ______ credits.

Signature: _______________________________________

First name, MI ____________________________________

Last name, degree ________________________________

Title ___________________________________________

Affiliation _______________________________________

Specialty ________________________________________

Address ________________________________________

City _____________________ State _____ ZIP ________

Daytime telephone (_______) _______________________

Fax (________) ___________________________________

E-mail __________________________________________

Pharmacist — This program is approved for 3.0 contacthours (0.3 CEU).

ACPE program number: 812-000-03-016-H01.Release date: Dec. 15, 2003.Expiration date: Dec. 15, 2004.

Complete answer sheet/evaluation form and mail to:

Office of Continuing EducationThe Chatham Institute26 Main Street, 3rd FloorChatham, NJ 07928

Fax: (973) 701-2515

Credit will be awarded upon successful completion of thepost-test (a score of 70 percent or better) and activity eval-uation. If a score of 70 percent or better is not achieved, nocredit will be awarded and the registrant will be notified.

Please allow up to 6 weeks for processing.

The cost of this activity is provided at no charge to the par-ticipant through an educational grant from Allergan.

CMC3000

EXAMINATION: Place an X through the box of the letterthat represents the best answer to each question on pages42 and 45.There is only ONE answer per question. Place allanswers on this answer form:

A B C D E1. �� 2. �� 3. �� 4. �� 5. �� 6. �� 7. �� 8. �� 9. �� 10. �� 11. �� 12. �� 13. �� 14. �� 15. �� 16. �� 17. �� 18. �� 19. �� 20. ��

PROGRAM EVALUATIONTo receive continuing education credit, please answer allinformation requested below.This assures prompt and ac-curate issuance of your continuing education certificate.

Please rate this program as follows:Very

Excellent good Good Fair Poor

Overall quality of program 5 4 3 2 1Content 5 4 3 2 1Relevance to objectives 5 4 3 2 1Effectiveness of

this format for learning 5 4 3 2 1Value to me in my

daily responsibilities 5 4 3 2 1

How long did it take you to complete this continuingeducation activity?Hours ______ Minutes _______

Requested topics/skills to address in future programs:

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CONTINUING EDUCATION ANSWER SHEET/REQUEST FOR STATEMENT OF CREDITP&T DigestDry Eye Syndrome

44 P&T DIGEST

®

13. If inflammation is considered to be a cause of dry eye syndrome, then suppressing thecytokine-mediated inflammation responsethat occurs at a histological level can apply to dry eye regardless of the disease-state association.a. True.b. False.

14. In tears, lipid is:a. A mixture of water, salt, and proteins.b. A surface layer that retards evaporation.c. The film that coats the corneal surface.d. A secretion that degrades the quality of the

tears.

15. The use of tear substitutes is indicated for pa-tients with mild dry eye syndrome. For pa-tients with more severe disease, which of thefollowing is not necessarily indicated?a. Spectacle side shields.b. Nonpreserved tear substitutes or ointments,

gels, and emulsions.c. Laser surgery.d. Moisture inserts.e. None of the above.

16. A 1998 study of individuals with Sjögren’ssyndrome found that, on average, this subsetof dry eye patients experiences ocular irrita-tion that interferes with activities of daily living on all but 29 days each year.a. Trueb. False.

17. Overutilization costs in dry eye syndrome frequently arise from:a. Corneal transplantation.b. Low patient satisfaction with palliative ther-

apy.c. A loss of productivity.d. None of the above.

18. In a survey of patients with dry eye disease,which quality-of-life factor was most oftenmentioned as being affected by the disease?a. Decrease of leisure time.b. Decrease of work time.c. Depression, unhappiness.d. Loss of confidence.

19. Which of the following statements is true?a. Cytokines are hormone-like proteins that reg-

ulate the immune response.b. Cytokines are a subset of leukocytes involved

in signal transduction in the cell membrane.c. Cytokines have antigen-receptor complexes

on their surfaces.d. The underproduction of cytokines can dam-

age tissue.

20. In dry eye syndrome, cyclosporine A:a. Mediates mucosal secretions.b. Promotes cytokine release to reduce inflam-

mation.c. Prevents release of cytokines that incite in-

flammation.d. Inhibits release of a collagenous enzyme that

incites inflammation.

CONTINUING EDUCATION SELF-TEST, continued

P&T DigestDry Eye Syndrome

DRY EYE SYNDROME 45

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