Dry Eye Syndrome

Transcription

Dry Eye Syndrome

P&T DIGEST
A PEER-REVIEWED COMPENDIUM OF FORMULARY CONSIDERATIONS
DRY EYE SYNDROME
• Historical
perspectives
• Prevalence
and economic
implications
• Etiology of disease
• 2003 AAO
guidelines
for treatment
• Drug-therapy
review
• Pharmacoeconomic
data
Continuing education credit for physicians and pharmacists
sponsored by The Chatham Institute
• Proper
medication use
SUPPLEMENT TO
M
A
N
A
G
E
D
Care
Vol. 12, No. 12
December 2003
This program is supported by an educational grant
from Allergan
A B O U T T H I S P U B L I C AT I O N
P&T DIGEST
Chief Medical Editor
John D. Sheppard, MD, MMSc
Faculty
Eric D. Donnenfeld, MD
Richard G. Fiscella, RPh, MPH
Jan D. Hirsch, PhD
Henry D. Perry, MD
Steven E.Wilson, MD
Editor
Michael D. Dalzell
Consulting Editor
John A. Marcille
Contributing Editors
Tony Berberabe
Bob Carlson
Frank Diamond
William W. Edelman
Linda Felcone
Maxine Losseff
Jack McCain
Paula Sirois
Design Director
Philip Denlinger
Group Publisher
Timothy P. Search, RPh
Director, New Product Development
Timothy J. Stezzi
Eastern Sales Manager
Scott MacDonald
Senior Account Manager
Blake Rebisz
Midwest Sales Manager
Terry Hicks
Director, Production Services
Waneta Peart
MANAGED CARE (ISSN 1062-3388) is published monthly by
MediMedia USA Inc., at 780 Township Line Road,Yardley, PA
19067.This is Volume 12, Issue 12. Periodical postage paid at
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685-2782. Copyright ©2003 MediMedia USA Inc.
A Tool for Formulary Decision Makers
T
he understanding of keratoconjunctivitis sicca (KCS), also
known as dry eye syndrome, has changed in the past 5 years.
Until recently, it was thought to have been due to aqueous insufficiency. Today, it is understood that KCS is a multifactorial disease that also involves inflammation of the ocular surface and
lacrimal gland, neurotrophic deficiency, and meibomian dysfunction. This change in understanding, reflected in the 2003 AAO Dry
Eye 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 pharmacists
who serve on pharmacy and therapeutics committees up-to-date
information about the most efficacious and cost-effective medical
treatments available. Relatively little published data exist in a centralized format about medical therapies for dry eye syndrome,
compared with information about other chronic conditions. This
publication, a digest of existing knowledge and best practices, serves
as a valuable tool for formulary decision makers and is an important contribution to the medical literature.
Editorial Advisory Board
Chairman, Editorial Advisory Board and Chief Medical Editor
P&T Digest | Dry Eye Syndrome
Program Director, Department of Ophthalmology
Eastern Virginia Medical School
Norfolk, Va.
Richard G. Fiscella, RPh, MPH
Assistant Director, Clinical Services/Ambulatory Care
University of Illinois at Chicago (UIC) Hospital
Department of Pharmacy
Clinical Associate Professor
UIC Department of Pharmacy Practice
Clinical Coordinator
UIC Eye and Ear Infirmary
Chicago
This publication is made possible by an educational grant from
Allergan.
P&T DIGEST
DRY EYE
SYNDROME
Chief Medical Editor
P&T DIGEST
DRY EYE SYNDROME
Continuing education objectives
and accreditation statements .......................................................4
INTRODUCTION
Dry Eye Moves Beyond Palliative Therapy ................................6
Keratoconjunctivitis sicca, or dry eye syndrome, is a complex condition characterized by
inflammation of the ocular surface and tear-producing glands. When dry eye is controlled, there is significant potential for improved quality of life and cost savings.
JOHN D. SHEPPARD, MD, MMSC
OVERVIEW
Dry Eye: Prevalence, Utilization,
and Economic Implications .........................................................9
Epidemiological reports worldwide vary, but about one in seven American adults may
experience frequent symptoms of dry eye syndrome. Untreated disease drives unnecessary resource utilization and poses risks for expensive complications.
MICHAEL D. DALZELL
ETIOLOGY
Inflammation: A Unifying Theory for the Origin
of Dry Eye Syndrome ..................................................................14
Dry eye syndrome has been difficult to diagnose and treat, due to its heterogeneity. These
difficulties are being overcome, however, as evidence of a common etiology emerges. An
inflammatory mechanism appears to underlie the condition.
STEVEN E. WILSON, MD
DETECTION AND TREATMENT
Guidelines for the Treatment of Chronic Dry Eye Disease...20
Recently released guidelines from the American Academy of Ophthalmology provide a
framework for managing this chronic disorder. With the treatment approaches outlined
in this article, symptoms and signs can be alleviated and the potential for ocular surface
damage and impaired vision can be minimized.
PHARMACOTHERAPEUTIC OPTIONS
Medications for Dry Eye Syndrome:
A Drug-Therapy Review.............................................................26
Early interventions attempted to replace water lost from the tear film. Emerging therapies are directed at underlying inflammation. This new focus uses pharmacologic agents
to manage dry eye disease and to control or reverse corneal damage.
HENRY D. PERRY, MD
ERIC D. DONNENFELD, MD
COST-EFFECTIVENESS
Considerations in the Pharmacoeconomics of Dry Eye..........33
Until recently, all treatments for dry eye have been palliative. A new treatment,
cyclosporine A ophthalmic emulsion, addresses the disease’s underlying causes.
It warrants pharmacoeconomic analysis to determine its place in managed care.
JAN D. HIRSCH, PHD
CHRONIC THERAPY
Issues in the Use of Preservative-Free Topicals ........................39
Preservative-free ophthalmologic agents can be easily contaminated once the patient
opens the container. Clinicians must acknowledge this and protect patients from using
contaminated medication and to assure optimal clinical outcomes.
HENRY D. PERRY, MD
CONTINUING EDUCATION
Post-test .......................................................................................42
Physician CME answer sheet/evaluation form ........................43
Pharmacist CPE answer sheet/evaluation form.......................44
Cover art:
Paul Klee, 1914, 217
St. Germain near Tunis
(Inland)
21.8 x 31.5 cm
Watercolor on paper
Musée national d'art
moderne, Centre Georges
Pompidou, Paris
© 2003 Artists Rights
Society (ARS), New York /
VG Bild-Kunst, Bonn
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
P&T DIGEST
Dry Eye Syndrome
GENERAL INFORMATION
CONTINUING EDUCATION
Continuing education credit is offered to physicians
and pharmacists who read pages 6 through 41 of this
publication, complete the post-test on pages 42 and 45,
and fill out the appropriate evaluation form on either
page 43 (physicians) or 44 (pharmacists).
Medical accreditation
The Chatham Institute is accredited by the Accreditation Council for Continuing Medical Education (ACCME)
to provide continuing medical education for physicians.
The Chatham Institute designates this educational
activity for a maximum of 3.0 category 1 credits toward
the AMA Physician’s Recognition Award. Each physician
should claim only those credits that he/she actually
spent in the activity.
This activity has been planned and implemented in
accordance with the ACCME Essential Areas, Elements,
and Policies.
PURPOSE AND OVERVIEW
This activity is designed to educate health care practitioners and managed care professionals about current
and emerging treatments for dry eye syndrome. Recent
developments in the etiology of dry eye have triggered
the development of new pharmacotherapeutic treatment strategies, prompting physicians, patients, and
payers to request information about the status and
effectiveness of current and emerging therapies.The
content of this program was developed on the basis of
faculty perceptions of significant trends or issues.
Educational objectives
After reading this publication, the participant should
be able to:
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 Ophthalmology
guidelines for treatment of KCS and design appropriate treatment for patient care.
4. Explain the mechanisms of action of pharmacotherapies for KCS.
5. Summarize pharmacoeconomic data of emerging
anti-inflammatory agents for KCS.
6. Identify considerations in proper handling and
administration of preservative-free topical agents
for KCS.
Target audiences
Managed care organization medical directors and
pharmacy directors; practicing primary care physicians,
ophthalmologists, and pharmacists; members of pharmacy and therapeutics committees.
Continuing education credit sponsored by
The Chatham Institute.
4
P&T DIGEST
Pharmacy accreditation
The Chatham Institute is approved by the
American 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 be
awarded upon successful completion of the post-test
and 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 members
John D. Sheppard, MD, MMSc, professor of ophthalmology, microbiology, and immunology, Eastern Virginia
Medical School; Timothy P. Search, RPh, group publisher,
MANAGED CARE, published by MediMedia USA; Michael D.
Dalzell, editor, custom publications, Managed Markets
Publishing Group, MediMedia USA.
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
PRIMARY FACULTY
Eric D. Donnenfeld, MD
Founding Partner
Ophthalmic Consultants of Long Island
Lynbrook, N.Y.
Jan D. Hirsch, PhD
Director, Clinical Research
Prescription Solutions
Costa Mesa, Calif.
Henry D. Perry, MD
Senior Founding Partner
Lynbrook, N.Y.
John D. Sheppard, MD, MMSc, acknowledges grant
and research support from Alcon, Allergan, Bausch &
Lomb, Ciba Vision, GlaxoSmithKline, Insite Pharmaceuticals, Isis Pharmaceuticals, Ista Pharmaceuticals,
Lumenis, Novartis, Santen, and Science-Based Health.
He has consulting relationships with Allergan, Bausch &
Lomb, Ciba Vision, Insite Pharmaceuticals, Isis Pharmaceuticals, Ista Pharmaceuticals, Novartis, Santen, and
Science-Based Health. He is on speaker’s bureaus for
Alcon, Allergan, Bausch & Lomb, Ciba Vision, GlaxoSmithKline, Lumenis, Novartis, Santen, and ScienceBased Health.
Steven E.Wilson, MD, acknowledges a consulting
relationship with Allergan. He is on the speaker’s
bureau for Allergan.
PUBLISHER’S STATEMENT
Professor of Ophthalmology, Microbiology,
and Immunology
Norfolk,Va.
Steven E.Wilson, MD
Professor and Chairman,
Department of Ophthalmology
Grace E. Hill Professor in Vision Research
University of Washington
Seattle
Conflict-of-interest policy and disclosures
of significant relationships
As an accredited provider, The Chatham Institute
requires that its faculty comply with ACCME Standards for
Commercial Support of Continuing Medical Education
and disclose the existence of any significant financial
interest or any other relationship a faculty member may
have with the manufacturer(s) of any commercial product(s) or device(s). It also requires the faculty to disclose
discussion of off-label uses in their presentations.
The opinions expressed herein are those of the symposium faculty, and do not necessarily reflect the views
of Allergan Inc.,The Chatham Institute, or the publisher,
editor, or the editorial boards of this publication or
those of the journals MANAGED CARE and P&T.
Clinical judgment must guide each clinician in
weighing the benefits of treatment against the risk of
toxicity. Dosages, indications, and methods of use for
products referred to in this special supplement may
reflect the clinical experience of the authors or may
reflect the professional literature or other clinical
sources, and may not necessarily be the same as indicated on the approved package insert. Please consult
the complete prescribing information on any products
mentioned in this special supplement before administering.
Eric D. Donnenfeld, MD acknowledges grant and
research support from Allergan. He also has a consulting relationship with Allergan.
Richard G. Fiscella, RPh, MPH acknowledges grant
and research support from Allergan, Merck, and Pharmacia. He has consulting relationships with Allergan,
Merck, and Pharmacia.
Jan D. Hirsch, PhD, acknowledges stock ownership in
Allergan.
Henry D. Perry, MD, acknowledges grant and research
support from Allergan. He also has a consulting relationship with Allergan.
DRY EYE SYNDROME
5
INTRODUCTION
INTRODUCTION
Dry Eye Moves Beyond
Palliative Therapy
JOHN D. SHEPPARD, MD, MMSC1
SUMMARY
Keratoconjunctivitis sicca, or dry eye syndrome, is a complex condition characterized
by inflammation of the ocular surface and
tear-producing glands. Emerging awareness
of the etiology of dry eye has led to the development of highly effective therapy.When
dry eye is controlled, there is significant potential for cost savings.
D
ry eye syndrome, also known as keratoconjunctivitis sicca, is a common condition reported by patients who seek ophthalmologic
care. 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 eye
not producing sufficient tear flow is understood within
the ophthalmologic community to be a multifactorial
disease. Many family physicians and payers, however,
may still perceive dry eye to be little more than an irritation and thus may not be aware of emerging specific
potent therapies.
Research has shown that dry eye is a complex condition, the hallmark of which is inflammation of the ocular surface and tear-producing glands (Stern 1998). This
awareness has fostered the development of highly effective anti-inflammatory therapies. These treatments boast
the potential for dramatic advances in quality of life for
millions of people whose condition interferes with activities of everyday living.
Improved patient satisfaction and clinical outcomes
alone should be the raison d’être for this volume of P&T
Digest, which seeks to promote awareness of dry eye and
innovative treatment strategies. The reality of medical
practice in a managed care environment, however, is that
therapy must not only be effective, but cost efficient.
Anti-inflammatory therapy carries prospects for favorable pharmacoeconomics, in terms of reduced office visits and avoidance of complications, let alone enhanced
6
P&T DIGEST
patient satisfaction. When
it comes to formulary considerations, health plans
seek data that demonstrate
each drug’s therapeutic effectiveness and potential for
cost offset. The information
herein is intended to help
pharmacy and therapeutic
committees with this task.
ETIOLOGY AND
PREVALENCE
The theory and epidemi- John D. Sheppard, MD, MMSc
ology of dry eye and therapeutic considerations are discussed at length elsewhere
in this volume of P&T Digest. In general, dry eye comprises a heterogeneous assortment of conditions involving aqueous insufficiency, inflammation of the ocular
1
John D. Sheppard, MD, MMSc, received a Masters in
Medical Science and his MD from Brown University on a
full Armed Forces Health Professions Scholarship. He spent
four years with the U.S. Navy as 6th Fleet medical officer
and chief of Family Practice. He completed his Ophthalmology residency at the University of Pittsburgh Eye and
Ear Institute and a 30-month fellowship in corneal diseases,
uveitis, third-world blindness, and ocular immunology at
the Proctor Research Foundation at the University of
California–San Francisco. In 1989, Sheppard joined Virginia Eye Consultants and the ophthalmology, microbiology,
and immunology faculty of Eastern Virginia Medical School,
where he now serves as Ophthalmology program director
and as clinical director of the Thomas R. Lee Center for Ocular Pharmacology. Sheppard has served as an associate examiner for the American Board of Ophthalmology for seven
years and is now a mentor examiner. He has participated
as principal investigator in more than 45 clinical research
trials. Sheppard has authored more than 100 peer-reviewed
abstracts, articles, and chapters. He received the American
Academy of Ophthalmology Honor Award in 1995.
INTRODUCTION
surface and lacrimal glands, neurotrophic deficiency,
and meibomian gland dysfunction. Iatrogenic disease, in
which topical prescription medications create hypersensitivity or toxicity in the eye and oral medications create lacrimal hyposecretion, also can induce symptoms of
dry eye.
Estimates of the prevalence of dry eye syndrome vary
widely (see the following chapter, beginning on page 9),
but as many as 40 million Americans may either have
symptoms of dry eye or remain at risk for it. Postmenopausal women may be the largest risk group, due to
decreases in hormonal levels that can lead to loss of antiinflammatory protection and decreased lacrimal function.
Individuals with concomitant inflammatory conditions,
particularly allergies, asthma, and collagen vascular disease, are also at risk. Patients who have had eye surgery
that could compromise the neurogenic support of the
cialty — making it difficult to diagnose and treat ocular
conditions adequately in a family physician’s office, clinic,
or emergency room.
NEW TREATMENT, COST-SAVING POTENTIAL
Before medical research transformed our understanding of dry eye, treatment had been limited to the use
of artificial tears, ointments, and such nonpharmacologic
therapies as punctal occlusion, environmental control,
moisture-retaining eyewear, and surgery. Each had limited effectiveness, and few produced lasting improvement in patients’ quality of life.
Today, dry eye can be treated successfully with antiinflammatory agents, the most beneficial of which is
topical cyclosporine. In four multicenter, randomized,
controlled clinical studies of approximately 1,200 patients with moderate to severe keratoconjunctivitis sicca,
HUMAN FACTORS — QUALITY OF LIFE AND PATIENT SAFETY —
SHOULD MERIT CONSIDERATION WHEN DECISIONS ABOUT ACCESS
TO NEW MEDICATIONS ARE MADE.
ocular-surface epithelium — LASIK, transplants, or older
extracapsular cataract procedures, for instance — could
have moderate to severe dry eye, but this condition is
frequently unrecognized. This suggests at least some degree of undiagnosed disease that belies published estimates of prevalence; more importantly, these groups,
taken together, make up a sizeable universe of dry eye candidates, with an equally impressive price tag.
This impressive demographic emphasizes the importance of early detection and effective treatment, not only
from the perspective of function or comfort, but also in
terms of recognition of what may be a systemic disease
with potentially devastating effects on the individual.
Patients with dry eye are at direct risk for potentially
blinding infections, including bacterial keratitis (Lemp
1997), and they present with higher risks for routine
procedures, such as LASIK. Indirectly, dry eye can be a
marker for secondary conditions. The cornea has more
nociceptors or pain receptors per square millimeter than
any other place in the body, making it one of the most
painful targets of diffuse autoimmune conditions. The
ophthalmologist or primary care physician, then, must
be attuned to the likelihood that a systemic disease is behind the patient’s complaints of dry eye.
Family physicians should always refer complaints of
dry eye to an ophthalmologist. Ocular problems are
unique — unfamiliar to many other physicians, in part
because the instrumentation is foreign to every other spe-
cyclosporine ophthalmic emulsion (0.05 percent)
demonstrated statistically significant increases in
Schirmer wetting at 6 months (Allergan 2003). This is the
first prescription product for dry eye targeting well beyond palliative therapy, addressing the root inflammation
of dry eye. Thus, demand for cyclosporine within this patient population may well prove to be high.
If so, this product will get the attention of managed
care pharmacy directors and, one hopes, that of medical
directors as well. Managed care organizations are routinely criticized for looking at expenditures in silo fashion, yet new systemic agents increasingly demonstrate a
marked potential for offsetting nonpharmacy costs.
When dry eye is controlled, there is significant potential
for cost savings in a number of areas: complication costs,
overutilization costs, opportunity costs, and intangibles.
Some complication costs are derived from sequelae of
untreated dry eye and can be significant. For instance,
bacterial keratitis, mentioned earlier, is costly and can
lead to corneal transplantation — a $20,000 procedure.
Other complication costs can result from elective surgery.
There are 1.5 million laser procedures and another 1.5
million cataract surgeries annually in the United States
(Moretti 2000, Desai 2001), and dry eye is a potential
complication of both procedures. When surgical patients
take longer to heal and require more follow-up visits,
there is added expenditure to the system.
Overutilization cost offsets represent another group
DRY EYE SYNDROME
7
INTRODUCTION
of potential savings. Some of these are easily identified,
such as decreased use of artificial tears or reduced officevisit utilization that stems from poor patient satisfaction
and compromised lifestyle due to dry eye symptoms.
Until very recently, practitioners have been able to offer
patients only palliative therapy; many of these individuals jump from physician to physician in search of relief
from their progressively debilitating condition. In their
modest way, these patients chronically and unnecessarily tax the health care system.
Other overutilization costs are more subtle. The more
than 3 million elective eye procedures each year in the
United States often involve patients who are predisposed
to dry eye; cataract patients, for instance, tend to be
older, while some LASIK patients dislike their contact
lenses — often because their dry eyes make wearing
contacts irritating or unbearable. Some of these elective
procedures can, in fact, be avoided altogether by controlling the dry eye.
Yet another group of potential savings is in opportunity costs outside the health care system. These include
indirect costs, such as loss of productivity attributed to
morbidity, and reduced comfort and convenience to patients. Bacterial keratitis may result in permanent scarring. Without a corneal transplant, these patients can suffer loss of effectiveness relative to areas such as work
performance, night driving, caring for family members,
or engaging in a favorite activity. The projections can play
out in various ways — a prospective fiscal analysis of this
nature would hinge on the variables selected for study.
Nevertheless, when opportunity costs are factored in, the
overall costs to the health care system and to society are
logarithmically accelerated.
Finally, intangibles include a satisfied patient population being offered a first-in-class drug therapy that represents a new paradigm in dry eye treatment. Contented
patient clients reflect well on any health care organization, creating goodwill, an open dialog, new patient referrals, less confrontation, and more personable and appropriate access patterns.
NONECONOMIC CONSIDERATIONS
Opportunity 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 satisfaction, and patient safety — merit consideration when
decisions about access to new medications are made.
Dry eye is the most prevalent chronic ocular surface
disease. Ophthalmologists share the frustration experienced by patients for whom artificial tears and punctal
occlusion are ineffective. These treatments also are inconvenient; in such environments as airplanes, dry climates, or heated or air conditioned rooms, some patients
8
P&T DIGEST
must apply artificial tears several times each hour, with
little lasting relief exacerbated by protracted blurred vision. Health plans can improve the satisfaction of millions of members who have moderate to severe dry eye
disease by imparting appropriate access to newer treatments. Further gains might also be achieved through
tasteful and intellectually sound marketing of newly
available technology to selected existing patients, physicians, and potential clients. Rightly, such publicity should
be limited through concerns regarding creation of excessive unnecessary demand.
Safety is a primary ingredient in the success of outcomes-driven medical practice. With the knowledge that
has been obtained through study of the pathogenesis of
dry eye, our approach to treatment has changed accordingly; over the past few years, ophthalmologists have
begun to prescribe custom formulations of cyclosporine
for dry eye patients. While these formulations have been
reasonably efficacious in treating disease, they can be
uncomfortable, difficult for patients to obtain, and — as
off-formulary compounds — expensive for patients
(Wilson 2001). Moreover, these compounds inherently
possess a more threatening side-effect profile than do
products that have or will eventually receive approval
from the U.S. Food and Drug Administration.
We have learned that dry eye is a systemic disease and
that it responds well to cyclosporine anti-inflammatory
therapy. Agents coming to market and in development
have altered the paradigm of treatment radically. This is
an exciting time for medical professionals and for patients, who undoubtedly will clamor for access to these
therapies. As new therapeutic options become available,
an opportunity exists to create standards for their utilization that balances everyone’s interests while making
them accessible to people who will benefit the most from
them.
REFERENCES
Allergan, 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 vision
and hearing among older Americans. U.S. Centers for Disease Control and Prevention, National Center for Health
Statistics. 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 deficiencies. In: Tasman W, Jaeger E, eds. Duane’s Clinical Ophthalmology. Philadelphia: Harper and Row. 1997.
Moretti M. U.S. laser vision correction market explodes. Eye
World. 2000;12:29–31.
Stern ME, Beuerman RW, Fox RI, et al. The pathology of dry eye:
the interaction between the ocular surface and lacrimal
glands. Cornea. 1998;17(6):584–589.
Wilson SE. Dry Eye Disease: New Paradigm, New Treatment?
Research to Prevent Blindness, New York. 2001.
OVERVIE W
OVERVIE W
Dry Eye: Prevalence, Utilization,
and Economic Implications
MICHAEL D. DALZELL1
D
ry eye syndrome is believed to affect more
than 4 million Americans (Schein 1997).
The nature of the condition, however,
suggests that the universe of individuals
with untreated disease — whether the symptoms
are ocular or otherwise in origin — may be larger.
Dry eye is a common disorder, characterized by inflammation of the ocular surface and lacrimal
glands. Often, dry eye symptoms serve as a marker
for systemic illness.
This would suggest that health plans and practitioners that place an emphasis on detection and
treatment of dry eye syndrome — sometimes dismissed as a trivial complaint — will benefit from
improved clinical and financial outcomes. Beyond
considerations of systemic illness, untreated dry
eye itself can lead to corneal damage and visual impairment (Lemp 1987).
The next several pages provide a statistical snapshot of dry eye syndrome: its prevalence, populations at risk, potential complications, associated
conditions, the demands dry eye places on health
care utilization, and the ramifications for payers.
1
Michael D. Dalzell is editor of P&T DIGEST and is managing editor of MANAGED CARE, a peer-reviewed journal.
EPIDEMIOLOGY
The most commonly cited estimate of prevalence in the United States is derived from a population-based
study of 2,482 elderly people in Maryland. About 1 in 7 subjects age 65 to 84 reported symptoms of dry eye
often or all of the time. Extrapolated to the general population, Schein (1997) estimated that 4.3 million Americans in this age cohort suffer from ocular irritation and that 1 million have diagnosable disease. Moss (2000) reported similar overall prevalence (14.4 percent) in a larger cohort (3,722 subjects between ages 48 and 91).
While Schein found no correlation of disease with age or sex, other researchers have made such associations.
Moss noted that after age 59, prevalence more than doubled. A separate Australian study of 926 subjects age 40
and older found generally higher prevalence of dry eye in women (Figure 1).
FIGURE 1 Prevalence by age and sex
%
35
31.8
Clinical signs of dry eye (%)*
30
31.3
Symptoms of dry eye (%)†
25
20.0
20
15
13.6
12.6
10.0
10
6.0
5.9
5
4.1
4.7
6.9
6.3
2.5
3.2
4.4 3.9
6.3
4.7
2.5 2.4
0
Sex:
Age:
F
M
40–49
F
M
50–59
F
M
60–69
F
M
70–79
F
M
80–89
* As diagnosed by one or more tests.
† Self-reported symptoms, not including subjects with hay fever.
SOURCE: MCCARTY 1998
DRY EYE SYNDROME
9
OVERVIE W
EPIDEMIOLOGY, continued
ology of dry eye. As such, definitions of dry eye
syndrome have differed from study to study, making results incomparable (Brewitt 2001).This is
complicated by the lack of a standardized clinical
testing protocol to diagnose the condition.
The effect of this diagnostic void is illustrated in
Figure 3. In one study, four diagnostic tests yielded
wide differences in results among patients who
complained of one or more severe dry eye symptoms; the tests also varied greatly in their ability to
discriminate between signs and symptoms. Relatively few patients received diagnoses compatible
with their symptoms.
Claims-based studies
Claims-based prevalence estimates provide a
different perspective from population-based
studies. Claims studies measure the impact of
symptoms that require medical attention —
a perspective that is valuable to payers.
In one study of claims data in a managed care
environment covering 12 million lives, researchers
noted a strong connection between dry eye and
both advancing age and sex (Figure 2). Females
were more likely to have a dry eye-related diagnosis or procedure.Women experienced a sharp increase in prevalence earlier than men — around
age 45, or roughly the onset of menopause.
FIGURE 3 Test used to detect clinical signs
FIGURE 2 Rates of diagnoses and
procedures, by age and sex
Percentages are of patients reporting ≥1 severe symptom
Test result (%)
Rate per 100,000
33
1997
Abnormal (diagnosis)
1653.4
1998
Normal (no diagnosis)
1427.8
20
18
12
9
8
9
9
689.6
567.7
385.9
273.0 221.8
319.6
Fluorescein
Rose bengal
Schirmer Tear-film breakup
Figures are rounded to nearest whole percentage point.
SOURCE: MCCARTY 1998
Female
Male
Age <65
Age ≥65
Each of these diagnostic tests has limited usefulness when performed alone, yet performing multiple
tests is rarely feasible or cost-effective. Pflugfelder
(1998) has proposed an algorithm for determining
the diagnostic utility of tests. Meanwhile, the emerging recognition of dry eye as a multifactorial inflammatory condition may lead to consensus on diagnostic testing, as well as a more thorough understanding
of iatrogenic contributions to dry eye syndrome.
SOURCE:YAZDANI 2001
Explaining variability in prevalence
Epidemiological studies of dry eye syndrome in
the United States and other countries suggest
wide differences in prevalence.The difficulty in
pinpointing the extent of disease stems, in part,
from a previous lack of understanding of the etiHIGH-RISK POPULATIONS FOR 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 cataract
surgery
• 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)
ADAPTED FROM: AAO 2003, BREIL 2002, MCCARTY 2000, MOSS 2000, SCHAUMBERG 2001
10
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OVERVIE W
UTILIZATION TRENDS
Low patient satisfaction has been documented
among individuals with moderate to severe dry eye
syndrome (Lubniewski 1990).The chronic symptomatology of dry eye, as well as relatively ineffective traditionally available treatment modalities, spawns
frustration and high health-resource utilization
among patients seeking relief from the condition.
Office visits
In the Schein (1997) study, 73 percent of subjects
who reported frequent dry eye symptoms visited an
eye care professional in the past year. A smaller survey, conducted among patients participating in
phase 2 trials of a cyclosporine A topical preparation
for dry eye syndrome, found that 60 percent of dry
eye patients visited a physician more than twice in
the past year for their symptoms (Nelson 2000).
Forty-two percent of these patients had undergone
punctal occlusion at least once in the past.
Surveys of subpopulations have identified higher
office utilization and frequent visits; Hirsch (1998), for
instance, reported that 89 percent of Sjögren’s dry
eye patients visited an ophthalmologist an average
of 3.1 times per year for their symptoms, and more
than one fourth of all subjects had visited other
physicians at least once in the past year for their condition.
Pharmaceutical interventions
A recent study of resource utilization among nonSjögren’s dry eye patients found high utilization of
medical therapies — among products specifically
designed to treat dry eye symptoms as well as other
drugs (Figures 4 and 5).
FIGURE 4 Medications used by dry eye patients
In the past 3 months
Used regularly or always (subset of “used at all”)
Used at all
Lubricant ointments
Lubricant drops
13%
Used
at all:
87%
Not used
16%
40%
44%
61%
Used
at all:
56%
Used
at all:
40%
60%
FIGURE 5 Additional medications used to treat dry eye symptoms
In the past 3 months
Analgesics
12.8%
Antibiotics
5.7%
Anti-inflammatory agents
5.7%
Any additional medications
27.0%
SOURCE: NELSON 2000
Future trends
With the advent of medical therapy that addresses the underlying inflammatory nature of dry eye syndrome,
there is potential for increased patient satisfaction — and, thus, fewer office visits and reduced utilization of tear
substitutes and other pharmaceutical therapies. Studies that document this potential are reported in the chapter on pharmacoeconomics that begins on page 33.
DRY EYE SYNDROME
11
OVERVIE W
ECONOMIC IMPLICATIONS
Relatively few data exist on direct and indirect
costs of dry eye and its sequelae. Likely, this is due to
the fact that until recently, when the etiology of this
common disease became more fully understood, dry
eye was viewed largely as an irritant and not necessarily a serious condition worthy of medical attention. Nelson (2000) challenged this view from an economic standpoint, arguing that older treatment
modalities can lead to unacceptable costs and progressive use of health care resources. Emerging scientific knowledge about dry eye may prompt payers
or the government to conduct comprehensive data
analyses of the economic impact of dry eye.
Moss also examined lifestyle factors, finding a surprise protective effect of caffeine and a contributing
factor in multivitamin use (Figure 7).This research
also identified an opportunity for physicians to
counsel patients who smoke or drink heavily.
FIGURE 7 Lifestyle factors*
Behavior
Odds ratio2
Current smoker
Multivitamin use
FIGURE 6 Prevalence of comorbidities*
Condition
Odds ratio2
Arthritis
1.91
History of gout
1.42
History of thyroid disease
1.41
Diabetes
1.38
Total-to-HDL
-to-HDL cholesterol
cholesterol ratio†
ratio†
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1.31
Caffeine
0.75
* Adjusted for age and sex. 95-percent confidence interval.
SOURCE: MOSS 2000
Dry eye is a direct complication of large-incision
cataract procedures, corneal transplantation, and
LASIK. Moss reported a 1.39 odds ratio in patients
who had undergone any sort of lens surgery, while
Breil (2002) found that dry eye is one of the most
common postoperative complications of LASIK.
Indirect costs
Dry eye syndrome has the potential to reduce
employee productivity significantly. In one study,
dry eye patients experienced an average of 184 work
days of reduced productivity, at an estimated annual
cost of $5,362 per individual (Kozma 2000).
Another study — this of a subset of dry eye patients, those with Sjögren’s syndrome — indicated
that symptoms interfered with the activities of daily
living in all but 29 days of the year (Figure 8).
FIGURE 8 Interference with activities
Days per year among Sjögren’s patients
Days lost from work: 5
Leisure days with
symptom interference: 123
Days worked with symptoms: 208
0.93
* Adjusted for age and sex. 95-percent confidence interval.
† Per increment of 1 unit.
SOURCE: MOSS 2000
1.41
History of heavy alcohol use
Direct medical costs and complications
Small-scale models have been developed to estimate the cost of office visits, drugs, and procedures
attributed specifically to dry eye. In one study, the
cost of managing and treating dry eye patients with
palliative medications, punctal plugs, and surgery,
over the course of 1 year, was $357,050 for an organization covering 500,000 lives (Lee 2000).The authors
speculated that a more effective dry eye intervention could improve cost effectiveness by decreasing
patient demand for physician visits and procedures.
The multifactorial nature of dry eye makes a full
accounting of direct medical costs complex. Because
dry eye can be a marker for systemic illnesses, costs
of treating dry eye symptoms are often figured
under other diagnoses. Moss (2000) used a logistic
model to calculate factors associated with dry eye,
including arthritis and diabetes.This research also
discovered a protective effect in total-to-HDL (highdensity lipoprotein) cholesterol ratio (Figure 6).
1.82
SOURCE: HIRSCH 1998
No reported effects: 29
2 An odds ratio is calculated by dividing the odds in the
treated group by the odds in the control group. Factors
that cause harm have an odds ratio >1.0. An odds ratio
of 2.0 represents a 100-percent increased risk.
OVERVIE W
SUMMARY
Dry eye syndrome is far more prevalent than previously considered.There are significant comorbidities,
associated diseases, and behavioral and environmental factors that may contribute to the severity of
dry eye. Dry eye syndrome has significant economic
implications, including costs associated with increased health care utilization, missed school and
work, and leisure and quality-of-life issues. Dry eye
presents important economic challenges to patients,
physicians, and health care delivery organizations.
REFERENCES
AAO (American Academy of Ophthalmology). Preferred Practice Pattern: Dry Eye Syndrome. San Francisco: AAO, 2003.
Breil P, Frisch L, Dick HB. Diagnosis and therapy of LASIKinduced 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 quality
of life impact of dry eye symptoms: a Sjögren’s patient
survey. Invest Ophthalmol Vis Sci. 1998;39:S65. Abstract.
Kozma CM, Hirsch JD,Wojcik AR. Economic and quality of life
impact of dry eye symptoms. Poster presented at the
Annual Meeting of the Association for Research in Vision
and Ophthalmology, April 30–May 5, 2000, Ft. Lauderdale,
Fla.
Lee JT,Teale CW. Development of an economic model to assess costs and outcomes associated with dry eye disease.
Poster presented at the 2000 Spring Practice and Research Forum of the American College of Clinical Pharmacy, 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 dry
eye and ocular surface disorders. Ophthalmol Clin North
Am. 1990;3:575–594.
McCarty CA, Bansal AK, Livingston PM, et al.The epidemiology
of dry eye in Melbourne, Australia. Ophthalmology.
1998;105:1114–1119.
McCarty DJ, McCarty CA. Survey of dry eye symptoms in Australian pilots. Clin Experiment Ophthalmol.
2000;28:169–171.
Moss SE, Klein R, Klein BE. Prevalence and risk factors for dry
eye syndrome. Arch Ophthalmol. 2000;118:1264–1268.
Nelson JD, Helms H, Fiscella R, Southwell Y, Hirsch JD. A new
look at dry eye disease and its treatment. Adv Ther.
2000;17:84–93.
Pflugfelder SC,Tseng SC, Sanabria O, et al. Evaluation of subjective assessments and objective diagnostic tests for diagnosing tear-film disorders known to cause ocular irritation. Cornea. 1998;17:38–56.
Schaumberg DA, Buring JE, Sullivan DA, Dana MR. Hormone replacement therapy and dry eye syndrome. JAMA.
2001;286:2114–2119.
Schein OD, Munoz B,Tielsch JM, et al. Prevalence of dry eye
among the elderly. Am J Ophthalmol. 1997;124:723–728.
Yazdani C, McLaughlin T, Smeeding JE,Walt JG. Prevalence of
treated dry eye disease in a managed care population.
Clin Ther. 2001;23:1672–1682.
DRY EYE SYNDROME
13
ETIOLOGY
ETIOLOGY
Inflammation: A Unifying Theory
For the Origin of Dry Eye Syndrome
STEVEN E. WILSON, MD1
Cole Eye Institute, Cleveland Clinic Foundation
SUMMARY
Dry eye syndrome has been difficult to diagnose and treat, due to its heterogeneity.
These difficulties are being overcome, however, as evidence becomes available about a
common etiology. An inflammatory mechanism apparently underlies the condition.
This theory has been proven by use of
immunomodulators that show efficacy in
treating patients with dry eye syndrome.
K
eratoconjunctivitis sicca (KCS), or dry eye syndrome, is a common ophthalmologic abnormality involving bilateral disruption of the
precorneal tear film. It is caused either by inadequate tears or an inability to maintain an effective tear
film. In KCS, the tear film is disrupted, causing a variety
of symptoms (Table 1). Dry eye syndrome can occur in
any age group, but is especially prevalent in people over
age 65. It estimated that 10 to 15 percent of Americans
in this age group have one or more symptoms of this disease (Schein 1997). In serious cases, dry eye syndrome
can lead to photophobia and vision loss.
It is evident from its name that KCS is a drying inflammation: kerato (corneal) conjunctivitis (conjunctival inflammation) sicca (from the Latin sicco, meaning “to
dry”). KCS can occur sporadically or as a chronic condition that becomes a self-perpetuating syndrome. This article will explore current trends in KCS etiology research.
Destruction of corneal and bulbar conjunctival epithelium 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 and
mouth. Sjögren’s syndrome can occur with or without
rheumatoid arthritis, lupus, or scleroderma. In Sjögren’s
KCS, the exocrine glands secreting tears, saliva, and gastric excretions are inadequate. KCS — either Sjögren’s or
non-Sjögren’s — is now believed to be an autoimmune
state in which the epithelial cells of the lacrimal glands are
detected as antigens by the immune system and attacked,
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damaged, or killed by activated T-cell lymphocytes.
A variety of factors can
exacerbate KCS (Table 2).
New evidence has shown
that regardless of the predisposing factor(s), most
KCS results from a localized
immune-mediated inflammation affecting both the
lacrimal glands and the ocular surface (Stern 2002).
Historically, KCS has
been frustrating to study
and treat, in part due to its Steven E.Wilson, MD
diverse symptoms and disease variables. The heterogeneity of dry eye creates challenges in the diagnosis and treatment of individual cases.
The high degree of variability in patient populations
makes data analysis extremely difficult. Thus, the ability
to postulate and prove a unifying etiology has been hindered by the multifactorial nature of KCS and the clinical conundrum of matching patients’ symptoms and diagnostic test results with patients’ actual disease severity.
1
Steven E. Wilson, MD, is director of corneal research at
the Cole Eye Institute of the Cleveland Clinic Foundation.
A board-certified ophthalmologist, Wilson recently came
to Cleveland from the University of Washington in Seattle,
where he directed an NEI-supported laboratory that investigates the function of growth factors and cytokines
in controlling corneal wound healing. He has authored
more than 300 papers, abstracts, and book chapters. After
earning his medical degree from the University of
California–San Diego, Wilson completed an ophthalmology residency at the Mayo Clinic and a fellowship in
cornea, external disease, and refractive surgery at the
Louisiana State University Eye Center in New Orleans.
Wilson, who holds memberships in numerous professional
societies, serves on the board of trustees of the Association
of Research in Vision and Ophthalmology and on the executive board of the ISRS-RSIG for the American Academy
of Ophthalmology.
ETIOLOGY
A COMMON UNDERLYING ETIOLOGY
of secretions from primary and secondary glands loThe pathophysiology of KCS has long been known to
cated under the eyelids and from sebaceous glands on the
involve a disruption of the layer of tears that protects and
flat rims of the eyelids that secrete an antievaporation
nourishes the delicate eye tissues. The goal of therapy has
lipid layer (Figure 2, page 16).
been to normalize tear volume and composition, so that
The tear drainage system is also important in normalthe eye tissues are properly lubricated, nourished, and
izing hydration of the eye. Inflammation-induced dysprotected. This has been accomplished to some extent by
function in this drainage system can precipitate KCS. The
increasing tear secretion, reducing tear turnover, and/or
system includes the punctal opening (the tiny hole in the
promoting epithelial healing on the ocular surface using
upper and lower eyelids). Blinking causes tears to enter the
lubricants and emollients. If the KCS results from a syspunctae, where they are drained through canaliculi into
temic disorder, the systemic disease can be treated and the
the lacrimal sac and the nasolacrimal duct into the nose.
symptoms thereby decreased.
Part of the function of tears is to protect the eye from
Local treatment strategies for the eye (aside from treatmicrobial invasion. In a normally functioning adult eye,
ing infections) have been essentially palliative, however,
an anti-inflammatory component keeps the disruptive
and do not address the inflammatory response. The treateffect of irritation to a minimum. When this component
ment goal of this new approach to disease is to suppress
is lacking, however, or when irritation is not controlled,
the body’s immune system activates its inflammatory Tthe inflammation that underlies symptoms and signs.
The recent discovery of a neurological-inflammatory
lymphocytes.
component has provided an explanation for the pathoCytokines are hormone-like proteins that regulate the
physiology of KCS. If inflammation in KCS is considered
immune response. They also damage tissue when overnot a symptom but a cause, then suppressing the
abundant (Table 3, page 17). Cytokines and other proinflammatory mediators lead to activation of more T-cells,
cytokine-mediated inflammatory response that occurs at
a histological level can be applied to KCS regardless of
production of more inflammatory substances, and tissue
disease-state association. An emerging strategy for treatdamage.
ment of KCS is therapy with immunomodulators that address the local inTABLE 1 Symptoms of keratoconjunctivitis sicca
flammation caused by cytokines that
Dry sensation
Foreign body or “gritty” sensation
circulate in the lacrimal glands and conDry sensation
Blurred vision
junctiva, regardless of whether any assoIrritation/redness
Contact lens intolerance
ciated disease state is local or systemic.
Redness
Increased frequency of blinking
According to this new theory of KCS
Tearing
Mucous discharge
etiology, a cyclical syndrome causes the
SOURCE: PFLUGFELDER 2000a
Burning/stinging
lacrimal glands to suffer from neurogenic
inflammation, T-cell activation, and cytokine secretion into tears. The cytokineTABLE 2 Variables in keratoconjunctivitis sicca
laden tears inflame the ocular surface, disrupting sensory signals from the surface of
Precipitating factors
the eye, so the normal stimulus for tear seMedication (e.g., anticholinergics)
cretion is curtailed. In addition, the
Environmental conditions (e.g., wind)
lacrimal glands, both primary and secTrauma (e.g., chemical burns) or corneal dystrophies
ondary, may be damaged or destroyed.
Reading for lengthy periods (especially from a computer screen)
This leads to a virtual shutdown of the
Severity potential
lacrimal system and to a self-perpetuating
Annoyance only
inflammation that cannot be ameliorated
Acute increase in severity (e.g., photophobia and blepharospasm)
by the eye’s normal defense system. The
Loss of normal configuration of conjunctival fornices
immune system itself is the problem
Ulceration, vascularization, and scarring of cornea
(Figure 1, page 16). This localized inflamSevere visual disability
mation cycle can be demonstrated in both
Duration
Sjögren’s and non-Sjögren’s patients.
The normal lacrimal system
Normally, the integrity of the lacrimal
system is maintained by a precise interplay
Sporadic, reversible
Chronic nonreversible deficiency of tear production
• Waxing or waning
SOURCE: STERN 2002
• Constant condition
DRY EYE SYNDROME
15
ETIOLOGY
FIGURE 1 Dry eye: an immune-mediated inflammatory disorder
Lacrimal glands:
• Neurogenic
inflammation
• T-cell activation
• Cytokine
secretion
into tears
Interrupted secretometer
nerve impulses
Tears inflame ocular surface
Cytokines
disrupt neural arc
FIGURE 2 The three major components of normal tear film
Lipid layer
Soluble
proteins
Aqueous/
mucin gel
Layer
Function
Anterior
Lipid layer, which acts as vapor barrier
Middle
Aqueous electrolytes and proteins that constitute 98 percent of the total tear film.This layer
contains nutrients, enzymes, cytokines, and
antimicrobials.
Posterior
Heavily glycosylated proteins, mucins
(adjacent to • Immunoglobulins
epithelium) • Antimicrobial proteins
• Growth factors (e.g., transforming growth
factor-alpha or epidermal growth factor)
SOURCE: PFLUGFELDER 2000b
Ordinarily, when any kind of an invasion or disruption is detected, more tears are produced to flush out the
entire lacrimal system. In autoimmune diseases, however,
the inflammatory response in the eye can attack healthy
epithelial cells with enzymes that are meant to lyse invaders, damaging the matrix of tears and the conjunctiva.
Evidence from canine research shows that the origin
of KCS is associated with lymphocytic infiltrations in
both the conjunctiva and the lacrimal glands. Biopsies
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from dogs with dry eye syndrome
demonstrate such lymphocytes (Figure 3). Total T-cells that are abnormally increased in dry eye syndrome
can be seen by fluorescing T-cells in
the conjunctiva of Sjögren’s and nonSjögren’s patients.
The main and accessory lacrimal
glands may be susceptible to inflammation due to an age- and hormonerelated degenerative process. The
change in tear secretions leads to the
pathophysiology described above as a
neurological inflammatory disease
that becomes a constant cycle (Figure
4, page 18). As sensory input to the
lacrimal glands decreases, the quantity and quality of tears is reduced,
causing further irritation of the ocular surface.
Cyclosporine as an antiinflammatory agent in dry eye
Soluble
Marsh (1999) showed that cortimucins
costeroids could be used for treating
severe dry eye in humans. Nevertheless, use of corticosteroids was
Membrane
limited by the known side effects of
mucins
cataract formation, glaucoma, and
infection. Cyclosporine A (CsA) was
Epithelium
tested and found efficacious by ophOrigin
thalmologists experimenting with it
in severe, treatment-resistant KCS paMeibomian glands
tients. Now, it is available as a topical
Lacrimal glands
anti-inflammatory for dry eye syndrome, formulated at doses thousands of times smaller than those
used to avoid graft-versus-host disGoblet cells in conease in tissue transplantation.
junctiva and corneal
and conjunctival
Cyclosporine is an immunomoduepithelial cells
lator that primarily is used systemically in transplant, psoriasis, and
rheumatoid arthritis patients. This
agent’s anti-inflammatory effects arise
primarily from its ability to prevent the activation of Tcells and resulting production of cytokines and other inflammatory agents. Until recently, there was no commercially available preparation of CsA for topical use in the
eye. The preparation had to be custom formulated in irritating oils by pharmacists for ophthalmologists. Despite
the fact that this use of CsA had not been systematically
tested in humans, many ophthalmologists reported good
results with few complications other than stinging.
ETIOLOGY
CsA was approved in the United
States in 1995 to treat chronic dry
eye disease in dogs. Now that CsA
has been tested in humans at a
dose of 0.05 percent in a special
vehicle, it can be used to increase
tear production in patients whose
production levels are presumed to
be suppressed due to ocular inflammation associated with KCS.
The effect of CsA ophthalmic
emulsion on inflammation arises
from its ability to inhibit activation of T-cells by blocking their
intracellular signal transduction
cascade responsible for upregulation of NF-AT and NF-kB regulated genes, including genes for
many cytokines (Table 4).
TABLE 3 The role of cytokines and T-cells in adaptive immunity
Immunomodulator
Description and function
Cytokines
(Examples:
interferon,
interleukin,
lymphokines)
These are proteins released by various types of cells
including lymphocytes and corneal epithelial cells.
Cytokines regulate the process of T-cell proliferation and differentiation, and serve an antiviral and
anti-tumor function in the immune system.They
promote allergic reactions, boost T-cell functions,
and thus are used to evaluate immune activity.
T-cells
These are lymphocytes with antigen-receptor
complexes on their surfaces.They are produced by
the thymus and have the ability to lyse foreign or
virus-infected cells.They reside primarily in the
lymphatic system and secrete hormone-like peptides that mediate the immune response; they also
regulate erythroid cell maturation in bone marrow.
CD3 cells
These are a subset of leukocytes involved in
signal transduction in the cell membrane.
Phase 2 and 3 clinical studies
of cyclosporine for KCS
A phase 2 study of CsA among
FIGURE 3 Evidence of inflammation in dry eye syndrome
162 patients was undertaken
using doses ranging from 0.05
percent to 0.40 percent twice a
day. The results determined that
doses of 0.05 percent to 0.10 percent were effective and well tolerated (Stevenson 2000).
At the small doses used in the
phase 3 study, there was no evidence of the increased risk of infections and tumors observed
Conjunctiva
Lacrimal gland
with large doses of cyclosporine
T- cell infiltrations
used for transplantation. With the
(Dark-stained cells; canine biopsy)
fractional dose used for KCS
SOURCE: STERN 1998
(2,500 times smaller), there were
no ocular infections related to
TABLE 4 Anti-inflammatory activity of cyclosporine A
CsA, nor was the drug detected
in the blood of patients who were
• Binds to an intracellular protein
administered a 0.05 percent dose.
• Inhibits an activation enzyme (calcineurin)
The 1-year results of phase 3
• Inhibits expression of numerous genes essential for T-cell activation
study of CsA (both Sjögren’s and
and proliferation
non-Sjögren’s) are briefly de• Prevents replication of T-cells by blocking a transcription factor
scribed in Tables 5–7 on page 19,
• Keeps T-cells from expressing some cytokines or “homing” to
and then in more detail in the
inflammation site
chapter “Medications for Dry Eye
• Promotes a gene (transforming growth factor) that inhibits the
inflammatory response
Syndrome: A Drug-Therapy
Review,” which begins on page 26.
was evident especially during the first arm of the study
Use of cyclosporine resulted in both clinical improve(Sall 2000).
ments and a decrease in markers of immunity and inThe efficacy of the vehicle used for a comparison in the
flammation in conjunctival biopsies. This improvement
DRY EYE SYNDROME
17
ETIOLOGY
lymphocyte cell marker CD3 in
Sjögren’s and non-Sjögren’s dry
eye patients showed a reduction
1. When the ocular surface and
in T-lymphocyte infiltration
Chronic
lacrimal glands are chronically
after treatment with CsA.
irritation
irritated,T-cells become actiComparing baseline stains with
vated.
those after 6 months of CsA
2. These activated T-cells recruit
treatment, there was a 3- to 5additional T-cells and cause an
fold decrease in the number of
immune-based local inflammaSymptoms
CD3-positive cells in the contion.
develop
Immune
junctiva of Sjögren’s and non3. Cytokines are released in tears;
activation
Sjögren’s patients. These similar
this further irritates the ocular
results in Sjögren’s and nonsurface and blocks messages to
the lacrimal gland.
Sjögren’s patients are consistent
4. As a result, normal tear secretion
with a similar pathophysiology
is reduced, and chronic dry eye
for both conditions (Figure 5).
syndrome symptoms develop.
Inflammation
Disruption of the tear film
overlying
the cornea generates
SOURCE: STERN 1998
variable irregular astigmatism.
This results in blurred vision,
FIGURE 5 Decreased inflammation in Sjögren’s
an important efficacy measure
and non-Sjögren’s patients
of treatment. Blurred vision and
reliance on artificial tears were
CD3-stained T-lymphocytes in conjunctival biopsies
included as endpoints in the
Sjögren’s
Non-Sjögren’s
phase 3 study (Table 7).
Patients in all groups were allowed to instill preservative-free
artificial tears between doses of
3965
Baseline
2291
study medication throughout
cells/mm2
cells/mm2
the trial. Reduced utilization of
artificial tears was a gauge of
symptom relief.
It should be noted that in
clinical studies, CsA did not in819
CsA 0.05%
762
crease tear production in pacells/mm2
6 months
cells/mm2
tients already taking topical
anti-inflammatory drugs. This
evidence served to confirm the
unifying hypothesis of inflamSOURCE: KUNERT 2000
mation as the etiology of dry
eye syndrome.
phase 3 study unexpectedly proved to be palliative for
Although the anti-inflammatory theory has been corsymptoms in and of itself, and it was later developed as
roborated by clinical efficacy of CsA in KCS, the dry eye
a separate artificial tear product. This was apparently a
induced by LASIK surgery is not expected to be eligible
result of the emulsion that contained both aqueous and
for anti-inflammatory treatment, as it has a different
oil components, thus maintaining the multilayer tear
neurotrophic origin. LASIK patients who had preexistfilm rather than comprising an aqueous solution alone.
ing dry eye may, however, benefit from CsA treatment.
It was partially due to the positive effect of the emulsion
CONCLUSION
vehicle itself that the second arm of the CsA study
showed less dramatic results than the first. Also, the secTraditionally, KCS was difficult to diagnose and treat,
ond 6-month extension of the phase 3 study included padue to its heterogeneity. An inflammatory mechanism
tients with less severe disease.
apparently underlies the condition. This unifying theory
Staining of conjunctival tissue for immune Thas been proven by use of imunomodulators that showed
FIGURE 4 Steps in the cycle of inflammation in KCS
18
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ETIOLOGY
TABLE 5 Phase 3 study
Subjects
235 subjects with KCS (moderate to severe, with or
without Sjögren’s syndrome),
Design
Multicenter, double-blind, randomized parallel trial
that lasted for 6 months with most patients remaining
through another treatment period of 6 months (total: 1
year)
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 improvement in tear production from baseline in Schirmer scores at
6 months (n=238). Of these, 44 percent had a 1–9 mm increase and
15 percent had ≥10 mm increase (all patients had ≤5 mm prior to
treatment).
With CsA 0.05 percent emulsion, patients showed statistically and
clinically 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
reliance
Overall use of artificial tears fell by a third
at month 6.
• Increase in
the number
of goblet cells
Mucopolysaccharide secretory cells in the
epithelium increased by 191 percent in the
treated group vs. 13 percent in the vehicletreated controls (p=.013).
efficacy in treating patients with KCS. The
topical CsA phase 2 and phase 3 studies
provided evidence of inflammation reduction after treatment. These findings
were accompanied by subjective and objective symptom improvements.
Difficulties in studying and treating this
disease are being overcome as more evidence becomes available about a common
etiology. For patients, this will mean less irritation and inflammation. It also should
translate to a reduced reliance on artificial
tears and ointments and fewer office visits.
REFERENCES
AAO (American Academy of Ophthalmology).
Preferred Practice Pattern: Dry Eye
Syndrome. San Francisco: AAO, 1998.
Kunert KS, Tisdale AS, Stern ME, et al. Analysis
of topical cyclosporine treatment of patients with dry eye syndrome: effect on
conjunctival lymphocytes. Arch
Ophthalmol. 2000;18:1489–1496.
Marsh P, Pflugfelder SC. Topical nonpreserved
methylprednisolone therapy for keratoconjunctivitis sicca in Sjögren’s syndrome.
Ophthalmology. 1999;106:811–816.
Pflugfelder SC, Solomon A, Stern ME. The diagnosis and management of dry eye: a 25year review. Cornea. 2000a;19:644–649.
Pflugfelder SC, Liu Z, Monroy D, et al. Detection
of sialomucin complex (MUC4) in human
ocular surface epithelium and tear fluid.
Invest Ophthalmol Vis Sci. 2000b;41:
1316–1326.
Sall K, Stevenson OD, Mundorf TK, Reis BL and
the CsA phase 3 study group. Two multicenter, randomized studies of the efficacy
and safety of cyclosporine ophthalmic
emulsion in moderate to severe dry eye disease. Ophthalmology. 2000;107:631–639.
Schein OD, Tielsch JM, Munoz B, et al. Relation
between signs and symptoms of dry eye in
the elderly: a population-based perspective.
Ophthalmology. 1997;104:1395–1401.
Stern ME, Beuerman RW, Fox RI, et al. The
pathology of dry eye: the interaction between the ocular surface and lacrimal
glands. Cornea. 1998;17:584–589.
Stern ME, Gao J, Schwalb TA, et al. Conjunctival
T-cell subpopulations in Sjögren’s and nonSjögren’s patients with dry eye. Invest
Ophthalmol Vis Sci. 2002;43:2609–2614.
Stevenson D, Tauber J, Reis BL. Efficacy and
safety of cyclosporine A ophthalmic emulsion in the treatment of moderate to severe
dry eye disease: a dose-ranging, randomized trial. The Cyclosporine A Phase 2
Study Group. Ophthalmology.
2000;107:967–974.
SOURCE FOR TABLES 5–7:
SALL 2000
DRY EYE SYNDROME
19
D E T E C T I O N A N D T R E AT M E N T
Guidelines for the Treatment
Of Chronic Dry Eye Disease
SUMMARY
Keratoconjunctivitis sicca (KCS), also known as
dry eye syndrome, dry eye disease, chronic
dry eye disease, or keratitis sicca, refers to disorders of the tear film caused by reduced tear
production, poor tear quality, or excessive tear
evaporation.These disorders are associated
with such symptoms of ocular discomfort as
irritation, foreign body sensation, or redness,
and may cause disease of the ocular surface.
C
hronic dry eye disease (CDED) is highly heterogeneous, and patients present in many different ways. For example, patients with severe
symptoms may reveal minimal signs upon examination, while patients with a multitude of seemingly
significant findings at the slit lamp may have few complaints. The American Academy of Ophthalmology’s
newly released guidelines for diagnosis, treatment, and
management reflect a universal acceptance by clinicians
of dry eye — alone or in combination with other conditions — as an inflammatory ocular surface disorder that
can be a cause of visual morbidity and may compromise
the results of corneal surgery, cataract surgery, or other
ocular surface procedures. Dry eye symptoms often improve with treatment, but the disease usually is not curable. Many of the ocular surface changes associated with
KCS can be reversed with specific treatment.
To preserve or improve vision, prevent or minimize
structural damage to the ocular surface, and alleviate patient discomfort, clinicians must be aggressive both in diagnosing possible underlying systemic inflammatory disease and in making ocular surface anti-inflammatory
therapy a key component of their treatment approach. Environmental control, as well as a careful evaluation of systemic medications, also may yield clinical improvement.
Epidemiology of dry eye
The heterogeneity of dry eye, the lack of uniformity in
its definition, and the inability of any single diagnostic test
20
P&T DIGEST
or set of tests to confirm or rule out dry eye definitively
have limited the comparability of epidemiological data for
this condition.
One clinic-based study found that 17 percent of 2,127
consecutive new outpatients were diagnosed with dry eye
following a comprehensive examination (Hikichi 1995).
In a population-based study in Australia, 16.3 percent
and 10.8 percent of 926 participants, ages 40 to 97, tested
positively for dry eye, based on a low Schirmer test or a
high rose bengal score, respectively (McCarty 1998). An
evaluation of claims data for nearly 10 million enrollees
in managed care plans found that dry eye was diagnosed
or treated in 0.5 percent of enrollees (Yazdani 2001).
Risk factors for dry eye include advanced age and female gender (McCarty 1998, Moss 2000, Yazdani 2001),
arthritis (McCarty 1998, Moss 2000), smoking, multivitamin use (Moss 2000), and hormone replacement
therapy (Schaumberg 2001).
Pathogenesis of dry eye
The ocular surface and tear-secreting glands function
as an integrated unit to refresh the tear supply and to clear
used tears (Stern 1998). Disease or dysfunction of this
unit results in ocular irritation and dry eye syndrome.
Decreased tear secretion and clearance initiate an inflammatory response on the ocular surface, and research
suggests that this inflammation plays a role in the pathogenesis of dry eye (Pflugfelder 2000).
Dysfunction may develop from aging, a decrease in
supportive factors (such as androgen hormones), systemic inflammatory diseases (such as rheumatoid arthritis), ocular surface diseases (e.g., herpes zoster ophthalmicus), surgery that disrupts the trigeminal afferent
sensory nerves (including laser in situ keratomileusis
[LASIK], extracapsular cataract extraction, or penetrating keratoplasty), and systemic diseases or medications
that disrupt the efferent cholinergic nerves that stimulate tear secretion (Bacman 2001).
Associated conditions
Symptoms caused by dry eye may be exacerbated by systemic medications such as diuretics, antihistamines, anti-
cholinergics, antidepressants, HMG co-A reductase inhibitors, 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, subjects with blepharitis associated with meibomitis were
twice as likely to have dry eye symptoms as those without signs of meibomitis (Schein 1997).
Systemic diseases associated with dry eye include Sjögren’s syndrome, rosacea, viral infections such as acquired immune deficiency syndrome (Lucca 1990), hepatitis C (Abe 1999, Siagris 2002), primary and persistent
Epstein-Barr virus infections (Pflugfelder 1987, MerayoLloves 2001, Pflugfelder 1993), and graft-versus-host
disease in recipients of allogenic bone marrow or stem
cell transplants (Ogawa 1999).
In Sjögren’s syndrome, an inflammatory cellular infiltration of the lacrimal gland leads to deficient tear
production. Rosacea is associated with posterior blepharitis, poor tear quality, accelerated tear film breakup
time (TBUT), and increased tear evaporation. Aqueous
tear deficiency may develop in conditions such as lymphoma, sarcoidosis (Drosos 1989), hemochromatosis,
and amyloidosis (Fox 1994).
Diseases such as ocular cicatricial pemphigoid and
Stevens-Johnson syndrome produce tear deficiency due
FIGURE 1
to inflammation, scarring, and destruction of the conjunctival goblet cells. Atopy may produce dry eye due to
systemic antihistamine use or blepharitis and eczema.
Natural history
CDED varies in severity, duration, and etiology (Lemp
1995). In most patients, it does not threaten sight but is
characterized by troublesome symptoms of irritation.
When dry eye is caused by an irreversible deficiency of tear
production or a chronic condition such as blepharitis
that leads to increased tear evaporation, symptom severity may wax and wane, or gradually increase over time.
Reversible conjunctival squamous metaplasia and
punctate epithelial erosions of the conjunctiva and cornea
develop in many patients who have moderate to severe dry
eye. Rarely, patients with severe dry eye will develop complications such as ocular surface keratinization; corneal ulceration, scarring, thinning (ectasia), or neovascularization; microbial keratitis; and sterile corneal keratolysis,
with possible perforation and severe visual loss.
DIAGNOSIS,TREATMENT, AND MANAGEMENT
According to guidelines established in the AAO’s 2003
Preferred Practice Pattern, the goals of diagnosing, treating, and managing patients with dry eye are: to establish
the diagnosis of dry eye, differentiating it from other
causes of irritation and redness; to identify the causes of
Modified diagnostic classification scheme for dry eye
1. Ocular irritation syndrome
2. Tear film instability
DRY EYE
3. Ocular surface disease
Increased
evaporative loss
Deficient aqueous
tear production
Sjögren’s
Non-Sjögren’s
Blepharitis/
Meibomian gland
dysfunction
SOURCE: LEMP 1995
Exposure
Other factors
1. Contact lenses
2. Blink abnormality
3. Environmental
DRY EYE SYNDROME
21
dry eye; to establish appropriate therapy; to relieve discomfort; to prevent complications, including visual loss,
infection, and structural damage; and to educate patients and involve them in managing their disease.
In moderate to severe cases that are unresponsive to
treatment or when systemic disease is suspected, timely
referral to an ophthalmologist with experience in managing this condition is recommended. Referral to an internist or rheumatologist can be considered for patients
with systemic immune dysfunction or for individuals requiring immunosuppressive therapy (AAO 2003).
The most important aspects of caring for patients with
dry eye are to educate them about the chronic nature of
the disease process and to provide specific instructions for
therapeutic regimens. It is helpful to discuss realistic expectations, in terms of therapeutic goals. It also is essential to assess, periodically, the extent of their understanding of the disease and adherence to treatment.
Diagnosis
Many ocular surface diseases produce symptoms similar to those associated with dry eye, such as foreignbody sensation, mild itching, burning, blurred vision, irritation, and soreness. The initial evaluation of a patient
presenting with symptoms that are suggestive of dry eye
should include those features of the comprehensive adult
eye evaluation relevant to dry eye (AAO 2003).
It is often difficult to diagnose patients with mild dry
eye syndrome because of the inconsistent correlation between reported symptoms and clinical signs (Schein
1997) and the relatively poor sensitivity and/or specificity
of existing diagnostic tests (AAO 2003). When environmental factors and other potential causes of ocular irritation (see page 10) have been eliminated from consideration, patients with suggestive symptoms who do not
have overt signs of disease should be placed on trial treatments, such as artificial tears or, where appropriate, trial
discontinuation of systemic antihistamines (AAO 2003).
Because most dry eye conditions are chronic, repeat
observation and the reporting of symptoms over time
will allow a more accurate clinical diagnosis of dry eye.
A diagnostic classification scheme, adapted from a National Eye Institute Workshop, is shown in Figure 1 on
page 21 (Lemp 1995). Participants in this workshop
agreed that two major factors — deficient aqueous tear
production and increased evaporative loss — may cause
dry eyes independently but also may contribute concurrently to dry eye symptoms and signs.
Patient history
According to the AAO 2003 guidelines, the history of
the patient’s illness should include symptoms and signs relating to the eyes such as dry sensation, irritation, tearing,
22
P&T DIGEST
burning, stinging, foreign-body sensation, photophobia,
blurred vision, contact lens intolerance, redness, mucous
discharge, increased frequency of blinking, itching, and diurnal fluctuation; exacerbating conditions, such as wind,
air travel, or low humidity; prolonged visual effort that is
associated with a decreased rate of blinking; duration of
symptoms; and any topical medications that have been
used, as well as their effects on symptoms.
The patient’s ocular and medical histories should include the factors listed in Table 1. In addition, the medical history should describe use of systemic medications,
including antihistamines, diuretics, hormones and hormonal antagonists, antidepressants, cardiac antiarrhythmic drugs, diphenoxylate/atropine, isotretinoin, beta
blockers, chemotherapy agents, HMG co-A reductase
inhibitors, and any drug with anticholinergic effects.
Physical examination
The physical examination should include a visual acuity measurement, an external examination, and a slitlamp biomicroscopy. The external examination and the
biomicroscopy serve to document signs of dry eye, assess
the presence and severity of deficient aqueous tear production and/or increased evaporative loss, and exclude
other causes of ocular irritation.
The examination and biomicroscopy should focus on
factors listed in Table 2. Additionally, at the slit lamp, the
clinician should direct attention toward the four punctums, noting patency or closure, juxtaposition to the bulbar conjunctiva, and the size of the opening when patent.
Diagnostic tests
The poor correlation between reported symptoms
and clinical signs, coupled with the aforementioned
limitations of clinical tests, make it difficult to diagnose
dry eye in its mild form. For patients with mild irritation
symptoms, a rapid TBUT may detect an unstable tear
film with normal aqueous tear production, and ocular
surface dye staining may detect a minimal pattern or no
pattern. For patients with moderate to severe aqueous
tear deficiency, the diagnosis can be made with one or
more of the following tests: TBUT, ocular surface dyestaining pattern (rose bengal, fluorescein, or lissamine
green), or Schirmer wetting test.
These tests should be performed in the above sequence, because the Schirmer test can disrupt tear film
stability and cause false-positive ocular surface dye staining. Other tests may be helpful in evaluating selected
patients, but some have limited availability. These tests
include tear osmolarity, fluorescein clearance, impression
cytology, tear function index, and tear protein analysis
(including lactoferrin, lysozyme, immunoglobulin, and
albumin) (AAO 2003).
Corneal sensation should be
assessed when trigeminal nerve
dysfunction is suspected (Heigle 1996).A laboratory and clinical evaluation for autoimmune
disorders should be considered
for patients with significant dry
eyes, other signs and symptoms
of an autoimmune disorder
(e.g., dry mouth, rash, arthritis,
colitis, or renal dysfunction), or
a family history of autoimmune
disorders.
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 immunodeficiency virus
• Surgery (bone marrow transplant, head and neck surgery)
• Radiation of orbit
• Neurological conditions (including Parkinson’s disease, Bell’s palsy, and RileyDay syndrome)
• Xerostomia (dry mouth), dental cavities, and oral ulcers
Treatment
Patients with a clinical diagnosis of mild dry eye may benefit from behavioral and environmental modification, such
as learning to take breaks while
reading, lowering the computer
monitor to decrease lid aperture, and humidification of the
environment (Nordstrom 1995).
SOURCE: AAO 2003
Because dry eye can be iatrogenic, elimination of exogenous medical factors, such as
prescription regimens that include ocular topical preservatives or systemic antihistamines or diuretics, may help.
For patients with mild disease, use of tear substitutes is
indicated. As the severity of dry eye increases, nonpreserved tear substitutes or emulsions, gels, and ointments
may be used instead of conventional preserved tear substitutes. Noninvasive therapies such as spectacle side
shields, moisture inserts, and moisture chambers are appropriate for more severe disease, but these tend to be unpopular among patients for cosmetic reasons (AAO 2003).
Medications
Pilocarpine and cevimeline, two cholinergic agonists,
have been approved by the U.S. Food and Drug Administration to treat the symptoms of dry mouth in patients
with Sjögren’s syndrome (Vivino 1999, Fox 2001). These
oral medications stimulate secretion of the salivary and
sweat glands and appear to improve tear production, but
most clinical studies demonstrate greater improvement
in dry mouth than dry eye (Vivino 1999, Nelson 1998).
Patients treated with pilocarpine at a dosage of 5 mg
orally, 4 times daily, experienced a significantly greater
overall improvement in the ability to focus their eyes during reading, as well as improvements in symptoms of
blurred vision, compared to placebo-treated patients.
(AAO 2003, Vivino 1999). The most common side effect
from this medication class is excessive sweating, which
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 characteristic 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 defects, punctate staining with rose bengal or fluorescein dyes, mucous plaques, keratinization, pannus formation, thinning, infiltrates, ulceration,
neovascularization, and scarring)
SOURCE: AAO 2003
DRY EYE SYNDROME
23
occurred in more than 40 percent of patients.
Cevimeline also has been found to improve ocular irritation symptoms and aqueous tear production (Petrone 2002) and may have fewer adverse systemic side effects than oral pilocarpine (AAO 2003).
Anti-inflammatory therapies may be considered in
addition to aqueous enhancement therapies. In clinical
trials, topical cyclosporine has been reported to increase
aqueous tear production and decrease ocular irritation
symptoms in dry eye treatment (Gunduz 1994, Sall 2000).
Clinically significant improvements in Schirmer wetting,
punctuate keratopathy, quality-of-life measures, and artificial tear use proved sufficient for FDA approval of the
first prescription medication for dry eye disease on Dec.
24, 2002 — a topical, preservative-free 0.05 percent cyclosporine emulsion. The proprietary emulsion preparation is ideally formulated to distribute the relatively insoluble cyclosporine molecule to the ocular surface with
maximal bioavailability. Previous formulations by compounding pharmacies utilizing much higher concentrations — as high as 4 percent — do not achieve tissue levels equivalent to the approved emulsion.
Cyclosporine is an 11-amino-acid cyclopeptide, produced as a metabolite by the fungus species Beauveria
nivea. Cyclosporine prevents activation and nuclear
translocation of cytoplasmic transcription factors that are
required for T-cell activation and inflammatory cytokine
production. It also inhibits mitochondrial pathways of
apoptosis and has been reported to heal paracentral sterile corneal ulcers associated with Sjögren’s syndrome and
rheumatoid corneal ulceration (Kervick 1992). Cyclosporine therapy appears to address all three tear film
components (aqueous, oil, and mucin), and therefore
the three types of tear deficiency that may occur in various combinations in dry eye disease.
Nonpreserved topical corticosteroids have been reported to decrease ocular irritation symptoms, reduce
corneal fluorescein staining, and improve filamentary
keratitis (Marsh 1999, Prabhasawat 1998). Low-dose
corticosteroid therapy can be used at infrequent intervals for short-term (2-week) suppression of irritation
secondary to inflammation.
Patients with systemic disease such as primary Sjögren’s syndrome, or with connective tissue disease such
as rheumatoid arthritis, should be managed in conjunction with the appropriate medical specialist. Antiinflammatory/immunosuppressive therapy may be appropriate for patients with a systemic disease such as
rheumatoid arthritis (AAO 2003).
Surgical treatment
Surgical treatment is generally reserved for patients
with symptomatic, moderate, or severe disease, and for
24
P&T DIGEST
whom medical treatment has been inadequate or impractical (AAO 2003).
Aqueous enhancement by means of punctal occlusion can be accomplished surgically with semipermanent
plugs (silicone or thermal labile polymer) that are lodged
at 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 be
placed in most patients’ lower punctum. Because an occluded punctum can trap inflammatory mediators, inflammation, logically, should be controlled prior to punctal occlusion. Nevertheless, many patients with successful
or partially helpful punctal occlusion procedures obtain
additional benefit from subsequent initiation of topical
anti-inflammatory therapy.
Eyelid abnormality as a result of blepharitis, trichiasis, or lid malposition (e.g., entropion/ectropion, lagophthalmos) should be corrected prior to permanent
punctal occlusion (AAO 2003).
Semipermanent plugs are reversible if the patient develops symptoms of epiphora, while cautery is not readily reversible. Therefore, a trial occlusion with collagen
plugs should be performed first. To minimize the possibility of epiphora, no more than one punctum should be
cauterized in each eye. The lower punctum is preferable
for occlusion, as it is usually larger and more accessible.
It is important to inspect the upper punctum first for
both patency and integrity, before occluding the lower
punctum. In general, laser cautery is not as effective as
thermal cautery in achieving permanent, complete occlusion and is more expensive.
Tarsorrhaphy can be performed to decrease tear evaporation in patients with severely dry eyes, and for whom
all other medical and surgical therapies have been exhausted.
Management
The purpose of the follow-up evaluation, as outlined
in the AAO 2003 guidelines, is to assess the patient’s response to therapy and the need to adjust treatment, to
monitor for structural ocular damage, and to provide reassurance to the patient. The follow-up evaluation’s frequency and composition is determined by disease severity, the therapeutic approach, a patient’s personality and
adherence to therapy, and the response to therapy.
Patients with mild dry eyes can be seen once or twice
per year for follow-up if symptoms are controlled by
therapy. Patients with sterile corneal ulceration associated
with dry eye require careful, sometimes daily, monitoring. Patients with existing dry eye, on the other hand,
should be cautioned that LASIK or photorefractive keratectomy may worsen their condition.
CONCLUSIONS
The AAO Preferred Practice Pattern for dry eye syndrome was developed as practitioners of ophthalmology
and optometry have come to understand the inflammatory nature of the condition. Since then, discoveries
about the etiology of dry eye disease and the subsequent
development of new therapies to treat — rather than palliate — have effectively launched a new era for millions
of people who suffer from the sometimes devastating
consequences of dry eye.
Eye care professionals are engaged in discussions regarding the appropriate use of these emerging therapies
as first-line treatments. Certainly, high-risk individuals,
postmenopausal females, patients requiring 4 or more
drops of artificial tears per day, and patients with rheumatologic conditions should strongly be considered candidates for anti-inflammatory therapy. Clinicians are well
aware that the severely dry patient of today, with compromised vision due to central corneal ulceration, was the
mildly dry eye patient of yesterday. CDED is progressive
and intimately associated with the aging process, akin to
glaucoma, hypertension, and hypercholesterolemia. Perhaps early intervention and preventive strategies will not
only avoid significant morbidity and discomfort, but enable overall cost savings through proactive selective intervention. Ultimately, decisions will be made on the basis
of everyday clinical evidence, just as the FDA has ruled on
the precision of prospective clinical trial data analysis. Patients and payers, meanwhile, are watching.
The potential for improved quality of life, decreased
routine and emergent visits to the ophthalmologist, and
the implications for reducing costs and complications of
treatment are enormous. These considerations, discussed
throughout this publication, represent state-of-the-art,
patient-oriented, quality-conscious eye care.
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sicca and chronic HCV infection. Infection. 2002;30: 229–233.
Stern ME, Beuerman RW, Fox RI, et al. The pathology of dry eye: the
interaction between the ocular surface and lacrimal glands.
Cornea. 1998;17:584–589.
Vivino FB, Al-Hashimi I, Khan Z, et al. Pilocarpine tablets for the
treatment of dry mouth and dry eye symptoms in patients with
Sjögren 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 treated
dry eye disease in a managed care population. Clin Ther.
2001;23:1672–1682.
DRY EYE SYNDROME
25
PHARMACOTHER APEUTIC OPTIONS
Medications for Dry Eye Syndrome:
A Drug-Therapy Review
HENRY D. PERRY, MD1
ERIC D. DONNENFELD, MD2
SUMMARY
Early interventions were palliative, attempting to replace water lost from the tear film.
Today, therapy is directed at the underlying
inflammation, a recognized component of
dry eye syndrome, and at the resulting progressive changes to the ocular surface.This
approach offers promise of lasting relief to
patients with moderate to severe symptoms.
R
esearch into dry eye syndrome (keratoconjunctivitis sicca) has advanced dramatically in
the last decade, providing a better understanding of the pathophysiology, underlying mechanisms, and natural history of the disease. This advance
in knowledge has been accompanied by a more focused
therapeutic approach, with new treatments targeted at
underlying pathophysiologic processes. Whereas early
interventions for dry eye syndrome attempted to simply
replace water lost from the tear film, today there exists a
new therapy directed at the underlying inflammation,
now a recognized component of dry eye syndrome, and
at the progressive changes in the ocular surface that occur
over time with the disease (Table 1, page 28).
More than 4 million people in the United States are
thought to suffer from dry eye syndrome (Schein 1997),
and as much as 25 percent of patients visiting eye care
clinics describe dry eye symptoms (Hikichi 1995;
Doughty 1997). The United States Food and Drug Administration’s recent approval of cyclosporine ophthalmic emulsion 0.05 percent as the first prescription
medication to treat keratoconjunctivitis sicca may herald the start of a new therapeutic era. This new therapeutic focus corrects underlying pathologies that lead to
dry eye and uses pharmacologic agents with antiinflammatory/immunomodulatory mechanisms to
manage the signs and symptoms of disease and to control or reverse corneal damage. Other novel and exciting
26
P&T DIGEST
treatments are in the pipeline as well, and these could
contribute to this evolving paradigm.
TREATMENT APPROACHES: AN OVERVIEW
Traditionally, the approach to the treatment of dry eye
syndrome has been palliative, relying predominantly on
replacement of tears to curb symptoms without addressing the underlying disease process. Over the years,
improvements were made in the formulation of artificial
tears and lubricants — including the addition of demulcents to improve viscosity and lubricant properties, and
the development of preservative-free solutions to avoid
causing corneal toxicity. Yet, despite their widespread
1 Henry D. Perry, MD, is clinical associate professor of Oph-
thalmology at the Weill School of Medicine, Cornell University, and the senior founding partner of Ophthalmic
Consultants of Long Island. He graduated from the University of Cincinnati College of Medicine and completed his
internship and residency at Nassau County Medical Center and the University of Pennsylvania Scheie Eye Institute.
He went on to complete fellowships in ophthalmic pathology at the Armed Forces Institute of Pathology in Washington and in cornea and external disease at the Massachusetts Eye and Ear Infirmary, Harvard University. He
reviews for and serves on the editorial board for several journals, and has authored over 150 peer review articles on diseases and surgery of the cornea and ophthalmic pathology.
2 Eric
D. Donnenfeld, MD, is a founding partner of Ophthalmic Consultants of Long Island. A board-certified ophthalmologist, he is experienced in laser vision correction, including LASIK and PRK. Donnenfeld graduated magna
cum laude with a bachelor’s degree from Dartmouth College. He received his medical degree from Dartmouth Medical School, graduating in the top 5 percent of his class. After
completing his ophthalmology residency at Manhattan
Eye, Ear, and Throat Hospital, Donnenfeld completed a fellowship in disease, treatment, and surgery of the cornea at
Wills Eye Hospital in Philadelphia. He has been president
of numerous professional societies and has written more than
100 papers and books on refractive and corneal surgery.
use and proven activity relative to improving ocular lubrication, increasing humidity at the ocular surface, and
even contributing to improved vision, these products
generally failed to accurately reproduce natural tears,
could not acceptably substitute for the continuous flow
of natural tears, and did not correct underlying pathology or tissue damage that can occur over time with dry
eye syndrome (Calonge 2001, Lemp 1994, Murube 1998a,
Murube 1998b, Pflugfelder 1998, Liu 1999).
Alternative therapeutic interventions were aimed at
tear preservation or stimulation of natural tears. Canalicular or punctal tamponade occlusion is a popular nonpharmacologic approach to improving aqueous tear film
content (both quantity and quality), with the result of
improving signs and symptoms of dry eye (Lemp 1994,
Murube 1996, Willis 1987). While this technique can be
helpful for relieving dry eye symptoms, it carries a risk of decreased
tear production, clearance, and
ocular surface sensation (Yen 1999)
and exacerbates the already delayed
tear clearance and turnover rate
(Macri 2000), ultimately resulting
in desensitization of the corneal
surface and possible inflammation.
Overall, these palliative thera- Henry D. Perry, MD
pies have been recognized as having limited value for
long-term control or cure of progressive dry eye syndrome. In the last quarter century, however, research
began to focus more aggressively on the pathophysiology
of dry eye syndrome, yielding several important findings
that suggest an inflammatory etiology.
It is now recognized that dry eye syndrome results
from an underlying cytokine and receptor-mediated inflammatory process affecting the lacrimal glands (Mircheff 1994, Pflugfelder 1986, Pflugfelder 1999, Stern 1998,
Williamson 1973). The observed inflammation, in turn,
can either decrease tear production or alter the contents
of the tear film and disrupt homeostasis at the ocular surface, ultimately leading to keratoconjunctivitis sicca.
These findings have redirected treatment efforts toward
more targeted therapies aimed at resolving the underlying inflammation. Anti-inflammatory/immunomodulatory treatments — most notably cyclosporine A — are
now becoming standard therapy for moderate to severe
dry eye syndrome.
Review of drug therapy options3
Newer agents
Cyclosporine A. Cyclosporine A is a well-known
immunomodulator, most commonly used to prevent rejection after organ/tissue transplantation. It also confers
anti-inflammatory activity and, in dry eye syndrome,
thereby prevents T-cells from releasing cytokines (primarily interleukin-6) that incite the inflammatory component of dry eye. Early studies suggesting its utility in dry
eye syndrome came from dog studies in which topical application of cyclosporine ophthalmic emulsion twice daily
reduced lymphocyte infiltration in the lacrimal glands
and conjunctiva (Kaswan 1989, Gao 1998, Tsubota 1998).
Cyclosporine A also was associated with reduced apoptosis of lacrimal glands and conjunctival epithelial cells in
dogs, effects that contribute to reduced inflammation
and clinical improvement of dry eye (Gao 1998).
The earliest human studies in keratoconjunctivitis
sicca revealed that topical eye treatment with cyclosporine A relieved the signs and symptoms of the disease
(Power 1993, Gunduz 1994, Laibovitz 1993). More recent
data from two United States phase 3 randomized, multicenter, double-blind, 6-month
protocols establish the efficacy,
safety, and anti-inflammatory activity of cyclosporine A ophthalmic emulsion compared with
castor oil-based topical emulsion
vehicle alone in patients with
moderate to severe dry eye syndrome (Sall 2000). In the comEric D. Donnenfeld, MD
bined results from these studies
(N=877), both objective (corneal staining, Schirmer test)
and subjective (blurred vision, need for concomitant artificial tears, physician evaluation of global response to
treatment) measures of treatment efficacy were significantly better with cyclosporine 0.05 percent emulsion
than with vehicle (p<.05). Especially notable is the improvement in corneal staining (Figure 1, page 29), which
indicates that cyclosporine ophthalmic emulsion suppresses the inflammatory processes underlying dry eye
syndrome in these patients, and by doing so, improves the
integrity of the ocular surface. This pathophysiologic
benefit contributes to enhanced vision and normalized
lacrimal gland response to blinking and other stimuli —
and hence to the Schirmer value improvements in this
study (Figure 2, page 30).
The first (and currently only) cyclosporine ophthalmic emulsion 0.05 percent was recently approved by the
FDA for the safe and effective treatment of underlying inflammation in dry eye syndrome. This is the only treatment available that addresses the immunogenic and inflammatory causes of dry eye syndrome and is not solely
palliative. It is a sterile, preservative-free emulsion that
appears white opaque to slightly translucent. It has a favorable safety profile, the most common adverse event
being mild ocular burning and stinging — effects that
3 Table
2,page 29, lists the trade names of generic agents.
DRY EYE SYNDROME
27
also were common with the vehicle alone. Changes were
not detected in intraocular pressure, vision, or the cornea
as assessed by biomicroscopy (Sall 2000).
Topical corticosteroids. Immunomodulation with
topical nonpreserved corticosteroid therapy — such as
TABLE 1
methylprednisolone or lotaprednol etabonate — has
been shown to reduce early inflammation in dry eye
syndrome (Marsh 1999, Prabhasawat 1998). This effect
has been linked to reduced levels of the chemotactic
cytokine IL-8 in the conjunctival epithelium (Pflugfelder
Options for dry eye syndrome
List is not inclusive
Product
Targeted therapies
Immunomodulators:
Cyclosporine A
Mucolytic agents:
N-acetylcysteine
Antibiotics:
Topical: various, e.g.:
bacitracin, chlortetracycline
Systemic: doxycycline
Palliative therapies
Artificial tears:
Low viscosity (carboxymethylcellulose
based): various, e.g.:
GenTeal
Refresh Plus
Refresh Tears
TheraTears
Moderate viscosity (hydroxymethylcellulose based): various, e.g.:
Bion Tears
Ocucoat
High viscosity: various, e.g.:
Refresh Celluvisc
Refresh Liquigel
AquaSite
Murocel
Gel formulations: various, e.g.:
GenTeal Gel
Tears Again
Lubricating ointments:
HypoTears
Refresh PM
Tears Naturale PM
Therapeutic plug
Hydroxypropyl cellulose insert
Secretagogues:
Eledoisin
Pilocarpine
Corticosteroids:
Loteprednol etabonate
Prednisolone acetate
ADAPTED FROM PACKAGE INSERTS
28
P&T DIGEST
How supplied
Dosing
unit dose vials (0.4 mL)
1 drop 2x daily
10–20% drops
1–2 drops up to 4x daily
loading dose, then
1–2 drops 2x daily
100 mg 2x daily
multi dose
unit dose
multi dose
unit and multi dose
1–2 drops as needed
unit dose, preservative free
unit dose, preservative free
best for nocturnal instillation
tube delivery system
tube delivery
fingertip application into cul de sac
fingertip application
(1/4 inch) into cul de sac
5 mg water-soluble rod
1–2 rods per eye daily
5 mg tablets 1 daily
1–2 drops
2 drops
4x daily
4x daily
ful in mild dry eye syndrome for the simple relief of dry eye symptoms, including scratchiness
and dryness. These over-the-counter products
are formulated from one of a variety of linear
Generic
Trade name
polymers that simulate the cell-surface glycoproteins that maintain ocular hydration. Over the
Bacitracin/polymyxin B
Polysporin
years, manufacturers have attempted to closely
Cyclosporine ophthalmic emulsion Restasis
mimic natural tears, which contain lipid (surface
Hydroxypropyl cellulose
Lacrisert
N-acetylcysteine
Mucomyst
layer that retards evaporation), substantial
Loteprednol etabonate
Lotemax
amounts of water with dissolved salt and proteins
Pilocarpine
Salagen
(aqueous layer), and mucin (the film that coats
Prednisolone acetate
Pred Forte
the corneal surface). Despite these attempts to
Sodium carboxymethylcellulose
TheraTears (0.25 percent)
improve composition, however, these products
have inherent limitations; natural tears have a
complex composition that artificial tears cannot
1999). Symptomatic relief has been reported to extend for
fully substitute, while the mucus layer of the tear film has
not been satisfactorily reproduced (Calonge 2001).
months after the steroid application has been stopped
Artificial tear products currently are available in
(Marsh 1999). Long-term use of this class, however, is asvarious
formulations, including solutions, gels, and ointsociated with severe side effects, including ocular hyments.
The
key differences in these products are viscospertension, cataract formation, glaucoma, and infection.
ity,
composition,
and preservative vs. preservative-free
For this reason, these drugs should be reserved for sympformulation.Viscosity
describes the relative density of the
toms that are severe and recalcitrant to aggressive appliformulation
—
which
reflects its mucoadhesive propercation of artificial tears, and used only for acute treatment
ties
and
therefore
the
degree
of contact time with the oc(<2 weeks) of dry eye exacerbations.
ular surface — and generally ranges from 1.5 mL pas
(Pascal seconds, a standard of measurement for viscosOlder agents
ity) to 15 mL pas, with an average of 5.0 mL pas. Agents
Tear substitutes. Until the recent identification of inadded to artificial tears to increase viscosity include carflammation as an important etiology in dry eye synboxymethylcellulose, dextran 70, gelatin, glycerin, hydrome, the most commonly used treatment for dry eyes
droxymethylcellulose, hydroxypropyl methylcellulose,
was topically applied artificial tears and lubricants. Almethylcellulose, PEG, poloxamer 407, polysorbate 80,
though solely a palliative therapy, artificial tears are usepropylene glycol, polyvinyl alcohol,
and polyvinylpyrrolidone. Products
FIGURE 1 Changes from baseline (mean + standard error)
with low viscosity commonly are
in corneal staining
used early in the progression of dry
Related to application of cyclosporine ophthalmic solution
eye syndrome, as they are less likely to
0.05 percent, 0.1 percent, and vehicle alone
disrupt vision. As dry eye syndrome
Month 1
Month 3
Month 4
Month 6
0
progresses, more viscous tear products are needed to achieve symptomatic control, but these are associated
–0.2
with progressive blurring of vision.
Lubricant ointments are reserved primarily for overnight treatment.
–0.4
Compounds included to replicate the lipid occlusive layer are white
–0.6
petrolatum, mineral oil, lanolin, or
lanolin alcohols. The mucin layer,
which allows the solution to spread
CsA 0.05%
–0.8
over the ocular surfaces, is simulated
CsA 0.10%
* p ≤ .05 vs. vehicle
by use of polysorbate 20 and 80,
Vehicle
† p ≤ .62 vs. vehicle
†
poloxamer 282, or tyloxapol. In ad–1.0
dition, many tear supplements conSOURCE: SALL 2000
tain preservatives to stabilize the proChange in staining score
TABLE 2 Generic/trade-name pharmaceutical
conversion chart
*
*
*
DRY EYE SYNDROME
29
As a rule, these agents are infrequently prescribed due to the limited
data, absence of compelling evidence
of improvement, and the associated
Cyclosporine ophthalmic emulsion 0.05 percent, 0.1 percent,
vs. vehicle alone (testing performed under anesthesia)
adverse effects, including generalized
nausea, sweating, and rashes. Fur* p ≤ .05 vs. vehicle
0.6
CsA 0.05%
thermore, some authors have sugCsA 0.10%
gested that generating tears from inVehicle
flamed lacrimal glands may worsen
0.4
dry eye by distributing proinflammatory cytokines to the ocular surface;
0.2
when the glands are substantially
damaged, this approach may fail to
produce tears at all (Calonge 2001).
0.0
Therapeutic ocular inserts. An artificial tear insert that provides longterm slow release of artificial tear
–0.2
polymers is an alternative, if rarely
used, therapy for moderate-to-severe
–0.4
Month 3
Month 6
dry eye. This approach is most beneficial for those patients with moderCategorized Schirmer values graded on 5-point scale: 1=<3mm/5 min;
ate dry eye for whom artificial tear lu2=3-6mm/5min; 3=7-10mm/5 min; 4=11-14mm/5min; 5=>14mm/5min.
brication does not resolve symptoms
or is required at increasingly frequent
SOURCE: SALL 2000
intervals. There is currently only one
therapeutic
insert
manufactured, which contains hyduct for longer periods. Benzalkonium chloride (BAK),
droxypropyl
cellulose
in a sterile, translucent, water-solbenzethonium chloride, cetylpyridinium chloride,
uble
rod.
Each
insert,
applied
once or twice daily inside
chlorobutanol, EDTA, phenylmercuric nitrate, phenylthe
inferior
cul
de
sac
of
the
eyelid,
dissolves over 14 to
mercuric acetate, methyl/propylparaben, thimerosal,
phenylethyl alcohol, sodium benzoate, sodium propi18 hours. The slow release of the tear substance stabilizes
onate, and sorbic acid are the most commonly used adand thickens the precorneal tear film and prolongs tear
ditives. Preservatives — extensive data have been refilm breakup time. It also lubricates the eye and, in some
ported on BAK — can induce corneal desquamation or
patients, may halt or reverse progressive visual damage.
cause irritation or allergic reactions, particularly as daily
The system, however, is difficult to handle, and many pause increases due to worsening dry eye (Becquet 1998,
tients find it uncomfortable.
Burstein 1980, Lopez Bernal 1991, Tripathi 1989); the deMucolytics. Patients with keratoconjunctivitis sicca
velopment of preservative-free products has relieved
are prone to development of corneal mucous plaques,
some of the burden of this potential complication (Debwhich are composed of mucus, epithelial cells, and probasch 2001). While preservative-free solutions do not
teinaceous and lipoidal material that cling to the corneal
worsen corneal barrier function, however, they have not
surface (Lemp 1994, Thermes 1991). These plaques may
been found to normalize it either.
collect external dust and bacteria and cause vision diffiSecretagogues. There are a number of drugs that
culties, foreign body sensation, and substantial pain.
have been used with some success to stimulate the
Topical mucolytic agents, such as N-acetylcysteine 20
lacrimal glands to produce tears. Pilocarpine in particpercent (Mucomyst) diluted to a 10-percent solution
ular has been shown to increase tear volume and flow and
with artificial tears, can be used to break down mucin
improve dry eye symptoms in patients with Sjögren’s
molecules, dissolve corneal filaments, and release the
syndrome (Mathers 2000, Vivino 1999). Eledoisin, an
mucoid plaque in patients with this condition. This soendekapeptide, has yielded improved tear production
lution may smell like rotten eggs, requires refrigeration,
and flow (Gobbels 1991), although clinical improveand, if formulated without preservatives, must be disment of dry eye signs and symptoms has never been
carded after 30 days. It is not commercially available as
formally documented. Bromhexine and ambroxol have
a topical agent, though it can be readily compounded but
met with equivocal results in clinical trials (Ichikawa
at high expense for a relatively small amount.
1988, Avisar 1988).
Antibiotics. Some patients who experience poor conFIGURE 2 Schirmer value changes from baseline
(mean + standard error)
Change in Schirmer score
*
30
P&T DIGEST
*
*
trol of moderate dry eye symptoms with artificial tears
will benefit from antibiotic therapy. Antibiotics contribute to reduced inflammation and improved lipid
production in dry eye syndrome. Topical bacitracin
polymyxin B or tetracycline-based ointments can be
used to supplement hot compresses and lid scrubs to
some benefit. Systemic administration of low doses of
doxycycline, which decreases the viscosity of naturally secreted oils, may also yield positive results in patients
with meibomian gland dysfunction over a 6- to 8-week
course of therapy (Gilbard 1999).
of IL-1 as part of the inflammatory process. Tetracyclines are potent inhibitors of this enzyme and are being
investigated for a role in the management of inflammation in the genesis of dry eye syndrome (Solomon 2001).
Retinoic acid. Retinol is present in tears and deficient
in dry eye syndrome, leading some investigators to suggest a role for retinol replacement therapy. Results with
topical administration of retinoic acid have been variable,
however, with evidence that its particular value is to reverse keratinization, which occurs only in extremely severe cases of dry-eye related disease (Calonge 2001).
Treatments under investigation
Hormones. Sexual hormones have been reputed to
contribute to an anti-inflammatory state at the ocular
surface (Stern 1998, Sullivan 1999a), leading investigators to consider their potential role in the therapy of dry
eye syndrome. Topical application of an estradiol ointment to 22 postmenopausal women was shown in one
study to confer modest improvement in Schirmer tests
and rose Bengal staining (Akramian 1998). Additionally,
the presence of androgen receptors on the ocular surface
may indicate a potential therapeutic role in dry eye syndrome that warrants further study (Smith 1999). In animal models, systemic administration of androgens has
reduced lymphocytic infiltration at the lacrimal gland
and improved lacrimal gland function (Sullivan 1997,
Sullivan 1999b). Currently, an androgen ointment product is in phase 3 trials.
P2Y2 receptor agonists. The P2Y2 receptor in the eye
stimulates ocular hydration and lubrication by mediating
mucosal 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 maintains
tear stability and protects against damage to the ocular
surface. Stimulation of the P2Y2 receptor can be accomplished by administration of adenine analogues in both
rabbits and humans (Jumblatt 1998), suggesting a novel
pathway for therapeutic modulation of tear film. A phase
2 study of a novel P2Y2 receptor agonist has been completed at 12 ophthalmology centers in the United States.
Dequafosol, a P2Y2 agonist in topical eye drop form,
provided both objective and subjective improvements in
ocular parameters when compared with placebo in the
treatment of moderate to severe dry eye syndrome (Li
2001). Phase 3 studies will determine the precise role of
these agents in the treatment of dry eye syndrome.
Tetracyclines. A collagenase enzyme — MMP9 — has
been found to be elevated in the ocular fluid of patients
with aqueous tear deficiency (related to Sjögren’s syndrome) compared with normal controls. This elevated
enzyme level might reflect a mechanism by which proinflammatory molecules are cleaved to achieve activation
CONCLUSION
The treatment of dry eye syndrome has relied predominantly on artificial tears and lubricants. This palliative approach generally has been successful at relieving the signs and symptoms of mild to moderate disease
and, in rare cases, has slowed the progressive damage to
the cornea and conjunctiva that occur over time with dry
eye. Nevertheless, these products do not address the underlying disease process and, in some cases (particularly
with artificial tears containing BAK or certain other
preservatives), can be toxic and allergenic, worsening
the clinical markers of the disease.
Increasing research and advancing knowledge has
identified an inflammatory component to dry eye syndrome and has focused treatment efforts at addressing this
newly identified etiology. Topical cyclosporine emulsion
0.05 percent is the first and currently only FDA-approved
targeted immunomodulatory/anti-inflammatory product
to combat the underlying source of disease. Other similarly targeted agents are under investigation and, if approved, will likely contribute to the start of an entirely new
management standard — one based on control of inflammatory sources and immunologic mechanisms — for
the treatment of dry eye syndrome.
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Smith RE, Taylor CR, Rao NA, et al. Immunohistochemical identification 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-inflammatory
forms of interleukin-1 in the tear fluid and conjunctiva of
patients 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 lacrimal
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Sullivan DA, Edwards JA. Androgen stimulation of lacrimal
gland function in mouse models of Sjögren’s syndrome. J
Steroid Biochem Mol Biol. 1997;60:237–245.
Sullivan DA, Krenzer KL, Sullivan BD, et al. Does androgen insufficiency cause lacrimal gland inflammation and aqueous
tear deficiency? Invest Ophthalmol Vis Sci.
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Sullivan DA, Wickham LA, Rocha EM, et al. Androgens and dry
eye in Sjögren’s syndrome. Ann NY Acad Sci.
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Tsubota K, Saito I, Ishimaru N, Hayashi Y. Use of topical cyclosporine A in a primary Sjögren’s syndrome mouse model.
Invest Ophthalmol Vis Sci. 1998;39:1551–1559.
Vivino FB, Al-Hashimi I, Khan Z, et al. Pilocarpine tablets for
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lacrimal gland in keratoconjunctivitis sicca. Br J Ophthalmol. 1973;57:852–858.
Willis RM, Folberg R, Krachmer JH, Holland EJ. The treatment
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CO S T E F F E C T I V E N E S S
CO S T E F F E C T I V E N E S S I S S U E S
Considerations in the
Pharmacoeconomics of Dry Eye
JAN D. HIRSCH, PHD1
Prescription Solutions
SUMMARY
Dry eye disease diminishes the quality of
patients’ lives and drives utilization of health
care resources. Until recently, all treatments
for dry eye have been palliative. A new treatment, cyclosporine A ophthalmic emulsion,
addresses the disease’s underlying causes.
It warrants pharmacoeconomic analysis to
determine its place in managed care.
P
harmacoeconomic (PE) research identifies,
measures, and compares the costs and consequences of pharmaceutical product and service
utilization. In this definition, costs refers to resources consumed; the consequences of using pharmaceutical products and services are considered to be the
outcomes derived. A system for classifying the full range
of outcomes is the ECHO (Economic, Clinical, and
Humanistic Outcomes) model, proposed by Kozma
(1993). Economic outcomes in the ECHO model include direct medical costs, such as the costs of the drug,
administration, and treatment of adverse effects; direct
nonmedical costs, such as patient transportation; indirect costs, such as lost work days, lost earnings, and de1
Jan D. Hirsch, PhD, is the director for post-launch clinical research at Prescription Solutions, a Costa Mesa, Calif.based pharmacy benefit management company. Hirsch
leads the clinical research group’s Real World Prospective
Outcomes Research program, which evaluates the value,
safety, and effectiveness of FDA-approved medications and
devices in actual patient care settings and focuses specifically on such managed care environments as HMOs, IPAs,
medical groups, and integrated health systems. A pharmacist by initial training, Hirsch earned her PhD in
pharmacy administration from the University of South
Carolina. She has authored book chapters in multiple
pharmacoeconomic texts and has written numerous journal articles on the value of specific pharmaceutical agents.
creased productivity; and
intangible costs related to
pain and suffering. Clinical
outcomes include efficacy,
onset of action, percentage
of patients who become
free of symptoms, symptom recurrence, and adverse effects. Humanistic
outcomes include healthrelated quality of life, return
to normal functioning, and
patient satisfaction with
therapy. Some variables
may relate not only to pa- Jan D. Hirsch, PhD
tients but also to caregivers
and significant others.
This chapter considers the economic and quality-oflife burden of moderate to severe chronic dry eye syndrome, then introduces PE analysis techniques that can
be used to evaluate treatments for chronic disease.
BURDEN OF DRY EYE
Dry eye syndrome is common, but its prevalence is
somewhat difficult to pinpoint, primarily because the
disease is multifactorial, definitions differ, and research
is sparse. Furthermore, diagnostic techniques lack standardization and are inconclusive in milder cases. Clinical
signs do not always correlate with symptoms, except in
moderate to severe cases and in association with autoimmune diseases, such as Sjögren’s syndrome (Nichols
1999).
In a German study, 22.8 percent of women and 9.9
percent of men age 55 to 59 reported often experiencing
a sandy sensation in the eyes. In the Canadian Dry Eye
Epidemiology Study, optometrists surveyed all patients
using a standard questionnaire; researchers reported
that, across all age groups, 28.7 percent reported dry eye
symptoms, 7.6 percent indicated constant but moderate
symptoms, and 1.6 percent complained of severe symptoms (Brewitt 2001). In the United States, researchers at
DRY EYE SYNDROME
33
the Schepens Eye Research Institute — using a broad definition of dry eye syndrome — estimate that 10 million
Americans suffer from its symptoms (Schepens 2001).
Other estimates of prevalence are reported elsewhere in
this publication.
Because this chapter focuses on treatment of moderate to severe dry eye syndrome, it is useful to consider the
prevalence of the disease in terms of the percentage of patients with symptoms severe enough to seek health care
services. In a survey of third-party payers, Nelson and
colleagues (2000) reported the prevalence of dry eye syndrome to be 0.19 percent among managed care plan participants, 0.21 percent among persons covered by commercial payers, 0.35 percent among Medicaid recipients,
and 1.30 percent among Medicare recipients.
Many factors — ranging from autoimmune diseases
such as Sjögren’s syndrome to age-related changes (e.g.,
menopause) to environmental conditions (e.g., contactlens wear) — can cause dry eye syndrome (Albietz 2001).
Persistent uncontrolled dry eye can lead to superficial
punctate staining, epithelial erosions, corneal filaments,
and persistent epithelial defects. In the most severe cases,
corneal ulcers occur. Clearly, moderate to severe dry eye
is painful and debilitating, and the burden of dry eye can
be substantial in terms of both economic and humanistic
outcomes.
Economic impact
Until the recent market availability of cyclosporine A
(CsA) ophthalmic emulsion, then-available treatments
not only failed to provide adequate relief of symptoms
but also failed to stop progression of the disease. Dry eye
is a chronic progressive inflammatory condition and is
by no means self-limited. In turn, as dry eye severity increased, both individual and societal treatment costs increased.
A survey of Sjögren’s syndrome patients indicated that
sufferers used drops and ointments, on average, more
than 7 times daily, and nearly 1 in 3 had received punctal occlusion. Despite these measures, 89 percent visited
their ophthalmologist an average of 3.1 times a year for
relief from their symptoms, and 28 percent consulted
other physicians for help with their dry eye problems. On
average, these patients went to work despite their symptoms on 208 days annually and missed 5 work days due
to their dry eye symptoms or treatment. Patients also reported that dry eye symptoms interfered with leisure
activities 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 chronic
and devastating; on average, patients responding to the
study had been diagnosed 9.23 +/– 7.19 years previously,
52 percent described their symptoms as severe or very se-
34
P&T DIGEST
vere, and 22 percent indicated their symptoms were moderate. Half of the patients who revealed their ages were at
least 65. Of the 70 respondents, only two reported using
no topical treatments, such as artificial tears and lubricants; at least 61 percent reported using them always or
regularly. More than 40 percent had received punctal occlusion; 27 percent reported using other medications —
analgesics, antibiotics, anti-inflammatory agents — to
treat their dry eye; 60 percent said they visited a physician
at least twice in the past year because of dry eye, and 84
percent sought the aid of an ophthalmologist.
These researchers also noted that about 73 percent of
respondents indicated that, despite all the treatments
they were using, dry eye interfered with the activities of
daily life; 76 percent (53 of 70) indicated that their symptoms had not improved or had worsened over the course
of the previous year. This team’s findings of the impact
of the symptoms of dry eye on quality of life are summarized in Table 1. Annually, these patients lost 2 work
days because of their dry eye symptoms, and went to
work despite the interference on 191 days, presumably reducing their efficiency and effectiveness.
Reviewing cases from a managed care database, researchers showed that patients with dry eye syndrome experienced a significantly greater increase in total costs
after diagnosis than a matched control group (Smeeding
2001). These researchers suggested a link between dry eye
and several other costly ophthalmic conditions, such as
glaucoma. After dry eye syndrome diagnosis, total
charges increased significantly more in the dry eye group
(22 percent) as compared to the control group (15 percent, p<0.001). The higher management costs associated with dry eye syndrome were primarily from more
frequent visits to physicians. In addition, dry eye patients were also more likely than controls to receive artificial tears, ophthalmic antibiotics, and corticosteroids.
Although artificial tear preparations are sold over the
counter, topical antibiotics and corticosteroids are both
costly and fraught with potential side effects that increase the need for clinical evaluation — thereby increasing utilization costs.
Humanistic impact
Recognizing that the impact of moderate to severe
dry eye is symptom-driven, several research groups have
developed patient questionnaires to quantify the impact
of dry eye in terms of clinical outcomes (e.g., pain) and
functional activities (e.g., daily activity impairment).
Studies evaluating the validity and reliability of these
instruments also provide insight into the effect of dry eye
symptoms on patients’ daily lives.
In a study testing the performance and repeatability of
the National Eye Institute Visual Function Question-
naire, researchers confirmed that the 25-question VFQ25 is a reliable tool for quantifying dry eye pain and
concluded that low-vision patients with diagnostically
confirmed dry eye experience more ocular pain than do
other low-vision persons. Further, the VFQ-25 can be
used to stage dry eye (Nichols 2002). Table 2, on page 36,
lists sample questions from the VFQ-25; the entire questionnaire can be viewed online at «www.nei.nih.gov/
resources/visionfunction/vfq_ia.pdf».
Citing poor correlation between dry eye symptom assessment and objective test results, another team of researchers evaluated the Dry Eye Questionnaire (DEQ) in
an assessment of confirmed dry eye patients (with and
without Sjögren’s syndrome) and controls. Concentrating on frequency and intensity of symptoms, they
found that 10 percent of controls, 30 percent of dry eye
patients without Sjögren’s syndrome, and 60 percent of
dry eye patients with Sjögren’s syndrome had so much
eye pain and trouble that they frequently halted their
daily activities and closed their eyes to gain relief. The researchers also determined that symptom intensity increases as the day progresses, and they suggested that further testing of the DEQ is needed (Begley 2002).
Using another set of patient questionnaires, the Dry
Eye Disease Impact Questionnaire (DEDIQ), the Ocular
Surface Disease Index (OSDI, a valid and reliable tool for
measuring disease severity, which has the psychometric
properties necessary to be used as a clinical-trial end
point [Schiffman 2000]), the Facial Expression Subjective
Scale, and the SF-12 Health Survey, researchers determined that 53 percent of dry eye patients rated their
symptoms as severe to very severe; their average OSDI
score was 0.41 (Kozma 2000). In the OSDI system, a
score of 0 indicates no disability and a score of 1 means
complete disability due to dry eye symptoms. Their SF12 physical and mental summary scores were 42.3 and
50.2, respectively, compared to a United States norm of
50.0. Only 25 percent of these patients reported symptom improvement after 1 year of treatment, while the
other 75 percent complained that their symptoms failed
to improve or worsened.
Although researchers have used several validated instruments to assess dry eye, each of the available methodologies constructs a multidimensional profile of the patient’s health status. In a landmark study, researchers
applied, for the first time, several standard methodologies for assessing an indexed type of humanistic outcome
called utilities (Walt 2001). Health utilities are fundamental values that represent a subject’s preferences for
specific outcomes, relative to states of health or treatments, and can be used to compare the relative impact
of different diseases. In the OSDI study, patients with the
severe 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 interfered
with activities most or all of the time (%)
Quality-of-life factors
Loss of confidence
Decrease of leisure time
Frustration with daily activities
Change of activities
Depression, unhappiness
Need for assistance
Missed outings
Decrease of work time
Change of work
Other
None of the above
Vision-related activities
Nighttime driving
Reading
Working at electronic monitor
Watching television
38.6
35.7
34.3
25.7
25.7
14.3
12.9
11.4
7.1
22.9
27.1
32.3
27.5
25.7
17.9
SOURCE: NELSON 2000
III/IV angina (see Figure, page 36). They suggested that
an effective dry eye treatment could be expected to restore
patient benefits of a magnitude comparable to those associated with treating severe angina. This study also indicated that dry eye utilities vary in a manner consistent
with disease severity.
TREATMENT OPTIONS AND RELATIVE COSTS
As the above research suggests, dry eye symptoms persist or worsen despite standard therapies. Typically, as
with mild dry eye, patients with moderate to severe dry
eye rely on artificial tears. The mainstay of therapy for dry
eye syndrome, artificial tears are palliative, applied several times daily, to substitute for natural tears that are deficient in quality or quantity. Other treatment options for
more severe dry eye syndrome include punctal occlusion
with temporary or permanent plugs, electrocautery
surgery, and, for patients with Sjögren’s syndrome, hormone replacement therapy.
Recently approved by the United States Food and Drug
Administration, topical CsA is intended to address the
underlying inflammatory causes of dry eye syndrome
and provide far more than palliative therapy for many dry
eye patients (Allergan 2002). Although the exact mechanism of action of this product is not fully understood,
it is thought to act as a partial immunomodulator and
anti-inflammatory, arresting T-cell activation, thereby
preventing T-cells from releasing cytokines that begin the
inflammatory cycle of dry eye. As CsA is utilized and its
DRY EYE SYNDROME
35
TABLE 2
NEI VFQ-25: sample questions
From version 2000.Weighted kappa values (Kw) are used
to determine the repeatability of individual VFQ-25
questions.2
Question 4 (Kw = 0.42). How much pain or discomfort have you had in and around your eyes (e.g.,
burning, itching, or aching)? Would you say it is:
(Choose one)
None
Mild
Moderate
Severe
Very severe
Question 16 (Kw = 0.85). How much difficulty do you
have driving at night:
No difficulty at all
A little difficulty
Moderate difficulty
Extreme difficulty
Have stopped doing this because of eyesight
Have 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 time
Most of the time
Some of the time
A little of the time
None of the time
Question 20 (Kw = 0.90). I stay home most of the
time because of my eyesight:
Definitely true
Mostly true
Not sure
Mostly false
Definitely 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
place in practice becomes clearer, the role of traditional
palliative agents may change significantly.
Pharmacoeconomic analysis of dry eye
The burden of dry eye syndrome has been assessed
across the full range of outcomes. However, in the routine assessment of its therapies, researchers customarily
36
P&T DIGEST
FIGURE
Comparing utilities among dry eye,
other conditions
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.
Mild psoriasis
0.89
Mild dry eye
0.81
Asymptomatic dry eye
0.78
Moderate dry eye
0.78
Moderate angina
0.75
Severe dry eye
0.72
Class III/IV angina
0.71
Disabling hip fracture
0.65
Severe dry eye with tarsorrhaphy
Moderate stroke
0.62
0.39
Complete blindness 0.33
AIDS
0.21
SOURCE:WALT 2001
have focused mainly on safety and efficacy factors. A
comprehensive evaluation of these treatments should
also include investigation of their broader impact, focusing on their ability to relieve the economic and humanistic burdens of dry eye syndrome on both individual patients and society. Only a few studies have included
economic or humanistic assessments of any kind, notably
studies for punctal occlusion and the newly approved
ophthalmic cyclosporine formulation.
Punctal occlusion
Although punctal occlusion has been used to treat
dry eye patients for 40 years, few clinical studies have adequately characterized the benefits of this procedure.
In a controlled, double-masked, prospective study, researchers in Mexico recently determined that patients
who received bilateral collagen and silicone lacrimal occlusion implants in both the superior and inferior canaliculi experienced progressive clinical improvement over
time (Nava-Castaneda 2003). At 8 weeks, suffering had
been relieved by more than 90 percent, compared with
baseline readings. At 6 months, 86 percent of treated pa-
tients remained free of symptoms. In contrast, symptoms remained unchanged
among patients in the sham procedure
group. In addition, the researchers also reported a change in resource utilization; 76
percent of patients had stopped the daily
use of eye lubricants, thus relieving a portion
of the patient’s economic burden.
Retrospectively, researchers at Wills Eye
Hospital, Philadelphia, established that punctal plug insertion is a simple method that is
safe and effective in the treatment of a wide
range of diseases of the ocular surface and
aqueous tear deficiency, including toxic epitheliopathy that cannot be controlled by artificial tears (Ming-Chen 2002). In addition,
they focused on a common event that has an
economic impact — spontaneous plug extrusion, which requires repeated medical visits and procedures. Of 312 plugs inserted, 14
were removed — 11 because of epiphora and
three due to conjunctival erosions. Overall
success was about 77 percent, but would have
been about 10 percentage points higher if
only patients with dry eye had been included
in the study. One reason for suboptimal clinical results was undiagnosed blepharitis,
which often coexists with dry eye. The authors also noted that clinicians should carefully choose plug size and monitor patients;
these could have added economic benefits.
Using data from the literature and expert
opinion, Lee and colleagues developed a
Markov economic model to assess the medical costs and outcomes of dry eye syndrome
(Lee 2000). They reported that, over the
course of 1 year, the cost of managing and
treating a population of dry eye patients
with palliative medications, punctal plugs,
and surgery is estimated to be $357,050 for
an organization covering 500,000 lives.
These researchers suggest their model could
be used to quantitatively assess the impact of
new treatments on health-system budgets
and speculated that a more effective dry eye
intervention could improve cost effectiveness by decreasing patient demand for physician visits and procedures.
Cyclosporine A ophthalmic emulsion
With the recent approval of CsA ophthalmic emulsion, investigators have renewed reason to apply PE assessment to dry
Basic principles of
pharmacoeconomic research
P
E evaluations estimate the value of the economic, clinical, and
humanistic outcomes resulting from different treatments,
which are compared to help decision makers determine optimal
therapeutic approaches for their patient populations. Several
types of analyses are available, including cost-minimization, costeffectiveness, cost-benefit, and cost-utility analyses. Each type of
analysis expresses resources consumed in terms of monetary
units, but uses a different unit to express the outcome.
Cost minimization is the simplest of these analyses, because it
assumes that the outcomes of the therapies being compared have
been proven equivalent among treatment groups.This reduces
the analysis to a monetary comparison of resources consumed.
A cost-effectiveness comparison of two or more treatments analyzes the dollars spent in consumed resources and the clinical
outcomes derived from this expenditure. Because it uses natural
units of medical outcomes (e.g., life-years gained, percentage of
successfully treated patients) to compare medical treatments, this
type of PE analysis — more than any — parallels the medical
thought process and is intuitively accepted within the medical
community.That is why, in medical-decision making, cost effectiveness is the most commonly performed of the four analyses. A
cost-effectiveness evaluation, however, cannot be used to compare treatments with dissimilar outcomes.
In a cost-benefit analysis, the outcomes of two dissimilar treatment groups, inherently expressed in dissimilar natural units, can
be estimated in terms of monetary units.This conversion allows
the investigator to compare dollars with dollars: dollars spent in
consumed resources with the dollar value gained in clinical outcomes.Thus, a cost-benefit analysis allows the investigator to
compare costs and outcomes of unrelated health care interventions, such as the treatment of glaucoma and dry eye syndrome.
A cost-utility analysis evaluates the effect of treatment on societal outcomes, typically expressing results in terms of health utilities or quality-adjusted life years. A cost-utility evaluation allows
the investigator to include the humanistic outcomes of patient
preferences or quality of life when comparing products or programs with dissimilar outcomes measures.This analysis technique, in effect, expands cost-benefit analyses beyond expressing outcomes as monetary units.
The clinical characteristics of a disease and the resulting burden determine the relevance of each type of outcome for a PE
analysis. For example, lost work days are relevant in the evaluation of asthma or migraine, in which symptoms can temporarily
debilitate sufferers. More relevant to a symptom-silent disease
(such as early-stage glaucoma) would be, for example, the cost of
noncompliance, which generates greater downstream expenditures associated with more invasive therapies. In the case of
moderate to severe dry eye syndrome, the burden of disease
data indicates that both economic and humanistic outcomes are
important to consider.
DRY EYE SYNDROME
37
eye treatments. So far, studies have included analyses
from the economic perspective regarding reduction in artificial tear and medication use after CsA treatment.
In a double-masked phase 2 study of CsA, the use of
artificial tears generally decreased at weeks 4, 8, and 12
during therapy, and at weeks 2 and 4 after it (Stevenson
2000).
In a phase 3 trial of 0.05 percent and 0.1 percent CsA
emulsions, patients instilled 1 drop of the study medication in each eye twice daily and were allowed to use artificial tears as adjunctive medication at will. Over the
course of the study, patients applying the CsA formulation decreased their reliance on artificial tears (Sall 2000).
A 1-year observational study using the DEDIQ determined that CsA 0.05 percent is highly efficacious in treating dry eye syndrome. Of 181 enrolled subjects in a private ophthalmology practice, more than 60 percent
reported symptom improvement. From an economic
perspective, total medication orders, including those
used for dry eye (nonsteroidal anti-inflammatory drugs,
antihistamines, artificial tears, ophthalmic antibiotics,
and ophthalmic/antibiotic steroid combinations) fell 55
percent in the post-CsA treatment period (Cross 2002).
CONCLUSION
Providing optimal medical care of dry eye syndrome
requires planning that is based not only on drug safety
and efficacy, but also on data relating the full value of
medical treatments, that is, changes in economic and
humanistic outcomes that are achieved due to the treatment effect. Applying PE methods to assess the value of
treatments systematically can improve both the overall
quality and efficacy of dry eye medical care.
Although full-range PE studies of dry eye syndrome remain to be conducted, the course of such analyses is clear.
Researchers must determine which therapies or regimens
provide the greatest effect in terms of relieving the clinical, economic, and humanistic burden of dry eye syndrome, for specific patient groups at the most effective cost.
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CHRONIC THER APY
«PRODUCT HED»
Issues in the Use
Of Preservative-Free Topicals
HENRY D. PERRY, MD
SUMMARY
In a perfect world, patients would use medications as prescribed. In reality, patients may
cut corners, especially if they may save
money by doing so. Clinicians and pharmacists must acknowledge this tendency, yet at
the same time protect patients from using
contaminated ophthalmologic agents and
strive to achieve optimal clinical outcomes.
I
n treating dry eye syndrome, appropriate product
administration is an important but often neglected
issue. At present, concerns about product administration apply only to topical artificial tear preparations, but in the future physicians will have the option of
treating the underlying cause of the disease, rather than
its effects, in many patients. This is because the Food and
Drug Administration recently approved a new dry eye
medication, a 0.05 percent cyclosporine A (CsA) ophthalmic formulation, marketed by Allergan as Restasis
(Allergan 2002). CsA is contraindicated in patients with
active ocular infection or suspected or known hypersensitivity to any of its components, and therefore is not
appropriate for a subset of patients.
In brief, CsA restores tear function. Unlike artificial tear
medications, which dry eye sufferers may apply four or
more times daily, CsA is applied twice daily. Because its
clinical benefits become apparent after about 3 months
of therapy, it is reasonable to suspect that patients put on
a CsA regimen will continue to use artificial tear formulations during the initial months of therapy. They also may
continue to use artificial tears adjunctively thereafter, but
probably at a lower daily dosage and with an end in sight.
Until CsA gains broad utilization, the artificial tear
preparations — liquids, gels, and ointments — will continue to represent the mainstay of dry eye treatment. By
increasing humidity at the ocular surface, improving lubrication, and smoothing the corneal surface, artificial
tears provide temporary, albeit strictly palliative, relief
from the effects of dry eye.
Common artificial tear ingredients include tonicity,
buffering, viscosity, wetting, and lubricating agents; antioxidants; 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 the
eye’s drainage ducts, to extend its usefulness. Wetting
agents facilitate the spread of the material over the ocular surfaces, and lubricating agents supplement the lipid
occlusive layer. Antioxidants prevent deterioration of the
product when it is exposed to oxygen. Preservatives retard the growth of bacteria, increasing the shelf life of artificial 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 than
nonpreserved formulations, are packaged in multipledose bottles. Preservative-free formulations are sold in
single-dose vials. The FDA and the U.S. Pharmacopoeia
mandate the inclusion of preservatives for all multidose
topical ophthalmic medications (Abelson 2002). Over the
years, pharmaceutical companies have replaced harsher
preservatives in artificial tear preparations with gentler
ingredients.
Preservatives have benefits when used in ophthalmic
topical medications, but experts caution against prolonged use of artificial tears containing preservatives,
especially benzalkonium chloride (BAK) and chlorobutanol, which have been shown to irritate users (Abelson 2002). They further advise that, in contrast to BAK,
sorbic acid infrequently causes adverse reactions, polyquaternium-1 causes only superficial epithelial damage,
and sodium perborate converts to hydrogen peroxide
on exposure to air and then breaks down into oxygen and
water. Stabilized oxychloro complex has been found to
be safe and well tolerated, even with frequent use.
DRY EYE SYNDROME
39
CHRONIC THER APY
Although preservative-free artificial tear solutions
were developed for patients who demonstrate sensitivity to preservatives, the general avoidance of preservatives
may be wise. In a rat model, researchers demonstrated
that, especially over the long term, most preservatives
used in ophthalmic eyedrops have the potential to damage human conjunctival and corneal epithelial cells (Becquet 1998). Although preservatives interfere with the
growth, multiplication, and metabolism of microbes,
they have a similar effect on eukaryotic cells, which explains their cytotoxicity and inflammatory cell response.
Even at lower concentrations, and after a single instillation, BAK was toxic to the corneoconjunctival surface.
These researchers warn that prolonged exposure to
preservatives is likely to produce subclinical inflammation, which might lead to chronic irritation and fibrosis
that can worsen dry eye syndrome.
Several researchers indicate that the negative effects of
preservative-free artificial tears on the eye are minor, if
not negligible (Albietz 2001a, Albietz 2001b, Berdy 1992,
Pisella 2002, Schein 1992). The primary concern relating
to the use of preservative-free artificial tear formulations is contamination of the contents once the patient
opens the container and applies the medication. The
contamination typically is due to contact with the patient’s cornea, conjunctiva, eyelashes, or hands. Even
bacteria that are not pathologic may alter the pH value
of the medication and interfere with efficacy.
A decade ago, researchers determined that patients
using ocular-surface medications can trigger a cycle of
microbial contamination between their conjunctivae
and the container (Schein 1992). This team studied 220
in-use medications obtained from 101 patients with
nonmicrobial ocular-surface disease. They cultured the
bottle caps, a drop from each bottle obtained by inversion, and the contents of the bottle. They also obtained
conjunctival cultures from the patients using the medications and 50 age-matched controls. They harvested
pathological organisms from the conjunctivae of 34 percent (34/101) of patients but only 10 percent (5/50) of the
controls.
To test the susceptibility of unpreserved eye drops to
contamination, British researchers inoculated 21 different unpreserved eye drop formulations with a known
quantity of four different microorganisms and stored the
containers at different temperatures for as long as 28
days (Oldham 1996). They recommend that unpreserved
eye drops be stored at between 2 degrees and 8 degrees
Celsius (35.6 to 46.4 degrees Fahrenheit) after opening,
and confirmed that, in general, drops containing alkyloids or antibiotics should be discarded after 7 days. The
Lothian Joint Formulary (NHS 2002) recommends that
eye drops in multiple-use containers be discarded 4 weeks
40
P&T DIGEST
after opening and that unpreserved drops be discarded
1 week after opening. Neither of these products need refrigeration.
PRODUCT USE ISSUES
For patients who need to instill artificial tears several
times daily, larger containers of medication are desirable.
British researchers observed that patients who frequently
apply eye drops may need to carry multiple single-dose
containers, which are cumbersome (Oldham 1996). They
also recognized that purchasing single-dose containers
can be more than 1,000 percent as expensive.
It can be expected, then, that patients who purchase
unpreserved medications in single-dose vials will try to
derive the most benefit from their dollars. A single-dose
vial can provide 10 or more drops, all of which may be
used to relieve symptoms in one eye; a patient who uses
the entire vial in a day does not risk contamination. Yet
a patient requiring 4 drops daily may be tempted to save
the remaining medication for use beyond the first day.
In our practice, we therefore advise patients that
preservative-free artificial tears are free of contamination
the day they are opened, are probably not contaminated
on the second day, but are likely contaminated on the
third day and must be discarded. Our goal is to make sure
that the patient at least reduces the risk of infection to a
level with which we are relatively comfortable. Considering that the dry eye medications we prescribe have
been tested and remained uncontaminated when exposed to room air for as long as 28 days, we are confident
that our warning suffices to prevent patients from instilling contaminated medications.
Compliance
Patients with dry eye may become noncompliant with
an established regimen for different reasons. Some will
use too much medication because their artificial tears
provide insufficient relief. Some may be unable to apply
the medication correctly.
In a study of noncompliance in 200 patients using
eyedrops (mean age, 26 years; range, 9 to 92 years), the
main reasons that emerged for noncompliance were poor
motivation (stemming from inadequate understanding
of the function of the medication) and inability to use eye
drops properly (Winfield 1990). Sixty-two percent consistently self-administered their drops, 17 percent selfmedicated when no help was available, 21 percent always
obtained help, and 8 percent never tried to administer
their medication. Approximately half the patients had
difficulty aiming the drop. Other problems included inability to squeeze the container well enough, blinking,
and inability to see the tip of the container. In particular, arthritic patients experienced physical difficulties
CHRONIC THER APY
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/or
opaqueness 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 to
form 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 eye
for about 30 seconds after instilling drop.
• Use only 1 drop at a time.
• The eye’s conjunctival fornix can accommodate only 1 drop at a time. Any fluid beyond 1
drop will overflow.
Ointment
• Start at inside corner of eye.
• Squeeze thin line (about 0.5 cm) of medication
along inside of lower lid.
• Blink.
with administration. These researchers also reported
that most patients were reluctant to admit they were experiencing problems with the process.
In a separate survey of patients by telephone, 50 percent (114/229) of patients with dry eye said they continued to use the artificial tear solutions they had been
prescribed, while 53 percent (47 of 89) reported discontinued use of prescribed ointments (Swanson 1998).
This research detected “extreme” variability in the
amount of artificial tear medication used, from patient
to patient, and day to day. Patients appeared to titrate
their artificial tear dosage to their symptoms on a daily
basis; this researcher recommends patient education to
foster compliance.
Product administration
To help patients achieve optimal benefit from ophthalmic medications, clinicians and pharmacists need
to discuss the benefits of the chosen therapy with patients
and their at-home care providers, and the correct way to
apply the medication (see Table).
CONCLUSION
Although new ophthalmic drug-delivery systems alleviate dry eye somewhat, and a new CsA ophthalmic
emulsion may alleviate the syndrome in many patients,
proper administration of dry eye medications remains
vital to successful treatment. The trend toward preservative-free medications means patients and their caregivers must exercise care during administration to prevent contamination of the remaining contents in the
vial. Patients should be cautioned not to instill more
than one drop of medication at a time, to prevent wasting the medication. Eye care clinicians can help patients
achieve optimal relief by providing a combination of the
most appropriate medication with the education on
proper self-medication.
REFERENCES
Abelson MB, Washburn S. The downside of tear preservatives.
Rev Ophthalmol. 2002;9(5).
Albietz JM. Dry eye: an update on clinical diagnosis, management and promising new treatments. Clin Exp Optom.
2001a;84:4–18.
Albietz JM, Bruce AS. The conjunctival epithelium in dry eye
subtypes: effect of preserved and non-preserved topical
treatments. Curr Eye Res. 2001b;22:8–18.
Allergan, Inc. Allergan’s Restasis approved by the FDA [press release]. December 26, 2002.
Becquet F, Goldschild M, Moldovan MS, et al. Histopathological
effects of topical ophthalmic preservatives on rat corneoconjunctival surface. Curr Eye Res. 1998;17:419–425.
Berdy GJ, Abelson MB, Smith LM, George MA. Preservative-free
artificial tear preparations: assessment of corneal epithelial
toxic 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 in
unpreserved eyedrops. Br J Ophthalmol. 1996;80:588–591.
Pisella PJ, Pouliquen P, Baudouin C. Prevalence of ocular symptoms and signs with preserved and preservative free glaucoma 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 contamination
of in-use ocular medication. Arch Ophthalmol.
1992;110:82–85.
Swanson M. Compliance with and typical usage of artificial tears
in dry eye conditions. J Am Optom Assoc. 1998;69:649–655.
Winfield AJ, Jessiman AJ, Williams A, Esakowitz L. A study of the
causes of non-compliance by patients prescribed eyedrops.
Br J Ophthalmol. 1990;74:477–480.
DRY EYE SYNDROME
41
CONTINUING EDUCATION POST-TEST
P&T Digest
Dry Eye Syndrome
Please tear out the combined answer sheet/evaluation form on page 43 (physicians) or page 44 (pharmacists).
On the answer sheet, place an X through the box of the letter corresponding with the correct response for each
question.There is only one correct answer to each question.
1. Symptoms of dry eye syndrome, or keratoconjunctivitis sicca, include all but which of
the following?
a. Gritty sensation under eyelids.
b. Numbness.
c. Mucous discharge.
d. Increased frequency of blinking.
e. Redness.
2. Despite improving ocular lubrication and increasing humidity at the ocular surface, artificial 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 but
which of the following goals for managing
patients 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 present
in:
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 artificial
tear 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.
42
P&T DIGEST
7. Dry eye can occur sporadically or as a chronic
condition that becomes a self-perpetuating
syndrome.
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 exacerbations of dry eye syndrome.
d. Answers a and c.
e. All the above.
9. For patients with severe dry eye, a diagnosis
usually 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 dry
eye 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 developed:
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, prevalence
of dry eye syndrome among persons covered
by commercial plans was determined to be:
a. 0.21 percent.
b. 0.35 percent.
c. 1.30 percent.
d. 10.00 percent.
continued on page 45
CONTINUING EDUCATION ANSWER SHEET/CERTIFICATE REQUEST
P&T Digest
Dry Eye Syndrome
CME CREDIT FOR PHYSICIANS
Sponsored by The Chatham Institute
See page 44 for answer sheet for pharmacists
I certify that I have completed this educational activity
and post-test and claim ______ credits.
Signature: _______________________________________
First name, MI ____________________________________
Last name, degree ________________________________
EXAMINATION: Place an X through the box of the letter
that represents the best answer to each question on pages
42 and 45.There is only ONE answer per question. Place all
answers on this answer form:
A B C D E
A B C D E
11. ■ ■ ■ ■
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PROGRAM EVALUATION
Title ___________________________________________
So that we may assess the value of this self-study program,
we ask that you please fill out this evaluation form.
Affiliation _______________________________________
Have the activity’s objectives been met?
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 Ophthalmology guidelines for treatment of KCS.
4. Explain the mechanisms of action of
pharmacotherapies for KCS.
5. Summarize pharmacoeconomic data of
emerging anti-inflammatory agents for KCS.
6. Identify considerations in proper handling and
administration of preservative-free topical
agents for KCS.
Specialty ________________________________________
Address ________________________________________
City _____________________ State _____ ZIP ________
Daytime telephone (_______) _______________________
Fax (________) ___________________________________
E-mail __________________________________________
Physician — Maximum of 3.0 category 1 credits toward
AMA Physician’s Recognition Award.
To receive CME credit, complete answer sheet/evaluation
form and mail or fax to:
Office of Continuing Education
The Chatham Institute
26 Main Street, 3rd Floor
Chatham, NJ 07928
Fax: (973) 701-2515
Credit will be awarded upon successful completion of assessment questions (70 percent or better) and completion
of program evaluation. If a score of 70 percent or better is
not achieved, no credit will be awarded and the registrant
will be notified.
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If no, please explain: _______________________________
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Did this educational activity meet my needs, contribute
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CMC3000
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DRY EYE SYNDROME
43
CONTINUING EDUCATION ANSWER SHEET/REQUEST FOR STATEMENT OF CREDIT
P&T Digest
Dry Eye Syndrome
CPE CREDIT FOR PHARMACISTS
Sponsored by The Chatham Institute
See page 43 for answer sheet for physicians
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and post-test and claim ______ credits.
Signature: _______________________________________
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EXAMINATION: Place an X through the box of the letter
that represents the best answer to each question on pages
42 and 45.There is only ONE answer per question. Place all
answers on this answer form:
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D
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PROGRAM EVALUATION
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To receive continuing education credit, please answer all
information requested below.This assures prompt and accurate issuance of your continuing education certificate.
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Release date: Dec. 15, 2003.
Expiration date: Dec. 15, 2004.
Overall quality of program
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daily responsibilities
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Complete answer sheet/evaluation form and mail to:
Office of Continuing Education
The Chatham Institute
26 Main Street, 3rd Floor
Chatham, NJ 07928
Fax: (973) 701-2515
Credit will be awarded upon successful completion of the
post-test (a score of 70 percent or better) and activity evaluation. If a score of 70 percent or better is not achieved, no
credit 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 participant through an educational grant from Allergan.
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CMC3000
44
P&T DIGEST
CONTINUING EDUCATION SELF-TEST, continued
P&T Digest
Dry Eye Syndrome
13. If inflammation is considered to be a cause
of dry eye syndrome, then suppressing the
cytokine-mediated inflammation response
that 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 patients with mild dry eye syndrome. For patients with more severe disease, which of the
following 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.
18. In a survey of patients with dry eye disease,
which quality-of-life factor was most often
mentioned 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 regulate 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 damage tissue.
20. In dry eye syndrome, cyclosporine A:
a. Mediates mucosal secretions.
b. Promotes cytokine release to reduce inflammation.
c. Prevents release of cytokines that incite inflammation.
d. Inhibits release of a collagenous enzyme that
incites inflammation.
16. A 1998 study of individuals with Sjögren’s
syndrome found that, on average, this subset
of dry eye patients experiences ocular irritation that interferes with activities of daily
living on all but 29 days each year.
a. True
b. False.
17. Overutilization costs in dry eye syndrome
frequently arise from:
a. Corneal transplantation.
b. Low patient satisfaction with palliative therapy.
c. A loss of productivity.
d. None of the above.
DRY EYE SYNDROME
45

Dry Eye Syndrome

Transcription

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