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`Dry Eye
`Syndrome
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`AMERKAN ACADEMY”
`a? Cszammmmocv
`I'M fiyix VJ} r-fissmrialim:
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`APOTEX 1044, pg. 1
`
`APOTEX 1044, pg. 1
`
`
`
`Secretary for Quality of Care
`Anne L. Coleman, MD, PhD
`
`Academy Staff
`Nicholas P. Emptage, MAE
`Nancy Collins, RN, MPH
`Doris Mizuiri
`Jessica Ravetto
`Flora C. Lum, MD
`
`Medical Editor:
`
`Susan Garrett
`
`Design:
`
`Socorro Soberano
`
`Approved by:
`
`Board of Trustees
`September 21, 2013
`
`Copyright © 2013 American Academy of Ophthalmology®
`All rights reserved
`
`AMERICAN ACADEMY OF OPHTHALMOLOGY and PREFERRED PRACTICE PATTERN are
`
`registered trademarks of the American Academy of Ophthalmology. All other trademarks are the property of
`their respective owners.
`
`This document should be cited as follows:
`
`American Academy of Ophthalmology Cornea/External Disease Panel. Preferred Practice Pattern®
`Guidelines. Dry Eye Syndrome. San Francisco, CA: American Academy of Ophthalmology; 2013. Available
`at: www.aao.org/ppp.
`
`Preferred Practice Pattern® guidelines are developed by the Academy’s H. Dunbar Hoskins Jr., MD Center
`for Quality Eye Care without any external financial support. Authors and reviewers of the guidelines are
`volunteers and do not receive any financial compensation for their contributions to the documents. The
`guidelines are externally reviewed by experts and stakeholders before publication.
`
`APOTEX 1044, pg. 2
`
`APOTEX 1044, pg. 2
`
`
`
`Dry Eye Syndrome PPP
`
` CORNEA/EXTERNAL DISEASE PREFERRED
`
`PRACTICE PATTERN DEVELOPMENT
`
`~~
`
`PROCESS AND PARTICIPANTS
`
`The Cornea/External Disease Preferred Practice Pattern® Panel members wrote the Dry Eye
`Syndrome Preferred Practice Pattern® guidelines (“PPP”). The PPP Panel members discussed
`and reviewed successive drafts of the document, meeting in person twice and conducting other
`review by e-mail discussion, to develop a consensus over the final version of the document.
`
`Cornea/External Disease Preferred Practice Pattern Panel 2012—2013
`Robert S. F eder, MD, Co—chair
`Stephen D. McLeod, MD, Co—chair
`Esen K. Akpek, MD, Cornea Society Representative
`Steven P. Dunn, MD
`Francisco J. Garcia-Fetter, MD
`Amy Lin, MD
`Francis S. Mah, MD
`Audrey R. Talley-Rostov, MD
`Divya M. Varu, MD
`David C. Musch, PhD, MPH, Methodologist
`
`The Preferred Practice Patterns Committee members reviewed and discussed the document
`
`during a meeting in March 2013. The document was edited in response to the discussion and
`comments.
`
`Preferred Practice Patterns Committee 2013
`
`Stephen D. McLeod, MD, Chair
`David F. Chang, MD
`Robert S. Feder, MD
`Timothy W. Olsen, MD
`Bruce E. Prum, Jr., MD
`C. Gail Summers, MD
`David C. Musch, PhD, MPH, Methodologist
`
`The Dry Eye Syndrome PPP was then sent for review to additional internal and external groups
`and individuals in June 2013. All those returning comments were required to provide disclosure of
`relevant relationships with industry to have their comments considered. Members of the
`Cornea/External Disease Preferred Practice Pattern Panel reviewed and discussed these
`comments and determined revisions to the document.
`
`Academy Reviewers
`Board of Trustees and Committee of Secretaries
`Council
`General Counsel
`Ophthalmic Technology Assessment Committee
`Cornea and Anterior Segment Disorders Panel
`Basic and Clinical Science Course Subcommittee
`Practicing Ophthalmologists Advisory Committee
`for Education
`
`Invited Reviewers
`AARP
`Asia Cornea Society
`Cornea Society
`National Eye Institute
`Ocular Microbiology and Immunology Group
`Sjogrens Syndrome Foundation
`Carol L. Karp, MD
`Stephen C. P'llugfelder, MD
`
`APOTEX 1044, pg. 3
`
`APOTEX 1044, pg. 3
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`
`
`Dry Eye Syndrome PPP
`
`FINANCIAL DISCLOSURES
`
`
`
`Em/fi
`
`In compliance with the Council of Medical Specialty Societies’ Code for Interactions with Companies
`(available at \mrnxcmssorel/codel‘orinteraetionsaspx), relevant relationships with industry are listed. The
`Academy has Relationship with Industry Procedures to comply with the Code (available at
`http:ffoncaaobrgjcE/PracticeGuidclines/PPPaspx). A majority (70%) ofthe members of the
`Cornea/External Disease Preferred Practice Pattern Panel 2012—2013 had no financial relationship to disclose.
`
`Cornea/External Disease Preferred Practice Pattern Panel 2012—2013
`
`Esen K. Akpek, MD: No financial relationships to disclose
`Steven P. Dunn, MD: No financial relationships to disclose
`Robert S. Feder, MD: No financial relationships to disclose
`Francisco J. Garcia—Ferrer: No financial relationships to disclose
`Amy Lin, MD: No financial relationships to disclose
`Francis S. Mah, MD: Alcon Laboratories, Inc. — Consultant/Adviser; Allergan, Inc. — Consultant/Adviser,
`Lecture fees; ForeSight — Consultant/Advisor; Ista Pharmaceuticals — Consultant/Adviser; Nicox —
`Consultant/Adviser; Omeros - ConsultanUAdvisor
`Stephen D. McLeod, MD: No financial relationships to disclose
`David C. Musch, PhD, MPH: Abbott Laboratories — Consultant fees (member of Independent Data
`Monitoring Committee); CIinReg Consulting Services, Inc. — Consultant/Advisor
`Audrey R. Talley-Rostov, MD: Addition Technology — Lecture fees; Allergan, Inc. — Lecture fees
`Divya M. Varu, MD: No financial relationships to disclose
`
`Preferred Practice Patterns Committee 2013
`
`David F. Chang, MD: Abbott Medical Optics — Consultant/Adviser; Allergan, Inc. — Lecture fees; SLACK,
`Inc. — Patent/Royalty
`Robert S. Feder, MD: No financial relationships to disclose
`Stephen D. McLeod, MD: No financial relationships to disclose
`David C. Musch, PhD, MPH: Abbott Laboratories — Consultant fees (member of Independent Data
`Monitoring Committee); ClinReg Consulting Services, Inc. — Consultant/Adviser
`Timothy W. Olsen, MD: A Tissue Support Structure — Patents/Royalty; Scleral Depressor — Patents/Royalty
`Bruce E. Prum, Jr., MD: Pfizer Ophthalmics — Lecture fees
`C. Gail Summers, MD: No financial relationships to disclose
`
`Secretary for Quality of Care
`Anne L. Coleman, MD, PhD: Allergan, Inc. — Consultant/Advisor; Pfizer Ophthalmics ~ Consultant/Adviser
`
`Academy Staff
`Nicholas P. Emptage, MAE: No financial relationships to disclose
`Nancy Collins, RN, MPH: No financial relationships to disclose
`Susan Garratt, Medical Editor: No financial relationships to disclose
`Flora C. Lum, MD: No financial relationships to disclose
`Doris Mizuiri: No financial relationships to disclose
`Jessica Ravetto: No financial relationships to disclose
`
`The disclosures of relevant relationships to industry of other reviewers of the document from January to
`August 2013 are available online at www.aao.org[gmg.
`
`ii
`
`APOTEX 1044, pg. 4
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`APOTEX 1044, pg. 4
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`
`
`Dry Eye Syndrome PPP
`
`TABLE OF CONTENTS
`
`M O
`
`BJECTIVES OF PREFERRED PRACTICE PATTERN GUIDELINES ............................................ 2
`
`METHODS AND KEY TO RATINGS .................................................................................................. 3
`HIGHLIGHTED FINDINGS AND RECOMMENDATIONS FOR CARE .............................................. 4
`
`INTRODUCTION ................................................................................................................................. 5
`
`Disease Definition ................................................................................................................................ 5
`
`Patient Population ................................................................................................................................ 5
`
`Clinical Objectives ................................................................................................................................ 5
`BACKGROUND ................................................................................................................................... 5
`
`Prevalence and Risk Factors ............................................................................................................... 5
`
`Pathogenesis ....................................................................................................................................... 7
`Associated Conditions ......................................................................................................................... 7
`
`Natural History ..................................................................................................................................... 8
`CARE PROCESS ................................................................................................................................ 9
`
`Patient Outcome Criteria ...................................................................................................................... 9
`
`Diagnosis ............................................................................................................................................. 9
`History ........................................................................................................................................ 10
`Examination ............................................................................................................................... 11
`
`Diagnostic Tests ........................................................................................................................ 11
`
`Classification of Dry Eye Syndrome .................................................................................................. 13
`
`Management ...................................................................................................................................... 13
`
`Mild Dry Eye ............................................................................................................................... 15
`
`Moderate Dry Eye ...................................................................................................................... 15
`
`Severe Dry Eye .......................................................................................................................... 17
`Follow-up Evaluation ................................................................................................................. 17
`
`Provider and Setting .......................................................................................................................... 17
`
`Counseling and Referral .................................................................................................................... 18
`Socioeconomic Considerations ......................................................................................................... 18
`
`APPENDIX 1. QUALITY OF OPHTHALMIC CARE CORE CRITERIA ........................................... 20
`APPENDIX 2. PREFERRED PRACTICE PATTERN RECOMMENDATION GRADING ................. 22
`
`APPENDIX 3. SJOGREN SYNDROME ............................................................................................ 27
`APPENDIX 4. DIAGNOSTIC TESTS ................................................................................................ 29
`
`APPENDIX 5. DRY EYE SEVERITY GRADING SCHEMES ............................................................ 31
`
`RELATED ACADEMY MATERIALS ................................................................................................. 32
`
`REFERENCES .................................................................................................................................. 32
`
`APOTEX 1044, pg. 5
`
`APOTEX 1044, pg. 5
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`
`
`Dry Eye Syndrome PPP
`
`
`
`
`
`
`OBJECTIVES OF PREFERRED
`PRACTICE PATTERN® GUIDELINES
`
`As a service to its members and the public, the American Academy of Ophthalmology has developed a series
`of Preferred Practice Pattern® guidelines that identify characteristics and components of quality eye care.
`Appendix 1 describes the core criteria of quality eye care.
`
`The Preferred Practice Pattern® guidelines are based on the best available scientific data as interpreted by
`panels of knowledgeable health professionals. In some instances, such as when results of carefully conducted
`clinical trials are available, the data are particularly persuasive and provide clear guidance. In other instances,
`the panels have to rely on their collectivejudgment and evaluation of available evidence.
`
`These documents provide guidance for the pattern of practice, not for the care ofa particular
`individual. While they should generally meet the needs of most patients, they cannot possibly best meet the
`needs of all patients. Adherence to these PPPs will not ensure a successful outcome in every situation. These
`practice patterns should not be deemed inclusive of all proper methods of care or exclusive of other methods
`of care reasonably directed at obtaining the best results. It may be necessary to approach different patients’
`needs in different ways. The physician must make the ultimatejudgment about the propriety of the care of a
`particular patient in light of all of the circumstances presented by that patient. The American Academy of
`Ophthalmology is available to assist members in resolving ethical dilemmas that arise in the course of
`ophthalmic practice.
`
`Preferred Practice Pattern® guidelines are not medical standards to be adhered to in all individual
`situations. The Academy specifically disclaims any and all liability for injury or other damages of any kind,
`from negligence or otherwise, for any and all claims that may arise out of the use of any recommendations or
`other information contained herein.
`
`References to certain drugs, instruments, and other products are made for illustrative purposes only and are
`not intended to constitute an endorsement of such. Such material may include information on applications
`that are not considered community standard, that reflect indications not included in approved US. Food and
`Drug Administration (FDA) labeling, or that are approved for use only in restricted research settings. The
`FDA has stated that it is the responsibility ofthe physician to determine the FDA status of each drug or
`device he or she wishes to use, and to use them with appropriate patient consent in compliance with
`applicable law.
`
`Innovation in medicine is essential to ensure the future health of the American public, and the Academy
`encourages the development of new diagnostic and therapeutic methods that will improve eye care. It is
`essential to recognize that true medical excellence is achieved only when the patients’ needs are the foremost
`consideration.
`
`All Preferred Practice Pattern® guidelines are reviewed by their parent panel annually or earlier if
`developments warrant and updated accordingly. To ensure that all PPPs are current, each is valid for 5 years
`from the “approved by” date unless superseded by a revision. Preferred Practice Pattern guidelines are
`funded by the Academy without commercial support. Authors and reviewers of PPPs are volunteers and do
`not receive any financial compensation for their contributions to the documents. The PPPs are externally
`reviewed by experts and stakeholders, including consumer representatives, before publication. The PPPs are
`developed in compliance with the Council of Medical Specialty Societies” Code for Interactions with
`Companies. The Academy has Relationship with Industry Procedures (available at
`
`
`.9..aau.tzrgziC‘
`P
`‘ guidelih stitititiasns) to comply with the Code.
`
`The intended users of the Dry Eye Syndrome PPP are ophthalmologists.
`
`APOTEX 1044, pg. 6
`
`APOTEX 1044, pg. 6
`
`
`
`Dry Eye Syndrome PPP
`
`METHODS AND KEY TO RATINGS
`
`Preferred Practice Pattern® guidelines should be clinically relevant and specific enough to provide useful
`information to practitioners. Where evidence exists to support a recommendation for care, the
`recommendation should be given an explicit rating that shows the strength of evidence. To accomplish these
`aims, methods from the Scottish Intercollegiate Guideline Networkl (SIGN) and the Grading of
`Recommendations Assessment, Development and Evaluation2 (GRADE) group are used. GRADE is a
`systematic approach to grading the strength of the total body of evidence that is available to support
`recommendations on a specific clinical management issue. Organizations that have adopted GRADE include
`SIGN, the World Health Organization, the Agency for Healthcare Research and Policy, and the American
`College of Physicians.3
`
`0 All studies used to form a recommendation for care are graded for strength of evidence individually, and
`that grade is listed with the study citation.
`
`0 To rate individual studies, a scale based on SIGNI is used. The definitions and levels of evidence to rate
`individual studies are as follows:
`
`I++
`
`1+
`
`I—
`II++
`
`II+
`
`II—
`
`III
`
`High-quality meta-analyses, systematic reviews of randomized controlled trials (RCTs), or
`RCTs with a very low risk of bias
`
`
`Well-conducted meta—analyses, systematic reviews of RCTs, or RCTs with a low risk of bias
`
`Meta—analyses, systematic reviews of RCTs, or RCTs with a high risk of bias
`High—quality systematic reviews of case—control or cohort studies
`High-quality case—control or cohort studies with a very low risk of confounding or bias and a
`high probability that the relationship is causal
`Well—conducted case-control or cohort studies with a low risk of confounding or bias and a
`
`moderate probability that the relationship is causal
`Case-control or cohort studies with a high risk of confounding or bias and a significant risk that
`the relationship is not causal
`Nonanalytic studies (e.g., case reports, case series)
`
`9 Recommendations for care are formed based on the body of the evidence. The body of evidence quality
`ratings are defined by GRADEZas follows:
`
`Good quality
`
`Further research is very unlikely to change our confidence in the estimate of
`effect
`
`Moderate quality
`
`Insufficient quality
`
`Further research is likely to have an important impact on our confidence in the
`
`estimate of effect and may change the estimate
`
`Further research is very likely to have an important impact on our confidence in
`the estimate of effect and is likely to change the estimate
`Any estimate of effect is very uncertain
`
`0 Key recommendations for care are defined by GRADE2 as follows:
`
`Strong
`Used when the desirable effects of an intervention clearly outweigh the
`
`recommendation
`undesirable effects or clearly do not
`
`Discretionary
`recommendation
`
`Used when the trade-offs are less certain—either because of low-quality
`evidence or because evidence suggests that desirable and undesirable effects are
`closely balanced
`
`o The Highlighted Findings and Recommendations for Care section lists points determined by the PPP
`panel to be of particular importance to vision and quality of life outcomes.
`0 All recommendations for care in this PPP were rated using the system described above. To locate ratings
`for specific recommendations, see Appendix 2 for additional information.
`0 Literature searches to update the PPP were undertaken in June 2012 and January 2013 in PubMed and the
`Cochrane Library. Complete details of the literature search are available at waziaocrafppp.
`'1
`J
`
`APOTEX 1044, pg. 7
`
`APOTEX 1044, pg. 7
`
`
`
`Dry Eye Syndrome PPP
`
` HIGHLIGHTED FINDINGS AND
`N *4 RECOMMENDATIONS FOR CARE
`
`
`Dry eye is a common ocular condition that has a high impact on the quality oflife ofafflicted individuals
`owing to discomfort or visual disability. Although the symptoms improve with treatment, the condition is
`usually not curable. Dry eye can be a cause of visual disability and may compromise results ofcorneal,
`cataract, and refractive surgery.
`
`
`No single test is adequate for establishing the diagnosis of dry eye. The constellation of findings from
`multiple tests can add greatly to the clinician’s understanding of the patient’s condition. Evaluation of
`conjunctival staining is helpful but underutilized.
`WWW-“WWW
`
`About 10% of patients with clinically significant aqueous deficient dry eye have an underlying primary
`Sjogren syndrome. Patients with moderate punctate staining of the cornea and/or conjunctiva should be
`considered for testing for an underlying Sjogren syndrome, as these patients will require a multidisciplinary
`approach.
`WWWWMWWW
`
`Pharmacological and procedural treatments are associated with improvements in patient symptoms and
`clinical signs, although chronic therapy and patient compliance are necessaIy for long—term management.
`WWW—mm
`
`Punctal plugs may be helpful in moderate to severe cases of aqueous deficient dry eye. However, patients
`treated with punctal plugs should be monitored regularly to ensure that the plugs are present and in the proper
`position.
`WWmeWW
`
`Omega—3 fatty acid products without ethyl esters may be beneficial in the treatment of dry eye, though the
`evidence is insufficient to establish the effectiveness of any particular formulation and may increase the risk
`of prostate cancer.
`WWW
`
`Cyclosporine treatment has been shown to have shorteterm clinical benefits in the treatment of dry eye.
`However, insofar as dry eye is a life—long condition whose symptoms and signs wax and wane, cost
`considerations and the lack of data on long-term effectiveness are important factors in the decision to
`prescribe cyclosporine. It is also unclear whether the estimated benefit is observed in all patient
`subpopulations.
`
`
`Dry eye patients considering keratorefractive surgery, particularly LASIK, should be cautioned that the dry
`eye condition could become worse after surgery. Dry eye symptoms are common in the first few months after
`surgery and tend to subside with time. Patients can safely undergo LASIK surgery if a pre-existing dry eye
`condition can be controlled preoperatively.
`
`
`Patients with severe dry eye are at greater risk for contact lens intolerance and associated complications.
`Patients with pre—existing dry eye should be cautioned that keratorefractive surgery, particularly LASIK, may
`worsen their dry eye condition.
`
`APOTEX 1044, pg. 8
`
`APOTEX 1044, pg. 8
`
`
`
`Dry Eye Syndrome PPP
`
`\Q
`
`
`
`gfiINTRODUCHON
`
`
`DISEASE DEFINITION
`
`Dry eye syndrome (ICD—9 #375,15; 1CD-10 #1-104.12— [(—) = 1, right eye; 2, left eye; 3, bilateral])
`
`For the purpose of this PPP, dry eye syndrome refers to a group ofdisorders of the tear film that are
`due to reduced tear production or excessive tear evaporation, associated with ocular discomfort and/or
`visual symptoms and possible disease of the ocular surface.
`
`PATIENT POPULATION
`
`The patient population includes individuals of all ages who present with symptoms and signs
`suggestive of dry eye, such as ocular irritation, redness, mucous discharge, fluctuating vision, and
`decreased tear meniscus or break—up time.
`
`CLINICAL OBJECTIVES
`
`9 Establish the diagnosis of dry eye and differentiate it from other causes of irritation and redness that
`may complicate both patient care and research on tear deficiency
`0 Identify the local and systemic causes of dry eye syndrome
`0 Establish appropriate therapy
`0 Relieve discomfort
`
`o Prevent worsening of symptoms and clinical findings
`0 Educate and involve the patient in the management of this disease
`
`
`
`BACKGROUND
`
`Dry eye, either alone or in combination with other conditions, is a frequent cause of ocular irritation that
`leads patients to seek ophthalrnologic care.4While these symptoms often[mprove with treatment, the disease
`usuallyrs not curable, which may be a source of patient and physician frustration Dry eye can be a cause of
`visual morbidity and may compromise results of corneal, cataract, and refractive surgery.
`
`PREVALENCE AND RISK FACTORS
`
`Epidemiological information on dry eye syndrome has been limited by lack of uniformity in its
`definition and the inability of any single diagnostic test or set of diagnostic tests to confirm or rule out
`the condition. Dry eye syndrome is a common condition that causes varying degrees of discomfort
`and disability. While clinic—based studies confirm its frequency (17% of 2127 consecutive new
`outpatients were diagnosed with dry eye following comprehensive examination), such studies may not
`reflect the overall population.5 In a population—based sample of 2520 elderly (65 or older) residents of
`Salisbury, Maryland, 14.6% were symptomatic, which was defined as reporting one or more dry eye
`symptoms often or all the time.4 The combination of being symptomatic and having a low Schirmer
`test (55 mm with anesthesia) or a high rose bengal score (25) was seen in 3.5% ofthe residents.4
`Depending on which ofthese two percentages is used, extrapolating to the US. population aged 65 to
`84 yields estimates of approximately 1 million to 4.3 million people who have dry eye. A population—
`based study of dry eye conducted in Melbourne, Australia, using different diagnostic criteria reported
`higher percentages of the 926 participants aged 40 to 97 who had a low Schirmer test (16.3% $8 mm)
`or a high rose bengal score (10.8% 24).6 The prevalence of self-reported dry eye in 3722 participants
`ofthe Beaver Dam (Wisconsin) Eye Study varied from 8.4% of subjects younger than 60 to 19.0% of
`those over 80, with an overall prevalence of 14.4%.7 The Men’s Health Study revealed that the
`prevalence of dry eye disease in men increased from 3. 90% to 7. 67% when men aged 50 to 54 were
`compared with men over 80 (n— 25 ,.444) Dry eye was defined as a reported clinical diagnosis or
`symptoms of both dryness and irritation either constantly or often.8 In a similar Women s Health
`Study of over 39,000 women, the prevalence of dry eye was 5.7% among women younger than 50 and
`increased to 9. 8% among women over 75. This was a survey in which dry eye was defined as above.
`In a clinic setting, the proportion of 224 subjects identified with dry eye were far more likely to
`5
`
`APOTEX 1044, pg. 9
`
`APOTEX 1044, pg. 9
`
`
`
`Dry Eye Syndrome PPP:
`Prevalence and Risk Factors
`
`exhibit signs of evaporative dry eye resulting from meibomian gland disfunction (MOD) than from
`pure aqueous deficient dry eye.10
`Estimates of dry eye prevalence based on treatment—derived data yield much lower percentages. A
`study evaluating medical claims data for nearly 10 million enrollees in managed care plans found that
`dry eye was diagnosed or treated with punctal occlusion in 0.4% to 0.5% of the enrollees.8’9’“
`Many risk factors for dry eye have been proposed (see Table 1). Older age and female gender have
`been identified as risk factors for dry eye.6’7’“‘l4 A Japanese study found an increased prevalence of
`dry eye disease among Japanese office workers using visual display terminals.15 Concurrent use of
`benzalkonium chloride (BAK)-containing glaucoma medications was also shown to be a risk factor in
`glaucoma patientslé’17 Arthritis was evaluated as a risk factor in two studies and found to be
`associated with an increased risk of dry eye in both.6’7 The Beaver Dam Eye Study found that after
`controlling for age and gender, smoking, and multivitamin use were associated with an increased risk
`of dry eye, whereas caffeine use was associated with a decreased risk.7 An update to the Beaver Dam
`Study14 found that additional risk factors for dry eye included the use of antihistamines, antidepressant
`and antianxiety medications, and oral corticosteroids. Angiotensin~converting enzyme inhibitors were
`associated with a lower risk. Within the 25,665 postmenopausal women in the Women’s Health
`Study, hormone replacement therapy, and, in particular, estrogen use alone, was associated with an
`increased risk of clinically diagnosed dry eye syndrome or severe symptoms.18 More recent reports
`have suggested a relationship between botulinum toxin injection and dry eye.”'21
`A study of dry eye and quality of life found decreased quality of life for all severity levels of dry eye
`syndrome, with an effect on quality of life for severe dry eye comparable with that reported for
`moderate angina.22 One study of a cohort of dry eye patients found a strong association with anxiety
`and depression.23 Several other studies demonstrated a relationship between depression and dry eye
`symptoms (with or without dry eye signs) independent of the medications used to treat depression.”’25
`Other research suggests that patients with dry eye are more likely to report pain, limitations of
`activities ofdaily living, and lower quality oflife.]7’26‘27
`
`TABLE 1
`
`RISK FACTORS FOR DRY EYE
`
`Level of Evidence
`
`Mostly Consistent‘
`
`Suggestivel
`
`. Olderage
`- Female gender
`. Postmenopausal estrogen therapy
`. Low dietary intake ofomega-S fattyacids
`. Medications
`- Antihistamines
`. Connective-tissue disease
`~ LASIK and refractive excimer laser surgery
`. Radiation therapy
`- Hematopoietic stem cell transplantation
`
`. Vitamin A deficiency
`. HepatitisCinfection
`. Androgen deficiency
`
`. Asian ethnicity
`. Medications
`. Tricyciic antidepressants
`- Selective serotonin reuptake inhibitors
`- Diuretics
`- Beta-blockers
`. Diabetes mellitus
`’ HIV/HTLVl infection
`‘ Systemic chemotherapy
`' Largeincision ECCE and penetrating
`keratoplasty
`sotretinoin
`|
`.
`,
`_
`- Low~humidityenvrronments
`- Sarcoidosis
`
`.
`
`Uncleari
`
`. Cigarette smoking
`0 Hispanic ethnicity
`. Medications
`. Anticholinergics
`. Anxiolytics
`- Antipsychotics
`. Alcohol use
`' Menopause
`. Botuiinum toxin injection
`- Acne
`. Gout
`
`. Oral contraceptives
`. Pregnancy
`
`
`. Ovarian dysfunction
`
`Reproduced with permission from Smith JA (Chair). Epidemiology Subcommittee of the international Dry Eye Workshop. The epidemiology of dry eye
`disease: report of the Epidemiology Subcommittee of the international Dry Eye Workshop (2007). Ocul Surf 2007 :5299.
`
`ECCE = extracapsular cataract extraction; HlV = human immunodeficiency virus; HTLV = human T-Iymphotropic virus
`* Mostly consistent evidence implies the existence of at least one adequately powered and otherwise well-conducted study published in a peer-
`reviewed journal, along with the existence of a plausible biological rationale and corroborating basic research or clinical data.
`TSuggestive evidence implies the existence of either 1) inconclusive information from peer«reviewed publication or 2) inconclusive or limited information
`to support the association, but either not published or published somewhere other than in a peer~reviewed journal.
`I Unclear evidence implies either directly conflicting information in peer-reviewed publications or inconclusive information butwith some basis for a
`biological rationale.
`
`APOTEX 1044, pg. 10
`
`APOTEX 1044, pg. 10
`
`
`
`Dry Eye Syndrome PPP
`
`PATHOGENESIS
`
`The ocular surface and tear-secreting glands function as an integrated unit.28 Disease or dysfunction of
`this functional unit results in an unstable and poorly maintained tear film that causes ocular irritation
`symptoms and possible damage to the ocular surface epithelium. Dysfunction of this integrated unit
`may develop fi‘om aging, a decrease in supportive factors (such as androgen hormones), systemic
`inflammatory diseases (such as Sjb'gren syndrome or rheumatoid arthritis), ocular surface diseases
`(such as herpes simplex virus [HSV] keratitis) or surgeries that disrupt the trigeminal afferent sensory
`nerves (e.g., LASIK), and systemic diseases or medications that disrupt the efferent cholinergic nerves
`that stimulate tear secretion.29 Decreased tear secretion and clearance initiates an inflammatory
`response on the ocular surface that involves both soluble and cellular inediatOi's,3°’31 Clinical and basic
`research suggests that this inflammation plays a role in the pathogenesis of dry eye (see Figure l).32’33
`
`Rheumatoid Arthritis
`Sjogren's Syndrome
`
`Meibomian Gland
`Secretory Dysfunction
`
`Lacrimal Gland
`
`Female Gender
`Androgen Deficrency
`
`Tears
`
`Ocular Surface Inflammation
`
`v
`
`V
`
`Adhesion
`Molecules
`
`T Cell
`Infiltration
`
`V
`
`V
`
`MMPs
`
`Apoptosis
`
`Ocular Surface Epithelial Disease
`/ (Dry Eye)
`Hyperosmolar
`I
`
`\
`
`
`
`
`Cytokines
`Chemokines
`
`FIGURE 1. INFLAMMATORY MEDIATORS IN DRY EYE
`
`Modified from Pflugfelder SC. Antiinflammatory therapy for dry eye. Am J Ophthalmol 2004;137:338, with permission from Elsevier.
`MMPs = matrix metalloproteinases
`
`ASSOCIATED CONDITIONS
`
`Symptoms caused by dry eye may be exacerbated by the use of systemic medications such as
`diuretics, antihistamines, anticholinergics, antidepressants, and systemic retinoids (e.g.,
`isotretinoin).7’8’14’16’34'37 lnstillation of any eye medications, especially when they are instilled
`frequently (e.g., more than four drops a day), may prevent the normal maintenance of the tear film and
`cause dry eye symptoms. In addition, environmental factors, such as reduced humidity and increased
`wind, drafts, air conditioning, or heating may exacerbate the ocular discomfort of patients with dry
`eye. Exogenous irritants and allergens, although not believed to be causative of dry eye, may
`exacerbate the symptoms.
`
`Hyposecretory MGD may be a precursor to obstructive MGD and may play a role in the pathogenesis
`of dry eye disease.38
`Rosacea is a disease of the skin and eye that is observed more frequently in fair-skinned individuals,39
`but it can occur in people of all racial origins. Characteristic