MYLAN - EXHIBIT 1047
`Mylan Pharmaceuticals Inc. et al. v. Allergan, Inc.
`IPR2016-01127, -01128, -01129, -01130, -01131, & -01132
`
`

`

`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:
`Design:
`
`Susan Garratt
`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 PATTERNare
`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 lrancisco, CA: American Academyof Ophthalmology; 2013. Available
`at: www.aao.ore/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
`guidclines are externally reviewed by experts and stakeholders before publication.
`
`

`

`é
`
`CORNEA/EXTERNAL DISEASE PREFERRED
`PRACTICE PATTERN DEVELOPMENT
`PROCESS AND PARTICIPANTS
`
`Dry Eye Syndrome PPP
`
`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 é-mail discussion, to develop a consensus over the final version of the document.
`
`Cornea/Externa! Disease Preferred Practice Pattern Panel 2012-2013
`Robert S. Feder, MD, Co-chair
`Stephen D. McLeod, MD, Co-chair
`Esen K. Akpek, MD, Cornea Society Representative
`Steven P. Dunn, MD
`Francisco J. Garcia-Ferrer, MD
`Amy Lin, MD
`Francis 8. Mah, MD
`AudreyR. Talley-Rostov, MD
`Divya M. Varu, MD
`David C. Musch, PhD, MPH, Mcthodologist
`
`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 Counscl
`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
`Sjégrens Syndrome Foundation
`Carol L. Karp, MD
`Stephen C. Pflugfelder, MD
`
`

`

`Dry Eye Syndrome PPP
`
`
`
`FINANCIAL DIANC DISCLOSU
`
`
`
`RES
`
`In compliance with the Council of Medical Specialty Societies’ Code for Interactions with Companies
`(available at www.cmss.ore/codeforinteractions.aspx), relevant relationships with industry are listed. The
`Academyhas Relationship with Industry Procedures to comply with the Code (available at
`http:/fone.wao.ore/CE/PracticeGuidclines/PPP.aspx). A majority (70%) of the members of the
`Cornea/External Disease Preferred Practice Pattern Panel 2012-2013 had no financial relationship to disclose.
`
`Cornca/External Disease Preferred Practice Pattern Panel 2012-2013
`Esen kK. Akpek, MD: Nofinancial relationships to disclose
`Steven P. Dunn, MD: Nofinancial relationships to disclose
`Robert S. Feder, MD: Nofinancialrelationships to disclose
`Francisco J. Garcia-Ferrer: No financial relationships to disclose
`Amy Lin, MD: Nofinancial relationships to disclose
`Francis S. Mah, MD: Alcon Laboratories, Inc. — Consultant/Advisor; Allergan, Inc. — Consultant/Advisor,
`Lecture fees; ForeSight — Consultant/Advisor; Ista Pharmaceuticals — Consultant/Advisor; Nicox —
`Consultant/Advisor; Omeros — Consultant/Advisor
`Stephen D. McLeod, MD: Nofinancial relationships to disclose
`David C. Musch, PhD, MPH: Abbott Laboratories — Consultant fees (memberof Independent Data
`Monitoring Committee); ClinReg Consulting Services, Inc. - Consultant/Advisor
`Audrey R. Talley-Rostovy, MD: Addition Technology — Lecture fees; Allergan, Inc. — Lecture fees
`Divya M. Varu, MD: Nofinancial relationships to disclose
`
`Preferred Practice Patterns Committee 2013
`David F. Chang, MD: Abbott Medical Optics ~ Consultant/Advisor; Allergan, Inc. — Lecture fees; SLACK,
`Inc. — Patent/Royalty
`Robert S. Feder, MD: No financial! relationships to disclose
`Stephen D. McLeod, MD: Nofinancial relationshipsto disclose
`David C. Musch, PhD, MPH: Abbott Laboratories — Consultant lees (memberof Independent Data
`Monitoring Committee); ClinReg Consulting Services, Inc. ~ Consultant/Advisor
`Timothy W. Olsen, MD: A Tissue Support Structure — Patents/Royalty; Scleral Depressor — Patents/Royalty
`Bruce E, Prum, Jr., MD: Pfizer Ophthalmics — Lecture fees
`Cc, Gail Summers, MD: Nofinancial relationships to disclose
`
`Quality of Care
`Secretary for
`Anne L. Coleman, MD, PhD: Allergan, Inc. — Consultant/Advisor; Pfizer Ophthalmics ~ Consultant/Advisor
`
`AcademyStaff
`Nicholas P. Emptage, MAE: Nofinancial relationships to disclose
`Nancy Collins, RN, MPH: No financial relationships to disclose
`Susan Garratt, Medical Editor: No financial relationships to disclose
`Vlora 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.ago.ore/ppp.
`
`

`

`Dry Eye Syndrome PPP
`
`TABLE OF CONTENTS
`
`SW
`
`OBJECTIVES OF PREFERRED PRACTICE PATTERN GUIDELINES 00000. ceee eens 2
`METHODS AND KEY TO RATINGS ooo... ccceccceecceec cee cecc ces ecneneeceneecaeecneeesesseecaecnaesusscaeensecsescreteteaes 3
`HIGHLIGHTED FINDINGS AND RECOMMENDATIONS FOR CARE ooo ecccsseseccneereenerseenaerane 4
`INTRODUCTION ooo. cece cc ceccceeeecreececeeeceeeceeseeaeereeegccecedenesnnessieeesaeseaeeceeeesneeseaeescasassaesaaeescneaseanes 5
`Disease Definition oo eeccreeee etree eee eteae erie eeneetnaeeceeeeneaeaaeee seep aeenaeesesieegnaaespeessessesnessisesseaeneees 5
`
`Patient Population... ccs ceecceeeeeeesesseeeneeerereeseeenecseadcseeareneneserreseaeireseectenisensesietiessareneenreenseees 5
`Clinical ODj@ctives o.oo eee cic cence ence cence cere seeeesaeeeneeeseeseaeeseesssceeceaeenseseaseseneeceestsreeneeesnresieeeeaes 5
`BACKGROUND. .00o.oo occ cecceccee cece eee ceneeeeeesnieeceaeecseeceseecee centeceeeeceecesseeeseacerseseiaeeneeensessiaeeeatens 5
`Prevalence and RiSk FaCtors ........ccccccccceesceeeee cece ce eeeecenee cee caeeeebenesccsaaeeeecseeeecaeaeeseceecedcquaeeseseaeeesneaaesad 5
`
`PathOQeNnesis .......ccccccccccenccecsneececenseeecneeeecceeeeeeee ee cGeaeeeeeeae st CLEA Ge eer DEES ECCAHEe HEL GEE EE OnaeeHeoe nde estar eaeeadeenennasentaa 7
`
`Associated Conditions 0.0... eeeeeeeees
`Natural History oo... ccc cceccseceeceeeneeeeeeecteecereneaescoseaeeepeetscesenseeensesscisesneeecnrsnedeseeesgaeesssseseeerenresenternates 8
`CARE PROCESS o.oo. ccccc cece ee eee EEE REED E EE EEE Eee eR EE EEE cee ee EER EEL Eee eee ee eeeeteeeeeneeeenenteeeeenteregs 9
`Patient Outcome Criteria... ccc cence cece cent cents ee care ttn ee cece deep caee ees cneeeesaeeeegendeesnaeeescnageeenies 9
`
`DIAGNOSIS oo. ec cece tee cece eer nee ene ene E EEE LD DE EERE SDE ESD DU ES LEA CEES DEE OS EOE OR EE SnOH EEE EE DDO E rae dep EAS AOE pH OpEEE EE 9
`Lo]OED CO EOE EOEESEOOESE SESOOTESOOSEELELOOOSSSESEIIEOVEOLOSEOTIOONETOOSOO® 10
`EXAMINATION ooo. ccccceesencesceccceceeccecceeucesnsereeeeseeeceaeecceeeeeaeseaeeecseeeeaeesineescsaeeeeeceaeeesaeessaresnersneeenaes 41
`
`Diagnostic Tests oo... ceeeeeeeaeee
`Classification of Dry Eye Syndrome oo... ii ccc cece cee ce cee ceenee cere eceeeeeaeeseeecsreeeeneevenssecreseneeepateseerennass 13
`FelateC=)8to]||eee SESE ESSE SO OSEEOSSOSISSSSOSSEOOSOOSIOEOOSSOSOOSESTOSSIOEOVESSEEOSSESION 13
`Mild Dry Eye... ceeecceecccceceeceneteesceceee eee en epee eed ene eebe seen eeneS dns seCGaSeUs Sse seceesnaseesacaaaeaeeasesseeeaseas 15
`Moderate Dry Eye oo... ccecececcseeereeeeenrereeseessaeesercassessanscecsnennsseerssepaesaeeessesseseaveaeseascseaeay eas 15
`Severe Dry Eye... ceccecccceeceeee ene eceee ener reece nde eee Ft ee cee nS erie Skee ndseEES eee sceet secateneerseneiereaaseeed 17
`Follow-up Evaluation .0...00 cece cccceeeeeeestieceneeseneecceeeeneerapeescreenieesneessbeeeeseesssseniesesbeesnetsenaeesaaes 17
`Provider and Setting ......... cc ccceeceeeecceeeceneeeeesesceeceeeecnsscuseeceeeessesseseresseeeereseneeaenaetecseeneetnterntesnenents 17
`Counseling and Referral 0... ccc ccc et cee rien eer cnee tee teeceeteeeiaecneccmeeeesescesnaeensenenesseneseene 18
`Sacide@conomic Considerations 00.0... csc cence reer nn nee ender n nee Peer eer nS SMH ORS E KE DOSS enE Dasa te ne sanaeeneee 18
`
`APPENDIX 1. QUALITY OF OPHTHALMIC CARE CORE CRITERIA oo... cere reeteee 20
`APPENDIX 2. PREFERRED PRACTICE PATTERN RECOMMENDATION GRADING .............0... 22
`APPENDIX 3. SJOGREN SYNDROME uu... cccccccccsccsescseceenensnseseeuenenensnscenetenececececenetenevsteceneveneeey 27
`APPENDIX 4. DIAGNOSTIC TESTS o.oo. cece cence tence rere scene ceeeeneesesaneeeeeenereceaeesepessniteneeeeees 29
`APPENDIX 5. DRY EYE SEVERITY GRADING SCHEMES©... eeeeeeecececeeeeteeenteeneneneas 31
`RELATED ACADEMY MATERIALS. 00.0... cceecccccccccceneecetersetecneeeneeertreespeeseecenepeenssenieesneeenatenas 32
`REFERENCES. oon... ccccccccccccccceeenceeeee ee ecer en ee ene eee ee ene ne DEE POCO nE SEE PETS CO OES ERC eE SCC e Catan sere eeenene 32
`
`

`

`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.
`Annendix 1 describes the core criteria of auality eve care
`Appendix 1 ceseribes the core criteria of quanty 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 whenresults of carefully conducted
`clinical trials are available, the data are particularly persuasive and provide clear guidance. In otherinstances,
`the panels have to rely on their collective judgment and evaluation of available evidence.
`
`These documents provide guidance for the pattern of practice, not for the care of a particular
`individual. While they should generally meet the needs of most patients, they cannot possibly best meet the
`needs ofall patients. Adherence to these PPPs will not ensure a successful outcome in every situation. These
`practice patterns should not be deemed inclusive ofall proper methods of care or exclusive of other methods
`of care reasonably directed at obtaining the best results, It may be necessary to approachdifferent patients’
`needs in different ways. The physician must make the ultimate judgment about the propriety of the care of a
`particularpatient in light of all of the circumstances presented by that patient. The American Academy of
`Ophthalmologyis available to assist members in resolving ethical dilemmasthat arise in the course of
`ophthalmic practice.
`
`Preferred Practice Pattern® guidelines are not medical standards to be adheredto in all individual
`situations. The Academyspecifically disclaims any and all liability for injury or other damages of any kind,
`from negligence or otherwise, for any and all claims that mayarise 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 communitystandard,that reflect indications not included in approved U.S. Food and
`Drug Administration (FDA) labeling, or that are approved for use only in restricted research settings. The
`FDAhasstated that it is the responsibility of the 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 cssential 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 orearlierif
`developments warrant and updated accordingly. To ensurethat 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 compensationfor their contributions to the documents. The PPPs are externally
`reviewed by experts and stakeholders, including consumerrepresentatives, before publication. The PPPs are
`developed in compliance with the Council of Medical Specialty Societies’ Code for Interactions with
`Companies. The Academyhas Relationship with Industry Procedures (available at
`
`
`
`
`
`
`
`‘fone, aao.ore/CL/PracticeGuidelines/PPP.aspx) to comply with the Code.
`
`
`The intended users of the Dry Eye Syndrome PPP are ophthalmologists.
`
`

`

`METHODSAND KEYTO RATINGS
`
`Dry Eye Syndrome PPP
`
`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 showsthe strength of evidence. To accomplish these
`aims, methods tromthe Scottish Intercollegiate Guideline Network’ (SIGN)and the Grading of
`Recommendations Assessment, Development and Evaluation® (GRADE)groupare used. GRADEis a
`systematic approach to grading the strength of the total body of evidencethat is available to support
`recommendations on a specific clinical managementissue. Organizations that have adopted GRADEinclude
`SIGN, the World Health Organization, the Agency for Healthcare Research and Policy, and the American
`College of Physicians.’
`¢@ All studies used to form a recommendation for care arc graded for strength of evidence individually, and
`that grade is listed with the study citation.
`# Torate individual studies, a scale based on SIGN! is used. The definitions and levels of evidenceto rate
`individual studies are as follows:
`
`+
`
`I+
`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 ofbias
`[+
`
`Meta-analyses, systematic reviews of RCTs, or RCTs with a high risk ofbias
`I-
`I++—High-quality systematic revicws of case-control or cohort studies
`High-quality case-control or cohort studies with a very lowrisk 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 orbias and a significant risk that
`
`the relationship is not causal
`Nonanalytic studies (e.g., case reports, case series)
`
`I-
`
`eat
`
`@ Recommendations for care are formed based on the body of the evidence. The body of evidence quality
`ratings are defined by GRADE’as follows:
`
`Good quality
`
`Further research is very unlikely to change our confidence in the estimate of
`effect
`
`Further research is likely to have an important impact on our confidence in the
`Moderate quality
`
`estimate of effect and may changethe estimate
`Furtherresearch is very likely to have an important impact on our confidence in
`the estimate of effect and is likely to change the estimate
`Anyestimate of effect is very uncertain
`
`Insufficient quality
`
`# Key recommendations for care are defined by GRADE”as follows:
`
`Strong
`Used whenthe desirable effects of an intervention clearly outweigh the
`
`recommendation
`undesirable effects or clearly do not
`Discretionary
`Used whenthe trade-offs are less certain—either because of low-quality
`recommendation
`evidence or because evidence suggests that desirable and undesirable effects are
`closely balanced
`
`@ The Highlighted Findings and Recommendations for Care section lists points determined by the PPP
`panelto be of particular importance to vision and quality of life outcomes.
`@ All recommendations forcare in this PPP were rated using the system described above. To locate ratings
`for specific recommendations, see Appendix 2 for additional information.
`@ 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 www.aso.ore/ppp.
`
`42
`
`

`

`Dry Eye Syndrome PPP
`
`HIGHLIGHTED FINDINGS AND
`“ RECOMMENDATIONS FOR CARE
`
`
`
`Dry eye is a common ocular condition that has a high impact on the qualityoflife of afflicted individuals
`owine to discomfort or visual disability. Although the svimptoms imorove with treatment.
`the condition i
`owing to GiscOniuort Or visual aisaoiity, Aitaougn ine symptoms improve witn treatment, ine Conaion 5
`usually not curable. Dry eye can be a causeofvisual disability and may compromise results of corneal,
`cataract, and refractive surgery.
`
`Nosingle 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.
`
`About 10% ofpatients with clinically significant aqueous deficient dry eye have an underlying primary
`Sjégren syndrome. Patients with moderate punctate staining of the cornea and/or conjunctiva should be
`considered for testing for an underlying Sjégren syndrome, as these patients will require a multidisciplinary
`approach.
`
`Pharmacological and procedural treatments are associated with improvementsin patient symptoms and
`clinical signs, although chronic therapy and patient compliance are necessary for long-term management.
`
`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.
`
`Omega-3 fatty acid products without ethyl esters maybe beneficial in the treatment of dry eye, though the
`evidenceis insufficient to establish the effectiveness ofany particular formulation and may increase the risk
`of prostate cancer.
`
`Cyclosporine treatment has been shown to have short-term clinical benefits in the treatment of dry eye.
`However, insofaras dry eyeis a life-long condition whose symptomsand signs wax and wane, cost
`considerations and the lack of data on long-termeffectiveness 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 ifa pre-cxisting dry cyc
`condition can be controlled preoperatively.
`
`Patients with severe dry eye are at greaterrisk 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.
`
`

`

`Dry Eye Syndrome PPP
`
`
`
`INTRODUCTION
`
`DISEASE DEFINITION
`
`Dry eye syndrome (ICD-9 #375.15; ICD-10 #H04,12- [(-) = 1, right eye; 2, left eye; 3, bilateral])
`Forthe purpose of this PPP, dry eye syndromerefers to a group ofdisorders of the tearfilm 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 ocularirritation, redness, mucous discharge, fluctuating vision, and
`decreased tear meniscus or break-up time.
`
`CLINICAL OBJECTIVES
`
`¢ Establish the diagnosis of dry eye and differentiate it from othercausesof irritation and redness that
`may complicate both patient care and research on tear deficiency
`Identify the local and systemic causes of dry eye syndrome
`Establish appropriate therapy
`Relieve discomfort
`
`Prevent worsening of symptomsandclinical findings
`Educate and involve the patient in the managementof this disease
`
`o¢¢¢
`
`BACKGROUND
`
`SW
`
`Dryeye, either alone or in combination with other conditions, is a frequent cause of ocularirritation that
`leads patients to seek ophthalmologic care.’ While these symptoms often improve with treatment, the disease
`usually is not curable, which may be a source ofpatient and physician frustration. Dry eye can be a cause of
`visual morbidity and may compromiseresults of corneal, cataract, and refractive surgery.
`
`PREVALENCE AND RISK FACTORS
`
`Epidemiological information on dry eye syndrome has beenlimited by lack of uniformityin its
`detinition and the inability of any single diagnostic test or set ofdiagnostic tests to contirm orrule out
`the condition. Dry eye syndromeis a common condition that causes varying degrecs 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.° 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
`symptomsoftenorall the time.’ The combination of being symptomatic and having a low Schirmer
`test (<5 mmwith anesthesia) or a high rose bengal score (25) was seen in 3.5% ofthe residents.’
`Depending on which of these two percentagesis used, extrapolating to the U.S. 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 Schirmertest (16.3% <8 mm)
`or a high rose bengal score (10.8% 24).° The prevalence of self-reported dry eye in 3722 participants
`of the 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%.’ The Men’s Health Study revealed that the
`prevalence of dry eye disease in menincreased from 3.90% to 7.67% when men aged 50 to 54 were
`compared with men over 80 (7 = 25,444). Dry eye was defined as a reported clinical diagnosis or
`symptomsof both dryness andirritation cither constantly or often.* In a similar Women’s Health
`Study of over 39,000 women, the prevalence of dry eye was 5.7% among women youngerthan 50 and
`increased to 9.8% among womenover 75. This was 2 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 likelyto
`5
`
`

`

`Dry Eye Syndrome PPP:
`Prevalence and Risk Factors
`
`exhibit signs of evaporative dry eye resulting from meibomian gland disfunction (MGD)than from
`pure aqueousdeficient dry eye°
`Estimates of dry eye prevalence based on treatment-derived data yield much lower percentages. A
`study evaluating medical claims data for ncarly 10 million enrollees in managed care plans found that
`dry eye was diagnosedortreated with punctal occlusionin 0.4% to 0.5% ofthe enrollees»?
`Manyrisk factors for dry eye have been proposed (sce Table 1). Older age and female gender have
`been identified as risk factors for dry eye.>”'!" A Japanese study found an increased prevalence of
`dry eye disease among Japanese office workers using visual display terminals.’> Concurrent use of
`benzalkonium chloride (BAK)-containing glaucoma medications was also shownto be a risk factorin
`glaucomapatients.!*!” Arthritis was evaluated as a risk factor in two studies and foundto be
`associated with an increased risk of dry eye in both.®’ The Beaver Dam Eye Study foundthat after
`controlling for age and gender, smoking, and multivitamin use were associated with an increasedrisk
`of dry eye, whereas caffeine use was associated with a decreased risk.’ An update to the Beaver Dam
`Study" found that additionalrisk factors for dry eye included the use of antihistamines, antidepressant
`and antianxiety medications, and oral corticosteroids. Angiotensin-converting enzyme inhibitors were
`associated with a lowerrisk. 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 syndromeor severe symptoms.More recent reports
`have suggested a relationship between botulinumtoxin injection and dry eye.'?!
`A study of dry eye and quality oflife found decreased quality oflife 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.” Onestudyof a cohort ofdry eye patients found a strong association with anxiety
`_
`and depression.”Several other studies demonstrated a relationship between depression and dry eye
`symptoms(with or without dry eye signs) independent of the medications usedto treat depression."
`Otherresearch suggests that patients with dry eye are more likely to report pain, limitations of
`activities of daily living, and lower quality of life.'7°°?’
`
`
`
`TABLE 1 RiSkK FACTORS FOR Dry EYE
`Level of Evidence
`
`
`
` Mostly Consistent” Suggestive! Uncleart
`
`
`« Older age
`® Asian ethnicily
`* Cigarette smoking
`» Female gender
`¢ Medications
`¢ Hispanic ethnicity
`« Postmenopausal estrogen therapy
`+ Tricyclic antidepressants
`« Medications
`* Low dietary intake of omega-3 fatty acids
`+ Selective serotonin reuptakeinhibitors
`+ Anticholinergics
`e Medications
`+ Diuretics
`« Anxiolytics
`» Antihistamines
`+ Beta-blockers
`« Antipsychotics
`« Connective-tissue disease
`« Diabetes mellitus
`e Alcohol use
`« LASIK and refractive excimerlaser surgery
`« HIVIHTLV1infection
`* Menopause
`e Radiation therapy
`« Systemic chemotherapy
`« Botulinum toxin injection
`* Hematopoietic stem cell transplantation
`« Large-incision ECCE and penetrating
`* Acne
`« Vitamin A deficiency
`keratoplasty
`« Gout
`» Hepatitis C infection
`Isotretinoin
`e Oral contraceptives
`*
`* Androgen deficiency
`® Low-humidity environments
`» Pregnancy
`* Sarcoidosis
`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 ofthe International Dry Eye Workshop (2007). Ocul Surf 2007'5:99.
`
`ECCE = extracapsular cataract extraction; HIV = human immunodeficiency virus; HTLV = human T-lymphotropic virus
`*Mosily consistent evidence implies the existence ofat least one adequately powered and othenwise well-conducted study published in a peer-
`reviewed journal, along with the existenceof a plausible biological rationale and corroborating basic research orclinical data.
`t Suggestive evidence implies the existenceofeither 1) inconclusive information fram peer-reviewed publication or 2} inconclusive or limited information
`to support the association, but either not published or published somewhere otherthan in a peer-reviewed journal.
`t Unclear evidence implies eitherdirectly conflicting information in peer-reviewed publications orinconclusive information but with some basis for a
`biological rationaie.
`
`

`

`Dry Eye Syndrome PPP
`
`PATHOGENESIS
`The ocularsurface and tear-secreting glands function as an integrated unit.” Disease or dysfunction of
`this functional unit results in an unstable and poorly maintained tear film that causes ocularirritation
`symptomsand possible damageto the ocular surface epithelium. Dysfunction ofthis integrated unit
`may develop from aging, a decrease in supportive factors (such as androgen hormones), systemic
`inflammatory diseases (such as Sjogren syndromeor rheumatoid arthritis), ocular surface diseases
`(such as herpes simplex virus [HSV] keratitis) or surgeries that disrupt the uigeminal afferent sensory
`nerves (e.g., LASIK), and systemic diseases or medications that disrupt the efferent cholinergic nerves
`that stimulate tear secretion.” Decreased tear secretion and clearanceinitiates an inflammatory
`response on the ocular surface that involves both soluble and cellular mediators.***! Clinical and basic
`research suggests that this inflammation playsa role in the pathogenesis of dry eye (see Figure 1)?
`
`Rheumatoid Arthritis
`Sjogren’s Syndrome
`
`Meibomian Gland
`Secretory Dysfunction
`
`Lacrimal Gland
`
`Female Gender
`Androgen Deficiency
`
`Ocular Surface Epithelial Disease
`(Dry Eye)
`oe”
`|
`Hyperosmolar
`Tears
`
`ee
`
`
`
`
`~
`
`MMPs
`
`¥
`
`Apoptosis
`
`Cytokines
`Chemokines
`
`Ocular Surface Inflammation
`
`~
`
`+
`
`Adhesion
`Molecules
`
`T Cell
`Infiltration
`
`FIGURE 1. INFLAMMATORY MEDIATORSIN DRY EYE
`Modified from Pflugfelder SC. Antiinflammatory therapyfor dry eye. Am J Ophthalmol 2004 ;137:338, with permission from Elsevier.
`MMPs= matrix metalloproteinases
`
`Symptoms caused by dry cye may be exacerbated by the use of systemic medications such as
`diuretics, antihistamines, anticholinergics, antidepressants, and systemic retinoids (e.g.,
`isotretinoin).”*'*'***"Instillation of any eye medications, especially when they areinstilled
`frequently (e.g., more than four drops a day), may prevent the normal maintenanceof thetear 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. Exogenousirritants and allergens, although not believed to be causative of dry eye, may
`exacerbate the symptoms.
`Hyposecretory MGD may be a precursorto obstructive MGD and mayplay a role in the pathogenesis
`ofdry eye disease.”
`Rosaceais a disease of the skin and eye that is observed more frequently in fair-skinned individuals,”
`but it can occurin people ofall racial origins. Characteristic facial skin findings include erythema,
`telangiectasia, papules, pustules, prominent sebaceous glands, and rhinophyma. Rosacea may be
`difficult to diagnose in patients with darker skin tones because of the difficulty in visualizing
`telangiectasia or facial flushing.” While rosacea is more prevalent in women,it can be more severe
`whenit occurs in men.“**! Because manypatients exhibit only mild signs, such as telangiectasia and a
`history of easy facial flushing, the diagnosis of rosacea is often overlooked, especially in children who
`maypresent with chronic recurrent blepharokeratoconjunctivitis, punctate erosions, peripheral
`
`

`

`Dry Eye Syndrome PPP:
`Natural History
`
`keratitis, MGD,or recurrent chalazia and have subtle signs of rosacea.” Children with ocular rosacea
`often present with corneal involvement and asymmetryof ocular disease, and the potential for sight-
`threatening visual impairment should be considered. Cutaneous rosacea Is less frequent in children
`and associated atopy is common." Children with a history of styes have an increased risk of
`developing adult rosacea.”
`Whenthere is an associated systemic disease such as Sjogren syndrome, an inflammatory cellul