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
`
`Susan Garrett
`Medical Editor:
`
`Design: Socorro Soberano
`
`guidelines are externally reviewed by experts and stakeholders before publication.
`
`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 ofOphthalmology; ml 3. Available
`at: wwwaaoorg/ppg.
`
`Approved by:
`
`Board of Trustees
`September 2i , 20l 3
`
`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.
`
`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
`
`

`

`Dry Eye Syndrome PPP
`
`CORNEA/EXTERNAL DISEASE PREFERRED
`
`PRACTICE PATTERN DEVELOPMENT
`
`PROCESS AND PARTICIPANTS
`
`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. Feder, MD, Co-chair
`Stephen D. McLeod, MD, Co—chair
`Escn K. Akpek, MD, Cornea Society Represontative
`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, Mcthodologist
`
`Stephen C. P'llugfelder, MD
`
`Stephen D. McLeod, MD, Chair
`David F. Chang, MD
`Robert S. Feder, MD
`Timothy W. Olsen, MD
`Bruce E. Prum, J12, MD
`C. Gail Summers, MD
`David C. Muscli, 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
`
`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 oi‘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 1.. Karp, MD
`
`

`

`Dry Eye Syndrome PPP
`
`FIN N lAL I
`A C
`DSCLOSU
`
`RES
`
`In compliance with the Council ochdical Specialty Societies’ Code for Interactions with Companies
`(available at www.cmssorel/codelhrinteractions.215px), relevant relationships with industry are listed. The
`Academy has Relationship with Industry Procedures to comply with the Code (available at
`
`4'»
`st,
`« ,“ i
`-
`r
`~n
`I
`t
`1v”
`"
`I
`II;
`9
`’ 9;
`e I.' ‘II!..!
`
`1'
`
`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—Fewer: No financial relationships to disclose
`Amy Lin, MD: No financial relationships to disclose
`Francis S. Mah, MD: Alcon Laboratories, Inc. — Consultant/Adviser; Allergan, Inc. 7 Consultant/Adviser,
`Lecture fees; ForeSight — Consultant/Adviser; Ista Pharmaceuticals — Consultant/Adviser; Nicox —
`Consultant/Advisor; Omeros — ConsultanUAdvisor
`Stephen D. McLeod, MD: No financial relationships to disclose
`David C. Musch, PhD, MPH: Abbott Laboratories — Consultant fees (member oflndependent Data
`Monitoring Committee); ClinReg Consulting Services, Inc. — Consultant/Adviser
`Audrey R. Talley-Rostov, MD: Addition Technology v Lecture fees; Allergen, Inc. 7 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; Seleral Depressor -— Patents/Royalty
`Bruce E. Prum, Jr., MD: Pfizer Ophthalmics v Lecture fees
`C. Gail Summers, MD: No financial relationships to disclose
`
`The disclosures ol‘relevant relationships to industry of other reviewers of the document from January to
`
`August 2013 are available online at wwwaaooraf 'y i 3.
`
`unlit of Care
`Secretarv for
`Anne L. Coleman, MD, PhD: Allergan, Inc. — Consultant/Adviser; Pfizer Ophthalmics~ Consultant/Advisor
`
`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
`l’lora C. Lum, MD: No financial relationships to disclose
`Doris Mizuiri: No financial relationships to disclose
`Jessica Ravetto: No financial relationships to disclose
`
`

`

`Dry Eye Syndrome PPP
`
`TABLE OF CONTENTS
`
`OBJECTIVES OF PREFERRED PRACTICE PATTERN GUIDELINES .......................................... .2
`METHODS AND KEY TO RATINGS ................................................................................................ ..3
`
`
`HIGHLIGHTED—FINBI—NGS—ANDRECOMMENDATJGNS—FGIMRE ............................................ ..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
`
`REFERENCES ................................................................................................................................ ..32
`
`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
`
`

`

`Dry Eye Syndrome FPP
`
`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.
`
`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 of a 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 ultimate judgment 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.
`
`The intended users of the Dry Eye Syndrome PPP are ophthalmologists.
`
`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 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 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
`‘ C 'P '
`‘
`‘
`‘
`‘ "icli
`*‘ Pig, 9,73) to comply with the Code.
`
`

`

`METHODS AND KEY TO RATINGS
`
`Dry Eye Syndrome PFP
`
`c To rate individual studies, a scale based on SIGNl is used. The definitions and levels of evidence to rate
`individual studies are as follows:
`
`High—quality meta—analyses, systematic reviews of randomized controlled trials (RCTs), or
`I++
`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 of bias
`High—quality systematic reviews of ease—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 ease-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)
`
`ll—
`
`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 Network'TS’IGN) 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
`6 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.
`
`J
`
`llI
`
`0 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
`
`Further research is likely to have an important impact on our confidence in the
`Moderate quality
`
`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
`
`insufficient quality
`
`Key recommendations for care are defined by GRADE2 as follows:
`
`Used when the desirable effects ofan intervention clearly outweigh the
`Strong
`
`recommendation undesirable effects or clearly do not
`Discretionary
`Used when the 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
`panel to be of particular importance to vision and quality of life outcomes.
`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.
`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 marmoorafppp.
`,,
`
`

`

`Dry Eye Syndrome PPP
`
`HIGHLIGHTED FINDINGS AND
`
`RECOMMENDATIONS FOR CARE
`
`Dry eye is a common ocular condition that has a high impact on the quality oflife of afflicted individuals
`
`cataract. and refractive surgery.
`
`worsen their dry eye condition.
`
`Cyclosporine treatment has been shown to have short—term 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 cyclosporlne. It 15 also unclear whether the estimated benefit is observed in ail patient
`subpopulations.
`
`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 ofthe patient‘s condition. Evaluation of
`conjunctival staining is helpful but underutilized.
`
`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.
`
`Pharmacological and procedural treatments are associated with improvements in 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 diy 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 may be beneficial in the treatment of dry eye, though the
`evidence is insufficient to establish the effectiveness ofany particular formulation and may increase the risk
`of prostate cancer.
`
`Dry eye patients considering keratoreti‘active surgery, particularly LASIK, should be cautioned that the dry
`eye condition could become worse afier surgeiy. 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 prc-cxisting 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 pro—existing dry eye should be cautioned that keratorefi‘active surgery, particularly LASIK, may
`
`

`

`Dry Eye Syndrome PPP
`
`TIN RODUCTION
`
`DISEASE DEFINITION
`
`Dry eye syndrome (ICD—9 #375,15; lCD-lO #1-104.12— [(—) = 1, right eye; 2, left eye; 3, bilateral])
`
`For Eli—0TH???“purpose i
`
`, dry eye syndrome reters to a group ot‘disorders ofthe 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 ofirritation 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 symptoms and clinical findings
`Educate and involve the patient in the management of this disease
`
`BACKGROUND
`
`e A
`
`Dry eye, either alone or in combination with other conditions, is a frequent cause of ocular irritation that
`leads patients to seek ophthalmologic care.4 While these symptoms often improve with treatment, the disease
`usually is 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.
`
`5
`
`PREVALENCE AND RISK FACTORS
`Epidemiological information on dry eye syndrome has been limited by lack of uniformity in its
`definition and the inability oi any smgle diagnostic test or set 0t diagnost1c tests to contu‘m or rule out
`the condition. Dry cye syndrome is a common condition that causes varying degrees ofdiseomfort
`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
`symptoms often or all the time.4 The combination ofbeing symptomatic and having a low Schirmer
`test ($5 mm with anesthesia) or a high rose bengal score (25) was seen in 3.5% of the residents.4
`Depending on which ofthcsc 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% 38 mm)
`or a high rose bengal score (10.8% 241° 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 ot‘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.9
`In a clinic setting, the proportion of224 subjects identified with dry eye were far more likely to
`
`

`

`Dry Eye Syndrome PPP:
`Prevalence and Risk Factors
`
`TABLE 1
`
`RISK FACTORS FOR DRY EYE
`
`Mostly Consistent‘
`
`Suggestive1
`
`Level of Evidence
`
`0 Older age
`Female gender
`Postmenopausal estrogen therapy
`Low dietary intake of omega-3 fatty acids
`Medications
`- Antihistamines
`Connective-tissue disease
`
`LASIK and refractive excimer laser surgery
`Radiation therapy
`Hematopoletic stem cell transplantation
`Vitamin A deficiency
`Hepatitis C infection
`Androgen deficiency
`
`- Asian ethnicity
`o Medications
`. Tricyclic antidepressants
`- Selective serotonin reuptake inhibitors
`- Diuretics
`- Beta-blockers
`Diabetes mellitus
`HiV/HTLVl infection
`Systemic chemotherapy
`Large~inclsion ECCE and penetrating
`keratoplasty
`Isotretlnoin
`
`exhibit signs of evaporative dry eye resulting from meibomian gland disfunction (MGD) 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 enrollecs in managed care plans found that
`dry eye was diagnosed or treated with punctal occlusion in 0.4% to 0.5% of the enrollees.8’9’11
`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 eve.6’7’“‘“1 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)—c0ntaining 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.7An update to the Beaver Dam
`Studyl4 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 l—lcalth
`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.”3 More recent reports
`have suggested a relationship between botulinum toxin injection and dry eye.”‘“
`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 depi‘ession.24’2’
`Other research suggests that patients with dry eye are more likely to report pain, limitations of
`activities ofdaily living, and lower quality oflife.]7"3("27
`
`biological rationale.
`
`Low~humidity environments
`- Sarcoidosis
`- Ovarian dysfunction
`
`
`Reproduced with permission from Smith .lA (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 15:99.
`
`ECCE = exiracapsular cataract extraction; HlV = human immunodeficiency virus; HTLV = human T-Iymphotropic virus
`" Mosin consistent evidence implies the existence of at least one adequately powered and othenivise 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.
`iSuggeslive 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 but with some basis for a
`
`Unclear‘
`
`Cigarette smoking
`Hispanic ethnicity
`Medications
`. Anticholinergics
`. Anxiolytics
`- Antipsychotics
`Alcohol use
`
`Menopause
`Boiulinum toxin injection
`Acne
`Gout
`
`Oral contraceptives
`Pregnancy
`
`

`

`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 from 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 iHSVI keratitis) or surgeries that disrupt the trigeminai afferent sensory
`nerves (cg, LASIK), and systemic diseases or medications that disrupt the efferent cholinergic neives
`that stimulate tear secretion.29 Decreased tear secretion and clearance initiates an inflammatory
`response on the ocular surface that involves both soluble and cellular n‘iediators.30’31 Clinical and basic
`research suggests that this inflammation plays a role in the pathogenesis of dry eye (see Figure 0.3233
`
`9
`
`PATHOGENESIS
`
`Dry Eye Syndrome PPP
`
`Rheumatoid Arthritis
`Sjogren's Syndrome
`
`secremry Dy5fun3fi0”
`Lacnmal Gland
`Meibomian Gland
`
`Ocular Surface Epithelial Disease
`/ (Dry Eye)
`Hyperosmolar
`Tears
`
`\ Ocular Surface inflammation
`
`v
`
`v
`
`v
`
`
`
`Female Gender
`Al‘drogen DEfidEl‘CV
`
`Adhesion
`Molecules
`
`
`
`T Cell
`infiltration
`
`Cytokines
`Chemokines
`
`MMPs
`
`
`
`
`
`FlGURE 1. INFLAMMATORY MEDIATORS lN DRY EYE
`Modified from Pflugfeider SC. Anliinflammalory therapy for dry eye. Am J Ophthalmol 2004;137:338, with permission from Eisevier.
`MMPs = matrix melalloproteinases
`
`
`
`ASSGCWFEBfiGNBiTiGNS
`
`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’]4’1634’”lnstillation of any eye medications, especially when they are instilled
`fi'equently (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.
`
`Hyposccretory 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,3
`but it can occur in people of all 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 oftlie difficulty in visualizing
`telangiectasia or facial flushing.39 While rosacea is more prevalent in women, it can be more severe
`when it occurs in n1en.“°’41 Because many patients 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
`may present with chronic recurrent blepharokeratoconjunctivitis, punctate erosions, peripheral
`
`

`

`Dry Eye Syndrome PPP:
`Natural History
`
`Eyelid conditions associated with dry eye include eyelid malposition, lagophthalmos, and blepharitis
`as well as neuromuscular disorders that affect blinking (c.g., Parkinson disease, Bcll palsy).°6 Orbital
`surgery, radiation, and injury may also lead to d1y eye.
`
`NATURAL HISTORY
`
`keratitis, MGD, or recurrent chalazia and have subtle signs of rosacea.42 Children