PREFERRED PRACTICE PATTERN®
`
`Dry Eye
`Syndrome
`
`AMERICAN ACADEMY~
`OF OPHTHALMOLOGY
`
`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:
`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 PATTERN are
`registered trademarks ofthe 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
`
`

`

`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
`RobertS. 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 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
`RobertS. 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
`Sji:igrens Syndrome Foundation
`Carol L. Karp, MD
`Stephen C. POugfelder, MD
`
`APOTEX 1044, pg. 3
`
`

`

`Dry Eye Syndrome PPP
`
`FINANCIAL DISCLOSURES
`
`In compliance with the Council of Medical Specialty Societies' Code for Interactions with Companies
`(available at \\'WW.cmss.or;::/coJd(Jrinteradions.aspx), relevant relationships with industry are listed. The
`Academy has Relationship with Industry Procedures to comply with the Code (available at
`http://{mc.aao.or£/CE!PracticcGuiddincs/PPP.aspx). A majority (70%) ofthe members ofthe
`Cornea/External Disease Preferred Practice Pattern Panel2012-2013 had no financial relationship to disclose.
`
`Cornea/External Disease Preferred Practice Pattern Panel2012-2013
`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/Advisor; Allergan, Inc.- Consultant/Advisor,
`Lecture fees; ForeSight- Consultant/Advisor; Ista Pharmaceuticals- Consultant/ Advisor; Nicox(cid:173)
`Consultant/ Advisor; Om eros- Consultant/ Advisor
`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/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/Advisor; Allergan, Inc.- Lecture fees; SLACK,
`Inc.- Patent/Royalty
`Robert S. Fedet·, 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/Advisor
`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
`
`Sect·etary for Quality of Cat·e
`Anne L. Coleman, MD, PhD: Allcrgan, Inc.- Consultant/Advisor; 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
`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.orgfnnJ2·
`
`ii
`
`APOTEX 1044, pg. 4
`
`

`

`TABLE OF CONTENTS
`
`Dry Eye Syndrome PPP
`
`OBJECTIVES OF PREFERRED PRACTICE PATTERN GUIDELINES .. oooooooo . . oooooo . . ooooo . . Oo0oooooo . . o0ooo02
`METHODS AND KEY TO RATINGS ............................................ oo . . oooooooo . . oooooo . . oooooo . . . . oo . . . . . . oooooooo . . oo . . 3
`HIGHLIGHTED FINDINGS AND RECOMMENDATIONS FOR CARE .... oooooooooo . . . . oooooooooo . . oooo . . oooo . . ooo .4
`INTRODUCTION ooooooooooooooooo . . ooooOoooooooooooooo . . oOOOooOoo . . oooooooooo . . oOooo . . ooooo . . ooooooooooooooo . . oooooooo . . ooooooooooo . . oooooooooooo5
`
`D i s e a s e D e f in i t ion oooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooo . . ooooooooooo . . oooooooooooooooooooooooooooooooooooooooo . . o5
`
`P a t i e n t Popu l a t io n 0 0 0 0 0 0 00 0 . . 0 . . 0 0 0 0 0 0 000 0 0 0 0 0 0 . . 0 0 0 0 0 00 0 0 0 0 0 0 0 0 oo . . 0 0 0 0 0 00 0 00 0 0 0 0 0 00 0 . . 0 0 0 0 0 0 0 0 . . o 0 0 0 0 . . 0 0 0 0 0 0 0 0 0 0 00 0 00 . . 0 0 0 0 0 0 0 00 0 0 0 0 0 0 00 0 00 0 0 0 0 5
`
`C l in i c a l ObjectivesooooooooooooooooooooooooooooooooooooOOooooooooooooooooooo . . oooOOoooooooooOOOoooooooOOOooooOOOoooooOoooooooooooooooooooOooooooooo5
`
`BACKGROUNDooo o . . oooooooooooooOooOOooooooooooo . . oooOooooo . . oOOooOOOOOoOOooooOOOOOOOOooOOo . . oo . . oooOOoOOoOoooOOOOOoooo . . . . ooo . . ooo . . OooOooOOOoo5
`
`P r e v a l en c e an d R i sk F a c to r s oOOoOOOOoOOooooOoOOOooOoooooo . . ooooOOOoOoooOooOOOOOOOOOOOOOOOoooOOoOOOOOOOOoOooOOOOOOoOOOOOOOoo00000000000000005
`
`P a thog en e s i s 0 0 00 0 0 0 . . 0 0 0 0 0 0 0 0 00 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 00 00 0 0 0 0 00 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 00 00 0 0 0 0 0 0 00 00 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 00 0 000 0 0 0 0 7
`
`A s s o c i a t ed C ond i t io n s 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 00 0 0 0 0 0 0 0 0 000 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 . . 0 00 0 0 0 0 0 0 . . 0 0 0 0 00 7
`
`N a tu r a l H i s to ry o . . o 0000000 0 000 oooOooooooOoo 000 00 000 oooo 000 0 oooooooo 00 0 ooooooooooooooooo 0000 000 0000 000 0 000 000 000000 0 000000000000000000000 000 . . 00000008
`
`CARE PROCESS oooo . . oooooo . . oooooooooOoooooooooooOoo . . ooooooooOOooOOooooooooooooooooooooooooooooooooooooooooooooooo . . ooooOoOOoooooOOooooOOoOo09
`
`P a t i en t Ou t com e C r i t e r i a . . ooooooooooooooooooooooooooooooooooOooOoooOOOoooooooooooooooooooooooooooooooooooooooooooooooooooOOoooooooooooOooooo . . 9
`
`D i agno s i s oOooooooooooooooooooooooooOooooooooooOoOOooo . . ooooooooooooooooooooooooooooooooooooooooooooOOoooOooOooOoooooooooOoOOooooOooooooooooooooooooooo9
`
`H i s to ry ooo . . oooooooooooooooooooooooOoooooooooooooooOOooooo . . ooooOoooooooooo . . ooooooooooooooooooooOoOoooooooOOoOOOoooooooooooooooooooooooooooooo10
`
`Ex am in a t ion 0 0 0 0 0 0 00 0 00 0 0 0 0 0 0 0 0 0 00 0 00 0 0 0 0 . . 00 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 000 0 0 0 0 0 0 0 0 0 0 0 00 0 00 0 0 0 0 0 0 0 0 0 00 00 0 0 0 0 0 0 0 0 0 0 00 00 0 0 0 0 0 0 0 0 00 0 00 0 . . o 0 0 00 0 00 0 0 0 0 0011
`
`D i agno s t i c T e s t s oooooo . . oooooooooooooooOOoooooooooooooooooooooooooooooooo . . oooooooooooooooooooOooOOoooooo . . oooOooOoOOOOOoooooooooooooooo11
`
`C l a s s i f i c a t ion o f D r y Ey e Synd rom e oo . . 00 . . 00 00 00 . . . . . . . . oo . . 00 . . 00 . . . . 00 . . . . . . 00 . . 00 . . . . . . . . . . 00 oo . . oo 00 00 00 00 00 . . . . 00 00 . . . . . . . . 00 0013
`
`M a n a g em e n t 0 0 0 0 0 0 0 0 0 . . 0 . . 0 0 0 0 0 0 0 0 0 00 0 00 0 0 0 0 . . 0 . . 0 0 0 0 00 0 0 0 0 oo . . 0 00 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 . . 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 . . 0 0 0 000 0 0 0 00 . . 0 0 0 0 00 0 00 0 0 0 0 0 0 0 0 00 13
`
`M i ld D ry Ey e 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 . . 0 000 0 0 0 0 0 0 0 0 0 00 0 00 0 0 00 0 00 0 0 0 0 00 . . o 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 00 0 00 0 0 0 00 0 0 0 0 00 0 00 0 0 0 0 0 0 0 00 0 00 0 0 0 0 0 0 00 0 00 0 0 0 0 0 0 0 0015
`
`Mod e r a t e D r y Ey e . . 00 00 00 0 00 . . 00 00 00 0 00 . . . . 00 00 00 0 00 . . . . . . 00 . . 00 00 00 00 00 00 . . . . . . 00 00 . . . . . . 00 00 00 00 00 . . . . 00 . . . . 00 0 OOOo 00 00 oo . . oo . . 00 00 . . 15
`
`S ev e r e D ry Ey e 0 0 0 0 0 0 00 0 0 0 . . o 0 00 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 00 0 00 0 0 0 000 00 00 0 00 0 000 00 0 0 0 0 0 0 0 0 0 0 0 00 00 0 000 0 0 0 0 0 000 0 0 0 00 0 0 0 0 . . 0 0 00 0 0 0 0 0 0 0 0 0 00 0 00 0 0 0 00 0 00 017
`
`Fo l low -u p Ev a lu a t ion oooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooOoooooooooOooooooooOOoooooooOoOoOooooooooooooooo17
`
`P ro v id e r and S e t t i n g . . . . 00 00 0 00 0 00 . . . . . . 00 0 00 0 00 00 000 00 00 00 . . 00 0 00 . . . . o 0 00 . . . . . . 00 00 . . . . 00 00 . . . . 00 oo . . . . 00 . . 00 00 00 000 00 . . 00 0 000 oo . . . . 00 oo . . oo 017
`
`Cou n s e l ing and R e f e r r a l 0 00 0 00 0 0 0 0 0 0 0 0 0 . . 00 0 0 0 0 0 0 0 00 0 0 0 0 0 00 0 0 0 0 0 0 0 0 000 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 00 . . 0 0 0 0 0 0 0 0 00 0 0 0 0 00 0 . . 0 0 0 0 0 000 0 0 0 00 01 8
`
`So c io e conom i c C on s id e r a t io n s . . . . 00 00 . . 0 . . . . 00 00 . . 00 00 . . . . 00 00 . . . . . . . . 00 0 00 . . . . . . 00 0 00 0 00 00 00 00 00 00 00 . . 0 00 . . 00 00 00 0 0 000 00 . . oo . . . . . . 00 018
`
`APPENDIX 1. QUALITY OF OPHTHALMIC CARE CORE CRITERIA ...... oo . . . . oo . . . . . . oooooooo . . oooo . . oooo . . o20
`APPENDIX 2. PREFERRED PRACTICE PATTERN RECOMMENDATION GRADING Oo0000000000000o022
`APPENDIX 3. SJOGREN SYNDROME 000000 . . 000000000 00000000 0 00 ooOoooOoooOoOoooooOoo 000 ooooooooooooooooooooooooooooooooooooo o0027
`APPENDIX 4. DIAGNOSTIC TESTS ooooo . . . . oo . . . . oo . . . . oooo 0 OOOOOoOOOOOOOO 0 00 . . 0000000 00 oo . . 00 . . . . 000 0 oo . . . . . . oo ooOo . . oooo . . oo . . . . 29
`APPENDIX 5. DRY EYE SEVERITY GRADING SCHEMES000000000o00000o00 . . 00 . . . . . . . . . . . . . . . . . . . . . . oo . . oo . . . . . . . . oo31
`RELATED ACADEMY MATER IALS oo ooo oo ooooooooooooooooooOoooooo . . . . oooooooooooooooooooooooooooooo . . oo . . oooo . . ooooOooOooooOo0000032
`REFERENCES 000 . . 000000000000 00000000000000 0 ooOoOOoOOOOOOOO ooooooooooooOoOOOO oo . . oooOOOo oOooooOOoO 0 000 OOoOOoooooooooooo 0 000 00° 0 0 00 ooooooooo O oo32
`
`APOTEX 1044, pg. 5
`
`

`

`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 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 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.
`
`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,
`fi·om 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 U.S. 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 ofPPPs 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
`htJp;//QD..Q,;tfl.;!,mg!f-:E/er;~r;Us;gQLJidr;JiiJ.Y.?.Le!:P.,;J:>.Ps) to comply with the Code.
`
`The intended users of the Dry Eye Syndrome PPP are ophthalmologists.
`
`2
`
`APOTEX 1044, pg. 6
`
`

`

`METHODS AND KEY TO 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 shows the strength of evidence. To accomplish these
`aims, methods from the Scottish Intercollegiate Guideline Network 1 (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
`+ 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.
`+ To rate individual studies, a scale based on SIGN 1 is used. The definitions and levels of evidence to rate
`individual studies are as follows:
`
`I++
`
`I+
`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 ofRCTs, 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)
`
`+ Recommendations for care are formed based on the body of the evidence. The body of evidence quality
`ratings are defined by GRADE2as follows:
`
`Good quality
`
`Moderate quality
`
`Insufficient 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
`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
`
`+ Key recommendations for care are defined by GRADE2 as follows:
`
`Strong
`recommendation
`Discretionary
`recommendation
`
`Used when the desirable e!Tects of an intervention clearly outweigh the
`undesirable effects or clearly do not
`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
`
`+ 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 ofthe literature search are available at www.nao.om/ppp.
`
`3
`
`APOTEX 1044, pg. 7
`
`

`

`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 of life of aff1icted 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 of corneal,
`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.
`
`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.
`
`Puncta! plugs may be helpful in moderate to severe cases of aqueous deficient dry eye. However, patients
`treated with puncta! 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 of any 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, 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.
`
`4
`
`APOTEX 1044, pg. 8
`
`

`

`INTRODUCTION
`
`Dry Eye Syndrome PPP
`
`DISEASE DEFINITION
`Dry eye syndrome (ICD-9 #375. I 5; ICD- 10 #I-104.12- [(-) = I, right eye; 2, left eye; 3, bilateral])
`For the purpose of this PPP, dry eye syndrome refers to a group of disorders 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
`+ Establish the diagnosis of dry eye and differentiate it fi·om other causes of 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 symptoms and clinical findings
`+ Educate and involve the patient in the management of this disease
`
`BACKGROUND
`
`Dry eye, either alone or in combination with other conditions, is a fi·equent 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.
`
`PREVALENCE AND RISK FACTORS
`Epidemiological information on dry eye syndrome has been limited by Jack 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% of2127 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 of2520 elderly (65 or older) residents of
`Salisbury, Maryland, 14.6% were symptomatic, which was defined as repmiing one or more dry eye
`symptoms often or all the time.4 The combination of being symptomatic and having a low Schirmer
`test (:::::;5 mm with anesthesia) or a high rose bengal score (~5) was seen in 3.5% of the residents. 4
`Depending on which of these two percentages is 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(cid:173)
`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 (I 0.8% ~4 ).6 The prevalence of self-repmied 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%.7 The Men's Health Study revealed that the
`prevalence of dry eye disease in men increased fi·om 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.9
`In a clinic setting, the proportion of224 su~jects identified with dry eye were far more likely to
`5
`
`APOTEX 1044, pg. 9
`
`

`

`Dry Eye Syndrome PPP:
`Prevalence and Risk Factors
`
`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 enrollees in managed care plans found that
`dry eye was diagnosed or treated with puncta! 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
`7·11-14 A Japanese study found an increased prevalence of
`been identified as risk factors for d1y eye.6
`•
`d1y 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 patients. 16·17 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 d1y 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.19-21
`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 d1y eye signs) independent of the medications used to treat depression?4·25
`Other research suggests that patients with dry eye are more likely to report pain, limitations of
`27
`26
`activities of daily living, and lower quality of life. 17
`•
`•
`
`TABLE 1 RISK FACTORS FOR DRY EYE
`
`Mostly Consistent"
`
`• 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
`• Hematopoietic stem cell transplantation
`• Vitamin A deficiency
`• Hepatitis C infection
`• Androgen deficiency
`
`Level of Evidence
`Suggestive t
`
`• Asian ethnicity
`• Medications
`• Tricyclic antidepressants
`• Selective serotonin reuptake inhibitors
`• Diuretics
`• Beta-blockers
`• Diabetes mellitus
`• HIV/HTLV1 infection
`• Systemic chemotherapy
`• Large-incision ECCE and penetrating
`keratoplasty
`• lsotretinoin
`• Low-humidity environments
`• Sarcoidosis
`• Ovarian dysfunction
`
`Unclearl
`
`• Cigarette smoking
`• Hispanic ethnicity
`• Medications
`• Anticholinergics
`• Anxiolytics
`• Antipsychotics
`• Alcohol use
`• Menopause
`• Botulinum toxin injection
`• Acne
`• Gout
`• Oral contraceptives
`• Pregnancy
`
`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;5:99.
`
`ECCE= extracapsular cataract extraction; HIV =human immunodeficiency virus; HTLV =human T-lymphotropic virus
`* Mostly consistent evidence implies the existence of at least one adequately powered and otherwise well-conducted study published in a peer(cid:173)
`reviewed journal, along with the existence of a plausible biological rationale and corroborating basic research or clinical data.
`r Suggestive 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
`biological rationale.
`
`6
`
`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 fl-om aging, a decrease in supportive factors (such as androgen hormones), systemic
`inflammatory diseases (such as Sjogren syndrome or rheumatoid arthritis), ocular surface dise