Dry Eye Workshop

DEWS

Management and Therapy

Management and Therapy o Dry Eye Disease:  Report of the Management and Therapy Subcommittee of the International Dry Eye WorkShop (2007) ABSTRACT

I. InTRODuCTIOn

Te members members o te Maagemet Maagemet ad Terap Terap

Sbcommittee assessed crret dr ee terapies. Eac member wrote a sccict evidece-based review o a assiged aspect o te topic, ad te a report was writte ater review b ad wit cosess o a sbcommittee members ad te etire Dr Ee WorkSop membersip. I additio to its ow review o te iteratre, te Sbcommittee reviewed

hisreportsummarizesthemanagementandtherapeuticoptionsortreatingdr peuticoptionsor treatingdreedisease.The eedisease.Thelevel level oevidenceorsupportingdata oevidence orsupportingdataromthe romtheliterature literature isevaluatedaccordingtothemodiedAmericanAcadem oOphthalmologPreerredPracticesguidelines(Table1).

T

te Dr Ee Preerred Practice Patters o te America Academ o Optamoog ad te Iteratioa Task Force

II. GOAlS OF ThE MAnAGEMEnT AnD ThERAPy SuBCOMMITTEE

(ITF) Depi Pae o Dr Ee. Te Sbcommittee avored te approac take b te ITF, wose recommeded treatmets were based o eve o disease severit. Te recommedarecommeda tios o te Sbcommittee are based o a modicatio o 

Goalsothiscommitteeweretoidentiappropriate therapeuticmethodsorthe therapeuticmethods orthemanagemento managementodree dreedisease disease andrecommendasequenceorstrategortheirapplication, basedonevidence-basedreviewotheliterature. Thequalitotheevidenceintheliteraturewasgraded accordingtoamodicationotheschemeusedinthe  AmericanAcademoOphthalmologPreerredPractice Patternsseries.Whenpossible,peer-reviewedullpublications,notabstract tions ,notabstracts,wereused.Therep s,wereused.Thereportwasrevie ortwasreviewed wed

te ITF severit gradig sceme, ad sggested treatmets were cose rom a me o terapies or wic evidece o  terapetic eect ad bee preseted. KEyWORDS

DEWS, dr ee disease, Dr Ee WorkSop, WorkSop,

maagemet, terap

Tabe 1. Evidence grading scheme Ciica Stdies

 AcceptedorpublicationJanuar2007. ManagementandTherapSubcommitteemembers: Stephen C. Pfugelder, MD (Chair);GerdGeerling, (Chair);GerdGeerling,MD;Shigero MD;ShigeroKinoshita,MD;Michael Kinoshita,MD;MichaelA.Lemp, A.Lemp, MD;JamesMcCulle,MD;DanielNelson,MD;GarN.Novack,PhD;Jun Shimazaki,MD;CliveWilson,PhD. ProprietarinterestsoSubcommitteemembersaredisclosedonpages202 and204. Reprintsarenotavailable.Articlescanbeaccessedat:www.tearlm.org. CorrespondenceinregardtothethischaptershouldbeaddressedtoStephen C.PfugelderMD,Ophthalmolog-O C.PfugelderMD,Ophthalmol og-OcularSurCtr,CullenEeInstitute, cularSurCtr,CullenEeInstitute, 6565FanninStreetNC205,Houston,TX77030.Tel:713-798-4732.Fax: 713-798-1457.Email:[email protected]

leve 1. Evidence obtained rom at least one properly conducted, well-designed, randomized, controlled trial, or evidence rom well-designed studies applying rigorous statistical approaches. leve 2. Evidence obtained rom one o the ollowing: a well-designed controlled trial without randomization, a well-designed cohort or case-control analytic study, preerably rom one or more center, or a well-designed study accessible to more rigorous statistical analysis. leve 3. Evidence obtained rom one o the ollowing: descriptive studies, case reports, reports o expert committees, expert opinion. Basic Sciece Stdies leve 1. Well-perormed studies conrming a hypothesis with adequate controls published in a high-impact journal. leve 2. Preliminary or limited published study.

©2007 Ethis Communications, Inc. The Ocular Surface ISSN: 15420124. (No authors listed). Management and therapy o dry eye disease: report o the Management and Therapy Subcommittee Subcommittee o  the International Dry Eye WorkShop (2007). 2007;5(2):163-178.

leve 3. Meeting abstracts or unpublished presentations. This evidence grading scheme is based on that used in the American Academy o Ophthalmology Preerred Practice Pattern series.

The Ocular Ocular Surace Surace / april 2007, VOl. 5, NO. 2 /  www.tos.om

163

DEWSMANAGEMENTANDTHERAPy III. ASSESSMEnT OF CuRREnT DRy EyE ThERAPIES

OuTlInE

A. Tear Sppemetatio: lbricats

I. Introduction II. Goals o the Management and Therapy Subcommittee III. Assessment o current dr y eye therapies A. Tear supplementation: lubricants 1. General characteristics and eects 2. Preservatives 3. Electrolyte composition 4. Osmolarity 5. Viscosity agents 6. Summary B. Tear Retention 1. Punctal occlusion a. Rationale b. Types c. Clinical studies d. Indications and contraindications e. Complications . Summary 2. Moisture chamber spectacles 3. Contact lenses C. Tear stimulation: secretagogues D. Biological tear substitutes 1. Serum 2. Salivary gland autotransplantation E. Anti-infammatory therapy 1. Cyclosporine 2. Corticosteroids a. Clinical studies b. Basic research 3. Tetracyclines a. Proper ties o tetracyclines and their derivatives 1) Antibacterial properties 2) Anti-infammatory 3) Anti-angiogenic properties b. Clinical applications o tetracycline 1) Acne Rosacea 2) Chronic posterior blepharitis: meibomianitis, meibomian gland dysunction 3) Dosage and saety F. Essential atty acids G. Environmental strategies IV. Treatment recommendations V. Unanswered questions and uture directions

ballsubcommitteemembersandbtheentireDrEe  WorkShopmembership.Commentsandsuggestedrevisionswerediscussedbthesubcommitteemembersand incorporatedintothe report where deemed appropriate bconsensus. 164

1. General Characteristics and Eects Theterm“articialtears”isamisnomerormostproductsthatidentithemselvesassuch,becausethedonot mimicthecompositionohumantears.Mostunctionas lubricants,althoughsomemorerecentormulationsmimic theelectroltecompositionohumantears(TheraTears ® [AdvancedVisionResearch,Woburn,MA]). 1,2Theocular lubricantspresentlavailableintheUnitedStatesareapprovedbasedontheUSFoodandDrugAdministration (FDA)monographonover-the-counter( OTC)products (21CFR349)andarenotbasedonclinicalecac.The monographspeciespermittedactiveingredients(eg, demulcents,emulsiers,suractants,andviscositagents) andconcentrations,butgivesonllimitedguidanceon inactiveadditivesandsolutionparameters.Certaininactiveingredientsthatareusedinarticialtearssoldinthe US(eg,castoroilinEndura ™[Allergan,Inc.,Irvine,CA] andguarinSstane ®[Alcon,FtWorth,TX])arenotlisted inthemonograph. Itisdiculttoprovethataningredientinanocular lubricantactsasanactiveagent.Ithereisanactiveingredient,itisthepolmericbaseorviscositagent,but thishasproveddiculttodemonstrate.Thisiseither becauseitisnotpossibletodetecttheeectsordierences inclinicaltrialswithpresentlavailableclinicaltestsor becausethecurrentlavailable agentsdo nothavean discernableclinicalactivitbeondalubricationeect.  Althoughcertainarticialtearshavedemonstratedmore successthanothersin reducingsmptoms oirritation ordecreasingocularsuracedestaininginhead-to-head comparisons,therehavebeennolargescale,masked, comparativeclinicaltrialstoevaluatethewidevarieto ocularlubricants.  Whatistheclinicaleectoocularlubricantsorarticial tears?Dothelubricate,replacemissingtearconstituents, reduceelevatedtearlmosmolarit,diluteorwashout infammatororinfammation-inducingagents?Dothe, insomeinstances,actuallwashoutessentialsubstances oundinnormalhumantears?Thesequestionsremainto beansweredasmoresensitiveclinicaltestsbecomeavailabletodetectchangesintheocularsurace. Theoremostobjectivesincaringorpatientswithdr eediseasearetoimprovethepatient’socularcomortand qualitolie,andtoreturntheocularsuraceandtearlm tothenormalhomeostaticstate.Althoughsmptomscan rarelbeeliminated,thecanotenbeimproved,leading toanimprovementinthequalitolie.Itismoredicult todemonstratethattopicallubricantsimprovetheocular suraceandthetearlmabnormalitiesassociatedwithdr ee.Mostclinicalstudiesailtodemonstratesignicant correlation between smptomsand clinical test values orbetweentheclinicaltestvaluesthemselves. 3-5Itisnot unusualoradreewithonlmildsmptomstoshow signicantrosebengalstaining.Untilagentsaredeveloped thatcanrestoretheocularsuraceandtearlmtotheir

The Ocular Surace / april 2007, VOl. 5, NO. 2 /  www.tos.om

DEWSMANAGEMENTANDTHERAPy

normalhomeostaticstate,thesmptomsandsignsodr eediseasewillcontinue. Ocularlubricantsarecharacterizedbhpotonicor isotonicbueredsolutionscontainingelectroltes,suractants,andvarioustpesoviscositagents.Intheor,the idealarticiallubricantshouldbepreservative-ree,contain potassium,bicarbonate,andotherelectroltesandhavea polmericsstemtoincreaseitsretentiontime. 1,6-8Phsical propertiesshouldincludeaneutraltoslightlalkalinepH. Osmolaritiesoarticialtearshavebeenmeasuredtorange romabout181to354mOsm/L.9Themainvariablesinthe ormulationoocularlubricantsregardtheconcentration oandchoiceoelectroltes,theosmolaritandthetpe oviscosit/polmericsstem,thepresenceorabsenceo preservative,and,ipresent,thetpeopreservative. 2. Preservatives Thesinglemostcriticaladvanceinthetreatmentodr eecamewiththeeliminationopreservatives,suchasbenzalkoniumchloride(BAK ),romOTClubricants.Because otheriskocontaminationomultidoseproducts,most eithercontainapreservativeoremplosomemechanism orminimizingcontamination.TheFDAhasrequiredthat multidosearticialtearscontainpreservativestoprevent microbialgrowth.10Preservativesarenotrequiredinunit dosevialsthatarediscardedaterasingleuse.Thewidespreadavailabilitononpreservedpreparationsallows patientstoadministerlubricantsmorerequentlwithout concernaboutthetoxiceectsopreservatives.Forpatients withmoderate-to-severedreedisease,theabsenceo preservativesisomorecriticalimportancethantheparticularpolmericagentusedinocularlubricants.Theocular suraceinfammationassociatedwithdreeisexacerbated bpreservedlubricants;however,nonpreservedsolutions areinadequateinthemselvestoimprovethesuraceinfammationandepithelialpathologseenindreedisease.11 Benzalkonium chloride is themost requentlused preservativeintopicalophthalmicpreparations,aswellas intopicallubricants.Itsepithelialtoxiceectshavebeen wellestablished. 12-17ThetoxicitoBAKisrelatedtoits concentration,therequencodosing,theleveloramount otearsecretion, and the severito the ocular surace disease.Inthepatientwithmilddree,BAK-preserved dropsareusuallwelltoleratedwhenused4-6timesada orless.Inpatientswithmoderate-to-severedree,the potentialorBAKtoxicitishigh,duetodecreasedtear secretionanddecreasedturnover. 17Somepatientsmabe usingothertopicalpreparations(eg,glaucomamedications) thatcontainBAK,increasingtheirexposuretothetoxic eectsoBAK.Also,thepotentialortoxicitexistswith patientabuseootherOTCproductsthatcontainBAK, suchasvasoconstrictors. BAKcandamagethecornealandconjunctivalepithelium,aectingcell-to-celljunctionsandcellshapeand microvilli,eventuallleadingtocellnecrosiswithsloughing o1-2laersoepithelialcells. 17Preservative-reeormulationsareabsolutelnecessarorpatientswithseveredr

eewithocularsuracediseaseandimpairmentolacrimal gland secretion, or orpatients on multiple, preserved topicalmedicationsorchroniceedisease.Patientswith severedree,greatlreducedtearsecretion,andpunctal occlusionareatparticularriskorpreservativetoxicit.In suchpatients,theinstilledagentcannotbewashedout;i thisriskhasnotbeenappreciatedbtheclinician,preserved dropsmightbeusedathighrequenc.  AnotheradditiveusedinOTCormulationsisdisodium (EDTA).ItaugmentsthepreservativeecacoBAKand otherpreservatives,but,bitsel,itisnotasucientpreservative.Usedinsomenonpreservedsolutions,itma help limit microbial growthin opened unit-dose vials.  AlthoughuseoEDTAmaallowalowerconcentrationo preservative,EDTAmaitselbetoxictotheocularsurace epithelium.Astudcomparingtwopreservative-reesolutions,HpotearsPF ®(NovartisOphthalmics,EastHanover, NJ)containingEDTAandReresh ®(Allergan,Inc.,Irvine, CA)withoutEDTA,showedthatbothormulationshad identicalsaetprolesandwerecompletelnontoxicto therabbitcornealepithelium. 18Otherstudiesoundthat EDTA-containingpreparationsincreasedcornealepithelial permeabilit. 19,20Thepotentialexiststhatpatientswith severedreewillndthatEDTA-containingpreparations increaseirritation. Nonpreserved, single unit-dose tearsubstitutes are more costl orthe manuacturerto produce, more costlorthepatientstopurchase,andlessconvenient tousethanbottledocularlubricants.Forthesereasons, reclosableunitdosevials(eg,RereshFree[AllerganInc., Irvine,CA];TearsNaturalFree® [Alcon,Fort Worth, TX])wereintroduced.Lesstoxicpreservatives,suchas polquad(polquaternium-1),sodiumchlorite(Purite®), andsodiumperborateweredevelopedtoallowtheuse omultidosebottledlubricantsandtoavoidtheknown toxicitoBAK-containingsolutions.21,22The“vanishing” preservativesweresodiumperborateandsodiumchlorite (TheraTears®[AdvancedVisionResearch,Woburn,MA], Genteal®[Novartis,EastHanover,NJ],andRereshTears ® [AllerganInc.,Irvine,CA]). Sodiumchloritedegradestochlorideionsandwater uponexposuretoUVlightaterinstillation.Sodiumperborateisconvertedtowaterandoxgenoncontactwiththe tearlm.Forpatientswithseveredree,evenvanishing preservativesmanottotalldegrade,duetoadecreasein tearvolume,andmabeirritating.Patientspreerbottled preparationsorreasonsobothcostandeaseouse.The ideallubricantwouldcomeinamultidose,eas-to-use bottlethatcontainsapreservativethatcompleteldissipates beorereachingthetearlm,oriscompletelnontoxicand nonirritatingandmaintainsabsolutesterilitwithrequent use.Onesuchmulti-use,preservative-reeproducthas beenintroducedtothemarket(VisinePure-Tears ®[Pzer, Inc,NJ]). Ocularointmentsandgelsarealsousedintreatmento dreedisease.Ointmentsareormulatedwithaspecic mixtureomineraloilandpetrolatum.Somecontainlanolin,

The Ocular Surace / april 2007, VOl. 5, NO. 2 /  www.tos.om

165

DEWSMANAGEMENTANDTHERAPy

whichcanbeirritatingtotheeeanddelacornealwound healing.23Individualswithsensitivittowoolmaalsobe sensitivetolanolin. 23Someointmentscontainparabensas preservatives,andtheseointmentsarenotwelltolerated bpatientswithseveredree.Ingeneral,ointmentsdo notsupportbacterialgrowthand,thereore,donotrequire preservatives.Gelscontaininghighmolecularweightcrosslinkedpolmersoacrlicacid(carbomers)havelonger retentiontimesthanarticialtearsolutions,buthaveless visualblurringeectthanpetrolatumointments. 3. Electrolyte Composition Solutionscontainingelectroltesandorionshavebeen showntobebenecialintreatingocularsuracedamage duetodree.1,6,20,24,25 Todate,potassiumandbicarbonateseemtobethemostcritical.Potassiumisimportantto maintaincornealthickness. 7Inadr-eerabbitmodel,a hpotonictear-matchedelectroltesolution(TheraTears ® [AdvancedVisionResearch,Woburn,MA])increasedcon junctivalgobletcelldensitandcornealglcogencontent, andreducedtearosmolaritandrosebengalstainingater2 weeksotreatment.25Therestorationoconjunctivalgoblet cellsseeninthedr-eerabbitmodelhasbeencorroborated inpatientswithdreeaterLASIK.26 Bicarbonate-containingsolutionspromotetherecover oepithelialbarrierunctionindamagedcornealepithelium andaid in maintaining normal epithelialultrastructure. Themaalsobeimportantormaintainingthemucinlaer othetearlm.6Ocularlubricantsareavailablethatmimic theelectroltecompositionohumantears,eg,TheraTears ® (AdvancedVisionResearch,Woburn,MA)andBIONTears ® (Alcon,FortWorth,TX). 1,2Thesealsocontainbicarbonate, whichiscriticalorormingandmaintainingtheprotectivemucingelinthestomach.27Bicarbonatemaplaa similarroleorgel-ormingmucinsontheocularsurace. Becausebicarbonateisconvertedtocarbondioxidewhen incontactwithairandcandiusethroughtheplasticunit dosevials,oilpackagingotheplasticvialsisrequiredto maintainstabilit. 4. Osmolarity Tearsopatientswithdreehaveahighertearlm osmolarit(crstalloidosmolarit)thandothoseonormal patients.28,29Elevatedtearlmosmolaritcausesmorphologicalandbiochemicalchangestothecornealand conjunctivalepithelium18,30andispro-infammator.31This knowledgeinfuencedthedevelopmentohpo-osmotic articialtearssuchasHpotears ®(230mOsm/L[Novartis Ophthalmics,EastHanover,NJ])andsubsequentlTheraTears®(181mOsm/L[AdvanceVisionResearch,Woburn, MA]).32 Colloidal osmolalit is anotheractor that varies in articial tearormulations. Whilecrstalloid osmolarit isrelatedtothepresenceoions,colloidalosmolalitis dependentlargelon macromoleculecontent.Colloidal osmolarit,alsoknownasoncotic pressure,isinvolvedinthe controlowatertransportintissues.Dierencesincolloidal 166

osmolalitaectthenetwaterfowacrossmembranes,and waterfowiseliminatedbapplinghdrostaticpressure tothedownsideothewaterfow.Themagnitudeothis osmoticpressureisdeterminedbosmolalitdierences onthetwosidesothemembrane.Epithelialcellsswell due todamageto theircellular membranes ordueto a dsunctioninthepumpingmechanism.Followingthe additionoafuidwithahighcolloidalosmolalittothe damagedcellsurace,deturgescenceoccurs,leadingtoa returnonormalcellphsiolog.Theoreticall,anarticial tearormulationwithahighcolloidalosmolalitmabeo value.HollandEsquivelevaluatedmandierentarticial tearormulationsandshowedthatHpotears ®(Novartis Ophthalmics,EastHanover,NJ)hadthehighestcolloidal osmolalitoallotheormulationstested. 33Formulations withhighercolloidalosmolalithavesincebeenmarketed (Dwelle®[DrEeCompan,Silverdale,WA]). Protectionagainsttheadverseeectsoincreasedosmolarit(osmoprotection)hasledtodevelopmentoOTC dropsincorporatingcompatiblesolutes(suchasglcerin, erthritol,andlevocarnitine(Optive®[AllerganInc.,Irvine, CA]).Itisthoughtthatthecompatiblesolutesdistributebetweenthetearsandtheintracellularfuidstoprotectagainst potentialcellulardamageromhperosmolartears. 34 5. Viscosity Agents Thestabilitothetearlmdependsonthechemicalphsicalcharacteristicsothatlminteractingwiththe conjunctivalandcornealepitheliumviathemembranespanningmucins(ie,MUC-16andMUC-4).Intheclassical three-laeredtearlmmodel,themucinlaerisusuall thoughtoasasuractantorwettingagent,actingtolower thesuracetensionotherelativel hdrophobic ocular surace,renderingthecornealandconjunctivalcells“wet table.”33Currentl,thetearlmisprobablbestdescribed asa hdrated, mucin gel whose mucin concentration decreaseswithdistanceromtheepithelialcellsurace.It mahaveaprotectiverolesimilartothatomucininthe stomach.35Itmaalsoserveasa“sink”orstoragevehicle orsubstancessecretedbthemainandaccessorlacrimal glandsandtheocularsuracecells.Thismaexplainwh mostotheavailablewater-containinglubricantsareonl minimalleective in restoringthe normal homeostasis othe ocular surace.In additionto washing awa and dilutingoutirritatingortoxicsubstancesinthetearlm, articiallubricantshdrategel-ormingmucin.Whilesome patientswithdreehavedecreasedaqueouslacrimalgland secretion,alterationsordecienciesinvolvingmucinalso causedree. Macromolecularcomplexesaddedtoarticiallubricants actasviscositagents.Theadditionoaviscositagentincreasesresidencetime,providingalongerintervalopatient comort.Forexample,whenaviscous,anioniccharged carboxmethl-cellulose(CMC,100,000mw)solutionwas comparedwithaneutralhdroxmethlcellulose(HPMC) solution,CMCwasshowntohaveasignicantlslowerrate oclearanceromtheee. 36Viscousagentsinactivedrug

The Ocular Surace / april 2007, VOl. 5, NO. 2 /  www.tos.om

DEWSMANAGEMENTANDTHERAPy

ormulationsmaalsoprolongocularsuracecontact,increasingthedurationoactionandpenetrationothedrug.  Viscousagentsmaalsoprotecttheocularsurace epithelium.Itisknownthatrosebengalstainsabnormal cornealandconjunctivalepithelialcellsexpressinganalteredmucinglcocalx. 37Agentssuchashdroxmethcellulose(HMC),whichdecreaserosebengalstainingindr eesubjects, 38maeither“coatandprotect”thesurace epitheliumorhelprestoretheprotectiveeectomucins. IntheUS,carboxmethlcelluloseisthemostcommonlusedpolmeric viscositagent(IRIMarket Share Data,Chicago,IL),tpicallinconcentrationsrom0.25% to1%,withdierencesinmolecularweightalsocontributingtonalproductviscosit.Carboxmethlcellulose hasbeenoundtobindtoandberetainedbhumanepithelialcells.39OtherviscositagentsincludedintheFDA monograph(invariousconcentrations)includepolvinl alcohol,polethleneglcol,glcol400,propleneglcol hdroxmethlcelluloseandhdroxproplcellulose. Theblurringovisionandestheticdisadvantagesocakinganddringoneelashesaredrawbacksohighlviscous agentsthatpatientswithmildtomoderatedreewill nottolerate.Lowermolecular-weightviscousagentshelp tominimizetheseproblems.Becausepatientcompliance, comort,andconvenienceareimportantconsiderations,a rangeotearsubstituteormulationswithvaringviscositiesareneeded. Hdroxpropl-guar(HP-guar)hasbeenusedasagellingagentinasolutioncontainingglcol400andpropleneglcol(Sstane®,Alcon,FortWorth,TX).Ithasbeen suggestedthatHP-guarpreerentiallbindstothemore hdrophobic,desiccatedordamagedareasothesurace epithelialcells,providingtemporarprotectionorthese cells. 40,41Severalcommercialpreparationscontainingoilin theormocastoroil(Endura™[AllerganInc.,Irvine,CA]) ormineraloil(Soothe ®[Bausch&Lomb,Rochester,Ny]) arepurportedtoaidinrestoringorincreasingthelipidlaer othetearlm.42,43Haluronicacidisaviscositagentthat hasbeeninvestigatedorearsas an“active”compound addedtotearsubstituteormulationsorthetreatmento dree.Haluronicacid(0.2%)hassignicantllonger ocularsuraceresidence times than 0.3percentHPMC or1.4percentpolvinlalcohol.44Someclinicalstudies reportedimprovementin 44-48dreeinpatientstreated withsodiumhaluronate-containingsolutionscompared tootherlubricantsolutions,whereasothersdidnot. 48  AlthoughlubricantpreparationscontainingsodiumhaluronatehavenotbeenapprovedoruseintheUS,theare requentlusedinsomecountries. 6. Summary  Althoughmantopicallubricants,withvariousviscos itagents,maimprovesmptomsandobjectivendings, thereisnoevidencethatanagentissuperiortoanother. Mostclinicaltrialsinvolvingtopicallubricantpreparations willdocumentsomeimprovement(butnotresolution)o subjectivesmptomsandimprovementinsomeobjective

parameters.4However,theimprovementsnotedarenot necessarilanbetterthanthoseseenwiththevehicleor other nonpreservedarticiallubricants. Theelimination opreservativesandthedevelopmentonewer,lesstoxic preservativeshavemadeocularlubricantsbettertolerated bdreepatients.However,ocularlubricants,which havebeenshowntoprovidesomeprotectionotheocular suraceepitheliumandsomeimprovementinpatientsmptomsandobjectivendings,havenotbeendemonstrated incontrolledclinicaltrialstobe sucienttoresolve the ocularsuracedisorderandinfammationseeninmostdr eesuerers. B. Tear Retetio

1. Punctal Occlusion a. Rationale  Whiletheconceptopermanentloccludingthelacrimalpunctawithcautertotreatdreeextendsback70 ears,49and,althoughtherstdissolvableimplantswere used45earsago,50themoderneraopunctalpluguse beganin1975withthereportbFreeman. 51Freemandescribedtheuseoadumbbell-shapedsiliconeplug,which restsontheopeningothepunctumandextendsintothe canaliculus.Hisreportestablishedaconceptopunctalocclusion,whichopenedtheeldordevelopmentoavariet oremovable,long-lastingplugstoretardtearclearance inanattempttotreattheocularsuraceo patientswith decientaqueoustearproduction.TheFreemanstleplug remainstheprototpeormoststlesopunctalplugs. b. Types Punctalplugsaredividedintotwomaintpes:absorbableandnonabsorbable.Theormeraremadeocollagen orpolmersandlastorvariableperiodsotime(3das to6months).Thelatternonabsorbable“permanent”plugs includetheFreemanstle,whichconsistsoasuracecollar restingonthepunctalopening,aneck,andawiderbase.In contrast,theHerrickplug(Lacrimedics[Eastsound,WA]) isshapedlikeagolteeandisdesignedtoresidewithin thecanaliculus.Itisblueorvisualization;othervariations areradiopaque.AnewldesignedclindricalSmartplug ™ (MedenniumInc [Irvine,CA])expandsandincreasesin diameterinsituollowinginsertionintothecanaliculus duetothermodnamicpropertiesoitshdrophilicacrlic composition. c. ClinicalStudies  Avariet oclinicalstudiesevaluatingtheecaco punctalplugshavebeenreported. 52-56Theseseriesgenerall allintoLevelIIevidence.Theirusehasbeenassociated with objective andsubjective improvementin patients withbothSjogrenandnon-Sjogrenaqueousteardecient dree, lamentar keratitis, contactlens intolerance, Stevens-Johnson disease, severe trachoma, neurotrophic keratopath,post-penetratingkeratoplast,diabetickeratopath,andpost-photoreractivekeratectomorlaserin situkeratomileusis.Severalstudieshavebeenperormed

The Ocular Surace / april 2007, VOl. 5, NO. 2 /  www.tos.om

167

DEWSMANAGEMENTANDTHERAPy

toevaluatetheeectsopunctalplugsontheecaco glaucomamedications in reducingintraocular pressure, andthesestudies have reported confictingresults. 57,58 Benecialoutcomeindreesmptomshasbeenreported in74-86%opatientstreatedwithpunctalplugs.Objective indicesoimprovementreportedwiththeuseopunctal plugsincludeimprovedcornealstaining,prolongedtear lmbreakuptime( TFBUT),decreaseintearosmolarit, andincreaseingobletcelldensit.Overall,theclinicalutilitopunctalplugsinthemanagementodreedisease hasbeenwelldocumented. d. IndicationsandContraindications Inarecentreviewonpunctalplugs,itwasreported thatinamajoreeclinic,punctalplugsareconsidered indicatedinpatientswhoaresmptomaticodrees, haveaSchirmertest(withanesthesia)resultlessthan5 mmat 5 minutes,and show evidenceo ocular surace destaining.56 Contraindicationstotheuseopunctalplugsinclude allergtothematerialsusedintheplugstobeimplanted, punctalectropion,andpre-existingnasolacrimalductobstruction,whichwould,presumabl,negatetheneedor punctalocclusion.Ithasbeensuggestedthatplugsma becontraindicatedindreepatientswithclinicalocular suraceinfammation,becauseocclusionotearoutfow wouldprolongcontactotheabnormaltearscontainingproinfammatorctokineswiththeocularsurace. Treatmentotheocularsuraceinfammationpriorto pluginsertionhasbeenrecommended.Acuteorchronic inectionothelacrimalcanaliculusorlacrimalsacisalso acontraindicationtouseoaplug. e. Complications Themostcommoncomplicationopunctalplugsis spontaneousplugextrusion,whichisparticularlcommon withtheFreeman-stleplugs.Overtime,anextrusionrate o50%hasbeenreported,butmanotheseextrusions tookplaceaterextensiveperiodsoplugresidence.Most extrusions are osmall consequence, exceptor inconvenienceand expense.More troublesomecomplications includeinternalmigrationoaplug,biolmormationand inection,59andpogenicgranulomaormation.Removalo migratedcanalicularplugscanbedicultandmarequire surgertothenasolacrimalductsstem.60,61  f. Summary Theextensiveliteratureontheuseopunctalplugsin themanagementodreediseasehasdocumentedtheir utilit. Severalrecentreports, however, have suggested thatabsorptionotearsbthenasolacrimalductsintosurroundingtissuesandbloodvesselsmaprovideaeedback mechanismtothelacrimalglandregulatingtearproduction.62Inonestud,placementopunctalplugsinpatients withnormaltearproductioncausedasignicantdecrease intearproductionorupto2weeksaterpluginsertion. 63 Thiscautionarnoteshouldbeconsideredwhendeciding 168

whethertoincorporatepunctalocclusionintoadree diseasemanagementplan. 2. Moisture Chamber Spectacles Thewearingomoisture-conservingspectacleshasor manearsbeenadvocatedtoalleviateoculardiscomort associatedwithdree.However,theleveloevidencesupportingitsecacordreetreatmenthasbeenrelativel limited.Tsubota etal, using asensitivemoisturesensor, reportedanincreaseinperiocularhumiditinsubjects wearingsuchspectacles. 64Additionosidepanelstothe spectacleswasshowntourtherincreasethehumidit. 65 Theclinicalecacomoisturechamberspectacleshas beenreportedincasereports.66,67Kurihashiproposeda relatedtreatmentordreepatients,intheormoawet gauzeeemask.68Conversel,Nicholsetalrecentlreportedintheirepidemiologicstudthatspectaclewearerswere twiceaslikelasemmetropestoreportdreedisease. 69 Thereasonorthisobservationwasnotexplained. Therehavebeenseveralreportswithrelativelhigh level oevidence describing therelationship between environmentalhumiditanddree.Korbetalreported thatincreasesinperiocularhumiditcausedasignicant increaseinthicknessothetearlmlipidlaer.70Dree subjectswearingspectaclesshowedsignicantllonger interblinkintervalsthanthosewhodidnotwearspectacles, and duration oblink (blinking time) wassignicantl longerinthelattersubjects.70Instillationoarticialtears causedasignicantincreaseintheinterblinkintervaland adecreaseintheblinkrate.71Maruamaetalreportedthat dreesmptomsworsenedinsotcontactlenswearers whenenvironmentalhumiditdecreased.72 3. Contact Lenses Contact lenses ma help toprotect and hdrate the cornealsuraceinseveredreeconditions.Severaldierentcontactlensmaterialsanddesignshavebeenevaluated, includingsiliconerubberlensesandgaspermeablescleralbearinghardcontactlenseswithorwithoutenestration. 73-77 Improvedvisualacuitandcomort,decreasedcorneal epitheliopath,andhealingopersistentcornealepithelial deectshavebeenreported. 73-77Highloxgen-permeable materialsenableovernightwearinappropriatecircumstances.75Thereisasmallriskocornealvascularization andpossiblecornealinectionassociatedwiththeuseo contactlensesbdreepatients. C. Tear Stimatio: Secretogoges

Severalpotentialtopicalpharmacologic agents ma stimulateaqueous secretion, mucoussecretion, orboth. Theagentscurrentlunderinvestigationbpharmaceuticalcompaniesarediquaosol(oneotheP2y2receptor agonists),rebamipide,gearnate,ecabetsodium(mucous secretionstimulants),and15(S)-HETE(MUC1stimulant).  Amongthem,adiquaosoleedrophasbeenavorabl evaluatedinclinicaltrials.2%diquaosol(INS365,DE-089 [Santen,Osaka,Japan];Inspire[Durham,NC])provedto

The Ocular Surace / april 2007, VOl. 5, NO. 2 /  www.tos.om

DEWSMANAGEMENTANDTHERAPy

beeectiveinthetreatmentodreeinarandomized, double-maskedtrialinhumansto reduceocular surace staining.78Asimilarstuddemonstratedtheocularsaet andtolerabilitodiquaosolinadouble-masked,placebocontrolled,randomizedstud.79Thisagentiscapableo stimulatingbothaqueousandmucoussecretioninanimals andhumans.80-83Benecialeectsoncornealepithelial barrierunction,aswellasincreasedtearsecretion,has beendemonstratedintheratdreemodel.84Diquaosol alsohasbeenshowntostimulatemucinreleaseromgoblet cellsinarabbitdreemodel.85,86 Theeectsorebamipide(OPC-12759[Otsuka,Rockville,MD];Novartis[Basel,Switzerland])havebeenevaluatedinhumanclinicaltrials.Inanimalstudies,rebamipide increasedthemucin-likesubstancesontheocularsurace oN-acetlcsteine-treatedrabbitees. 87ItalsohadhdroxlradicalscavengingeectsonUVB-inducedcorneal damageinmice.88 Ecabetsodium(Senju[Osaka,Japan];ISTA[Irvine, CA])isbeingevaluatedinclinicaltrialsinternationall, butonllimitedresultshaveetbeenpublished.Asingle instillationoecabetsodiumophthalmicsolutionelicited astatisticallsignicantincreaseintearmucinindree patients.89 Gearnate (Santen[Osaka,Japan]) hasbeen evaluated inanimal studies.Gearnate promoted mucin productionaterconjunctivalinjurinmonkes.90GearnateincreasedPAS-positivecelldensitinrabbitconjunctivaand stimulated mucin-like glcoproteinstimulation romratculturedcornealepithelium. 91,92Aninvivorabbit experimentshowedasimilarresult.93,94 The agent15(S)-HETE,a uniquemolecule,can stimulateMUC1 mucin expression on ocular surace epithelium.9515(S)-HETEprotectedthecorneainarabbit modelodesiccation-inducedinjur,probablbecauseo mucinsecretion. 96 Ithasbeen showntohavebenecial eectsonsecretionomucin-likeglcoproteinbtherabbitcornealepithelium.97Otherlaboratorstudiesconrm thestimulatoreecto15(S)-HETE. 98-101Someothese agentsmabecomeuseulclinicaltherapeuticmodalities inthenearuture. Twooralladministeredcholinergicagonists,pilocarpineandcevilemine,havebeenevaluatedinclinicaltrials ortreatmentoSjogrensndromeassociatedkeratocon junctivitissicca(KCS).Patientswhoweretreatedwithpilocarpineatadoseo5mgQIDexperiencedasignicantl greateroverallimprovementthanplacebo-treatedpatients in“ocularproblems”intheirabilittoocustheireesduringreading,andinsmptomsoblurredvisioncompared with placebo-treated patients. 102Themostcommonl reportedsideeectromthismedicationwasexcessive sweating,whichoccurredinover40%opatients.Two percentothepatientstakingpilocarpinewithdrewrom thestudbecauseodrug-relatedsideeects.Otherstudieshavereportedecaco pilocarpineorocularsigns andsmptomsoSjogrensndromeKCS,103-105 including anincreaseinconjunctivalgobletcelldensitater1and 2monthsotherap. 106

Cevilemineisanotheroralcholinergicagonistthat wasoundtosignicantlimprovesmptomsodrness andaqueoustearproductionandocularsuracedisease comparedtoplacebowhentakenindoseso15or30mg TID.107,108Thisagentmahaveeweradversesstemicside eectsthanoralpilocarpine. D. Bioogica Tear Sbstittes

Naturalloccurringbiological,ie,nonpharmaceutical fuids,canbeusedtosubstituteornaturaltears.Theuse oserumorsalivaorthispurposehasbeenreportedin humans.Theareusuallunpreserved.Whenoautologous origin,thelackantigenicitandcontainvariousepitheliotrophicactors,suchasgrowthactors,neurotrophins, vitamins, immunoglobulins,and extracellular matrix proteinsinvolvedinocularsuracemaintenance.Biologicaltearsubstitutesmaintainthemorphologandsupport theprolierationoprimarhumancornealepithelialcells better than pharmaceutical tear substitutes. 109However, despite biomechanical andbiochemicalsimilarities, relevantcompositionaldierencescomparedwithnormal tears exist and are oclinical relevance. 110Additional practicalproblemsconcernsterilitandstabilit,anda labor-intensiveproductionprocessorasurgicalprocedure (saliva)isrequiredtoprovidethenaturaltearsubstituteto theocularsurace. 1. Serum Serumisthefuidcomponentoullbloodthatremains aterclotting.Itstopicaluseorocularsuracediseasewas much stimulated b Tsubota’s prolic work in thelate 1990s.111Thepracticalitiesandpublishedevidenceo autologousserumapplicationwererecentlreviewed. 112 Theuseobloodanditscomponentsasapharmaceuticalpreparationinmancountriesisrestrictedbspecic nationallaws.Toproduceserumeedropsandtouse themoroutpatients,alicensebanappropriatenational bodmaberequiredincertaincountries.Theprotocol usedortheproductionoserumeedropsdetermines theircompositionandecac.Anoptimizedprotocolor theproductionwasrecentlpublished.113Concentrations between20%and100%oserumhavebeenused.The ecacseemstobedose-dependent. Becauseosignicantvariationsinpatientpopulations, productionandstorageregimens,andtreatmentprotocols, theecacoserumeedropsindreeshasvariedsub stantiallbetweenstudies.113Threepublishedprospective randomizedstudieswithsimilarpatientpopulations(predominantlimmunediseaseassociateddree,ie,Sjogren sndrome)areavailable.Whencomparing20%serumwith 0.9%salineapplied6timesperda,Tananuvatetal ound onlatrendtowardimprovementosmptomsandsigns odrees, 114whereasKojimaetalreportedsignicant improvementosmptomscores,fuorescein-breakuptime (FBUT),andfuoresceinandrosebengalstaining.115  Aprospectiveclinicalcross-overtrialcompared50% serumeedropsagainstthecommerciallubricantpreviousl

The Ocular Surace / april 2007, VOl. 5, NO. 2 /  www.tos.om

169

DEWSMANAGEMENTANDTHERAPy

usedbeachpatient.Smptomsimprovedin10out16 patients,andimpressionctologicalndingsimprovedin 12outo25ees. 116Noda-Tsuruaandcolleaguesound that20%autologousserumsignicantlimprovedTFBUT anddecreasedconjunctivalrosebengalandcorneafuoresceinstaining1-3monthspostoperativel,comparedto treatmentwitharticialtears,whichdidnotchangethese parameters.117Additionalreportsosuccessultreatment o persistent epithelial deects—where successis more clearldenedas“healingothedeect”—withautologous serumsubstantiatetheimpressionthatthisis avaluable therapeuticoptionorocularsuracedisease.118 2. Salivary Gland Autotransplantation Salivarsubmandibularglandtransplantationiscapable oreplacingdecientmucinandtheaqueoustearlm phase.Thisprocedurerequirescollaborationbetweenan ophthalmologistandamaxilloacialsurgeon.Withappropriatemicrovascularanastomosis,80%o gratssurvive. Inpatientswithabsoluteaqueous teardecienc,viable submandibular gland grats, in the long-term, provide signicantimprovementoSchirmertestFBUT,androse bengalstaining,aswellasreductionodiscomortandthe needorpharmaceuticaltearsubstitutes.Duetothehpoosmolaritosaliva,comparedtotears,excessivesalivar tearingcaninduceamicrocsticcornealedema,whichis temporar,butcanleadtoepithelialdeects. 110Hence,this operationisindicatedonlinend-stagedreediseasewith anabsoluteaqueousteardecienc(Schirmer-testwetting o1mmorless),aconjunctivalizedsuraceepithelium,and persistentseverepaindespitepunctalocclusionandatleast hourlapplicationounpreservedtearsubstitutes.Forthis groupopatients,suchsurgeriscapableosubstantiall reducingdiscomort,butotenhasnoeectonvision. 119,120 E. Ati-Ifammator Terap

Diseaseordsunctionothetearsecretorglandsleads tochangesintearcomposition,suchashperosmolarit, thatstimulatetheproductionoinfammatormediatorson theocularsurace. 31,121Infammationma,inturn,cause dsunctionordisappearanceocellsresponsibleortear secretionorretention.122Infammationcanalsobeinitiated bchronicirritativestress(eg,contactlenses)andsstemic infammator/autoimmunedisease(eg,rheumatoidarthritis).Regardless otheinitiatingcause,aviciouscircle o infammationcandevelopontheocularsuraceindree thatleadstoocularsuracedisease.Basedontheconcept thatinfammationisakecomponentothepathogenesis odree,theecacoanumberoanti-infammator agentsortreatmentodreediseasehasbeenevaluated inclinicaltrialsandanimalmodels. 1. Cyclosporine Thepotentialocclosporine-A(CsA)ortreatingdr eediseasewasinitiallrecognizedindogsthatdevelop spontaneousKCS. 123ThetherapeuticecacoCsAor humanKCSwasthendocumentedinseveralsmall,single170

center, randomized,double-maskedclinical trials.124,125 CsAemulsionortreatmentoKCSwassubsequentl evaluatedinseverallargemulticenter,randomized,doublemaskedclinicaltrials. InaPhase2clinicaltrial,ourconcentrationsoCsA (0.05%,0.1%,0.2%,or0.4%)administeredtwicedail tobotheeso129patientsor12weekswascompared tovehicletreatmento33patients.126CsAwasoundto signicantldecreaseconjunctivalrosebengalstaining, supercialpunctatekeratitis,andocularirritationsmptoms(sandorgritteeling,drness,anditching)ina subseto90patientswithmoderate-to-severeKCS.There wasnocleardoseresponse;CsA0.1%producedthemost consistentimprovementinobjectiveendpoints,whereas CsA0.05%gavethemostconsistentimprovementinpatientsmptoms(LevelI). TwoindependentPhase3clinicaltrialscompared twice-dailtreatmentwith0.05%or0.1%CsAorvehicle in877patientswithmoderate-to-severedreedisease. 127  WhentheresultsothetwoPhase3trialswerecombined orstatisticalanalsis,patientstreatedwithCsA,0.05%or 0.1%,showedsignicantl(P<0.05)greaterimprovement intwoobjectivesignsodreedisease(cornealfuorescein stainingandanesthetizedSchirmertestvalues)comparedto thosetreatedwithvehicle.AnincreasedSchirmertestscore wasobservedin59%opatientstreatedwithCsA,with 15%opatientshavinganincreaseo10mmormore.In contrast,onl4%ovehicle-treatedpatientshadthismagnitudeochangeintheirSchirmertestscores(P<0.0001). CsA0.05%treatmentalsoproducedsignicantlgreater improvements(P<0.05)inthreesubjectivemeasuresodr eedisease(blurredvisionsmptoms,needorconcomitant articialtears,andtheglobalresponsetotreatment).No dose-responseeectwasnoted.BothdosesoCSAexhibitedanexcellentsaetprolewithnosignicantsstemic orocularadverseevents,exceptortransientburning smptomsaterinstillationin17%opatients.Burningwas reportedin7%opatientsreceivingthevehicle.NoCsAwas detectedinthebloodopatientstreatedwithtopicalCsA or12months.ClinicalimprovementromCsAthatwas observedinthesetrialswasaccompaniedbimprovement inotherdiseaseparameters.Treatedeeshadanapproximatel200%increaseinconjunctivalgobletcelldensit. 128 Furthermore,therewasdecreasedexpressionoimmune activationmarkers(ie,HLA-DR),apoptosismarkers(ie, Fas),andtheinfammatorctokineIL-6btheconjunctivalepithelialcells. 129,130ThenumbersoCD3-,CD4-,and CD8-positiveTlmphoctesintheconjunctivadecreased incclosporine-treatedees,whereasvehicle-treatedees showed an increased number o cells expressing these markers. 131Atertreatmentwith0.05%cclosporine,there wasasignicantdecreaseinthenumberocellsexpressing thelmphocteactivationmarkersCD11aandHLA-DR, indicatinglessactivationolmphoctescomparedwith vehicle-treatedees. Twoadditionalimmunophilins,pimecrolimusandtacrolimus,havebeenevaluatedinclinicaltrialsoKCS.

The Ocular Surace / april 2007, VOl. 5, NO. 2 /  www.tos.om

DEWSMANAGEMENTANDTHERAPy

2. Corticosteroids a. ClinicalStudies Corticosteroids arean eectiveanti-inlammator therapindreedisease.LevelIevidenceispublished oranumberocorticosteroidormulations.Ina4-week, double-masked, randomized stud in 64 patients with KCS and delaed tear clearance, loteprednol etabonate 0.5%ophthalmicsuspension(Lotemax[BauschandLomb, Rochester,Ny]),q.i.d.,wasoundtobemoreeectivethan itsvehicleinimprovingsomesignsandsmptoms.132 Ina4-week,open-label,randomizedstudin32patientswithKCS,patientsreceivingfuorometholoneplus articialtearsubstitutes( ATS)experiencedlowersmptom severitscoresandlowerfuoresceinandrosebengalstainingthanpatientsreceivingeitherATSaloneorATSplus furbiproen. 133  Aprospective,randomizedclinicaltrialcomparedthe severitoocularirritationsmptomsandcornealfuoresceinstainingintwogroupso patients,onetreatedwith topicalnonpreserved methlprednisolone or2 weeks, ollowedbpunctalocclusion(Group1),withagroup thatreceivedpunctalocclusionalone(Group2). 134Ater2 months,80%opatientsinGroup1and33%opatientsin Group2hadcompleterelieoocularirritationsmptoms. Cornealfuoresceinstainingwasnegativein80%oeesin Group1and60%oeesinGroup2ater2months.No steroid-relatedcomplicationswereobservedinthisstud. LevelIIIevidenceisalsoavailabletosupporttheecac ocorticosteroids.Inanopen-label,non-comparativetrial, extemporaneouslormulatednonpreservedmethlprednisolone1%ophthalmicsuspensionwasoundtobeclinicalleectivein21patientswithSjogrensndromeKCS. 135 Inareview,itwasstatedthat“…clinicalimprovemento KCShasbeenobservedatertherapwithanti-infammatoragents,includingcorticosteroids.”136 IntheUSFederalRegulations,ocularcorticosteroids receiving“classlabeling”areindicatedorthetreatment “…osteroidresponsiveinfammatorconditionsothe palpebral andbulbar conjunctiva, cornea andanterior segmentotheglobesuchasallergicconjunctivitis,acne rosacea,supercialpunctatekeratitis,herpeszosterkeratitis,iritis,cclitis,selectedinectiveconjunctivitides,when theinherenthazardosteroiduseisacceptedtoobtainan advisablediminutioninedemaandinfammation.”WeinterpretthatKCSisincludedinthislistosteroid-responsive infammatorconditions.137-140 b. BasicResearch Corticosteroids arethe standard anti-infammator agentornumerousbasicresearchstudiesoinfammation,includingthetpesthatareinvolvedinKCS.The corticosteroidmethlprednisolonewasnotedtopreserve cornealepithelialsmoothnessandbarrierunction inan experimentalmurine model odr ee. 141Thiswasattributedtoitsabilittomaintaintheintegritocorneal epithelialtightjunctionsanddecreasedesquamationo apicalcornealepithelialcells. 142Aconcurrentstudshowed

thatmethlprednislonepreventedanincreaseinMMP-9 protein inthe corneal epithelium, aswell as gelatinase activitinthecornealepitheliumandtearsinresponseto experimentaldree.141 Preparationsotopicallappliedandrogenandestrogensteroid hormones arecurrentl being evaluated inrandomizedclinicaltrials.Atrialotopicallapplied 0.03%testosteronewasreportedtoincreasethepercentageopatientsthathadmeibomianglandsecretionswith normalviscositandtorelievediscomortsmptomsater 6monthsotreatmentcomparedtovehicle. 143TFBUTand lipidlaerthicknesswereobservedtoincreaseinapatient with KCS who was treated with topical androgen or 3 months. 144Tearproductionandocularirritationsmptoms werereportedtoincreaseollowingtreatmentwithtopical 17beta-oestradiolsolutionor4months.145 3. Tetracyclines a. PropertiesofTetracyclinesandTheirDerivatives 1) Antibacterial Properties Theantimicrobialeectooraltetracclinetreatment analogues(eg,minoccline,doxcline)haspreviouslbeen discussedbShineetal,146Doughertetal,147andTaet al.148Itishpothesizedthatadecreaseinbacterialforaproducinglipolticexoenzmes146,148andinhibitionolipase production 147withresultantdecreaseinmeibomianlipid breakdownproducts 146macontributetoimprovementin clinicalparametersindree-associateddiseases. 2) Anti-Infammatory Properties The tetracclines have anti-infammator as wellas antibacterial properties that mamakethem useul or themanagementochronicinfammatordiseases.These agentsdecreasetheactivitocollagenase,phospholipase  A2,andseveralmatrixmetalloproteinases,andthedecreasethe productiono interleukin( IL)-1andtumor necrosisactor(TNF)-alphainawiderangeotissues, includingthecornealepithelium. 149-151Athighconcentrations,tetracclinesinhibitstaphlococcalexotoxin-induced ctokinesandchemokines.152,153 3) Anti-angiogenic Properties  Angiogenesis,theormationonewbloodvessels,occursinmandiseases.Theseincludebenignconditions(eg, rosacea)andmalignantprocesses(eg,cancer).Minoccline anddoxcclineinhibitangiogenesisinducedbimplanted tumorsinrabbitcornea.154Theanti-angiogeniceecto tetracclinemahavetherapeuticimplicationsininfammatorprocessesaccompaniedbnewbloodvesselormation.  Well-controlledstudiesmustbeperormed,atboththe laboratorandclinicallevels,toinvestigatethispotential. 155 b. ClinicalApplicationsofTetracycline 1) Acne Rosacea Rosacea,includingitsocularmaniestations,isaninfammatordisorder,occurringmainlinadults,withpeak severitinthethirdandourthdecades.Currentrecom-

The Ocular Surace / april 2007, VOl. 5, NO. 2 /  www.tos.om

171

DEWSMANAGEMENTANDTHERAPy

mendationsaretotreatrosaceawithlong-termdoxccline, minoccline,tetraccline,orerthromcin. 156Theserecommendationsmabetemperedbcertainrecentreportsthat inwomen,theriskodevelopingbreastcancerandobreast cancermorbiditincreasescumulativelwithdurationo antibioticuse,includingtetracclines.157,158 Anotherlarge studdidnotsubstantiatethesendings.159 Tetracclinesand their analoguesareeective inthe treatmentoocularrosacea,160,161orwhichasingledail doseodoxcclinemabeeective. 162Inadditiontothe anti-infammatoreects otetracclines,their abilitto inhibitangiogenesismacontributetotheireectivenessin rosacea-relateddisorders.Factorsthatpromoteangiogenesisincludeprotease-triggeredreleaseoangiogenicactors storedintheextracellularmatrix,inactivationoendothelial growthactorinhibitors,andreleaseoangiogenicactors romactivatedmacrophages.155,163 Tetracclinesarealsoknowntoinhibitmatrixmetalloproteinaseexpression,suggestingarationaleortheiruse inocularrosacea.164Althoughtetracclineshavebeenused ormanagementothisdisease,norandomized,placebocontrolled,clinicaltrialshavebeenperormedtoassess theirecac.153 2) Chronic Posterior Blepharitis: Meibomianitis, Meibomian Gland Dysunction Chronicblepharitisistpicallcharacterizedbinfammationotheeelids.Therearemultipleormsochronic blepharitis,includingstaphlococcal, seborrheic(alone, mixedseborrheic/staphlococcal, seborrheicwithmeibomian seborrhea, seborrheic with secondarmeibomitis), primarmeibomitis,andothers,likeatopic,psoriatic,and ungalinections.165Meibomianglanddsunction(MGD) hasbeenassociatedwithapparentaqueous-decientdr ee.Useotetracclineinpatientswithmeibomianitishas beenshowntodecreaselipaseproductionbtetracclinesensitiveaswellasresistantstrainsostaphlococci.This decreaseinlipaseproductionwasassociatedwithclinical improvement.147Similarl,minocclinehasbeenshownto decreasetheproductionodiglceridesandreeattacidsin meibomiansecretions.Thismabeduetolipaseinhibition btheantibioticoradirecteectontheocularfora. 146One randomized,controlledclinicaltrialotetracclineinocular rosaceacomparedsmptomimprovementin24patients treatedwitheithertetracclineordoxccline. 166Allbutone patientreportedanimprovementinsmptomsater6weeks otherap.Noplacebogroupwasincludedinthistrial.  A prospective,randomized, double-blind, placebocontrolled,partialcrossovertrialcomparedtheeecto oxtetracclinetoprovidesmptomaticrelieoblepharitis withorwithoutrosacea.Onl25%othepatientswith blepharitis without rosacearesponded to theantibiotic, whereas50%respondedwhenbothdiseaseswerepresent.167Inanothertrialo10patientswithbothacnerosaceaandconcomitantmeibomianitis,acnerosaceawithout concomitantocularinvolvement,orseborrheicblepharitis, minoccline50mgdailor2weeksollowedb100mg 172

dailoratotalo3monthssignicantldecreasedbacterialfora(P=0.0013).Clinicalimprovementwasseenin allpatientswithmeibomianitis.148 Becauseotheimprovementobservedinsmallclinical trialsopatientswithmeibomianitis,theAmericanAcademoOphthalmologrecommendsthechronicuseo eitherdoxcclineortetracclineorthemanagemento meibomianitis.165 Larger randomized placebo-controlled trialsassessingsmptomimprovementratherthansurrogatemarkersareneededtoclaritheroleothisantibiotic inblepharitistreatment. 153Tetracclinederivatives(eg, minoccline, doxccline)have been recommended as treatmentoptionsorchronicblepharitisbecauseotheir highconcentrationintissues,lowrenalclearance,longhallie,highlevelobindingtoserumproteins,anddecreased riskophotosensitization.168 Severalstudieshavedescribedthebenecialeectso minocclineandothertetracclinederivatives(eg,doxccline)inthetreatmentochronicblepharitis. 146,147,168,169 Studieshaveshownsignicantchangesintheaqueoustear parameters,suchastearvolumeandtearfow,ollowing treatmentwithtetracclinederivatives(eg,minoccline). Onestudalsodemonstratedadecreaseinaqueoustearproductionthatoccurredalongwithclinicalimprovement. 170  A recentlpublished randomized, prospectivestud byooSeetal compareddierentdoxcclinedosesin 150patients(300ees)whohadchronicmeibomiangland dsunctionandwhodidnotrespondtolidhgieneand topicaltherapormorethan2months. 171Alltopical therapwasstoppedoratleast2weekspriortobeginningthestud.AterdeterminingtheTFBUTandSchirmer testscores,patientsweredividedintothreegroups:ahigh dosegroup(doxccline,200mg,twiceada),alowdose group(doxccline,20mg,twiceada)andacontrolgroup (placebo).Ateronemonth,TFBUT,Schirmerscores,and smptomsimproved.Boththehigh-andlow-dosegroups hadstatisticall signicant improvementin TFBUTater treatment. Thisimpliesthat low-dose doxccline (20 mgtwiceada)therapmabeeectiveinpatientswith chronicmeibomianglanddsunction. 3) Dosage and Saety Sstemicadministrationotetracclinesiswidelrecog nizedortheabilittosuppressinfammationandimprove smptomsomeibomianitis. 172,173 Theoptimaldosing schedulehasnotbeenestablished;however,a varieto doseregimenshavebeenproposedincluding50or100mg doxcclineonceada,174oraninitialdoseo50mgada ortherst2weeksollowedb100mgadaoraperiod o2.5months,inanintermittentashion.146-148,170 Others haveproposeduseoalowdoseodoxccline(20mg) ortreatmentochronicblepharitisonalong-termbasis. 171 Thesaetissuesassociatedwithlong-termoraltetraccline therap,includingminoccline,arewellknown.Man managementapproacheshavebeensuggestedortheuseo tetracclineanditsderivatives;however,asaebutadequate optioninmanagementneedstobeconsideredbecauseo

The Ocular Surace / april 2007, VOl. 5, NO. 2 /  www.tos.om

DEWSMANAGEMENTANDTHERAPy

Tabe 2. Dry eye severity grading scheme Dr Ee Severit leve

1

2

3

4*

Discomort, severity & requency

Mild and/or episodic occurs under environ stress

Moderate episodic or chronic, stress or no stress

Severe requent or constant without stress

Severe and/or disabling and constant

Visual symptoms

None or episodic mild atigue

Annoying and/or activity limiting episodic

Annoying, chronic and/ or constant limiting activity

Constant and/or possibly disabling

Conjunctival injection

None to mild

None to mild

+/–

+/++

Conjunctival staining

None to mild

Variable

Moderate to marked

Marked

Corneal staining (severity/location)

None to mild

Variable

Marked central

Severe punctate erosions

Corneal/tear signs

None to mild

Mild debris, ↓ meniscus

Filamentary keratitis, mucus clumping, ↑ tear debris

Filamentary keratitis, mucus clumping, ↑ tear debris, ulceration

Lid/meibomian glands

MGD variably present

MGD variably present

Frequent

Trichiasis, keratinization, symblepharon

TFBUT (sec)

Variable

≤ 10

≤5

Immediate

Schirmer score (mm/5 min)

Variable

≤ 10

≤5

≤2

*Must have signs AND symptoms. TBUT: fuorescein tear break-up time. MGD: meibomian gland disease Reprinted with permission rom Behrens A, Doyle JJ, Stern L, et al. Dysunctional tear syndrome. A Delphi approach to treatment recommendations. Cornea 2006;25:90-7

thenewinormationregardingthepotentiallhazardous eectsoprolongeduseooralantibiotics.Arecentstud suggestedthata3-monthcourseo100mgominoccline mightbesucienttobringsignicantmeibomianitisunder control,ascontinuedcontrolwasmaintainedoratleast3 monthsatercessationotherap. 170 Inanexperimentalmurinemodelodree,topicall applieddoxcclinewasoundtopreservecornealepithelialsmoothnessandbarrierunction. 141Italsopreserved theintegritocornealepithelialtightjunctionsindrees, leadingtoamarkeddecreaseinapicalcornealepithelialcell desquamation. 142ThiscorrespondedtoadecreaseinMMP9proteininthecornealepitheliumandreducedgelatinase activitinthecornealepitheliumandtears.141 F. Essetia Fatt Acids

Essentialattacidsarenecessarorcompletehealth. Thecannotbesnthesizedbvertebratesandmustbe obtainedromdietarsources.Amongtheessentialatt acidsare18carbonomega-6andomega-3attacids.In thetpicalwesterndiet,20-25timesmoreomega-6than omega-3attacidsareconsumed.Omega-6attacidsare precursorsorarachidonicacidandcertainproinfammatorlipidmediators(PGE2andLTB4).Incontrast,certain omega-3attacids(eg,EPAoundinshoil)inhibitthe snthesisotheselipidmediatorsandblockproductiono IL-1andTNF-alpha.175,176  Abenecialclinicaleectoshoilomega-3attacidsonrheumatoidarthritishasbeenobservedinseveral

double-masked,placebo-controlledclinicaltrials.177,178Ina prospective,placebo-controlledclinicaltrialotheessential attacids,linoleicacidandgamma-linolenicacidadministeredoralltwicedailproducedsignicantimprovement inocularirritationsmptomsandocularsuracelissamine greenstaining.179DecreasedconjunctivalHLA-DRstaining alsowasobserved. G. Evirometa Strategies

Factorsthatmadecreasetearproductionorincrease tearevaporation,suchastheuseosstemicanticholinergicmedications(eg,antihistaminesandantidepressants) anddesiccatingenvironmentalstresses(eg,lowhumiditand airconditioning drats)should be minimized oreliminated. 180-182Videodisplaterminalsshouldbe loweredbeloweeleveltodecreasetheinterpalpebral aperture,andpatientsshouldbeencouragedtotakeperiodicbreakswitheeclosurewhenreadingorworking onacomputer. 183Ahumidiedenvironmentisrecommendedtoreducetearevaporation.Thisisparticularl benecialindrclimatesandhighaltitudes.Nocturnal lagophthalmoscanbetreatedbwearingswimgoggles, tapingtheeelidclosed,ortarsorrhap. IV. TREATMEnT RECOMMEnDATIOnS

Inadditiontomaterialpresentedabove,thesubcommitteemembersreviewedtheDrEePreerredPractice PatternsotheAmericanAcademoOphthalmologand theInternationalTaskForce(ITF)DelphiPanelondr

The Ocular Surace / april 2007, VOl. 5, NO. 2 /  www.tos.om

173

DEWSMANAGEMENTANDTHERAPy

Tabe 3. Dry eye menu o treatments Articial tears substitutes Gels/Ointments Moisture chamber spectacles Anti-infammatory agents (topical CsA and corticosteroids, omega-3 atty acids)

leve 1: Education and environmental/dietary modications Elimination o oending systemic medications Articial tear substitutes, gels/ointments Eye lid therapy leve 2: If Level 1 treatments are inadequate, add: Anti-infammatories Tetracyclines (or meibomianitis, rosacea) Punctal plugs Secretogogues Moisture chamber spectacles

Tetracyclines Plugs Secretogogues Serum Contact lenses Systemic immunosuppressives Surgery (AMT, lid surgery. tarsorrhaphy, MM & SG transplant) AMT = amniotic membrane transplantation; MM = mucous membrane; SG = salivary gland

eetreatmentpriortoormulatingtheirtreatmentguidelines.184,185 Thegroupavoredtheapproachtakenbthe ITF,which basedtreatmentrecommendationson disease severit.AmodicationotheITFseveritgradingscheme thatcontains4levelsodiseaseseveritbasedonsignsand smptomswas ormulated (Table2). Thesubcommittee memberschosetreatmentsoreachseveritlevelroma menuotherapiesorwhichevidenceotherapeuticeect hasbeenpresented(Table3).ThetreatmentrecommendationsbseveritlevelarepresentedinTable4.Itshould benotedthattheserecommendationsmabemodied bpractitionersbasedonindividualpatientprolesand clinicalexperience.Thetherapeuticrecommendationsor level4severitdiseaseincludesurgicalmodalitiestotreat orpreventsight-threateningcornealcomplications.Discussionothesetherapiesisbeondthescopeothisreport. V. unAnSWERED QuESTIOnS AnD FuTuRE DIRECTIOnS

Therehavebeentremendous advances inthe treatmentodreeandocularsuracediseaseinthelasttwo decades,includingFDAapprovalocclosporinemulsion asthersttherapeuticagentortreatmentoKCSinthe UnitedStates.Therehasbeenacommensurateincreasein knowledgeregardingthepathophsiologodree.This hasledtoaparadigmshitindreemanagementrom simpllubricatingandhdratingtheocularsuracewith articialtearstostrategiesthatstimulatenaturalproductionotearconstituents,maintainocularsuraceepithelial healthandbarrierunction,andinhibittheinfammator actorsthatadverselimpacttheabilitoocularsurace andglandularepitheliatoproducetears.Preliminarexperienceusingthisnewtherapeuticapproachsuggeststhat qualitoliecanbeimprovedormanpatientswithdr eeandthatinitiatingthesestrategiesearlinthecourseo thediseasemapreventpotentiallblindingcomplications odree.Itislikelthatuturetherapieswillocuson 174

Tabe 4. Treatment recommendations by severity level

leve 3: If Level 2 treatments are inadequate, add: Serum Contact lenses Permanent punctal occlusion leve 4: If Level 3 treatments are inadequate, add: Systemic anti-infammatory agents Surgery (lid surgery, tarsorrhaphy; mucus membrane, salivary gland, amniotic membrane transplantation) Modied rom: International Task Force Guidelines or Dr y Eye 185

replacingspecictearactorsthathaveanessentialrolein maintainingocularsuracehomeostasisorinhibitingke infammatormediatorsthat causedeathor dsunction otearsecretingcells.Thiswillrequireadditionalresearch toidentithesekeactorsandbetterdiagnosticteststo accuratelmeasuretheirconcentrationsinminutetear fuidsamples.Furthermore,certaindiseaseparameters mabeidentiedthatwillidentiwhetherapatienthas ahigh probabilito respondingto aparticulartherap. Basedontheprogressthathasbeenmadeandthenumber otherapiesinthepipeline,theutureodreetherap seemsbright. REFEREnCES (Parenthetical codes following references indicate level of evidence, as described in Table 1. CS = Clinical Study; BS = Basic Science.) 1. Gbd Jp, ross Sr, hyd KG. Otm sotons, t o s, nd  nq tt t t omton.  Am J Ophthalmol 1989;107:348-55 (BS1) 2. Gbd Jp. hmn t m toyt onnttons n t nd dyy dss. Int Ophthalmol Clin 1994;34:27-36 (CS2) 3. Sn O, Ts J, Mnoz B, t . rton btwn sgns nd symtoms o dy y n t dy. Ophthalmology 1997;104:1395-1400 (CS2) 4. Nson JD, Godon J. To bontn n t ttmnt o ktoon jntvts s. con Ktoonjntvts S Stdy Go. Am J  Ophthalmol 1992;114:441-7 (CS2) 5. Nson JD. imsson ytoogy. Cornea 1988;7:71-81 (BS1) 6. ubs J, Mctny M, lntz W, t . ets o svtv- t t sotons on on t stt nd nton. Arch Ophthalmol 1995;113:371-8 (BS1) 7. Gn K, MKn Dl, Sg T, cks l. T otssm ontbts to mntnn o on tknss. Ophthalmic Res 1992;24:99-102 (BS1)

The Ocular Surace / april 2007, VOl. 5, NO. 2 /  www.tos.om

DEWSMANAGEMENTANDTHERAPy 8. hoy , lm M. S msty o t t m: imtons o dy y syndoms, ontt nss, nd otm oyms. Contact Lens Soc Am J 1971;5:12-9 (BS2) 9. pgn DM, Mogn a, Qnto S, t . comson o osmoty vs o std o bnts. arVO 2004 ost ssson 449 10. Kmn B, Novk GD. comn sss n mntng o dgs. Ocul Surf 2003;1:80-5 11. abtz J, B a. T onjntv tm n dy y sbtys: et o svd nd nonsvd to ttmnts. Curr Eye Res 2001;22:8-18 (CS2) 12. Gsst ar, is Y, Kmn h, M T. cytotoxty o otm svtvs. Am J Ophthalmol 1974;78:98-105 (BS1) 13. Wson . advs xtn ts o to otm mdtons.Surv Ophthalmol 1979;24:57-88 (CS3) 14. Bstn N. con ytotoxty o toy d dgs, vs nd svtvs. Surv Ophthalmol 1980;25:15-30 (CS3) 15. Bstn N. T ts o to dgs nd svtvs on t ts nd on tm n dy y. Trans Ophthalmol Soc UK. 1985;104:402-9 (CS3) 16. Bbk r, Mln J. uss o t foootomt n gom s. Ophthalmology 1985;92:884-90 (BS1) 17. Smt l, Gog M, Bdy G, abson M. comtv ts o svtv  t sbsttts on t bbt on:  snnng ton moso vton ( ARVObstt). Invest Ophthalmol Vis Sci 1991;32 (S):733 (BS1) 18. Gbd Jp, s rl, Sntm J 2nd. Osmoty o t movoms n ktoonjntvts s. Arch Ophthalmol 1978;96:677-81 (BS2) 19. loz Bn D, ubs Jl. Qntttv vton o t on t b: t o t ts nd svtvs.Curr Eye Res 1991;10:64556 (BS1) 20. Bn Dl, ubs Jl. at t omoston nd omoton o ovy o t dmgd on tm. Cornea 1993;12:115-20 (BS1) 21. Nok r: ets o ommon otm svtvs on o t.  Adv Ther 2001;18:205-15 (CS1) 22. Tt BJ, Tt rc, Ko Sp: cytotoxty o otm svtvs on mn on tm. Lens Eye Toxicity Res 1992;9:361-75 (BS1) 23. hm J, dnwd J. rtdton o wond ng n t on tm by non. Am J Ophthalmol 1950;33:1421 (CS3) 24. Nson J, Dk M, Bw J, Ty M. evton o ysoog t sbsttt n tnts wt ktoonjntvts s. Adv Exp Med Biol 1994;350:453-7 (CS2) 25. Gbd Jp, ross Sr. an toyt-bsd soton tt nss on gyogn nd onjntv gobt- dnsty n  bbt mod o ktoonjntvts s. Ophthalmology 1992;99:600-4 (BS1) 26. lnton lM, abtz JM: et o mos-bsd t ts on t o s n ys t s n st ktomss. J Refract Surg 1999;15(2 S):S227-S231 (CS2) 27. Somny Bl, Somny a. ro o ms n gst mos otton.  J Physiol Pharmacol 1991; 42:147-61 (BS1) 28. Gbd Jp. T m osmoty nd ktoonjntvts s. CLAO J  1985;11:243-50 (CS1) 29. Gbd J. T m osmoty nd ktoonjntvts s. lbbok TX,Dy ey insttt, 1986 (CS3) 30. Gbd J, ct J, Sng D, t . Mooog t o yosmoty on bbt on tm. Ophthalmology 1984;91:1205-12 (BS1) 31. lo l, l D, cos r, pfgd S. hyosmo sn s  onfmmtoy stss on t mos o s. Eye Contact Lens 2005;31:18693 (BS1) 32. Gbd Jp, Knyon Kr. T dnts n t ttmnt o ktoonjntvts s. Ophthalmology 1985;92:646-50 (CS2) 33. hoy , esqv e. cood osmot ss o t ts. J Ocul Pharmacol 1985;1:327-36 (BS1) 34. Yny ph: Ogn osmoyts s omtb, mtbo nd onttng yoottnts n g osmoty nd ot stsss .J Exp Biol 2005;208:2819-30 (BS2) 35. hoy , lm M. Wttbty nd wttng o on tm. Exp Eye Res 1971;11:239-50 (BS1) 36. hw a, Smt T, Dgns G. a qntttv omson o t t n ts n mns sng gmm sntgy (arVO bstt). Invest Ophthalmol Vis Sci 1990;31 (S):517 (BS1) 37. agso p, Tsd a, S-Md S, t . Mn tsts o mn on-mb t s tt xd t os bng non dy. Invest Ophthalmol Vis Sci 2006;47:113-9 (BS1) 38. Vs p, Mto M, St , t . Dy y bo nd t ty

wt ydoxyoymtyos. Ophthalmologica 1989;198:152-62 (CS3) 39. Smmons pa, Gtt Q, X S, t . intton o boxymtyos wt mn on s. arVO2006, e-abstt 2759 (BS1) 40. cstnsn M, con S, rnt J,t . cn vton o n hpg gb bnt y do o t  o dynss o t y. Curr  Eye Res 2004;28:55-62 (CS2) 41. D ps Ma, Goto e, Tsng Sc. Sqnt ngs o d t m t t nstton o  sng do o  nw mson y do n dy y tnts. Ophthalmology 2004;111:783-91 (CS2) 42. Kob Dr, Sd rc, Gn JV, t . T t o two nov bnt y dos on t m d y tknss n sbjts wt dy y symtoms. Optom Vis Sci 2005;82:594-601 (CS2) 43. Snbson Gr, Gvs Jl, So ND, t . pon sdn tms o  sodm yont sotons stdd by qntttv gmm sntgy. Eye 1990;4:594-602 (CS3) 44. pok , MN M. T ttmnt o dy ys wt Na yont (hon). Cornea 1982;1:1333 (CS3) 45. Stt Jc, lnn JG. Dt sodm yont (hon) n t ttmnt o o s dsods. Ann Ophthalmol 1985;17:190-2 (CS3) 46. Dls V, ptson W. T s o to hon ts n t mngmnt o toy dy-y syndom. Ann Ophthalmol 1984;16:823-4 (CS3) 47. Snd B, Mn K, Non M. Sodm yont n t ttmnt o  ktoonjtvts s. Acta Ophthalmol 1989; 67:181-3 (CS3) 48. Nson JD, s rl. Sodm yont nd oyvny oo t t tons  omson n tnts wt ktoonjntvts s.  Arch Ophthalmol 1988;106:484-7 (CS2) 49. Btm Wp. mnty ktts. Trans Am Ophthalmol Soc 1936:33:41335 (CS1) 50. ods WS. intn gtn mnts n t ttmnt o ktoonjntvts s. Br J Ophthalmol 1961:45:625-7 (CS2) 51. mn JM. T ntm g: vton o  nw ttmnt o t dy y. Trans Am Acad Ophthalmol Otolaryngol 1975:79:Op874-9 (CS2) 52. Tbv aW, dk Wr, Wood TO. pnt oson n t dny syndoms. Ophthalmology 1982;89:1170-2 (CS2) 53. Ws rM, obg r, Km Jh, t . T ttmnt o qos-dnt dy y wt movb nt gs. a n nd mssonytoog stdy. Ophthalmology 1987;94:514-8 (CS2) 54. Gbd Jp, ross Sr, az DT, Gy Kl. et o nt oson by mn son g nston on t osmoty n dy y dsods. CLAO J 1989;15:216-8 (CS2) 55. Bm M, Smbg Da, Dn Mr. ey nd tobty otoms t nt oson wt son gs n dy y syndom. Am J  Ophthalmol 2001;131:30-6 (CS1) 56. Bxt Sa, lbson pr. pnt gs n t mngmnt o dy ysOcul Surf 2004;2:255-65 (CS3) 57. Bttt JD, Bon K, coss D, Gdd iB. ey o son nt gs s djnts to to moty o gom-- ot stdy. pnt pgs n Gom Stdy Go. J Am Optom Assoc 1996;67:664-8 (CS2) 58. hng Tc, l Da. pnt oson nd to mdtons o gom. Am J Ophthalmol 1989;107:151-5 (CS2) 59. Sgt J, Yoko N, wood NJ, t . T dtton o bt nd bt boms n nt g os. Cornea 2001;20: 362-5 (CS3) 60. Gdng h, Ks J, Bss h. Symtomt tz oson o  n t nston o hk m gs. Am J Ophthalmol 2003;136:926-8 (CS3) 61. l J, ngn Jc. comtons ssotd wt son ntn gs. Ophthal Plast Reconstr Surg 2001;17:465-9 (CS3) 62. psn . T mn m gnds.   Adv Anat Embryol Cell Biol 2003;170:iii-Xi,1-106 (BS1) 63. Yn MT, pfgd Sc,  WJ. T t o nt oson on t odton, t n, nd o s snston n nom sbjts. Am J Ophthalmol 2001;131:314-23 (CS2) 64. Tsbot K. T t o wng sts on t mdty o t y.  Am J Ophthalmol 1989;15;108:92-3 (BS2) 65. Tsbot K, Ymd M, uym K. St sd ns nd most nsts o t ttmnt o dy-y tnts. Cornea 1994;13:197-201 (BS1) 66. Gsst J, Smont p, Godon D. combnton o  sd sd wt n o most mb. Am J Optom Physiol Opt 1984;61:610-2 (CS3) 67. Sv De. a nw o to o most mbs. J Pediatr Ophthalmol Strabismus 1978;15:51-3 (CS3) 68. Ks K. Most d dng s o t ttmnt o dy y: wt gz y msk. Ophthalmologica 1994;208:216-9 (CS3) 69. Nos JJ, Zg c, Mt Gl, Nos KK. S-otd dy y ds-

The Ocular Surace / april 2007, VOl. 5, NO. 2 /  www.tos.om

175

DEWSMANAGEMENTANDTHERAPy s oss tv modts. Invest Ophthalmol Vis Sci 2005;46:1911-4 (CS2) 70. Kob Dr, Gn JV, Gonk T, t . et o o mdty on t t m d y. Cornea 1996;15:129-34 (BS2) 71. Tsbot K, ht S, Oksw Y, t . Qntttv vdog nyss o bnkng n nom sbjts nd tnts wt dy y. Arch Ophthalmol 1996;114:715-20 (BS1) 72. Mym K, Yoko N, Tkmt a, Knost S. et o nvonmnt ondtons on t dynms n sot ontt ns ws.Invest Ophthalmol Vis Sci 2004;45:2563-8 (BS1) 73. Bon aS, astn c, Dt JK. Son bb ontt nss o t omomsd on. Cornea 1994;13:422-8 (CS3) 74. pm KW, Wtng Ma, Bky rJ. S ontt nss: t xndng o. Cornea 2005;24:269-77 (CS3) 75. Tn MJ, pm KW, Bky rJ. S ontt nss o ovngt w n t mngmnt o o s dsods. Eye 2001;15(pt 2):168-72 (CS3) 76. romo-rng T, Stvo p, cott J, t . Gs-mb s ontt ns ty n o s dss. Am J Ophthalmol 2000;130:25-32 (CS3) 77. rosnt p, cott JM, Bm J. Ttmnt o sstnt on t dt wt xtndd w o  fd-vnttd gs-mb s ontt ns. Am J Ophthalmol 2000;130:33-41 (CS3) 78. Tb J, Dvtt W, Bokosky Je, t . Dob-mskd, bo-ontod sty nd y t o dqoso ttsodm (iNS365) otm soton o t ttmnt o dy y. Cornea 2004;23:784-92 (CS1) 79. Mndsd MV, Novk GD, agood Ve, t . O sty o iNS365 otm soton:  p2Y(2) gonst n ty sbjts. J Ocul Pharmacol Ther 2001;17:173-9 (CS1) 80. Mkm T, j T, hob Y, Nkm M. Dqoso ts nss n nt c- tnsot tog p2Y2 to stmton n bbt onjntv. Ophthalmic Res 2004;36:89-93 (BS1) 81. l DQ, loksw Bl, Soomon a, t . rgton o MMp-9 n mn on t s. Exp Eye Res 2001;73:449-59 (BS1) 82. Mkm T, jt h, j T, t . Nov nonnvsv snstv dtmnton o t vom ngs n nom ts. Ophthalmic Res 2002;34:371-4 (BS1) 83. Yx Br, Mndsd M, Syvst rN, t . O sty o iNS365 otm soton,  p2Y2 gonst, n tnts wt md to modt dy y dss. Adv Exp Med Biol 2002;506(pt B):1251-7 (BS2) 84. j T, Mkm T, jt h, t . imovmnt o on b nton by t p2Y(2) gonst iNS365 n  t dy y mod. Invest Ophthalmol Vis Sci 2001;42:96-100 (BS1) 85. j T, Mkm T, Ngno T, t . iNS365 ssss oss o  on t ntgty by ston o mn-k gyootn n  bbt sot-tm dy y mod. J Ocul Pharmacol Ther 2002;18:363-70 (BS1) 86. Yx Br, Dogss JG, en pp, t . potny nd dton o ton o  syntt p2Y2 to gonsts on Sm sos n bbts Adv Exp Med Biol 2002;506(pt a):261-5 (BS2) 87. usm h, Okmoto T, Tkj Y, t . rbmd nss t mont o mn-k sbstns on t onjntv nd on n t N-tyystn-ttd n vvo mod. Cornea 2004;23:613-9 (BS1) 88. Tnto M, Tkns T, Kdz S, t . cytoottv ts o bmd nd too ydood gnst tvot B-ndd on dmg n m. Invest Ophthalmol Vis Sci 2003; 44:2980-5 (BS3) 89. Msd K, Toksg h, Ogw T, t . et o to bt sodm on mn vs n t t fd o tnts wt dy y. Seri-arVO2003. 90. Tosd h, Nkt K, hmno T, t . et o gnt on t o s n sq monkys Cornea 2002;21:292-9 (BS3) 91. Nkm M, endo K, Nkt K, hmno T. Gnt nss paS ostv  dnsty n bbt onjntv. Br J Ophthalmol 1998;82:1320-3 (BS3) 92. Nkm M, endo K, Nkt K, hmno T. Gnt stmts ston o mn-k gyootns by on tm n vto nd otts on tm om dston n vvo.Exp Eye Res 1997;65:569-74 (BS3) 93. Tosd h, Nkt K, hmno T, t . Gnt stmts gobt  oton oowng n xmnt wond to t ts onjntv n t dy y bbt. Adv Exp Med Biol 2002;506(pt a):353-7 (BS 3) 94. hmno T. Dy y ttmnt wt y dos tt stmt mn odton. Adv Exp Med Biol 1998;438:965-8 (CS3) 95. Jmbtt Je, cnnngm l, Jmbtt MM. ets o 15(S)-heTe on mn onjntv mn ston.  Adv Exp Med Biol 2002;506(pt a):323-7 (BS1) 176

96. Gm Da, W ZY, Wm lK, t . con otton by t o mn stgog 15(S)-heTe n  bbt mod o dston-ndd on dt. J Ocul Pharmacol Ther 2002;18:349-61 (BS2) 97. Jkson rS 2nd, Vn Dykn SJ, Mctny MD, ubs Jl. T osnod, 15-(S)-heTe, stmts ston o mn-k gyootn by t on tm Cornea 2001;20:516-21 (BS2) 98. az rG, eds h. evton o t ts o 15(S)-heTe on on t s: n toysoog nd ytom stdy.  Adv Exp Med Biol 2002; 506(pt a):329-33 (BS3) 99. ubs Jl, a MD, Jkson rS 2nd, t . Toy d 15-(S)heTe stmts mn odton by on tm. Adv Exp Med Biol 2002;506(pt a):317-21 (BS2) 100. Gm Da, W ZY, Wm lK, t . psvton o on ntgty by t mn stgog 15(S)-heTe n  bbt mod o dstonndd dy y. Adv Exp Med Biol 2002;506(pt a):335-40 (BS2) 101. Jmbtt Je, cnnngm lT, l Y, Jmbtt MM. ctzton o mn o mn ston mdtd by 15(S)-heTe. Cornea 2002;21:818-24 (BS3) 102. Vvno B, a-hsm i, Kn K, t . pon tbts o t ttmnt o dy mot nd dy y symtoms n tnts wt Sjogn’s syndom.  Arch Intern Med 1999;159:174-81 (CS1) 103. Tky M, ikw Y, Ymd c, t . Ttmnt wt on ydood o s symtoms n Sjogn’s syndom. Ryumachi 1997;37:453-7 (CS2) 104. Tstk N, Ktsos G, psds ca, t . O on o t ttmnt o o symtoms n tnts wt Sjogn’s syndom:  ndomsd 12-wk ontod stdy. Ann Rheum Dis 2003;62:1204-7 (CS2) 105. ps aS, S YS, cny M, t . Sss ttmnt o dy mot nd dy y symtoms n Sjogn’s syndom tnts wt o on: a ndomzd, bo-ontod, dos-djstmnt stdy.J  Clin Rheumatol 2004;4:169-77 (CS1) 106. agon p, D pto r, Sn r, Mob M. conjntv tm movmnt t systm on n tnts wt Sjogn’s syndom. Br J Ophthalmol 2006;90:166-70 (CS2) 107. pton D, condm JJ,  r, t . Dob-bnd ndomzd boontod stdy o vmn n Sjogn’s syndom tnts wt xostom nd ktoonjntvts s. Arthritis Rheum 2002;46:748-54 (CS1) 108. Ono M, Tkm e, Snozk K, t . Tt t o vmn on dy y n tnts wt Sjogn’s syndom:  ndomzd, dobbnd n stdy. Am J Ophthalmol 2004;138:6-17 (CS1) 109. Gng G, Dns JT, Dt JK, t . Toxty o nt t sbsttts n  y dnd t mod o mn on t s.Invest Ophthalmol Vis Sci 2001;42948-56 (BS1) 110. Gng G, honnk K, Sod c, t . Qty o svy ts oowng toogos sbmndb gnd tnsntton o sv dy y. Graefes Arch Clin Exp Ophthalmol 2000;238:45-52 (BS1) 111. Tsbot K, Goto e, jt h, t . Ttmnt o dy y by toogos sm ton n Sjogn’s syndom. Br J Ophthalmol 1999;83:390-5 (CS2) 112. Gng G, htwg D. atoogos sm ydos o o s dsods, n rnd T, lkn  (ds). con nd xtn y dss. Bn, hdbg, Sng, 2005,  2-19 113. l l, htwg D, ho S, t . an otmsd otoo o t odton o toogos sm ydos. Graefes Arch Clin Exp Ophthalmol 2005;243:706-14 (BS1) 114. Tnnvt, N, Dn M, Svn lJ, t . contod stdy o t s o  toogos sm n dy y tnts. Cornea 2001;20:802-6 (CS1) 115. Kojm T, isd r, Dog M, t . T t o toogos sm ydos n t ttmnt o sv dy y dss:  ostv ndomzd s-onto stdy. Am J Ophthalmol 2005;139:242-6 (CS1) 116. Nob Ba, lo rS, Mlnnn S, t . comson o toogos sm y dos wt onvnton ty n  ndomsd ontod ossov t o o s dss. Br J Ophthalmol 2004;88:647-52 (CS1) 117. Nod-Tsy T, asno-Kto N, Tod i, Tsbot K. atoogos sm y dos o dy y t laSiK. J Refract Surg 2006;22:61-6 (CS1) 118. Sz SD, Skndo W,Ko p.atoogos sm o t ttmnt o  on t bsons n dbt tnts ndgong vttomy.  Am J Ophthalmol 2006;142:207-11(BS1) 119. Gng G, Sg p, Bstn GO, lq h. Tnsntton o t toogos sbmndb gnd o most sv ss o ktoonjntvts s. Ophthalmology 1998;105:327-35 (CS2) 120. Sod, Sg p, mm c, t . [Tnsntton o t sbmndb gnd n bsot dy ys. et on t o s]. Klin Monatsbl  Augenheilkd 2002;219:494-501 (CS2) 121. lo l, l DQ, Dos a, t . exmnt dy y stmts odton

The Ocular Surace / april 2007, VOl. 5, NO. 2 /  www.tos.om

DEWSMANAGEMENTANDTHERAPy o nfmmtoy ytokns nd MMp-9 nd tvts MapK sgnng twys on t o s. Invest Ophthalmol Vis Sci 2004;45:4293301 (BS1) 122. Ndkon JY, Stn Me, pfgd Sc, t . Dstng stss nds T -mdtd Sjogn‘s syndom-k m ktoonjntvts.J  Immunol 2006;176:3950-7 (BS1) 123. Kswn rl, Ssby Ma, Wd Da. Sontnos nn ktoonjntvts s. a s mod o mn ktoonjntvts s: ttmnt wt yoson y dos. Arch Ophthalmol 1989;107:1210-16 (BS2) 124. Gndz K, Ozdm O. To yoson ttmnt o ktoonjntvts s n sondy Sjogn’s syndom. Acta Ophthalmol 1994;72:3842 (CS2) 125. lbovtz ra, So S, andno J. pot t o yoson 1% otm ontmnt n t ttmnt o ktoonjntvts s. Cornea 1993;12:315-23 (CS1) 126. Stvnson D, Tb J, rs Bl. ey nd sty o yoson a otm mson n t ttmnt o modt-to-sv dy y dss. a dos-ngng, ndomzd t. Ophthalmology 2000;107:967-74(CS1) 127. S K, Stvnson OD, Mndo TK, rs Bl. Two mtnt, ndomzd stds o t y nd sty o yoson otm mson n modt to sv dy y dss. Ophthalmology 2000;107:631-9 (CS1) 128. Knt KS, Tsd aS, Gson iK. Gobt  nmbs nd t oton n t onjntv o tnts wt dy y syndom ttd wt yoson. Arch Ophthalmol 2002;120:330-7 (BS1) 129. Bgno , ps pJ, D Snt Jn M, t . ow ytomt nyss o  nfmmtoy mks n KcS: 6-mont ttmnt wt to yoson a. Invest Ophthalmol Vis Sci 2001;42:90-5 (BS1) 130. Tn K, pfgd Sc, J Z, t . intkn-6 vs n t onjntv tm o tnts wt dy y dss ttd wt yoson otm mson. Cornea 2000;19:492-6 (BS1) 131. Knt KS, Tsd aS, Stn Me, Smt Ja. anyss o to yoson ttmnt o tnts wt dy y syndom: t on onjntv ymoyts. Arch Ophthalmol 2000;118:1489-96 (BS1) 132. pfgd Sc, Mskn Sl, andson B, t . a ndomzd, dobmskd, bo-ontod, mtnt omson o otdno tbont otm ssnson, 0.5%, nd bo o ttmnt o  ktoonjntvts s n tnts wt dyd t n. Am J  Ophthalmol 2004;138:444-57 (CS1) 133. avndk aM, avndk Mc, Vn eD, Kmn he. T omson o s o to otostods nd nonstod ntnfmmtoy dos on dy y tnts: a n nd mmnoytom stdy. Am  J Ophthalmol 2003;136:593-602 (CS1) 134. Snz d  Mz S SM, Smon cstv c, Kbbn O. Nonsvd to stods nd nt oson o sv ktoonjntvts s.  Arch Soc Esp Oftalmol 2000;75:751-56 (CS1) 135. Ms p, pfgd Sc. To nonsvd mtydnsoon ty o ktoonjntvts s n Sjogn syndom.Ophthalmology 1999;106:811-6 (CS3) 136. pfgd Sc. antnfmmtoy ty o dy y. Am J Ophthalmol 2004;137:337-42 (CS3) 137. anonymos. ctn otm ntbot ombnton dgs o mn s; Dg y stdy mmntton. Fed Reg 1982;47:21296 138. anonymos. ctn stod tons o otm nd/o ot s. Fed Reg 1980;45:57776-80 139. anonymos. ctn otm ntbot ombnton dgs o mn s; Dg y stdy mmntton. Fed Reg 1980b;45:57780-3 140. anonymos. ctn stod tons o otm o ot s.Fed Reg 1976;41:34340-2 141. D pv cS, cos rM, V al, t . a on b dston n xmnt mn dy y s bogtd by mtydnsoon nd doxyyn. Invest Ophthalmol Vis Sci 2006;47:2847-56 (RS1) 142. D pv cS, cos rM, V al, t . cotostod nd doxyyn sss MMp-9 nd nfmmtoy ytokn xsson, MapK tvton n t on tm n xmnt dy y.Exp Eye Res 2006;83:526-35 (RS1) 143. Smn rM, Bdod r, Bnn B, t . a mtnt, dob-mskd, ndomzd, v-ontod, -go stdy to vt t sty nd y o tstoston otm soton n tnts wt mbomn gnd dysnton. arVO 2006, e-abstt 5608 (CS3) 144. Wod c, N J, hb Jc, Sto MO. Ttmnt o ktoonjntvts s wt to ndogn. Maturitas 2001;37:209-12 (CS3) 145. Sto MO, Jo ea, Goszwsk T, t . Ttmnt o mnos ktoonjntvts s wt to ostdo. Br J Obstet Gynaecol 1998;105:100-2 (CS2)

146. Sn We, Mcy Jp, pndy aG. Mnoyn t on mbomn gnd ds n mbomnts tnts. Exp Eye Res 2003;76:417–20 (CS2) 147. Dogty JM, Mcy Jp, Svny re, t . T o o ttyn n on bts. Invest Ophthalmol Vis Sci 1991;32:2970–5 (CS2) 148. T cN, Sn We, Mcy Jp, t . ets o mnoyn on t o fo o tnts wt n os o sbo bts. Cornea 2003;22:545–8 (CS2) 149. Soomon a, rosnbtt M, l DQ, t . Doxyyn nbton o ntkn-1 n t on tm. Invest Ophthalmol Vis Sci 2000;41:2544-57 (CS2) 150. l Y, Kng K, Yx B, t . rbbt onjntv tm tnsots fd, nd p2Y2(2) to gonsts stmt c(-) nd fd ston.  Am J Physiol Cell Physiol 2001;281:c595-602(BS1) 151. l DQ, lo l, cn Z, t . JNK nd erK Map knss mdt ndton o il-1bt, TN- nd il-8 oowng yosmo stss n mn mb t s. Exp Eye Res 2006;82:588-96. eb 2005 Ot 3 (BS1) 152. Kk T, Bky M. Doxyyn s nt-nfmmtoy nd nbts styoo xotoxn-ndd ytokns nd mokns. Antimicrob  Agents Chemother 2003;47:3630-3 (BS1) 153. Vos Sa, evns Me, ln MT, t . us o mods nd ttyns o on nfmmtoy dsss. Ann Pharmacother 2005;39:86-94 (CS3) 154. Tmgo rJ, Bok ra, Bm h. angognss nbton by mnoyn. Cancer Res 1991;51:672-5 (BS1) 155. Sdn aN, smj r. Ttyns: Nonntbot ots nd t n mtons J Am Acad Dermatol 2006;54:258-65 (CS3) 156. hb Tp. cn dmtoogy, 4t d. St los:Mosby-Y Book, 2004,  162-89 (CS3) 157. V cM, hkbt Sr, lm JW, t . antbot s n ton to t sk o bst n. JAMA 2004;291:827–35 158. V cM, hkbt Sr, rtt c, t . assoton btwn ntbot s o to bst n dgnoss nd bst tmo tsts (untd Stts). Cancer Causes Control (Netherlands) 2006;17:307-13 159. Gı rodıgz la , Gonzz-pz a. us o ntbots nd sk o  bst n. Am J Epidemiology 2005;161:616-9 160. Mdond a, w M. po dmtts: toogy nd ttmnt wt ttyn. Br J Dermatol 1972;87:315-9 (CS3) 161. Jnsn T, pwg G. ros: sston nd ttmnt. J R Soc Med 1997;90:144-50 (CS3) 162. t-py J, cyt aS, dmn ST, t . T t o doxyyn on o os. Am J Ophthalmol 1989;107:434-5 (CS2) 163. Wkn JK. ros. toysoogy nd ttmnt.  Arch Dermatol 1994;130:359-62 (BS1) 164. Ston Du, codos J. O ttyns o o os: n vdnbsd vw o t tt. Cornea 2004;23:106-9 (CS1) 165. Mcy Jp, Dogty JM, Dn DG. csston o on bts. Ophthalmology 1982;89:1173-80 (CS2) 166. t-py J, Sg e, hmo i, ev-hdn p. ey o doxyyn nd ttyn n o os. Am J Ophthalmol 1993;116:88-92 (CS1) 167. S DV, Wgt p, pk l, t . pbo ontod t o sd d g nd oxyttyn o nt bts nd os.Br J Ophthalmol 1995;79:42-5 (CS1) 168. ho pD, Ws DM. enty o o ttyns nto sv nd ts. Antimicob Agents Chemother 1974;3:330–6 (BS1) 169. Gbnkn a, Mys J, s D. hmst fnk ogn ydos nd s tvty. J Invest Dermatol 1980;75:289–92 (BS1) 170. aonowz JD, Sn We, O D, t . Sot tm o mnoyn ttmnt o mbomnts. Br J Ophthalmol 2006;90:856-60 (CS2) 171. Yoo Se, l Dc, cng Mh. T t o ow-dos doxyyn ty n on mbomn gnd dysnton. Korean J Ophthalmol 2005;19:25863 (CS2) 172. Bownng DJ, po aD. O os. Surv Ophthalmol 1986;31:145– 58 (CS3) 173. esty NB, Konsky JS, y Nl, t . Nto motxs n tnts wt n vng o ttyn ty.  Arch Dermatol 1984;120:1308-13 (BS1) 174. Gbd Jp. T snt ontxt nd bss o t moog mngmnt o dy ys. Ophthalmol Clin North Am 2005;18:475-84,v (CS3) 175. Jms MJ, Gbson ra, cnd lG. Dty oynsttd tty ds nd nfmmtoy mdto odton.  Am J Clin Nutr 2000;71(1 S):343S-8S (BS2) 176. ends S, Gobn r, Ky Ve, t . T t o dty smntton wt n-3 oynsttd tty ds on t syntss o ntkn-1 nd tmo noss to by monon s. N Engl J Med

The Ocular Surace / april 2007, VOl. 5, NO. 2 /  www.tos.om

177

DEWSMANAGEMENTANDTHERAPy 1989;320:265-71 (BS1) 177. Jms MJ, cnd lG. Dty n-3 tty ds nd ty o mtod tts. Semin Arthritis Rheum 1997;27:85-97 (CS3) 178. Km JM. n-3 tty d smnts n mtod tts. Am J Clin Nutr 2000;71(1 S):349S-51S (CS1) 179. Bbno S, rondo M, cmon p, t . Systm no nd gmmnon d ty n dy y syndom wt n nfmmtoy omonnt. Cornea 2003;22:97-101 (CS2) 180. Sdo Ja, lmbts D, Bgmnn rB, py hD. mnty ktts ssotd wt dnydmn ydood (Bndy). Am J Ophthalmol 1986;101:376-7 (CS3)

178

181. Moss Se, Kn r, Kn Be. pvn o nd sk tos o dy y syndom. Arch Ophthalmol 2000;118:1264-68 182. Md Th, Sttng rD. Ktoonjntvts s sd by dnoxyt ydood wt ton st (lomot).  Am J Ophthalmol 1991;111:377-8 (CS2) 183. Tsbot K, Nkmo K. Dy ys nd vdo dsy tmns. N Engl J  Med 1993;25;328:584(CS2) 184. Mtob aY, hs DJ, Mk DB, t . Dy y syndom, amn admy o Otmoogy, 2003 185. Bns a, Doy JJ, Stn l, t . Dysnton t syndom: a D o to ttmnt ommndtons.Cornea 2006;25:900-7

The Ocular Surace / april 2007, VOl. 5, NO. 2 /  www.tos.om