巩膜镜控制干眼症(英文).pdf

Use of Fluid-Ventilated,Gas-Permeable Scleral Lensfor Management of Severe Keratoconjunctivitis SiccaSecondary to Chronic Graft-versus-Host DiseaseKikuchi Takahide,1Pablo M.Parker,2Michael Wu,3William Y.K.Hwang,4Paul A.Carpenter,1,3Carina Moravec,1Barbara Stehr,2Paul J.Martin,1,3Perry Rosenthal,5Stephen J.Forman,2Mary E.D.Flowers1,31Fred Hutchinson Cancer Research Center,2Hematology and Hematopoietic Cell Transplantation,City of HopeNational Medical Center,3University of Washington,Seattle,Washington;4Singapore General Hospital,SingHealth,Singapore;and5Harvard Medical School and Boston Foundation for Sight,Boston,MassachusettsCorrespondence and reprint requests:Mary E.D.Flowers,MD,Clinical Research Division,Fred HutchinsonCancer Research Center,1100 Fairview Avenue N,D5-290,Seattle,WA 98109(e-mail:mflowersfhcrc.org).Received March 21,2007;accepted May 7,2007ABSTRACTKeratoconjunctivitis sicca(KCS)occurs in 40%-60%of patients with chronic graft-versus-host-disease(cGVHD)after allogeneic hematopoietic cell transplantation.Although immunosuppressive therapy is theprimary treatment of chronic GVHD,ocular symptoms require measures to improve ocular lubrication,decrease inflammation,and maintain mucosal integrity.The liquid corneal bandage provided by a fluid-ventilated,gas-permeable scleral lens(SL)has been effective in mitigating symptoms and resurfacing cornealerosions in patients with KCS related to causes other than cGVHD.We report outcomes in 9 consecutivepatients referred for SL fitting for cGVHD-related severe KCS that was refractory to standard treatments.Allpatients reported improvement of ocular symptoms and reduced the use of topical lubricants after SL fittingresulting from decreased evaporation.No serious adverse events or infections attributable to the SL occurred.The median Ocular Surface Disease Index improved from 81(75-100)to 21(6-52)within 2 weeks after SLfitting,and was 12(2-53)at the time of last contact,1-23 months(median,8.0)after SL fitting.Disabilityrelated to KCS resolved in 7 patients after SL fitting.The use of SL appears to be safe and effective in patientswith severe cGVHD-related KCS refractory to conventional therapies.2007 American Society for Blood and Marrow TransplantationKEY WORDSGraft-versus-host diseaseKeratoconjunctivitis siccaAllogeneic hematopoietic cell transplantationINTRODUCTIONThe term keratoconjunctivitis sicca(KCS)denotesinflammation caused by dryness of the conjunctiva andcornea.Ocularchronicgraft-versus-hostdisease(cGVHD)can cause acute conjunctival inflammation,pseudomembranous and cicatricial conjunctivitis,andKCS.Dry eyes or KCS occurs in approximately 40%-60%of patients with cGVHD after allogeneic hema-topoietic cell transplantation(HCT)1-3 and mayrepresent the only,or most significant,clinical man-ifestation and sequelae of cGVHD in some patients.Patients with KCS may develop corneal erosionsand filaments causing severe pain and photophobia.If inadequately managed,corneal epitheliopathy canprogress to persistent epithelial defects,sterile cor-neal ulcers,secondary infectious keratitis,and cor-neal perforation,leading to stromal scarring andloss of vision 4.Systemic immunosuppressive therapy may beneeded to halt inflammatory processes,and is some-times indicated when cGVHD of the eye is resistant tolocal therapy or associated with other organ involve-ment 5.cGVHD can cause irreversible damage tosebum and tear-producing cells,with sequelae result-ing in considerable disability.For these patients,an-cillary and supportive care for the eye is directed toimproving ocular surface lubrication and decreasinginflammation.Such treatments include artificial tears,Biology of Blood and Marrow Transplantation 13:1016-1021(2007)?2007 American Society for Blood and Marrow Transplantation1083-8791/07/1309-0001$32.00/0doi:10.1016/j.bbmt.2007.05.0061016long-acting ocular lubricants,punctal occlusion orcauterization,ophthalmic cyclosporine 6,topicalcorticosteroids,autologous serum eye drops 7,mois-ture chamber eyewear 8,and oral administration ofcholinergic agents 2-5.Supportive care for patients with severe cGVHDof the eye can improve the quality of life of afflictedindividuals.The liquid corneal bandage provided by afluid-ventilated,gas-permeable scleral lens(SL)hasbeen effective in mitigating symptoms and resurfacingcorneal erosions in the treatment of KCS because ofother disorders 9,10.We therefore analyzed ourexperience on the use of SL in individuals withcGVHD-related severe KCS refractory to other ther-apies.We report outcomes in 9 consecutive patientsreferred for SL fitting as treatment for cGVHD-related severe KCS that was refractory to standardtherapies.PATIENTS AND METHODSBetween April 2004 and July 2006,9 patients werefitted with SL for refractory KCS because of cGVHDfollowing allogeneic HCT at the Fred HutchinsonCancer Research Center or the City of Hope.A ret-rospective analysis was performed in November 2006to describe the outcome of these 9 consecutive pa-tients referred to the Boston Foundation for Sight,anonprofit organization.In all cases,the decision totreat patients by fitting SL was prompted by debili-tating ocular discomfort,visual impairment,or kera-topathy despite systemic and local therapies as well asother supportive care.The status of cGVHD beforelens placement was determined by patient interviews anda retrospective review of patient records.The involve-ment of other organs by cGVHD at any time before lensplacement and at the time of lens placement was re-corded,as was the duration of eye cGVHD prior tofitting the SL.Records were reviewed for prior topicaltherapy for dry eyes,including the use of artificialtears,cellulose ophthalmic inserts(Lacriserts),cyclo-sporine eye drops,doxycycline eye drops,punctalplugs,autologous serum tears,and moisture chambereye wear.Data was also gathered regarding the use ofsystemic immunosuppressive treatments and cGVHDmanifestations before and at the time of SL fitting andat the time of last contact.Fitting of SL was performed by the Boston Foun-dation for Sight as previously described 9,10.TheSL,known as the Boston Scleral Lens,is lathed froma special polymer with an oxygen permeability value of128?10?11cm2mL O2/second mL mmHg and acenter thickness ranging from 0.25 to 0.39 mm8.Incustomizationthe curvature of the central back sur-face of each lens is designed to maintain shallow butdefinite clearance of the cornea and limbus after thelens settles,so that it is supported entirely by the scleraand not touching the cornea.The optimal lens vaultand perimeter of the individual lenses are determinedby on-eye evaluations of diagnostic lenses and othermeasurements.The response to the SL was assessed by use of theOcular Surface Disease Index(OSDI).The OSDI is a12-item questionnaire based on 3 subscales:vision-related function,ocular symptoms,and environmentaltriggers(Table 1).Answers to questions are graded ona scale of 0 to 4,where 0 indicates none of the time,1indicates some of the time,2 indicates half of the time,3 indicates most of the time,and 4 indicates all of thetime.The OSDI has been validated as a reliable in-strument used to assess severity of dry eye symptomsand vision-related function on a 0-100 scale,withhigher scores correlating with increasing symptomseverity and vision-related disability 11.From a setof 12 questions(Table 1)administered,a score iscalculated according to the formula:OSDI?(sumof scores for all questions answered)?25/totalnumber of questions answered 11.From thisscore,the severity of ocular surface disease is de-rived according to a color scale,as depicted inFigure 1.In addition,questionnaires were adminis-tered retrospectively to inquire about symptoms andthe use of artificial tears,punctal plug placement,use of moisture chamber eyewear,and disabilitybecause of eyes symptoms before and after SLplacement and,at the time of last contact.Table 1.Ocular Surface Disease Index QuestionnaireHave you experienced any of the following during the last week?1.Eyes that are sensitive to light?2.Eyes that feel gritty?3.Painful or sore eyes?4.Blurred vision?5.Poor vision?Have problems with your eyes limited you in performing any ofthe following during the last week?6.Reading?7.Driving at night?8.Working with a computer or bank machine(ATM)?9.Watching TV?Have your eyes felt uncomfortable in any of the followingsituations during the last week?10.Windy conditions?11.Places or areas with low humidity(very dry)?12.Areas that are air conditioned?Answers to questions are graded on a scale of 0 to 4,where 0indicates none of the time;1,some of the time;2,half of thetime;3,most of the time;and 4,all of the time.The subtotalscores for answers 1 to 5(A),answers 6 to 9(B),and answers 10to 12(C)are added together(A?B?C)to obtain D(sum ofscores for all questions answered).(E)is the total number ofquestions answered(excluding questions answered N/A).Reproduced with permission from Allergan.Chronic Graft-versus-Host Disease of the Eyes1017RESULTSPatient demographics are summarized in Table 2.Diagnoses at time of HCT were acute or chronicleukemia(n?5),myelodysplastic syndrome(n?2),aplastic anemia(n?1)and multiple myeloma(n?1).Median patient age at the time of SL fitting was 56(range:25-64)years.All patients had prior cGVHDinvolving multiple sites that required systematic im-munosuppressive therapy including corticosteroidsand cyclosporine.Four patients were receiving corti-costeroids and 3 patients were receiving cyclosporineat the time of SL fitting.Two patients had also re-ceived treatment with azathioprine,6 patients re-ceived mycophenolate mofetil,and 2 patients hadbeen treated with PUVA therapy before SL fitting(Table 2).The most common cGVHD sites otherthan eyes at the time of SL fitting were 6 mucosalsurfaces(oral and vagina),liver(n?3),skin(n?2),followed by gut(n?1)and lungs(n?1).At the timeof SL fitting,7 patients were receiving systemic im-munosuppressive medications and 2 patients had dis-continued administration of all systemic immunosup-pressive medications after nonocular manifestations ofcGVHD had resolved.Three patients had no activemanifestation of cGVHD other than KCS at the timeof SL fitting.Table 3 presents patient-reported outcomes.Theuse of the SL led to improvement in ocular symptomsin all cases.No serious adverse events or infectionsattributable to the SL occurred.All 9 patients usedtopical lubricants frequently during the day beforefitting the SL(baseline).In all patients,the frequencyof topical lubricant use was reduced after SL fitting totwice daily or less(n?3),2 to 6 times daily(n?4),or by a 50%reduction from baseline(n?2).Pre-scription moisture chamber eye wear was needed in 3patients before SL and no longer required in 2 of thepatients at last contact.All 9 patients subjectively as-sessed themselves to have disability before fitting theSL,and 6 patients were no longer disabled after lensplacement.One patient had significant difficulty in-serting the SL,even with assistance(Patient 3).The response to the SL was assessed by patient-reported ocular disability,use of ancillary eye care,and by use of the OSDI.As seen in Table 3,themedian OSDI available improved from 81(75-100)to21(6-52)within 2 weeks of SL fitting and was 12(2-53)at the time of last contact,1-23 months(me-dian,8.0)after SL fitting.In Patient 1,SL fitting coincided with reinstitu-tion of systemic immunosuppressive treatment,andcGVHD subsequently improved at other sites.Al-though the OSDI decreased promptly after SL fitting,systemic treatment could have contributed to the res-olution of eye symptoms.Patient 2,who had healingof a persistent corneal epithelial defect after SL fitting(Figure 2),resumed therapy with prednisone and ta-crolimus for management of other manifestations ofcGVHD at 9 months after SL fitting.Patient 3 wasthe only patient among the 9 who had significantdifficulty inserting the SL,even with assistance.Thispatient had significant initial improvement with reg-ular use of the SL,but at present wears the SL onlytwice monthly for no more than 4 hours becausemucous debris accumulates on the outside surface ofthe lens and interferes with vision during longer periodsof use.Patients 4,5 and 8 had significant improvementin ocular symptoms and also reported a significant re-duction in the use of topical lubricants to once or twicedaily after SL fitting.Patients 6 and 7 had debris collec-tiononthelensesthathasrequiredremovalandcleaning1-2timesaday.Patient9,despiteimprovementinocularsymptoms,remained disabled with impairment in hisability to read and drive at night.DISCUSSIONOur results document the response of chronicocular GVHD-associated KCS to SL fitting.KCS isoften accompanied by cGVHD activity in other or-gans,but may also represent the only manifestation ofcGVHD 1.The myriad and debilitating symptomsof KCS include burning,irritation,pain,foreign bodysensation,blurred vision,and photophobia.Treat-ment measures that can control KCS or mitigate itssymptoms are therefore important in restoring thequality of life of individuals after HCT.Supportive care for the treatment of cGVHD ofthe eye has been recently summarized in the NationalInstitutes of Health Consensus Development Projecton Criteria for Clinical Trials in Chronic Graft-versus-Host Disease 4,and involves lubrication,con-Figure 1.The OSDI scoring system.Using the sum of scores for allquestions answered(D)and the number of questions answered(E),the corresponding score for the patient is then derived from thechart.The OSDI chart has a color scheme for computation of theseverity of ocular surface disability.Reproduced with permissionfrom Allergan.K.Takahide et al.1018Table 2.Patient DemographicsCasesCharacteristics123456789DiagnosisAplastic AnemiaCMLCPCMLBCMDS/RACMMLCMLBCCLLMMAMLAge at SL fitting(years)392556645643595258Chronic GVHDInitial onset after HCT(months)377127261226Involved organs other thaneyesSkin,liver,mouth,gutSkin,liver,mouthSkin,liver,mouth,vaginaSkin,liver,lung,gut,mouthSkin,liver,lungSkin,gut mouthMouth,joints,vaginaSkin,mouthSkin,mouthTotal duration(months)208203811015646426936Total Duration of eyecGVHD(months)206203411015528426936Duration of eye cGVHDbefore SL fitting(months)1927109214725366336Involved Organs at time ofSL fittingLiver,mouth,GItractNoneSkin,liver,mouth,vaginaNoneNoneSkin,eyesMouth,eyesMouth,eyesEyes,lungsPrior Therapies for cGVHDPDN,CSP,TAC,PUVA,AZAPDN,CSP,TAC,MMFPDN,CSP,TAC,MMFPDN,CSP,MMFPDN,CSP,TAC,AZA,PUVAPDN,CSP,MMFPDN,CSP,MMFPDN,CSP,TACPDN,CSP,MMFPrior Topical therapy for dryeyesArtificial Tears(AT)YesYesYesYesYesYesYesYesYesSlow release AT(Lacriserts)NoYesYesNoNoNoNoNoNoCyclosporine eye dropsYesYesYesYesNoYesYesYesYesCorticosteroidsNoNoNoNoYesNoNoNoYesPunctal plugsYesYesYesYesYesYesYesYesYesAutologous serum tearsYesNoNoNoNoNoNoNoNoMoisture chamber eye wearYesNoYesYesNoNoNoNoNoSystemic immunosuppressivetreatment at time of SLfittingPDN,TACNonePDN,MMFNonePDNPDN,CSP,MMF,RAPACSPTACCSP,MMFCML indicates chronic myelogenous leukemia;CP,chroni