Veterinry Ophthlmology (2015) 18, 3, 234 241 DOI:10.1111/vop.12173 Use of episclerl cyclosporine implnts in dogs with kertoconjunctivitis sicc: pilot study Lur rchetti,* ntonell Rmpzzo, Crlo M. Mortellro,* Stefni Scevol* nd rin C. Gilger *Deprtment of Veterinry Science nd Pulic Helth, Fculty of Veterinry Medicine, University of Miln, Miln, Itly; Istituto Veterinrio di Novr, Grnozzo con Monticello, Itly; nd North Crolin Stte University, Rleigh, NC, US ddress communictions to: L. rchetti Tel.: +39 347 9530911 Fx: +39 02 503 17817 e-mil: lurrchetti@yhoo.it strct Purpose To descrie the use, tolerility, nd efficcy of episclerl silicone mtrix cyclosporine (ESMC) implnts in dogs with kertoconjunctivitis sicc (KCS). Methods Retrospective study. ESMC implnts (1.9 cm length, 30% wt/wt Cs in silicone; with pproximtely 12 mg of Cs loded into them) were used in dogs with KCS responsive to topicl Cs (good cndidte, GC) or not responsive (poor cndidte, PC). Oculr surfce inflmmtion scores, Schirmer ter test (STT) vlues, nd oculr dischrge quntity were evluted nd compred. Results Twenty-seven eyes (15 dogs) received n ESMC implnt for KCS; 15 eyes were considered GC, nd 12 were considered PC. oth GC eyes nd PC eyes showed significnt increse in STT vlues (increse of 7.7 nd 8.5 mm/min; P = 0.023 nd P = 3, respectively) fter plcement of ESMC implnts (men follow-up 18 2 nd 10.4 15 months, respectively). Clinicl signs improved significntly in oth groups during the sme follow-up, with reduction in conjunctivl hyperemi (P < 1), cornel neovsculriztion (P = 4), cornel opcity (P = 3), nd oculr dischrge (P = 2). ESMC implnts were well tolerted y ll dogs, ut two eyes lost the device t 12-months nd 1-week follow-up, respectively. Conclusions Results from this study suggest tht the EMSC implnts were well tolerted nd efficcious in dogs with KCS responsive to topicl Cs s well s dogs with poor response to topicl therpy. Further study is needed to determine the durtion of efficcy nd optiml dose of Cs. Key Words: cyclosporine, dog, dry eye, implnt, kertoconjunctivitis sicc, sustined relese delivery INTRODUCTION Kertoconjunctivitis sicc (KCS) is common oculr disese in the dog. 1,2 It is chrcterized y queous ter deficiency resulting in desicction nd inflmmtion of the conjunctiv nd corne, oculr pin, nd reduced vision. 1,2,3 While the list of possile cuses of KCS is extensive, in mny cses, the definitive cuse is not determined. 1,2 Histopthologic studies of the lcriml tissue from dogs ffected with idiopthic KCS hve reveled vrying degrees of lymphocytic plsmcytic cellulr infiltrte nd cinr trophy, therey suggesting n immunologic sis for the disese. 1,2 KCS my e ssocited with systemic utoimmune conditions, ut cnine KCS ppers to occur more often s tissue-specific immune-medited disorder. 1,2,4,5 In niml models of immune-medited lcriml disese, the lnce etween T-suppressor nd T-helper cells plys n importnt role in lcriml glnd regultion. In lcriml tissue, T-suppressor cells normlly predominte, ut in immune-medited KCS, T-helper cells ecome the prevlent T lymphocytes. 1,2 Therefore, y inhiiting T-helper cells in KCS, Cs my llow T-suppressor cells to sustin norml lcriml function nd stimulte tering. 4,6 9 Therefore, Cs hs oth immunomodulting nd ter-stimulting properties. 10 15 Topicl oculr therpy with Cs in dogs with KCS is generlly recommended every 8 12 h, severl weeks of continuous tretment re usully needed efore sustntil improvement in Schirmer ter test (STT) vlues nd/or clinicl signs is oserved. 9,15 19 Sustined relese oculr implnts hve een developed over the pst decde tht llows delivery of constnt 2014 mericn College of Veterinry Ophthlmologists
episclerl cyclosporine implnt in kcs 235 therpeutic levels of drug to the eye. 20 25 Oculr implnts re prticulrly useful in the tretment of chronic oculr prolems, such s horses with equine recurrent uveitis (ERU) or immune-medited kertitis (IMMK), 26 31 or dogs with KSC or chronic superficil kertitis (CSK). 32 35 This sustined relese oculr drug delivery technology hs lso the dvntge to eliminte or minimize the effect of ptient nd/or owner noncomplince in drug dministrtion. 20,21,26 Severl types of oculr drug delivery methods hve een descried, such s solid implnts (e.g., silicone), iodegrdle implnts (PLG, chitosn, etc.), thermosensitive injectle gels, nd microprticle/nnoprticle suspensions. 20 23,27,29,31,35 39 The method of oculr drug delivery must correlte with the intended disese in terms of site of drug trget nd durtion of effect. 20,21,23,25 In generl, suconjunctiv/episclerl implnttion is used for nterior segment diseses, 26,32 34,40 wheres intrvitrel or suprchoroidl methods re typiclly used to tret posterior segment diseses. 27 31 Intrsclerl implnts cn e used for either oculr segment. 36 Silicone mtrix episclerl implnts hve een demonstrted to deliver drugs such s Cs to the corne in sustined relese mnner nd re in development in humns for the tretment of high-risk cornel trnsplnts nd grft-versus-host disese. 40 These implnts hve een descried for the long-term tretment of ilterl kertoconjunctivis sicc in red wolf. 32,34,40 Episclerl silicon mtrix cyclosporine implnts llow sustined relese of Cs elow toxic levels nd llow higher concentrtions of the drug thn topicl therpy without systemic side effects. 21,32 These implnts mesure 1.9 cm y 2 mm y 1 mm, nd contin pproximtely 12 mg of Cs. 26,32 34 Cs relese hs een determined in vitro t 27 lg/dy of Cs for the first month, followed y stedy stte relese of 15 lg/dy for the following 2 3 months, nd n verge of out 17 lg/dy for the first 6 months. 32,40 The estimted durtion of relese in vitro is 18 24 months. 32,40 The purpose of this retrospective study ws to descrie the use of episclerl silicone mtrix cyclosporine (ESMC) implnts in dogs with KCS, with evlution of tolerility nd retention of implnts nd their efficcy for mngement of KCS. MTERILS ND METHODS Criteri for selection of cses This retrospective study ws performed y reviewing records of dogs dignosed with immune-medited KCS nd implnted with one ESMC implnt from 2010 to 2013 t North Crolin Stte University, University of Miln nd Istituto Veterinrio di Novr. The North Crolin Stte University Institutionl niml Cre nd Use Committee nd the Veterinry Helth Center Hospitl ord pproved this study for dogs enrolled t North Crolin Stte University. The cses were selected to e implnted sed on the discretion of the ttending ophthlmologist. ll the dogs were considered ffected y immune-medited KCS, ecuse ll the other possile KCS etiologies were excluded. Dogs with residul STT vlues of >5 ut <10 mm/min were considered good cndidtes (GC) for tretment, while dogs with STT of 5 mm or less were considered poor cndidtes (PC) for tretment. The GC dogs were usully included, ecuse the owners could not fford tretment with more conventionl topicl therpy or ecuse of the ptient nd/or owner noncomplince in drug dministrtion. The PC received previously topicl therpy with cyclosporine or tcrolimus without ny improvement. oth groups of dogs were implnted nd followed in response to therpy. ll dog owners signed written consent efore initition of this experimentl procedure nd were fully informed tht long-term outcome, complictions, nd efficcy of the implnts in dogs with KCS were not known. Implnt mnufcturing The implnts were mde s descried previously, using polytetrfluoroethylene mold with impressions on the surfce. 32 Implnts mesured 1.9 cm long, 2 mm wide, nd 1 mm high, nd they hve rounded side nd flt side. Cyclosporine powder (Xenos ioresources, Inc., Snt rr, C) ws mixed with medicl grde silicone with pltinum cure system (Nusil Technology, Crpinteri, C) so tht the weight of the drug s percentge of the totl weight of the implnt (wt/wt) ws 30%, resulting in pproximtely 12 mg of cyclosporine loded into ech implnt. The impressions were filled with the cyclosporine-silicone pste nd cured for minimum of 24 h t room temperture. The implnts were sterilized with gmm irrdition (25 30 kgy). Procedures The surgicl implnttion ws performed while the dogs were under generl nesthesi. fter surgicl septic preprtion of the eye, 3-mm incision ws mde through the conjunctiv nd episclerl tissue, 3 5 mm posterior to the dorso-temporl limus. pocket ws formed in the episclerl spce prllel to the limus, nd one implnt ws plced into this pocket. The flt side of the implnt ws pplied to the episcler nd the rounded side towrd the overlying conjunctiv. The conjunctiv nd Tenon s cpsule were closed with single interrupted or crucite sorle suture. Following surgery, topicl rod-spectrum ntiiotic ws pplied for 5 7 dys, nd topicl cyclosporine nd/ or rtificil ters prescried previously to mnge the dog s KCS were continued for 30 dys, then discontinued. Schirmer ter test vlues were recorded efore strting the topicl therpy (t 1), t the time of surgery (t 0) nd during the follow-up time. Degree of oculr dischrge, conjunctivl hyperemi, cornel neovsculriztion, cornel opcity ws ll scored from 0, if sent, to 4, if severe, t the sme times s STT ws evluted. In prtic- 2014 mericn College of Veterinry Ophthlmologists, Veterinry Ophthlmology, 18, 234 241
236 rchetti ET L. ulr, the oculr dischrge ws grded s 1 if only poor nd mucous, 2 if moderte nd mucous, 3 if moderte nd mucous-purulent, nd 4 if undnt nd purulent. Conjunctivl hyperemi ws considered 1 if poor, 2 if moderte, 3 if severe, nd 4 if severe with esily leeding conjunctiv. Cornel neovsculriztion nd cornel opcity were grded 1 if the involved corne ws <25%, 2 if more thn 25% ut <50%, 3 if more thn 50% ut <80%, 4 if more thn 80%. Recommended follow-up exmintions fter the implnt were 1, 2, nd 4 weeks, then monthly. Dt nlysis nd sttisticl methods Prmetric normlly distriuted dt (i.e., ge, disese durtion, follow-up time, STT) were compred y time point for ech group using one-wy NOV models with Tukey Krmer post hoc nlysis. In dogs tht hd oth eyes treted, there were no significnt differences in overll men of vlues or grdes etween the right nd left eyes; therefore, dt from these eyes were verged to give one vlue per dog to eliminte etween-eye correltion. For nonprmetric dt (i.e., gender), Wilcoxon tests were conducted per niml y time point. Differences were considered significnt t P < 0.05. Results nd proilities were clculted using computerized sttisticl softwre (JMP 10; SS Inc., Cry, NC). RESULTS Overll, 27 eyes of 15 dogs were treted with ESMC implnts for KCS, 15 eyes (seven dogs) were considered GC for Cs therpy, nd 12 eyes (eight dogs) were considered PC. Severl reeds were represented, including two shih tzu, two English ulldog, two mixed, one order Collie, one Yorkshire T, one Jck Russel terrier, one West highlnd white terrier, one Mltese, one Dogue de ordeux, one Tietn Spniel, one Lhs pso, nd one Germn Shepherd. There were five mles, three neutered mles, five femles, two spyed femles. Men ge of dogs treted ws 5.63 3.41 (stndrd devition) yers. The men follow-up ws of 18 2 months for eyes considered GC nd 10.4 15 months for eyes considered PC. Over the follow-up period, complictions or signs of toxicity ssocited with implnts or Cs were not oserved. The devices were well tolerted nd retined y the dogs, except for n implnt lost 1 week fter implnttion nd nother lost t 12 months fter surgery. Sttisticlly significnt increses in STT vlues fter implnttion compred with the STT prior to surgery (seline) were oserved in oth GC nd PC groups (Fig. 1). The mximum STT increse ws chieved t 90 dys fter surgery in oth groups, including 7.7 mm/ min STT increse in the GC nd n 8.5 mm/min STT increse in PC eyes compred with seline. However, y 330 dys in the GC eyes nd 300 dys in the PC eyes, there ws no significnt improvement in STT compred with seline (Fig. 1). ll the clinicl scores showed significnt improvement from 60 to 90 dys, which remined significnt up for 480 540 dys (Figs 2 6). Dogs tht showed severe preopertive conjunctivl hyperemi, the presence of mucous-purulent dischrge, nd severe cornel opcity nd neovsculriztion hd n improvement in the clinicl signs fter implnttion, with significnt reduction in the inflmmtory scores t 60 with further improvement y 90 dys FU (Fig. 2). DISCUSSION In this study, we descrie the results of the use of solid, silicone mtrix episclerl implnts designed to relese cyclosporine in therpeutic concentrtions to the oculr surfce for n extended period of time for the tretment of KCS in dog. () () (c) (d) Figure 1. One of the PC cses, the eye of n English ulldog. () In the preopertive picture of the eye, there were severe conjunctivl hyperemi, the presence of mucous-purulent dischrge nd severe cornel opcity nd neovsculriztion. () Then it is possile to pprecite the improvement of the clinicl signs over the FU periods with significnt reduction in the inflmmtory scores t 60 (c) nd etter t 90 (d) dys FU. PC, poor cndidte. 2014 mericn College of Veterinry Ophthlmologists, Veterinry Ophthlmology, 18, 234 241
episclerl cyclosporine implnt in kcs 237 3 Good Cndidtes Men STT (mm/min) 25.00 2 15.00 1 d Cndidtes 5.00 Dys er implnt on Figure 2. sttisticlly significnt increse in Schirmer ter test (STT) vlues ws chieved in oth good cndidte (GC) nd poor cndidte (PC) groups. The mximum increse ws detected t 90 dys in oth groups, nd ws of 7.7 mm/min in the GC (P = 0.023) nd 8.5 mm/min in PC (P = 3). significnt reduction in the STT strted from 330 dys in the GC nd 300 dys in the PC. Mens with different letters re significntly different (P < 0.05). 4.00 3.50 Good Cndidtes d Cndidtes Men Score - Cornel Neovsculriz on 3.00 2.50 2.00 1.50 1.00 0.50 Dys er implnt on Figure 3. Overll the mximum sttisticlly significnt reduction in cornel neovsculriztion ws chieved t 90 dys (P = 4) nd remined significnt up for 540 dys. Mens with different letters re significntly different (P < 0.05). 2014 mericn College of Veterinry Ophthlmologists, Veterinry Ophthlmology, 18, 234 241
238 rchetti ET L. 4.00 3.50 3.00 Good Cndidtes d Cndidtes Men Score - Cornel Opcity 2.50 2.00 1.50 1.00 0.50 Dys er implnt on Figure 4. Overll the mximum sttisticlly significnt reduction in cornel opcity ws chieved t 90 dys (P = 3) nd remined significnt up for 480 dys. 4.00 3.50 Good Cndidtes d Cndidtes Men Score - Conjunc vl Hyperemi 3.00 2.50 2.00 1.50 1.00 0.50 Dys er implnt on Figure 5. Overll the mximum sttisticlly significnt reduction in conjunctivl hyperemi ws chieved t 60 dys (P < 1) nd remined significnt up for 540 dys. Mens with different letters re significntly different (P < 0.05). In preclinicl evlution of silicone mtrix episclerl implnts, Kim et l. 32 evluted the toxicity ssocited with two devices plced into the superotemporl episclerl spce of rits nd dogs. Over 6-month period, clinicl exmintions showed no signs of oculr toxicity nd only one cyclosporine implnt (of 24 totl) ws 2014 mericn College of Veterinry Ophthlmologists, Veterinry Ophthlmology, 18, 234 241
episclerl cyclosporine implnt in kcs 239 4.00 3.50 Good Cndidtes d Cndidtes 3.00 Men Score - Oculr Dischrge 2.50 2.00 1.50 1.00 0.50 Dys er implnt on Figure 6. Overll the mximum sttisticlly significnt reduction in oculr dischrge ws chieved t 60 dys (P = 2) nd remined significnt up for 480 dys. Mens with different letters re significntly different (P < 0.05). extruded t 5.5 months fter implnttion. Histologiclly, these eyes demonstrted no toxicity of the oculr tissues or lcriml glnds; however, fine, firous encpsultion surrounding the implnt tht secured it to the episcler ws oserved. Over 6-month period, the men Cs concentrtion in the conjunctiv, lcriml glnd, nd corne ws significntly higher thn drug concentrtions necessry for inhiition of firolst prolifertion nd T- cell ctivtion. 32 Cs tissue levels of implnttion were lso higher thn tissue drug concentrtions in the lcriml glnd chieved with topicl nd orl cyclosporine formultions. 32,41,42 In our study, one implnt ws lost t 1 week fter implnttion nd nother implnt t 12 months fter surgery. The cuse of the implnt extrusions is unknown, ut the erly loss ws likely from loss of surgicl incision integrity. No other evidence of implnt complictions or toxicity ws oserved in these clinicl ptients. nother purpose of this study ws to determine whether ESMC implnts hve efficcy in the tretment in cnine KCS. Use of n ESCM hs een descried for the tretment of KCS in red wolf, which hd the disese controlled for >12 months fter ilterl implnttion. 34 In preclinicl evlution of ESCM for grft-versus-host disese in humns, the phrmcodynmics of the implnts were studied in cnine model of queous ter deficiency nd KCS. 32 The Cs implnt ws evluted in dogs with nturlly occurring KCS (STT <5 mm/min). smller implnt (1.3 cm long, 2 mm wide, nd 1 mm high) ws inserted in the superotemporl episclerl spce of eight eyes of six dogs. fter follow-up of 6 months, ll the implnt-recipient eyes mintined STT scores of more thn 10 mm/min nd were le to discontinue topicl cyclosporine. None of the treted eyes exhiited recurrence of KCS symptoms such s conjunctivl hyperemi or dischrge. In ddition, there ws no implnt extrusion or toxicity relted to the cyclosporine implnt in this group of dogs. 32 In our study, the mximum effect on STT vlues nd clinicl scores ws evident from 60 to 90 dys fter implnttion, nd ws effective for 10 months for STT nd 17 months for clinicl scores. This supports therpeutic effect ner, or slightly elow, the estimted therpeutic relese time determined from in vitro studies. 32,40 s it could e expected in smll retrospective study, the present study hs its limittions. Clinicl scores were sujective, negtive or shm implnt control group ws not included, nd the numer of eyes treted ws smll. Furthermore, mesuring Cs concentrtions in ters, conjunctiv, or lcriml glnd would hve further supported our clinicl findings. However, the improvement of clinicl signs nd STT vlues compred to seline in our study nd the similrity of our results to previous studies support our conclusion tht the use of the implnts resulted in sustined therpy of KCS in the dogs of this study. The episclerl implnt tht is descried nd used in this report hs mny dvntges, including the ility to deliver 2014 mericn College of Veterinry Ophthlmologists, Veterinry Ophthlmology, 18, 234 241
240 rchetti ET L. constnt therpeutic levels of drug directly to the site of oculr disese, while minimizing systemic side effects. 20,21 In ddition, cses tht re refrctory to tretment due to ptient nd/or owner non-complince in drug dministrtion would enefit from this sustined relese oculr drug delivery technology. This noniodegrdle implnt hs lso the dvntge of stedy, controlled relese of drug during potentilly long periods of time ut the disdvntge of removl nd/or replcement when the drug is depleted. 20,21,23,32 In ddition, it requires surgicl procedure to e implnted, so its routine use would require multiple surgeries in dog over its lifetime. 20,21 Devices with longer durtion of relese nd injection technologies using microprticles, nnoprticles, or gel-forming solutions tht do not require surgery for ppliction would e desirle for tretment of chronic oculr disese in dogs. The results of this study support the further development nd evlution of episclerl cyclosporine implnts in dogs with KCSU. dditionl studies, using prospective, controlled studies, re needed to determine the solute therpeutic role, tolernce, durtion of effect, nd optiml numer of ESMC implnts for the tretment of cnine KCS. REFERENCES 1. Crter R, Colitz CMH. The cuses, dignosis nd tretment of cnine kertoconjunctivitis sicc. Veterinry Medicine 2002; 97: 683 694. 2. guirre GD, Ruin LF, Hrvey CE. Kertoconjunctivitis sicc in dogs. Journl of the mericn Veterinry Medicl ssocition 1971; 158: 1566 1579. 3. Perry HD, Donnenfeld ED. Dry eye dignosis nd mngement in 2004. Current Opinion in Ophthlmology 2004; 15: 299 304. 4. Izci C, Celik I, lkn F et l. Histologic chrcteristics nd locl cellulr immunity of the glnd of the third eyelid fter topicl ophthlmic dministrtion of 2% cyclosporine for tretment of dogs with kertoconjunctivitis sicc. mericn Journl of Veterinry Reserch 2002; 63: 688 694. 5. 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