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Keywords:

  • cyclosporine;
  • horse;
  • immune-mediated;
  • keratitis;
  • sustained release

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Purpose

To describe the use of episcleral silicone matrix cyclosporine (ESMC) drug delivery devices in horses with immune-mediated keratitis (IMMK) with evaluation of tolerability and efficacy in long-term control of inflammation.

Methods

Retrospective study. ESMC implants (1.2 cm length, 30% wt/wt cyclosporine (CsA) in silicone; with approximately 2 μg/day steady-state release for at least 400 days) were used.

Results

Nineteen horses (20 eyes) received two or more ESMC implants for superficial stromal (n = 9), midstromal (n = 3), or endothelial (n = 5) IMMK. Three additional horses received two or more ESMC implants for pigmentary keratouveitis (PK). Nine eyes of eight horses with superficial and five eyes of five horses with endothelial IMMK were well controlled after placement of ESMC implants (mean follow-up 176.8 and 207.2 days, respectively). Horses with midstromal IMMK and PK were not controlled with ESMC implants alone, but instead required frequent use of other medications or surgery to control the disease. The mean duration of disease prior to ESMC implantation of horses with midstromal IMMK was 495 ± 203.9 days, compared with 121.6 ± 92.7 days with superficial IMMK. ESMC implants were well tolerated by all horses without documented loss of the device.

Conclusions

Results from this preliminary retrospective study suggest that the ESMC implants were well tolerated and associated with treatment success with superficial and endothelial IMMK, especially if placed early in the disease process. Further study is needed to determine the duration of efficacy, number of implants required, and better therapies for chronic midstromal IMMK and pigmentary keratouveitis.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Immune-mediated keratitis (IMMK) is a common, nonulcerative keratitis of horses that is characterized by corneal opacification, vascularization, and variable degrees of ocular pain. The etiopathogenesis is largely unknown but is presumed to be immune mediated based on lack of etiologic organisms identified, a predominant T-cell-mediated infiltrate, and favorable response to immunosuppressive therapy.[1-3] Several types of equine IMMK have been described, and clinical features are based on the location of inflammation within the cornea, namely superficial, stromal, endothelial, and newly described pigmentary keratouveitis.[1-6] Treatment for IMMK differs somewhat based on the location of the inflammation; however, the mainstay of therapy is topical immunosuppressant medications, especially CsA.[2] Unfortunately, topical medication is required chronically if not for the remainder of the horses’ life. This chronic treatment is difficult in horses, especially when needed multiple times a day, and enthusiasm and thus compliance by the horse owner to administer this medication wanes with time. Therefore, adequate control of chronic disease, such as IMMK in horses, is challenging.

Sustained release ocular drug delivery devices, or implants, have been developed over the past decade, which allow a low dose of medication to be released to the eye for an extended period of time.[7-15] A major advantage of such drug delivery devices in veterinary medicine is that ocular therapy does not rely on patient or owner compliance. Intraocular delivery of medications has been successfully achieved using intravitreal or suprachoroidal space implant devices.[7, 10, 13, 14] These implants direct drug delivery to the ocular posterior segment with little or no drug exposure to the anterior segment of the eye or cornea. To direct drug to the cornea, silicone matrix implant devices placed in the episcleral space (i.e., subconjunctival, subtenons, adjacent to the sclera) have been demonstrated to deliver drugs such as CsA to the cornea in a sustained release manner and are in development in humans for treatment for high-risk corneal transplants, keratoconjunctivitis sicca, and graft-vs.-host disease.[8, 9, 11] Cyclosporine/silicone matrix implants have been demonstrated to be well tolerated in animals and release a high amount (2–5 μg/day) of drug over the initial 5 months followed by a steady-state release of 1–2 μg/day up for at least 400 days.[11] These episcleral CsA implants have been shown to be well tolerated and efficacious in dogs with keratoconjunctivitis sicca.[9, 16]

The purpose of this study was to describe the use of episcleral silicone matrix cyclosporine (ESMC) drug delivery devices in horses with IMMK with evaluation of tolerability and efficacy in long-term control of inflammation.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

This retrospective study was performed by reviewing records of horses diagnosed with IMMK or pigmentary keratouveitis and implanted with ESMC implants from 2005 to 2013 at North Carolina State University, The Ohio State University, and a private equine ophthalmology practice in Brescia, Italy. Immune-mediated keratitis was diagnosed based on criteria described previously.[1, 2, 4, 5] Briefly, IMMK was characterized by corneal opacification localized to the superficial stromal, middle stroma, or endothelium; corneal vascularization; mild or lack of ocular pain; no etiologic organisms identified; and favorable response to immunosuppressive therapy.[1, 2, 4, 5] Pigmentary keratouveitis (PK), a disease that is similar to IMMK, was diagnosed based on clinical criteria described recently, which included signs of corneal edema, pigmented keratic precipitates, anterior uveitis, and iridal depigmentation.[6] Selection of cases that received ESMC implants was based solely on the discretion of the ophthalmologist, but the most common indications considered for implantation were favorable disease response to topical CsA (Optimmune, Schering-Plough Animal Health, Union, NJ or compounded 1–2% CsA) and inability of the owner to provide ongoing topical therapy. Horse owners were provided consent for this experimental procedure and were fully informed that long-term outcome, complications, and efficacy of the implants in horses with IMMK were not known. Because the drug delivery rate from the ESMC implants was designed for the human eye and not for the much larger equine eye,[17] and because of previous studies that demonstrated adequate safety margins of the use of multiple implants in dogs and rabbits,[8, 11] clinicians elected to place two to four implants per eye for treatment for IMMK.

Implants were created as described previously.[8, 11] Briefly, the implants were made in a polytetrafluoroethylene mold with impressions on the surface measuring 12 mm long, 2 mm wide, 1 mm in height. Cyclosporine powder (Xenos Bioresources, Inc., Santa Barbara, CA, USA) was mixed with medical grade silicone (Nusil Technology, Carpinteria, CA, USA) so that the weight of the drug as a percentage of the total weight of the implant (wt/wt) was 30% resulting in approximately 12 mg of CsA loaded into each implant.[8, 11] This CsA silicone paste was placed in the impressions of the mold and cured for a minimum of 24 h at room temperature (Fig. 1). Each implant was sterilized with gamma irradiation (25–30 kGy).

image

Figure 1. Episcleral silicone matrix cyclosporine implants; 12 mm long, 2 mm wide, 1 mm in height.

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The surgical implantation was performed in standing, tranquilized horses after application of topical anesthetic (proparacaine HCL ophthalmic solution, USP 0.5%, Akorn, Inc., Lake Forest, IL, USA) with or without a retrobulbar nerve block (lidocaine HCL, Phoenix Scientific, Inc., St. Joseph, MO, USA),[18] or in some cases under a short acting general anesthesia (e.g., a ‘triple drip’ consisting of ketamine [100 mg/mL, Vetaket®; Lloyd, Shevandoah, IA, USA], 5% guaifenesin [Butler, Columbus, OH, USA], and xylazine HCL [Xylaject®; Akorn Inc., Buffalo Grove, IL, USA] to effect). After surgical aseptic preparation of the eye, a 3-mm incision was made through the superior temporal conjunctiva and tenon's capsule 5 mm posterior to the limbus. A pocket was formed in the episcleral space, adjacent to the sclera, and two to four implants were placed into the one or more pockets oriented parallel to the limbus. Selection of the number of implants to be used was based on clinician preference. The conjunctiva was closed with a single interrupted or cruciate absorbable suture (e.g., Vicryl; Ethicon Inc, Somerville, NJ, USA). Following implantation, medications given previously were continued with addition of a topical antibiotic (e.g., triple antibiotic ophthalmic ointment, Bausch & Lomb, Rochester, NY, USA) given for at least 5 days. After implantation, topical medications were tapered over 30 days, and the horse was maintained on the minimum effective medication to control the IMMK. Recheck examinations were recommended every 1–2 months after implantation and included a complete ophthalmic examination including slit-lamp biomicroscopy and indirect ophthalmoscopy.

Outcome parameters

The IMMK was considered ‘controlled’ if the disease was considered inactive (i.e., receded vascularization, clearing of corneal cellular infiltrate, improvement in or elimination of corneal edema) when medications were tapered to one topical medication or less administered.[2, 4, 5] Outcome measures and end points regarding clinical improvement are difficult to define in retrospective studies; however, in this study, postimplant ‘treatment success’ was defined as improvement from preimplant corneal vascularization, cellular infiltrate, corneal edema, and signs of ocular discomfort. In the horses of this report, ‘treatment failure’ after the implant was defined as those horses that did not have an improvement in clinical signs of IMMK (i.e., no reduction in vascularization, no clearing of corneal cellular infiltrate, or persistent corneal edema), developed corneal perforation, or required the eye to be enucleated. Use of additional medications or surgery (i.e., rescue therapy) was based on development of signs of progressive disease, such as increase corneal edema, vascularization, and cellular infiltrate compared with prior to the implant procedure.

Data and statistical analysis

Parametric normally distributed data (i.e., age, disease duration, follow-up time) were compared by time point for each group using 1-way ANOVA models with Tukey–Kramer post hoc analysis. For nonparametric data (i.e., gender), Wilcoxon tests were conducted per animal by time point. Differences were considered significant at < 0.05. Results and probabilities were calculated using computerized statistical software (JMP 10; SAS Inc. Cary, NC, USA).

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Overall, 20 eyes of 19 horses were treated with ESMC implants for IMMK or pigmentary keratouveitis. ESMC implants were placed in nine eyes of eight horses that were diagnosed with superficial stromal IMMK, three eyes of three horses with midstromal IMMK, five eyes of five horses with endothelial IMMK, and four eyes of three horses with pigmentary keratouveitis (Table 1). Several breeds were represented in this study, with warmbloods being most common (four of the 19 horses). There were 12 geldings and seven mares treated. Mean age of horses treated for IMMK or pigmentary keratouveitis was 15.6 years, with no significant difference in age or gender between the treatment groups (Table 1).

Table 1. Diseases and signalment of horses receiving episcleral cyclosporine implants
DiseaseNumber of eye/number of horsesBreedsSexAge (range and mean) in years
  1. IMMK, immune-mediated keratitis.

  2. a

    Same horse – one eye had superficial IMMK, the other had midstromal IMMK.

Superficial stromal IMMK9a/8Arabian, German, aHalflinger, Holsteiner, Paint, Percheron, Thoroughbred, Warmblood

5 geldings

3 maresa

8–23 (12.25)
Midstromal IMMK3a/3Holsteiner, Germana, Selle Français

2 geldings

1 marea

11–17 (14)
Endothelial5/5Warmblood (3), Oldenburg, Quarterhorse

2 geldings

3 mares

9–24 (14.6)
Pigmentary keratouveitis3/4Hanovarian (2), Quarterhorse3 geldings9–22 (15.3)
Total20/19Warmblood (4), Holsteiner (2), Hanovarian (2), Quarterhorse (2), Arabian, German, Halflinger, Oldenburg, Paint, Percheron, Thoroughbred, Selle Français (1)

12 geldings

7 mares

8–24 (15.6)

There were no reported adverse effects of implantation of the ESMC implants, they appeared well tolerated by the horses, and there were no reports of loss of the implants. There were also no statistically significant differences between the number of implants placed and duration of disease prior to surgery among superficial stromal, midstromal, or endothelial IMMK, or with pigmentary keratouveitis disease categories (Table 2). Furthermore, there were no significant differences in follow-up time after ESMC implants among the disease categories (Table 2).

Table 2. Treatment and outcome of horses receiving episcleral cyclosporine implants
Disease treatment statusNumberMean duration prior to implantMean duration after implantMean number of implants placed (and range)Other procedures (number of eyes treated with procedure [s])Other medications (number of eyes treated with medication)
  1. AMT, amnion membrane transplantation; PK, pigmentary keratouveitis.

Superficial stromal
 SuccessAll 9 eyes121.6 ± 92.7 days176.8 ± 155 days2.5 (2–4)Keratectomy (2)Topical CsA (2)
Midstromal
 FailureAll 3 eyes495 ± 203.9 days160 ± 124.9 days2 (2)Keratectomy and AMT (3) Enucleation (1)Topical dexamethasone (3) Topical CsA (3)
Endothelial
 SuccessAll 5 eyes300.08 ± 447.3 days207.2 ± 193.9 days2.2 (2–3)NoneTopical bromfenac (3)
PK
 FailureAll 3 eyes291.7 ± 149.2 days100 ± 62 days2.3 (2–3)Enucleation (1) Suprachorodial implant (1)Topical bromfenac (3) Topical dexamethasone (3) Oral flunixin meglumine (3)

Superficial immune-mediated keratitis

Two implants were placed in seven eyes and four implants in two eyes (Table 2). The IMMK in nine of nine eyes (in eight horses) was reported to be controlled, and thus considered treated successes, after placement of ESMC implants (Fig. 2), although two horses had a keratectomy performed in addition to the implant placement and two horses were maintained on topical CsA once a day after implantation (Table 2). One of these horses was tapered off all medications but had an IMMK flare-up 14 months after the ESMC implantation, which responded to use of topical CsA (Table 2). The mean duration of disease prior to ESMC implantation of horses with superficial IMMK was 121.6 ± 92.7 (SD) days, and mean follow-up after implantation was 176.8 ± 155 days (Table 2).

image

Figure 2. Superficial immune-mediated keratitis (IMMK) treated with episcleral silicone matrix cyclosporine (ESMC) implants. (a) Horse with superficial IMMK prior to surgical placement of the ESMC implants. (b) Same horse as in (a), 14 months after ESMC implantation. (c) Horse with diffuse superficial IMMK prior to surgical implantation with ESMC implants; (d) 1 month after surgery; (e) 100 days after implantation. Arrows show implants visible in the episcleral space.

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Midstromal immune-mediated keratitis

All three eyes with midstromal IMMK received two ESMC implants. The midstromal IMMK of the three eyes of three horses was not controlled after implantation of ESMC devices (Fig. 3) and thus considered treated failures (Table 2). All three horses were subsequently treated with superficial keratectomy and amnion membrane transplantation (AMT) because of failure of the implants to control the inflammation. One of these three horses had the eye enucleated because of corneal perforation, while the other two eyes ultimately developed residual corneal scars and pigmentation (Table 2). All horses were treated with tapering doses of topical dexamethasone (triple antibiotic ointment with dexamethasone, Falcon Pharmaceuticals, Ltd., Ft. Worth, TX, USA) and CsA. The mean duration of disease prior to ESMC implantation of horses with midstromal IMMK was 495 ± 203.9 days, which was much longer than the disease duration in horses with superficial IMMK, but this difference was not statistically significant. Mean follow-up after implantation in midstromal IMMK eyes was 160 ± 124.9 days (Table 2).

image

Figure 3. Midstromal immune-mediated keratitis (IMMK) treated with episcleral silicone matrix cyclosporine (ESMC) implants. (a) Horse with midstromal IMMK prior to surgical placement of the ESMC implants. (b) Same horse as in (a), 30 days after ESMC implantation with corneal perforation. This eye was enucleated.(c) Horse with midstromal IMMK prior to surgical implantation with ESMC implants; (d) 1 month after surgery without clinical improvement; (e) 300 days after implantation and 240 days after superficial keratectomy and amnion membrane transplantation.

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Endothelial immune-mediated keratitis

Two ESMC implants were placed in four eyes and three implants in one eye with endothelial IMMK (Table 2). All five eyes of five horses treated with ESMC implants were considered to have their disease controlled (Fig. 4) and thus considered treated successes (Table 2); however, three of five eyes were also treated with topical bromfenac (Xibrom, ISTA pharmaceuticals; q24 to q48 h). Residual corneal edema was present in three eyes (although cellular infiltrate resolved), corneal scarring occurred in one eye, and complete clearing of the corneal opacity occurred in one eye. The mean duration of disease prior to ESMC implantation of horses with endothelial IMMK was 300.08 ± 447.3 days, and mean follow-up after implantation was 207.2 ± 193.9 days (Table 2).

image

Figure 4. Endothelial immune-mediated keratitis (IMMK) treated with episcleral silicone matrix cyclosporine (ESMC) implants.(a) Horse with endothelial IMMK prior to surgical implantation with ESMC implants; (b) 1 month after surgery; (c) 510 days after surgery. This horse is also being treated with topical bromfenac once a day.(d) Horse with endothelial IMMK prior to surgical implantation with ESMC implants; (e) 1 month after surgery; (f) 170 days after surgery.

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Pigmentary keratouveitis

Two ESMC implants were placed in two eyes and three implants in one eye with PK (Table 2). All four eyes of three horses that were diagnosed with PK treated with ESMC implants were not controlled after surgery, all required multiple concurrent therapies (topical dexamethasone, topical bromfenac, systemic flunixin meglumine [Banamine, Schering-Plough Animal Health, Union, NJ, USA]; Fig. 5), and were considered treatment failures (Table 2). One eye had persistent uveitis, keratitis, and discomfort and was subsequently enucleated. The other eyes had slowly progressive disease despite topical and systemic therapy. The mean duration of disease prior to ESMC implantation of horses with PK was 291.7 ± 149.2 days, and mean follow-up after implantation was 100 ± 62 days (Table 2).

image

Figure 5. Pigmentary keratouveitis treated with episcleral silicone matrix cyclosporine (ESMC) implants. (a) Horse prior to ESMC implantation with typical clinical signs of pigmentary keratouveitis consisting of diffuse corneal edema, pigmented keratouveitis, iris depigmentation, and mild anterior uveitis (b) Same horse as in (a), 120 days after EMSC implantation with worsening of clinical signs, despite topical and systemic anti-inflammatory therapy. This eye was enucleated.

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Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

This report describes the pilot results of the use of solid, silicone matrix episcleral implants designed to release CsA in therapeutic concentrations to the ocular surface for an extended period of time for the treatment for the noninfectious, chronic, corneal disease of horses (i.e., immune-mediated keratitis). One goal of this study was to determine tolerability of the implant. Because no adverse affects were reported and implants were retained, ESMC implants were considered well tolerated by horses in this study. This clinical finding of good tolerability of the ESMC implants in horses was expected because excellent tolerability and lack of toxicity of multiple ESMC implants in both rabbits and dogs for up to a year have been reported.[8, 9, 11]

Another goal of this preliminary study was to determine whether ESMC implants have efficacy in the treatment for equine IMMK. Because this was an open label, uncontrolled study, determining efficacy of the implants in this disease, was difficult. Because this design was uncontrolled and four disease manifestations of IMMK were studied, each with low group numbers, there were variable stages of disease at presentation, and concurrent therapies were used, which made assessment of efficacy of the ESMC implants difficult to determine. However, despite these design deficiencies common in small retrospective studies, the 100% treatment success was achieved in superficial stromal and endothelial IMMK after implant placement suggests that the devices were therapeutic. These results support further study of sustained release therapy for treatment for equine IMMK. However, prospective, controlled studies are needed with comparison with placebo implants and topical therapy to determine the absolute therapeutic role ESMC implants have in treatment for equine IMMK.

In vitro release of CsA from the ESCM implants suggested a therapeutic duration of approximately 18 months.[8, 11] In a report of the use of ESCM implants in a red wolf with keratoconjunctivitis sicca, no additional medications were administered, and the keratoconjunctivitis sicca was controlled with only the ESCM implants in this wolf for greater than 12 months.[9] Although mean follow-up time in horses treated with superficial IMMK in this report was less than a year, one horse with superficial IMMK had disease controlled for 14 months prior to a flare-up and three horses with superficial IMMK had greater than 14 months follow-up without recurrence of disease. This suggests an in vivo therapeutic effect near the estimated therapeutic release time of 12–18 months of CsA determined from in vitro studies. Further studies or follow-up is needed to determine duration of therapeutic effect of ESMC implants in the treatment for IMMK of horses.

In this study, superficial IMMK appeared to have a better outcome with the use of ESMC implants compared with midstromal IMMK. It is possible that midstromal IMMK is the natural progression of disease that initially appears as superficial IMMK. The longer duration of disease in midstromal IMMK compared with superficial IMMK provides some support to this theory. The lack of improvement after treatment in midstromal IMMK may be because the disease is in a later stage and thus less amendable to therapy in general. These results are similar to our previous study of equine IMMK in which greater than 90% of superficial IMMK, but only 50% of midstromal IMMK, was successfully controlled with topical medical therapy.[2] Additionally, only 2 ESMC implants per eye were used in the midstromal IMMK eyes, while a mean of 2.5 implants per eye in the superficial IMMK group. It is possible, therefore, that additional implants (i.e., greater than two per eye) may be needed to control midstromal IMMK. Finally, successful use of keratectomy and amniotic membrane grafts has been described previously for treatment for midstromal IMMK,[19] and two of three horses with midstromal IMMK in this study improved with this procedure.

The improved therapeutic success in treatment for superficial corneal and endothelial disease may also have occurred because CsA, a highly lipophilic drug, distributes better to the more lipophilic superficial cornea (via the corneal epithelium) and corneal endothelium, compared with the hydrophilic corneal stroma. Although the distribution of CsA to the various corneal layers has not been determined from the episcleral space, topical CsA has been shown to distribute at high concentrations to the corneal epithelium and endothelium, with lowest distribution to the corneal stroma in the human eye.[20]

The results of the use of ECSM implants in this report suggest that successful clinical response to local sustained release therapy is possible in chronic diseases of the horse's eye. However, the ESMC implant is very simple in design and has some disadvantages. One of the main disadvantages is that it requires a surgical procedure to implant it. Any equine surgical procedure requires appropriate surgical preparation, anesthesia, and restraint. Surgical procedures therefore can be more costly to the horse owner and require more aftercare, especially if complications develop, such as surgical incision infections. Furthermore, although the ESCM device has a relatively long duration of release of 12–18 months, routine use of the implant would still require multiple implantation surgeries in a horse over its lifetime. Devices with longer duration of release or injection technologies using microparticles, nanoparticles, or gel-forming solutions that do not require surgery for application would be desirable for use in horses.[21-23] These more practical approaches are being developed in our laboratory.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

The authors thank Damian Launer, Erin Matheson, Melissa Hamman, and Kelley Norris for technical, data collection, and image access assistance. The authors also thank Dr. Mike Robinson for review of this manuscript.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References
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