Article Text
Abstract
Aim: To evaluate the efficacy of combined treatment with commercially available 0.05% topical ciclosporin and topical corticosteroid compared with treatment with topical corticosteroids only after high-risk keratoplasty.
Patients and methods: A total of 47 high-risk keratoplasties were randomly divided into two groups based on the postoperative immunosuppression. Twenty-five eyes (group 1) were treated with 0.05% ciclosporin and dexamethasone 0.1%, and 22 eyes (group 2) were treated with dexamethasone only. The clinical outcome of penetrating keratoplasty was evaluated by the rate of rejection-free graft survival and graft survival evaluation by the Kaplan–Meier logrank test.
Results: The average length of follow-up was 20.2 (SD 7.1) months in group 1 and 18.5 (6.6) months in group 2 (p = 0.421). Rejection-free graft survival rates were 60.8% in group 1 and 54.5% in group 2 (Kaplan–Meier logrank test, p = 0.474). In group 1, the graft survival rate was 73.9%; in group 2, the graft survival rate was 68.1%. The difference in the graft survival rates between the groups was also not statistically significant (Kaplan–Meier logrank test, p = 0.518).
Conclusion: In high-risk corneal grafts, the efficacy of 0.05 percent commercially available topical ciclosporin combined with dexamethasone topically was not better than that of dexamethasone alone in preventing rejection.
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Keratoplasty is the most common form of human solid tissue transplantation. Despite prophylactic postoperative medical management, corneal allograft rejection is the leading cause of graft failure in corneal transplantation.1 2 Topical corticosteroids remains the mainstay for the prevention and treatment of corneal graft rejection; however, the role of newer agents, including topical ciclosporin, is expanding.3
Ciclosporin is a selective immunosuppressive agent with specificity against a variety of functions of T lymphocytes, cells that play a central role in mediating allograft rejection.4 5 It is most commonly used systemically to prevent rejection of transplanted tissues including corneal transplantation.6–8 Systemic administration is, however, associated with unavoidable side effects including nephrotoxicity, hepatotoxicity and hypertension. The role of topical use for prevention of corneal allograft rejection has been a subject of interest in recent years.
It was reported that the majority of surgeons who use immunosuppressive agents in high-risk corneal grafts preferred topical ciclosporin.3 9 Results of different concentrations and formulations of topical ciclosporin were reported. Although some studies showed improvement of corneal allograft survival with topical use of ciclosporin 2% in both low- and high-risk adults,10 11 and in paediatric patients with transplants,12 its beneficial effect on the prevention of corneal graft rejection is still disputable.13 14
Commercially available topical 0.05% ciclosporin ophthalmic emulsion has been approved for treatment of keratoconjunctivitis sicca. Its role in prevention of graft rejection in low-risk corneal transplants was evaluated.15 The purpose of the current study was to compare the rates of corneal allograft rejections in high-risk patients receiving topical dexamethasone combined with topical ciclosporin 0.05% and those treated with topical dexamethasone alone. This prospective study is the first to evaluate the efficacy of commercially available topical ciclosporin 0.05% (Restasis, Allergan, Irvine, CA) on rejection rates in high-risk corneal graft patients.
MATERIALS AND METHODS
This prospective randomised study was conducted at Akdeniz University Medical Faculty Department of Ophthalmology. The research followed the tenets of the Declaration of Helsinki. A total of 47 subjects undergoing high-risk penetrating keratoplasty were included after having properly obtained written informed consent. All grafts were provided by our own cornea bank (Akdeniz University Cornea Bank).
All study patients were older than 21 years old. Criteria for high-risk patients were as follows: presence of corneal vessels (presence in two or more quadrants, deep stromal vascularisation or extension to graft–host junction), history of graft rejection in the same eye, previous history of herpetic eye disease, dry eye, previous ocular inflammation or infection or previous chemical injury. Table 1 shows the primary corneal pathology in study groups.
Detailed donor information was available in all cases. We did not perform tissue matching for HLA. The donor age ranged from 2 to 84 years. Corneoscleral buttons were stored in Optisol GS solution. The death-to-enucleation time ranged from 1 to 6 h, and utilisation time from 0 to 3 days.
All patients underwent penetrating keratoplasty under general or retrobulbar anaesthesia by the same surgeons (MÜ, IY). The donor cornea was trephined from the endothelial surface. Trephine size was selected according to recipient corneal size (range 7.5–8 mm), and the donor–recipient disparity was 0.25–0.50 mm (oversized). 10-0 nylon suture material was used. The technique of suturing was interrupted or a combination of a single running and interrupted.
After surgery, all patients received topical antibiotic drops at least until the graft was covered with a complete epithelial layer. Group 1 consisted of 25 patients who began using one drop of topical ciclosporin 0.05% (Restasis, Allergan, Irvine, CA) four times a day, and they simultaneously began receiving topical dexamethasone 0.1% 6 times a day. Both drugs were begun at the first postoperative day. A further 22 patients (group 2) received six drops of dexamethasone 0.1% tapered off appropriately.
Study subjects were examined at 1 day, 1 week, 1 month and every month thereafter. At each follow-up visit, a complete ocular examination was performed. This included recording visual acuity with Snellen chart, tonometry, anterior and posterior segment evaluation with a slit lamp, and indirect ophthalmoscopy. Secondary glaucoma and cataract development were recorded.
The corneal grafts were evaluated for clarity and signs of immune response such as epithelial and/or endothelial rejection line, corneal oedema and anterior chamber inflammatory reaction. Patients with mild immune reactions were treated with dexamethasone 0.1% eye-drops hourly with or without subconjunctival steroid injection. Intravenous methylprednisolone 3 mg/kg/day for 3 days or oral prednisolone acetate 1 mg/kg/day was also administered in severe cases. Graft failure secondary to rejection was defined as when failure was thought to be due primarily to rejection. Failures due to other causes such as glaucoma or infection were excluded from the analysis.
Clear graft survival and rejection-free interval were the main outcome measures. Drug-related complications were also recorded.
The Student t test, Fisher exact χ2 test and Kaplan–Meier logrank test were used to compare the study group with the control group for the reviewed data. A p value less than 0.05 was considered to show a statistically significant difference.
RESULTS
A total of 47 high-risk keratoplasties were included in this prospective study. There were 25 patients in group 1 and 22 patients in group 2. Data for two patients in group 1 who had graft failure due to infection and trauma were excluded from the analysis. Primary corneal pathology and patient demographics were shown on tables 1, 2, respectively. There were no statistically significant differences between the groups in relation to age and gender (p>0.05). The average length of follow-up was 20.2 (SD 7.1) months (range 7–30 months) in group 1 and 18.5 (6.6) months (range 6–30 months) in group 2. Follow-up periods were not different between the groups (p = 0.421).
The mean duration of immunosuppression with dexamethasone was 9.5 (2.2) months in group 1 and 10.8 (3.9) months in group 2. This difference was also not statistically significant (p = 0.095). The mean duration of topical ciclosporin use in Group 1 was 12.0 (3.6) months (range 10–24 months).
In group 1, the rejection-free graft survival rate was 60.8%; in group 2, the rejection-free graft survival rate was 54.5%. The difference in the rejection-free graft survival rate was not statistically significant (Kaplan–Meier logrank test, p = 0.474; fig 1). In group 1, the graft survival rate was 73.9%, and in group 2, the graft survival rate was 68.1%. The difference in the graft survival rates between the groups was also not statistically significant (Kaplan–Meier logrank test, p = 0.518; fig 2).
Postoperatively, two eyes in group 2 and one eye in group 1 developed cataract. Ocular surface disorders occurred in one patient in each group. Glaucoma that could be controlled with antiglaucoma medications developed in two patients in group 2. None of the complications differed between the groups (p>0.05).
Intravenous steroid treatment was needed in three rejection cases in group 1, and two cases in group 2 (p>0.05). Oral prednisolone acetate treatment was administered in two patients in each group (p>0.05).
DISCUSSION
Ciclosporin is a potent immunomodulator that acts selectively and locally when administered at the ocular surface. Although many surgeons currently use topical ciclosporin in addition to topical steroids for routine management of high-risk corneal grafts,3 9 there were no previous reports regarding the efficacy of commercially available topical ciclosporin 0.05% (Restasis, Allergan, Irvine, CA) on rejection rates in high-risk corneal graft patients. The only study to evaluate the role of topical ciclosporin 0.05% in low-risk corneal transplants was performed by Price and Price, and they reported that topical ciclosporin 0.05% was not as effective as the use of topical prednisolone acetate for prevention of graft rejection.15
Before approval of topical ciclosporin 0.05% for keratoconjunctivitis sicca, several studies reported the results of different concentrations and formulations of prepared topical ciclosporin. Belin et al and Inoue et al showed improvement of corneal allograft survival with topical use of ciclosporin 2% in both high- and low-risk adults respectively.10 11 Favourable effects of 2% solution were also reported in paediatric keratoplasty patients,12 but its beneficial effect on the prevention of corneal graft rejection is still disputable.13 14 Furthermore, there is no agreement on the ideal concentration and formulation of topical ciclosporin. In the current study, we did not find the combination of commercially available topical ciclosporin 0.05% and steroids as effective as topical steroids alone for prevention of rejection in high-risk corneal grafts.
Topical ciclosporin has also been evaluated for adjunctive use in the postoperative management of patients with corneal transplants to reduce the need for topical steroids and to prevent steroid-related complications. In the current study, although not statistically significant, cataract and glaucoma development were less frequent in group 1 than in group 2. This may be due to shorter use of topical steroids in group 1. We tapered off corticosteroids earlier in group 1 because of simultaneous use of topical ciclosporin. It was previously reported that topical ciclosporin may be substituted for topical corticosteroids to aid in the management of postkeratoplasty patients with glaucoma.16 17
One of the explanations for ineffectiveness of topical ciclosporin in this study may be that the commercially available formulation evaluated has a relatively low ciclosporin concentration (0.05%). However, commercial solution has also its advantages. This formulation contains a castor oil and water emulsion. Upon instillation directly into the eye, ciclosporin partitions from the oil droplets into the ocular surface tissues. The ocular retention time for this emulsion is approximately 2 h, which exceeds that observed for viscous and saline solution formulations (in the range of several minutes),18 and one of the advantages is that this commercial formulation is more comfortable for the patient than prepared formulations.
Patients included in the study had a high risk for rejection. Despite all the prophylactic measures taken, including systemic immunosuppression, rejection is still the most frequent cause of graft failure after penetrating keratoplasty. The frequency of graft rejection is lower in normal-risk keratoplasty than with high-risk keratoplasty eyes. Therefore, the use of other immunospressive measures other than steroids may become mandatory in high-risk grafts. The rate of rejection episodes varies widely in several studies. The reported incidence of corneal graft rejection varies from 2.3% to 68%. About 12% of graft-rejection cases in patients with good prognostic keratoplasty and 40% in complicated cases have been reported to lead to subsequent graft failure.19 In the current study, rejection rates in both groups were comparable with previous studies.
Several studies have reported that topical ciclosporin was effective in prevention of immune rejection of corneal graft in humans only when combined with topical corticosteroids.20–22 Currently, there is no consensus on the best time to begin and end steroid tapering.23 Some surgeons prefer to taper patients off steroids within 2–3 months after surgery, whereas others contend that taking patients off steroids too soon may increase the risk of rejection episodes. We routinely prefer long-term combined topical steroid and ciclosporin therapy in all high-risk grafts. In the current study, we used topical dexamethasone for a relatively long time in both groups, but adjunctive use of ciclosporin in group 1 did not cause a decrease in graft rejection rate.
On the other hand, topical ciclosporin use after keratoplasty may have other advantages. It has been shown to increase tear production as well as increasing goblet cell numbers and preventing lymphocyte infiltration within the lacrimal and accessory glands and conjunctiva.24 We had only one dry eye in the ciclosporin group, and we did not note any change in Schirmer test results. Another advantage is that ciclosporin has been shown to have antiviral activities against several viruses, including HSV, vaccinia virus, human immunodeficiency virus type 1, and hepatitis C virus in vitro.25 26 On the other hand, corticosteroids are often associated with many potentially serious adverse events that include the recurrence of herpetic disease.
In conclusion, we found that dosing four times a day with commercially available topical ciclosporin 0.05% with topical dexamethasone was not as effective as topical dexamethasone alone in high-risk corneal grafts. Prepared formulations with higher ciclosporin concentrations may be needed.
Acknowledgments
The authors thank Ö Tosun, for the statistical analysis.
REFERENCES
Footnotes
Funding: This study was supported by Akdeniz University Scientific Research Projects Unit.
Competing interests: None.
Ethics approval: Ethics approval was obtained from the Ethics Committee of Akdeniz University Medical Faculty.
Patient consent: Obtained.
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