Article Text
PDF
Abstract
Backgrounds To evaluate the efficacy of 2% topical ciclosporin A in treating and preventing graft rejection episodes after penetrating keratoplasty (PKP) in patients with a history of graft rejection episodes.
Methods In this prospective, randomised, double-blind clinical trial, a group of PKP patients were randomly given 2% topical ciclosporin A (group 1) or a placebo (group 2) in addition to a corticosteroid regimen upon an episode of subepithelial or endothelial graft rejection. The topical ciclosporin and placebo were continued for 6 months. The duration of corticosteroid application and the time to resolution of the rejection episode for which ciclosporin or placebo was started, the number of concurrent and subsequent rejection episodes, and the rate of rejection-free survival were compared between the two groups.
Results 22 eyes of 22 patients (12 men) were in group 1 and 21 eyes of 21 patients (10 men) were in group 2. Mean patient age was 32.48 (11.9) years and 35.48 (11.7) years in groups 1 and 2, respectively (p=0.42). Mean follow-up period was 16.6 (6.1) months and 16.0 (6.3) months (p=0.75) and the episode for which 2% topical ciclosporin or placebo was started completely resolved after 25.6 (21.0) days and 33.2 (16.7) days in groups 1 and 2, respectively (p=0.22). The rejection-free graft survival rate was 34.8% in group 1 and 31.7% in group 2 at month 20 (p=0.89).
Conclusion 2% topical ciclosporin A did not add any advantage to conventional corticosteroid treatment in terms of treating and preventing graft rejection in PKP patients with previous history of rejection episodes.
- Ciclosporin
- graft rejection
- rejection-free graft survival rate
- cornea
Statistics from Altmetric.com
Corneal transplantation is one of the most common organ transplantations, with a success rate of up to 95% over a 4-year follow-up.1 Rejection is the most common cause of graft failure,2 with graft survivals of 42.6% at 1 year and 36.1% at 3 years after a severe endothelial rejection episode.3 Topical corticosteroids still constitute our most important therapeutic intervention for preventing and treating corneal graft rejection,4 but are associated with serious ocular complications.5
Introduced in 1969, ciclosporin A has been used for several systemic and ocular diseases. Graves' ophthalmopathy, corneal peripheral melting, and intermediate and posterior uveitis are among the ocular diseases that have been treated with ciclosporin.6–8 Recently, ciclosporin A has been proposed as an alternative for prevention of corneal graft rejection, alone or in combination with corticosteroids, with different success rates.9–15 However, its exact role in this regard remains to be elucidated.
In this clinical trial, we evaluate the efficacy of 2% topical ciclosporin A in the treatment and prevention of subepithelial and endothelial graft rejection reactions in a group of patients undergoing penetrating keratoplasty (PKP), who experienced at least one episode of graft rejection.
Materials and methods
In this prospective, randomised, double-blind clinical trial (NCT01028443, Protocol Registration System, http://register.clinicaltrials.gov/) conducted in a private practice setting, patients undergoing PKP for underlying pathologies such as keratoconus, corneal stromal dystrophy, Fuchs' endothelial dystrophy and corneal scars without vascularisation, who had at least one episode of graft rejection before entering the study, were enrolled. Graft rejection reaction was defined as follows: the presence of subepithelial infiltration, the presence of keratic precipitates with or without anterior chamber reaction, or graft oedema in a previously clear graft with or without keratic precipitates or anterior chamber reaction. In the case of graft oedema without keratic precipitates or anterior chamber reaction, oedema reversal after taking corticosteroids differentiated graft rejection from endothelial decompensation. The presence of other ocular pathologies that could increase the risk of graft rejection and failure such as iridocorneal adhesion, corneal vascularisation, previous graft failure, high intraocular pressure, uveitis and herpetic eye disease led to patient exclusion. Ethics committee approval was received, and informed consent was obtained after explaining the purpose of study to the participants.
Upon graft rejection, the participants were randomly given 2% topical ciclosporin A (prepared in olive oil; Sina Darou Pharmacy Co., Tehran, Iran) or placebo (olive oil; Sina Darou Pharmacy Co.) four times a day for 6 months in addition to corticosteroid treatment. The participants and the ophthalmologist (S.F.) who analysed the results were unaware of the type of drops. Based on the severity of graft rejection reaction, corticosteroid treatment consisted of 0.1% topical betamethasone every 1 h during waking hours with its ophthalmic ointment during sleep, alone (in the presence of subepthelial infiltration or some scattered keratic precipitates) or in combination with 1 mg/kg oral prednisolone for 2 weeks (in the presence of rejection lines or graft oedema overlying the keratic precipitates). The topical corticosteroid was gradually tapered off over 2 weeks after resolution of the rejection episode, which was defined as complete clearance of keratic precipitates and/or anterior chamber reaction. Graft rejection episodes recurring after the termination of ciclosporin were treated with corticosteroids as usual. The patients were followed up every week until complete resolution of the graft rejection episode and then every month for 3 months, every 2 months for 1 year and every 6 months onwards. The participants had free access to the ophthalmologist and in the case of visual acuity reduction or eye redness; they were examined between the follow-up examinations as seen necessary.
Statistical analysis
Considering α error=5.0%, power=85%, d=50% (reduction in recurrence) and SD of recurrence=55%,16 the sample size was calculated to be 21 patients in each group. The main outcomes compared between the study groups included (1) previous, concurrent and subsequent numbers of rejection episodes; (2) the duration of corticosteroid administration and the time to resolution of the rejection episode for which 2% topical ciclosporin A or placebo was started; and (3) time interval from the initiation of study to the first recurrence of subepithelial or endothelial graft rejection. The efficacy of ciclosporin A was also evaluated by the rate of rejection-free graft survival using Kaplan–Meier survival curve and log-rank test.
Kolmogrov–Smirnov test was used within each group to determine which parameters had normal distribution. This test is a nonparametric test of equality of one-dimensional probability distributions used to compare a sample with a reference probability distribution (one-sample K–S test) or to compare two samples (two-sample K–S test). It can be modified to serve as a goodness-of-fit test by which samples are standardised and compared with a standard normal distribution. For normally distributed parameters expressed in mean and SD, Student t test was applied to compare the measured parameters. Parameters without normal distribution, presented in median and IQR (instead of mean and SD), were compared with U Mann–Whitney test. A p value <0.05 was considered significant.
Results
In this clinical trial, 44 eyes of 44 patients were initially sampled. One case belonging to the treated group was excluded because of medication intolerance. Therefore, 43 eyes (18 right) of 43 patients (22 men) remained in the study to be analysed. The primary indications for PKP are shown in table 1.
Indications for penetrating keratoplasty in each group
The patients were randomly given 2% topical ciclosporin eyedrops (22 eyes; group 1) or a placebo (21 eyes; group 2) in addition to a corticosteroid regimen upon an episode of graft rejection. The mean patient age was 32.48 (11.9) (range 18–58) years and 35.48 (11.7) (range 17–59) years in groups 1 and 2, respectively (p=0.42). The median of time interval from transplantation to the prescription of topical ciclosporin A and placebo was 21.6 (IQR 6.5–49.8) months and 19.3 (IQR 6.9–33.1) months, respectively (p=0.41). The median of graft rejection episodes before the initiation of study was 2 in groups 1 and 2 with an IQR of 1–4 and 1–3.5, respectively (p=0.44). Mean follow-up period after the cessation of either topical ciclosporin A or placebo was 16.6 (6.1) (range 5–33) months in group 1 and 16.0 (6.3) (range 2–30) months in group 2 (p=0.75). Table 2 gives further information about each group.
Demographic data of study groups
For the episode of graft rejection in which topical ciclosporin or placebo was started, the participants in groups 1 and 2 received 0.1% betamethasone eyedrop for 50.6 (10.6) (range 31–68) days and 60.3 (21.1) (range 36–124) days, respectively (p=0.08). The episode took 25.6 (21.0) days in group 1 and 33.2 (16.7) days in group 2 to completely resolve (p=0.22).
Afterwards, group 1 experienced a mean 2.7 (1.8) (range 0–5) episodes of graft rejection (48% endothelial and 52% non-endothelial) and group 2 had an average of 1.4 (1.2) (range 0–4) episodes (43% endothelial and 57% non-endothelial) during the follow-up period (p=0.03). Of these, 1.7 (1.4) (range 0–4) episodes occurred while the participants of group 1 were receiving topical ciclosporin A, and 1.0 (0.9) (range 0–3) episodes recurred in group 2 during the corresponding period of receiving placebo (p=0.14). The first recurrent rejection episode occurred after a mean of 5.8 (3.1) (range 2–12) months and 6.6 (3.8) (range 2–16) months in groups 1 and 2, respectively (p=0.57).
The rejection-free graft survival rate measured with Kaplan–Meier survival curve and compared with log-rank test was 34.8% in group 1 and 31.7% in group 2 at 20 months (p=0.89) (figure 1) The mean length of rejection-free graft survival was 10.5 (0.5) months in group 1 and 14.2 (2.7) months in group 2 with a median of 8 months in both groups.
Rejection-free graft survival rate measured with the Kaplan–Meier method. This rate was 34.8% in the ciclosporin group and 31.7% in the placebo group at month 20 (p=0.89).
No significant complications occurred during the study. As mentioned, only one case from group 1 was excluded due to medication intolerance. Graft failure occurred only in one case with the primary diagnosis of iridocorneal endothelial syndrome (Chandler variant) who had received topical ciclosporin A. Otherwise, all grafts remained clear at the final follow-up examination with a mean best corrected visual acuity of 0.23 (0.31) (range 0–1.5) logMAR and 0.19 (0.12) (range 0–0.30) logMAR in groups 1 and 2, respectively (p=0.53).
Discussion
A survey by Randleman et al17 evaluating the trend in the prevention and treatment of corneal graft rejections among the members of The Cornea Society demonstrates that 48% of the respondents prescribed topical ciclosporin A for routine management of high-risk grafts, while only 7–13% used it for definite or probable graft rejection episodes. The efficacy of ciclosporin in the treatment and prevention of graft rejection still remains a matter of controversy. Although some studies9–13 have reported its effectiveness in preventing rejections in adults as well as in paediatric patients for the treatment of acute graft rejection reactions, other animal18 and clinical14 15 studies failed to demonstrate any benefit.
In the current study, adding topical ciclosporin A to the corticosteroid regimen for an episode of graft rejection reaction did not alter the duration of betamethasone application nor did it shorten the resolution period. It has been shown that ciclosporin should be taken for several weeks to several months to achieve maximum efficacy.19 For this reason, it cannot be considered as a sole treatment in episodes of graft rejection, and corticosteroids remain our first choice in this regard.
There was no significant difference between our study groups in terms of the number of graft rejection episodes during the period in which the treated group received topical ciclosporin A. Also, ciclosporin could not postpone the first recurrent rejection episode in the treated group. This finding is in contrast to that reported by Cosar et al12 in which treatment with 2% topical ciclosporin and topical corticosteroid in combination was more effective in preventing corneal graft rejection episodes in paediatric keratoplasty than the use of corticosteroids alone. Price et al14 observed that 0.05% topical ciclosporin A was not as effective as 1% topical prednisolone for the prevention of graft rejection episodes in low-risk corneal transplants. Evaluating the efficacy of systemic ciclosporin A in preventing rejection and graft failure in high-risk keratoplasty, a study by Poon et al15 failed to show a significant difference between the ciclosporin A group and the control group in terms of rate of rejection and graft failure due to rejection. The authors considered the more severe underlying pathology among the ciclosporin A group as a probable explanation for this observation. However, this explanation is not applicable to our findings as the study groups were comparable concerning the underlying corneal pathologies leading to transplantation. Unal and Yucel16 started a combination of 0.1% dexamethasone and 0.05% topical ciclosporin for a long period (between 10 and 24 months) immediately after PKP for a group of high-risk corneal transplants and did not find further reduction in the rate of graft rejection in comparison with another high-risk group receiving only 0.1% topical dexamethasone postoperatively.
An important difference between aforementioned studies11–16 and ours is that we started topical ciclosporin just after an episode of graft rejection rather than after transplantation. This explains why the rate of rejection-free survival in our study is much lower. Our participants were chosen from those who had already experienced at least one episode of graft rejection. Although the rate of graft rejection after PKP can be as low as 2.3%, it increases dramatically in corneal transplants with previous rejection episodes, regardless of whether the primary indication for transplantation is among low-risk or high-risk indications.20
From a clinical point of view, prolonged ciclosporin A administration is required for the prevention of graft rejection.11 Interestingly, our treated group clinically but not statistically experienced more episodes of graft rejection than the placebo group after cessation of topical ciclosporin. The 6-month period of topical ciclosporin administration was probably not long enough to alter the immunologic response to the donor antigen for a long period.
In conclusion, we did not find 2% topical ciclosporin A effective for treating and preventing graft rejection episodes. One limitation of this study is evaluating the two types of graft rejection, subepithelial and endothelial, at the same time. Although these are caused by the recipient immunologic response against foreign antigens, the subepithelial type has a better outcome and rapidly responds to medications, making the study groups heterogeneous and hence drawing a definite conclusion more difficult. Another limitation is selecting the sample from the indications with inherently low risk of rejection (such as keratoconus and non-vascularised corneal scar) probably even after an episode of rejection reaction. Since excluding high-risk indications (iridocorneal adhesion, corneal vascularisation and previous graft failure) decreases the risk ratio, a larger sample size might be required to reach a significant difference between the treatment arms. Therefore, further investigation on a larger sample using the medication for a longer period seems to be necessary to evaluate the role of this alternative in the management of graft rejection reaction.
References
Footnotes
Funding Sina Daru Pharmacy Co, Tehran, Iran.
Competing interests Ahmad Karbasian is the executive manager of Sina Daru Pharmacy Co, from which 2% topical ciclosporin and placebo were procured. The other authors had no financial or propriety interest in any of the materials used in this article.
Patient consent Obtained.
Ethics approval This study was conducted with the approval of the Ophthalmic Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Provenance and peer review Not commissioned; externally peer reviewed.
Linked Articles
- At a glance