Topical corticosteroids are the mainstay for short-term control of postoperative ocular inflammation, long-term treatment of ocular conditions involving immune hyperreactivity, and long-term prevention and treatment of immunologic rejection of corneal grafts (off-label use).1 The principal drawbacks, particularly with long-term use, include both cataract formation and steroid-induced ocular hypertension with the potential for steroid-induced glaucoma, which can cause irreversible vision loss. The incidence varies with the type of corticosteroid, dosing frequency, and treatment duration.1
Corneal transplantation offers a unique opportunity to assess how long-term corticosteroid use affects intraocular pressure (IOP) without the confounding effects seen with immune hyperreactivity disorders. Surveys of corneal surgeons have found that all use topical corticosteroids to prevent transplant rejection and that most prefer prednisolone acetate 1% solution.2 In a recent review of glaucoma in endothelial keratoplasty patients, the longest reported follow-up was 3 years.3 The purpose of this study was to quantify longer-term risk of steroid-induced ocular hypertension/glaucoma with long-term use of topical prednisolone acetate.
METHODS
We retrospectively reviewed long-term outcomes among consecutive patients, who had Descemet stripping endothelial keratoplasty (DSEK) between December 2003 and January 2006. The work was compliant with Good Clinical Practices, the Declaration of Helsinki 1996, and the Health Insurance Portability and Accountability Act. An independent review board (Advarra, Columbia, MD) provided an exempt determination for this retrospective chart review.
The study inclusion criteria were patients who had DSEK between December 2003 and January 2006 and used prednisolone acetate 1% long-term thereafter to prevent immunologic rejection (off-label use; n = 320). The exclusion criteria were a preexisting glaucoma diagnosis at baseline (n = 63, 19%) and patients who followed up for less than 1 year at our center (n = 46, 14%). The definition of preexisting glaucoma included any of the following: documented history of glaucoma, preoperative use of antiglaucoma medications, preoperative IOP ≥24 mm Hg, preoperative cup-to-disc ratio ≥0.6, or previous glaucoma filtration surgery. Patients with a history of narrow angle or laser iridotomy were not classified as having preexisting glaucoma unless they met other aforementioned criteria. In 58 patients (18%) who had DSEK in both eyes during the surgical period, the eye with longer follow-up was selected for inclusion in the study. Seven patients had an initial DSEK graft that failed to adequately attach and clear, so a regraft was performed within 2 months and the outcomes were assessed afterward.
The topical steroid dosing regimen used after DSEK matched the standard regimen we used after penetrating keratoplasty (PK), that is, patients were instructed to instill topical prednisolone acetate 1% 4 times daily for 4 months, then taper by 1 drop per month to once daily use, which was continued indefinitely unless the patient developed ocular hypertension. If a rejection episode was suspected or confirmed, topical prednisolone acetate 1% dosing was increased, ranging from 8 times per day up to hourly while awake, depending on rejection severity. After 1 week, if the rejection episode seemed to be successfully resolving, the prednisolone acetate was gradually tapered to 4 times per day and maintained at that dosage for 3 to 4 months, then gradually tapered to a maintenance dose of 1 more drop per day than was being used when the rejection episode occurred.
In patients who developed steroid-responsive ocular hypertension, the prednisolone acetate 1% was usually changed to a less potent steroid such as fluorometholone 0.1% or loteprednol etabonate 0.5%, and dosing was adjusted as needed to adequately lower IOP. Additional measures used as needed to control IOP included initiation of glaucoma medication, discontinuation of topical corticosteroids, and glaucoma filtration surgery (trabeculectomy or aqueous shunt).
Statistical Methods
The main outcome measures were IOP (assessed by Goldmann tonometry) and postoperative use of glaucoma medications or filtration surgery to control IOP. Ocular hypertension was defined as an IOP reading ≥24 mm Hg or an IOP increase of ≥10 mm Hg over the baseline preoperative reading without evidence of glaucomatous nerve damage. Glaucoma treatment was defined as initiation of chronic glaucoma medication use or filtration surgery to control IOP. Descriptive statistics were reported as median and range or as a proportion, as appropriate. The cumulative risks of developing ocular hypertension, requiring glaucoma treatment, or experiencing an initial rejection episode were assessed with Kaplan–Meier analysis and the log-rank test, which are methods that take lost to follow-up into consideration. Data were analyzed with SAS version 9.4 (SAS Institute, Cary, NC). The analyses were 2-sided and P values less than 0.05 were considered significant.
RESULTS
The study included 211 eyes of 211 DSEK recipients without preexisting glaucoma. The median age was 70 years (range 34–94 years) and 66% were female. Fuchs endothelial corneal dystrophy (FECD) was the most common indication for DSEK (n = 185, 88%), followed by pseudophakic corneal edema (n = 15, 7%), early failure of DSEK for FECD (n = 7, 3%), and failed PK (n = 4, 2%). The median follow-up duration was 7 years (range 1–17 years).
The cumulative risk of experiencing steroid-induced ocular hypertension was 29% by 1 year, 41% by 5 years, and 49% by 10 years with long-term, off-label use of prednisolone acetate 1% to prevent transplant rejection, Figure 1. The risk was greatest in the first 6 months while dosing was 2 to 4 times per day and declined thereafter as dosing was maintained at once per day, Figure 1. The risk of developing ocular hypertension after 8 years was low, although 1 patient developed ocular hypertension after using prednisolone acetate for 13 years, Figure 1. The median IOP was 28 mm Hg (range 22–51 mm Hg) at the time ocular hypertension was diagnosed.
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FIGURE 1.: Kaplan–Meier plot showing the cumulative risk of developing steroid-induced ocular hypertension with long-term use of topical prednisolone acetate 1% by keratoplasty recipients without preexisting glaucoma.
Twenty-eight eyes (13%) experienced an immunologic rejection episode between 3 weeks and 11 years after DSEK. The cumulative risk of an initial rejection episode was 8% at 1 year and 14% at 5 and 10 years. Steroid-induced ocular hypertension tended to show up somewhat sooner in eyes that experienced a rejection episode, although the long-term risk did not differ significantly between groups (P = 0.71, Fig. 2).
FIGURE 2.: Kaplan–Meier plot showing the cumulative risk of developing steroid-induced ocular hypertension with long-term use of topical prednisolone acetate 1%, segregated by whether the keratoplasty recipients experienced a graft rejection episode.
The cumulative risk of requiring medical or surgical glaucoma treatment in eyes without a preoperative glaucoma diagnosis was 11% by 1 year, 17% by 5 years, and 25% by 10 years (Fig. 3). Overall, 35 of the 211 eyes required glaucoma treatment; when last seen, 28 were managed medically with 1 (n = 14), 2 (n = 13), or 3 (n = 1) glaucoma medications and 7 (20% of those who developed glaucoma) had undergone glaucoma filtration surgery.
FIGURE 3.: Kaplan–Meier plot showing the cumulative risk of developing steroid-induced glaucoma with long-term use of topical prednisolone acetate 1% by keratoplasty recipients without preexisting glaucoma.
The risks of steroid-induced ocular hypertension or need for glaucoma treatment did not differ significantly between surgical indications, but the relatively small sample sizes in the non-FECD groups limited the statistical power to assess differences. The 10-year risk of ocular hypertension was 51% in 192 eyes treated for FECD or early failure of DSEK for FECD, 47% in 15 eyes treated for pseudophakic corneal edema, and 25% in 4 eyes treated for failed PK (P = 0.39). The 10-year risk of medical or surgical glaucoma treatment was 26% in 192 eyes treated for FECD or early failure of DSEK for FECD, 43% in 15 eyes treated for pseudophakic corneal edema, and 25% in 4 eyes treated for failed PK (P = 0.82).
DISCUSSION
Use of topical prednisolone acetate 1% was associated with a cumulative risk of steroid-induced ocular hypertension of 29%, 41%, and 49% at 1, 5, and 10 years, respectively. These results were consistent with reported rates of steroid-induced ocular hypertension with intravitreal administration of corticosteroids. Aref et al4 found the cumulative risk of developing ocular hypertension was 32% at 1 year, 43% at 2 years, and 47% at 3 years with use of intravitreal triamcinolone 4 mg for retinal vein occlusion. Similarly, Maturi et al5 found that 42% of participants required IOP-lowering medication within 36 months after implantation of a 0.7-mg dexamethasone insert for diabetic macular edema.
Both in this study, which assessed topical administration of prednisolone acetate, and in studies that assessed intravitreal administration of corticosteroids, the risk of steroid-induced ocular hypertension was greatest in the first year and declined exponentially with longer exposure. However, there were still patients as late as 13 years postoperatively in this study who developed ocular hypertension, indicating that the risk for a steroid response still exists for patients even with a long history of uneventful ocular steroid use. Thus, regular examinations to check IOP are necessary to avoid damage to the optic nerve and associated vision loss whenever patients are using ocular steroids such as prednisolone acetate 1%, even if it is only once daily.
The timing and extent of steroid response to a given corticosteroid regimen are influenced by an individual's genetic susceptibility.1 Other factors that could have influenced the outcomes in this study were the significant between-subject variability in how well topically applied ocular medications penetrate into the aqueous humor, and uncertainty regarding patient compliance with prescribed medication use. Studies suggest that at least 30% of patients are not compliant with long-term medication use,6 which could lead to underestimating the risk of steroid-induced ocular hypertension in those who do continue steroid use. However, the cumulative risk in this study was similar to that reported in studies that assessed intravitreal administration of corticosteroids, where patient compliance and variable absorption were not concerns and ocular hypertension tended to manifest earlier.
The significant morbidity we documented with long-term use of topical prednisolone acetate is a compelling reason to whenever possible choose a keratoplasty procedure with the lowest possible risk of rejection to allow early steroid reduction. Descemet membrane endothelial keratoplasty (DMEK) uses substantially less donor tissue (<20 μm thickness) than DSEK (50–200 μm thickness) or PK (480–620 μm thickness) and has a significantly lower risk of immunologic rejection episodes (<1% through 2 years) than other keratoplasty procedures.7 Randomized studies have shown that DMEK recipients can be changed from prednisolone acetate 1% to less potent steroids as soon as 1 month after surgery to lower the risk of steroid-induced ocular hypertension without significantly increasing the risk of graft rejection.8,9 The 1-year risk of steroid-induced ocular hypertension was only 7% in DMEK recipients without preexisting glaucoma who changed from prednisolone acetate 1% to loteprednol etabonate 0.5% at 1 month after DMEK9 and 6% in those who changed to fluorometholone 0.1% at 1 month,8 as compared with 30% in the present study with continued use of prednisolone acetate.
Another option to control IOP is to discontinue topical corticosteroids after corneal transplants. However, this increases the risk of immunologic graft rejection episodes and graft failure. In 2 studies that randomized PK recipients to continue or discontinue topical corticosteroids, the rates of graft rejection episodes and graft failure were significantly higher among those who stopped topical steroids.10,11 Similarly, in a study where patients could choose whether to discontinue steroid eye drops 1 year after DMEK, the risk of a graft rejection episode in the following year was 6% among the 67% who chose to stop steroids versus 0% among the 33% who continued using a low-potency topical steroid once daily.12 Hence, another advantage of DMEK for patients with endothelial dysfunction is the reduced risk of rejection episodes if topical steroids are stopped due to either patient preference or a need to control IOP.
In conclusion, half of the DSEK recipients without preexisting glaucoma who used topical prednisolone acetate 1% long-term developed steroid-induced ocular hypertension and 25% required glaucoma treatment. Frequent monitoring of IOP is needed with use of prednisolone acetate 1%, even if dosing is only once a day, to avoid damage to the optic nerve and irreversible vision loss. For patients who need a corneal transplant, it is preferable whenever possible to use a procedure, such as DMEK, that has minimal risk of rejection to allow early reduction of steroid potency and thereby reduce long-term steroid side effects and associated morbidity.
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