What to Expect When Treating Uveitis
Clinical trials and experience support the effectiveness of targeted intraocular therapy and management of side effects.
Uveitis is a term that encompasses a broad range of manifestations of inflammation affecting the iris, ciliary body and/or choroid. Because it can be associated with a large number of potential causes, its incidence and prevalence can be difficult to determine.1 While often referred to as a rare condition, uveitis is not uncommon, and nearly all retinal physicians see patients who have it.
Even though all retinal physicians are trained to manage uveitis, many prefer to send patients to a uveitis/ocular immunology specialist. This is especially true with noninfectious posterior uveitis, which tends to be bilateral, chronic and sight-threatening more often than uveitis affecting other parts of the uveal tract. There is a level of discomfort with the nonocular aspects of the treatment regimen. When high doses of systemic corticosteroids for extended periods of time are required to control inflammation, patients are at risk for potentially serious complications, such as hypertension, hyperglycemia, osteopenia, Cushingoid features, bone marrow suppression and infection and avascular necrosis. In addition, when immunomodulatory agents are used in an effort to reduce dependence on steroids or because steroids were not effective, they carry their own set of risks.
Although it is preferrable to refer a patient to a uveitis/ocular immunology specialist, it is, unfortunately, sometimes impractical to do so because access to care can be limited. Only approximately 100 physicians in the world have advanced training in ocular immunology.2 Similarly, the American Uveitis Society counts its members at approximately 70.
Retisert® (fluocinolone acetonide intravitreal implant 0.59 mg, Bausch + Lomb), which was approved by the FDA in 2005, provides retinal physicians with an opportunity to treat uveitis patients whom they may have been reluctant to keep in their care in the past. Retisert is indicated for the treatment of chronic noninfectious uveitis affecting the posterior segment of the eye. My first experience with the implant was as a fellow monitoring patients in the initial studies. In my own practice, I have found it to be a helpful treatment (See “Evaluating Two Challenging Cases” in this issue). For a large number of my Retisert patients, high-dose systemic steroids and immunomodulatory agents have been taken completely out of the picture.
The fluocinolone implant is by no means a “silver bullet” for all posterior uveitis patients nor is it without side effects of its own. However, when I weigh the risks and benefits of the entire spectrum of treatment options for each patient, Retisert often emerges as the preferred strategy for continuous long-term control of ocular inflammation affecting the posterior segment. Such control may be an effective means of protecting patients from permanent vision loss, which is believed to result from the cumulative effects of repeated inflammatory occurrences, even at low levels.3 Furthermore, the implantation procedure itself is fairly straightforward for a retinal surgeon, in many cases, (See “Implantation and Removal Procedures” in this issue) and the ocular side effects can be managed.
This article and those that follow review key Retisert clinical trial data and provide additional information that retinal physicians should find helpful when considering use of the implant in their practices.
EVIDENCE OF EFFICACY
Retisert is designed to release fluocinolone acetonide at a controlled, sustained rate for approximately 2.5 years.
In the clinical trials leading to FDA approval, two versions of the implant, 0.59-mg and 2.1-mg, were evaluated. Only efficacy data on the 0.59-mg implant were considered, and approval was based on 34-week results.4 The primary efficacy endpoint in the studies was the rate of recurrence of uveitis in the study eye in the 34 weeks prior to implantation compared with the rate of recurrence 34 weeks, 1 year, 2 years and 3 years after implantation. In two randomized, double-masked, multi-center, controlled clinical trials, 224 patients received a 0.59-mg Retisert implant, which significantly reduced recurrence rates.5
ADDITIONAL CONSIDERATIONS IN TREATING NON-INFECTIOUS POSTERIOR UVEITIS
In many cases of non-infectious posterior uveitis, cystoid macular edema (CME) is present. CME is a well-documented cause of vision loss in patients with uveitis.6 CME is an indicator of active inflammation; therefore, reversal of CME provides further evidence of the anti-inflammatory effects of Retisert (fluocinolone acetonide intravitreal implant 0.59 mg, Bausch + Lomb) and further supports its indication to treat uveitis.6
Callanan and colleagues7 published 3-year results of a multicenter, randomized, historically controlled trial in which 110 patients received the 0.59-mg implant and 169 patients received the 2.1-mg implant. In addition to favorable reductions in rates of uveitis recurrence, they reported the effect of Retisert treatment on visual acuity, CME and the need for adjunct systemic medications.
Between baseline and 3 years, 23% of eyes that received the 0.59-mg implant had improved visual acuity (gain of ≥3 lines) compared with 6% of fellow non-implanted eyes. In contrast, there was no significant difference between implanted and non-implanted fellow eyes in terms of vision deterioration. Among eyes implanted with a 0.59-mg Retisert, 13% had a decrease in visual acuity of ≥3 lines compared with 19% of fellow non-implanted eyes.
The study also found a significant correlation between visual acuity improvement and reduction in area of CME. At 1 year after implantation in the 0.59-mg group, reduction in area of CME was seen in 86% of eyes. At 3 years after implantation, area of CME was decreased in 73% of eyes. Mean area of CME decreased from 33 mm2 to 7 mm2 from screening to 34 weeks after implantation. Area of CME remained statistically significantly lower than baseline at the 1-, 2- and 3-year post-implantation visits.
Also notable in this study, was the reduced need for systemic medications to control uveitis once Retisert was implanted. The number of patients requiring systemic medications was reduced by nearly 80%.
ANTICIPATING AND MANAGING OCULAR SIDE EFFECTS
The ability of Retisert to control uveitis while reducing or eliminating the need for systemic corticosteroids and/or other immunomodulatory therapies can be an advantage for doctors and patients. In cases where systemic corticosteroids can be eliminated, patients can avoid the associated side effects and laboratory testing required for those on such treatment.
In the clinical trials, the most frequent ocular side effects of Retisert (fluocinolone acetonide intravitreal implant 0.59 mg, Bausch + Lomb) implantation were cataract, increased IOP, complications related to the implantation procedure itself and eye pain. Callanan and colleagues reported that cataract formation in implanted phakic eyes during their 3-year study was nearly universal. They noted that in other studies of the implant, the incidence of cataract formation ranged from 50-100%.
To evaluate the incidence and management of elevated IOP in Retisert-treated eyes, Goldstein and colleagues pooled data from three multicenter, double-masked, randomized, controlled, phase 2b/3 clinical trials (N=584).8 In those studies, patients received either the 0.59-mg or 2.1-mg implant. According to the analysis, during 3 years of follow-up, 71% of implanted eyes had an IOP increase of 10 mmHg or more compared with baseline levels. IOP reached 30 mmHg or higher in 55% of eyes, 40 mmHg or higher in 25% of eyes, and 50 mmHg or higher in 6% of eyes.
Investigators in the studies used topical IOP-lowering medications as first-line treatment for elevated pressure. Overall, 74.8% of study patients were prescribed topical medical therapy. On average, the time from implantation to the initiation of IOP-lowering topical therapy was 409.3 ± 18.7 days.
In cases where topical medications did not lower IOP adequately, surgeries were performed. The percentage of patients that underwent surgery was 36.6%. In most cases, the type of surgery was chosen by glaucoma specialists. Trabeculectomy was chosen most often, 76.2% of the time. The next most frequently performed procedure was implantation of a glaucoma drainage device, which was done in 20.6% of cases. Time to IOP-lowering surgery was significantly longer for patients who received a 0.59-mg implant. On average in that group, surgery was performed 898.4 ± 19 days after Retisert implantation.
In general, the outcomes of IOP-lowering surgery were favorable. Approximately 50% were considered a complete success, defined as IOP between 6 mmHg and 21 mmHg without the use of medication 1 year after the procedure. Also at 1 year after an IOP-lowering procedure, 25-30% were considered a qualified success, defined as IOP between 6 mmHg and 21 mmHg with the help of medication. In some cases, a second or third surgical procedure was required to maintain IOP control.
In my practice, I have seen some patients, especially if they are relatively young, maintain clear lenses during their treatment with Retisert and experience only a slight increase in IOP. However, a more common scenario is that by the time a patient comes to me, he has already been taking oral steroids and/or has had several periocular or intravitreal steroid injections, which have led to cataract formation. In this situation, I consider lens extraction at the time of Retisert implantation. Alternatively, in cases where early cataracts have formed but extraction is not performed initially and elevated IOP subsequently requires surgery, the anterior segment surgeon may perform cataract extraction/IOL implantation and glaucoma surgery at the same time, sparing the patient two separate surgical procedures.
It is important to keep in mind that elevated IOP can occur at any time after implantation of Retisert.
Therefore, consistent follow up is necessary. A panel of uveitis experts recently offered the following general guidelines for monitoring IOP:9
■ first 18 months after implantation: every 2-3 months
■ if IOP is elevated: every 4 weeks
■ 18-24 months after implantation: every 3-4 months.
Retinal physicians utilizing Retisert should also be aware of the potential for the formation of vitreous bands. This finding was first described by Galor and colleagues10 in 2007. In four implanted eyes, band- or sheet-like opacities that appeared more dense than typical inflammatory vitreous condensations were observed extending from the posterior pole to the implant. Most of the bands appeared more than 3 years after implantation. In three patients they were associated with a decrease in vision, secondary to vitreous opacities and vitreomacular traction. The authors noted that when vitreous bands cause visually significant traction, vitreoretinal surgery may be beneficial. They recommended that surgery to remove or exchange a Retisert implant in patients with visible vitreous bands be accompanied by a complete vitrectomy to avoid retinal traction.
With the efficacy and side-effect profile of Retisert well established, research surrounding its use is increasingly aimed at determining whether it may be more or less effective against specific types of non-infectious posterior uveitis as well as how it compares directly with other treatment options.
For example, a published case report from Yale University School of Medicine detailed the use of the fluocinolone implant in a patient with serpiginous choroiditis.11 After one intravitreal injection of triamcinolone, which brought the disease under control, the patient received a Retisert implant. The treating physicians reported that after 14 months, the disease, which had been threatening the fovea, remained controlled. They concluded that Retisert should be recognized as a potential treatment option for serpiginous choroiditis.
At the University of Iowa, the outcomes of Retisert implantation in eight patients with active sympathetic ophthalmia were evaluated after follow-up periods between 6 months and 2 years.12 Vision stabilized or improved in all eight patients. In addition, the use of systemic medications to control inflammation was significantly reduced in all patients, although two had recurrent inflammatory episodes requiring the resumption of an oral immunosuppressive agent.
In a larger, randomized, controlled, phase 2b/3, open-label, multicenter study, the Fluocinolone Acetonide Study Group compared the safety and efficacy of Retisert with standard systemic therapy in 140 patients with noninfectious posterior uveitis.13 Patients were treated with either Retisert or systemic corticosteroid monotherapy, combined with an immunosuppressive medication if deemed necessary. Based on longer time to recurrence of uveitis as well as a lower rate of recurrence (18.2% vs. 63.5%), the implant provided control of inflammation. Surgery for high IOP was required in 21.2% of eyes treated with Retisert; cataract extraction was required in 87.8% of phakic eyes. No patient in the Retisert group experienced a treatment-related nonocular adverse event, whereas 25.7% of patients in the standard therapy group did.
By the end of 2011, the highly anticipated results from the National Eye Institute-sponsored Multicenter Uveitis Steroid Treatment (MUST) trial should be available. This multicenter, randomized, controlled clinical trial (NCT00132691) is comparing the effectiveness of Retisert with that of oral corticosteroids with immunosuppressive agents as needed in approximately 250 patients with severe noninfectious intermediate uveitis, posterior uveitis, or panuveitis. Patients were enrolled at clinical centers in the United States, United Kingdom and Australia. The primary outcome measure is difference in visual acuity after 2 years of follow-up. Secondary measurements include retinal morphology, intraocular inflammation, ocular complications of uveitis and of therapy, systemic complications of therapy and adverse events. The MUST trial is also evaluating mortality, quality of life and cost-effectiveness of treatment, which should provide valuable guidance for clinical practice.
PRELUDE TO THE FUTURE
Sustained drug delivery devices have been an active area of ophthalmic research and development for several years. As only the second such intraocular device to be approved by the FDA, Retisert is at the vanguard of these efforts. Given the encouraging results so far in terms of the effectiveness of targeted therapy and the potential to reduce costs and burden of treatment for doctors and patients, other delivery device/drug combinations for uveitis and additional ocular conditions will surely follow.