Article Date: 6/1/2012

Fluocinolone Implant for Uveitis Secondary to Vogt-Koyanagi-Harada Syndrome

Fluocinolone Implant for Uveitis Secondary to Vogt-Koyanagi-Harada Syndrome

Rationale for use and results in a particularly challenging case

Quan Dong Nguyen, MD, MSC • Yasir J. Sepah, MBBS • Mohamed A. Ibrahim, MD

Despite available treatment options and expanding knowledge, uveitis remains a very challenging condition to manage. Posterior uveitis, characterized by inflammation of the choroid and/or the retina, is responsible for more vision loss than uveitis that affects other parts of the uveal tract.1 In many cases, it is idiopathic, but it can be caused by or associated with a multitude of infectious or non-infectious conditions. Infectious etiologies can be viral, bacterial, fungal or parasitic in nature. Noninfectious posterior uveitis can be associated with malignancies or autoimmune diseases, and can accompany the underlying disease or be localized to an ocular structure (such as in serpiginous choroidopathy or birdshot retinochoroidopathy).2

Noninfectious posterior uveitis is often chronic. It is now widely accepted that the effects of chronic or recurrent ocular inflammation, even at low levels, are cumulative and can result in significant damage to the structures of the eye, which can lead to vision loss.3 The goal of uveitis treatment should be complete and continuous control of inflammation while maintaining an optimal risk-to-benefit ratio.

Treatments used in clinical practice for noninfectious posterior uveitis include periocular and intravitreal steroid injections, oral steroids and immunomodulatory drugs.* While these treatments may be effective, they have limitations and can put patients at risk for systemic side effects. Locally injected steroids must be administered repeatedly and may cause ptosis, periocular fibrosis and globe perforation. Furthermore, the patient is susceptible to the deleterious effects of recurrent inflammation between injections. Because oral steroids may need to be administered at high doses for extended periods of time in order to control inflammation, they can lead to complications including Cushingoid features, bone marrow suppression and infection, avascular necrosis, hyperglycemia and osteopenia, among others.4 In many cases refractory to oral steroids or when steroids cannot be tapered to acceptable levels, immunomodulatory therapy (IMT) with pharmacologic agents such as antimetabolites (e.g., methotrexate, azathioprine), calcineurin inhibitors (i.e., cyclosporine) and anti-tumor necrosis factor (TNF) agents (e.g., infliximab) are often employed.4 Treatments with IMT are clinically adopted, but not approved by the FDA for uveitis. These medications, however, may induce serious sequelae such as hepatotoxicity, bone marrow suppression, or renal failure.5 The American Uveitis Society and the American Academy of Ophthalmology, among others, have recommended that corticosteroids should not be used to maintain disease quiescence if patients require 10 mg or more of prednisone (or the equivalent) daily and that in such cases, IMT should be employed. Unfortunately, a recent study has shown that the majority of physicians who are managing patients with uveitis do not know or adhere to these treatment guidelines.6

ROLE OF SUSTAINED STEROID DELIVERY DEVICES

As an alternative to the treatments mentioned above, several steroid sustained-release devices have been developed. These devices are surgically placed directly into the vitreous. One such device, Retisert® (fluocinolone acetonide intravitreal implant 0.59 mg, Bausch + Lomb) was approved by the FDA in 2005. Retisert is indicated for the treatment of chronic noninfectious uveitis affecting the posterior segment of the eye. It is designed to release fluocinolone acetonide in the posterior segment at a nominal initial rate of 0.6 µg/day, decreasing over the first month to a steady state between 0.3-0.4 µg/day for approximately 2.5 years.

FDA approval of Retisert was based on the results of two multicenter, double-masked, randomized, controlled clinical trials evaluating the safety and efficacy of a 0.59-mg and a 2.1-mg intravitreal implants.7 The trials involved patients with chronic noninfectious uveitis affecting the posterior segment, including intermediate, posterior uveitis, or panuveitis. The majority of patients in the trials were noted to have idiopathic uveitis. Efficacy data with the 0.59-mg implant were reviewed by FDA, and approval was based on 34-week postimplantation results.8 Subsequently, the 3-year follow-up data were published.9

Uveitis Recurrence Rates in Retisert Pivotal Trials
Time Point Trial 1 Trial 2
Uveitis Recurrence Rates*† (N-108) (N-116)
34 weeks pre-implantation 54% 40%
34 weeks post-implantation 2% 13%
1 year post-implantation 4% 13%
2 years post-implantation 10% 14%
3 years post-implantation 20% 17%
3 years post-implantation** 31% 24%
* Recurrence of uveitis for all post-implantation time points was compared to the 34 weeks pre-implantation time point.
† p-value<0.01 from McNemar's Chi squared test
** Results presented include imputed recurrences. Recurrences were imputed when a subject was not seen within 10 weeks of their final scheduled visit.

The primary efficacy endpoint in the Retisert trials was the rate of recurrence of uveitis in the study eye in the 34-week period prior to implantation compared with the rate of recurrence in the 34 weeks after implantation. Recurrence rates at 1, 2, and 3 years after implantation were also compared with the 34-week pre-implantation period. It was noted that the implant significantly reduced recurrences of uveitis. Recurrence rates for the 0.59-mg implant are shown above.

Important Risk Information for Retisert®
■ Surgical placement of RETISERT® is contraindicated in active viral, bacterial, mycobacterial or fungal infections of the eye.

■ Based on clinical trials with RETISERT®, during the 3-year post-implantation period, nearly all phakic eyes are expected to develop cataracts and require cataract surgery.
As with any surgical procedure, there is risk involved. Potential complications accompanying intraocular surgery to place RETISERT® into the vitreous cavity may include, but are not limited to, the following: cataract formation, choroidal detachment, temporary decreased visual acuity, endophthalmitis, hypotony, increased intraocular pressure, exacerbation of intraocular inflammation, retinal detachment, vitreous hemorrhage, vitreous loss, wound complication, wound site erythema and wound dehiscence.

■ Following implantation of RETISERT®, nearly all patients will experience an immediate and temporary decrease in visual acuity in the implanted eye which lasts for approximately one to four weeks post-operatively.

■ Use of corticosteroids may result in elevated IOP and/or glaucoma. Based on clinical trials with RETISERT®, within 3 years post-implantation, approximately 77% of patients will require IOP lowering medications to control intraocular pressure and 37% of patients will require filtering procedures to control intraocular pressure.

■ Patients should be advised to have ophthalmologic follow-up examinations of both eyes at appropriate intervals following implantation of RETISERT®. Physicians should periodically monitor the integrity of the implant by visual inspection.
The most frequently reported ocular adverse events in clinical trials with RETISERT® occurring in 50-90% of patients included: cataract, increased intraocular pressure, procedural complications and eye pain. Thirty five to forty percent (35-40%) of patients reported ocular/conjunctival hyperemia, reduced visual acuity and conjunctival hemorrhage. The most common non-ocular event reported was headache (>33%).

In the pivotal trials, changes in visual acuity and the need for adjunctive uveitis therapies were also evaluated as secondary endpoints. Between baseline and 3 years, 23% of eyes (22 of 94) that received the 0.59-mg implant had improved (gain of ≥3 lines) visual acuity compared with 6% of non-implanted fellow eyes (6 of 90). In 13% of implant-treated eyes (12 of 94), visual acuity deteriorated (≥3 lines lost) compared with 19% of fellow eyes (17 of 90) [p < 0.01].

Please see Important Risk Information on page 3.

RETISERT IMPLANT FOR UVEITIS SECONDARY TO VOGT-KOYANAGI-HARADA SYNDROME

Patients with chronic noninfectious uveitis may be considered potentially appropriate candidates for Retisert implantation if they meet one or more of the following criteria:

■ having chronic noninfectious uveitis (duration longer than 3 months)
■ having sight-threatening posterior segment uveitis (intermediate, posterior or panuveitis)
■ the ocular disease, rather than a systemic condition, is driving treatment decisions
■ having disease responsive to steroids
■ being intolerant of, or nonresponsive to, standard therapy
■ having no severe glaucomatous nerve damage.

However, it is of paramount importance to understand that each case of noninfectious posterior uveitis is unique and requires the physician to weigh the potential risks and benefits of Retisert implantation specific to each individual. The following case illustrates how the implant may also be appropriate for patients with chronic, noninfectious uveitis secondary to systemic disease.

The patient, a 36-year-old Native American female, was referred to our clinic at the Wilmer Eye Institute by a retina specialist. During the previous 4 months, she had been treated for bilateral panuveitis and choroiditis with two intravitreal injections of triamcinolone acetonide in each eye. During the same time period, she was also taking a relatively high dose of oral prednisone, 70 mg per day. Despite treatment, the patient's uveitis did not resolve completely, and she developed an exudative retinal detachment in the left eye. Visual acuity in that eye had deteriorated to hand motion.

During the review of systems, the patient reported a history of significant tinnitus and headaches and difficulty in tolerating the side effects of prednisone. In addition to severe posterior segment inflammation and exudative retinal detachment, examination was notable for poliosis. No signs of an infectious etiology were present.

Based on the ocular and systemic findings, it was determined that the patient was suffering from Vogt-Koyanagi-Harada (VKH) syndrome, a rare inflammatory condition that affects the eyes, inner ear, skin, hair and lining of the brain. VKH is believed to have an autoimmune pathogenesis. Such belief is supported by the frequent presence of HLA-DR4, an antigen commonly associated with other autoimmune diseases. In addition to uveitis, other ocular complications of VKH include glaucoma and cataracts, which may be secondary to the uveitis.

Standard first-line treatment for the ocular manifestations of VKH is systemic steroids. High doses of corticosteroids are usually needed to bring the inflammation under control. IMT may also be used.* Based on the aggressiveness of the patient's uveitis, her need for long-term systemic treatment for the under-lying VKH, and her intolerance of the high dosage of prednisone required to control the ocular disease, Retisert was recommended to control the uveitis in the left eye. Rather than subjecting the patient to an increase in systemic medications, Retisert could provide the necessary intensive local therapy for the left eye, while allowing for a lower daily dose of oral steroids for the systemic manifestations of the VKH.

After the patient was counseled on the risks and benefits of Retisert, she agreed to proceed. It is crucial for patients to understand that Retisert implantation will likely necessitate therapy for IOP elevation and additional surgical procedures for cataract and possibly glaucoma management. Based on the Retisert clinical trial results, nearly all phakic eyes can be expected to develop cataracts after implantation. In addition, approximately 77% of the patients will require topical IOP-lowering medications,10 and approximately 37% will require an IOP-lowering procedure. In addition, candidates for Retisert must be willing and able to comply with scheduled follow-up visits, since noncompliance with regular evaluations may lead to undetected ocular hypertension, glaucomatous damage and vision loss.

Prior to Retisert implantation in the left eye, the patient was treated with intravenous steroids to resolve the exudative retinal detachment and control the perioperative inflammation. Vitrectomy was also performed at the time of implantation in an effort to remove intraocular inflammatory cytokines. Figure 1 shows the placement of the Retisert in the inferotemporal quadrant of the left eye.

Figure 1. Wide-angle fundus photograph (Optos P200) of the left eye with the Retisert implant in the inferotemporal quadrant.

In this particular case, 6 months following Retisert implantation, a preexisting cataract (given her use of systemic corticosteroids) continued to progress and IOP increased to an unacceptable level. Therefore, subsequent to implantation, the patient underwent cataract surgery and placement of an Ahmed valve.

Since the cataract extraction and valve placement in the left eye, the patient's IOP has remained under control. Her vision has improved from hand motion to 20/70. It is not predictable whether her vision will improve further given the extent of her chorioretinopathy. The patient continues to take only a minimal daily dose of oral prednisone along with other medications for her neurologic symptoms, mainly ear pain and chronic headache.

Nine months after the placement of Retisert in the left eye, the right eye also developed worsening of the uveitis, while the patient remained stable with her neurological diseases. Therefore, a decision was made to implant Retisert in the right eye (Figure 2). Given the ocular hypertension that has developed in the left eye, at the time of Retisert implantation in the right eye, placement of an Ahmed valve was also performed. Since then, the patient has been maintaining her vision at 20/40 in the right eye and 20/60 in the left eye, and her IOP is stable as well.

Figure 2. Wide-angle fundus photograph (Optos P200) of the right eye showing placement of the Retisert implant in the inferotemporal quadrant.

Both eyes have remained in complete quiescence since the placement of Retisert, with absence of any iridocyclitis, vitreous cells or haze, or macular edema; the exudative retinal detachment also has not recurred.

A WELCOME THERAPEUTIC OPTION FOR CAREFULLY SELECTED PATIENTS

As illustrated by the index case of a patient with VKH and secondary uveitis, the fluocinolone acetonide sustained release intravitreal implant can provide long-term control of inflammation in chronic noninfectious posterior uveitis, while successfully addressing many of the concerns related to other current therapies and not subjecting the patient to high doses of systemic corticosteroids or IMT.*

As such, Retisert may provide physicians with an additional therapeutic option that can be a good choice for properly selected patients, provided that both physicians and patients recognize its benefits and potential risks.

Dr. Quan Dong Nguyen is Associate Professor of Ophthalmology for Diseases of the Retina and Vitreous, and Uveitis at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore. He serves on the Scientific Advisory Board for Bausch + Lomb. Dr. Yasir J. Sepah and Dr. Mohamed Ibrahim are post-doctoral fellows in the Retinal Imaging Research and Reading Center at the Wilmer Eye Institute and have no conflict of interests to disclose. The Johns Hopkins University has received research funding from Bausch + Lomb to conduct research studies at the University.

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Retinal Physician, Volume: , Issue: June 2012, page(s): 2 - 6