Managing Birdshot Chorioretinitis in Clinical Practice

How to provide long-term therapy while minimizing systemic adverse events.

Omar Saleh, MD • Debra A. Goldstein, MD

Retina specialists face many challenges in treating uveitis. The relative dearth of cases compared to other posterior segment conditions — the worldwide prevalence of uveitis is 38 to 730 people per 100,000¹ — hinders recruitment of subjects for clinical trials in large numbers. In the United States, the prevalence of uveitis is approximately 115 per 100,000,² and its incidence is about 200 new cases per 100,000 people per year, with the majority of cases affecting those between the ages of 20 and 50.¹

Uveitis management is also complicated by the term's relative lack of specificity, as it encompasses a constellation of diseases characterized by inflammation of the uveal tract that may lead to structural damage and eventual loss of vision. One of the most widely accepted classifications depends on the primary site of inflammation and divides uveitis into anterior, intermediate, posterior and panuveitis. Uveitis is further classified as infectious or non-infectious, acute or chronic, granulomatous and non-granulomatous, and as isolated eye disease or associated with a systemic condition.³

Uveitis is also responsible for a disproportionate number of cases of legal blindness. Approximately 10-15% of all cases of legal blindness in the United States can be attributed to posterior uveitis, which constitutes about 15-22% of all uveitis cases and most of the blindness that results from this disease.^4-6

Birdshot chorioretinitis (BC) is an uncommon cause of uveitis. It usually is considered one of the idiopathic inflammatory chorioretinopathies or white-dot syndromes. It commonly affects Caucasian females of northern European descent after their fourth decade of life. There is a strong correlation with the HLA-A29 haplotype (95.7%).⁷

The natural course of BC is one of gradual deterioration of visual function. Few patients are able to maintain good visual function without appropriate therapy.⁸ Cystoid macular edema is a common structural change in patients with ocular inflammatory disease, and is one of the major causes of vision loss in these patients.⁹ However, patients can continue to lose visual function even in the absence of CME.

It is believed that the ocular structural alterations that degrade visual function in most cases of uveitis are the result of chronic or recurrent inflammation rather than isolated or acute inflammatory episodes. Thus, it is crucial to adequately control intraocular inflammation in a continuous rather than episodic fashion to prevent resulting visual loss.⁶

TREATMENT MODALITIES

Managing posterior uveitis has always been challenging. Topical steroids are generally ineffective because therapeutic concentrations do not reach the posterior segment.¹⁰

The therapeutic options for non-infectious posterior uveitides are either local or systemic. Systemic corticosteroids are commonly used as initial therapy for many systemic autoimmune diseases, many of which may have ocular involvement. They are very useful in controlling acute exacerbations of systemic and ocular inflammatory disease. The chronic use of systemic steroids is limited by a wide array of serious side effects including growth retardation in children, weight gain, decreased bone density, hypertension, hyperglycemia, increased risk of infection, cataract and glaucoma. Furthermore, acute adverse reactions to steroids may arise even with short-term use: these include anxiety, sleeplessness, mood changes and, rarely, psychosis.

The use of systemic corticosteroids should therefore be limited. Most specialists aim to reduce the dose of prednisone to less than 5-10 mg/day by three to six months into the treatment cycle.¹¹

A variety of drugs may be used to taper oral steroids or in cases where systemic corticosteroids are insufficient to control inflammation. These immunomodulatory agents include antimetabolites such as azathioprine, methotrexate and mycophenolate mofetil; T-cell inhibitors such as cyclosporine and tacrolimus; alkylating agents including cyclophosphamide and chlorambucil; and biologic agents, such as the TNF-inhibitors infliximab and adalimumab. While these agents may be effective for controlling inflammation, all carry their own risk of serious systemic adverse events.

Antimetabolites are generally well tolerated and have a good safety profile. However, they commonly cause gastrointestinal upset, bone marrow suppression and hepatotoxicity. Therefore, it is recommended that physicians regularly monitor complete blood count and liver function tests in patients using these drugs.¹¹

The major concerns with T-cell inhibitors are nephrotoxicity and hypertension. Less common effects include neurotoxicity, hepatotoxicity, gingival hyperplasia and hirsutism, especially with cyclosporine. Blood pressure and renal function should be measured regularly.¹¹

Alkylating agents can be very effective in controlling inflammation in certain settings, but they carry a risk of malignancy that may be life threatening. Other side effects of this group include bone marrow suppression, teratogenicity, infertility and alopecia.¹¹ Proper patient counseling, including possible sperm or ovum banking, and continuous monitoring of side effects are essential.

Biologic agents are being used with increasing frequency for the treatment of non-infectious inflammatory disease. In a prospective clinical trial involving 31 patients with two-year follow up, 75% of patients demonstrated an initial favorable response with treatment of refractory uveitis with intravenous infliximab. However, some patients developed thromboses, solid malignancies, drug-induced lupus and congestive heart failure.¹²

The other viable modality of treatment for patients with non-infectious posterior uveitis is local corticosteroid therapy in the form of periocular or intravitreal injections, which may require frequent repetition, or through a sustained-release intravitreal implant. Although each of these delivery routes has its own safety concerns, they all share the risk of steroid-induced IOP elevation and cataract.

Periocular corticosteroid injections, most commonly triamcinolone acetonide, usually are given in the posterior sub-Tenon's space. They are effective in controlling intraocular inflammation and resulting CME, but the effect may be transient, and the injection may need to be repeated every two to four months to maintain adequate control.¹³ Injections rarely may be complicated by globe perforation, orbital fat herniation or frozen globe.¹⁴ Transient ptosis is common.

Intravitreal triamcinolone also has been used for the treatment of uveitis and resulting CME.¹⁵ Characterized by a transient effect as well, this route carries with it the possible complications of vitreous hemorrhage, endophthalmitis and retinal detachment.¹⁶

In addition, periocular and intravitreal injections commonly cause steroid-induced IOP elevation. Intraocular pressure of ≥21 mm Hg has been reported in 30% and 42% of eyes receiving sub-Tenon's and intravitreal triamcinolone injections, respectively.¹⁷

A novel route of local steroid delivery was introduced in 2005 when Retisert (0.59 mg fluocinolone acetonide implant, Bausch + Lomb) was approved by the FDA for the treatment of chronic noninfectious posterior and panuveitis. It is designed to deliver the synthetic corticosteroid fluocinolone acetonide directly to the site of ocular inflammation in a linear fashion over 30 months,¹⁸ thus avoiding systemic absorption of the drug.

In a three-year, multicenter, randomized, historically controlled trial, the efficacy and safety of 0.59-mg vs 2.1-mg fluocinolone acetonide intravitreal implants in a total of 278 patients with recurrent non-infectious posterior uveitis were studied. The rate of uveitis recurrence over one, two and three years post-implantation, as well as the need for systemic and periocular steroids, were significantly less for implanted compared to non-implanted eyes.¹⁹ In addition, visual acuity was improved in more implanted than nonimplanted eyes. However, elevated IOP, development of cataract, the need for surgery for controlling IOP and removing the cataract all were significantly higher in the implanted eyes. There were no statistically significant differences in all the aforementioned parameters between the 0.59-mg and 2.1-mg fluocinolone acetonide intravitreal implants.¹⁹

Pooled data from three multicenter, double-masked, randomized, controlled clinical trials evaluating the efficacy and safety of 0.59-mg or 2.1-mg fluocinolone acetonide intravitreal implants demonstrated that, during a three-year follow-up period, 71% of implanted eyes had an IOP increase of 10 mm Hg or more.²⁰ In addition, topical glaucoma medications and IOP-lowering surgeries, mostly trabeculectomies, were needed in 74.8% and 36.6% of implanted eyes, respectively. Intraocular pressure-lowering surgery was considered a success (postoperative IOP of 6 to 21 mm Hg with or without glaucoma medications) in 85.1% of operated eyes.²⁰

A retrospective observational study that compared the initial implantation and the re-implantation of Retisert implants showed a similar ocular inflammatory control and complication profile.²¹

In September 2010, the FDA approved a biodegradable dexamethasone implant for the treatment of non-infectious uveitis involving the posterior segment (Ozurdex, Allergan). This implant is designed to release drug for only up to six months, but it may result in less elevation in IOP than the Retisert.²² Its place in the armamentarium of agents used to treat uveitis is still being defined.

CASE STUDY

We present a case of a 40-year-old Caucasian female, with a chief complaint of gradually decreasing vision in both eyes for one year. Previous therapy included multiple periocular triamcinolone injections OU over a period of six months prior to presentation to us.

On examination, best-corrected visual acuity was 20/200 OU. Dilated fundus exam revealed 1+ cells in the anterior vitreous of both eyes, early PSC cataract and florid CME in both eyes. In addition, both eyes showed arteriolar attenuation and subtle non-pigmented chorioretinal lesions. Her work up was significant for a positive HLA-A29 haplotype, and OCT confirmed CME in both eyes (Figure 1).

Figure 1. OCT scans of the left eye (top image) and the right eye (bottom image) at time of presentation.

We diagnosed Birdshot chorioretinitis, and started the patient on an anti-inflammatory regimen that included 60 mg of oral prednisone daily as well as periocular injection of triamcinolone acetonide OU. However, there was no significant improvement in visual acuity or CME (Figure 2).

Figure 2. Left eye (top image) and right eye (bottom image) six weeks after starting systemic and periocular therapy.

After the risks and benefits of systemic immunomodulatory and local therapy were explained, the patient elected to have Retisert placement in her left eye. Visual acuity improved to 20/80 four weeks after treatment. Eight weeks after treatment, acuity was 20/60.

Two months after implant placement OS, the right eye was implanted. VA was 20/200 OD and 20/60 OS at that time. Four weeks after implantation OD, VA improved to 20/60 OD, and then to 20/40 OD eight weeks later (Figure 3). OCT nine months later showed dramatic resolution of CME (Figure 4). The pre-existing PSC cataract progressed. Phacoemulsification surgery with in-the-bag IOL implantation was performed OS 11 months after Retisert implantation in that eye. Vision improved from 20/80 to 20/50 after the surgery.

Figure 3. OCT of the left eye (upper image) and right eye (lower image) after Retisert placement.

Figure 4. OCT of the left eye (upper image) and right eye (lower image) 14 months after initial presentation.

Intraocular pressure increased to 36 mm Hg OD and 37 OS despite maximum medical therapy, and tube shunt procedures were performed six months after Retisert implantation OD and five months after implantation OS.

At last follow-up, more than two years after the first implantation, VA was 20/30 OD and 20/25 OS. IOP was well controlled off drops. There was no change in appearance of the optic nerves or visual fields.

REDUCING CME TO PRESERVE VISION

CME, one of the most common complications of uveitis, is a major cause of loss of visual function. Systemic steroid and different families of systemic immunosuppressive medications can be used to control posterior segment inflammation. These drugs are generally effective; however, they carry risks of systemic adverse reactions.

Periocular and intravitreal triamcinolone injections are useful tools in temporarily suppressing ocular inflammation and resolving CME, but a more prolonged effect can be achieved by using intravitreal sustained-release implants. In addition to the risks associated with any intravitreal procedure, sustained corticosteroid delivery systems are associated with a high rate of cataract formation and elevated IOP. Therefore, it is important to carefully screen patients before using the implant, and ensure close follow-up after insertion to monitor IOP. Patients who are not willing to comply with frequent follow-up visits to monitor IOP are not good candidates for Retisert.

This case demonstrates a dramatic improvement in CME that was refractory to systemic and periocular corticosteroids. The patient required cataract and glaucoma surgeries, but has experienced a significant improvement in vision and in her quality of life. The risks of systemic side effects associated with immunomodulatory therapy were avoided, and the patient is now able to drive and read again. It is possible that the more constant steady-state suppression of inflammation observed with a Retisert implant compared with repeated intravitreal or periocular steroid injections may result in better outcomes, because it effectively breaks the cycle of mediator release, vascular leakage and cellular recruitment seen in chronic uveitis. RP

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