Background

Chronic uveitis can lead to ocular tissue damage and vision loss due to repeated bouts of inflammation [1]. Uveitis is a major cause of visual morbidity among working-age adults (age 20 to 65 years). A study conducted by Durrani et al. showed prolonged visual loss in two-thirds of patients with non-infectious uveitis, with 22% meeting the criteria for legal blindness [2, 3]. Uveitis is typically classified according to primary location of inflammation along the uveal tract [4, 5]. Intermediate, pan-, and posterior uveitis, while less common than anterior uveitis, often require either systemic or intraocular corticosteroid treatment to effectively manage inflammation [1, 6]. Posterior uveitis can affect the choroid and/or the retina, and is the second most common form of uveitis [4, 6], with 67–90% of posterior uveitis cases being non-infectious [7,8,9,10]. Prior ocular surgery is another common cause of acute and chronic uveitis accompanied by macular edema [4, 7]. Non-infectious uveitis affecting the posterior segment (NIU-PS), though not a pre-defined clinical term in the literature, is an umbrella term referring to inflammation affecting the back of the eye (encompassing intermediate, posterior, and panuveitis) of non-infectious origin. This includes, but is not limited to, idiopathic causes, autoimmune conditions, or surgical insults that result in recurrent inflammation of the posterior eye segment [4, 7].

NIU-PS is often managed with systemic corticosteroids, but long-term use of high-dose corticosteroids can be associated with systemic and ocular side effects. Intraocular and periocular corticosteroids reduce systemic exposure and incidence of adverse events by providing adequate concentration of drug at the site of inflammation. Long-acting intraocular implants have the potential to provide extended control of disease and decrease patient burden by reducing the need for repeated injections and the frequency of disease flares, resulting in better overall control of inflammation [11, 12].

Table 1 Baseline characteristics
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Approved by the United States Food and Drug Administration (FDA), the intravitreal fluocinolone acetonide implant (FAi) is indicated for use in patients with chronic NIU-PS [13]. The safety and efficacy of treating NIU-PS with a low-dose, sustained-release 0.18-mg intravitreal FAi has been demonstrated in randomized, sham injection controlled, double-masked, phase 3 clinical trials (ClinicalTrials.gov identifiers: NCT01694186 and NCT02746991) and in multiple individual case reports [11,12,13,14]. Herein, we report a series of 18 eyes from 15 patients with recurrent NIU-PS and postoperative uveitic cystoid macular edema (CME) that achieved long-term inflammation control when treated with 0.18-mg FAi.

Table 2 Effectiveness and safety outcomes after 0.18-mg FAi insertion
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Methods

As available from patient medical records, the following data were collected: sex, age, affected eye(s), medical history, ocular history, time since diagnosis, previous treatments, concomitant treatments, number of recurrences, time to recurrence, intraocular pressure (IOP), central subfield thickness (CST), and visual acuity (VA) as measured by each practitioner. Each retrospective case was conducted in accordance with the tenets of the Declaration of Helsinki and the Health Insurance Portability and Accountability Act of 1996. Consent was requested and obtained from the patients for study inclusion.

Investigators determined recurrence of uveitis according to their individual practice patterns, using criteria such as increase in cellular activity or vitreous haze attributable to NIU-PS, deterioration in visual acuity, increase in macular edema as measured by CST, and/or the need for additional anti-inflammatory medications.

Results

Eighteen eyes diagnosed with non-infectious uveitis and CME were treated by 6 practitioners with the 0.18-mg FAi during active inflammation (Table 1). At baseline, this population had a mean age of 72 years (range: 46 to 93 years), were 53% male, had a mean follow-up of 16.5 months post-FAi (range: 2 to 42.5 months), and had a mean disease duration of 3 years (range: 1 to 19 years) with uncontrolled uveitis before 0.18-mg FAi administration (Table 1). Individual patient narratives and diagnoses are described in detail in the Supplementary Appendix.

All patients were diagnosed with noninfectious uveitis and CME, and for most (14/15 [93%]), a history of cataract or retinal surgery preceded and/or aggravated the diagnosis. Ten patients received their diagnosis prior to cataract or retinal surgery, and 5 patients were diagnosed with post-operative non-infectious uveitis with CME. Of the 15 patients, 8 patients were diagnosed with posterior uveitis, 3 with intermediate uveitis, 2 with panuveitis (1 of these 2 had anterior segment involvement), 1 with pars planitis, and 1 with posterior cyclitis. All patients underwent a diagnostic workup for their uveitis, which included laboratory investigation (Table 1 legend), clinical examination, and ophthalmic imaging, including slit-lamp and dilated fundus examination, optical coherence tomography (OCT), fluorescein angiography, and fundus autofluorescence. One patient had myopic degeneration and posterior vitreous detachment in both eyes, and the left eye had severe pars planitis, leading to chronic and uncontrolled NIU-PS.

Of the 18 eyes in this series, 11 (61%) had 5 or more recurrences of uveitis since initial diagnosis, with an average time to recurrence around 12 weeks (range: 1 to 27). One eye (case #6) had no recurrences before receiving the 0.18-mg FAi (Table 1). The two most common ocular medications used to manage NIU-PS recurrence before treatment with the 0.18-mg FAi were short-acting intravitreal injection (IVI) corticosteroids, including triamcinolone acetonide (56% for each eye) and dexamethasone implant (78% for each eye). Less common IVI medications used in this case series were off-label bevacizumab (1 eye) and off-label methotrexate (3 eyes) (Table 1). Following treatment with the 0.18-mg FAi, all eyes had improvement in VA and decrease in CST as measured by OCT (Table 2).

Of the 18 eyes, 2 were treated with adjunctive intraocular therapy for NIU-PS recurrence following the 0.18-mg FAi: 1 eye (case #13) received a single dexamethasone IVI 7 weeks after the FAi without the need for additional corticosteroid IVI, and another eye (case #3) received ongoing dexamethasone IVI every 17 weeks after the implant (total of 4 dexamethasone IVI), which represented a substantial reduction in IVI corticosteroid treatment frequency (previously every 4 to 6 weeks). Another eye (case #1) required ongoing topical prednisolone for recurrent anterior segment inflammation. Two eyes (case #11) had uveitis recurrence 36 months after 0.18‑mg FAi; this patient then received dexamethasone IVI in both eyes, followed by a second round of 0.18‑mg FAis in both eyes.

Safety events after treatment with the 0.18-mg FAi were tolerable. Only 1 eye from the case series developed persistent IOP elevation after the FAi was injected, and this eye was treated with topical brimonidine tartrate drops; no eyes required surgical intervention for elevated IOP. One eye developed culture-negative endophthalmitis after FAi insertion, and this eye received intravitreal antibiotics. Six weeks after antibiotics were given, the patient’s VA returned to baseline, and the 0.18-mg FAi inhibited uveitis recurrence for more than a year (case #15) (Table 2).

Discussion

Eyes that undergo multiple intraocular surgeries are at risk for inflammation-related sequelae, including CME, proliferative vitreoretinopathy, and chronic NIU-PS. The mainstay of treatment to manage NIU-PS is local corticosteroids administered topically or via peri/intraocular injection [15]. However, patients with chronic uveitis are at increased risk of secondary glaucoma and cataract formation due to prolonged intraocular inflammation and corticosteroid use [16]. Patients with uveitis also tend to undergo cataract surgery at a younger age than those without uveitis [17,18,19,20] and may be at increased risk of postoperative CME and limited visual recovery [21, 22].

There are three FDA-approved IVI FAi dose formulations in the United States, including the high dose 0.59-mg formulation (RETISERT; Bausch + Lomb) indicated for chronic NIU-PS and 2 lower dose formulations, 0.19-mg (ILUVIEN; Alimera Sciences) for diabetic macular edema, and the 0.18-mg FAi (YUTIQ; Alimera Sciences) for chronic NIU‑PS [23]. In phase 3 clinical trials, the 0.18-mg FAi prevented and/or delayed uveitic recurrences, improved VA, and reduced the need for adjunctive therapy among patients with NIU-PS over 36 months [24, 25]. The 0.18-mg FAi is administered in an office setting and delivers a daily dose of 0.2 µg of fluocinolone acetonide [24]. The 0.59-mg FAi, on the other hand, must be surgically implanted [23, 26]. Injection of the 0.18-mg FAi represents an alternative to repeated treatments with shorter-acting corticosteroids, potentially reducing injection-related risks and overall treatment burden, as well as improving long term outcomes by minimizing inflammation recurrences.

As the use of any intraocular corticosteroid may result in IOP elevation, patients should be routinely monitored. Many patients in this case series received intraocular steroid therapy before placement of the 0.18-mg FAi, making the likelihood of an IOP response more predictable. It is hypothesized that the lower dose of fluocinolone (relative to the 0.59-mg implant) and near zero-order kinetics of the long-acting 0.18-mg FAi may be associated with a relatively low propensity for triggering significant increases in IOP [24, 27].

This case series demonstrates real-world experiences and treatment patterns with the 0.18‑mg FAi in eyes with chronic and/or recurrent NIU-PS. In most of these cases, uveitic inflammation was resolved or decreased in intensity for the duration of the FAi lifespan, without the need for additional IVIs (4 eyes required additional steroid IVI post-FAi to help lower inflammation).

In summation, across various surgeons and presentations, the eyes in this series experienced control of NIU-PS and improved vision after treatment with the 0.18 mg FAi, with no new safety signals. Additional studies should enhance our understanding of outcomes with follow up beyond the expected life of the implant.

Conclusion

Eyes with chronic and/or recurrent non-infectious uveitis affecting the posterior segment had sustained resolution of CME and inflammation after receiving the 0.18-mg FAi, with no new adverse effects.