Use of fluocinolone acetonide intravitreal implant to manage chronic panuveitis for long-term inflammatory control without interfering with systemic immunity

Summary

We report 2 patients with chronic panuveitis who were treated with fluocinolone acetonide intravitreal implant (Yutiq, EyePoint Pharmaceuticals Inc, Watertown, MA) intended to control ocular inflammation long term without interfering with systemic immunity. The first case was a man in his 50s referred for ocular complaints in the setting of ongoing immunotherapy for the treatment of metastatic melanoma. He was diagnosed with bilateral drug-induced panuveitis. Treatment objectives were outlined as reduction of inflammation, prevention of uveitis recurrence, and continuation of systemic immunomodulatory therapy in order to maintain malignancy remission; the patient was treated with fluocinolone acetonide intravitreal implant bilaterally and at 18 months’ follow-up had 20/20 bilateral visual acuity and no inflammation. In case 2, a woman in her 70s, presented with a 2-month history of worsening floaters and blurry vision. She was phakic, with bilateral nuclear sclerotic cataracts, 1+ vitreous cells and 2+ haze, diffuse vasculitis, and central leakage around the optic nerve and posterior pole. She was diagnosed with bilateral idiopathic panuveitis with retinal vasculitis. The patient continued to do well at 1 year following intravitreal implantation with fluocinolone acetonide.

Introduction

Uveitis causes 10%–15% of all cases of blindness in the developed world, and 67%–90% of these cases are due to noninfectious uveitis.1 Noninfectious uveitis affecting the posterior segment (NIU-PS) derives from various etiologies. Treatment for NIU-PS aims to reverse inflammation and its effects and to prevent recurrence.2 Panuveitis, which can share features with noninfectious posterior uveitis, is typically treated with systemic (oral or intravenous) corticosteroids or antimetabolites rather than topical corticosteroid drops because these drugs must reach the posterior segment and adjacent ocular compartments. Other acceptable routes for corticosteroid delivery include periorbital injections, intravitreal injections, and placement of a sustained-release intravitreal implant. Local therapy may be preferred when disease is unilateral or significantly worse in one eye or when the potential for toxicity associated with systemic anti-inflammatory therapy is great.

The following cases describe patients with chronic panuveitis treated with 0.18 mg fluocinolone acetonide intravitreal implant to achieve local, long-term inflammatory control while avoiding interference with systemic immunity. Designed for in-office placement via a preloaded injector, this implant delivers a continuous low dose of fluocinolone acetonide to the vitreous, retina, choroid, and adjacent ocular tissues for up to 36 months.2

Local, long-acting fluocinolone acetonide intravitreal implants (FAis) are indicated for treatment of chronic NIU-PS.3 Although corticosteroids remain a mainstay of treatment for acute uveitic flares, they may not be appropriate treatment for patients with recurrent or chronic inflammatory attacks, given the adverse effects associated with long-term glucocorticoid therapy.2 However, not all patients are candidates for systemic steroid-sparing immunomodulatory therapy (IMT), including those who develop a significant adverse reaction with IMT, those who are at increased risk for infection due to age-related waning of immune potency, those with ongoing or recent diagnosis of malignancy, and patients who wish to conceive.

Case Reports

Case 1 was a 52-year-old man who was referred to Massachusetts Eye Research & Surgery Institution (MERSI) for ophthalmic evaluation for redness, photophobia, and floaters in both eyes for several weeks. Symptoms began in the setting of treatment for metastatic melanoma with 2 cycles of combination ipilimumab (Yervoy, Bristol-Myers Squibb, Princeton, NJ) and nivolumab (Opdivo, Bristol-Myers Squibb, Princeton, NJ), which are immune checkpoint inhibitors (ICI) that augment cancer-fighting immunity by blocking the cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) and programmed cell death protein-1 (PD-1) immune suppression pathways, respectively.4 The patient’s oncology team felt strongly that the combination immunotherapy was halting—and perhaps even reversing—the metastases in his brain and liver.

On presentation, the patient’s visual acuity was 20/40 bilaterally. Examination revealed 3+ anterior chamber cells and 1+ vitreous cells bilaterally. Fluorescein angiography (FA) identified punctate hyperfluorescence with dye pooling in the peripapillary and macular regions as well as late-phase optic disc hyperfluorescence (Figure 1). Macular optical coherence tomography (OCT) confirmed pockets of subretinal fluid consistent with angiography findings (Figure 2).

Figure 1.

Case 1. Pretreatment wide-field fluorescein angiography (FA) of right eye (A) and left eye (B) showing multifocal punctate hyperfluorescence and dye pooling around the optic nerve and the posterior pole. The patient has bilateral senile retinoschisis accounting for the peripheral hyperfluorescence.

Figure 2.

Case 1. Optical coherence tomography (OCT) images of right eye (A) and left eye (B) showing multiple pockets of subretinal fluid corresponding to the area of subretinal dye pooling seen on FA.

The patient was diagnosed with bilateral, drug-induced panuveitis. In consultation with the referring oncologist, treatment objectives were outlined as reduction of inflammation and control of uveitis, prevention of uveitis recurrence, and continuation of systemic immunomodulatory therapy in order to maintain malignancy remission. Systemic corticosteroids were not initiated, because the patient was enrolled in a clinical trial at the time, and treatment would have terminated his trial participation.

Topical prednisolone acetate 1% was initiated at six times per day in both eyes and tapered over several weeks, which helped to resolve the anterior segment inflammation. However, the posterior segment inflammation did not improve, and his central vision remained affected with a visual acuity of 20/30 in both eyes. Given the persistent vision-threatening inflammation in the posterior segment and anticipating ongoing need for cancer immunotherapy, fluocinolone acetonide intravitreal implant was recommended for both eyes.

Two months following the intravitreal implant, examination revealed no anterior chamber or vitreous cells, and visual acuity was 20/20 bilaterally. Imaging showed that the subretinal fluid and leakage around the optic nerve had resolved (Figures 3 and 4). Approximately 3 months after injection, he developed mild ocular hypertension with intraocular pressure (IOP) in the mid-20s, which was responsive to dorzolamide-timolol alone and did not result in any glaucomatous damage over his 18-month follow-up. His cataracts became visually significant approximately 12 months after the injection, rendering it difficult to drive at night. He underwent successful cataract surgery and achieved best-corrected visual acuity of 20/20 postoperatively. In the 18 months following placement of the intravitreal implant, the patient’s inflammation remains quiescent, and visual acuity remained 20/20 bilaterally. The patient’s stage 4 melanoma remained controlled with ongoing immunotherapy.

Figure 3.

Case 1. Post-fluocinolone acetonide intravitreal implant FA of the right eye (A) and left eye (B) demonstrating resolution of the abnormal multifocal punctate hyperfluorescence.

Figure 4.

Case 1. OCT images of the right eye (A) and left eye (B), showing the return of normal macular anatomy.

Case 2 was a 73-year-old woman who was referred to MERSI with a 2-month history of worsening floaters and blurry vision during the COVID-19 pandemic. On examination, she had bilateral nuclear sclerotic cataracts. Visual acuity was 20/30 in each eye. The anterior segment was void of cells, but the vitreous had 1+ cells and 2+ haze in each eye. Fundus photography showed sheathing around the vessels from diffuse vasculitis. Fluorescein angiography showed bilateral central leakage around the optic nerve and posterior pole, left worse than right. Scattered retinal vascular wall hyperfluorescence consistent with retinal vasculitis was observed. There were no subretinal lesions that resembled lymphomatous infiltration (Figure 5).

Figure 5.

Case 2. Pretreatment FA of the right eye (A) and left eye (B) showing diffuse vascular wall hyperfluorescence consistent with retinal vasculitis.

After unremarkable serological workup for her intraocular inflammation, the patient was diagnosed with bilateral idiopathic panuveitis with retinal vasculitis. There was no macular edema; however, she was at risk for developing macular edema and central vision loss if the inflammation was not addressed promptly. Typically, in our practice, a patient with this diagnosis would be offered treatment with a systemic IMT, such as an antimetabolite or a tumor necrosis factor-alpha inhibitor. Because the patient came to us at the height of the pandemic, however, there was significant concern for increased risk for infection with immunosuppression, given her age. Therefore, local therapy with fluocinolone acetonide intravitreal implant was elected.

At the 1- and 2-month follow-ups, vitritis resolved completely, and FA revealed a marked improvement, with central and limited peripheral vascular wall hyperfluorescence still present (Figure 6). Because the patient lived far from the office and preferred to avoid frequent travel, she elected to follow up with her local ophthalmologist, who reported that the patient continued to do well almost 1 year after the placement of the intravitreal implant (follow-up FA images are unavailable).

Figure 6.

Case 2. Post-treatment FA of the right eye (A) and left eye (B) showing significant improvement of vasculitis after 2 months.

Discussion

Recent ICI therapies, including ipilimumab and nivolumab, have transformed the treatment of advanced melanoma and provided hope for prolonged tumor regression and improved patient survival.4 The list of indications for ICIs is growing and includes lymphoma, lung cancer, and urologic cancers.5

Side effects with ICI therapy are common and have been reported to be 10% more likely compared with standard chemotherapy.6 These ICI-related adverse effects (irAEs) may affect any organ, most commonly the gastrointestinal tract and the skin. Ocular irAEs, including episcleritis, keratitis, inflammatory orbitopathy, macular edema, and retinal detachment, are not as common, occurring in 1%–3% of patients receiving ICIs.5,6 Dry eyes and uveitis are the most common ocular irAEs and may occur at any point during or after therapy.5 However, these irEAs may be a marker of ICI efficacy.5

The American Society of Clinical Oncology (ASCO) guidelines recommend permanently stopping ICI therapy and initiating systemic corticosteroids for posterior uveitis, panuveitis, and other grade 3 adverse events.7 In these patients, grading of disease severity is performed after a detailed ophthalmic evaluation, assessing visual acuity in each eye individually, color vision, funduscopic examination, pupil size, shape, and reactivity, red reflex, and anterior segment examination. Conversely, some oncologists argue in favor of continuing potentially life-saving ICI therapy whenever possible. They also advocate for local treatment of ocular irAEs in lieu of systemic corticosteroids.5

In case 1, we opted to continue ICI anticancer therapy without interruption because the patient’s metastases had responded well to therapy. The decision was made to treat with a sustained-delivery intravitreal corticosteroid device bilaterally for long-term inflammatory control to avoid side effects of systemic steroids as well as potential interference of systemic IMT with anticancer therapy. The fluocinolone acetonide intravitreal implant resolved his panuveitis and prevented recurrence over 18 months of follow-up; another 18 months of anti-inflammatory effect is expected, because the implant delivers medication for up to 36 months.3

We know from case series reports that uveitis may recur because such implants become depleted toward the third and subsequent years. In a retrospective review of 12 patients treated with FAi for chronic uveitis, Cai et al8 reported that 5 patients experienced recurrence 23–61 months after insertion. Of these 5 patients, 3 experienced increased vitreous haze, and all had increased anterior chamber cells. The authors estimated that the probability of remaining uveitis-free at 36 months was 0.67 (range, 0.34–0.86), with 95% confidence intervals. There are currently no known predictors for recurrence of noninfectious uveitis, with no differences observed with regard to baseline central subfoveal thickness, duration of uveitis, or age between patients with recurrences versus those without.8 In general, regular examination and testing with FA and OCT should be performed toward the tail-end of the known period of duration of therapy to detect any subtle inflammatory recurrence that would prompt repeat FAi placement. In our practice, we examine all post-FAi patients every 3–4 months to monitor IOP and start performing regular imaging surveillance 24–30 months into FAi therapy.

Known risks of long-term localized corticosteroid exposure include increased IOP and cataract development among phakic individuals.3 In the first case, the patient required cataract surgery after intravitreal implant placement, most likely related to the combination of corticosteroid exposure and the inflammatory state induced by the checkpoint inhibitors.9,10

The incidence of cataract formation with fluocinolone acetonide intravitreal implant was evaluated in a phase 3 clinical trial consisting of 87 patients in the intravitreal implant group and 42 patients in the control (sham injection) group. Among those who were phakic at baseline, the intravitreal implant was associated with increased risk for cataract formation requiring surgery at 12 months compared with the sham injection group (33% vs 12% [P < 0.01]).9 This trend persisted through 36 months, with 73.8% of those receiving the intravitreal implant requiring cataract surgery compared with 23.8% in the sham-treated group. No other adverse events in the intravitreal implant group were observed to be markedly higher compared with the sham group.10

After implant placement, the first patient required treatment with an IOP-lowering drop once daily, but he did not require glaucoma surgery. This is consistent with the safety data of this intravitreal implant from clinical trials. In phase 3 trials, 26% of patients in each group (fluocinolone acetonide intravitreal implant vs sham injection) required IOP-lowering therapy at 12 months. At 36 months, 42.5% of fluocinolone acetonide intravitreal implant-treated vs 33.3% of sham-treated patients required IOP-lowering medical therapy. The need for glaucoma surgery was lower in those who received fluocinolone acetonide intravitreal implant versus sham injection at 12 months (3.4% vs 4.5%, resp.) and at 36 months (5.7% vs 11.9%).9,10

Use of the fluocinolone acetonide intravitreal implant in case 2 allowed for improvement of panuveitis and retinal vasculitis via sustained, local, low-dose corticosteroid treatment. It should be noted that follow-up for this patient was more limited than for case 1.

Immunosenescence (the waning of immune potency with age) places elderly individuals at increased risk for influenza, varicella zoster, and other potentially severe viral infections.11 Not surprisingly, the COVID-19 pandemic disproportionately affected elderly individuals, with risk for related severe disease, hospitalization, and death increasing linearly with age.12 It is important that healthcare practitioners support their patients by considering the effects of proposed therapies on patients’ immune defenses and helping them to reduce susceptibility to viral infection whenever possible.

Review of a large registry of patients in Spain showed that exposure to repeated courses of corticosteroids was associated with poor outcomes among patients with autoimmune disease who became infected with COVID-19.13 Taken together, it seems prudent to limit systemic corticosteroid exposure during a viral pandemic, especially if effective local alternatives are available.

A robust systemic immune system is essential for fighting cancer and preventing severe infection. Treatment of NIU-PS with the intravitreal fluocinolone acetonide implant may be a treatment for patients who need to avoid the potential immunocompromise associated with systemic corticosteroids and steroid-sparing anti-inflammatory medications.