Treatment options for NIU-PS include corticosteroids (systemic, topical, periocular, intravitreal), antimetabolites, calcineurin inhibitors, alkylating agents, and biological agents [11, 30,31,32,33,34,35]. Among them, systemic corticosteroids are considered as the first line treatment for NIU-PS, due mainly to their efficacy and rapid control of inflammation [11, 33, 34]. Corticosteroids can be administered topically, periocularly, intraocularly, or systemically, depending on the disease severity and the type of ocular involvement [11, 33, 34]. However, the prolonged use of systemic therapies, including corticosteroids, classic immunomodulators, and biologics, have been associated with both systemic (e.g., diabetes, Cushing's syndrome, major psychiatric disorders, or gastroduodenal ulcer) and ophthalmological (cataract, raised intraocular pressure) [11, 36]; while short-acting localized corticosteroids are problematic as they are short-acting and do not control the underlying inflammation or flare-ups that occur with NIU-PS, with oscillating periods of functional and structural amelioration and worsening, which means a greater probability of cumulative and permanent visual damage [37].

Since NIU-PS is a chronic disease, long-lasting therapeutic options, which minimize the incidence of recurrences and systemic/local side effects, are highly desirable [24].

Recent technology has permitted the development of long-lasting low-dose sustained release intravitreal corticosteroid implants which have changed the treatment paradigm of NIU-PS [10]. Compared to systemic, periocular, and other intravitreal corticosteroids (i.e., triamcinolone acetonide and dexamethasone implant), 0.2 µg/day FAc implants offer the advantage of a gradual and sustained localized release of the corticosteroid to the posterior segment of the eye, resulting in reduced rates of relapses and fewer injections, and significantly reducing the systemic immunomodulation load requirements [10, 11].

In a systematic review published in 2021, the main conclusion drawn from the survey, regarding effectiveness, was that implants reduced the incidence of recurrences and the need for adjuvant therapies [38]. This suggests clearly the systemic immunomodulation sparing effect that slow-release local therapies have. Regarding safety, adverse events were as expected and they were safely managed within the studies [38].

Up to now, there are four sustained release intravitreal corticosteroid implants, one of dexamethasone 700 µg (Ozurdex®, AbbVie Company, Dublin, Ireland); and three of fluocinolone acetonide with different doses, namely 0.59 mg (Retisert®, Bausch and Lomb, Inc. USA), 180 µg (Yutiq®; Alimera Sciences Inc., Alpharetta, Georgia, USA), and 190 µg (ILUVIEN®; Alimera Sciences, Dublin, Ireland). ILUVIEN® is currently available in EU and the United Kingdom.

The intravitreal 0.59-mg fluocinolone acetonide implant (Retisert®, Bausch and Lomb, Inc. USA) was the first US FDA-approved implant for treatment of NIU-PS, but it requires surgical implantation and has been associated with several complications (hypotony, resistant intraocular pressure elevation, endophthalmitis). In addition, the use of Retisert® (Bausch and Lomb, Inc. USA) is only available in the USA, since it has not been approved in Europe.

Both 190 µg and 180 µg fluocinolone acetonide implants are injected intravitreally, by a preloaded applicator with a 25-gauge needle through the pars plana. Both implants were designed to release fluocinolone acetonide at a rate of 0.2 μg/day over a 3-year period, progressively decreasing to 0.1 μg/day [12, 39,40,41].

An overview of published evidence for the 0.2 µg/day FAc implant is summarized in Table 3.

Table 3 Summary of published studies for injectable 0.2 µg/day fluocinolone acetonide implants in non-infectious uveitis

PSME is a primary cause of reduced vision following both cataract and successful vitreoretinal surgery, whose incidence following modern cataract surgery ranged between 0.1 and 3.4% [61, 62]. Although mostly self-limiting, persisting cases can pose a major therapeutic challenge to ophthalmologists, and can mean an increased burden for healthcare systems [63]. Additionally, persistent PSME is often referred to uveitis specialists when the condition has become chronic and manifests as recurrent intraocular inflammation [52].

Although there is no unanimous agreement on the fact of considering relapsing PSME as a uveitis, inflammation plays a key role in its development [61, 62]. Despite this lack of agreement, the panel recommended the use of the FAc implant in these patients (90% agreement) but only in relapsing and chronic cases.

According to the results obtained after the second round of the survey, "strong consensus" (> 95% of the participants agree) or consensus (> 75% to ≤ 95% of the participants agree) was obtained on most of the points addressed.

The panel did not reach consensus (≤ 50% of the participants agree) in two statements:

1.

There is no evidence supporting the use of FAc implant as preferable treatment in eyes with inflammatory choroidal neovascularization; therefore, only 50% of the panel recommended its use in these cases.

The second statement on which the panel members did not reach a consensus was the use of the FAc implant, either as monotherapy or as adjunctive therapy, in patients with Tubulointerstitial nephritis and uveitis (TINU). Although there is no prospective, randomized clinical report regarding the treatment of TINU syndrome in the literature, the uveitis in TINU syndrome responds well to topical or systemic steroids in most of the cases [64,65,66]. However, the disease tends to recur and a slower tapering and long-term treatment with systemic corticosteroids is required [64, 65].

Despite this, the lack of direct evidence evaluating the effectiveness of FAc implant in patients with TINU could be the reason that motivated the lack of a panel consensus.

Safety: intraocular pressure/cataract

Intravitreal corticosteroid implants may increase the risk of elevated intraocular pressure and cataract formation [67].

Jaffe et al. reported that in eyes with NIU-PS who received a 0.2 µg/day FAc implant, mean intraocular pressure increased by 1.3 ± 3.57 mmHg at month-12 [68]. However, at month-36, the change from baseline was only 0.8 ± 5.0 mmHg and was lower than that observed in the sham-treated group where mean intraocular pressure increased by 1.4 ± 5.7 mmHg [15]. This finding may be related to the fact that in the sham-treated group, many eyes received other systemic and/or topical corticosteroids as a standard of care [15].

In addition to raised intraocular pressure, development of cataract is one of the major concerns when using intravitreal corticosteroids [10, 15, 67,68,69]. According to the results of the clinical trials, cataract surgery was more frequently required in the FAc implant treated group than in the sham-treated group (73.8% vs. 23.8% of eyes, respectively) [15, 68]. Regarding cataract surgery outcomes, the effect on visual acuity was similar in the FAc implant and sham groups (+ 20.3 letters for the FAc implant-treated group vs. + 23.4 letters for the sham-treated group) [15].

In a post-hoc analysis of a phase-3 randomized clinical trial [15], Pavesio and Heinz [24] compared the clinical outcomes of eyes treated with FAc implant with those of the fellow eye receiving conventional treatments. According to their findings, cataract surgery was more frequently required over 36 months in the FAc implant treated eyes (72%) than in the fellow eyes (37.0%) [24].

Lens status (Phakic/Pseudophakic/aphakic eyes)

Regarding the use of the FAc implant depending on the state of the lens, the panel showed a strong agreement on the use of FAc implant in pseudophakic eyes (its use is recommended) and in aphakic eyes (its use is not recommended due to the risk of anterior chamber migration, although FAc implant could be considered if sutured to the sclera [51, 53].

With regards to phakic eyes, the panel agreed to recommend the use of the FAc implant. However, the age of the patient, uveitis severity, and the individual limitations for an adequate systemic immunomodulatory therapy need to be considered. Additionally, the use of the FAc implant would be considered in the presence of presbyopia, cataract, or when the patient is undergoing cataract surgery after the implant has been administered.

Quiescent eye/previous steroid

In order to control active intraocular inflammation in patients with NIU-PS, the panel agreed that DEX-i would be considered as a first-line therapy. This is intended to determine the functionality of corticosteroids, evaluate the incidence of adverse effects (e.g., elevation of intraocular pressure) and whether NIU-PS recurs.

However, it has been published that injecting a DEX-i prior to a FAc implant did not provide better outcomes than inject a FAc implant as first choice [29]. Moreover, there was consensus on the use of the FAc implant in the control of NIU-PS recurrence, when inflammation reoccurs after 1–2 successive DEX-i. In fact, Kessler et al. [27] found that the more corticosteroids administered prior to the FAc implant, the greater the need for combination therapy after FAc implant.

As far as we know, there are no studies comparing FAc implant and repeated injections of DEX-i in patients with NIU-PS. However, it should be highlighted that these implants have been licensed for different indications [12, 70]. While DEX-i was marketed for treating active inflammation, FAc implant is intended to be used to prevent relapses in recurrent NIU-PS. Moreover, the long-lasting effect of FAc implant compared to DEX-i makes FAc implant more effective in the long-term prevention of relapses in recurrent NIU-PS [37], with a significant decrease in the number of intravitreal injections and this represents a reduction in disease burden to the patient.

Systemic therapies

Current evidence suggests that the 0.2 µg/day FAc implant is effective in reducing the need for subsequent treatment with systemic medication [14, 15, 19, 24, 25, 58, 68, 71, 72].

According to the results of the two pivotal phase 3 randomized, clinical trials, the eyes treated with the 0.2 µg/day FAc implant required fewer adjunctive local and systemic treatments than the eyes treated with sham + standard of care [15, 68, 71].

Jaffe et al. [68] reported that throughout the first 12 months after treatment, the proportions of eyes requiring at least 1 systemic corticosteroids or immunosuppressant treatment was lower in the 0.2 µg/day FAc implant group than in the sham + standard of care treated group (19% versus 40%, respectively).

Throughout the 36-month follow-up period, the proportion of eyes receiving any adjunctive medication in the 0.2 µg/day FAc implant group was 57.5% compared with 97.6% in the sham + standard of care treated group. Moreover, the mean number of adjunctive treatments per eye in the 0.2 µg/day FAc implant group was 0.48 compared with 1.52 in the sham + standard of care treated group [15].

Finally, the results of a retrospective study, conducted on 103 eyes with NIU-PS who underwent treatment with the 0.2 µg/day FAc implant and were followed-up for at least 12 months, found that 55% of patients on oral prednisone and 35% of patients on systemic immunomodulatory therapy at baseline were able to discontinue the therapy by month 12 [72].

Limitations

It is important to highlight important limitations in this study. Firstly, the clinical experience in some etiologies associated with NIU-PS was limited, and in some cases, absent, which may impact clinical recommendation in these cases. Nevertheless, the broad clinical experience of the panel members, as well as the available evidence with other etiologies might reduce this limitation. In addition, all consensus documents should be considered within an evolving environment and should be regularly revised to implement novel findings as they occur and future evidence as it becomes available.