Background

Non-infectious uveitis affecting the posterior segment of the eye (NIU-PS) is an inflammatory disease, which may result in severe visual impairment and tissue damage when it is not adequately treated and controlled [1]. Additionally, the prevalence of bilateral involvement is high, and it is estimated that it accounts for approximately 10%-15% of cases of blindness in developed countries [2]. Unlike other retinal diseases, uveitis is the fifth most common cause of vision loss in high-income countries, accounting for 5% to 20% of legal blindness [3, 4], with the highest incidence of disease in the working-age population [5] with significant social and economic impact [6, 7].

Many etiologies have been associated with NIU-PS, including Birdshot retinochoroiditis, Behçet’s disease, sarcoidosis, and intermediate uveitis [2, 8, 9].

Current treatment strategies of NIU-PS attempt to control active inflammation and to prevent recurrences. This is done to avoid the potential reduction of visual function and is initially achieved using systemic corticosteroids and then secondary using immunosuppressive agents as they are steroid sparing agents. Since both local and/or systemic treatments may be associated with significant side effects, new strategies for delivering the drug to the site of inflammation, the vitreous cavity, have been developed [10, 11].

Fluocinolone acetonide sustained-release 0.2 µg/day intravitreal (FAc) implants (ILUVIEN®; Alimera Sciences, Dublin, Ireland and YUTIQ®; Alimera Sciences Inc., Alpharetta, Georgia, USA) are indicated for the prevention of relapse in recurrent NIU-PS [12] and for the for the treatment of chronic non-infectious uveitis affecting the posterior segment of the eye [13], respectively.

The results of a pilot study, conducted on eleven eyes from 11 patients with a history of recurrent NIU-PS, showed FAc implants improved the best-corrected visual acuity (BCVA) from 0.56 ± 0.43 logMAR at baseline to 0.17 ± 14 logMAR at month-24 (p = 0.0016). None of the studied eyes experienced a recurrence during the follow-up period [14].

Additionally, the 36-month effectiveness and safety of FAc implants were evaluated in a phase 3, prospective, double-masked, and multicenter study [15]. Patients with NIU-PS were randomly assigned to receive treatment with the 0.2 μg/day FAc implant or Sham treatment (sham injection plus standard of care) treatment. BCVA significantly improved by + 9.1 letters in the FAc implant group compared with + 2.5 letters for the sham-treated group (p = 0.020). Over 36 months the cumulative uveitis recurrence rate was significantly lower in the FAc- implant group (65.5%) compared with 97.6% in the sham-treated group (p < 0.001) [15]. At month 36, the time to first recurrence in FAc-treated eyes was significantly longer compared with sham-treated eyes (median 657.0 days and 70.5 days, respectively; P < 0.001). Moreover, the number of recurrences per eye occurring over 36 months was also significantly lower in the FAc-treated group compared with the sham-treated group (mean 1.7 vs. 5.3 respectively, P < 0.001) [15] Intraocular pressure was well controlled in both study groups and approximately half as many eyes in the FAc-treated group when compared with the sham-treated group underwent IOP-lowering surgery (5.7% vs. 11.9%) [15].

Despite the good clinical outcomes reported in these trials, they did not provide any information about the etiology of the NIU-PS [14, 15]. Since FAc implants have become available in the USA and some European countries, more clinical experience has been gained and more studies evaluating FAc implants in different clinical scenarios have been published [15,16,17,18,19,20,21,22,23,24,25,26,27,28] showing that the FAc implants are effective for preventing recurrence of ocular inflammation in patients with NIU-PS [14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29].

Despite this evidence, there are still certain doubts regarding the clinical management of NIU-PS in daily clinical practice using the 0.2ug/day fluocinolone acetonide intravitreal implants.

The aim of this review was to generate consensus-based recommendations from a group of uveitis experts with substantial experience of treating NIU-PS with 0.2ug/day FAc implants in their clinical practice.

Methods

A European Clinical expert group of 10 Uveitis/retinal specialists from France; Germany; Italy; Spain; and United Kingdom, with significant experience in using the FAc implant in patients with NIU-PS, was formed to collaborate to develop a consensus report on different issues related to the most valuable applications on the use of the FAc implants (ILUVIEN®; Alimera Sciences Ltd., Hampshire, UK and YUTIQ®; Alimera Sciences Inc., Alpharetta, Georgia, USA) in patients with different clinical presentations and etiologies of NIU-PS in daily practice.

This project was carried out in six phases: (1) Initial phase, where the expert panel members reviewed the currently available scientific evidence. (2) The panel selected and agreed different topics relating to the use of FAc implants in patients with NIU-PS and developed a questionnaire; (3) the panel of experts answered the questionnaire; (4) the experts reviewed and discussed the results of the survey in a virtual meeting held on April 2023; (5) The panel performed a second round of the survey; and (6) The panel reviewed, analyzed, and validated the data from the second-round survey in a virtual meeting held on May 2023.

The degree of consensus was determined at the end of the process (Table S1).

Scientific evidence

A literature search of Pubmed/MEDLINE conducted by using a combination of keywords related to uveitis (non-infectious/non-infectious uveitis; inflammation; Behçet disease; sarcoidosis uveitis; birdshot retinochoroiditis; post-surgical macular edema; prevalence; incidence; corticosteroids). The search period ranged from January 2000 to June 2023. References cited in the individual papers were also reviewed to identify any relevant reports. In addition, relevant national and international guidelines were reviewed.

Questionnaire development

After reviewing the literature, the Clinical expert panel identified and discussed those aspects that may generate expert discussion and controversy, and decided which were to be included in the questionnaire.

The questionnaire included 21 items involving the use of the FAc implants and the management of patients with NIU-PS (see Annex I).

Results

Survey

The survey aimed at answering the diverse queries that arise about the clinical management of patients with NIU-PS and the use of the 0.2 µg/day FAc implants in these patients in clinical practice.

Table 1 shows the expert panel responses to the different survey questions after completing the first and second survey.

Table 1 Overview of the expert panel responses to the different survey questions after the first and second rounds
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The different survey questions could be framed in the following subjects:

  • Unilateral/Bilateral NIU-PS

According to the panel, 0.2 µg/day FAc implants can be used in cases of unilateral or asymmetric inflammation without associated systemic involvement, contraindications to systemic treatments, refractory damage and/or macular oedema. In cases of bilateral symmetric involvement and/or associated systemic involvement, the first course of treatment is general systemic treatment followed by a reduction, more or less associated with sparing treatment in cases of corticosteroid dependence. The use of 0.2 µg/day FAc implants in monotherapy or in combination with systemic treatment will depend on the patient’s lens status and previous treatments.

  • NIU-PS in relation to systemic involvement

0.2 µg/day FAc implants might be used in eyes with NIU-PS without systemic involvement, either in monotherapy or in combination with systemic treatment, depending on the presence of deep choroidal inflammation (100% agreement). On the other hand, 0.2 µg/day FAc implants could be chosen in uveitis in association with systemic involvement in combination with systemic therapy to control the ophthalmic inflammation. (e.g., in Behcet disease patients) (90% agreement).

  • Lens status

The panel considered that 0.2 µg/day FAc implants can be used in pseudophakic eyes with NIU-PS (100% agreement), but not in aphakic eyes with NIU-PS (100% agreement). According to the panel, 0.2 µg/day FAc implants might be used in phakic eyes with NIU-PS (80% agreement), although patient age (young patients), uveitis severity (greater inflammatory activity), and the need for combination therapy need to be considered. In addition, the use of 0.2 µg/day FAc implants would be considered in patients with presbyopia, cataract, or planned cataract surgery after the implant.

Treatment algorithms and recommendations

The panel has developed two fundamental treatment algorithms, based both on the currently available scientific evidence and on the experience of its members. One that refers to the practical management of patients with NIU-PS in clinic and another that establishes the best clinical scenarios for the use of 0.2 µg/day FAc implants, both as monotherapy and as combination therapy.

Additionally, the panel has developed a table that includes the main uveitic etilogies for use of the 0.2 µg/day FAc implants in a clinical setting.

Figure 1 shows the treatment algorithm of eyes with NIU-PS. This algorithm considered various aspects relating to the disease, such as the presence of intraocular inflammation with or without systemic inflammation, the presence or absence of active systemic inflammation, or its bilaterality, amongst others.

Fig. 1
figure 1

Treatment algorithm of eyes with non-infectious uveitis affecting the posterior segment. FAc: Fluocinolone acetonide sustained-release 0.2 µg/day intravitreal implant

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According to the panel's recommendations:

  • Intravitreal/periocular triamcinolone (which is off-label in many countries) would be considered in cases where intravitreal implants are not recommended: e.g., aphakia, large iridectomy.

  • To use 0.2 µg/day FAc implants after recurrence of inflammation and/or macular edema as adjunctive to systemic or topical therapy.

  • The use of 0.2 µg/day FAc implants could be considered before recurrence of inflammation and/or macular edema to local therapy if there is previous knowledge about the patient’s response to a prior dexamethasone implant (DEX-i).

According to the panel, FAc implant would be considered for use in patients in:

  • Unilateral NIU-PS.

  • Bilateral asymmetrical NIU-PS.

  • Bilateral symmetrical NIU-PS.

  • NIU-PS with no systemic involvement.

  • NIU-PS with systemic involvement as an adjunctive therapy.

  • NIU-PS with deep choroidal involvement as an adjunctive therapy in cases of retinal or superficial choroidal inflammation.

  • Pseudophakia or pre-existing cataract.

  • NIU-PS with macular edema.

  • Systemic treatment burdensome or contraindicated.

Figure 2 shows the degree of agreement of the members of the panel about the use of the FAc implant amongst the different NIU-PS etiologies.

Fig. 2
figure 2

Degree of agreement of the members of the panel about the use of the fluocinolone acetonide 0.2 µg/day intravitreal (FAc) implant among the different etiologies associated with the onset of non-infectious uveitis affecting the posterior segment (NIU-PS) of the eye. *Macular edema includes Cystoid macular edema and diffuse macular edema (this is not frequent). FAc: Fluocinolone acetonide 0.2 µg/day intravitreal implant; NIU-PS: Non-infectious uveitis affecting the posterior segment

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The Table 2 summarizes the role of FAc implant in different NIU-PS etiologies associated with the onset of NIU-PS.

Table 2 Role of the Fluocinolone acetonide 0.2 µg/day intravitreal (FAc) implant in the different etiologies associated with the onset of non-infectious uveitis affecting the posterior segment (NIU-PS) of the eye
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As a combination therapy, the FAc implant would be a valuable treatment option in the following etiologies: Birdshot retinochoroiditis, multifocal choroiditis and panuveitis, sarcoidosis, intermediate uveitis, post-surgical macular edema (PSME), serpiginous choroiditis, or Behçet’s disease, among others (degree of agreement ≥ 80% each, respectively). However, its use in eyes with multiple evanescent white dot syndrome was not considered a good option (degree of agreement ≥ 0% ≤ 20%) (Fig. 2 and Table 1).

As a monotherapy, the FAc implant could be considered in post-surgical macular edema (degree of agreement ≥ 80%), as well as in sarcoidosis, intermediate uveitis, and multifocal choroiditis and panuveitis (degree of agreement ≥ 50% < 80% each) (Fig. 2 and Table 1).

Discussion

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
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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. 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.

Conclusions

According to the panel recommendations, there was agreement that the FAc implant can be considered for use in patients with unilateral, bilateral asymmetrical, and bilateral symmetrical NIU-PS. FAc implant would be used in pseudophakic NIU-PS eyes, but not in aphakic eyes. Regarding the use of the FAc implant in phakic eyes with NIU-PS, the age of the patient, uveitis severity, and the individual limitations for an adequate systemic immunomodulatory therapy need to be considered.

With regards to the use of the FAc implant based on the etiology, its use was recommended as adjunctive/combination therapy in birdshot retinochoroiditis, multifocal choroiditis and panuveitis, serpiginous choroiditis, sarcoidosis, and pars planitis, among others. While its use was not recommended in multiple evanescent white dot syndrome, and acute retinal pigment epitheliitis, due to their transient /self-limiting nature.

This consensus highlights relevant points that may help specialists optimize outcomes in patients with NIU-PS. Moreover, it could serve as a basis to standardize approaches to the management of patients with NIU-PS and to achieve the best outcomes for the patient.