Intravitreal steroid implants in the management of noninfectious intermediate and posterior uveitis

Abstract

The management of intermediate and posterior uveitis poses a significant challenge of achieving adequate drug concentrations in the posterior segment over the chronic nature of the disease. Systemic agents seldom reach effective drug levels, and even with low maintenance or tapering doses, it is hard to avoid systemic toxicity. The use of intravitreal and periocular injections is often unable to prevent recurrences due to their short half-life. Since the emergence of intravitreal implants (Vitrasert, Retisert), it has become possible to circumvent these therapeutic challenges. A detailed review in the PubMed index yielded 155 articles, of which 22 were analyzed based on exclusion criteria. A recent shift from surgically sutured to minimally invasive injectable implants mainly indicated for noninfectious uveitis is evident from the literature. This review article also provides insights into dexamethasone (Ozurdex) and recent fluocinolone acetonide (Yutiq, Iluvien) implants with particular emphasis on their improved safety and efficacy. Dexamethasone implants favor the therapeutic goal of prevention of recurrences, whereas the use of fluocinolone implants helps to attain better visual outcomes due to their longer duration of action. Thus, the review provides recent literature supporting the role and indication of sustained release intravitreal implants in the management of noninfectious intermediate and posterior uveitis.

Uveitis refers to a diverse group of infectious and noninfectious etiologies that incite inflammation in the vascular layer of the eye and lead to irreversible blindness in approximately 35% of patients. It accounts for 15% of blindness in developed countries and 25% in developing ones. It has an incidence of around 1.04–1.8% in India.[1,2,3]

It can broadly be categorized as infectious and noninfectious. Noninfectious uveitis (NIU) can occur with systemic or localized autoimmune diseases to the eye, which constitute the majority of uveitis cases (67–90%) in the developed world.[4,5,6] On the contrary, infectious uveitis is caused by endogenous or exogenous microbial agents directly invading the structures or cross-reacting at molecular levels to cause inflammation.[7]

Intermediate and posterior uveitis are the major causes of visual morbidity in patients with uveitis. Loss of vision can occur due to secondary complications such as vitreous haze or membranes, macular edema (ME), choroidal neovascular membrane, glaucoma, optic nerve involvement, and cataract formation.[8,9] Use of various modes of steroids for the treatment of NIU can also be a contributing factor in the development of cataract and causing vision loss.

The conventional treatment modalities for such uveitis include topical medications, periocular injections/depot preparations, and systemic corticosteroids in noninfectious/inflammatory conditions, whereas injectable or oral antimicrobials specific to microbes in infectious causes.[10] However, the systemic and local ocular side effects associated with prolonged administration limit their use. Also, the presence of blood–retinal barriers significantly restricts the systemic agents from reaching their therapeutic concentrations in the posterior segment.[10]

Direct corticosteroid delivery into the eye allows therapeutic concentrations to reach the posterior segment while minimizing systemic side effects. Periocular injections and depot preparations are minimally invasive modalities with less systemic side effects but only provide transient therapeutic effects for about 6 weeks with uncertainty in the drug concentrations reaching adequate levels at the target site.[11] It is due to the inadvertent partial absorption of the active agent into the highly vascular choroidal circulation.

However, intravitreal implants circumvent these challenges by providing a higher concentration of the drug at the target site with slow release over a longer duration.[12] Additionally by decreasing or eliminating the need for frequent adjunctive therapy, side effects related to these treatments can be reduced.

This article reviews the latest evidence related to the safety and efficacy of using intravitreal implants in intermediate and posterior uveitis for improvement in best-corrected visual acuity (BCVA), reduction in severity, preventing recurrences, and reduction of associated ME.

Literature review

A detailed review of literature was conducted in the PubMed index with the four following search blocks:

• #1 “Safety”[Title] OR “Efficacy”[Title] OR “Study”[Title] OR “Usage”[Title] OR “Comparison”[Title] OR “effect”[Title] OR “Analysis”[Title]

• #2 “Non Infectious”[Title] OR “Chronic”[Title] OR “Posterior”[Title] OR “Uveitis”[Title] OR “Uveitic”[Title] OR “Treatment”[Title]

• #3 “Intravitreal”[Title/Abstract] OR “Sustained”[Title] OR “Release”[Title] OR “Insert”[Title] OR “Implant”[Title]

• #4 “Fluocinolone”[Title] OR “Iluvien”[Title] OR “0.19”[Title] OR “Dexamethasone”[Title] OR “Yutiq”[Title] OR “0.18”[Title] OR “Retisert”[Title] OR “Ozurdex”[Title] OR “0.7”[Title]

These search blocks were then combined with “AND” operators in the query box to retrieve 155 results. Predefined eligibility criteria relevant to the review were used for screening. Titles of those retrieved articles were screened to exclude irrelevant articles, duplicate records, animal studies, unpublished journal articles, and non-English language records. Articles published till March 2024 were included in the review. Other relevant studies were identified from the bibliographies of the retrieved articles.

Data related to improvement in BCVA in the logarithm of the minimum angle of resolution (logMAR), change in central retinal thickness (CRT), and incidence of adverse events mainly cataract formation and intraocular pressure (IOP) rise were collected onto a standardized form. The following data were included: author, study design, sample size, study outcomes, and safety profile of intravitreal implants.

Implants

Implants can be biodegradable (BI) or nonbiodegradable (NBI). NBIs contain a permeable membrane made of polyvinyl alcohol, which allows diffusion of the drug from the reservoir and ethylene vinyl acetate, a nonpermeable hydrophobic polymer used to restrict drug release. This allows for near-zero-order pharmacokinetics. They have a larger size compared to BIs; therefore, they require large incisions for surgical implantation and removal, once empty. In chronic uveitis where multiple such implants might be required, structural damage from NBIs can lead to unwarranted complications.[13]

On the other hand, BIs are made of polylactic acid, polyglycolic acid, or polycaprolactones. They have a more flexible structure that can be inserted through microincisional techniques. They disintegrate over time, thus bearing an advantage of not needing removal/replacement over time.[14]

Ganciclovir implant (VITRASERT, Bausch and Lomb, Rochester, NY) was the first implantable device used clinically in 1992 for the treatment of acquired immunodeficiency syndrome-related cytomegalovirus (CMV) infection and later approved by the Food and drug administration (FDA) for CMV retinitis.[15,16] Following the success of intravitreal implants in treating infectious uveitis, RETISERT (Bausch and Lomb, Rochester, NY), a fluocinolone acetonide (FA) implant was approved in 2005 for chronic NIU.[17] Vitrasert and Retisert are first-generation intravitreal implants that require surgical implantation through a scleral incision overlying the pars plana region.

Newer generation implants are designed to be inserted intravitreally through pars plana using provided injectors of progressively smaller diameters over the years. Dexamethasone implant (DEX/OZURDEX, Allergan Inc., Irvine, CA, United States) was approved by FDA in 2010 for treating noninfectious posterior uveitis and can be inserted with a 22-gauge single-use applicator.[13] Similarly, fluocinolone acetonide implants (FAi) with 25-gauge intravitreal insertion techniques like YUTIQ (EyePoint Pharmaceuticals, Inc., MA, USA) and ILUVIEN (Alimera Sciences Inc., Alpharetta, GA; pSivida Inc, Watertown, MA) were introduced for intravitreal use, the former of which was approved by the FDA in 2018 for NIU.[13,18]

Following intravitreal implantation, complications such as conjunctival hyperemia or hemorrhage, vitreous hemorrhage, hypotony, choroidal/retinal detachment, accidental lens touch or cataract formation, intraocular inflammation, and wound dehiscence (in surgically placed implants) can be accounted.[19,20] However, with newer implants, such complications are rarely seen.

Cataract formation and ocular hypertension are common adverse effects of intraocular steroids seen over multiple studies included in this review. However, both of these can be managed easily with cataract surgery and antiglaucoma medications (AGM), respectively. Thus, they have minimal overall impact on the efficacy of the implant, yet are encountered in every clinical setting.[21]

Intravitreal corticosteroids

Corticosteroids such as dexamethasone and fluocinolone are the first-line therapy for the management of NIU.[21] Corticosteroids exert their potent anti-inflammatory properties by inhibiting synthesis of vascular endothelial growth factor, prostaglandins, and proinflammatory cytokines, preventing leukocyte migration, and also by stabilizing the endothelial cell tight junctions, which reduces cellular and fluid extravasation.[22]

In the POINT trial, head-to-head comparison between periocular triamcinolone, intravitreal triamcinolone (IVTA) and intravitreal dexamethasone implant in the management of uveitic ME was done.[23] The trial concluded that intravitreal therapy proved to be superior to periocular triamcinolone with moderate risk of IOP elevation. The test of superiority for intravitreal implant against IVTA injection at 8 weeks showed more reduction in the central subfield thickness; however, it did not achieve the levels of statistical superiority (P = 0.035, threshold = 0.00132).[23]

The safety profiles were also similar among the different groups. The limitations of the POINT trial include the necessity of frequent retreatment in the triamcinolone arm (at 8 weeks) compared to the dexamethasone arm (at 12 weeks) due to the shorter duration of action. Forty-one percent of eyes assigned to the periocular group were retreated with IVTA and 7% eyes assigned to IVTA received the intravitreal implant, which led to convergence of results due to overlapping treatment. Also, the longer acting fluocinolone implants were not comparatively evaluated against the other agents.[23]

Thus, IVTA can be considered as a cost-effective option for reducing inflammation and improving visual outcomes in uveitic patients. However, due to its shorter duration of action, more frequent retreatment is required with potential risk of encountering more adverse effects like IOP rise compared to the more durable option of intravitreal implant.

Dexamethasone implant (Ozurdex)

Dexamethasone is a small molecule that is rapidly cleared from the vitreous, with an estimated half-life of only 5.5 Hours. This limitation in the pharmacokinetics can be overcome with newer sustained-release intravitreal implants to release corticosteroids over a prolonged duration of time in small doses.[24] The dexamethasone intravitreal implant, Ozurdex (0.7 mg, DEX implant), is a BI, sustained-release injectable implant. It slowly releases dexamethasone into the vitreous cavity at low doses for about 6 months. It was first approved by the FDA for the treatment of ME secondary to retinal vein occlusion based on the results of phase III, randomized Global Evaluation of implantable Dexamethasone in Retinal Vein Occlusion with Macular Edema (GENEVA) study.[25,26]

Subsequently, the approval was extended for its use in noninfectious posterior uveitis based on the safety and efficacy results from the Chronic Uveitis Evaluation of the Intravitreal Dexamethasone Implant (HURON) study.[21] HURON trial was a landmark study that paved the way for the approval of the dexamethasone implant in the treatment of NIU. It was a 26-week trial where the study group was equally randomized into either 0.7 mg DEX or 0.35 mg DEX or sham group. Higher percentage of eyes in the implant arms experienced improvement in BCVA than in the sham-treated arm. It also provided the yardstick to compare the subsequent trials and helped investigators construct better study designs in real-world settings to overcome its limitations.

Other studies have also reported improvement in BCVA with DEX implant irrespective of type of uveitis, status of macula, and previous treatment. Early BCVA improvement at 1 month after injection has been documented and found to sustain till about 6 months.[21,27,28,29] In one study by Zarranz-Ventura et al.,[30] BCVA improvement sustained till 12 months as well. Bodaghi et al.[31] also reported improved BCVA despite prior treatment with intravitreal/periocular injections.

The aim of using the DEX implant is to reduce local inflammatory sequelae such as vitreous haze and ME. According to the HURON trial, the implant was successful at reducing vitreous haze significantly at 8 weeks.[21]

ME is one of the leading causes of vision loss in NIU.[32] In treating such patients, it is not only important to decrease the CRT but also to prevent recurrence by decreasing the frequency of the edema. Reduction of CRT was noted across the studies with peak effect obtained at 3 months,[32] which sustained till 10–12 months.[27,33] More reduction was observed in treatment-naive patients than previously treated ones.[31]

More than one implant was necessary to maintain the macular contour in 30% and 26.2% eyes in studies by Hasanreisoğlu et al. and Ratra et al., respectively.[28,33] Need for a repeat implant was found at around 6 months, precisely when the effect started wearing off.[28,30] No significant difference in implant efficacy between the first and repeat injection was noted.[28,29] However, by the third injection, the functional and anatomical responses started showing ceiling effects.[28]

Thus, by improving local inflammation, DEX can prevent local recurrences and prevent exacerbations. The steroid sparing effect of DEX implant was also seen up to 40–50% in one study.[33] Thus, it can be used as monotherapy in select unilateral cases. Hasanreisoğlu et al.[28] have reported that the DEX implant is ideal in reducing acute attacks and providing local control of inflammation in patients already on systemic immunosuppression. However, using the implant did not always translate to complete omission of systemic immunosuppression. On the contrary, with FAi in the Multicenter Uveitis Steroid Treatment (MUST) trial, the implant reduced the requirement of systemic immunosuppression. This can be attributed to the longer duration of action of FAi.[34]

Studies have found the DEX implant to cause a transient rise in IOP initially at 1-month postinjection, which rarely sustains beyond 6 months and can easily be managed with AGM.[27,28]

In the HURON trial, the percentage of eyes with intraocular pressure of ≥25 mmHg was 7.1% for the 0.7-mg dexamethasone implant, 8.7% for the 0.35-mg dexamethasone implant, and 4.2% for the sham (P > 0.05 at any visit).[21] Similar results were found by Bodaghi et al. and Hasanreisoğlu et al.[28,31] In another retrospective study of 1110 eyes treated with DEX, only 65 eyes required topical AGM, 5 patients underwent laser trabeculoplasty, and incisional surgery was not needed in any patients.[35]

The incidence of cataract reported in the phakic eyes was 15% in the 0.7-mg dexamethasone implant arm, 12% in the 0.35-mg dexamethasone implant arm, and 7% in the sham arm (P > 0.05).[21] Similar results have been reported in various real-world studies as well.[28,31,33] Tsang et al.[29] in their study reported only progression of subcapsular cataract in two eyes with the implant. No new cataracts were reported.

There have been a few reports of rare adverse effects involving both anterior and/or posterior segments. Rare anterior segment complications include anterior chamber migration of the implant (1–2%) in patients with posterior capsule defects, prior vitrectomy or aphakia.[28,30] Almost 90% of such migrations eventually resulted in significant corneal edema and 80% required surgical intervention. Intralenticular implantation (0.5%) in another such rare side effect often leads to posterior capsule rupture. Vitreomacular traction (0.5%), retinal detachment, proliferative vitreoretinopathy (0.2%) and endophthalmitis (0.1%) are among the rare reported posterior segment adverse effects with the use of Ozurdex implant.[36,37] Despite their rarity, such consequences almost always require surgical management. Careful patient selection and identification of risk factors can help avoid serious complications.[33,38]

Table 1 summarizes the studies assessing the safety and efficacy of Ozurdex implant.

Table 1.

Studies assessing the use of dexamethasone implant in noninfectious uveitis

Author	Design	Sample Size (Patients)/Eyes	Uveitis Type, Diagnosis	Follow-Up (Months)	Efficacy	Safety
Lowder et al.[21]	Prospective multicenter randomized control trial (RCT)	229 eyes randomized 1:1:1 into 0.7-mg DEX (77), 0.35-mg DEX (76) or sham (76)	Noninfectious uveitis (NIU)	26 weeks (Primary endpoint) 6 months (follow-up)	>15 ETDRS letter BCVA gain from baseline seen in the DEX group compared to sham. Significant decrease in CRT in both DEX groups at 26 weeks. Mean decrease in CRT was greater in the 0.7-mg group.	23% of eyes with 0.7 mg implant required AGM. 15% in 0.7 mg, 12% in 0.35 mg, and 7% in sham required cataract surgery (P>0.05).
Gupta et al.[27]	Retrospective	30/39	NIU, Idiopathic (73.33%)	12	BCVA improved from 0.285 at baseline to 0.175 at 1 month and sustained thereafter. Mean CRT decreased from 392 to 318 µm at 12 months. 46% success was demonstrated beyond 10 months.	Peak IOP rise at 1 month, which came to baseline at 10 months. 1 eye required cataract surgery.
Bodaghi et al.[31]	Prospective, multicenter	245 enrolled patients (only 97 implanted with DEX and included in efficacy analysis)	NIU, Idiopathic (36.7%)	2 (Primary outcome) 18 (Secondary outcome)	20.5% patients at 2 months gained BCVA of at least 15 letters. Reduction in CRT of 27.4 µm from baseline at 2 months.	Raised IOP in 6.9% patients. Cataract surgery required in 1.2% of patients.
Ratra et al.[33]	Retrospective	34/42	91% Intermediate uveitis (IU)	19.2±2.2	The mean BCVA improved from 0.48±0.06 to 0.34±0.1 at follow-up. Mean CRT reduced from 472.2±35 to 274.7±60.6 µm. Repeat implants were needed in 26.2% of eyes	AGMs were required in 16.6% of eyes. Incisional glaucoma surgery needed in 2.4% of eyes. 14.3% of the eyes developed significant cataracts.
Hasanreisoğlu M et al.[28]	Retrospective	44/62	IU, Idiopathic (43.2%)	6 (Efficacy endpoint) 12 (Safety endpoint)	Mean BCVA improved from 0.55 to 0.35 at 6 months. Mean CRT decreased from 386 to 302 μm. 30% of the eyes required multiple implants.	8% eyes required AGM. 18 phakic eyes underwent cataract surgery.
Zarranz-Ventura J et al.[30]	Multicenter retrospective	63/82	Non differentiated uveitis (54.8%)	35	Improvement in BCVA from 0.68±0.4 at baseline to 0.52±0.5 at 12 months. Reduction in CRT from 469±193 μm at baseline to 355±160 μm at 12 months.	Mean IOP remained similar at 12 months from baseline. 39% required AGM. 2.4% of the eyes required glaucoma surgery.
Tsang et al.[29]	Retrospective	15/25	NIU	12	91.4% eyes had a reduction in CRT. 80% of eyes had improved BCVA. After the first implant, BCVA improved from 0.61 to 0.35 and CMT reduced from 590 to 370 μm at 3 months.	2 patients had cataract progression. 3 patients developed macular complications (macular hole or epiretinal membrane). None had IOP rise >21 mmHg.

Thus, it can be concluded that a single dexamethasone intravitreal implant can significantly reduce intraocular inflammation, improve BCVA, and reduce CRT for up to 6 months and can sustain till 12 months an average of 63.75% (58–70%) of patients in the presence of adequate systemic immunosuppression.[27,30,31,33] It has an improved safety profile compared to its predecessor (Retisert), which had higher rates of cataract progression and the need for intervention for raised IOP. Even in refractory or chronic ME cases, the efficacy of DEX is comparable to other modalities.[29,38]

Fluocinolone acetonide implants

FA is a synthetic corticosteroid which has an increased half-life in the vitreous without a special delivery system. It has low solubility in aqueous solutions, which leads to sustained release of higher concentrations over a longer period of time with very low systemic absorption.[39,40]

Retisert

Retisert is a NBI, sustained-release intraocular implant approved by the FDA for the treatment of chronic NIU in 2005. It is available in two doses of 0.59 mg or 2.1 mg.[41]

The 0.59-mg implant releases fluocinolone acetate at 0.6 µg/day initially for 1 month, following which the levels decrease to reach a steady state between 0.3 and 0.4 µg/day.[42] On the contrary, the 2.1-mg implant has a dual release mechanism and releases FA at a rate of 2 µg/day initially and then to 1 µg/day. It is designed to release the drug for about 30 and 36 months and has demonstrated effective control of intraocular inflammation in noninfectious posterior uveitis.[43,44]

The implant is secured surgically through a scleral incision over pars plana using a 20-gauge needle, 4-mm posterior to the limbus. Any prolapsed vitreous at the incision site is removed by pneumatic vitrector and the implant is sutured to the sclera.[44]

Retisert being an NBI may need reimplantation in chronic uveitis. Reimplantation can also be done with leaving the previous implant in situ, as there are high chances of dissociation during removal or exchange.[45,46]

The MUST trial was conducted to study the relative effectiveness and safety of FAi against systemic corticosteroids and immunosuppressives in 255 patients (479 eyes) with active noninfectious posterior uveitis. The study showed greater decrease in macular thickness with FAi compared to systemic therapy. However, the risk of side effects was higher in the implant group. In total, 77.9% eyes required AGM against 34% in the systemic therapy group and the incidence of cataract surgery was also found to be higher in the implant group.[34]

In another trial involving 278 patients with noninfectious posterior uveitis, findings at 34 weeks were evaluated. The patients were randomized into 0.59-mg (n = 110) or 2.1-mg (n = 168) implants. Recurrence rate, BCVA outcomes, the need for adjunctive therapy, and safety outcomes were studied.[17] Improvement in BCVA was noted in 87% of implanted eyes. Eyes that required adjunctive rescue treatment in the form of systemic medications, periocular injections, and topical corticosteroids decreased from 52.9, 63.0, and 35.7%, respectively, preimplantation to 12.1, 2.2, and 16.5% postimplantation (P < 0.0001).[47] At 34 weeks, 51.1% of implanted eyes required AGM and 5.8% needed glaucoma surgery. Cataract surgery was needed in 9.9% eyes.[17] Due to high incidence of glaucoma, it is recommended to monitor the IOP every 6–12 weeks after Retisert implantation.[34]

Retisert is also associated with other complications such as spontaneous dissociation or dislocation of pellet from support strut, hypotony, and CMV endotheliitis.[48]

A single Retisert 0.59-mg implant can adequately control inflammation for up to 3 years reducing the need for reinjection. Whereas with the DEX implant, similar efficacy can only be achieved with multiple implantations due to shorter duration of action.[49,50]

But on the other hand, Retisert is associated with higher incidence of side effects compared to DEX implant, with 45% of patients requiring glaucoma filtering surgery and about 80–100% of patients requiring cataract surgery within 3 years.[50,51]

Due to the availability of newer implant devices that can be inserted using microincision techniques (22/25-gauge), unforeseen complications with Retisert implants such as uncontrolled IOP, spontaneous dissociation from anchoring strut, lysis of anchoring suture, endophthalmitis, hypotony, scleral necrosis and melt, and implant protrusion can now be avoided.[41,42] Results of various studies related to the Retisert implant have been summarized in Table 2.

Table 2.

Studies assessing the use of fluocinolone implant (0.59 mg vs 2.1 mg or standard treatment) in noninfectious uveitis

Author	Design	Sample Size (Patients)/Eyes	Uveitis Type, Diagnosis	Follow-Up (Months)	Efficacy	Safety
Jaffe et al.[17]	Prospective RCT (0.59 mg vs 2.1 mg FAi)	278/278 110 eyes (0.59 mg) 168 eyes (2.1 mg)	Noninfectious posterior uveitis (NIPU)	34 weeks	Reduced rates of recurrences from 51/4 to 6.1% postimplantation. Reduced need for adjunctive treatment.	9.9% required cataract surgery. 5.8% required glaucoma surgery. RD in 2.2%, endophthalmitis in 0.4%.
Callanan et al.[41]	Prospective RCT (0.59 mg vs 2.1 mg FAi)	278/278 110 eyes (0.59 mg) 168 eyes (2.1 mg)	NIPU	36	No significant improvement in BCVA at 3 years from baseline. Significant reduction in ME and in need of adjunctive treatment.	Cataract surgery rates of 70% and 65% in 0.59 vs 2.1 mg FAi, respectively. Similar retinal detachment rates were 4–5% in both groups. >10 mmHg rise in IOP in 67% (0.59 mg) vs 79% (2.1 mg).
Sangwan et al.[42]	Prospective RCT (0.59 mg vs 2.1 mg FAi)	239/239 106 eyes (0.59 mg) 105 eyes (2.1 mg)	NIPU	36	Significant improvement in BCVA at 2 and 3 years. ME reduction at 34 weeks in both groups but relapsed at 3 years in 2.1-mg group. Reduced recurrence rates throughout in 0.59 mg vs relapsed in 2.1-mg group at 3 years or earlier.	95% of eyes required cataract surgery. Raised IOP in 67.8% of 0.59 mg FAi vs 71.3% in 2.1-mg FAi.
Pavesio et al.[51]	Prospective RCT (0.59 mg FAi vs Standard of care)	140 patients 66 (0.59 mg FAi) 74 Standard of care (SOC)	NIPU	24	Delayed onset and reduced rate of recurrence in the FAi group. More BCVA fluctuations in the FAi group.	Raised IOP in 55.4% of FAi vs 10.8% in SOC. 21.2% vs 2.7% requiring glaucoma surgery in FAi vs SOC groups, respectively. Cataract surgery is required in 87.8% of Fai vs 19.3% of SOC patients. RD in 1.5% vs 2.7% eyes.

Yutiq

Yutiq is a sterile NBI that contains 0.18-mg FA. It was approved in 2018 by the FDA for 36 months with a daily drug dissemination rate of 0.25 µg. It can be safely administered through a custom-designed 25-gauge needle injector as an outpatient procedure.[52] It was designed to deliver a reduced intravitreal steroid dose to improve on the safety of prior implants while maintaining the similar efficacy in treating uveitis.[53]

Multiple studies summarized in Table 3 have demonstrated the efficacy of YUTIQ in increasing the time to onset of recurrence,[53,54,55,56,57] reduced recurrence rates, and reducing the requirement for systemic rescue therapy compared to other modalities.[18]

Table 3.

Studies assessing the use of fluocinolone implant (0.18 mg) in noninfectious uveitis

Author	Design	Sample Size (Patients)/Eyes	Uveitis Type, Diagnosis	Follow-Up (Months)	Efficacy	Safety
Suhler et al.[53]	Prospective, double-masked, multicenter study	282 eye (188 FAi vs 94 sham)	NIPU	6	Recurrence rate in FAi eyes (26.6%) was lower than in sham eyes (73.4%, P<0.001). ME resolved in 65.9% of FAi eyes and only 39.1% of sham eyes.	IOP elevation >12 mmHg in 12.2% of eyes with FAi (2 requiring surgery) and 4.3% sham. Cataract surgery in phakic 6.8% Fai and 8.9% in sham eyes.
Jaffe et al.[54]	RCT	11/11	Anterior with intermediate uveitis, sarcoidosis (36.3%)	24	Mean BCVA improved from 0.56 to 0.17 at 24 months. No recurrences and rescue adjunctive treatment during follow-up	.
Jaffe and Pavesio et al.[55]	Prospective, double-masked, multicenter study	129 eyes (87 FAi vs 42 sham)	NIPU	36	Recurrence rate of 65.5% with FAi vs 97.6% with sham. Mean recurrence episodes 1.7 FAi vs 5.3 with sham. Adjunctive therapy needed in 57.5% eyes with Fai vs in 97.6% with sham.	IOP (mmHg) rise of 14.5±5.1 with FAi vs 14.8±5.3 with sham. IOP-lowering surgery in 5.7% eyes with FAi vs 11.9% with sham. Cataract surgery rate of 73.8% in FAi vs 23.8% in sham
Cai et al.[56]	Retrospective study of 2-year prospective trial and 1-year longitudinal follow-up	12/12	NIU	24 (study period) + 12 (longitudinal follow up)	Recurrence rate 42% with mean time for recurrence of 36.1 months. BCVA maintained over the period from 0.32 to 0.37 logMAR.	2 eyes needed cataract surgery during the first 24 months. Transient hypotony in 3 eyes. 4 eyes had IOP elevation, 2 of which required surgery.
Biswas J et al.[57]	Multicenter double-masked prospective trial Randomized 2:1 into 0.18 FAi vs sham	153/153 (101 FAi vs 52 sham)	NIPU	6 (Primary outcome) 36 (Secondary outcome)	Time to first recurrence and mean episodes of recurrence were less in the FAi group. 46.5% recurrence rate in the FAi-treated group compared to 75% in the sham at 36 months Similar letter gain and BCVA improvement between FAi vs sham group. Mean CRT in the FAi group reduced from 262.1 μm to 207.9 vs from 254.4 to 226.1 μm in sham.	AGM was needed in 74.3% FAi vs 73.1% sham group; however, the acute rise of >25 or >30 mmHg occurred more in the FAi group. Only 2 eyes (both from the FAi group) required glaucoma surgery. Cataract surgery rate was higher in the FAi group (70.5%) vs sham (26.5%).

Cumulative results of randomized control trials (RCTs) at regular follow-up intervals showed significantly fewer recurrences over 36 months in FAi-treated eyes compared to sham.[55,57] The FAi-treated eyes required fewer adjunctive treatments and had a longer mean time to onset of recurrences.[57] At the end of study period, 34.5% eyes remained recurrence free without any adjective treatment compared to 2.4% in the sham group.[54]

In another study, YUTIQ^TM demonstrated a significantly reduced uveitis recurrence rates at 6 month (28 vs 91% sham) and 12 month (38 vs 98% sham).[18]

Cai et al. also demonstrated significantly reduced recurrence rates with mean time to recurrence of 36.1 months (earliest at 23 months), thus establishing efficacy of FAi over 36 months, comparable to other corticosteroid implants.[55,56]

Cataract surgery rates differed among individual studies depending on the phakic status of the study population. In a prospective RCT at 6 months, the cataract surgery rates were comparable between FAi and sham groups (6.8% vs 8.9%, respectively).[53]

However, the 12-month and 36-month results by Jaffe et al.[55,58] showed that the FAi group had higher rates of cataract (33 and 73%) compared to the sham group (12 and 23.8%), respectively. Cai et al.[56] in their retrospective study had only 16.7% of eyes requiring cataract surgery.

IOP was generally well controlled with AGM in the FAi-treated patients in most studies.[18,53,55,56,57] However, in one study, rates of antiglaucoma medication use were similar between groups (26% in FAi study eyes and 26% in sham).[58]

The reduced rates of requirement of glaucoma surgery in the FAi-treated group compared with the sham-treated group differs from prior studies of Retisert implant, which resulted in a higher rate of IOP surgery (36.6%) compared with the dexamethasone implant in one study.[38,56,59]

Thus, it can be concluded that the reduced dose of fluocinolone implant has noninferior efficacy to other steroid implants with equally well-tolerated safety profile for long-term use over 36 months.[56,57] However, a single FAi may not be effective as monotherapy for uveitis in all patients.[60]

Iluvien

Iluvien is a NBI injectable intravitreal implant containing 0.19-mg FA, designed to release over 3 years at the dissemination rate of 0.2 µg per day. It is 3.5 mm long and 0.37 mm wide and inserted with a 25-gauge needle.[61]

A number of real-world studies summarized in Table 4 have successfully established the effectiveness of Iluvien in chronic and recurrent NIU, with almost similar efficacy and safety in multiple settings. Biases in patient selection and the timing of FAi during the course of uveitis could have influenced the outcomes observed in such small groups. Apart from that, shorter-acting intravitreal steroids (DEX implant or triamcinolone acetonide injection) were also employed during the course of treatment in some settings prior to FA implant,[62] or subsequently to treat recurrences.[63,64]

Table 4.

Studies assessing the use of fluocinolone implant (0.19 mg) in noninfectious uveitis

Author	Design	Sample Size (Patients)/Eyes	Uveitis Type, Diagnosis	Follow-Up (Months)	Efficacy	Safety
Moll-Udina A et al.[65]	Prospective	22/26	IU, Unclassified (31%)	>12	Significant improvement in BCVA and CMT reduction (-92.4 μm) from baseline (433.5 μm) at 12 months (P<0.01) Failure in 42.3% of eyes at least once, with estimated survival of 57.7% at 12 months	IOP elevation in 2 eyes (7.7%) at the endpoint VF deterioration not recorded Cataract in 2 patients (7.7%)
Battista et al.[66]	Retrospective	7/10	NIU, Idiopathic (57.1%)	12	BCVA improved from 0.67±0.41 logMAR at baseline to 0.45±0.37 logMAR at month 12 (P<0.01) mean CMT decreased from 449±105 μm at baseline to 336±118 μm at month 12 (P<0.001)	No recurrences and no need for rescue adjunctive treatment. 1 patient required IOP lowering.
Buhl L et al.[67]	Retrospective	57/76	NIU	12	Similar BCVA at the endpoint Decrease mean CMT (362.7 vs 309.1 μm; P=0.04) Decreased inflammation	IOP elevation (13.68% vs 15.6%; P=0.0507) cataract development in 20% of phakic eyes
Hikal et al.[68]	Retrospective	26./34	IU, Idiopathic	18	BCVA improved in 58.5% of eyes Macular edema completely resolved in 70.6% of eyes	Relapse after 23.2±14 months in 5 eyes 8.8% eyes required IOP-lowering medication. Immediate post op hypotony in 2 patients. 1 out of 4 phakic eyes underwent cataract surgery 2.5 years after implantation
Pockar S et al.[63]	Retrospective	11/11	NIU	12	Baseline CMT of 435 μm±176, improving to 296 μm±67 at 12 months. Mean BCVA stable at the endpoint.	No observed recurrences. Raised IOP with maximal increase of 6.75 mmHg±4.43 in two eyes. No cataract as only pseudophakic patients included.
Weber et al.[64]	Retrospective	8/11	IU, Idiopathic (37.5%)	42	Maximum CMT reduction of 168±202 μm throughout. 9 eyes showed BCVA improvement	Cataract developed in 18.2% of eyes. IOP rise in 27.3% patients, no additional treatment.

Most recent studies demonstrated that the 0.19-mg FA implant was effective in 57.7% of eyes for the initial 12 months of the study. However, the effectiveness fluctuated between 3 and 6 months.[65,67]

The improvement in BCVA was in line with the trial results for 0.18-mg FAi from Jaffe et al.,[55] which produced rapid and sustained BCVA gain during 3-year follow-up. These findings reflect the pharmacokinetic properties of the implant, in which the level of fluocinolone in the aqueous peak at 3 months reaches a steady state from the 6^th to the 36^th month.[69] Thus, with FAi, more favorable outcomes can be achieved in eyes at an earlier stage in their chronic disease.

Typically, 0.19-mg FA implant has also shown to be effective in reduction of CRT in multiple studies. Two different retrospective studies have demonstrated a significant reduction in mean CRT of approximately 150 µm with a complete resolution of ME in about 70% of the cases over 12 months.[63,68,70] In a study with a cohort of 11 eyes with chronic NIU with ME, Weber et al.[64] reported a mean decrease in CRT of 220 µm at 4–6 months post implant. However, Studsgaard et al.[62] in their study could only show a 45-µm reduction in CRT vs baseline (314 µm [189–459 µm]) at 12 months. This was expected to be due to lower mean baseline CRT in their study. Battista et al.[66] have also found a similar correlation between baseline CRT and implant efficacy.

Major adverse events related to implantation were cataract formation and elevated IOP. Cataract formation requiring surgery ranged from 7.7[65] to 18.2%.[64] Similarly, the rate of IOP elevation varied from 7.7[65] to 27.3%,[70] which were found to be lower compared to prior FAis.[58] Studsgaard et al.[62] reported a mean IOP increase of only 3 mmHg, with an absolute peak increase of 45 mmHg. Other adverse effects rarely seen with intravitreal injections of steroids such as endophthalmitis and retinal detachment were not observed.

Conclusion

Uveitis can have a chronic course, with multiple drug delivery methods employed in a single patient, often simultaneously. This may require strict adherence to a complex regimen by the patients over many years which can be frustrating and can increase treatment burden on both patients and the caregiver, leading to missed visits.

Intravitreal implants over the years have shown improved results in multiple real-world settings in treating the varied profile of intermediate and posterior uveitis. They can be used as monotherapy in settings such as unilateral uveitis, refractory ME or to provide higher drug concentrations at the target site. They can additionally be used in conjunction with systemic treatment to prevent and delay the recurrence of the inflammation. Their clinical use can be justified with the amount of evidence available from various studies. However, they should be employed with due caution, keeping the advantages and disadvantages in mind. A tailored approach for individual patients based on disease severity, duration, systemic control, drug toxicity, and visual prognosis can help maximize the advantage of these implants.

Conflicts of interest:

There are no conflicts of interest.

Funding Statement

Nil.