The eye benefits from immune privilege.1 which protects the vital organ from frequent inflammatory insults. Reparative mechanisms have evolved in response to transport immune cells to affected areas. While inherently protective, excessive release of inflammatory markers can jeopardize visual acuity and contribute to fibrosis.2
Various common pathologies, including diabetes, hypertension, autoimmune disorders, and age-related conditions, trigger the release of inflammatory markers in the eye, underscoring the importance of successful treatment in managing these responses.
This article will primarily discuss the utilization of Ozurdex, Yutiq, Retisert, and Iluvien for treating ocular pathologies. However, it is worth noting the ongoing advancements in corticosteroid therapies targeting the suprachoroidal space and existing options for steroid therapy in the sub-tenon space.
Features of intravitreal corticosteroid implants
Rapid-onset and short-acting agents
Systemic anti-inflammatories have been utilized to reach the posterior segment of the eye. Still, side effects are many, ocular specificity is low, and the blood-retinal barrier presents a significant barrier to drug entry.3,4
Topical treatment for ocular inflammation faces challenges, such as corneal toxicity, low bioavailability (less than 5%),5 and issues with patient compliance. Intravitreal injections offer a more targeted approach by delivering drugs through the pars plana directly into the vitreous, thereby reducing the risk of systemic side effects.
In the 1970s, Graham and Peyman pioneered using intravitreal dexamethasone with antibiotics to treat Pseudomonas infection, demonstrating its effectiveness in reducing inflammation compared to antibiotics alone.6
This approach marked a significant advancement in addressing eye inflammation. Intravitreal injection facilitates rapid drug uptake in the eye. The frequent necessity for retreatment, however, restricts its utility.5,7
Long-acting and extended-release implants
Sustained-release drug delivery systems, including biodegradable and nonbiodegradable intravitreal implants, are emerging treatment options for intraocular inflammation and other posterior segment diseases.8
This approach presents advantages, including targeted delivery, maintenance of high drug concentration at the treatment site, and prolonged duration of action. These qualities render intravitreal corticosteroid implants suitable for managing chronic inflammatory ocular diseases.9
Intravitreal implants, which target the retinal layer of the eye, can be broadly categorized into two main groups: biodegradable and nonbiodegradable formulations.
Biodegradable formulation: Ozurdex
Biodegradable implants (BI), such as Ozurdex, comprise polymers naturally metabolized by the body. These implants typically offer drug efficacy for a duration ranging from 3 to 6 months.10,11 Since BIs are eliminated through physiologic processes, they require a single implantation procedure.5
Nonbiodegradable formulations: Retisert, Iluvien, and Yutiq
Nonbiodegradable implants (NBI)—such as Retisert, Iluvien, and Yutiq—are made of materials unaffected by their biological environment and retain structural integrity throughout the treatment.
Consequently, this treatment approach can provide 2 to 3 years of therapeutic effects, with both Iluvien and Yutiq providing a therapeutic effect for up to 36 months.10,11 Retisert requires both an implantation and removal procedure; Iluvien and Yutiq do not require removal.5
Indications for intravitreal corticosteroid implants
Corticosteroid intravitreal implants are a therapeutic option for various ocular conditions characterized by inflammation, edema, and neovascularization. The decision to utilize corticosteroid intravitreal implants is typically guided by the patient's clinical presentation and specific indications.
Common scenarios warranting the use of corticosteroid intravitreal implants include:
- Diabetic Macular Edema (DME): DME is the leading cause of global visual impairment among the working-age population.12 Corticosteroid implants offer an alternative or adjunctive treatment avenue for DME, especially in cases where anti-vascular endothelial growth factor (VEGF) therapy proves ineffective or unsuitable.13
- Macular Edema, Secondary to Retinal Vein Occlusion (RVO): RVO ranks prominently among the causes of retinal vascular blindness. While laser photocoagulation therapy has been the conventional approach for branch retinal vein occlusion (BRVO), it falls short in addressing macular edema (ME) secondary to central RVO (CRVO).
- Hence, corticosteroid intravitreal implants are promising to mitigate macular edema associated with CRVO or BRVO and enhance best-corrected visual acuity.14,15
- Macular Edema Secondary to Ocular Inflammatory Conditions: Corticosteroid implants exhibit efficacy in reducing macular edema and the number of recurrences in rarer yet well-known inflammatory ocular conditions, such as Vogt-Koyanagi-Harada disease and sympathetic ophthalmia, which may arise post-penetrating trauma or ocular surgery.16,17,18
- Chronic Non-Infectious Anterior Uveitis: Uveitis, characterized by uveal inflammation, ranks as the fifth leading cause of vision loss in affluent nations, with a pronounced incidence among the working-age population.19
- It has known associations with non-infectious systemic conditions such as HLA-B27-associated conditions, systemic lupus erythematosus, systemic sarcoidosis, and rheumatoid arthritis.
- In chronic non-infectious anterior uveitis resistant to topical or systemic corticosteroids, intravitreal corticosteroid implants offer sustained intraocular anti-inflammatory effects.20
Non-infectious posterior uveitis
Corticosteroid implants find application in managing non-infectious uveitis encompassing posterior segment inflammation, intermediate uveitis, and panuveitis. Intravitreal corticosteroids are generally recommended for non-infectious posterior uveitis.
They are also sometimes administered for non-infectious anterior uveitis, though not always as a first-line treatment. Treating uveitis affecting the posterior segment poses a therapeutic challenge, as topical steroids often fail to achieve therapeutic concentrations in the vitreous.
Consequently, individuals with posterior uveitis frequently necessitate oral corticosteroids, local steroid injections, or intravitreal corticosteroid implants for effective management.21
Furthermore, intravitreal corticosteroid implants have been explored. They can be considered as adjunctive or alternative therapy for hypotony, pseudophakic/aphakic cystoid macular edema, neovascular age-related macular degeneration, choroidal neovascularization, and other inflammatory processes impacting the choroid.22
Contraindications for intravitreal corticosteroid implants
While intravitreal corticosteroid implants offer effective treatment for various ocular conditions, it is crucial to consider specific contraindications and precautions before use.
In addition to a known hypersensitivity to the components of the corticosteroid implant, some contraindications include:
Active ocular infections
Patients with active ocular infections, including bacterial, fungal, viral endophthalmitis, or ocular tuberculosis, are unsuitable candidates for intravitreal corticosteroid implants due to the heightened risk of exacerbating the condition.
Further clinical trials or observations are necessary to establish definitive conclusions regarding the efficacy versus harm of intravitreal corticosteroid implants for these infections.23,24
Ocular herpetic infections
Patients with a history of ocular herpetic infections, such as herpes simplex virus or herpes zoster virus, should refrain from receiving intravitreal corticosteroid implants due to the risk of viral reactivation and exacerbation of the infection.
Studies have shown that anabolic steroids negatively affect cell-mediated immunity, which is crucial for preventing viral infection and recurrence rates.25
Glaucoma (including uncontrolled and steroid-induced types)
Individuals with uncontrolled glaucoma or a history of significant intraocular pressure (IOP) elevation in response to corticosteroid therapy are unsuitable candidates for intravitreal corticosteroid implants. Corticosteroids can induce elevated IOP, potentially triggering or worsening glaucoma.
The mechanism behind this rise in pressure involves factors, such as reduced aqueous outflow due to increased trabecular meshwork resistance, heightened sensitivity of the trabecular meshwork to glucocorticoids, diminished prostaglandin levels, and possible mechanical obstruction from steroid particles.26,27
History of steroid-induced cataracts
Prolonged exposure to corticosteroids can expedite the development of cataracts or exacerbate pre-existing ones. Steroids' tissue-binding properties can influence various cellular processes, including proliferation, transmembrane transport, and reactive oxygen species activity, thereby contributing to cataractogenesis.
Current research underscores how dexamethasone may disrupt crucial pathways governing lens cell regulation, potentially necessitating earlier cataract surgery for affected patients.28,29
Pregnancy and lactation
Although some cases have shown the efficacy of intravitreal dexamethasone therapy in pregnant patients with DME, the safety of intravitreal corticosteroid implants during pregnancy and lactation has not been well established. Therefore, their use is generally avoided in pregnant or breastfeeding women unless the potential benefits outweigh the risks.30,31
Ophthalmologists must meticulously evaluate each patient's medical history, ocular conditions, and potential risk factors before recommending intravitreal corticosteroid implants. They must also closely monitor for adverse effects after implantation.
Potential complications with intravitreal corticosteroid implants
Complications associated with corticosteroid intravitreal implants can vary depending on the specific type of implant used, patient characteristics, or underlying ocular conditions. As previously alluded, some potential complications directly coincide with contraindications.
The two most prevalent adverse effects are increased IOP and cataract formation. Other possible complications include:
Vitreous hemorrhage
Though uncommon, the implantation procedure itself may precipitate vitreous
hemorrhage, marked by bleeding into the vitreous cavity. While most cases resolve spontaneously, a small fraction may require surgical intervention.32 It should be noted that vitreous hemorrhage and corneal edema are not typically associated with Iluvien or Yutiq but may be more relevant to other implants or procedures.
hemorrhage, marked by bleeding into the vitreous cavity. While most cases resolve spontaneously, a small fraction may require surgical intervention.32 It should be noted that vitreous hemorrhage and corneal edema are not typically associated with Iluvien or Yutiq but may be more relevant to other implants or procedures.
Implant dislocation and anterior chamber migration
Corticosteroids, particularly fluocinolone acetonide implants like Retisert, helped revolutionize the treatment of chronic intraocular inflammations, such as sympathetic ophthalmia, as seen in Figure 1 below.
Figure 1: Courtesy of David RP Almeida, MD, MBA, PhD.
These sustained-release devices are designed to provide a long-term therapeutic effect, minimizing the systemic side effects associated with oral corticosteroids. However, instances of implant dislocation, as observed in pseudophakic patients, underscore the mechanical challenges associated with intraocular devices. Such events necessitate surgical interventions and highlight the importance of vigilant post-operative monitoring.
Clinicians must be acutely aware of the potential for mechanical failures, which, although rare, can lead to significant visual morbidity, as shown in Figure 2.
Figure 2: Courtesy of David RP Almeida, MD, MBA, PhD.
The evolving design improvements and surgical techniques aim to mitigate these risks, ensuring that the therapeutic benefits of corticosteroid implants continue to outweigh their complications. Studies by Stavrakas et al. and Khurana et al. highlight implant dislocation and migration into the anterior chamber, particularly in patients with aphakia or a history of vitrectomy.
Such complications pose corneal edema and decompensation risks, underscoring the importance of promptly removing the implant to safeguard the endothelium and minimize potential long-term corneal damage.33,34 In addition to these, endophthalmitis, retinal detachment, choroidal neovascularization, and retinal toxicity exist as adverse effects, albeit with an incidence of less than 1%.
Before treatment initiation, healthcare providers must engage in comprehensive discussions with patients regarding the potential risks and benefits of intravitreal corticosteroid implants. Furthermore, close monitoring for complications and swift management and pharmacotherapeutic treatment of any adverse effects are vital for optimizing patient outcomes.
Iluvien, Ozurdex, Retisert, and Yutiq
Four intravitreal steroid implants, brand names Retisert, Yutiq, Iluvien, and Ozurdex, are currently on the market for various indications. These implants have effectively treated resistant DME, non-infectious posterior uveitis, RVO, and other inflammatory processes.
The following is a brief breakdown of the drugs and their current uses as described in the literature.
Iluvien
Iluvien is an implantable form of fluocinolone acetonide (FAc) manufactured by Alimera. The FDA first approved it for use in 2014. This implant contains 0.19mg of corticosteroid, which generates a strong anti-inflammatory effect in both the anterior and posterior poles of the eye.35 The implant is injected into the vitreous with a 25g injector and slowly releases 0.2ng/mL daily over 36 months.36
During its extended release, the implant maintains a concentration of 2ng/mL for the first 3 months, then decreases to 0.5 to 1.0ng/mL for the remaining months.35 Iluvien is approved for treating DME.36,37
A study by Bailey et al. revealed improved vision and lower recurrence in patients with persistent DME treated by Iluvien. Furthermore, they reported a significant improvement in patients with previous resistance to anti-VEGF regimens.
Retisert
Retisert is another FAc-formulated intravitreal implant that Bausch & Lomb manufactures. It was approved for use by the FDA in 2005. This drug has a dose of 0.59mg and maintains a therapeutic concentration for 30 months.
Retisert releases a concentration of 0.6µg/day for 1 month following implantation, then slows its release to 0.3 to 0.4µg/day for the remaining period.38 Retisert is primarily used for its anti-inflammatory effects in patients with non-infectious posterior uveitis.
Jaffe et al. completed a cohort study that showed lower recurrence of posterior uveitis, improved vision, and reduced secondary macular edema in patients treated with Retisert.39
Another study by Leinonen et al. examined the effectiveness of Retisert in patients with chronic non-infectious uveitis secondary to juvenile-induced arthritis. They reported no recurrence of the uveitis within 5 years following implantation with improved vision.40
Yutiq
The third FAc intravitreal implant discussed here is Yutiq. EyePoint Pharmaceuticals manufactured this implant, which was first approved for use in 2018.
This implant has a dose of 0.18mg with an extended release of 0.2µg/day for up to 36 months. Akin to Retisert, this drug is indicated for use in non-infectious posterior uveitis and macular edema secondary to inflammatory processes.
In a study done by Walter et al., the efficacy of Yutiq was compared to that of Ozurdex in patients with non-infectious posterior uveitis. They reported that Yutiq was as effective as Ozurdex in resolving macular edema. Sheth et al. further noted the utility of Yutiq as fewer appointments are needed for implantation than Ozurdex.41,42
Ozurdex
Unlike the previously discussed implants, Ozurdex is a dexamethasone implant. This intravitreal implant was developed by Allergan and was approved for use in 2009. This implant is approved for use in DME, RVO, and posterior uveitis.41,42 This drug has a dose of 0.7mg and maintains a therapeutic concentration for 3 months.43
Chi et al. completed a meta-analysis on the efficacy of Ozurdex vs. anti-VEGF therapy in treating DME.44 While there were no significant differences between Ozurdex and anti-VEGF in nonresistant DME, Ozurdex had a better response in DME and visual acuity in patients with treatment-resistant DME.45
Garweg and Zandi discuss the utility of Ozurdex as it requires fewer implantation visits than anti-VEGF with efficacy in diagnoses such as vein occlusions, persistent DME, and posterior uveitis.46
3 pearls for injecting intravitreal corticosteroid implants
1. Consider prior conditions in patient selection
As with any treatment, care should be taken to avoid patient complications. Careful patient selection, with consideration of previous ocular conditions, systemic health, and previous treatment success, is essential.
For example, Iluvien is contraindicated for glaucoma patients with a cup-to-disc ratio greater than 0.8, active ocular infections, a history of viral retinitis, dendritic keratitis, and varicella, mycobacterial, and fungal infections.
Additionally, corticosteroids can dramatically increase IOP in certain patients. It is essential to treat these patients with caution and assess patients who have prior exposure to topical steroids.
2. Remember proper preparation is key
Administering a subconjunctival lidocaine injection before injecting a corticosteroid implant allows for adequate anesthesia and patient comfort during the procedure.
3. Hone your technique
Utilize a gliding motion with the insertion device to deliver the implant smoothly into the eye. Position yourself directly across from the injection site to visualize the implant entering the eye. Use an indirect ophthalmoscope to confirm proper delivery of the implant.
Post-operative care for intravitreal corticosteroid implants
Close monitoring for adverse effects and management of complications is warranted. Endophthalmitis, inflammation, increased IOP, and retinal detachments are common with intravitreal injections and should be monitored.
Conclusions
In conclusion, managing intraocular inflammation poses unique challenges that demand a tailored therapeutic approach. Intravitreal corticosteroid implants have emerged as a promising option for offering targeted delivery, prolonged drug release, and reduced systemic side effects.
Careful patient selection, meticulous implantation techniques, and vigilant monitoring can optimize outcomes. Continued research and innovation in this field can improve the quality of care for patients with inflammatory eye diseases.
