Corticosteroids remain a primary treatment for many ocular conditions, including vascular and uveitic macular edema.¹ The advancement of sustained-release steroid implants has introduced treatment options that provide an added benefit of reducing patient visits and medication burden. This reduced visit burden has been particularly relevant during the COVID-19 coronavirus pandemic because it decreases patient and provider exposure. This brief review explores the different types of intraocular and periocular injections that can deliver safe and effective corticosteroid treatment to the eye with few systemic side effects, all while limiting patient interaction during a global pandemic and beyond.

PERIOCULAR STEROIDS

Periocular triamcinolone acetonide (Kenalog; Bristol-Myers Squibb Company)² is delivered either inferiorly along the orbital floor or superiorly as a posterior superior sub-Tenon injection,³ with lasting effect on average of 2 to 3 months. This therapy has the benefit of being the most cost-effective method of sustained steroid treatments available at this time with results observed as early as 15 days after injection and a sustained duration for at least 180 days.⁴ Limiting factors include particle size, crystallinity, and dispersion ability that contributes to the dissolution kinetics once in the eye.² These factors can affect the duration of effect based on the vial used and the inability to reverse the therapy if complications such as uncontrolled intraocular pressure were to ensue. Repeated periocular injections may also lead to complications, including globe perforation, orbital fibrosis, and ptosis. Periocular steroids are considered more efficacious when used for noninfectious uveitis and cystoid macular edema than edema from vascular causes.^4,5

INTRAVITREAL STEROIDS

Intravitreal injections have a superior therapeutic effect when compared to sub-Tenon injections, particularly in uveitic macular edema.³ Intravitreal corticosteroids can be delivered via short-acting agents, such as the preservative-free triamcinolone formulations Triesence (Alcon Pharmaceuticals) and Trivaris (Allergan), and long-acting implants, including Ozurdex (Allergan), Yutiq (Eyepoint Pharmaceuticals), Iluvien (Alimera Sciences), and Retisert (Bausch + Lomb).

Short-acting preservative-free triamcinolone intravitreal injections provide more uniformly sized crystals compared to the aforementioned Kenalog, allowing for a more predictable treatment duration of 4 weeks to 6 weeks. Otherwise, these injections often need to be repeated at regular intervals. Frequent intravitreal steroid injections can lead to the well-known side effects of cataract formation, glaucoma, and a sawtooth loss of vision due to repeated recurrence of macular edema,⁶ making them a less desirable option for chronic therapy when compared to other intravitreal steroids.

Ozurdex (dexamethasone intravitreal 0.7-mg implant) is an implant that is injected directly into the vitreous cavity and provides a duration of action between 3 months and 4 months. The polymer implant slowly degrades to lactic acid and glycolic acid that, over time, leaves no residue in the eye.¹ Maximum effectiveness occurs between 60 and 90 days, and is particularly beneficial in postvitrectomized eyes.^1,7 Clinical studies have shown that despite the more maintained therapy, patients still should be followed up at a 4-week to 6-week interval after implant deployment due to a rise in IOP. Further, given the relatively shorter lifespan of this agent, some patients may still require frequent injections to control ocular disease. Overall, this implant is beneficial in reducing the need for other topical and systemic therapies in uveitis and macular edema, but does not significantly reduce the need for frequent office follow-up visits, especially in the initial stages of its use.

Retisert (0.59-mg fluocinolone acetonide implant) is an FDA-approved implant for the treatment of chronic noninfectious uveitis with a treatment span of up to 3 years. Eyes receiving Retisert have delayed onset and a lower rate of recurrence of uveitis as compared to standard-of-care eyes, making it particularly beneficial in reducing office visit burden for patients with chronic uveitis.⁸ This treatment has shown comparable results to systemic treatment in the MUST trial after 5 years, with a decline in vision after 7 years, likely due to a gradual decrease in intravitreal steroid concentration after that time point.⁹ Limitations of this device include the need for intraoperative implantation compared to other intravitreal therapies.

Iluvien (0.19-mg fluocinolone acetonide) is an in-office injectable, nonerodible intravitreal device that lasts for 36 months for treatment of diabetic macular edema (DME).¹⁰ Patients with DME for longer than 3 years at the onset of treatment experienced almost a doubling of treatment effect when compared to sham groups in the approval trials.⁷ In real-world practice, this likely correlates to a reduced need in frequency of anti-VEGF medications, and therefore office visits as a whole for these patients. Unlike Ozurdex, Iluvien is nonerodible and remains in the vitreous cavity even after drug release has been exhausted; however, its long-acting benefits allow for a more infrequent use.

Yutiq (0.18-mg fluocinolone acetonide intravitreal implant) is virtually identical to Iluvien, but approved for noninfectious uveitis.¹¹ In clinical trials, Yutiq-treated patients were almost half as likely to experience a recurrence of posterior uveitis requiring steroid rescue or systemic treatment at 1 year, allowing for better control of disease with less frequent in-office monitoring.¹¹

SUPRACHOROIDAL STEROIDS

The suspension of triamcinolone acetonide formulated for administration via the suprachoroidal space (suprachoroidal CLS-TA, brand name Xipere; Clearside Biomedical) is currently completing phase 3 clinical trials and pending FDA approval. Results of this trial were recently published by Yeh et al in the Journal of Ophthalmology. In the CLS-TA arm, 47% of patients gained 15 or more ETDRS letters in BCVA vs 16% in the control arm (P<.001) and mean reductions in CST from baseline were 153 μm vs 18 μm (P<.001) with effects lasting past the 24-week time point of the study.¹² This provides a promising new option on the horizon for the long-term treatment of macular edema by utilizing a novel approach through the suprachoroidal space.¹²

DISCUSSION

Due to the chronic nature of many ocular diseases, long-term patient compliance with prescribed medications and office visits is an obligation that has been made even more challenging due to the COVID-19 pandemic. The pandemic has forced the restructuring of ophthalmologic practice, with fewer routine visits and longer follow up intervals for patients undergoing active treatment.

The advent of sustained corticosteroid delivery methods have had a monumental impact on the management of noninfectious uveitis and macular edema. With these new routes of administration, physicians and patients are now provided the possibility of longer term treatment with less reliance on topical therapies and, in the case of uveitis, systemic immunosuppression.

The modalities outlined in this article have an added benefit of allowing for a reduction in the reliance on office visits and a decrease in the dependence on topical and systemic therapies, all while maintaining control of vision threatening disease. Sustained steroids, while particularly beneficial during this time of reduced patient interaction, are also the future for recalcitrant macular edema and chronic noninfectious uveitis.

Although longer-acting steroids carry the above benefits, the fact remains that cataract formation and glaucoma are true adverse effects to be taken into consideration. Therefore, sustained steroid use, while potentially more relevant in situations such as the treatment of uveitis where systemic immunosuppression carries greater threat during a pandemic, may still be a second-choice therapeutic option to anti-VEGF therapy in the setting of macular edema secondary to vascular causes, given the side-effect profile. However, practitioners may be quicker to move to sustained steroid options in patients with DME or RVO requiring monthly anti-VEGF therapy whose comorbidities increase the risks associated with frequent office visits during a pandemic.

The effects of the pandemic will likely persist even after the immediate threat of disease is gone. It is feasible that sustained steroid therapies will become increasingly popular to decrease the need of frequent office visits in patient populations that are especially vulnerable to infection. RP

REFERENCES

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