Uveitis is a potentially blinding disease, with an estimated 35% of uveitis patients worldwide suffering from vision impairment and legal blindness.¹ In the United States, uveitis contributes to about 30,000 new cases of legal blindness each year and 10% to 15% of total causes of blindness in the country.² The exact mechanism by which uveitis occurs is not always understood. Frequent causes of uveitis include infection, injury, and autoimmune diseases.¹ Herpes and toxoplasmosis are the most common etiologies of infectious uveitis, while in the case of injury, it is thought that cell death triggers the release of proinflammatory markers.³ Autoimmune uveitis may occur due to molecular mimicry, where the immune system confuses retinal autoantigens with nonocular antigens, resulting in inflammation.⁴ However, the underlying cause of noninfectious uveitis remains unknown in 30% to 60% of patients.¹ Corticosteroids are the most commonly used first-line treatment for uveitis and can be administered topically, locally, or systemically. This article will focus on the topical and local steroid options for noninfectious uveitis.

CORTICOSTEROIDS

Corticosteroids work by inhibiting phospholipase A₂, the enzyme that converts phospholipids into arachidonic acid and downregulates inflammatory markers like leukotrienes and thromboxanes.⁶ The goals of therapy are to reduce inflammation, prevent damage to ocular structures, and prevent long-term vision loss while minimizing risks to the patient. Although they are incredibly useful to control inflammation, they are not without side effects, such as cataracts and intraocular pressure (IOP) elevation. It is estimated that 30% to 40% of individuals taking corticosteroids will experience an IOP increase of 5 mmHg during treatment.⁵ This likely occurs due to a buildup of extracellular matrix material in the trabecular meshwork, which leads to an impairment of aqueous outflow.⁵ Systemic side effects of corticosteroids include hyperglycemia, diabetes mellitus, osteopenia, weight gain, and Cushing syndrome, among others.

Topical Corticosteroids

Various forms of topical corticosteroids exist, and this review will focus on the drops most commonly used for uveitis. The most common indication for topical corticosteroids is anterior uveitis, and in infrequent cases, intermediate and posterior uveitis with macular edema. Prednisolone acetate (1% suspension) is the most commonly used form. It has greater anti-inflammatory effects compared to dexamethasone or betamethasone due to its higher concentration and increased penetrance of the cornea and aqueous humor.⁵ Difluprednate (0.05% emulsion) is a synthetic fluorinated prednisolone derivative, and the presence of 2 fluorination sites leads to increased specificity to the glucocorticoid receptor. Difluprednate is more potent than prednisolone acetate; 1 study reports that QID dosing of 0.05% difluprednate is as effective as dosing 1% prednisolone acetate 8 times.⁶ Difluprednate also penetrates the vitreous better than prednisolone acetate, but it also has a greater side effect profile, increasing IOP rise and cataract.⁵ Thus, difluprednate must be used with caution. Other side effects of topical steroids include crystalline keratopathy, superimposed cornealinfection, and impairment of corneal and scleral wound healing.⁷ Drawbacks of topical treatment include frequent dosing, and a limited inability to penetrate the posterior ocular structures.

Periocular Corticosteroids

Periocular corticosteroids include triamcinolone acetonide, with a typical dose of 40 mg/1 mL suspension. The duration of treatment is often less than three months.⁷ The advantages of periocular steroids include greater posterior segment penetration and sustained local administration to posterior structures with less cataract risk.⁷ The drug can be administered via the posterior subtenon approach or a transseptal injection. In certain cases of scleritis, the drug can be administered subconjunctivally, but some uveitis specialists prefer to not use this in cases of scleral thinning associated with scleritis. Side effects of treatment IOP risk, ptosis, cataract, and globe perforation.⁷

Suprachoroidal Injections

Several trials have shown an advantage with suprachoroidal injection for the treatment of noninfectious uveitis, especially in terms of drug localization.⁸ One study found that concentrations of triamcinolone acetonide (TA) remained fairly localized to the retina, choroid, and sclera when given via suprachoroidal injection, with minimal exposure to the vitreous humor and no detection in the aqueous humor.⁹ Another phase 1/2 clinical study found that when 7 patients with noninfectious uveitis were followed for 26 weeks after suprachoroidal triamcinolone injection, all showed improvements in macular edema with no reports of ocular hypertension.¹⁰ In addition, 4 had an improvement in visual acuity of greater than 2 lines.¹⁰ Finally, the DOGWOOD, PEACHTREE, and MAGNOLIA studies evaluated the efficacy and safety of suprachoroidal injections in treating noninfectious uveitis.^11-13

The 2019 phase 2 DOGWOOD study enrolled 22 adults with macular edema due to noninfectious uveitis and evaluated central subfield thickness after a single suprachoroidal injection of CLS-TA (4.0 mg and 0.8 mg in a 4:1 ratio). After 2 months, 69% of subjects who received 4.0 mg had a 20% or more reduction in central subfield thickness and 65% had improvements in BCVA of 5 or more letters gained.¹¹ The 2020 phase 3 PEACHTREE study enrolled 160 patients with macular edema due to noninfectious uveitis. Patients received either suprachoroidal injections of CLS-TA or sham treatments (3:2 ratio, respectively) with administrations at baseline and week 12. The primary endpoint of the study was an improvement of 15 or more ETDRS letters at week 24. The secondary endpoint was a decrease from baseline of central subfield thickness at week 24. Forty-seven percent of patients receiving CLS-TA injections met the primary endpoint compared to 16% receiving the sham treatment (P<.001).¹² Most recently, the 2022 MAGNOLIA study followed patients from the PEACHTREE study for an additional 24 weeks and evaluated time to rescue, safety, visual acuity, and retinal central subfield thickness. The median time to rescue therapy was 257 days in the CLS-TSA group, significantly higher than the 55.5 days for the sham group. Fifty percent of CLS-TA patients did not require rescue therapy through 9 months following the second treatment. Finally, there was a mean gain of 12.1 letters and mean central subfield thickness reduction of 174.5 µm at week 48.¹³

Intravitreal Injections

Indications for intravitreal injections and implants include noninfectious intermediate and posterior uveitis, and for patients who cannot tolerate immunomodulating therapy.⁵ The most common dosage for triamcinolone acetonide is 4 mg/0.1 mL, with peak effects often lasting 2 months to 4 months. Common side effects include cataract and steroid-related pressure response, along with the inherent risks of an intravitreal injection.

Intravitreal Implants

The dexamethasone intravitreal implant, Ozurdex (Allergan) is FDA approved for noninfectious uveitis. This 0.7-mg biodegradable implant provides a sustained release of dexamethasone over 3 to 6 months. The HURON study evaluated the safety and efficacy of the dexamethasone (DEX) intravitreal implant for the treatment of noninfectious intermediate or posterior uveitis over 26 weeks. Participants were randomized to receive a single treatment of either 0.7 mg DEX implant (n=77), 0.35 mg DEX implant (n=76), or a sham procedure (n=76). The proportion of eyes with a vitreous haze score of 0 at week 8 was evaluated. The percentage of those who met the endpoint was 47% with the 0.7 mg DEX implant, 36% with the 0.35 mg DEX implant, and 12% with the sham procedure (P<.001). This study showed that the DEX implant significantly improved intraocular inflammation and visual acuity.¹⁴

The newest steroid implant is a nonbiodegradable 0.18 mg fluocinolone injectable intravitreal implant, Yutiq (Eyepoint Pharmaceuticals), which is approved for chronic noninfectious posterior uveitis. A phase 3 study with 129 patients with noninfectious posterior uveitis compared those receiving the 0.18 mg intravitreal fluocinolone acetonide insert vs those receiving a sham injection. Results showed that at 12 months, only 37.9% of patients who received the implant experienced uveitis recurrence compared with 97.6% of control patients.¹¹ Advantages of this implant include a steady steroid release over several years. Disadvantages are that this implant is less potent than the 0.7 mg dexamethasone implant, so it may not be as effective in treating severe inflammation, along with the fact that it is not biodegradable.

Surgical Implants

There are several forms of sustained-release intraocular implants. A 0.59-mg fluocinolone acetonide implant, Retisert (Bausch + Lomb), exhibits sustained release over 3 years at about 0.3 μg to 0.4 μg per day. The Multicenter Uveitis Steroid Treatment (MUST) trial compared outcomes of 479 eyes of 255 uveitis patients receiving the fluocinolone acetonide implant vs those receiving systemic treatments. After 24 months, a statistically higher number of patients in the implant group (88%) controlled uveitis vs the 71% of those receiving systemic treatments, but at the 7-year follow-up, visual acuity was statistically better in the group receiving systemic therapy. Repeated implants and the patient’s tolerance for them is an important consideration. In the MUST trial, after 54 months of follow-up, 8% of eyes required 2 implants, and 2% required 3 implants.¹⁵

SUMMARY

Corticosteroids remain the first-line treatment for uveitis, with a variety of administration routes. Each carries its own advantages and disadvantages and should be weighed carefully against each other when selecting a treatment regimen for patients. RP

REFERENCES

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