Uveitis, a potentially blinding intraocular inflammatory disease, accounts for up to 10% of visual impairment globally, with approximately one-third of affected patients experiencing vision loss,¹ which can be particularly significant when presentation and diagnosis of uveitis are delayed.

According to the Standardization of Uveitis Nomenclature (SUN) Working Group, uveitis can be classified by anatomic location. Anterior uveitis primarily involves the anterior chamber of the eye, intermediate uveitis primarily involves the vitreous cavity, posterior uveitis primarily affects the retina and/or choroid, and panuveitis can affect all these sites with no site affected predominantly.² Although most studies have shown that anterior uveitis is most commonly observed, posterior or panuveitis have been reported to have the worst prognosis, because of their potential to cause irreversible damage to the macula, including macular edema and the potential for optic nerve involvement.¹

Uveitis can also be classified into infectious or noninfectious categories, because anti-inflammatory therapies are often required for the noninfectious variety but may make infectious uveitis worse if appropriate antimicrobials are not utilized. Examples of infectious uveitis include localized parasitic infections leading to ocular toxoplasmosis or infections that occur as part of a generalized systemic infection due to syphilis or Lyme disease. Noninfectious uveitis (NIU) is, however, commonly immune-mediated and may be associated with systemic diseases, exemplified by pulmonary and ocular involvement in sarcoidosis.^3,4

Although infectious forms of uveitis are treated with targeted antimicrobial therapies (eg, antiviral therapy for herpetic retinitis, often in conjunction with anti-inflammatory agents), NIU is treated according to several factors, such as the site of the inflammation and presence or absence of systemic involvement. Corticosteroids are the first line of treatment and are administered locally or via systemic administration. Steroid-sparing immunosuppression may also be required in conjunction with systemic corticosteroid.⁵

Given the side effects associated with systemic corticosteroid (eg, hyperglycemia, mood swings, weight gain) and immunosuppression, local options for corticosteroid administration have been utilized, demonstrating strong efficacy signals; yet the risks of elevated intraocular pressure and cataract need to be considered with local corticosteroid (ie, intravitreal triamcinolone, intravitreal dexamethasone, periocular corticosteroid). Potential limitations associated with drug administration via these routes used in clinical practice have been reviewed and studied in randomized controlled studies.^6-8

The suprachoroidal space (SCS) is a novel route for drug administration that has been studied extensively in animal models and multiple clinical trials for the treatment of macular edema. It is a potential space between the sclera and choroid that is not immune privileged because of its location outside the blood–retinal barrier.⁹ Multiple clinical trials have demonstrated the safety and efficacy of SCS drug delivery.¹⁰

This review article highlights the SCS as a potential route of drug administration to the eye in the treatment of uveitis. We discuss the benefits of the SCS as a drug delivery route in the treatment of uveitis and summarize literature findings associated with suprachoroidal drug delivery, particularly related to the recent FDA approval of suprachoroidal triamcinolone acetonide (Xipere; Clearside Biomedical/Bausch + Lomb) for the treatment of macular edema associated with NIU.

POSTERIOR SEGMENT DRUG DELIVERY INNOVATIONS

Intravitreal administration of therapeutic drugs is the most common procedure used to treat NIU and common posterior segment diseases (ie, age-related macular degeneration, diabetic retinopathy, and retinal vein occlusion) in clinical practice. However, other drug delivery routes used previously or under investigation to treat uveitis and posterior segment diseases include topical administration, the sub-Tenon route, subretinal delivery, and, more recently, delivery via the suprachoroidal space. Each of these delivery routes has its benefits and limitations, so retina specialists must consider several factors in choosing a treatment option that may include patients’ adherence and drug pharmacokinetics.¹¹

Intravitreal Drug Delivery

Intravitreal injection is the most common route of administration in clinical practice for treatment of posterior-segment eye diseases involving direct drug administration into the vitreous cavity. This route has been proven to help enable high and effective drug concentrations into the posterior segment of the eye. However, repeated injections given monthly or bimonthly may result in significant treatment burden, thereby producing a need for alternative innovations that allow more sustained-release systems that would enable a controlled release of therapeutic agents to maintain concentration in the vitreous cavity.¹¹ Rare complications associated with the intravitreal route of administration include endophthalmitis, elevated intraocular pressure, vitreous detachment, retinal hemorrhage, and cataract.¹² In phakic patients who are receiving intravitreal corticosteroid or sustained-release corticosteroid implants, cataract risk and intraocular pressure elevation that may prompt cataract or filtration surgery, respectively, are important considerations.^13,14

Suprachoroidal Delivery as an Alternative to Current Techniques

The suprachoroidal space (SCS) is located between the sclera and choroid. Drug delivery into the SCS aids targeting of the posterior segment structures with high levels of medication within chorioretinal structures. Access to the suprachoroidal space has been reported via the use of catheter and hollow microneedles.¹⁵ The SCS is located outside the blood–retinal barrier and can be visualized via advanced techniques of optical coherence tomography.¹⁵ Recent potential benefits of drug delivery via the SCS have been reported, including gene therapy.¹⁶ Yet, given this technique is not widespread in clinical practice, learnings about macular edema associated with NIU, nuances and techniques related to SCS drug administration, and potential for indications beyond uveitis are undergoing further study.

SUPRACHOROIDAL DELIVERY FOR NONINFECTIOUS UVEITIS

Recent multicenter, randomized controlled clinical trials have particularly investigated the use of the suprachoroidal route in the delivery of therapeutic agents for the management of macular edema associated with NIU and have demonstrated strong efficacy signals related to visual acuity and anatomic outcomes by optical coherence tomography. In addition, safety results have been promising, particularly related to rates of intraocular pressure elevation and cataract comparable to sham therapy.^17,18

FINDINGS FROM CLINICAL TRIALS

The multicenter, randomized phase 3 PEACHTREE trial investigated the safety and efficacy of suprachoroidally administered triamcinolone acetonide formulation (CLS-TA) by comparing 2 SC-injected CLS-TA (4 mg) to sham treatment at 12 weeks apart in 160 patients with macular edema associated with NIU. Patients were observed for clinical efficacy with a primary outcome of improvement in best-corrected visual acuity (BCVA) and additional clinical outcomes of reduction from baseline in central subfield thickness (CST) and improvements in inflammation over a 24-week period. In the CLS-TA study group, 47% of patients experienced a significant improvement (≥15 or more EDTRS letters in BCVA) compared to only 16% of patients in the control group (P<.001). Mean reductions in CST from baseline were 153 μm in the treatment group vs 18 μm in the control group (P<.001).

Corticosteroid-associated adverse events of elevated intraocular pressure were however observed in 11.5% of the treatment group and 15.6% of the control group, as well as cataract in 7.3% of the treatment group and 6.3% of the control group.¹⁷ Neither endophthalmitis nor choroidal hemorrhage were described in any patients who were enrolled in PEACHTREE or other recent clinical trials. The US Food and Drug Administration recently approved the triamcinolone acetonide injectable suspension Xipere for the treatment of macular edema in NIU based on the findings of this trial.¹⁹

The MAGNOLIA trial, an extension of the PEACHTREE trial, investigated the extended 48-week efficacy and safety of suprachoroidal CLS-TA among NIU patients with macular edema. Thirty-three patients (28 CLS-TA group and 5 control group) from the PEACHTREE trial were observed over 24 additional weeks. The median time to rescue therapy was 257 days in the treatment group compared to 55.5 days in the control group, while about 50% of patients in the suprachoroidal CLS-TA treatment group were found to avert additional rescue therapies for up to 9 months following last administration of CLS-TA.²⁰

The AZALEA trial investigated the safety of suprachoroidal CLS-TA injections in 38 patients with NIU. Two suprachoroidal injections of CLS-TA (4 mg) each were administered 12 weeks apart. Patients were then observed for adverse events alongside other visual and anatomic outcomes over a 24-week period. Suprachoroidal delivery of CLS-TA was found to be safe and well tolerated in patients with NIU with or without macular edema in the AZALEA trial, with inflammatory signs observed to also improve in a majority of the patients.²¹

CONCLUSIONS AND FUTURE DIRECTIONS

Although intravitreal injections of sight-preserving medications including anti-VEGF agents and corticosteroids remain a mainstay and clinical standard for many posterior-segment diseases, alternative platforms including SCS remain under investigation. Recent clinical trials with SCS injection of triamcinolone acetonide revealed promising results for patients with macular edema associated with NIU, leading to the recent FDA approval of Xipere for this clinical indication in October 2021.

The compartmentalization of medication as well as high levels of therapeutic to the retina and choroid also has the potential to limit exposure of anterior-segment structures to therapeutics and side effects. Other medications are currently under investigation for the SCS for other disease indications, including melanoma, diabetes, and age-related macular degeneration.^22-24 Future understanding of SCS drug delivery will include understanding of posterior-segment diseases that can be targeted by this method of drug delivery, nuances of SCS technique, and durability of medication into the SCS potential space for ophthalmologists and retina specialists implementing this technique into their clinical practice. RP

Editor’s note: This article is part of a special edition of Retinal Physician that was supported by Bausch + Lomb.

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