Among the risks associated with treating noninfectious uveitis is elevation in intraocular pressure (IOP), which may occur during treatment with systemic, topical, and locally administered steroids. Elevation of IOP, whether disease-related or treatment-related, is the most important risk factor for development and progression of glaucoma.¹ Watching for and addressing changes in IOP are essential aspects of care.²

Long-term intraocular steroid treatment represents a useful alternative to systemic therapy in chronic uveitis, offering proven effectiveness in controlling inflammation and preventing vision loss. The Multicenter Uveitis Steroid Treatment (MUST) trial spotlighted the risk of IOP elevation with the 0.59 mg fluocinolone acetonide intravitreal implant Retisert (Bausch + Lomb) compared to systemic treatment, raising concerns about this approach.³ However, in light of the advantages long-term intraocular therapy may offer to patients, it is important to explore current options and evolving data on their impact on IOP.

PREVALENCE AND RISK FACTORS OF IOP ELEVATION IN CHRONIC UVEITIS

The Systemic Immunosuppressive Therapy for Eye Diseases (SITE) group, which studied adults with noninfectious uveitis (N=7,062; 11,452 uveitic eyes), found that on entry, IOP was ≥21 mmHg for 13% of eyes and ≥30 mmHg for 2.5%.² Among eyes without elevated IOP at entry, annual incidence rates were 14.4% for ocular hypertension ≥21 mmHg and 5.1% for ≥30 mmHg. Over a 2-year period, 31% of the eyes with normal baseline IOP showed IOP ≥21 mmHg and 14% showed IOP ≥30 mmHg. The SITE analysis also identified characteristics associated with increased risk of IOP elevation.² Among these were indicators of uveitis severity. Poorer visual acuity, pars plana vitrectomy, peripheral synechiae, and high IOP in the fellow eye predicted IOP ≥30 mmHg over 2 years.

In addition, systemic corticosteroid dose of >7.5 mg prednisone/day or equivalent carried an approximately doubled risk of IOP ≥21 mmHg or ≥30 mmHg compared with no systemic steroids.² Topical corticosteroids were associated with a roughly 2-fold to 3-fold increase in risk — results by drop per day suggested a dose relationship — and periocular steroids similarly were linked with a 2-fold risk. Retisert implants were associated with a 10-fold greater risk of IOP increase.

CAUSES OF IOP ELEVATION

Both uveitis and its treatment can contribute to elevated IOP. It is thought that uveitis may disturb the balance between production and outflow of aqueous humor.⁴ In acute uveitis, concentration of proteins in the anterior chamber has been found to be increased, clogging the trabecular meshwork and reducing aqueous outflow.^5,6 Posterior or peripheral anterior synechiae may also reduce aqueous outflow and lead to IOP increase, especially in chronic cases.

For its part, corticosteroid treatment also appears to cause ocular hypertension through increased aqueous outflow resistance, experimental data indicate.⁷ Steroids, via trabecular meshwork glucocorticoid receptors, induce microstructural changes and accumulation of extracellular matrix materials in the meshwork that may increase resistance to outflow. Steroid-induced IOP increase has been found to be more manageable than that caused by inflammation, in terms of number of IOP-lowering medication drops required and proportion of eyes needing aqueous filtering surgery.⁸

CORTICOSTEROID AND IOP ELEVATION

Corticosteroid therapy by any route of administration can be associated with IOP elevation.^2,7 However, incidence is more common with local steroids, and whereas IOP generally increases after 3 to 6 weeks with topical steroids and over the course of several months with injected steroids, IOP response with systemic agents may take years.^7,9

Change in IOP following periocular injection of corticosteroids were evaluated in a SITE cohort study analysis, which included patients (N=914; 1,192 eyes) who had received at least 1 injection, typically triamcinolone acetonide 40 mg (Kenalog-40; Bristol-Myers Squibb) into the sub-Tenon space or orbital floor.¹⁰ Increases to ≥24 mmHg and ≥30 mmHg, expressed in events per eye-year, were 0.26 (95% CI 0.23, 0.31) and 0.13 (95% CI 0.10, 0.16). Cumulative increases to ≥24 mmHg and ≥30 mmHg within 12 months were 34% (95% CI 24.8, 45.4) and 15% (95% CI 11.8-19.1), respectively.

Randomized clinical trial data on IOP effects of periocular and intravitreal steroids have come from the PeriOcular vs INTravitreal corticosteroids for uveitic macular edema (POINT) study, reported in 2019.¹¹ The POINT study compared periocular Kenalog, intravitreal injectable triamcinolone acetonide (Triesence; Alcon), and a dexamethasone sustained-release implant (Ozurdex; Allergan) over 24 weeks in patients with uveitic macular edema (N=192; 235 affected eyes). In the trial, both Triesence and Ozurdex were found to be significantly superior to periocular injection, and Ozurdex was noninferior to Triesence. Increases in IOP ≥10 mmHg from baseline and of IOP ≥24 mmHg were more common in the Triesence and Ozurdex groups than in the Kenalog group. Compared with Kenalog, risks of IOP ≥24 mmHg were higher for both Triesence (HR, 95% CI: 1.83, 0.91-3.65) and Ozurdex (HR, 95% CI: 2.52, 1.29-4.91), as were risks of IOP ≥10 mmHg over baseline (HR, 95% CI: 1.92, 0.86-4.29 for Triesence; HR, 95% CI: 2.85, 1.30-6.28 for Ozurdex). Incidence of IOP ≥30 mmHg was low (≤6%) in all groups. Roughly comparable percentages of patients in the 3 groups (32% to 43%) received IOP-lowering medication. The 2 intravitreal treatments did not differ significantly in effects on IOP.

LONG-TERM INTRAOCULAR OPTIONS AND INTRAOCULAR PRESSURE

Three sustained-release intraocular treatments have been approved by FDA for chronic noninfectious uveitis. Ozurdex, approved in 2009, is active for up to 6 months, while Retisert, approved in 2005, and the 0.18 mg fluocinolone acetonide insert Yutiq (Eyepoint Pharmaceuticals), introduced in 2018, offer substantially longer-term control of inflammation — up to 3 years.¹²

Again, Retisert was compared with systemic steroid and immunosuppressant therapy in the MUST trial and follow-up study.^3,13,14 Visual acuity at 24 months (the primary outcome) was not different between the 2 groups; significantly fewer eyes in the implant group showed uveitis activity, but the implant group had higher rates of IOP elevation, cataract, and glaucoma (Table 1).³

Over the 24 months, incidence of IOP ≥30 mmHg was 33% for Retisert compared with 6% for systemic treatment; therapy to lower IOP was administered in 61% of implant eyes, vs 20% of systemic therapy eyes. Follow-up analysis at 54 months had similar results: Cumulative incidence of IOP-related events increased for both groups, but remained significantly higher for the implant.¹⁴

Yutiq was designed to improve on the performance of Retisert by delivering a lower dose of corticosteroid — at an initial rate of 0.25 μg/day — with the aim of providing sustained inflammation control over 3 years with a superior safety profile.¹² The Yutiq insert comprises a polyimide tube 3.5 mm in length with a core containing 0.18 mg fluocinolone acetonide, and it is administered as an in-office injection, unlike Retisert, which is implanted surgically through a pars plana incision.^12,15,16

Yutiq was approved for the treatment of chronic noninfectious uveitis affecting the posterior segment, on the basis of 2 sham-controlled randomized trials.¹⁵ The primary efficacy endpoint in these trials was the proportion of eyes with a recurrence of uveitis (ie, deterioration in visual acuity, vitreous haze attributable to noninfectious uveitis, or need for rescue medications) in the study eye within 6 months of follow-up. Recurrence rates and other efficacy results and safety data from up to 3 years of follow-up have been reported.^17,18

For the first of these trials, data have been reported for 24 and 36 months’ follow-up.^17-19 At 12 months, rates of IOP increase ≥12 mmHg from baseline were 18.4% and 9.5% for the Yutiq (n=87 eyes) and sham treatment (n=42) groups, respectively. Incidence of IOP ≥30 mmHg was 12.6% for the insert group and 4.8% for the sham group. Results on IOP at 24 and 36 months were consistent with those at 12 months.²⁰

At 12 months, equal percentages of eyes in the 2 groups (26%) received IOP-lowering medication, and rates of surgery for IOP elevation were comparably low (3.4% for Yutiq, 4.8% for sham).²⁰ By 36 months, 42.5% of eyes in the Yutiq group and 33.3% of eyes in the sham group had received IOP-lowering medication.¹⁹ Of note, over the 36 months, 5.7% of eyes in the Yutiq group underwent IOP-lowering surgery vs 11.9% in the sham group. This contrasts with a 37% incidence of IOP-lowering surgery over 3 years seen in trials of Retisert.¹⁶

MONITORING AND MANAGING IOP

Some authors have suggested protocols, based on clinical trial data, for monitoring of IOP in patients with uveitis according to type of treatment administered.²¹ Others, such as the SITE research group, have advised checking pressures at every visit.² I recently analyzed the timing of significant IOP increases in the first 36-month study of Yutiq, with the aim of determining the timepoints at which IOP monitoring might be particularly important.²² Median time for IOP ≥30 mmHg events in the Yutiq group up to 36 months was day 153 (about 5 months), and two-thirds of those events were observed within the first 6 months of treatment. This pattern suggested that evaluations at 7 days and 1, 3, 6, and 18 months could detect the majority of severe IOP increases.

After Yutiq injection, I evaluate patients for increased IOP at 1 week, 1 month, 3 months, and then every 3 months after that. I am able to detect a significant increase in IOP. If I see a spike in IOP to 30 mmHg or higher or perhaps even to 25 mmHg or above, I will prescribe an IOP-lowering medication and probably have the patient return in 1 to 2 weeks.

If IOP remains importantly elevated, the next steps are to adjust dosage of the IOP-lower medication or modify the treatment, and, if that fails, refer to a glaucoma specialist for possible selective laser trabeculoplasty. I typically order a visual field (VF) test in patients who have a history of IOP elevations or if patients develop increased IOP. Persistent IOP elevation, whether due to failure of treatment or, in some cases, adherence problems, will typically prompt referral to a glaucoma specialist.

In the reported trial, IOP increases were managed primarily with standard topical medications. Among those Yutiq-treated eyes that exhibited IOP ≥30 mmHg, no significant impact on progression of visual field loss was observed compared with the fellow eye.²²

CONCLUSION

Intraocular pressure elevation is one of many safety-related variables to consider in choosing treatment for patients with chronic noninfectious uveitis and following these patients. In treating our patients, it is the challenge of the ophthalmologist to consider and manage these risks while keeping a focus on controlling inflammation with the goal of preserving vision. With evolving understanding and newer treatment options, this challenge has become easier to meet. RP

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