Chronic noninfectious uveitis is among the most challenging diseases retinal specialists treat. There is substantial diversity in both presentation and history of systemic disease among these patients, and the course is often unpredictable. Chronic noninfectious uveitis is by definition a relapsing disease, but in each individual patient, we do not know when the next flare will occur, how severe that flare will be, or how it may impact vision in the long term.

Moreover, the stakes are high. With every uveitis flare, there is cumulative damage. Even though some recovery typically occurs with treatment, vision tends to worsen over the long term, in what has been termed a “saw-tooth” decline.¹ Uveitis has been a major cause of blindness in the United States, and patients who do not seek or receive appropriate treatment (or whose disease is refractory) face significant risk of major vision loss.^2,3 In response to this challenge, various systemic immunomodulatory agents and biologics, as well as novel means of localized drug delivery, have been evaluated in chronic noninfectious uveitis.

CHALLENGES IN TREATMENT OF CHRONIC NONINFECTIOUS UVEITIS

The goals of treatment in chronic noninfectious uveitis are to eliminate local immune response and thereby prevent irreversible tissue damage and consequent visual loss, while minimizing drug exposure.^4,5 Corticosteroids — topical, injected, or systemic — have long been the mainstay of treatment.^6,7 When systemic disease is absent or inactive and only one eye needs treatment, more localized treatment can be an attractive option.⁸ Conversely, active systemic disease or bilateral uveitis may favor systemic therapy. In addition, local therapy may be attractive as an adjunct, when a patient experiences flares of ocular inflammation despite systemic therapy.

Localized therapy can avoid the well-known systemic adverse effects of steroids. The penetration of topical corticosteroids limits their utility to anterior uveitis.^6,7 Periocular corticosteroids, such as triamcinolone acetonide (eg, Kenalog-40; Bristol Myers Squibb), often used for intermediate, posterior, or panuveitis, produce sustained high intraocular steroid levels with little systemic penetration, but the therapeutic effect lasts only about 2 months.^6,7 Triamcinolone acetonide injected directly into the vitreous (Triesence; Alcon) has a longer duration of therapeutic effect, at approximately 3 to 7 months.⁸

Systemic corticosteroids play a vital role in initial control of uveitis; for example, in patients with sarcoidosis, steroids have dramatically reduced risk of vision loss.⁶ However, due to the various adverse effects of steroids, high-dose therapy is generally limited to a few weeks, and the dose is tapered (to no more than 10 mg/d for prednisone).^1,6 As steroid dose is reduced, risk of relapse increases.⁹ For this reason, longer-term treatment may be initiated with an immunosuppressant — in most cases, an antimetabolite (eg, azathioprine [Imuran; Sebela Pharmaceuticals, and others], methotrexate [Trexall; Teva, and others) or a calcineurin inhibitor (eg, cyclosporine [Sandimmune; Novartis, and others], tacrolimus [Prograf; Astellas, and others]).¹ These medications can control uveitis while maintaining a low steroid dose, although their effectiveness varies. More recently, biologics, particularly anti-tumor necrosis factor-alpha (TNF-α) agents have been used for systemic immunosuppression in chronic uveitis, with adalimumab (Humira; AbbVie) approved by the US Food and Drug Administration for treatment of noninfectious posterior uveitis.¹

Conventional immunosuppressants or TNF-α inhibitors commonly used in treating ocular inflammation do not appear to increase risk of cancer-related or overall mortality.^10,11 However, all of these agents impose burdens of possible systemic adverse effects or long-term safety risks that may require monitoring or intervention.¹ In addition, oral agents generally require daily dosing, raising adherence issues.

INTRAOCULAR IMPLANTS

An alternative to continuous systemic treatment or episodic localized steroid treatment in chronic uveitis is long-term localized therapy with an implant that continuously delivers a steroid at a controlled dose. This approach aims to provide sustained control of inflammation over months or even years while minimizing systemic exposure and adverse events.¹² Also, sustained-release intraocular therapy may reduce inconvenience to the patient and the risk of complications associated with repeated intravitreal injections.¹³ This approach does carry risks of IOP elevation and cataractogenesis.¹³

A FOCUS ON YUTIQ

Yutiq (Eyepoint Pharmaceuticals) follows Retisert (Bausch + Lomb), approved in 2005, and Ozurdex (Allergan), approved in 2010, as a sustained-release intraocular option for treating chronic noninfectious uveitis affecting the posterior segment. Like Retisert, Yutiq is designed to release fluocinolone acetonide for up to 3 years, but it does so at about one-third the dose.¹² Also in contrast to Retisert, which is implanted surgically, Yutiq is administered in the office via a pars plana injection. Ozurdex, a bioerodible implant that releases dexamethasone, is also administered via an intravitreal injection, but it has a shorter therapeutic lifespan (up to 6 months).^8,14

The efficacy and safety of Yutiq have been evaluated in 2 randomized, sham-controlled, double-masked phase 3 clinical trials with patient follow-up continuing for 3 years.¹⁵ These trials enrolled adults with noninfectious uveitis affecting the posterior segment in at least 1 eye (with or without anterior uveitis) for at least 1 year. The primary endpoint was the difference between study groups in frequency of uveitis recurrences by month 6. In both trials, recurrence was defined as a uveitis-associated increase in the vitreous haze of at least 2 steps or a deterioration in BCVA of at least 15 letters compared with baseline or a prior timepoint.

In the 2 trials, a total of 282 patients were enrolled and randomized 2:1 to the implant (n=188) or sham injection (n=94).¹⁶ In the first study, at all timepoints through 3 years, the recurrence rate remained significantly lower for the Yutiq than for the sham group (56% vs 93% at 3 years) (Table).¹⁷ BCVA gains of ≥3 lines were more common with Yutiq than with sham injection (33% vs 15%), while losses of ≥3 lines were more common with the sham injection than with Yutiq (9% vs 1%).¹⁷ At the 3-year follow up, 42% of eyes in the Yutiq group and 33% in the sham group required IOP-lowering medication, and 6% of Yutiq group and 12% of sham group eyes needed surgery to control IOP. Rates of cataract surgery in phakic eyes were 74% and 24% for Yutiq and sham groups.¹⁷

Similarly, in the second study, the 3-year recurrence rate in the Yutiq group was significantly lower than in the sham-treated group (47% vs 75%). In this study, 74% of Yutiq-treated eyes and 73% of sham-treated eyes received IOP-lowering drops, and 2% and 0%, respectively, had IOP-lowering surgery through 3 years. Of eyes that were phakic at baseline, 71% of Yutiq-treated eyes and 27% of sham-treated eyes had cataract surgery.¹⁸

YUTIQ PRACTICAL CONSIDERATIONS

From my personal experience, I consider Yutiq for patients who have responded well to previous steroid injections and who are likely to return for follow-up. Adherence is critical, particularly for patients who need multiple medications to control their disease. I encounter patients — often younger people who are working — who are motivated to adhere to treatment but run into practical problems with daily medications. Yutiq is an attractive option for these patients.

Yutiq’s potential adherence advantages notwithstanding, I take care not to imply that the treatment alone will take care of the patient’s disease for 3 years. Instead, I emphasize the advantage of regular, sustained reduction of inflammatory burden in the eye and what it can mean for the disease over the long term.

Yutiq, an injectable insert 3.5 mm in length, offers the advantage of administration in the office setting. As it is a unique injection procedure, it may be helpful to have a practice injector onsite (these are available from Eyepoint). Instructional videos are also available.

I follow patients 4 weeks after stabilization, then quarterly, doing visual assessments, slit-lamp examination, IOP measurements, and optical coherence tomography to look for edema. I have found that patients receiving Yutiq have better adherence to follow-up than some of my other patients — they tend to have less anxiety that the visit will entail another intraocular injection.

INTRAOCULAR PRESSURE AND IMPLANTS

Concern about elevated IOP has sometimes deterred practitioners from considering intraocular steroid implants, even when they may be appropriate. Yet IOP elevations can also occur when uveitis is untreated or undertreated, or when the disease is treated with steroids by another route, and IOP monitoring is always warranted.¹⁹ In studies of Yutiq, rates of IOP elevation were comparable to sham injection/standard of care.^17,18

Yutiq’s attributes may make it suited to certain subtypes of noninfectious uveitis. Patients with Behçet disease often present with severe flares, and this supports use of a treatment that is efficacious in reducing recurrence risk. On the other hand, birdshot chorioretinopathy is more of an insidious disease in which patients may not immediately notice vision loss. This may call for continuous, consistent delivery of anti-inflammatory therapy.

CONCLUSION

The current pandemic and the restrictions it has placed on retina specialists and patients highlights the need for more durable therapies. Reducing the number of clinic visits by using longer-acting therapies keeps everyone safer. For those who have been treated with Yutiq and stable for months, we have been able to reschedule visits knowing they have a therapy in place to keep their eye and vision stable.

In treating chronic noninfectious uveitis, we face the challenge of “getting ahead of the curve,” to prevent long-term, irreversible structural damage and vision loss, rather than reactively managing flares. With Yutiq, we have an option that has been designed for this treatment goal. RP

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