Which treatment paradigm — local or systemic therapy — best treats bilateral noninfectious uveitis?
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Systemic therapy offers sustained control, avoids cataract formation
There are distinct advantages of systemic therapy in terms of achieving control in both eyes, at a steady state, and without the risks for cataract and elevated IOP. Younger patients appreciate being able to preserve their accommodation and avoiding cataract surgery. Systemic therapy also avoids the sawtooth decline in vision that is seen with short-term local steroid delivery when the effect wears off and there is recurrence of inflammation.
There is robust data demonstrating the long-term superiority of systemic treatment. Systemic therapy refers to steroid-sparing immunosuppression as long-term corticosteroid use has serious side effects, and there is good agreement that immunosuppressant medications should be added if inflammation cannot be controlled with 10 mg per day or less of prednisone within 3 months. The MUST trial randomly assigned patients to undergo systemic therapy (corticosteroids and immunosuppression) or the 0.59 mg fluocinolone acetonide implant (Retisert, Bausch + Lomb) placement. They observed that at 2 years and 4.5 years, visual acuity outcomes were slightly better with Retisert. However, when followed over 7 years, systemic therapy produced greater visual acuity improvement, better control of uveitis and macular edema, and fewer patients with severe visual field loss.
Although there is often concern among patients about the side effects of immunosuppressive medications, there is extensive data demonstrating the safety of these drugs. The SITE study looked at overall and cancer mortality in patients with uveitis receiving immunosuppressive medications. Alkylating agents cyclophosphamide and chlorambucil had an increased risk for malignancy, and these agents are now used only for selected severe cases. Calcineurin inhibitors cyclosporine and tacrolimus and the antimetabolites azathioprine, methotrexate and mycophenolate mofetil showed no increased mortality or cancer risk. The safety and efficacy of TNF inhibitor adalimumab is well established through the phase 3 VISUAL trials. There is also extensive data on the safety of these immunosuppressive medications in the rheumatology literature, including in children.
The reality is that we have no therapy that is perfectly safe and perfectly efficacious for uveitis. With every patient, you have to weigh the risks and benefits of the treatment choice. We are certainly in exciting times for systemic uveitis treatments. Gilead Sciences is evaluating filgotinib, an oral selective JAK1 inhibitor for treatment of noninfectious uveitis. There are also several reports of the efficacy of anti-interleukin-6 agents such as tocilizumab and sarilumab. Newer agents will offer greater treatment options with more convenient dosing, allowing treatment to be personalized to each patient.
Dilraj Grewal, MD, is a vitreoretinal and uveitis specialist at Duke Eye Center. Disclosure: Grewal reports no relevant financial disclosures.
Local therapy controls disease while avoiding systemic risks
Noninfectious uveitis often develops as an ocular manifestation of systemic disease and can frequently affect both eyes either simultaneously or sequentially. Many patients require systemic immunosuppression for control of their underlying autoimmune condition, and this systemic therapy can have beneficial effects on control of ocular inflammation. However, some patients may have active bilateral uveitis in the setting of quiescent systemic disease or even idiopathic uveitis without concomitant systemic disease. Given the growing number of effective and safe locally administered treatment options, these patients are best served with local treatment as opposed to systemic treatment.
Allergan’s dexamethasone intravitreal implant (Ozurdex) has been FDA approved for the treatment of macular edema secondary to noninfectious uveitis since 2010. The current version of the delivery device has been improved significantly with a sharper needle, allowing smoother and safer injection in the office with minimal discomfort to patients. The implant effectively controls inflammation and reduces macular edema for 3 to 6 months, with an acceptable safety profile. Patients with uveitis often develop cataracts at a young age due to ocular inflammation and the steroids required to control the disease, and the Ozurdex implant can effectively quiet ocular inflammation in the perioperative period to allow safe cataract surgery with reduced risk for postoperative rebound inflammation and macular edema. Elevated IOP is generally transient, lasting weeks or months, controlled with topical IOP-lowering agents, and not additive with subsequent injections when needed.
The recent FDA approval of EyePoint’s Yutiq fluocinolone implant in 2018 provides us with a sustained-release office-based treatment option for noninfectious uveitis. The implant is injected via a 25-gauge needle and effectively reduces inflammation severity and recurrences for up to 36 months. The majority of patients in the phase 3 clinical trials developed cataract progression, but only 2% required IOP-lowering surgery, and 43% required IOP-lowering topical therapy.
The coming year may bring approval of Clearside Biomedical’s suprachoroidal formulation of triamcinolone for treatment of macular edema secondary to noninfectious uveitis. This route of administration appears to provide high drug levels to target tissue in the posterior pole, while reducing steroid levels near the lens and trabecular meshwork, potentially reducing the risk for cataract formation and IOP elevation.
Given the exciting expansion of effective, safe local options in our noninfectious uveitis treatment armamentarium, systemic therapies and their potentially severe side effects should be avoided in patients with idiopathic uveitis and in those with quiescent systemic disease.
Ankur M. Shah, MD, is a retina specialist at Prairie Eye Center, Springfield, Illinois. Disclosure: Shah reports he is a consultant for Allergan, Alimera and EyePoint.