Alice Goodman

November 27, 2013

NEW ORLEANS — Uveitis, a significant cause of ocular morbidity worldwide, will undergo major changes as biologic therapies enter the field, delegates heard here at the American Academy of Ophthalmology 2013 Annual Meeting.

"Treatment will look different in the next 10 years, with many more agents available to doctors," said Russell Van Gelder, MD, from the University of Washington School of Medicine in Seattle.

The goal of uveitis treatment is to avoid the use of steroids. Standard therapies, such as methotrexate, azathioprine, mycophenolate mofetil, and cyclosporine, are about 6% to 70% effective in sparing steroids. "But all treatments have side effects," Dr. Van Gelder pointed out.

The implication of immune-mediated inflammatory pathways in uveitis and the explosion of biologic agents to treat rheumatic and other inflammatory-mediated diseases has led to a wealth of potential therapies — systemic and local — for uveitis.

The success in rheumatology of the TNF alpha inhibitors adalimumab and infliximab over the past several years has led to their use in uveitis, in particular in patients with Behcet's disease and for early use in patients with juvenile idiopathic arthritis who have not benefited from methotrexate.

Difluprednate ophthalmic emulsion, a topical corticosteroid, is approved for use in patients with anterior uveitis. "This is a 2-edged sword, with an increased risk of intraocular pressure, especially in children. Close monitoring is required," Dr. Van Gelder said.

Several sustained-release implants are approved for intermediate and posterior uveitis, including fluocinolone acetonide and dexamethasone. These are highly potent medications with an increased risk for cataracts and glaucoma, he reported.

Intravitreal methotrexate is being studied, but this agent has known corneal toxicity. The optimal dosing and treatment protocol is unknown, Dr. Van Gelder explained. "One study suggests that about 70% of responders need a single injection. Long-lasting remission was seen in posterior uveitis, but this study needs replication," he added.

TNF Alpha Inhibitors

Intravitreal anti-TNF alpha injections showed efficacy in uveitis, but multiple injections led to severe inflammation. Therefore, a moratorium was recommended, and no randomized controlled trial has been conducted.

Six-month data from the phase 3 SAVE trial of the mTOR inhibitor sirolimus are encouraging, he said. However, the phase 3 study of voclosporin for uveitis did not meet the primary end point of sparing steroids, so the New Drug Application was withdrawn.

Biologics — approved by the US Food and Drug Administration for rheumatoid arthritis and other rheumatic diseases — are emerging treatments for uveitis, Dr. Van Gelder noted. These include the anti-CD20 inhibitors rituximab and ocrelizumab, the anti-TNF inhibitors certolizumab and golimumab, the interleukin-6 inhibitor tocilizumab, the interleukin-1 inhibitor canakinumab, the anti-CTLA-4 inhibitor abatacept, and the small molecule JAK inhibitor tofacitinib.

 
The first experience with the anti-TNF inhibitors etanercept, infliximab, and adalimumab gave us fantastic results in uveitis.
 

Because the pool of patients with uveitis is not that large, it is not easy to do clinical trials, said Anat Galor, MD, from the University of Miami and the Miami Veterans Affairs Medical Center. "Some types of uveitis are autoimmune, so we borrow from our rheumatology colleagues when treating uveitis," she explained.

"The first experience with the anti-TNF inhibitors etanercept, infliximab, and adalimumab gave us fantastic results in uveitis. We also had good results with rituximab in patients with uveitis who didn't do well on anti-TNF agents," she noted.

"The new explosion of rheumatic drugs gives us a wealth of choices. But it is not clear which drugs are best for which subcondition. The more we learn about the biology of uveitis, the better we can treat it," Dr. Galor said. "I agree with Dr. Van Gelder that the future looks bright for uveitis. The new treatments not only help our patients, they help us understand the pathophysiology of the disease."

Dr. Van Gelder reports financial relationships with Alcon Laboratories, Chromologics, the National Eye Institute, and Theravance. Dr. Galor reports financial relationships from the VA Career Development Award and a University of Miami grant.

American Academy of Ophthalmology (AAO) 2013 Annual Meeting. Presented November 16, 2013.

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