By Eric B. Suhler, MD, MPH
Ophthalmologists who treat uveitis use a variety of local and systemic agents to control intraocular inflammation, as well as one of its main sight-robbing complications, cystoid macular edema (CME). The most commonly employed agents for local therapy, corticosteroid injections, often accelerate cataractogenesis or increase intraocular pressure. The current study's authors investigated the use of an alternative intraocularly injected agent, methotrexate, for the treatment of uveitis and uveitis-related CME and concluded that it shows promise for these indications. Methotrexate was chosen due to its long track record as a systemic treatment for ocular inflammation, as well as its more recent success as an intravitreal treatment for intraocular lymphoma.
The authors enrolled in this pilot study 15 patients with unilaterally-active intermediate or posterior-segment uveitis or panuveitis involving intraocular inflammation with CME, with resultant vision of 20/40 or worse. Four patients were previously treated with intravitreal steroids; seven were on stable doses of systemic steroids and/or immunosuppressives. All patients were documented corticosteroid pressure-responders.
The study's main outcome measures were a 10-letter improvement in visual acuity combined with control of intraocular inflammation. Other measures included time to relapse, ability to taper steroids and other immunosuppressives, ocular coherence tomography (OCT) findings and occurrence of therapy-related complications. All patients received a single methotrexate injection of 400 μg in 0.1 ml administered according to standard aseptic procedures. Post-injection, the researchers followed up with patients after one week and monthly up to six months. Initial responders were allowed to taper systemic medications starting at the two-month visit and were permitted repeat injections for flares after at least three months for recurrent inflammation, CME or a five-letter reduction in acuity. Bilateral reactivations lead to systemic steroid therapy and study termination.
Thirteen of 15 patients (87 percent) demonstrated at least transient response as defined above, although one initial responder and two nonresponders withdrew from the study prior to six months of follow-up. There was a rapid initial improvement in mean visual acuity and macular thickness as measured by OCT at one week post-injection, which was sustained and even improved up to six months. Three of seven patients on systemic therapy were able to taper these medications. A modest recrudescence was noted between months three and four due to disease recurrence in five patients. Four elected to undergo repeat methotrexate injection to which they all responded. Corneal epitheliopathy in an additional patient lead to transient vision reduction and recovery with conservative therapy. No other side effects were clearly related to methotrexate therapy, although one patient had a dramatic worsening of pseudophakic posterior capsular opacification.
The authors are to be commended for developing this prospective trial investigating a novel treatment for intraocular inflammation and CME, especially in patients with known steroid response in whom options are often limited. However, it would have been useful if they had correlated the etiologic diagnoses with outcomes, as well as the anatomic diagnoses. It would have also been helpful to discuss whether the duration or amount of CME or other prognostic factors were associated with response to therapy. Longer term follow-up will be useful to see whether cataractogenesis is accelerated by methotrexate's antimetabolic effects. However, the authors rightly conclude that further study is indicated and intravitreal methotrexate therapy holds great promise for the treatment of refractory inflammation and/or CME, especially in patients with unilateral disease or history of steroid-induced pressure response.
Financial Disclosures
Dr. Suhler has received grant support from the National Eye Institute, Genentech, Inc., Allergan, Inc., Bausch and Lomb, Inc., Lux Biosciences, Inc., Centocor, Inc., Abbott Pharmaceuticals, EyeGate Pharma and Cerimon Pharmaceuticals, Inc.