Translational Studies

Current Therapies

When steroid therapy was introduced in the latter half of the 20th century for various autoimmune conditions, steroids were rapidly applied to sight-threatening uveitis [59, 60], and both topical and systemic preparations are the mainstay of current treatments. However, prolonged use of steroids, particularly systemic steroids, is associated with unacceptable side effects, and many patients return to their pre-treatment vision-losing inflammation as the steroids are tapered. Steroid-sparing agents such as azathioprine and methotrexate are also widely used, but they are less effective and also have side effects.

A major problem in this area of research is the lack of good clinical evidence based on well-controlled randomized clinical trials (RCTs), and this is partly due to difficulties in developing standardized entry and exclusion clinical criteria. In preclinical studies, EAU has provided a benchmark for evaluating the effects of immunosuppressants in autoimmune inflammatory disease and in this respect provides an excellent model for translational research. Early studies in EAU showed the value of this model in developing the use of a wide variety of immunosuppressants for uveitis, including cyclosporine A, FK506, rapamycin, and mycophenolate, all of which are now in clinical use in the treatment of ocular inflammation [61-64]. Direct comparisons of the efficacy of some of these drugs have been reported recently: for instance, FK506 has been shown to be slightly superior to cyclosporine A in the treatment of human uveitis, and to have a better 'quality-of-life' outcome [65].

All of these drugs have major side effects, the most important of which are the life-threatening effects, such as tumor induction, renal toxicity and failure, bone marrow aplasia and hypertension. Accordingly, it is essential in considering the use of these drugs in patients with uveitis to perform a full pretreatment medical assessment including renal, biochemical and hematological function studies. Appropriately trained ophthalmic physicians are necessary to correctly treat these patients.

Newer Approaches to the Management of

Sight-Threatening Uveoretinitis

The explosion in the use of 'biologics' in therapy of many human diseases from cancer to aging disorders and autoimmune disease has had significant impact on the treatment of intraocular inflammation/uveitis. Early studies with T cell-depleting drugs, e.g. anti-CD3 and anti-CD52 (Campath 1h), proved to be effective in several conditions, including ocular inflammation [66], but particularly in the latter case, profound effects on marrow function have restricted its use.

Despite the theoretical arguments against the likelihood of a therapy directed against a single cytokine proving effective in inflammatory disorders, the remarkable effectiveness of anti-TNF-a therapy in rheumatoid arthritis generated opportunities for its use in other conditions such as uveitis [67, 68]. Several studies have now reported good therapeutic benefit from anti-TNF-a treatment in uveitis and it has a firm place on the pharmacy shelf despite its high cost. Particular indications include juvenile idiopathic arthritis-associated uveitis with secondary retinal involvement and severe retinal vasculitis with macular disease.

More recently, other biologics have been proposed for use in severe, sight-threatening retinal vasculitis, particularly Behçet's disease. IFN-a therapy was recently reported to have >90% effectiveness in patients with retinal vasculitis who had failed on other therapies, and this has been confirmed in other less extensive studies in both patients with non-Behçet's sight-threatening uveitis [69]. Remarkably, in a bedside-to-bench investigation, patients with uveitis have now been shown to demonstrate a defect in function of circulating plasmacytoid dendritic cells, the constitutive INF-a-producing cells in the body, in which they fail to produce INF-a in response to Toll receptor 9 stimulation [70], perhaps explaining the effectiveness of INF-a treatment in this condition. Problems with IFN-a therapy relate to side effects since many patients feel lassitude and have other side effects such as hair loss, weight loss and depression. In addition, titrating the dose can be difficult since IFN may itself induce a retinopathy which is difficult to differentiate from some of the features of retinal vasculitis. However, in those patients with few or no side effects or who can tolerate the therapy, the effect can transform their lives from the side effects of prolonged use of moderate steroids in combination with one or more immunosuppressants, only just maintaining visual function. In some situations it seems to be more beneficial than anti-TNF-a [71].

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