Behcet's disease is an idiopathic, multisystem inflammatory disorder defined by intraocular inflammation, oral and mucosal ulcerations, skin lesions and inflammation in other body organs. Ocular Behcet's disease is a significant cause of acquired blindness characterized by recurrent, explosive episodes of an obliterative retinal vasculitis. Evidence suggests that interleukin-2 receptor bearing T cells may play an important role in the disease pathogenesis. Treatment of ocular Behcet's requires the use of systemic immunosuppressive agents (corticosteroids, cyclosporine, methotrexate, azathioprine, mycophenolate mofetil, methotrexate, cyclophosphamide and chlorambucil) and is often complicated by the side effects of the therapy. Consequently, a safer and effective therapy for the treatment of ocular Behcet's is an important research goal. Daclizumab (HAT, Zenapax) is a recombinant monoclonal antibody that recognizes the IL-2R-TAC protein and inhibits IL-2 mediated biologic responses of activated lymphoid cells. We investigated the safety and efficacy of daclizumab in controlling the ocular manifestations of Behcet's disease. Patients with a history of ocular Behcet's experiencing at least two prior ocular attacks and requiring treatment with two or more immunosuppressive agents were eligible for enrollment in this randomized, placebo-controlled, double masked clinical trial. Enrolled patients were randomized to either intravenous placebo or daclizumab (1m/kg) infusions given every two weeks for 6 weeks and then every 4 weeks. Concomitant immunosuppressive medications were continued and at 6 months tapered if the ocular disease was considered quiescent. The study primary safety endpoints were the development of a life threatening complication or a severe opportunistic infection. Primary efficacy outcomes were the number of ocular attacks and an assessment of amount of systemic immunosuppressive medications required during the study including the ability to taper concomitant immunosuppressive therapy using a medication grading scale. Seventeen patients (2 with active disease and 3 pediatric) were randomized (9 to daclizumab; 8 to placebo) and followed from 1 to 34 months. Two patients randomized to daclizumab discontinued study therapy; the first for at 28 weeks for unwillingness to comply with protocol mandates and the second for abnormal baseline laboratory values discovered after the first infusion at 2 weeks. No patient experienced a safety endpoint and the visual acuity remained stable in all patients during the course of the study. More adverse events that were perceived as greater in severity occurred in patients receiving placebo than daclizumab. Ten patients (6 daclizumab, 4 placebo) experienced ocular attacks requiring therapy. The median ocular attack rate during the study was greater in the daclizumab arm than the placebo arm (1.27 vs 0.17 attacks/year). Patients in the placebo arm also experienced a greater reduction in the level of prescribed immunosuppressive medications compared to patients receiving placebo (-4.0 vs -1.0). The observed results in the placebo group demonstrate that careful follow-up and treatment with standard combination immunosuppressive therapy can be effective for management of ocular Behcet's. In our small study, there was no suggestion of benefit of daclizumab in comparison with placebo. However, the low observed attack rate in the placebo group limited our ability to make a definitive treatment group comparison. Based on these study results future studies evaluating biologic therapies including daclizumab at higher doses, infliximab and interferon alpha are now being considered for the treatment of the ocular complications of Behcet's disease.
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