Intravitreal sustained-release cyclosporine in the treatment of experimental uveitis

Abstract

Uveitis often is a chronic disease requiring long-term medical therapy. Despite treatment, the disease may be difficult to control and may produce serious, vision-threatening ocular complications. In this study, the authors determined whether an intravitreal cyclosporine-sustained delivery device was effective in the treatment of ocular inflammation in a rabbit model of uveitis. New Zealand White rabbits were immunized subcutaneously with Mycobacterium tuberculosis H37Ra antigen. Fourteen days later, sustained-release cyclosporine devices were implanted into the vitreous cavity of the right eye of experimental rabbits. Control animals received sham devices. Seven days after device implantation, rabbits were challenged with an intravitreal injection of tuberculin antigen. To simulate chronic inflammation with exacerbations, some animals were rechallenged with intravitreal antigen on day 21 after device implantation. Inflammation was assessed clinically by a masked observer who graded anterior chamber cells, flare, corneal neovascularization, iris congestion, and vitreous opacity daily until day 7 and on day 13 after the initial intravitreous challenge, and on days 1 and 2 after the rechallenge. Retinal function was evaluated by electroretinography. Animals were killed 3, 6, 8, and 14 days after the initial intravitreal challenge and on the second day after rechallenge for aqueous leukocyte count, protein measurement, and histologic examination. The number of aqueous and peripheral blood proliferating lymphocytes and the subset of CD4+ T cells were determined by flow cytometry. High-performance liquid chromatography was used to measure cyclosporine A levels in vitreous and peripheral blood. Light microscopy was used to evaluate the eyes histopathologically. By clinical criteria, treated eyes had significantly less inflammation than untreated eyes. The number of aqueous cells and protein concentration determined quantitatively paralleled the clinical assessment of anterior chamber cells and flare. The electroretinography B-wave was depressed significantly in untreated eyes compared with that of treated eyes (P < 0.02). Histopathologic examination results showed marked inflammation and tissue disorganization in untreated eyes, whereas cyclosporine-treated eyes had preserved architecture and greatly reduced inflammatory cells. Intravitreal cyclosporine remained at therapeutic levels for at least 6 months after intravitreal device implantation, whereas blood levels were low to nondetectable. The intravitreal cyclosporine A device effectively suppresses ocular inflammation in a rabbit model of uveitis. This device may be useful in the treatment of patients with severe chronic uveitis who are intolerant to currently available therapies.