Local Therapies for Inflammatory Eye Disease

Abstract and Introduction

Abstract

Despite their side-effects and the advent of systemic immunosuppressives and biologics, the use of corticosteroids remains in the management of patients with uveitis, particularly when inflammation is associated with systemic disease or when bilateral ocular disease is present. The use of topical corticosteroids as local therapy for anterior uveitis is well-established, but periocular injections of corticosteroid can also be used to control mild or moderate intraocular inflammation. More recently, intraocular corticosteroids such as triamcinolone and steroid-loaded vitreal inserts and implants have been found to be effective, including in refractory cases. Additional benefits are noted when ocular inflammation is unilateral or asymmetric, when local therapy may preclude the need to increase the systemic medication.

Implants in particular have gained prominence with evidence of efficacy including both dexamethasone and fluocinolone loaded devices. However, an appealing avenue of research lies in the development of non-corticosteroid drugs in order to avoid the side-effects that limit the appeal of injected corticosteroids. Several existing drugs are being assessed, including anti-VEGF compounds such as ranibizumab and bevacizumab, anti-tumour necrosis factor alpha antibodies such as infliximab, as well as older cytotoxic medications such as methotrexate and cyclosporine, with varying degrees of success. Intravitreal sirolimus is currently undergoing phase 3 trials in uveitis and other inflammatory pathways have also been proposed as suitable therapeutic targets. Furthermore, the advent of biotechnology is seeing advances in generation of new therapeutic molecules such as high affinity binding peptides or modified high affinity or bivalent single chain Fab fragments, offering higher specificity and possibility of topical delivery.

Introduction

Inflammatory eye disease encompasses a wide range of clinical phenotypes, and uveitis can be classified anatomically into either anterior, intermediate and posterior uveitis or panuveitis; and as acute or chronic disease, depending on whether it lasts more or less than 3 months in duration.^[1] The Standardisation of Uveitis Nomenclature (SUN) criteria now form the standard for reporting uveitis clinical data.^[2] The commonest type is acute anterior uveitis, in which 50% of people are HLA B27 positive, although they do not necessarily have an associated systemic disorder.^[3] Chronic anterior uveitis lasts longer than 3 months and may or may not be associated with systemic disease. The rest of the disorders tend to be chronic, and the more serious types with posterior segment involvement have an increased incidence of visual loss, and approximately half of these patients have an associated systemic disease.

Corticosteroids remain the mainstay of treatment of all types of uveitis. Anterior uveitis is treated to control symptoms of pain, photophobia and redness, and to reduce complications such as posterior synechiae, cataract and macular oedema. Posterior segment inflammation usually requires treatment as it generates sight-threatening sequelae such as retinitis, macular oedema, optic disc oedema, chorioretinitis and retinal vasculitis. Topical corticosteroids are inadequate for this as they do not penetrate beyond the lens, so oral corticosteroids and second-line immunosuppressive agents are used, particularly in patients with an associated systemic disease and in those with bilateral ocular inflammation requiring treatment. Nevertheless, systemic administration is associated with significant side-effects, so there has been increasing interest in the local delivery of drugs to the eye and periocular tissues in order to avoid these complications.

This approach is not new. Traditionally, periocular injections of corticosteroids such as triamcinolone and methlyprednisolone have proved effective in controlling vitritis and mild to moderate macular edema in unilateral disease, but their use is limited by the need for repeat injections, IOP rises in corticosteroid responders and the induction of ptosis, orbital fat atrophy or orbital fat protrusion as a consequence of both the corticosteroid and the mode of injection.^[4,5] More recently, intraocular delivery of corticosteroids has become widespread. Initially triamcinolone was used, but long-acting inserts are now becoming available, e.g. Retisert (Bausch & Lomb, Rochester, NY, USA) and Ozurdex (Allergan, Irvine, CA, USA).

Nevertheless, the local side-effects of corticosteroid delivery remain. Care also needs to be taken in cases of diagnostic uncertainty to ensure that there is not an infective cause for the uveitis, as this may be worsened by local therapy and depot corticosteroids can be difficult to remove, whereas oral corticosteroids can be rapidly stopped.

Owing to these side-effects, researchers have tried to move towards new non-corticosteroid alternatives. Some of these are old drugs, such as methotrexate, and others are based on the new so-called biological agents, in which monoclonal antibodies are directed against specific targets within the immune system, such as the anti-tumour necrosis factor (TNF)-alpha agents and the anti-vascular endothelial growth factor (VEGF) agents. This review article aims to outline agents currently in use for the local therapy of non-infectious uveitis, as well as those currently in translation from the laboratory to clinical use.