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New agents may revolutionize treatment of uveitis
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Uveitis can be infectious or noninfectious. The most common form of noninfectious uveitis is secondary to surgical or accidental trauma, and every ophthalmologist is familiar with its treatment of topical, subconjunctival or intraocular steroids and NSAIDs. The other forms of noninfectious uveitis include a heterogenous collection of diseases affecting the uveal tract that are usually autoimmune in etiology.
A useful classification for me is to divide autoimmune uveitis into anterior (iridocyclitis), intermediate (pars planitis), posterior (vitreitis, choroiditis and retinitis) and panuveitis in which all regions of the eye are involved. Anterior uveitis accounts for about two-thirds of cases and in general responds better to treatment with less potential for blindness.
The incidence of uveitis is approximately one per 4,500, which would generate about 80,000 cases per year in the U.S. and 1.6 million worldwide. Uveitis can cause significant collateral ocular tissue damage through cell and tissue destruction caused by inflammation mediated by neutrophils, macrophages, T cells and their associated cytokines. The tissues at risk for damage include the corneal endothelium with potential bullous keratopathy, the trabecular meshwork with potential secondary glaucoma, the natural lens with potential secondary cataract, and the choroid and retina with the potential for macular edema or retinitis/vasculitis with retinal necrosis.
Uveitis is often undertreated by the ophthalmologist, making it the fourth leading cause of blindness in the U.S. While the treatments for uveitis have the potential for side effects, studies confirm that it is in the patient’s best interest to treat uveitis aggressively and then manage the side effects of treatment as needed.
Many of us who trained 30 or more years ago received rudimentary training in immunology when compared with our younger colleagues. A brief review was helpful in my understanding of this group of diseases.
Cytokines are proteins that are secreted by cells and serve as signaling molecules, basically telling a cell how to act. As we all know, our natural immune system, including the traditional and the complementary pathway of inflammation generation, is required for us to survive in what is arguably a hostile external environment.
However, we do not want to turn our bodies’ killer cells on when all is OK and there is no external threat, such as an invading microorganism or a cancerous cell. Our killer cells include lymphocytes, especially the so-called T cells, polymorphonuclear leukocytes including neutrophils, eosinophils and basophils, and macrophages. In the normal state, these killer cells are held in check by a group of cytokines produced in the eye by dendritic cells and microglia. In particular, transforming growth factors (TGF), especially TGF-alpha and TGF-beta, are cytokines that respectively induce or suppress inflammation by controlling cellular proliferation, differentiation and migration. In addition, interleukins, of which there are 36 named to date, also serve as cytokines (secreted proteins) that are signaling messengers for the immune system to either turn on or turn off.
In an autoimmune disease such as uveitis, the inflammatory cascade is inappropriately turned on for one reason or another — in some cases secondary to a systemic disease process such as rheumatoid arthritis, in others related to a genetic predisposition, such as HLA-B27 (anterior uveitis), HLA-B29 (birdshot chorioretinopathy) or HLA-B51 (Behçet’s disease), and in many for no discernible reason (idiopathic).
The goal of therapy in acute uveitis is to rapidly eliminate intraocular inflammation in order to prevent collateral intraocular tissue damage and permanent vision loss. If recurrent and acute, the goal is the same: Suppress inflammation as rapidly as possible. In chronic uveitis, it is often impossible to completely eradicate all signs of inflammation, as permanent damage occurs to blood vessels secondary to immune-mediated vasculitis. In these cases, a mild residual flare representing protein in the eye and an occasional cell, usually graded as trace or less, must often be tolerated.
The treatment is local ocular or systemic immunosuppression with anti-inflammatory medications, usually steroids, anti-metabolites, T cell suppressants, cycloplegic agents and occasionally an NSAID. As mentioned in the cover story, we have many effective agents in all these classes.
I like to treat any intraocular inflammation aggressively and find anterior uveitis to be a good indication for frequent application of our most potent steroid, difluprednate, at a regimen of every 2 hours to start. My preferred cycloplegic is 5% homatropine given two to four times daily. If subconjunctival injections are necessary, I usually use triamcinolone acetate. If the patient has intermediate, posterior or panuveitis, I prefer to refer them to a specialist who is comfortable with the use of long-term oral steroids, intraocular steroids and antimetabolites. Limiting myself to the treatment of anterior uveitis, these agents are rarely needed, and if they are, I again refer.
It is important to remember to rule out the more common associated diseases, either alone or in collaboration with the patient’s personal physician. These include HLA-B27, ankylosing spondylitis and systemic autoimmune diseases such as rheumatoid arthritis, lupus erythematosus, sarcoid and the like. In addition, syphilis, toxoplasmosis, tuberculosis, herpes simplex and herpes zoster can cause uveitis and require targeted systemic therapy. Fuchs’ heterochromic iridocyclitis sometimes requires a walk to a window where natural lighting helps highlight the differences in iris color from one eye to the other.
Ruling in or out systemic disease entities is something I prefer to delegate because they require a panel of blood tests, X-rays and, in some cases, tissue biopsy. An interested personal physician, rheumatologist or uveitis specialist is, in my opinion, better suited to diagnose and, if necessary, treat these diseases.
Many companies are investigating cytokine inhibitors that might, if effective, revolutionize the treatment of severe intermediate, posterior and panuveitis in a fashion similar to the impact of anti-VEGF agents on wet age-related macular degeneration. Promising treatments include several agents that impact the complement pathway of inflammation, especially C5 factor inhibitors, as well as several molecules that interact with TGF or interleukins.
Many drugs are already on the market to treat systemic autoimmune systemic diseases, but none are approved for local therapy in the eye. As in so many categories, there remain many major unmet needs in the field of uveitis treatment. It is incumbent on all of us to support investment in the innovation cycle and encourage the collaboration between research scientists, clinicians, industry and our regulatory agencies that is required to bring a new treatment for uveitis from bench to bedside.