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  • Uveitis

    Introduction

    In the last decade, there has been an explosion of interest in and development of biologic therapies for the treatment of inflammatory diseases. Much of the effort, and a commensurate majority of the FDA approvals, has been directed toward developing better treatments of common inflammatory diseases such as rheumatoid arthritis. However, off-label use of biologics for other putative autoimmune diseases, including ocular diseases, has gained rapid popularity. Treatment of inflammatory ocular disease with corticosteroids and immunosuppressive agents has been widely reported to prevent ocular morbidity and improve quality of life; however, long-term effectiveness may be limited by potential toxicity, and none are universally effective. In this review the authors will summarize the biologic therapies that recently have been studied as alternatives for refractory inflammatory eye diseases,1 including uveitis, retinal vasculitis, scleritis, orbital inflammatory diseases, and ocular cicatricial pemphigoid.

    Biologics Overview

    Biologics are defined as proteins produced by recombinant DNA or monoclonal antibody technology that are used therapeutically based on the understanding of the molecular mechanism of disease. Monoclonal antibodies (mAb), when used as medications, are given a generic name ending in -mab. An antecedent u (-umab) indicates a human antibody; and xi (-ximab) indicates a chimeric, or mixed human-animal antibody. Generally speaking, antibodies created fully or in part from nonhuman DNA are more likely to cause hypersensitivity reactions than human-derived antibodies and are also more likely to lead to the creation of neutralizing antibodies. This definition does not encompass other naturally occurring molecules such as intravenous immunoglobulin, which have been included under this heading in some literature.

    As previously noted, the available biologic agents act on different immunologic targets; although most have been studied for rheumatoid arthritis, there is variability in their approved indications. Examples of systemic biologics and their properties including the FDA approval data for systemic indications and side effects are briefly discussed in Table 1.

    Table created by Sirichai Pasadhika, M.D. and Eric B. Suhler, M.D., M.P.H.
    Table 1 shows examples of biologics and their properties and systemic indications approved by the United States Food and Drug Administration (as of 03/12/2008)

    The most commonly used biologics to date are tumor necrosis factor (TNF) inhibitors, including infliximab, etanercept, and adalimumab. Class effects of TNF blockers prominently include risk of serious infection, most significantly including reactivation of tuberculosis, and potential increased risks of malignancy. Both of these side effects appeared to be dose-related. Other uncommon but potentially severe side effects are initiation or worsening of demyelinating disease, thromboembolic events, congestive heart failure, and lupus-like syndrome. Infliximab is a chimeric mouse-human monoclonal antibody, and adalimumab is fully human. Etanercept is a dimeric fusion protein that links soluble human TNF-α receptor to the Fc component of human immunoglobulin G1 (IgG1). Infliximab is given intravenously and can cause infusion reactions; however, these are mild and usually treatable with antihistamines and/or corticosteroids. Etanercept and adalimumab are administered by subcutaneous injection, and may cause self-limited inflammatory responses at the injection site.1

    Other biologics can also cause drug reactions, flu-like symptoms, gastrointestinal side effects, and also may increase risk of malignancy and infection. A comprehensive review of toxicity is beyond the scope of this article, however, Natalizumab, which blocks an integrin molecule vital to leukocyte diapedesis into inflamed tissues, has been shown to contribute to the development of progressive multifocal leukoencephalopathy, which has limited its widespread popularity for the treatment of multiple sclerosis.

    Biologics for Ocular Inflammatory Diseases

    Biologics are relatively new medications in the treatment of systemic inflammatory disease, and data on efficacy for ophthalmic indications are limited and based primarily on interventional or retrospective case series; these reports are summarized in Table 2. TNF inhibitors are by far the most commonly studied biologics for eye diseases at this writing. Clinical trials are ongoing for many biologics, and they may be found on websites such as www.clinicaltrials.gov; they are reported here as the authors are aware.

    Table created by Sirichai Pasadhika, M.D. and Eric B. Suhler, M.D., M.P.H.
    Table 2. Reports on the use of biologic therapies in ocular inflammatory conditions (as of 03/12/2008)

    Noninfectious Uveitis
    Infliximab has been shown to be a rapid, effective, and safe therapy of vision-threatening ocular inflammation in Behcet's disease and various refractory uveitides. In 2005, the authors published results from the first 23 patients with diverse uveitis diagnoses enrolled in our prospective, phase II clinical trial on infliximab for refractory autoimmune uveitis. Seventy-eight percent of subjects met criteria for clinical success, which was judged by the composite clinical outcome of visual acuity, control of inflammation, ability to taper concomitant medication, and improvement on fluorescein angiography and/or optical coherence tomography. The high initial success was tempered by a higher frequency of severe toxicity than other published series.2 Longer term follow-up after the study completed in December 2006 has supported the observations of sustained efficacy in selected patients.

    Etanercept has also been studied for ophthalmic indications. There are no randomized clinical trials to date comparing infliximab with etanercept for the treatment of uveitis.  However, based on retrospective analysis, etanercept appears to be less effective for the treatment of intraocular ocular inflammation than infliximab.3 Moreover, a possible increase in uveitis in susceptible patients taking etanercept has been postulated, although definite causation has not been shown. Limited reports on adalimumab have indicated promise in the treatment of refractory childhood uveitis,4 and a Phase II, multicenter, prospective clinical trial of adalimumab for the treatment of refractory noninfectious uveitis in adults is ongoing. Clinically, the dose and frequency of administration of infliximab can be modified in more variable range than those of etanercept and adalimumab.

    Daclizumab, an interleukin-2 (IL-2) receptor antagonist, is given intravenously for treatment of solid organ transplant rejection, and was effective and safe in the treatment of 7/10 refractory uveitis patients with 4 years' follow-up, with similar success seen in a pilot study of subcutaneous administration.5 No benefit was found in a randomized study for Behcet's uveitis.6 Case reports supporting benefits of anakinra and rituximab for uveitis treatment have been published. Prospective clinical trials of efalizumab, which blocks CD11a, a molecule expressed by all leukocytes, for noninfectious intermediate uveitis and posterior uveitis with macular edema, and of daclizumab for active anterior uveitis associated with juvenile idiopathic arthritis (JIA) are ongoing at the National Eye Institute. Efficacy of other biologics for uveitis are essentially unstudied, though the authors list selected molecules of potential high interest for future trials in the Table 1 and Table 2.

    Scleritis and Orbital Inflammatory Disease
    Based on several small case series, infliximab,7 etanercept,8 the IL-1 receptor blocker anakinra,9 and the B-cell blocker rituximab10 may be effective to treat scleritis with and without peripheral keratopathy. Similar case series reporting efficacy of infliximab,11 etanercept,12 adalimumab,13 and rituximab for the treatment of orbital inflammatory diseases, including thyroid-related orbitopathy, granulomatosis with polyangiitis (formerly Wegener's granulomatosis), and idiopathic orbital inflammation. In one case report, daclizumab was also an effective treatment for orbital myositis.14 An open-label, phase I/II study of the rituximab for scleritis and orbital inflammatory disease, which depletes B cells by binding the pan-B-cell antigen (CD20), is currently underway at the authors' institution, with promising early results in some patients.

    Ocular Cicatricial Pemphigoid
    Ocular cicatricial pemphigoid (OCP) is a rare but potentially devastating immune-mediated disease affecting the ocular surface. There are limited data on the role of biologics for OCP; however, etanercept and daclizumab have been suggested to be effective in some reports.

    Summary

    New biologic therapies are appearing at an exponential rate, and will continue to do so as our understanding of immune processes and pathophysiology improves and is capitalized upon by the pharmaceutical industry. These drugs will continue to provide new options for the treatment of ocular inflammatory diseases, and it is expected that in the years to come, many similar reviews such as this will be able to be written with exciting new data from the authors' and others' ongoing studies, hopefully revealing targeted therapies with more favorable toxic/therapeutic indices. Given limited data on efficacy and long-term safety, as well as cost, the authors reserve these treatments for patients with recalcitrant diseases that are refractory or intolerant to immunosuppressive therapy.

    References

    1.   Lim L, Suhler EB, Smith JR. Biologic therapies for inflammatory eye disease. Clin Experiment Ophthalmol. 2006;34(4):365-374.

    2.   Suhler EB, Smith JR, Wertheim MS, et al. A prospective trial of infliximab therapy for refractory uveitis: preliminary safety and efficacy outcomes. Arch Ophthalmol. 2005;123(7):903-912.

    3.   Galor A, Perez VL, Hammel JP, Lowder CY. Differential effectiveness of etanercept and infliximab in the treatment of ocular inflammation. Ophthalmology. 2006;113(12):2317-2323.

    4.   Biester S, Deuter C, Michels H, et al. Adalimumab in the therapy of uveitis in childhood. Br J Ophthalmol. 2007;91(3):319-324.

    5.   Nussenblatt RB, Peterson JS, Foster CS, et al. Initial evaluation of subcutaneous daclizumab treatments for noninfectious uveitis: a multicenter noncomparative interventional case series. Ophthalmology. 2005;112(5):764-770.

    6.   Buggage RR, Levy-Clarke G, Sen HN, et al. A double-masked, randomized study to investigate the safety and efficacy of daclizumab to treat the ocular complications related to Behcet's disease. Ocul Immunol Inflamm. 2007;15(2):63-70.

    7.   Murphy CC, Ayliffe WH, Booth A, et al. Tumor necrosis factor alpha blockade with infliximab for refractory uveitis and scleritis. Ophthalmology. 2004;111(2):352-356.

    8.   Hernandez-Illas M, Tozman E, Fulcher SF, et al. Recombinant human tumor necrosis factor receptor Fc fusion protein (Etanercept): experience as a therapy for sight-threatening scleritis and sterile corneal ulceration. Eye Contact Lens. 2004;30(1):2-5.

    9.   Botsios C, Sfriso P, Ostuni PA, et al. Efficacy of the IL-1 receptor antagonist, anakinra, for the treatment of diffuse anterior scleritis in rheumatoid arthritis. Report of two cases. Rheumatology (Oxford). 2007;46(6):1042-1043.

    10. Cheung CM, Murray PI, Savage CO. Successful treatment of Wegener's granulomatosis associated scleritis with rituximab. Br J Ophthalmol. 2005;89(11):1542.

    11. Garrity JA, Coleman AW, Matteson EL, et al. Treatment of recalcitrant idiopathic orbital inflammation (chronic orbital myositis) with infliximab. Am J Ophthalmol. 2004;138(6):925-930.

    12. Paridaens D, van den Bosch WA, van der Loos TL, et al. The effect of etanercept on Graves' ophthalmopathy: a pilot study. Eye. 2005;19(12):1286-1289.

    13. Adams AB, Kazim M, Lehman TJ. Treatment of orbital myositis with adalimumab (Humira). J Rheumatol. 2005;32(7):1374-1375.

    14. Garcia-Pous M, Hernandez-Garfella ML, Diaz-Llopis M. Treatment of chronic orbital myositis with daclizumab. Can J Ophthalmol. 2007;42(1):156-157.

    Author Disclosure

    Dr. Pasadhika states that he has no financial relationship with the manufacturer or provider of any product or service discussed in this article or with the manufacturer or provider of any competing product or service.

    Dr. Suhler has received research support from Genentech, LuxBio, Abbott, and Centocor.