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      Emerging Therapies for Noninfectious Uveitis: What May Be Coming to the Clinics

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          Abstract

          Corticosteroids along with other immunomodulatory therapies remain as the mainstay of treatment tor all patients with noninfectious uveitis (NIU). However, the systemic side effects associated with the long-term use of these drugs has encouraged the development of new therapeutic agents in recent times. This review article discusses upcoming therapeutic agents and drug delivery systems that are currently being used to treat patients with NIU. These agents mediate their actions by blocking specific pathways involved in the inflammatory process. Agents discussed in this review include full or recombinant monoclonal antibodies against interleukins such as IL-17 (secukinumab), IL-l (gevokizumab), and IL-6 (tocilizumab and sarilumab), antibody fragments against inflammatory cytokines such as TNF- α (ESBA 105) and T-cell inhibitors such as fusion proteins (abatacept), and next generation calcineurin inhibitors (voclosporin). In addition, administration of immune modulatory therapies using methods such as iontophoresis (EGP-437) and intravitreal injection (sirolimus) for the treatment of NIU' uveitis has also been discussed.

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          Effects of AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheumatoid arthritis, and uveitis.

          Wolfgang Hueber, Dhavalkumar Patel, Thaddeus Dryja … (2010)
          Interleukin-17A (IL-17A) is elaborated by the T helper 17 (T(H)17) subset of T(H) cells and exhibits potent proinflammatory properties in animal models of autoimmunity, including collagen-induced arthritis, experimental autoimmune encephalomyelitis, and experimental autoimmune uveitis. To determine whether IL-17A mediates human inflammatory diseases, we investigated the efficacy and safety of AIN457, a human antibody to IL-17A, in patients with psoriasis, rheumatoid arthritis, and chronic noninfectious uveitis. Patients with chronic plaque-type psoriasis (n = 36), rheumatoid arthritis (n = 52), or chronic noninfectious uveitis (n = 16) were enrolled in clinical trials to evaluate the effects of neutralizing IL-17A by AIN457 at doses of 3 to 10 mg/kg, given intravenously. We evaluated efficacy by measuring the psoriasis area and severity index (PASI), the American College of Rheumatology 20% response (ACR20) for rheumatoid arthritis, or the number of responders for uveitis, as defined by either vision improvement or reduction in ocular inflammation or corticosteroid dose. AIN457 treatment induced clinically relevant responses of variable magnitude in patients suffering from each of these diverse immune-mediated diseases. Variable response rates may be due to heterogeneity in small patient populations, differential pathogenic roles of IL-17A in these diseases, and the different involvement or activation of IL-17A-producing cells. The rates of adverse events, including infections, were similar in the AIN457 and placebo groups. These results support a role for IL-17A in the pathophysiology of diverse inflammatory diseases including psoriasis, rheumatoid arthritis, and noninfectious uveitis.
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            Secukinumab in the treatment of noninfectious uveitis: results of three randomized, controlled clinical trials.

            Ilknur Tugal-Tutkun, Manfred Zierhut, J. Foster … (2013)
            To determine the efficacy and safety of different doses of secukinumab, a fully human monoclonal antibody for targeted interleukin-17A blockade, in patients with noninfectious uveitis. Three multicenter, randomized, double-masked, placebo-controlled, dose-ranging phase III studies: SHIELD, INSURE, and ENDURE. A total of 118 patients with Behçet's uveitis (SHIELD study); 31 patients with active, noninfectious, non-Behçet's uveitis (INSURE study); and 125 patients with quiescent, noninfectious, non-Behçet's uveitis (ENDURE study) were enrolled. After an initial subcutaneous (s.c.) loading phase in each treatment arm, patients received s.c. maintenance therapy with secukinumab 300 mg every 2 weeks (q2w), secukinumab 300 mg monthly (q4w), or placebo in the SHIELD study; secukinumab 300 mg q2w, secukinumab 300 mg q4w, secukinumab 150 mg q4w, or placebo in the INSURE study; or secukinumab 300 mg q2w, secukinumab 300 mg q4w, secukinumab 150 mg q4w, or placebo in the ENDURE study. Reduction of uveitis recurrence or vitreous haze score during withdrawal of concomitant immunosuppressive medication (ISM). Other end points included best-corrected visual acuity, ISM use (expressed as a standardized ISM score), and safety outcomes. After completion or early termination of each trial, there were no statistically significant differences in uveitis recurrence between the secukinumab treatment groups and placebo groups in any study. Secukinumab was associated with a significant reduction in mean total post-baseline ISM score (P = 0.019; 300 mg q4w vs. placebo) in the SHIELD study. Likewise, secukinumab was associated with a greater median reduction in ISM score versus placebo in the INSURE study, although no statistical analysis of the difference was conducted because of the small sample size. Overall, there was no loss in visual acuity reported in any treatment group during follow-up in all 3 studies. According to descriptive safety statistics, the frequencies of ocular and nonocular adverse events seemed to be slightly higher among secukinumab groups versus placebo across the 3 studies. The primary efficacy end points of the 3 studies were not met. The secondary efficacy data from these studies suggest a beneficial effect of secukinumab in reducing the use of concomitant ISM. Copyright © 2013 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.
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              Upregulated IL-23 and IL-17 in Behçet patients with active uveitis.

              Wei Chi, Xuefei Zhu, Peizeng Yang … (2008)
              Behçet disease (BD) is a systemic inflammatory disease presumably caused by an autoimmune response. The interleukin (IL)-23/IL-17 pathway has been demonstrated to be involved in the development and maintenance of certain inflammatory diseases. This study was designed to investigate the role of IL-23 and IL-17 in BD. IL-23p19 mRNA in peripheral blood mononuclear cells (PBMCs) was examined using RT-PCR. The levels of IL-23, IL-17, and IFN-gamma in sera or PBMCs were detected by ELISA. Flow cytometry was used to evaluate the frequencies of IL-17-producing and IFN-gamma-producing T cells and the expression of CD45RO. Results showed that the expression of IL-23p19 mRNA, IL-23, IL-17, and IFN-gamma was markedly elevated in BD patients with active uveitis. The frequencies of IL-17-producing and IFN-gamma-producing T cells from PBMCs were significantly upregulated in BD patients with active uveitis. The increased IL-17 (3.10% +/- 0.53%) in BD patients with active uveitis was primarily produced by CD45RO(+) memory T cells. Recombinant (r) IL-23 could upregulate IL-17 production by polyclonally stimulated PBMCs, whereas interferon (IFN)-gamma downregulated IL-17 production. These findings reveal that the levels of IL-23, IL-17, and IFN-gamma are elevated in BD patients with active uveitis, and they suggest that the IL-23/IL-17 pathway together with IFN-gamma is associated with the active intraocular inflammation in BD patients.
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Ophthalmol
                Journal ID (iso-abbrev): J Ophthalmol
                Journal ID (publisher-id): JOPH
                Title: Journal of Ophthalmology
                Publisher: Hindawi Publishing Corporation
                ISSN (Print): 2090-004X
                ISSN (Electronic): 2090-0058
                Publication date (Print): 2014
                Publication date (Electronic): 24 April 2014
                Volume: 2014
                Electronic Location Identifier: 310329
                Affiliations
                Ocular Imaging Research and Reading Center, Stanley M. Truhlsen Eye Institute, University of Nebraska Medical Center, 3902 Leavenworth Street, 985540 Nebraska Medical Center, Omaha, NE 68198-5540, USA
                Author notes
                *Quan Dong Nguyen: quan.nguyen@ 123456unmc.edu

                Academic Editor: Manfred Ziehrut

                Article
                DOI: 10.1155/2014/310329
                PMC ID: 4020293
                PubMed ID: 24868451
                SO-VID: 85ac5f73-1dc7-4fc7-bb65-d9c50c7872f8
                Copyright © Copyright © 2014 Jose R. Maya et al.
                License:

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 16 January 2014
                Date revision received : 25 March 2014
                Date accepted : 25 March 2014
                Categories
                Subject: Review Article

                ScienceOpen disciplines: Ophthalmology & Optometry
                Data availability:
                ScienceOpen disciplines: Ophthalmology & Optometry

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