378
Views
3
CrossRef citations to date
0
Altmetric
Reviews

Moving forward in uveitis therapy: preclinical to phase II clinical trial drug development

, &
Pages 195-214 | Received 20 Oct 2015, Accepted 02 Dec 2015, Published online: 30 Dec 2015

References

  • Papers of special note have been highlighted as: • of interest •• of considerable interest
  • Larson T, Nussenblatt RB, Sen HN. Emerging drugs for uveitis. Expert Opin Emerg Drugs. 2011;16(2):309–322.

•• An exhaustive description of the current and future treatments of uveítis.

  • Lyon F, Gale RP, Lightman S. Recent developments in the treatment of uveitis: an update. Expert Opin Investig Drugs. 2009;18(5):609–616.
  • Acharya NR, Tham VM, Esterberg E, et al. Incidence and prevalence of uveitis: results from the pacific ocular inflammation study. JAMA Ophthalmol. 2013;131(11):1405–1412.
  • Gritz DC, Wong IG. Incidence and prevalence of uveitis in Northern California; the Northern California epidemiology of uveitis study. Ophthalmology. 2004;111(3):491–500. discussion 500
  • Tan LT, Isa H, Lightman S, et al. Prevalence and causes of phthisis bulbi in a uveitis clinic. Acta Ophthalmol. 2012;90(5):e417–8.
  • Suttorp-Schulten MS, Rothova A. The possible impact of uveitis in blindness: a literature survey. Br J Ophthalmol. 1996;80(9):844–848.
  • Nussenblatt RB. The natural history of uveitis. Int Ophthalmol. 1990;14(5–6):303.
  • Kim JS, Knickelbein JE, Nussenblatt RB, et al. Clinical trials in noninfectious uveitis. Int Ophthalmol Clin. 2015;55(3):79–110.

•• A very complete description of ongoing clinical trials in non-infectious uveitis with brief summaries of their most important results.

  • Lee RWJ, Dick AD. Current concepts and future directions in the pathogenesis and treatment of non-infectious intraocular inflammation. Eye. 2012;26(1):17–28.

• Schematic approach to future directions in uveitis treatment.

•• Comprehensive review for the understanding of the underlying immunomediated mechanisms in uveitis.

  • Gasparin F, Takahashi BS, Scolari MR, et al. Experimental models of autoimmune inflammatory ocular diseases. Arq Bras Oftalmol. 2012;75(2):143–147.
  • Commodaro AG, Bueno V, Belfort R, et al. Autoimmune uveitis: the associated proinflammatory molecules and the search for immunoregulation. Autoimmun Rev. 2011;10(4):205–209.
  • Jabs DA, Nussenblatt RB, Rosenbaum JT. Standardization of Uveitis Nomenclature (SUN) working group. Standardization of uveitis nomenclature for reporting clinical data. Results of the first international workshop. Am J Ophthalmol. 2005;140(3):509–516.
  • Khairallah M. Are the Standardization of the Uveitis Nomenclature (SUN) working group criteria for codifying the site of inflammation appropriate for all uveitis problems? Limitations of the SUN working group classification. Ocul Immunol Inflamm. 2010;18(1):2–4.
  • Lin P, Suhler EB, Rosenbaum JT. The future of uveitis treatment. Ophthalmology. 2014;121(1):365–376.

•• Essential review of emerging options in uveitis therapy and their correlation with pathogenic mechanisms.

  • Hazirolan D, Pleyer U. Think global–act local: intravitreal drug delivery systems in chronic noninfectious uveitis. Ophthalmic Res. 2013;49(2):59–65.

• Mini-review that summarizes several important considerations about local therapies in uveítis.

  • Siddique SS, Shah R, Suelves AM, et al. Road to remission: a comprehensive review of therapy in uveitis. Expert Opin Investig Drugs. 2011;20(11):1497–1515.
  • Srivastava A, Rajappa M, Kaur J. Uveitis: Mechanisms and recent advances in therapy. Clin Chim Acta Int J Clin Chem. 2010;411(17–18):1165–1171.

• Brief summary about the correlation between basic research knowledge and recent advances in uveitis clinical therapy.

  • Heiligenhaus A, Thurau S, Hennig M, et al. Anti-inflammatory treatment of uveitis with biologicals: new treatment options that reflect pathogenetic knowledge of the disease. Graefes Arch Clin Exp Ophthalmol. 2010;248(11):1531–1551.

•• Complete overview of molecules that might play a critical role in uveitis and their clinical applications.

  • Giuliari GP, Sadaka A, Hinkle DM. Biologic agents in experimental autoimmune uveitis. Int Ophthalmol. 2014;34(1):145–156.
  • Agarwal RK, Silver PB, Caspi RR. Rodent models of experimental autoimmune uveitis. Methods Mol Biol. 2012;900:443–469.
  • Huber A, Diedrichs-Möhring M, Wildner G. Spontaneously relapsing-remitting experimental autoimmune uveitis in rats allows successful therapeutic oral tolerance induction in ongoing disease. Mol Immunol. 2015;63(2):215–226.
  • Horai R, Caspi RR. Cytokines in autoimmune uveitis. J Interferon Cytokine Res. 2011;31(10):733–744.

•• An essential review for the understanding of the role of cytokines in uveitis pathogenesis, specifically regarding Th1/Th17 cells

•• A review about the role of Th1/Th17 cells in experimental uveitis models.

  • Lee RW, Nicholson LB, Sen HN, et al. Autoimmune and autoinflammatory mechanisms in uveitis. Semin Immunopathol. 2014;36(5):581–594.
  • Touchard E, Omri S, Naud M-C, et al. A peptide inhibitor of c-Jun N-terminal kinase for the treatment of endotoxin-induced uveitis. Invest Ophthalmol Vis Sci. 2010;51(9):4683–4693.
  • Suzuki J, Manola A, Murakami Y, et al. Inhibitory effect of aminoimidazole carboxamide ribonucleotide (AICAR) on endotoxin-induced uveitis in rats. Invest Ophthalmol Vis Sci. 2011;52(9):6565–6571.
  • Suzuki J, Yoshimura T, Simeonova M, et al. Aminoimidazole carboxamide ribonucleotide ameliorates experimental autoimmune uveitis. Invest Ophthalmol Vis Sci. 2012;53(7):4158–4169.
  • Yu C-R, Mahdi RR, Oh H-M, et al. Suppressor of cytokine signaling-1 (SOCS1) inhibits lymphocyte recruitment into the retina and protects SOCS1 transgenic rats and mice from ocular inflammation. Invest Ophthalmol Vis Sci. 2011;52(9):6978–6986.
  • Lennikov A, Kitaichi N, Noda K, et al. Amelioration of endotoxin-induced uveitis treated with an IκB kinase β inhibitor in rats. Mol Vis. 2012;18:2586–2597.
  • Yu C-R, Lee YS, Mahdi RM, et al. Therapeutic targeting of STAT3 (signal transducers and activators of transcription 3) pathway inhibits experimental autoimmune uveitis. PloS One. 2012;7(1):e29742.
  • Yang X, Jin H, Liu K, et al. A novel peptide derived from human pancreatitis-associated protein inhibits inflammation in vivo and in vitro and blocks NF-kappa B signaling pathway. PloS One. 2011;6(12):e29155.
  • Kalariya NM, Shoeb M, Ansari NH, et al. Antidiabetic drug metformin suppresses endotoxin-induced uveitis in rats. Invest Ophthalmol Vis Sci. 2012;53(7):3431–3440.
  • Bousquet E, Camelo S, Leroux Les Jardins G, et al. Protective effect of intravitreal administration of tresperimus, an immunosuppressive drug, on experimental autoimmune uveoretinitis. Invest Ophthalmol Vis Sci. 2011;52(8):5414–5423.
  • Dong Z, Iwata D, Kitaichi N, et al. Amelioration of experimental autoimmune uveoretinitis by inhibition of glyceraldehyde-derived advanced glycation end-product formation. J Leukoc Biol. 2014;96(6):1077–1085.
  • Kanai K, Itoh N, Yoshioka K, et al. Inhibitory effects of oral disulfiram on endotoxin-induced uveitis in rats. Curr Eye Res. 2010;35(10):892–899.
  • Pereira DV, Petronilho F, Pereira HRSB, et al. Effects of gold nanoparticles on endotoxin-induced uveitis in rats. Invest Ophthalmol Vis Sci. 2012;53(13):8036–8041.
  • Lennikov A, Kitaichi N, Noda K, et al. Amelioration of endotoxin-induced uveitis treated with the sea urchin pigment echinochrome in rats. Mol Vis. 2014;20:171–177.
  • Kalariya NM, Shoeb M, Reddy ABM, et al. Prevention of endotoxin-induced uveitis in rats by plant sterol guggulsterone. Invest Ophthalmol Vis Sci. 2010;51(10):5105–5113.
  • Agarwal R, Gupta SK, Agarwal P, et al. Topically applied standardized aqueous extract of Curcuma longa Linn. suppresses endotoxin-induced uveal inflammation in rats. Indian J Exp Biol. 2013;51(10):797–803.
  • Gardner PJ, Joshi L, Lee RWJ, et al. SIRT1 activation protects against autoimmune T cell-driven retinal disease in mice via inhibition of IL-2/Stat5 signaling. J Autoimmun. 2013;42:117–129.
  • Silver PB, Silver P, Horai R, et al. Retina-specific T regulatory cells bring about resolution and maintain remission of autoimmune uveitis. J Immunol. 2015;194(7):3011–3019.
  • Haruta H, Ohguro N, Fujimoto M, et al. Blockade of interleukin-6 signaling suppresses not only th17 but also interphotoreceptor retinoid binding protein-specific Th1 by promoting regulatory T cells in experimental autoimmune uveoretinitis. Invest Ophthalmol Vis Sci. 2011;52(6):3264–3271.
  • Keino H, Watanabe T, Sato Y, et al. Oral administration of retinoic acid receptor-alpha/beta-specific ligand Am80 suppresses experimental autoimmune uveoretinitis. Invest Ophthalmol Vis Sci. 2011;52(3):1548–1556.
  • Wang R-X, Yu C-R, Dambuza IM, et al. Interleukin-35 induces regulatory B cells that suppress autoimmune disease. Nat Med. 2014;20(6):633–641.
  • Tasso R, Ilengo C, Quarto R, et al. Mesenchymal stem cells induce functionally active T-regulatory lymphocytes in a paracrine fashion and ameliorate experimental autoimmune uveitis. Invest Ophthalmol Vis Sci. 2012;53(2):786–793.
  • Oh JY, Kim TW, Jeong HJ, et al. Intraperitoneal infusion of mesenchymal stem/stromal cells prevents experimental autoimmune uveitis in mice. Mediators Inflamm. 2014;2014:624640.
  • Okunuki Y, Usui Y, Nakagawa H, et al. Peroxisome proliferator-activated receptor-γ agonist pioglitazone suppresses experimental autoimmune uveitis. Exp Eye Res. 2013;116:291–297.
  • Manickam B, Jha P, Matta B, et al. Inhibition of complement alternative pathway suppresses experimental autoimmune anterior uveitis by modulating T cell responses. J Biol Chem. 2011;286(10):8472–8480.
  • Rao NA, Saraswathy S, Pararajasegaram G, et al. Small heat shock protein αA-crystallin prevents photoreceptor degeneration in experimental autoimmune uveitis. PloS One. 2012;7(3):e33582.
  • Chen S, Zhou S, Zang K, et al. CD73 expression in RPE cells is associated with the suppression of conventional CD4 cell proliferation. Exp Eye Res. 2014;127:26–36.
  • Oh K, Byoun O-J, Ham D-I, et al. Invariant NKT cells regulate experimental autoimmune uveitis through inhibition of Th17 differentiation. Eur J Immunol. 2011;41(2):392–402.
  • Ishida W, Fukuda K, Sakamoto S, et al. Regulation of experimental autoimmune uveoretinitis by anti-delta-like ligand 4 monoclonal antibody. Invest Ophthalmol Vis Sci. 2011;52(11):8224–8230.
  • Keles S, Halici Z, Atmaca HT, et al. The ocular endothelin system: a novel target for the treatment of endotoxin-induced uveitis with bosentan. Invest Ophthalmol Vis Sci. 2014;55(6):3517–3524.
  • Sande PH, Dorfman D, Fernandez DC, et al. Treatment with melatonin after onset of experimental uveitis attenuates ocular inflammation. Br J Pharmacol. 2014;171(24):5696–5707.
  • Schreck R, Meier B, Männel DN, et al. Dithiocarbamates as potent inhibitors of nuclear factor kappa B activation in intact cells. J Exp Med. 1992;175(5):1181–1194.
  • Kanai K, Itoh N, Ito Y, et al. Anti-inflammatory potency of oral disulfiram compared with dexamethasone on endotoxin-induced uveitis in rats. J Vet Med Sci Jpn Soc Vet Sci. 2011;73(4):517–520.
  • Daudin J-B, Monnet D, Kavian N, et al. Protective effect of pristane on experimental autoimmune uveitis. Immunol Lett. 2011;141(1):83–93.
  • Yadav UCS, Shoeb M, Srivastava SK, et al. Aldose reductase deficiency protects from autoimmune- and endotoxin-induced uveitis in mice. Invest Ophthalmol Vis Sci. 2011;52(11):8076–8085.
  • Kuno N, Fujii S. Biodegradable intraocular therapies for retinal disorders: progress to date. Drugs Aging. 2010;27(2):117–134.
  • Lobo A-M, Sobrin L, Papaliodis GN. Drug delivery options for the treatment of ocular inflammation. Semin Ophthalmol. 2010;25(5–6):283–288.
  • Suresh PK, Sah AK. Nanocarriers for ocular delivery for possible benefits in the treatment of anterior uveitis: focus on current paradigms and future directions. Expert Opin Drug Deliv. 2014;11(11):1747–1768.

• Comprehensive review about the potential benefits of treatment of uveitis with nanocarriers

  • Manna S, Banerjee RK, Augsburger JJ, et al Biodegradable chitosan and polylactic acid-based intraocular micro-implant for sustained release of methotrexate into vitreous: analysis of pharmacokinetics and toxicity in rabbit eyes. Graefes Arch Clin Exp Ophthalmol. 2015;253(8):1297–1305.
  • Ang M, Ng X, Wong C, et al. Evaluation of a prednisolone acetate-loaded subconjunctival implant for the treatment of recurrent uveitis in a rabbit model. PloS One. 2014;9(5):e97555.
  • Li W, He B, Dai W, et al. Evaluations of therapeutic efficacy of intravitreal injected polylactic-glycolic acid microspheres loaded with triamcinolone acetonide on a rabbit model of uveitis. Int Ophthalmol. 2014;34(3):465–476.
  • Souza MCM, Fialho SL, Souza PAF, et al. Tacrolimus-loaded PLGA implants: in vivo release and ocular toxicity. Curr Eye Res. 2014;39(1):99–102.
  • Gan L, Wang J, Zhao Y, et al. Hyaluronan-modified core-shell liponanoparticles targeting CD44-positive retinal pigment epithelium cells via intravitreal injection. Biomaterials. 2013;34(24):5978–5987.
  • Elbialy NS, Abdol-Azim BM, Shafaa MW, et al. Enhancement of the ocular therapeutic effect of prednisolone acetate by liposomal entrapment. J Biomed Nanotechnol. 2013;9(12):2105–2116.
  • Murata M, Sanbe A, Lee JW, et al. Laser-induced intrachoroidal dexamethasone drug delivery system to posterior eye segment. Invest Ophthalmol Vis Sci. 2013;54(13):8317–8324.
  • Fruchon S, Caminade A-M, Abadie C, et al. An azabisphosphonate-capped poly(phosphorhydrazone) dendrimer for the treatment of endotoxin-induced uveitis. Mol Basel. 2013;18(8):9305–9316.
  • Sabzevari A, Adibkia K, Hashemi H, et al. Improved anti-inflammatory effects in rabbit eye model using biodegradable poly beta-amino ester nanoparticles of triamcinolone acetonide. Invest Ophthalmol Vis Sci. 2013;54(8):5520–5526.
  • Eperon S, Rodriguez-Aller M, Balaskas K, et al. A new drug delivery system inhibits uveitis in an animal model after cataract surgery. Int J Pharm. 2013;443(1–2):254–261.
  • Kesavan K, Kant S, Singh PN, et al. Mucoadhesive chitosan-coated cationic microemulsion of dexamethasone for ocular delivery: in vitro and in vivo evaluation. Curr Eye Res. 2013;38(3):342–352.
  • Kesavan K, Kant S, Singh PN, et al. Effect of hydroxypropyl-β-cyclodextrin on the ocular bioavailability of dexamethasone from a pH-induced mucoadhesive hydrogel. Curr Eye Res. 2011;36(10):918–929.
  • Sakai T, Ishihara T, Higaki M, et al. Therapeutic effect of stealth-type polymeric nanoparticles with encapsulated betamethasone phosphate on experimental autoimmune uveoretinitis. Invest Ophthalmol Vis Sci. 2011;52(3):1516–1521.
  • Lajavardi L, Camelo S, Agnely F, et al. New formulation of vasoactive intestinal peptide using liposomes in hyaluronic acid gel for uveitis. J Control Release. 2009;139(1):22–30.
  • Shin JP, Park YC, Oh JH, et al. Biodegradable intrascleral implant of triamcinolone acetonide in experimental uveitis. J Ocul Pharmacol Ther. 2009;25(3):201–208.
  • He Y, Liu Y, Liu Y, et al. Cyclosporine-loaded microspheres for treatment of uveitis: in vitro characterization and in vivo pharmacokinetic study. Invest Ophthalmol Vis Sci. 2006;47(9):3983–3988.
  • Barcia E, Herrero-Vanrell R, Díez A, et al. Downregulation of endotoxin-induced uveitis by intravitreal injection of polylactic-glycolic acid (PLGA) microspheres loaded with dexamethasone. Exp Eye Res. 2009;89(2):238–245.
  • Miller DJ, Li SK, Tuitupou AL, et al. Passive and oxymetazoline-enhanced delivery with a lens device: pharmacokinetics and efficacy studies with rabbits. J Ocul Pharmacol Ther. 2008;24(4):385–391.
  • Hashida N, Ohguro N, Yamazaki N, et al. High-efficacy site-directed drug delivery system using sialyl-Lewis X conjugated liposome. Exp Eye Res. 2008;86(1):138–149.
  • Adibkia K, Omidi Y, Siahi MR, et al. Inhibition of endotoxin-induced uveitis by methylprednisolone acetate nanosuspension in rabbits. J Ocul Pharmacol Ther. 2007;23(5):421–432.
  • Adibkia K, Siahi Shadbad MR, Nokhodchi A, et al. Piroxicam nanoparticles for ocular delivery: physicochemical characterization and implementation in endotoxin-induced uveitis. J Drug Target. 2007;15(6):407–416.
  • Gilger BC, Salmon JH, Wilkie DA, et al. A novel bioerodible deep scleral lamellar cyclosporine implant for uveitis. Invest Ophthalmol Vis Sci. 2006;47(6):2596–2605.
  • He Y, Wang J-C, Liu Y-L, et al. Therapeutic and toxicological evaluations of cyclosporine a microspheres as a treatment vehicle for uveitis in rabbits. J Ocul Pharmacol Ther. 2006;22(2):121–131.
  • Sakai T, Kohno H, Ishihara T, et al. Treatment of experimental autoimmune uveoretinitis with poly(lactic acid) nanoparticles encapsulating betamethasone phosphate. Exp Eye Res. 2006;82(4):657–663.
  • Dong X, Shi W, Yuan G, et al. Intravitreal implantation of the biodegradable cyclosporin A drug delivery system for experimental chronic uveitis. Graefes Arch Clin Exp Ophthalmol. 2006;244(4):492–497.
  • Shen J, Gan L, Zhu C, et al. Novel NSAIDs ophthalmic formulation: flurbiprofen axetil emulsion with low irritancy and improved anti-inflammation effect. Int J Pharm. 2011;412(1–2):115–122.
  • Gilger BC, Abarca EM, Salmon JH, et al. Treatment of acute posterior uveitis in a porcine model by injection of triamcinolone acetonide into the suprachoroidal space using microneedles. Invest Ophthalmol Vis Sci. 2013;54(4):2483–2492.
  • Tian L, Yang P, Lei B, et al. AAV2-mediated subretinal gene transfer of hIFN-α attenuates experimental autoimmune uveoretinitis in mice. PloS One. 2011;6(5):e19542.
  • Tian L, Lei B, Shao J, et al. AAV2-mediated combined subretinal delivery of IFN-α and IL-4 reduces the severity of experimental autoimmune uveoretinitis. PloS One. 2012;7(6):e37995.
  • Durable Drug Delivery Coatings. SurModics, Inc.; 2013. [updated 2015 Aug 13]. Available from: http://www.surmodics.com/assets/uploads/documents/SurModics_Durable_Drug_Delivery_0513.pdf
  • Products&Technology. pSivida Corp; [updated 2015 Aug 14]. Available from: http://www.psivida.com/products.html
  • Verisome® Drug Delivery Technology. Icon Bioscience, Inc.; 2014. [updated 2015 Aug 14]. Available from: http://iconbioscience.com/verisome-drug-delivery-technology/
  • Encapsulated Cell Technology-ECT Platform. Neurotech Pharmaceuticals 2014-2015; [updated 2015 Aug 13]. Available from: http://www.neurotechusa.com/ect-platform.html
  • Cohen AE, Assang C, Patane MA, et al. Evaluation of dexamethasone phosphate delivered by ocular iontophoresis for treating noninfectious anterior uveitis. Ophthalmology. 2012;119(1):66–73.
  • EyeGate II Delivery System. EyeGate Pharma; 2015. [updated 2015 Aug 14]. Available from: http://www.eyegatepharma.com/technology/eyegate-ii-delivery-system/
  • Visulex system. Aciont Inc.; 2008. [updated 2015 Aug 14]. Available from: http://www.aciont.com/technologies/visulex
  • Rosenbaum JT. Future for biological therapy for uveitis. Curr Opin Ophthalmol. 2010;21(6):473–477.
  • The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances. WHO; 2011. updated 2015 Aug 10]. Available from: http://www.who.int/medicines/services/inn/StemBook_2011_Final.pdf
  • Optiquel® as Corticosteroid-sparing Therapy for Chronic Noninfectious Uveitis. ClinicalTrials.gov; [updated 2015 Aug 4]. Available from: https://clinicaltrials.gov/ct2/show/NCT01195948?term=uveitis+AND+therapy&rslt=With&phase=014&rank=1
  • Thurau SR, Diedrichs-Möhring M, Fricke H, et al. Molecular mimicry as a therapeutic approach for an autoimmune disease: oral treatment of uveitis-patients with an MHC-peptide crossreactive with autoantigen–first results. Immunol Lett. 1997;57(1–3):193–201.
  • Thurau SR, Fricke H, Burchardi C, et al. Long-term follow-up of oral tolerance induction with HLA-peptide B27PD in patients with uveitis. Ann N Y Acad Sci. 2004;1029:408–412.
  • Thompson DJS, Barron KS, Whitcup SM, et al. The safety and efficacy of chicken type II collagen on uveitis associated with juvenile rheumatoid arthritis. Ocul Immunol Inflamm. 2002;10(2):83–91.
  • Kenawy N, Cleary G, Mewar D, et al. Abatacept: a potential therapy in refractory cases of juvenile idiopathic arthritis-associated uveitis. Graefes Arch Clin Exp Ophthalmol. 2011;249(2):297–300.
  • Zulian F, Balzarin M, Falcini F, et al. Abatacept for severe anti-tumor necrosis factor alpha refractory juvenile idiopathic arthritis-related uveitis. Arthritis Care Res. 2010;62(6):821–825.
  • Tappeiner C, Miserocchi E, Bodaghi B, et al. Abatacept in the treatment of severe, longstanding, and refractory uveitis associated with juvenile idiopathic arthritis. J Rheumatol. 2015;42(4):706–711.
  • Hennig M, Bauer D, Wasmuth S, et al. Everolimus improves experimental autoimmune uveoretinitis. Exp Eye Res. 2012;105:43–52.
  • Copland DA, Liu J, Schewitz-Bowers LP, et al. Therapeutic dosing of fingolimod (FTY720) prevents cell infiltration, rapidly suppresses ocular inflammation, and maintains the blood-ocular barrier. Am J Pathol. 2012;180(2):672–681.
  • Kurose S, Ikeda E, Tokiwa M, et al. Effects of FTY720, a novel immunosuppressant, on experimental autoimmune uveoretinitis in rats. Exp Eye Res. 2000;70(1):7–15.
  • Commodaro AG, Peron JPS, Lopes CT, et al. Evaluation of experimental autoimmune uveitis in mice treated with FTY720. Invest Ophthalmol Vis Sci. 2010;51(5):2568–2574.
  • Raveney BJE, Copland DA, Nicholson LB, et al. Fingolimod (FTY720) as an acute rescue therapy for intraocular inflammatory disease. Arch Ophthalmol. 2008;126(10):1390–1395.
  • Zarbin MA, Jampol LM, Jager RD, et al. Ophthalmic evaluations in clinical studies of fingolimod (FTY720) in multiple sclerosis. Ophthalmology. 2013;120(7):1432–1439.
  • Letko E, Yeh S, Foster CS, et al. Efficacy and safety of intravenous secukinumab in noninfectious uveitis requiring steroid-sparing immunosuppressive therapy. Ophthalmology. 2015;122(5):939–948.
  • Hueber W, Patel DD, Dryja T, et al. Effects of AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheumatoid arthritis, and uveitis. Sci Transl Med. 2010;2(52):52ra72.
  • Zhang R, Qian J, Guo J, et al. Suppression of experimental autoimmune uveoretinitis by Anti-IL-17 antibody. Curr Eye Res. 2009;34(4):297–303.
  • Dick AD, Tugal-Tutkun I, Foster S, et al. Secukinumab in the treatment of noninfectious uveitis: results of three randomized, controlled clinical trials. Ophthalmology. 2013;120(4):777–787.
  • Schafer PH, Parton A, Gandhi AK, et al. Apremilast, a cAMP phosphodiesterase-4 inhibitor, demonstrates anti-inflammatory activity in vitro and in a model of psoriasis. Br J Pharmacol. 2010;159(4):842–855.
  • Apremilast in the Treatment of Uveitis. ClinicalTrials.gov; [updated 2015 Aug 4]. Available from: https://clinicaltrials.gov/ct2/show/NCT00889421?term=uveitis+AND+therapy&rslt=With&phase=014&rank=3
  • Bar-Yehuda S, Luger D, Ochaion A, et al. Inhibition of experimental auto-immune uveitis by the A3 adenosine receptor agonist CF101. Int J Mol Med. 2011;28(5):727–731.
  • Liang D, Zuo A, Shao H, et al. Anti-inflammatory or proinflammatory effect of an adenosine receptor agonist on the Th17 autoimmune response is inflammatory environment-dependent. J Immunol. 2014;193(11):5498–5505.
  • Microplasmin Intravitreal Administration in Participants With Uveitic Macular Edema. ClinicalTrials.gov; [updated 2015 August 5]. Available from: https://clinicaltrials.gov/ct2/show/NCT01194674?term=uveitis+AND+therapy&rslt=With&phase=014&rank=13
  • Jetrea full prescribing information. ThromboGenics, Inc.; 2012. [updated 2015 Aug 8]. Available from: http://jetrea.com/wp-content/uploads/JETREAPrescribingInformation.pdf
  • Stalmans P, Delaey C, De Smet MD, et al. Intravitreal injection of microplasmin for treatment of vitreomacular adhesion: results of a prospective, randomized, sham-controlled phase II trial (the MIVI-IIT trial). Retina. 2010;30(7):1122–1127.
  • Kükner A, Colakoğlu N, Serin D, et al. Effects of intraperitoneal vitamin E, melatonin and aprotinin on leptin expression in the guinea pig eye during experimental uveitis. Acta Ophthalmol. 2006;84(1):54–61.
  • Cid L, Pararajasegaram G, Sevanian A, et al. Anti-inflammatory effects of vitamin E on experimental lens-induced uveitis. Int Ophthalmol. 1992;16(1):27–32.
  • Pararajasegaram G, Sevanian A, Rao NA. Suppression of S antigen-induced uveitis by vitamin E supplementation. Ophthalmic Res. 1991;23(3):121–127.
  • Van Rooij J, Schwartzenberg SG, Mulder PG, et al. Oral vitamins C and E as additional treatment in patients with acute anterior uveitis: a randomised double masked study in 145 patients. Br J Ophthalmol. 1999;83(11):1277–1282.
  • Nussenblatt RB, Kim J, Thompson DJS, et al. Vitamin E in the treatment of uveitis-associated macular edema. Am J Ophthalmol. 2006;141(1):193–194.
  • Ibrahim MA, Sepah YJ, Watters A, et al. One-year outcomes of the SAVE study: sirolimus as a therapeutic approach for UVEitis. Transl Vis Sci Technol. 2015;4(2):4.
  • Nguyen QD, Ibrahim MA, Watters A, et al. Ocular tolerability and efficacy of intravitreal and subconjunctival injections of sirolimus in patients with non-infectious uveitis: primary 6-month results of the SAVE study. J Ophthalmic Inflamm Infect. 2013;3(1):32.
  • Sen HN, Larson TA, Meleth AD, et al. Subconjunctival sirolimus for the treatment of chronic active anterior uveitis: results of a pilot trial. Am J Ophthalmol. 2012;153(6):1038–1042.
  • Vigil EM, Sepah YJ, Watters AL, et al. Assessment of changes in quality of life among patients in the SAVE Study - Sirolimus as therapeutic Approach to uVEitis: a randomized study to assess the safety and bioactivity of intravitreal and subconjunctival injections of sirolimus in patients with non-infectious uveitis. J Ophthalmic Inflamm Infect. 2015;5:13.
  • Topical Interferon Gamma for Macular Edema Secondary to Uveitis. ClinicalTrials.gov; [updated 2015 Aug 4]. Available from: https://clinicaltrials.gov/ct2/show/NCT01376362?term=uveitis+AND+therapy&rslt=With&phase=014&rank=4
  • Saadoun D, Bodaghi B, Bienvenu B, et al. Biotherapies in inflammatory ocular disorders: interferons, immunoglobulins, monoclonal antibodies. Autoimmun Rev. 2013;12(7):774–783.
  • LeHoang P, Cassoux N, George F, et al. Intravenous immunoglobulin (IVIg) for the treatment of birdshot retinochoroidopathy. Ocul Immunol Inflamm. 2000;8(1):49–57.
  • Seider N, Beiran I, Scharf J, et al. Intravenous immunoglobulin therapy for resistant ocular Behçet’s disease. Br J Ophthalmol. 2001;85(11):1287–1288.
  • Onal S, Foster CS, Ahmed AR. Efficacy of intravenous immunoglobulin treatment in refractory uveitis. Ocul Immunol Inflamm. 2006;14(6):367–374.
  • Rosenbaum JT, George RK, Gordon C. The treatment of refractory uveitis with intravenous immunoglobulin. Am J Ophthalmol. 1999;127(5):545–549.
  • Tellier Z. Human immunoglobulins in intraocular inflammation. Ann N Y Acad Sci. 2007;1110:337–347.
  • Kim SJ, Doherty TJ, Cherney EF. Intravitreal ketorolac for chronic uveitis and macular edema: a pilot study. Arch Ophthalmol. 2012;130(4):456–460.
  • Barañano DE, Kim SJ, Edelhauser HF, et al. Efficacy and pharmacokinetics of intravitreal non-steroidal anti-inflammatory drugs for intraocular inflammation. Br J Ophthalmol. 2009;93(10):1387–1390.
  • Soheilian M, Karimi S, Ramezani A, et al. Pilot study of intravitreal injection of diclofenac for treatment of macular edema of various etiologies. Retina. 2010;30(3):509–515.
  • Kim SJ, Toma H, Shah R, et al. The safety, pharmacokinetics, and efficacy of intraocular celecoxib. Invest Ophthalmol Vis Sci. 2014;55(3):1409–1418.
  • Treatment of Non-infectious Intermediate and Posterior Uveitis Associated Macular Edema With Intravitreal Methotrexate. ClinicalTrials.gov; [updated 2015 Aug 3]. Available from: https://clinicaltrials.gov/ct2/show/NCT01314417?term=uveitis+AND+therapy&phase=014&rank=2
  • Taylor SRJ, Banker A, Schlaen A, et al. Intraocular methotrexate can induce extended remission in some patients in noninfectious uveitis. Retina. 2013;33(10):2149–2154.
  • Hosseini H, Safaei A, Khalili MR, et al. Intravitreal infliximab in experimental endotoxin-induced uveitis. Eur J Ophthalmol. 2009;19(5):818–823.
  • Yuksel E, Hasanreisoglu B, Yuksel N, et al. Comparison of acute effect of systemic versus intravitreal infliximab treatment in an experimental model of endotoxin-induced uveitis. J Ocul Pharmacol Ther. 2014;30(1):74–80.
  • Farvardin M, Afarid M, Shahrzad S. Long-term effects of intravitreal infliximab for treatment of sight-threatening chronic noninfectious uveitis. J Ocul Pharmacol Ther. 2012;28(6):628–631.
  • Markomichelakis N, Delicha E, Masselos S, et al. Intravitreal infliximab for sight-threatening relapsing uveitis in Behçet disease: a pilot study in 15 patients. Am J Ophthalmol. 2012;154(3):534-41.e1.
  • Farvardin M, Afarid M, Mehryar M, et al. Intravitreal infliximab for the treatment of sight-threatening chronic noninfectious uveitis. Retina. 2010;30(9):1530–1535.
  • Giganti M, Beer PM, Lemanski N, et al. Adverse events after intravitreal infliximab (Remicade). Retina. 2010;30(1):71–80.
  • Arias L, Caminal JM, Badia MB, et al. Intravitreal infliximab in patients with macular degeneration who are nonresponders to antivascular endothelial growth factor therapy. Retina. 2010;30(10):1601–1608.
  • Wu L, Hernandez-Bogantes E, Roca JA, et al intravitreal tumor necrosis factor inhibitors in the treatment of refractory diabetic macular edema: a pilot study from the pan-american collaborative retina study group. Retina. 2011;31(2):298–303.
  • Yeh S, Albini TA, Moshfeghi AA, et al. Uveitis, the comparison of age-related macular degeneration treatments trials (CATT), and intravitreal biologics for ocular inflammation. Am J Ophthalmol. 2012;154(3):429-35.e2.
  • Hamam RN, Barikian AW, Antonios RS, et al. Intravitreal adalimumab in active noninfectious uveitis: a pilot study. Ocul Immunol Inflamm. 2015:1–8. [Epub ahead of print].
  • Androudi S, Tsironi E, Kalogeropoulos C, et al. Intravitreal adalimumab for refractory uveitis-related macular edema. Ophthalmology. 2010;117(8):1612–1616.
  • De Smet MD, Taylor SRJ, Bodaghi B, et al. Understanding uveitis: the impact of research on visual outcomes. Prog Retin Eye Res. 2011;30(6):452–470.
  • Levy RA, De Andrade FA, Foeldvari I. Cutting-edge issues in autoimmune uveitis. Clin Rev Allergy Immunol. 2011;41(2):214–223.
  • Li Z, Liu B, Maminishkis A, et al. Gene expression profiling in autoimmune noninfectious uveitis disease. J Immunol. 2008;181(7):5147–5157.
  • Wang W, Milani M, Ostlie N, et al. C57BL/6 mice genetically deficient in IL-12/IL-23 and IFN-gamma are susceptible to experimental autoimmune myasthenia gravis, suggesting a pathogenic role of non-Th1 cells. J Immunol. 2007;178(11):7072–7080.
  • Ulbrich W, Lamprecht A. Targeted drug-delivery approaches by nanoparticulate carriers in the therapy of inflammatory diseases. J R Soc Interface. 2010;7(Suppl 1):S55–66.
  • Lima BR, Nussenblatt RB, Sen HN. Pharmacogenetics of drugs used in the treatment of ocular inflammatory diseases. Expert Opin Drug Metab Toxicol. 2013;9(7):875–882.
  • Liu B, Sen HN, Nussenblatt R. Susceptibility genes and pharmacogenetics in ocular inflammatory disorders. Ocul Immunol Inflamm. 2012;20(5):315–323.
  • Chu CJ, Barker SE, Dick AD, et al. Gene therapy for noninfectious uveitis. Ocul Immunol Inflamm. 2012;20(6):394–405.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.