Abstract
While corticosteroids are the typical first-line systemic medication used for immediate control of noninfectious uveitis, chronic or frequently recurrent disease, significant side effects related to corticosteroids, or intolerability warrant advancement of therapy to immunomodulatory therapy, including the broad classes of antimetabolites, calcineurin inhibitors (T-cell inhibitors), alkylating agents, and, more recently, biologics. While antimetabolites, calcineurin inhibitors, and alkylating agents have a long history of use in the setting of noninfectious uveitis, in the United States, they have all been used off-label. The only US Food and Drug Administration (FDA)-approved therapy for noninfectious uveitis (intermediate, posterior, or panuveitis) outside of corticosteroids is a biologic, adalimumab. Nevertheless, antimetabolites are most frequently used for corticosteroid-sparing control of uveitis. While calcineurin inhibitors and alkylating agents are still used, some agents, in particular, the alkylating agents, are reserved for extremely aggressive and sight-threatening ocular inflammatory diseases. The advent of biologics with targets for specific inflammatory pathway molecules signals a new era in managing uveitis more precisely.
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Rathinam SR, Babu M, Thundikandy R, et al. A randomized clinical trial comparing methotrexate and mycophenolate mofetil for noninfectious uveitis. Ophthalmology. 2014;121(10):1863–70.
Esterberg E, Acharya NR. Corticosteroid-sparing therapy: practice patterns among uveitis specialists. J Ophthalmic Inflamm Infect. 2012;2(1):21–8.
Elion GB, Hitchings GH, Vanderwerff H. Antagonists of nucleic acid derivatives. VI. Purines. J Biol Chem. 1951;192(2):505–18.
Elion GB. Nobel Lecture. The purine path to chemotherapy. Biosci Rep. 1989;9(5):509–29.
Hoffmann M, Rychlewski J, Chrzanowska M, Hermann T. Mechanism of activation of an immunosuppressive drug: azathioprine. Quantum chemical study on the reaction of azathioprine with cysteine. J Am Chem Soc. 2001;123(26):6404–9.
Liu H, Ding L, Zhang F, et al. The impact of glutathione S-transferase genotype and phenotype on the adverse drug reactions to azathioprine in patients with inflammatory bowel diseases. J Pharmacol Sci. 2015;129(2):95–100.
Greenwood AJ, Stanford MR, Graham EM. The role of azathioprine in the management of retinal vasculitis. Eye (London, England). 1998;12(Pt 5):783–8.
Pasadhika S, Kempen JH, Newcomb CW, et al. Azathioprine for ocular inflammatory diseases. Am J Ophthalmol. 2009;148(4):500–509.e502.
Jabs DA, Nussenblatt RB, Rosenbaum JT. Standardization of uveitis nomenclature for reporting clinical data. Results of the First International Workshop. Am J Ophthalmol. 2005;140(3):509–16.
Schatz CS, Uzel JL, Leininger L, Danner S, Terzic J, Fischbach M. Immunosuppressants used in a steroid-sparing strategy for childhood uveitis. J Pediatr Ophthalmol Strabismus. 2007;44(1):28–34.
Arellanes-Garcia L, Navarro-Lopez L, Recillas-Gispert C. Pars planitis in the Mexican Mestizo population: ocular findings, treatment, and visual outcome. Ocul Immunol Inflamm. 2003;11(1):53–60.
Mathews JD, Crawford BA, Bignell JL, Mackay IR. Azathioprine in active chronic iridocyclitis. A double-blind controlled trial. Br J Ophthalmol. 1969;53(5):327–30.
Yazici H, Pazarli H, Barnes CG, et al. A controlled trial of azathioprine in Behcet’s syndrome. N Engl J Med. 1990;322(5):281–5.
Hamuryudan V, Ozyazgan Y, Hizli N, et al. Azathioprine in Behcet’s syndrome: effects on long-term prognosis. Arthritis Rheum. 1997;40(4):769–74.
Andrasch RH, Pirofsky B, Burns RP. Immunosuppressive therapy for severe chronic uveitis. Arch Ophthalmol (Chicago, Ill.: 1960). 1978;96(2):247–51.
Cytotoxic drugs in treatment of nonmalignant diseases. Ann Intern Med. 1972;76(4):619–42.
Nielsen OH, Maxwell C, Hendel J. IBD medications during pregnancy and lactation. Nat Rev Gastroenterol Hepatol. 2014;11(2):116–27.
Galor A, Jabs DA, Leder HA, et al. Comparison of antimetabolite drugs as corticosteroid-sparing therapy for noninfectious ocular inflammation. Ophthalmology. 2008;115(10):1826–32.
Hooper PL, Kaplan HJ. Triple agent immunosuppression in serpiginous choroiditis. Ophthalmology. 1991;98(6):944–51; discussion 951-942.
Moore CE. Sympathetic ophthalmitis treated with azathioprine. Br J Ophthalmol. 1968;52(9):688–90.
Hakin KN, Pearson RV, Lightman SL. Sympathetic ophthalmia: visual results with modern immunosuppressive therapy. Eye (London, England). 1992;6(Pt 5):453–5.
Hellmund K, Fruhauf A, Seiler T, Naumann GO. Sympathetic ophthalmia 50 years after penetrating injury. A case report. Klin Monbl Augenheilkd. 1998;213(3):182–5.
Sisk RA, Davis JL, Dubovy SR, Smiddy WE. Sympathetic ophthalmia following vitrectomy for endophthalmitis after intravitreal bevacizumab. Ocul Immunol Inflamm. 2008;16(5):236–8.
Siemasko KF, Chong AS, Williams JW, Bremer EG, Finnegan A. Regulation of B cell function by the immunosuppressive agent leflunomide. Transplantation. 1996;61(4):635–42.
Manna SK, Aggarwal BB. Immunosuppressive leflunomide metabolite (A77 1726) blocks TNF-dependent nuclear factor-kappa B activation and gene expression. J Immunol (Baltimore, Md.: 1950). 1999;162(4):2095–102.
Robertson SM, Lang LS. Leflunomide: inhibition of S-antigen induced autoimmune uveitis in Lewis rats. Agents Actions. 1994;42(3–4):167–72.
Fang CB, Zhou DX, Zhan SX, et al. Amelioration of experimental autoimmune uveitis by leflunomide in Lewis rats. PLoS One. 2013;8(4):e62071.
Wang J, Xie QB, Zhao Y, Liu Y. Flare up of rheumatoid arthritis associated with Vogt-Koyanagi-Harada syndrome treated with leflunomide. Int J Ophthalmol. 2014;7(5):909–11.
Steigerwalt RD Jr, Bacci S, Valesini G. Severe uveitis successfully treated with leflunomide. Retin Cases Brief Rep. 2007;1(1):54–5.
Molina C, Modesto C, Martin-Begue N, Arnal C. Leflunomide, a valid and safe drug for the treatment of chronic anterior uveitis associated with juvenile idiopathic arthritis. Clin Rheumatol. 2013;32(11):1673–5.
Bichler J, Benseler SM, Krumrey-Langkammerer M, Haas JP, Hugle B. Leflunomide is associated with a higher flare rate compared to methotrexate in the treatment of chronic uveitis in juvenile idiopathic arthritis. Scand J Rheumatol. 2015;44(4):280–3.
Kremer JM, Genovese MC, Cannon GW, et al. Concomitant leflunomide therapy in patients with active rheumatoid arthritis despite stable doses of methotrexate. A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2002;137(9):726–33.
Fairbanks LD, Ruckemann K, Qiu Y, et al. Methotrexate inhibits the first committed step of purine biosynthesis in mitogen-stimulated human T-lymphocytes: a metabolic basis for efficacy in rheumatoid arthritis? Biochem J. 1999;342(Pt 1):143–52.
Kiely PD, Johnson DM. Infliximab and leflunomide combination therapy in rheumatoid arthritis: an open-label study. Rheumatology (Oxford, England). 2002;41(6):631–7.
Nurmohamed MT, van Halm VP, Dijkmans BA. Cardiovascular risk profile of antirheumatic agents in patients with osteoarthritis and rheumatoid arthritis. Drugs. 2002;62(11):1599–609.
Erice A. Resistance of human cytomegalovirus to antiviral drugs. Clin Microbiol Rev. 1999;12(2):286–97.
Andrassy J, Illner WD, Rentsch M, Jaeger G, Jauch KW, Fischereder M. Leflunomide: a treatment option for ganciclovir-resistant cytomegalovirus infection after renal transplantation. NDT Plus. 2009;2(2):149–51.
Chon WJ, Kadambi PV, Xu C, et al. Use of leflunomide in renal transplant recipients with ganciclovir-resistant/refractory cytomegalovirus infection: a case series from the University of Chicago. Case Rep Nephrol Dial. 2015;5(1):96–105.
Verkaik NJ, Hoek RA, van Bergeijk H, et al. Leflunomide as part of the treatment for multidrug-resistant cytomegalovirus disease after lung transplantation: case report and review of the literature. Transpl Infect Dis. 2013;15(6):E243–9.
Waldman WJ, Knight DA, Blinder L, et al. Inhibition of cytomegalovirus in vitro and in vivo by the experimental immunosuppressive agent leflunomide. Intervirology. 1999;42(5–6):412–8.
Heinle RW, Welch AD. Experiments with pteroylglutamic acid and pteroylglutamic acid deficiency in human leukemia. J Clin Invest. 1948;27(4):539.
Cress RH, Deaver NL. Methotrexate in the Management of Severe Psoriasis and Arthritis: report of a case. South Med J. 1964;57:1088–90.
Enderlin M. Experiences with antimetabolite therapy of malignant forms of progressive chronic polyarthritis. Helv Med Acta Suppl. 1966;46:171.
Gross D, Enderlin M, Fehr K. Immunosuppressive therapy of progredient chronic polyarthritis using antimetabolites and cytostatics. Schweiz Med Wochenschr. 1967;97(40):1301–10.
Fosdick WM. Cytotoxic therapy in rheumatoid arthritis. Med Clin North Am. 1968;52(3):747–57.
Wilke WS, Calabrese LH, Scherbel AL. Methotrexate in the treatment of rheumatoid arthritis; pilot study. Cleve Clin Q. 1980;47(4):305–9.
Hall PA, Levison DA. Review: assessment of cell proliferation in histological material. J Clin Pathol. 1990;43(3):184–92.
Spina D, Leoncini L, Del Vecchio MT, et al. Low versus high cell turnover in diffusely growing non-Hodgkin’s lymphomas. J Pathol. 1995;177(4):335–41.
Day RO, Furst DE, Riel PLCM, van Bresnihan B, editors. Antirheumatic therapy: actions and outcomes: Birhäuser Verlag. ISBN 978-3-7643-7726-7.
Jurgensen CH, Huber BE, Zimmerman TP, Wolberg G. 3-deazaadenosine inhibits leukocyte adhesion and ICAM-1 biosynthesis in tumor necrosis factor-stimulated human endothelial cells. J Immunol (Baltimore, Md.: 1950). 1990;144(2):653–61.
Jurgensen CH, Wolberg G, Zimmerman TP. Inhibition of neutrophil adherence to endothelial cells by 3-deazaadenosine. Agents Actions. 1989;27(3–4):398–400.
Nesher G, Moore TL. The in vitro effects of methotrexate on peripheral blood mononuclear cells. Modulation by methyl donors and spermidine. Arthritis Rheum. 1990;33(7):954–9.
Yukioka K, Wakitani S, Yukioka M, et al. Polyamine levels in synovial tissues and synovial fluids of patients with rheumatoid arthritis. J Rheumatol. 1992;19(5):689–92.
Morabito L, Montesinos MC, Schreibman DM, et al. Methotrexate and sulfasalazine promote adenosine release by a mechanism that requires ecto-5′-nucleotidase-mediated conversion of adenine nucleotides. J Clin Invest. 1998;101(2):295–300.
Cronstein BN, Rosenstein ED, Kramer SB, Weissmann G, Hirschhorn R. Adenosine; a physiologic modulator of superoxide anion generation by human neutrophils. Adenosine acts via an A2 receptor on human neutrophils. J Immunol (Baltimore, Md.: 1950). 1985;135(2):1366–71.
Cronstein BN, Daguma L, Nichols D, Hutchison AJ, Williams M. The adenosine/neutrophil paradox resolved: human neutrophils possess both A1 and A2 receptors that promote chemotaxis and inhibit O2 generation, respectively. J Clin Invest. 1990;85(4):1150–7.
Jundt JW, Browne BA, Fiocco GP, Steele AD, Mock D. A comparison of low dose methotrexate bioavailability: oral solution, oral tablet, subcutaneous and intramuscular dosing. J Rheumatol. 1993;20(11):1845–9.
Gangaputra S, Newcomb CW, Liesegang TL, et al. Methotrexate for ocular inflammatory diseases. Ophthalmology. 2009;116(11):2188–2198.e2181.
Hemady RK, Baer JC, Foster CS. Immunosuppressive drugs in the management of progressive, corticosteroid-resistant uveitis associated with juvenile rheumatoid arthritis. Int Ophthalmol Clin. 1992;32(1):241–52.
Weiss AH, Wallace CA, Sherry DD. Methotrexate for resistant chronic uveitis in children with juvenile rheumatoid arthritis. J Pediatr. 1998;133(2):266–8.
Foeldvari I, Wierk A. Methotrexate is an effective treatment for chronic uveitis associated with juvenile idiopathic arthritis. J Rheumatol. 2005;32(2):362–5.
Malik AR, Pavesio C. The use of low dose methotrexate in children with chronic anterior and intermediate uveitis. Br J Ophthalmol. 2005;89(7):806–8.
Heiligenhaus A, Mingels A, Heinz C, Ganser G. Methotrexate for uveitis associated with juvenile idiopathic arthritis: value and requirement for additional anti-inflammatory medication. Eur J Ophthalmol. 2007;17(5):743–8.
Herman RA, Veng-Pedersen P, Hoffman J, Koehnke R, Furst DE. Pharmacokinetics of low-dose methotrexate in rheumatoid arthritis patients. J Pharm Sci. 1989;78(2):165–71.
Prasad S, Tripathi D, Rai MK, Aggarwal S, Mittal B, Agarwal V. Multidrug resistance protein-1 expression, function and polymorphisms in patients with rheumatoid arthritis not responding to methotrexate. Int J Rheum Dis. 2014;17(8):878–86.
Wessels JA, van der Kooij SM, le Cessie S, et al. A clinical pharmacogenetic model to predict the efficacy of methotrexate monotherapy in recent-onset rheumatoid arthritis. Arthritis Rheum. 2007;56(6):1765–75.
Wessels JA, Kooloos WM, De Jonge R, et al. Relationship between genetic variants in the adenosine pathway and outcome of methotrexate treatment in patients with recent-onset rheumatoid arthritis. Arthritis Rheum. 2006;54(9):2830–9.
Sen HN, Chan CC, Byrnes G, Fariss RN, Nussenblatt RB, Buggage RR. Intravitreal methotrexate resistance in a patient with primary intraocular lymphoma. Ocul Immunol Inflamm. 2008;16(1):29–33.
Micsik T, Lorincz A, Gal J, Schwab R, Petak I. MDR-1 and MRP-1 activity in peripheral blood leukocytes of rheumatoid arthritis patients. Diagn Pathol. 2015;10(1):216.
Sotoudehmanesh R, Anvari B, Akhlaghi M, Shahraeeni S, Kolahdoozan S. Methotrexate hepatotoxicity in patients with rheumatoid arthritis. Middle East J Dig Dis. 2010;2(2):104–9.
Sakthiswary R, Chan GY, Koh ET, Leong KP, Thong BY. Methotrexate-associated nonalcoholic fatty liver disease with transaminitis in rheumatoid arthritis. TheScientificWorldJournal. 2014;2014:823763.
Jakubovic BD, Donovan A, Webster PM, Shear NH. Methotrexate-induced pulmonary toxicity. Can Respir J. 2013;20(3):153–5.
Troeltzsch M, von Blohn G, Kriegelstein S, et al. Oral mucositis in patients receiving low-dose methotrexate therapy for rheumatoid arthritis: report of 2 cases and literature review. Oral Surg Oral Med Oral Pathol Oral Radiol. 2013;115(5):e28–33.
Morgan SL, Baggott JE, Vaughn WH, et al. Supplementation with folic acid during methotrexate therapy for rheumatoid arthritis. A double-blind, placebo-controlled trial. Ann Intern Med. 1994;121(11):833–41.
Morgan SL, Baggott JE, Vaughn WH, et al. The effect of folic acid supplementation on the toxicity of low-dose methotrexate in patients with rheumatoid arthritis. Arthritis Rheum. 1990;33(1):9–18.
Shea B, Swinden MV, Ghogomu ET, et al. Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis. J Rheumatol. 2014;41(6):1049–60.
Lee WA, Gu L, Miksztal AR, Chu N, Leung K, Nelson PH. Bioavailability improvement of mycophenolic acid through amino ester derivatization. Pharm Res. 1990;7(2):161–6.
Morris RE, Hoyt EG, Murphy MP, Eugui EM, Allison AC. Mycophenolic acid morpholinoethylester (RS-61443) is a new immunosuppressant that prevents and halts heart allograft rejection by selective inhibition of T- and B-cell purine synthesis. Transplant Proc. 1990;22(4):1659–62.
Platz KP, Sollinger HW, Hullett DA, Eckhoff DE, Eugui EM, Allison AC. RS-61443—a new, potent immunosuppressive agent. Transplantation. 1991;51(1):27–31.
Platz KP, Bechstein WO, Eckhoff DE, Suzuki Y, Sollinger HW. RS-61443 reverses acute allograft rejection in dogs. Surgery. 1991;110(4):736–40; discussion 740-731.
Sollinger HW, Deierhoi MH, Belzer FO, Diethelm AG, Kauffman RS. RS-61443—a phase I clinical trial and pilot rescue study. Transplantation. 1992;53(2):428–32.
Staatz CE, Tett SE. Clinical pharmacokinetics and pharmacodynamics of mycophenolate in solid organ transplant recipients. Clin Pharmacokinet. 2007;46(1):13–58.
Siepmann K, Huber M, Stubiger N, Deuter C, Zierhut M. Mycophenolate mofetil is a highly effective and safe immunosuppressive agent for the treatment of uveitis : a retrospective analysis of 106 patients. Graefe’s Arch Clin Exp Ophthalmol. 2006;244(7):788–94.
Doycheva D, Zierhut M, Blumenstock G, Stuebiger N, Deuter C. Long-term results of therapy with mycophenolate mofetil in chronic non-infectious uveitis. Graefe’s Arch Clin Exp Ophthalmol. 2011;249(8):1235–43.
Thorne JE, Jabs DA, Qazi FA, Nguyen QD, Kempen JH, Dunn JP. Mycophenolate mofetil therapy for inflammatory eye disease. Ophthalmology. 2005;112(8):1472–7.
Cuchacovich M, Solanes F, Perez C, et al. Mycophenolate mofetil therapy in refractory inflammatory eye disease. J Ocul Pharmacol Ther. 2016;32(1):55–61.
Filler G, Hansen M, LeBlanc C, et al. Pharmacokinetics of mycophenolate mofetil for autoimmune disease in children. Pediatr Nephrol (Berlin, Germany). 2003;18(5):445–9.
Doycheva D, Deuter C, Stuebiger N, Biester S, Zierhut M. Mycophenolate mofetil in the treatment of uveitis in children. Br J Ophthalmol. 2007;91(2):180–4.
Sobrin L, Christen W, Foster CS. Mycophenolate mofetil after methotrexate failure or intolerance in the treatment of scleritis and uveitis. Ophthalmology. 2008;115(8):1416–21, 1421.e1411.
Bentley R. Mycophenolic Acid: a one hundred year odyssey from antibiotic to immunosuppressant. Chem Rev. 2000;100(10):3801–26.
Doycheva D, Jagle H, Zierhut M, et al. Mycophenolic acid in the treatment of birdshot chorioretinopathy: long-term follow-up. Br J Ophthalmol. 2015;99(1):87–91.
Zacharias LC, Damico FM, Kenney MC, et al. In vitro evidence for mycophenolic acid dose-related cytotoxicity in human retinal cells. Retina (Philadelphia, Pa.). 2013;33(10):2155–61.
Franklin JL, Rosenberg HH. Impaired folic acid absorption in inflammatory bowel disease: effects of salicylazosulfapyridine (Azulfidine). Gastroenterology. 1973;64(4):517–25.
Selhub J, Dhar GJ, Rosenberg IH. Inhibition of folate enzymes by sulfasalazine. J Clin Invest. 1978;61(1):221–4.
Baum CL, Selhub J, Rosenberg IH. Antifolate actions of sulfasalazine on intact lymphocytes. J Lab Clin Med. 1981;97(6):779–84.
Rhodes JM, Jewell DP. Motility of neutrophils and monocytes in Crohn’s disease and ulcerative colitis. Gut. 1983;24(1):73–7.
Munoz-Fernandez S, Hidalgo V, Fernandez-Melon J, et al. Sulfasalazine reduces the number of flares of acute anterior uveitis over a one-year period. J Rheumatol. 2003;30(6):1277–9.
Kaklamani VG, Kaklamanis PG. Treatment of Behcet’s disease—an update. Semin Arthritis Rheum. 2001;30(5):299–312.
Arcinue CA, Radwan A, Lebanan MO, Foster CS. Comparison of two different combination immunosuppressive therapies in the treatment of Vogt-Koyonagi-Harada syndrome. Ocul Immunol Inflamm. 2013;21(1):47–52.
Silman AJ, Petrie J, Hazleman B, Evans SJ. Lymphoproliferative cancer and other malignancy in patients with rheumatoid arthritis treated with azathioprine: a 20 year follow up study. Ann Rheum Dis. 1988;47(12):988–92.
Penn I. Cancers complicating organ transplantation. N Engl J Med. 1990;323(25):1767–9.
Kempen JH, Daniel E, Dunn JP, et al. Overall and cancer related mortality among patients with ocular inflammation treated with immunosuppressive drugs: retrospective cohort study. BMJ (Clinical research ed.). 2009;339:b2480.
Nussenblatt RB, Rodrigues MM, Wacker WB, Cevario SJ, Salinas-Carmona MC, Gery I. Cyclosporin a. Inhibition of experimental autoimmune uveitis in Lewis rats. J Clin Invest. 1981;67(4):1228–31.
Nussenblatt RB, Palestine AG, Rook AH, Scher I, Wacker WB, Gery I. Treatment of intraocular inflammatory disease with cyclosporin a. Lancet (London, England). 1983;2(8344):235–8.
Kacmaz RO, Kempen JH, Newcomb C, et al. Cyclosporine for ocular inflammatory diseases. Ophthalmology. 2010;117(3):576–84.
Murphy CC, Greiner K, Plskova J, et al. Cyclosporine vs tacrolimus therapy for posterior and intermediate uveitis. Arch Ophthalmol (Chicago, Ill.: 1960). 2005;123(5):634–41.
Tanaka H, Kuroda A, Marusawa H, et al. Physicochemical properties of FK-506, a novel immunosuppressant isolated from Streptomyces tsukubaensis. Transplant Proc. 1987;19(5 Suppl 6):11–6.
Kino T, Hatanaka H, Hashimoto M, et al. FK-506, a novel immunosuppressant isolated from a Streptomyces. I. Fermentation, isolation, and physico-chemical and biological characteristics. J Antibiot. 1987;40(9):1249–55.
Venkataramanan R, Jain A, Cadoff E, et al. Pharmacokinetics of FK 506: preclinical and clinical studies. Transplant Proc. 1990;22(1):52–6.
Mochizuki M, Masuda K, Sakane T, et al. A multicenter clinical open trial of FK 506 in refractory uveitis, including Behcet’s disease. Japanese FK 506 Study Group on Refractory Uveitis. Transplant Proc. 1991;23(6):3343–6.
Hogan AC, McAvoy CE, Dick AD, Lee RW. Long-term efficacy and tolerance of tacrolimus for the treatment of uveitis. Ophthalmology. 2007;114(5):1000–6.
Sloper CM, Powell RJ, Dua HS. Tacrolimus (FK506) in the treatment of posterior uveitis refractory to cyclosporine. Ophthalmology. 1999;106(4):723–8.
Kilmartin DJ, Forrester JV, Dick AD. Tacrolimus (FK506) in failed cyclosporin a therapy in endogenous posterior uveitis. Ocul Immunol Inflamm. 1998;6(2):101–9.
Auerbach C, Robson JM. Chemical production of mutations. Nature. 1946;157:302.
Osborne ED, Jordon JW, et al. Nitrogen mustard therapy in cutaneous blastomatous disease. J Am Med Assoc. 1947;135(17):1123–8.
Gubner R, August S, Ginsberg V. Therapeutic suppression of tissue reactivity. II. Effect of aminopterin in rheumatoid arthritis and psoriasis. Am J Med Sci. 1951;221(2):176–82.
Arnold H, Bourseaux F, Brock N. Chemotherapeutic action of a cyclic nitrogen mustard phosphamide ester (B 518-ASTA) in experimental tumours of the rat. Nature. 1958;181(4613):931.
Pujari SS, Kempen JH, Newcomb CW, et al. Cyclophosphamide for ocular inflammatory diseases. Ophthalmology. 2010;117(2):356–65.
Houssiau FA. Cyclophosphamide in lupus nephritis. Lupus. 2005;14(1):53–8.
Alberts DS, Chang SY, Chen HS, Larcom BJ, Evans TL. Comparative pharmacokinetics of chlorambucil and melphalan in man. Recent Results Cancer Res. 1980;74:124–31.
Ehrsson H, Wallin I, Simonsson B, Hartvig P, Oberg G. Effect of food on pharmacokinetics of chlorambucil and its main metabolite, phenylacetic acid mustard. Eur J Clin Pharmacol. 1984;27(1):111–4.
Tessler HH, Jennings T. High-dose short-term chlorambucil for intractable sympathetic ophthalmia and Behcet’s disease. Br J Ophthalmol. 1990;74(6):353–7.
Goldstein DA, Fontanilla FA, Kaul S, Sahin O, Tessler HH. Long-term follow-up of patients treated with short-term high-dose chlorambucil for sight-threatening ocular inflammation. Ophthalmology. 2002;109(2):370–7.
Miserocchi E, Baltatzis S, Ekong A, Roque M, Foster CS. Efficacy and safety of chlorambucil in intractable noninfectious uveitis: the Massachusetts Eye and Ear Infirmary experience. Ophthalmology. 2002;109(1):137–42.
Fiers W. Tumor necrosis factor. Characterization at the molecular, cellular and in vivo level. FEBS Lett. 1991;285(2):199–212.
Heller RA, Kronke M. Tumor necrosis factor receptor-mediated signaling pathways. J Cell Biol. 1994;126(1):5–9.
Lerman MA, Burnham JM, Chang PY, et al. Response of pediatric uveitis to tumor necrosis factor-alpha inhibitors. J Rheumatol. 2013;40(8):1394–403.
Rau R. Adalimumab (a fully human anti-tumour necrosis factor alpha monoclonal antibody) in the treatment of active rheumatoid arthritis: the initial results of five trials. Ann Rheum Dis. 2002;61(Suppl 2):ii70–3.
Weisman MH, Moreland LW, Furst DE, et al. Efficacy, pharmacokinetic, and safety assessment of adalimumab, a fully human anti-tumor necrosis factor-alpha monoclonal antibody, in adults with rheumatoid arthritis receiving concomitant methotrexate: a pilot study. Clin Ther. 2003;25(6):1700–21.
Suhler EB, Lowder CY, Goldstein DA, et al. Adalimumab therapy for refractory uveitis: results of a multicentre, open-label, prospective trial. Br J Ophthalmol. 2013;97(4):481–6.
Biester S, Deuter C, Michels H, et al. Adalimumab in the therapy of uveitis in childhood. Br J Ophthalmol. 2007;91(3):319–24.
Diaz-Llopis M, Garcia-Delpech S, Salom D, et al. Adalimumab therapy for refractory uveitis: a pilot study. J Ocul Pharmacol Ther. 2008;24(3):351–61.
Tynjala P, Kotaniemi K, Lindahl P, et al. Adalimumab in juvenile idiopathic arthritis-associated chronic anterior uveitis. Rheumatology (Oxford, England). 2008;47(3):339–44.
Androudi S, Tsironi E, Kalogeropoulos C, Theodoridou A, Brazitikos P. Intravitreal adalimumab for refractory uveitis-related macular edema. Ophthalmology. 2010;117(8):1612–6.
Giganti M, Beer PM, Lemanski N, Hartman C, Schartman J, Falk N. Adverse events after intravitreal infliximab (Remicade). Retina (Philadelphia, Pa.). 2010;30(1):71–80.
Pulido JS, Pulido JE, Michet CJ, Vile RG. More questions than answers: a call for a moratorium on the use of intravitreal infliximab outside of a well-designed trial. Retina (Philadelphia, Pa.). 2010;30(1):1–5.
Suhler EB, Smith JR, Wertheim MS, et al. A prospective trial of infliximab therapy for refractory uveitis: preliminary safety and efficacy outcomes. Arch Ophthalmol (Chicago, Ill.: 1960). 2005;123(7):903–12.
Suhler EB, Smith JR, Giles TR, et al. Infliximab therapy for refractory uveitis: 2-year results of a prospective trial. Arch Ophthalmol (Chicago, Ill.: 1960). 2009;127(6):819–22.
Riancho-Zarrabeitia L, Calvo-Rio V, Blanco R, et al. Anti-TNF-alpha therapy in refractory uveitis associated with sarcoidosis: multicenter study of 17 patients. Semin Arthritis Rheum. 2015;45(3):361–8.
Ardoin SP, Kredich D, Rabinovich E, Schanberg LE, Jaffe GJ. Infliximab to treat chronic noninfectious uveitis in children: retrospective case series with long-term follow-up. Am J Ophthalmol. 2007;144(6):844–9.
Rajaraman RT, Kimura Y, Li S, Haines K, Chu DS. Retrospective case review of pediatric patients with uveitis treated with infliximab. Ophthalmology. 2006;113(2):308–14.
Levy-Clarke G, Jabs DA, Read RW, Rosenbaum JT, Vitale A, Van Gelder RN. Expert panel recommendations for the use of anti-tumor necrosis factor biologic agents in patients with ocular inflammatory disorders. Ophthalmology. 2014;121(3):785–796.e783.
Vallet H, Seve P, Biard L, et al. Infliximab versus adalimumab in the treatment of refractory inflammatory uveitis: a multicenter study from the French Uveitis Network. Arthritis Rheumatol (Hoboken, N.J.). 2016;68(6):1522–30.
Yazgan S, Celik U, Isik M, et al. Efficacy of golimumab on recurrent uveitis in HLA-B27-positive ankylosing spondylitis. Int Ophthalmol. 2017;37(1):139–45.
Calvo-Rio V, Blanco R, Santos-Gomez M, et al. Golimumab in refractory uveitis related to spondyloarthritis. Multicenter study of 15 patients. Semin Arthritis Rheum. 2016;46(1):95–101.
Miserocchi E, Modorati G, Pontikaki I, Meroni PL, Gerloni V. Long-term treatment with golimumab for severe uveitis. Ocul Immunol Inflamm. 2014;22(2):90–5.
Galor A, Perez VL, Hammel JP, Lowder CY. Differential effectiveness of etanercept and infliximab in the treatment of ocular inflammation. Ophthalmology. 2006;113(12):2317–23.
Kaymakcalan Z, Sakorafas P, Bose S, et al. Comparisons of affinities, avidities, and complement activation of adalimumab, infliximab, and etanercept in binding to soluble and membrane tumor necrosis factor. Clin Immunol (Orlando, Fla.). 2009;131(2):308–16.
Van den Brande JM, Braat H, van den Brink GR, et al. Infliximab but not etanercept induces apoptosis in lamina propria T-lymphocytes from patients with Crohn’s disease. Gastroenterology. 2003;124(7):1774–85.
Isaacs A, Lindenmann J. Virus interference. I. The interferon. By A. Isaacs and J. Lindenmann, 1957. J Interf Res. 1987;7(5):429–38.
Zou W, Machelon V, Coulomb-L’Hermin A, et al. Stromal-derived factor-1 in human tumors recruits and alters the function of plasmacytoid precursor dendritic cells. Nat Med. 2001;7(12):1339–46.
Colonna M, Krug A, Cella M. Interferon-producing cells: on the front line in immune responses against pathogens. Curr Opin Immunol. 2002;14(3):373–9.
Vallin H, Perers A, Alm GV, Ronnblom L. Anti-double-stranded DNA antibodies and immunostimulatory plasmid DNA in combination mimic the endogenous IFN-alpha inducer in systemic lupus erythematosus. J Immunol (Baltimore, Md.: 1950). 1999;163(11):6306–13.
Wampler Muskardin T, Vashisht P, Dorschner JM, et al. Increased pretreatment serum IFN-beta/alpha ratio predicts non-response to tumour necrosis factor alpha inhibition in rheumatoid arthritis. Ann Rheum Dis. 2016;75(10):1757–62.
Okada AA, Keino H, Suzuki J, Sakai J, Usui M, Mizuguchi J. Kinetics of intraocular cytokines in the suppression of experimental autoimmune uveoretinitis by type I IFN. Int Immunol. 1998;10(12):1917–22.
Okada AA, Keino H, Fukai T, Sakai J, Usui M, Mizuguchi J. Effect of type I interferon on experimental autoimmune uveoretinitis in rats. Ocul Immunol Inflamm. 1998;6(4):215–26.
Stubiger N, Crane IJ, Kotter I, et al. Interferon alpha 2a in IRPB-derived peptide-induced EAU—part I. Adv Exp Med Biol. 2003;528:537–40.
Bodaghi B, Gendron G, Wechsler B, et al. Efficacy of interferon alpha in the treatment of refractory and sight threatening uveitis: a retrospective monocentric study of 45 patients. Br J Ophthalmol. 2007;91(3):335–9.
Gueudry J, Wechsler B, Terrada C, et al. Long-term efficacy and safety of low-dose interferon alpha2a therapy in severe uveitis associated with Behcet disease. Am J Ophthalmol. 2008;146(6):837–844.e831.
Hasanreisoglu M, Cubuk MO, Ozdek S, Gurelik G, Aktas Z, Hasanreisoglu B. Interferon alpha-2a therapy in patients with refractory Behcet uveitis. Ocul Immunol Inflamm. 2017;25(1):71–5.
Park JY, Chung YR, Lee K, Song JH, Lee ES. Clinical experience of interferon alfa-2a treatment for refractory uveitis in Behcet’s disease. Yonsei Med J. 2015;56(4):1158–62.
Butler NJ, Suhler EB, Rosenbaum JT. Interferon alpha 2b in the treatment of uveitic cystoid macular edema. Ocul Immunol Inflamm. 2012;20(2):86–90.
Doycheva D, Deuter C, Stuebiger N, Zierhut M. Interferon-alpha-associated presumed ocular sarcoidosis. Graefes Arch Clin Exp Ophthalmol. 2009;247(5):675–80.
Durand JM, Soubeyrand J. Interferon-alpha 2b for refractory ocular Behcet’s disease. Lancet (London, England). 1994;344(8918):333.
Fleischmann M, Celerier P, Bernard P, Litoux P, Dreno B. Long-term interferon-alpha therapy induces autoantibodies against epidermis. Dermatology (Basel, Switzerland). 1996;192(1):50–5.
Schilling PJ, Kurzrock R, Kantarjian H, Gutterman JU, Talpaz M. Development of systemic lupus erythematosus after interferon therapy for chronic myelogenous leukemia. Cancer. 1991;68(7):1536–7.
Becker MD, Adamus G, Davey MP, Rosenbaum JT. The role of T cells in autoimmune uveitis. Ocul Immunol Inflamm. 2000;8(2):93–100.
Caspi RR, Sun B, Agarwal RK, et al. T cell mechanisms in experimental autoimmune uveoretinitis: susceptibility is a function of the cytokine response profile. Eye (London, England). 1997;11(Pt 2):209–12.
Whitcup SM, Pleyer U, Lai JC, Lutz S, Mochizuki M, Chan CC. Topical liposome-encapsulated FK506 for the treatment of endotoxin-induced uveitis. Ocul Immunol Inflamm. 1998;6(1):51–6.
Parikh JG, Tawansy KA, Rao NA. Immunohistochemical study of chronic nongranulomatous anterior uveitis in juvenile idiopathic arthritis. Ophthalmology. 2008;115(10):1833–6.
Maloney DG, Grillo-Lopez AJ, White CA, et al. IDEC-C2B8 (Rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin’s lymphoma. Blood. 1997;90(6):2188–95.
Keogh KA, Wylam ME, Stone JH, Specks U. Induction of remission by B lymphocyte depletion in eleven patients with refractory antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum. 2005;52(1):262–8.
Lasave AF, You C, Ma L, et al. Long-term outcomes of rituximab therapy in patients with noninfectious posterior uveitis refractory to conventional immunosuppressive therapy. Retina. 2018;38(2):395–402.
Lopez-Gonzalez R, Loza E, Jover JA, et al. Treatment of refractory posterior uveitis with infliximab: a 7-year follow-up study. Scand J Rheumatol. 2009;38(1):58–62.
Miserocchi E, Modorati G, Berchicci L, Pontikaki I, Meroni P, Gerloni V. Long-term treatment with rituximab in severe juvenile idiopathic arthritis-associated uveitis. Br J Ophthalmol. 2016;100(6):782–6.
Heiligenhaus A, Miserocchi E, Heinz C, Gerloni V, Kotaniemi K. Treatment of severe uveitis associated with juvenile idiopathic arthritis with anti-CD20 monoclonal antibody (rituximab). Rheumatology (Oxford, England). 2011;50(8):1390–4.
Guex-Crosier Y, Raber J, Chan CC, et al. Humanized antibodies against the alpha-chain of the IL-2 receptor and against the beta-chain shared by the IL-2 and IL-15 receptors in a monkey uveitis model of autoimmune diseases. J Immunol (Baltimore, Md.: 1950). 1997;158(1):452–8.
Nussenblatt RB, Thompson DJ, Li Z, et al. Humanized anti-interleukin-2 (IL-2) receptor alpha therapy: long-term results in uveitis patients and preliminary safety and activity data for establishing parameters for subcutaneous administration. J Autoimmun. 2003;21(3):283–93.
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):764–70.
Sobrin L, Huang JJ, Christen W, Kafkala C, Choopong P, Foster CS. Daclizumab for treatment of birdshot chorioretinopathy. Arch Ophthalmol (Chicago, Ill.: 1960). 2008;126(2):186–91.
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.
Murray PI, Hoekzema R, van Haren MA, de Hon FD, Kijlstra A. Aqueous humor interleukin-6 levels in uveitis. Invest Ophthalmol Vis Sci. 1990;31(5):917–20.
Kramer M, Monselise Y, Bahar I, Cohen Y, Weinberger D, Goldenberg-Cohen N. Serum cytokine levels in active uveitis and remission. Curr Eye Res. 2007;32(7–8):669–75.
Calvo-Rio V, Santos-Gomez M, Calvo I, et al. Anti-Interleukin-6 receptor tocilizumab for severe juvenile idiopathic arthritis-associated uveitis refractory to anti-tumor necrosis factor therapy: a multicenter study of twenty-five patients. Arthritis Rheumatol (Hoboken, NJ). 2017;69(3):668–75.
Adan A, Mesquida M, Llorenc V, et al. Tocilizumab treatment for refractory uveitis-related cystoid macular edema. Graefes Arch Clin Exp Ophthalmol. 2013;251(11):2627–32.
Yamada A, Salama AD, Sayegh MH. The role of novel T cell costimulatory pathways in autoimmunity and transplantation. J Am Soc Nephrol. 2002;13(2):559–75.
Sayegh MH, Turka LA. The role of T-cell costimulatory activation pathways in transplant rejection. N Engl J Med. 1998;338(25):1813–21.
Birolo C, Zannin ME, Arsenyeva S, et al. Comparable efficacy of Abatacept used as first-line or second-line biological agent for severe juvenile idiopathic arthritis-related uveitis. J Rheumatol. 2016;43(11):2068–73.
Megget K. FEATURE: Follow the leader. 2015; http://www.pharmatimes.com/news/feature_follow_the_leader_971332. Accessed 12 Mar 2017.
Jacobs I, Petersel D, Isakov L, Lula S, Lea Sewell K. Biosimilars for the treatment of chronic inflammatory diseases: a systematic review of published evidence. BioDrugs. 2016;30(6):525–70.
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John Gonzales and Nisha Acharya declare that they have no conflict of interest. No human or animal studies were carried out by the authors for this chapter.
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Gonzales, J.A., Acharya, N. (2019). Noninfectious Uveitis: Immunomodulatory Agents and Biologicals. In: Rao, N., Schallhorn, J., Rodger, D. (eds) Posterior Uveitis. Essentials in Ophthalmology. Springer, Cham. https://doi.org/10.1007/978-3-030-03140-4_11
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