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TNF Inhibition for Ophthalmic Indications: Current Status and Outlook

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Abstract

Background

Tumor necrosis factors (TNF) are a group of cytokines that play a role in systemic inflammation, stimulating the acute phase reaction. They are involved in systemic rheumatologic conditions such as rheumatoid arthritis and juvenile idiopathic arthritis, as well as ocular inflammatory conditions in the uveitis spectrum. Several drugs were developed to inhibit the action of TNF, thereby reducing inflammation. The three most commonly used TNF inhibitors in the US are etanercept, infliximab, and adalimumab. Newer drugs include certolizumab and golimumab. In this review, we discuss the differences in the mechanism of action, route of administration, indication, and efficacy of TNF inhibitors used in the treatment of ocular inflammation.

Methods

A review of the literature in the PubMed, MEDLINE, and Cochrane databases was conducted to identify clinical trials, comparative studies, case series, and case reports describing the use of tumor necrosis factor inhibitors in uveitis therapy. The search was limited to primary reports published in English with human subjects from 1990 to the present, yielding 5,238 manuscripts. In addition, referenced articles from the initial searches were hand searched to identify additional relevant reports. After title and abstract selection, duplicate elimination, and manual search, 69 papers were selected for analysis. Exclusion criteria included review articles and case reports on the efficacy of etanercept, infliximab, and adalimumab. Manuscripts with fewer than 20 study subjects were excluded if other larger studies existed on the use of the same drug for a particular indication. Studies with <6 months of patient follow-up were also excluded, except in the case where no other data were available. Articles meeting these criteria were then reviewed by the three authors for inclusion in this review.

Results

Tumor necrosis factor inhibitors have been shown to decrease inflammation associated with a number of rheumatologic conditions. Three of the five commercially available TNF inhibitors—etanercept, infliximab, and adalimumab—have been studied for their efficacy in treatment of ocular inflammation. Etanercept appears to be inadequate in controlling ocular inflammation and is not recommended for the treatment of uveitis. Infliximab and adalimumab, however, have shown encouraging results in multiple trials. Serious potential side effects such as infection, including reactivation of latent tuberculosis, malignancy, and demyelinating disease, may limit the use of TNF inhibitors in uveitis. Proper screening of patients prior to initiating these therapies may decrease these risks.

Discussion

Early success with infliximab and adalimumab has paved the way for new TNF inhibitors and other corticosteroid-sparing drugs to emerge in the treatment of ocular inflammation. Future studies are on the horizon to determine the long-term safety and efficacy of newer TNF inhibitors such as certolizumab and golimumab.

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References

  1. 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.

    Article  PubMed  Google Scholar 

  2. Foster CS, Vitale AT. Diagnosis and treatment of uveitis. 1st ed. Philadelphia: WB Saunders; 2002. p. 17–23.

    Google Scholar 

  3. 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.

    Article  PubMed  Google Scholar 

  4. Chiang YP, Bassi LJ, Javitt JC. Federal budgetary costs of blindness. Milbank Q. 1992;70(2):319–40.

    Article  PubMed  CAS  Google Scholar 

  5. Nussenblatt RB. The natural history of uveitis. Int Ophthalmol. 1990;14(5–6):303–8.

    Article  PubMed  CAS  Google Scholar 

  6. Birnbaum AD, Little DM, Tessler HH, et al. Etiologies of chronic anterior uveitis at a tertiary referral center over 35 years. Ocul Immunol Inflamm. 2011;19(1):19–25.

    Article  PubMed  Google Scholar 

  7. Okharavi N, Odufuwa B, McCluskey P, et al. Scleritis. Surv Ophthalmol. 2005;50(4):351–63.

    Article  Google Scholar 

  8. Akpek EK, Thorne JE, Qazi FA, et al. Evaluation of patients with scleritis for systemic disease. Ophthalmology. 2004;111(3):501–6.

    Article  PubMed  Google Scholar 

  9. Saintz de la Maza MS, Molina N, Gonzalez-Gonzalez LA, et al. Clinical characteristics of a large cohort of patients with scleritis and episcleritis. Ophthalmology. 2012;119(1):43–50.

    Article  Google Scholar 

  10. Sainz de la Maza M, Jabbur NS, Foster CS. Severity of scleritis and episcleritis. Ophthalmology. 1994;101(2):389–96.

    PubMed  CAS  Google Scholar 

  11. Pfeffer K. Biologic functions of tumor necrosis factor cytokines and their receptors. Cytokine Growth Factor Rev. 2003;14(3–4):185–91.

    Article  PubMed  CAS  Google Scholar 

  12. Gullick NJ, Scott DL. Drug therapies of inflammatory arthritis. Clin Med. 2012;12(4):357–63.

    Article  PubMed  Google Scholar 

  13. Gregory AC, Kempen JH, Daniel E, Kaçmaz RO, et al; Systemic Immunosuppressive Therapy for Eye Diseases Cohort Study Research Group. Risk factors for loss of visual acuity among patients with uveitis associated with juvenile idiopathic arthritis: the systemic immunosuppressive therapy for eye diseases study. Ophthalmology. 2012. doi:10.1016/j.ophtha.2012.07.052.

  14. Scott DL. Etanercept in arthritis. Int J Clin Pract. 2005;59(1):114–8.

    Article  PubMed  CAS  Google Scholar 

  15. Nestorov J. Clinical pharmacokinetics of TNF antagonists: how do they differ? Semin Arthritis Rheum. 2005;34(5 Suppl 1):12–8.

    Article  PubMed  CAS  Google Scholar 

  16. Kavanaugh A, St Clair EW, McCune WJ, et al. Chimeric anti-tumor necrosis factor-alpha monoclonal antibody treatment of patients with rheumatoid arthritis receiving methotrexate therapy. J Rheumatol. 2000;27(4):841–50.

    PubMed  CAS  Google Scholar 

  17. Martel JN, Esterberg E, Nagpal A, et al. Infliximab and adalimumab for uveitis. Ocul Immunol Inflamm. 2012;20(1):18–26.

    Article  PubMed  CAS  Google Scholar 

  18. Bourne T, Fossati G, Nesbitt A. A PEGylated Fab′ fragment against tumor necrosis factor for the treatment of Crohn disease: exploring a new mechanism of action. Biodrugs. 2008;22(5):331–7.

    Article  PubMed  CAS  Google Scholar 

  19. Tlucek PS, Stone DU. Certolizumab pegol-therapy for rheumatoid arthritis associated scleritis. Cornea. 2012;31(1):90–1.

    Article  PubMed  Google Scholar 

  20. Shealy D, Cai A, Staquet K, et al. Characterization of golimumab, a human monoclonal antibody specific for human tumor necrosis factor A. MAbs. 2010;2(4) [Epub ahead of print].

  21. Cordero-Coma M, Salom D, Diaz-Llopis M, et al. Golimumab for uveitis. Ophthalmology. 2012;118(9):1892.e3–4.

    Article  Google Scholar 

  22. Markomichelakis N, Delicha E, Masselos S, et al. A single infliximab infusion versus corticosteroids for acute panuveitis attacks in Behcet’s disease: a comparative four-week study. Rheumatology. 2011;50(3):593–7.

    Article  PubMed  CAS  Google Scholar 

  23. Greenberg SB. Infections in the immunocompromised rheumatologic patient. Crit Care Clin. 2002;18:931–56.

    Article  PubMed  Google Scholar 

  24. Ruderman EM. Overview of safety of non-biologic and biologic DMARDs. Rheumatology. 2012;51(Suppl 6):vi37–43.

    Article  PubMed  Google Scholar 

  25. Keane J, Gershon S, Wise RP, et al. Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med. 2001;345(15):1098–104.

    Article  PubMed  CAS  Google Scholar 

  26. Cansu DU, Kalifoglu T, Korkmaz C. Short-term course of chronic hepatitis B and C under treatment with etanercept associated with different disease modifying antirheumatic drugs without antiviral prophylaxis. J Rheumatol. 2008;35:421–4.

    PubMed  CAS  Google Scholar 

  27. Ferri C, Ferraccioli G, Ferrari D, et al. Safety of anti-tumor necrosis factor-alpha therapy in patients with rheumatoid arthritis and chronic hepatitis C virus infection. J Rheumatol. 2008;35:1944–9.

    PubMed  CAS  Google Scholar 

  28. Van Dartel SA, Fransen J, Kierit W, et al. Difference in the risk of serious infections in patients with rheumatoid arthritis treated with adalimumab, infliximab and etanercept: results from the Dutch Rheumatoid Arthritis Monitoring (DREAM) registry. Ann Rheum Dis. 2012 [Epub ahead of print].

  29. Solomon AJ, Spain RI, Kruer MC, et al. Inflammatory neurological disease in patients treated with tumor necrosis factor alpha inhibitors. Mult Scler. 2011;17(12):1472–87.

    Article  PubMed  CAS  Google Scholar 

  30. Li SY, Birnbaum AD, Goldstein DA. Optic neuritis associated with adalimumab in the treatment of uveitis. Ocul Immuno Inflamm. 2010;18(6):475–81.

    Article  CAS  Google Scholar 

  31. Chung ES, Packer M, Lo KH, Fasanmade AA, et al. Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-alpha, in patients with moderate-to-severe heart failure: results of the anti-TNF Therapy Against Congestive Heart Failure (ATTACH) trial. Circulation. 2003;107(25):3133–40.

    Article  PubMed  CAS  Google Scholar 

  32. Debandt M, VIttecog O, Descamps V, Le Loet X X, et al. Anti-TNF-alpha-induced systemic lupus syndrome. Clin Rheumatol. 2003;22(1):56–61.

    Article  PubMed  CAS  Google Scholar 

  33. Lamirau T, Cezardo JP, Dabadie A, Goulet D. Efficacy and tolerance of infliximab in children and adolescents with Crohn’s disease. Inflamm Bowel Dis. 2004;10(6):745–50.

    Article  Google Scholar 

  34. FDA. 2008. Early communication about an ongoing safety review of tumor necrosis factor (TNF) blockers (marketed as remicade, Enbrel, humira, and cimzia). http://www.fda.gove/drugs/drugsafety/postmarketdrugesafetyinformationforpatientsandproviders/drugsafetyinformationforhealthcareprofessionals/UCM070725.

  35. Diak P, Siegel J, La Grenade L, et al. Tumor necrosis factor alpha blockers and malignancy in children; forty-eight cases reported to the Food and Drug Administration. Arthritis Rheum. 2010;62:2517–24.

    Article  PubMed  Google Scholar 

  36. Lehman TJ. Should the Food and Drug Administration warning of malignancy in children receiving tumor necrosis factor alpha blockers change the way we treat children with juvenile idiopathic arthritis? Arthritis Rheum. 2010;62:2183–4.

    Article  PubMed  Google Scholar 

  37. 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):903–12.

    Article  PubMed  CAS  Google Scholar 

  38. Suhler EB, Smith JR, Giles TR, et al. Infliximab therapy for refractory uveitis: 2-year results of a prospective trial. Arch Ophthalmol. 2009;127(6):819–22.

    PubMed  CAS  Google Scholar 

  39. Sobrin L, Kim EC, Christen W, et al. Infliximab therapy for the treatment of refractory ocular inflammatory disease. Arch Ophthalmol. 2007;125(7):895–900.

    Article  PubMed  CAS  Google Scholar 

  40. Lopez Gonzalez R, Loza E, Jover JA, et al. Treatment for refractory posterior uveitis with infliximab: a 7 year follow up study. Scand J Rheumatol. 2009;38(1):58–62.

    Article  PubMed  CAS  Google Scholar 

  41. Turan B, Pfister K, Diener PA, et al. Soluble tumor necrosis factor receptors sTNFR1 and sTNFR2 are produced at sites of inflammation and are markers of arthritis activity in Behçet’s disease. Scand J Rheumatol. 2008;37(2):135–41.

    Article  PubMed  CAS  Google Scholar 

  42. Tabbara KF, Al-Hemidal A. Infliximab effects compared to conventional therapy in the management of retinal vasculitis in Behçet disease. Am J Ophthalmol. 2008;146(6):845–50.

    Article  PubMed  CAS  Google Scholar 

  43. Yamada Y, Sugita S, Tanaka H, et al. Comparison of infliximab versus cyclosporine during the initial 6-month treatment period in Behçet disease. Br J Ophthalmol. 2010;94:284–8.

    Article  PubMed  Google Scholar 

  44. Yamada Y, Sugita S, Tanaka H, et al. Timing of recurrent uveitis in patients with Behçet’s disease receiving infliximab treatment. Br J Ophthalmol. 2011;95:205–8.

    Article  PubMed  Google Scholar 

  45. Giardina A, Ferrante A, Ciccia F, et al. One year study of efficacy and safety of infliximab in the treatment of patients with ocular and neurological Behçet’s disease refractory to standard immunosuppressive drugs. Rheumatol Int. 2011;31(1):33–7.

    Article  PubMed  CAS  Google Scholar 

  46. Keino H, Okada AA, Watanabe T, et al. Decreased ocular inflammatory attacks and background retinal and disc vascular leakage in patients with Behçet’s disease on infliximab therapy. Br J Ophthalmol. 2011;95(9):1245–50.

    Article  PubMed  Google Scholar 

  47. Iwata D, Namba K, Mizuuchi K, et al. Correlation between elevation of serum antinuclear antibody titer and decreased therapeutic efficacy in the treatment of Behcet’s disease with infliximab. Graefes Arch Clin Exp Ophthalmol. 2012;250(7):1081–7.

    Article  PubMed  CAS  Google Scholar 

  48. Ardoin SP, Kredich D, Rabinovich E, et al. Infliximab to treat chronic noninfectious uveitis in children: a retrospective case series with long-term follow-up. Am J Ophthalmol. 2007;144(6):844–9.

    Article  PubMed  CAS  Google Scholar 

  49. Kahn P, Weiss M, Imundo LF, et al. Favorable response to high-dose infliximab for refractory childhood uveitis. Ophthalmology. 2006;113(5):860–4.

    Article  PubMed  Google Scholar 

  50. Simonini G, Zannin ME, Caputo R, et al. Loss of efficacy during long-term infliximab therapy for sight-threatening childhood uveitis. Rheumatology. 2008;47(10):1510–4.

    Article  PubMed  CAS  Google Scholar 

  51. Milman N, Andersen CB, Hansen A, et al. Favourable effect of TNF-alpha inhibitor (infliximab) on Blau syndrome in monozygotic twins with a de novo CARD15 mutation. APMIS. 2006;114(12):912–9.

    Article  PubMed  Google Scholar 

  52. Gupta SR, Phan IT, Suhler EB. Successful treatment of refractory sympathetic ophthalmia in a child with infliximab. Arch Ophthalmol. 2011;129(2):250–2.

    Article  PubMed  Google Scholar 

  53. Khalifa YM, Bailony MR, Acharya NR. Treatment of pediatric Vogt–Koyanagi–Harada syndrome with infliximab. Ocul Immunol Inflamm. 2010;18(3):218–22.

    Article  PubMed  CAS  Google Scholar 

  54. Murphy CC, Ayliffe WH, Booth A, et al. Tumor necrosis factor alpha blockade with infliximab for refractory uveitis and scleritis. Ophthalmology. 2004;111(2):352–6.

    Article  PubMed  Google Scholar 

  55. Sen HN, Sangave A, Hammel K, et al. Infliximab for the treatment of active scleritis. Can J Ophthalmol. 2009;44(3):e9–12.

    Article  PubMed  Google Scholar 

  56. Doctor P, Sultan A, Syed S, et al. Infliximab for the treatment of refractory scleritis. Br J Ophthalmol. 2010;94:579–83.

    Article  PubMed  Google Scholar 

  57. Díaz-Llopis M, Garcia-Delpech S, Salom D, et al. Adalimumab treatment for refractory uveitis: a pilot study. J Ocul Pharmacol Ther. 2008;24:351–61.

    Article  PubMed  Google Scholar 

  58. Díaz-Llopis M, Salom D, Garcia-de-Vicuña C, et al. Treatment of refractory uveitis with adalimumab: a prospective multicenter study of 131 patients. Ophthalmology. 2012;119:1575–81.

    Article  PubMed  Google Scholar 

  59. Suhler EB, Lowder CY, Goldstein DA, et al. Adalimumab therapy for refractory uveitis: results of a multicenter, open-label, prospective trial. Br J Ophthalmol. [Published Online 2/2013]. doi:10.1136/bjophthalmol-2012-302292.

  60. Dhingra N, Morgan J, Dick AD. Switching biologic agents for uveitis. Eye. 2009;23(9):1868–70.

    Article  PubMed  CAS  Google Scholar 

  61. Olivieri I, Leccese P, D’Angelo S, et al. Efficacy of adalimumab in patients with Behcet’s disease unsuccessfully treated with infliximab. Clin Exp Rheumatol. 2011;29(4 Supp1 67):S54–7.

    PubMed  Google Scholar 

  62. Tynjala P, Kotaniemi K, Lindahl P, et al. Adalimumab in juvenile idiopathic arthritis-associated chronic anterior uveitis. Rheumatology. 2008;47(3):339–44.

    Article  PubMed  CAS  Google Scholar 

  63. Simonini G, Tiddio A, Cattalini M, et al. Prevention of flare recurrences in childhood refractory chronic uveitis: an open label comparative study of adalimumab versus infliximab. Arthritis Care Res. 2011;63:612–8.

    Article  CAS  Google Scholar 

  64. Bartelds GM, Krieckaert CL, Nurmohamed MT, et al. Development of antidrug antibodies against adalimumab and association with disease activity and treatment failure during long-term follow-up. JAMA. 2011;305(14):1460–8.

    Article  PubMed  CAS  Google Scholar 

  65. Takase K, Ohno S, Ideguchi H, et al. Successful switching to adalimumab in an infliximab-allergic patient with severe Behçet disease-related uveitis. Rheumatol Int. 2011;31(2):243–5.

    Article  PubMed  CAS  Google Scholar 

  66. Leccese P, Latanza L, D’Angelo S, et al. Efficacy of switching to adalimumab in a patient with refractory uveitis in Behçet’s disease to infliximab. Clin Exp Rheumatol. 2011;29(4 Suppl 67):S93.

    PubMed  Google Scholar 

  67. Restrepo JP, Molina MP. Successful treatment of severe nodular scleritis with adalimumab. Clin Rheumatol. 2010;29(5):559–61.

    Article  PubMed  Google Scholar 

  68. Reiff A, Takei S, Sadeghi S, et al. Etanercept therapy in children with treatment-resistant uveitis. Arthritis Rheum. 2001;44(6):1411–5.

    Article  PubMed  CAS  Google Scholar 

  69. Foster CS, Tufail F, Waheed NK, et al. Efficacy of etanercept in preventing relapse of uveitis controlled by methotrexate. Arch Ophthalmol. 2003;121(4):437–40.

    Article  PubMed  CAS  Google Scholar 

  70. Smith JA, Thompson DJ, Whitcup SM, et al. A randomized, placebo-controlled, double-masked clinical trial of etanercept for the treatment of uveitis associated with juvenile idiopathic arthritis. Arthritis Rheum. 2005;53(1):18–23.

    Article  PubMed  CAS  Google Scholar 

  71. Galor A, Perez VL, Hammel JP, et al. Differential effectiveness of etanercept and infliximab in the treatment of ocular inflammation. Ophthalmology. 2006;113(12):2317–23.

    Article  PubMed  Google Scholar 

  72. Wendling D, Paccou J, Berthelot JM, et al. New onset of uveitis during anti-tumor necrosis factor treatment for rheumatic diseases. Semin Arthritis Rheum. 2011;41(3):503–10.

    Article  PubMed  Google Scholar 

  73. Gaujoux-Viala C, Giampietro C, Gaujoux T, et al. Scleritis: a paradoxical effect of etanercept? Etanercept-associated inflammatory eye disease. J Rheumatol. 2012;39(2):233–9.

    Article  PubMed  CAS  Google Scholar 

  74. Smith JR, Levinson RD, Holland GN, et al. Differential efficacy of tumor necrosis factor inhibition in the management of inflammatory eye disease and associated rheumatic disease. Arthritis Care Res. 2001;45:252–7.

    Article  CAS  Google Scholar 

  75. Farvardin M, Afarid M, Mehryar M, et al. Intravitreal infliximab for the treatment of sight-threatening chronic noninfectious uveitis. Retina. 2010;30:1530–5.

    Article  PubMed  Google Scholar 

  76. 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.

    Article  PubMed  CAS  Google Scholar 

  77. Giganti M, Beer PM, Lemanski N, et al. Adverse events after intravitreal infliximab (Remicade). Retina. 2010;30(1):71–80.

    Article  PubMed  Google Scholar 

  78. Androudi S, Tsironi E, Kalogeropoulos C, et al. Intravitreal adalimumab for refractory uveitis-related macular edema. Ophthalmology. 2010;117(8):1612–6.

    Article  PubMed  Google Scholar 

  79. 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;154:534–41.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported in part by an unrestricted grant from Research to Prevent Blindness, New York, NY (DAG, ADB). The funding organization had no role in the design or conduct of this research.

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The authors have no conflicts of interest that are directly relevant to the content of this article.

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Authors and Affiliations

  1. Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

    Lana M. Rifkin, Andrea D. Birnbaum & Debra A. Goldstein

  2. Department of Ophthalmology, Northwestern Memorial Hospital, Northwestern Feinberg School of Medicine, 645 Michigan Ave, Chicago, IL, 60611, USA

    Debra A. Goldstein

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  1. Lana M. Rifkin
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Correspondence to Debra A. Goldstein.

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Rifkin, L.M., Birnbaum, A.D. & Goldstein, D.A. TNF Inhibition for Ophthalmic Indications: Current Status and Outlook. BioDrugs 27, 347–357 (2013). https://doi.org/10.1007/s40259-013-0022-9

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