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Update on intravitreal anti-tumor necrosis factor alpha therapies for ocular disorders

Abstract

Tumor necrosis factor alpha (TNF-?) is an important pro-inflammatory cytokine associated with a variety of ocular diseases. The currently available TNF-? inhibitors are etanercept, infliximab, adalimumab, golimumab, and certolizumab. Experimental and clinical studies on the intravitreal use of these agents have been reported with etanercept, infliximab, and adalimumab: etanercept has shown limited efficacy in scarce reports; infliximab has been associated with local safety concerns but appears to benefit certain cases; adalimumab has shown no efficacy in cases of age-related macular degeneration (AMD) or diabetic macular edema (DME), but the combination with bevacizumab may be effective in refractory cases of macular diseases. Further preclinical and clinical studies are warranted in order to be able to obtain a more robust conclusion on the use of intravitreal TNF-? inhibitors.

Review

Introduction

Inflammation has been implicated as one of the pivotal mediators of retinal injury in the pathogenesis of most sight-threatening ocular diseases including uveitis, diabetic retinopathy and diabetic macular edema (DME), and atrophic and neovascular age-related macular degeneration (AMD) [1],[2]. Thus, a variety of anti-inflammatory and immunomodulatory agents have been tested as potential single or combination therapies in the management of intraocular inflammation, hyperpermeability, and neovascularization. Traditionally, corticosteroids have been the standard approach to this inflammatory pathway inhibition. However, their systemic and ocular safety profiles limit their use [3].

Tumor necrosis factor alpha (TNF-?) is an important pro-inflammatory cytokine with pleiotropic functions synthesized mainly by T lymphocytes and macrophages and to a lesser extent by neutrophils and mast cells [4]. It plays a major role in the regulation of immune cells, inhibition of tumorigenesis, and inhibition of viral replication [5]-[8].

The currently available TNF-? inhibitors are etanercept, infliximab, adalimumab, golimumab, and certolizumab. Etanercept (Enbrel; Pfizer Inc; New York, NY, USA) is a TNF receptor-IgG fusion protein that mimics the inhibitory effects of naturally occurring soluble TNF receptors that is injected subcutaneously. Infliximab (Remicade; Schering-Plough, Rathdrum, Ireland) is a mouse-human chimeric antibody that neutralizes the biological activity of TNF-? by high-affinity binding to the soluble and transmembrane forms of TNF-?, therefore preventing the effective binding of TNF-? with its receptors. It is administered intravenously. Adalimumab (Humira; AbbVie Inc., North Chicago, IL, USA) is a fully human monoclonal antibody that also binds selectively all forms of TNF-?. It is also injected subcutaneously. Golimumab (Simponi; Centocor, Horsham, PA, USA, and Schering-Plough, Rathdrum, Ireland) is a fully human monoclonal antibody against TNF-? that is administered via a subcutaneous injection. Certolizumab (Cimzia; UCB Pharma, Brussels, Belgium) is a monoclonal antibody that combines the Fab fragment of the TNF antibody with polyethylene glycol that is delivered subcutaneously. Table?1 summarizes the main features of these molecules.

Table 1 Summary of the main features of the currently available tumor necrosis factor alpha inhibitors

Reported risks of the systemic administration (intravenous or subcutaneous) of TNF-? inhibitors include fatal blood disorders, secondary infections, and reactivation of latent infections, tumorigenesis, drug-induced lupus, or demyelinating central nervous system disorders among others. These potentially severe adverse events led to the investigation by ophthalmologists of alternative administration routes minimizing these risks but preserving the efficacy of the drugs. The possibility of performing intravitreal injection of TNF-? inhibitors could fulfill both needs [9]. However, no well-designated trials have been conducted to date [9]-[11], and the use of the intravitreal route of administration of TNF-? inhibitors has not been generalized.

The purposes of the present review are to analyze the current published evidence with regard to intravitreal injection of TNF-? inhibitors and to summarize the outcomes with this novel therapeutic approach.

Methods

A systematic review of all the peer-reviewed articles indexed in PubMed was performed. A comprehensive search of the literature was conducted using the online biomedical search engine PubMed. Search terms included the following: intravitreal, etanercept, infliximab, adalimumab, golimumab, certolizumab, tumor necrosis factor inhibitors. No publication date limit was applied, thus including all the available reports. Preclinical experimental models, clinical case reports, pilot studies, and case series were reviewed independently for the intravitreal use of etanercept, infliximab, and adalimumab. Relevant articles cited in papers retrieved from PubMed were also reviewed. No preclinical or clinical experience with intraocular administration of golimumab or certolizumab was found.

Intravitreal experience with etanercept

Experimental animal models showed that intravitreal injections of etanercept up to 2.5?mg may be well tolerated without significant toxic effects on the retina [12],[13].

Clinical experience has been limited to a small pilot study that included seven patients with refractory DME [14]. Following two intravitreal injections of 2.5?mg (0 and 1?mL) of etanercept with a 2-week interval, no adverse event was registered, obtaining no significant improvement in 3?months after initiation of this treatment [14]. There is no scientific background that may reinforce the use of intravitreal injections of etanercept for the management of ocular diseases.

Intravitreal experience with infliximab

Experimental animal models showed that intravitreal injections of infliximab were tolerated up to 2.0?mg. However, doses higher than 3.3?mg may be potentially toxic to the retina [15]-[20]. Also, Regatieri et al. showed in a laser-induced choroidal neovascularization model that intravitreal infliximab when injected at doses of 10 to 40 ?g has an anti-angiogenic effect, whereas higher doses (320 ?g) showed pro-angiogenic effects [21]. More recently, Yuksel et al. evidenced in a rabbit model of experimental endotoxin-induced uveitis that intravenous administration of infliximab was more effective than the intravitreal route in an acute period [22].

Beer et al. suggested that infliximab may be suitable for compounding and could be a cost-effective intravitreal medication for use in clinical practice [23]. A summary of the clinical experience reported is provided in Table?2.

Table 2 Summary of publications regarding the use of intravitreal infliximab

Theodossiadis and colleagues treated three patients with exudative AMD unresponsive to ranibizumab with two injections of 2?mg of infliximab given 2?months apart [24]. They reported visual improvement in all three cases (20/200 to 20/40; 20/200 to 20/70; and 20/100 to 20/30) with no safety concerns. In contrast, Giganti et al. reported that intravitreal infliximab at a dose of 0.5?mg in two eyes of DME and in two cases of neovascular AMD was associated with anatomic, electroretinographic, and microperimetric worsening, and three of these cases developed intraocular inflammation [25]. Arias et al. conducted a prospective interventional trial of four eyes with exudative AMD refractory to anti-vascular endothelial growth factor (VEGF) agents. They reported that intravitreal infliximab at a dose of 2?mg did not provide any visual or anatomic benefit. Furthermore, half of their patients developed a severe intraocular inflammatory reaction [26]. The Pan-American Collaborative Retina Study Group has published the largest series on the use of intravitreal infliximab in both DME and exudative AMD. In their series, eyes with refractory DME received a single intravitreal injection of infliximab 1.0?mg/0.05?mL (15 eyes) or 2.0?mg/0.10?mL (19 eyes). No significant anatomical or functional benefit was evidenced. In addition, 42% of eyes injected with 2?mg developed a severe uveitis, and three of these eyes (37.5%) required pars plana vitrectomy [27]. Similar results were found in 26 eyes with partially responsive neovascular AMD to intravitreal injections of VEGF inhibitors. No functional gains were seen, and in addition, 37.5% of patients developed a severe uveitis that resolved with intensive topical steroid therapy [28].

Farvardin et al. reported positive both short- and long-term (6 months) outcomes after intravitreal infliximab 1.5?mg/0.15?mL in ten eyes of seven patients with chronic persistent noninfectious uveitis without any ocular adverse event, showing a visual mean visual improvement from 1.37 logMAR to 0.67 logMAR 1 month after the injection, which was not sustained by month 6 due to recurrence of macular edema and vitreous haze [29],[30].

Markomichelakis et al. reported that a single intravitreal injection of infliximab 1.0?mg/0.05?mL controlled intraocular inflammation in 15 cases with relapsing posterior uveitis associated with Beh?et's disease [31].

Wu et al. found that a single intravitreal injection of infliximab 1.0?mg/0.10?mL achieved excellent outcomes after 6?months, without any intraocular inflammation, in seven cases of refractory pseudophakic cystoid macular edema [32].

Intravitreal experience with adalimumab

Experimental animal models have shown that intravitreal injections of adalimumab were tolerated up to 5.0?mg without electroretinographic or histological alterations [33]. However, doses of 10.0?mg have been associated with early retinal toxicity and a significant decrease in the photopic wave in the electroretinographic response [34],[35].

The Pan-American Collaborative Retina Study Group published their clinical experience with intravitreal injections of adalimumab for patients with refractory DME and partially responsive neovascular AMD to VEGF inhibitors. Intravitreal injections of adalimumab 2.0?mg/0.08?mL did not provide any anatomical or functional benefit in five cases of DME nonresponsive to conventional therapies and four cases of neovascular AMD. No ocular side effects were reported by the authors following intravitreal injections of adalimumab [26],[27].

The possible role of intravitreal adalimumab in combination with anti-angiogenic agents (bevacizumab) has also been analyzed by these authors. In their case series of seven eyes of five patients with macular edema of various etiologies including partially responsive neovascular AMD, a clinically relevant response was achieved after combination intravitreal treatment with adalimumab 2?mg/0.08?mL and bevacizumab 1.25?mg/0.05?mL [36].

Conclusions

Overall, the literature review of all published manuscripts regarding the use of intravitreal TNF-? inhibitors reveals the following conclusions: 1) intravitreal injections of etanercept may not be useful in the management of ocular diseases, 2) intravitreal injections of infliximab may potentially be related to severe intraocular inflammation, 3) intravitreal injections of infliximab do not appear to benefit cases of refractory DME or partially responsive neovascular AMD, 4) intravitreal injections of infliximab may benefit cases of persistent noninfectious posterior uveitis and refractory pseudophakic cystoid macular edema, 5) intravitreal injections of adalimumab do not appear to benefit cases of DME or neovascular AMD, 6) intravitreal combination of adalimumab and bevacizumab may be effective in the management of cases with partially responsive neovascular AMD and macular edema of various etiologies, and 7) no preclinical or clinical experience with intravitreal golimumab or certolizumab has yet been published.

It is important to emphasize that all the reviewed reports include small samples, variable endpoints and follow-up periods, and heterogeneity in the doses administered, the selection criteria, and the patient population [9]-[11]. The off-label intravitreal use of any drug should be cautiously considered given the potentially severe adverse events that this procedure may induce. Further preclinical and clinical studies are warranted in order to be able to obtain a more robust conclusion on the use of intravitreal TNF-? inhibitors.

Abbreviations

AMD:

age-related macular degeneration

DME:

diabetic macular edema

TNF:

tumor necrosis factor

VEGF:

vascular endothelial growth factor

References

  1. Noma H, Mimura T, Eguchi S: Association of inflammatory factors with macular edema in branch retinal vein occlusion. JAMA Ophthalmol 2013, 131: 160–165. 10.1001/2013.jamaophthalmol.228

    Article  CAS  PubMed  Google Scholar 

  2. Augustin AJ, Kirchhof J: Inflammation and the pathogenesis of age-related macular degeneration. Expert Opin Ther Targets 2009, 13: 641–651. 10.1517/14728220902942322

    Article  CAS  PubMed  Google Scholar 

  3. Wang Y, Wang VM, Chan CC: The role of anti-inflammatory agents in age-related macular degeneration (AMD) treatment. Eye (Lond) 2011, 25: 127–139. 10.1038/eye.2010.196

    Article  PubMed Central  Google Scholar 

  4. Theodossiadis PG, Markomichelakis NN, Sfikakis PP: Tumor necrosis factor antagonists: preliminary evidence for an emerging approach in the treatment of ocular inflammation. Retina 2007, 27: 399–413. 10.1097/MAJ.0b013e3180318fbc

    Article  PubMed  Google Scholar 

  5. Bazzoni F, Beutler B: The tumor necrosis factor ligand and receptor families. N Engl J Med 1996, 334: 1717–1724. 10.1056/NEJM199606273342607

    Article  CAS  PubMed  Google Scholar 

  6. Feldmann M, Maini RN: Anti-TNF-a therapy of rheumatoid arthritis: what have we learned? Annu Rev Immunol 2001, 19: 163–196. 10.1146/annurev.immunol.19.1.163

    Article  CAS  PubMed  Google Scholar 

  7. Sfikakis PP, Kollias G: TNF biology in experimental and clinical arthritis. Curr Opin Rheumatol 2003, 15: 380–386. 10.1097/00002281-200307000-00003

    Article  CAS  PubMed  Google Scholar 

  8. Croft M: The role of TNF superfamily members in T-cell function and diseases. Nat Rev Immunol 2009, 9: 271–285. 10.1038/nri2526

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. 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 2010, 30: 1–5. 10.1097/IAE.0b013e3181cde727

    Article  PubMed Central  PubMed  Google Scholar 

  10. Modorati G, Miserocchi E: Intravitreal injection therapy in the treatment of noninfectious uveitis. Dev Ophthalmol 2012, 51: 110–121. 10.1159/000336471

    Article  CAS  PubMed  Google Scholar 

  11. Tempest-Roe S, Joshi L, Dick AD, Taylor SR: Local therapies for inflammatory eye disease in translation: past, present and future. BMC Ophthalmol 2013,6(13):39. 10.1186/1471-2415-13-39

    Article  Google Scholar 

  12. Fauser S, Kalbacher H, Alteheld N, Koizumi K, Krohne TU, Joussen AM: Pharmacokinetics and safety of intravitreally delivered etanercept. Graefes Arch Clin Exp Ophthalmol 2004, 242: 582–586. 10.1007/s00417-004-0895-x

    Article  CAS  PubMed  Google Scholar 

  13. Kivilcim M, Peyman GA, Kazi AA, Dellacroce J, Ghobrial RN, Monzano R: Intravitreal toxicity of high-dose etanercept. J Ocul Pharmacol Ther 2007, 23: 57–62. 10.1089/jop.2006.0083

    Article  CAS  PubMed  Google Scholar 

  14. Tsilimbaris MK, Panagiotoglou TD, Charisis SK, Anastasakis A, Krikonis TS, Christodoulakis E: The use of intravitreal etanercept in diabetic macular oedema. Semin Ophthalmol 2007, 22: 75–79. 10.1080/08820530701418243

    Article  PubMed  Google Scholar 

  15. Olson JL, Courtney RJ, Mandava N: Intravitreal infliximab and choroidal neovascularization in an animal model. Arch Ophthalmol 2007, 125: 1221–1224. 10.1001/archopht.125.9.1221

    Article  CAS  PubMed  Google Scholar 

  16. Giansanti F, Ramazzotti M, Vannozzi L, Rapizzi E, Fiore T, Iaccheri B, Degl' Innocenti D, Moncini D, Menchini U: A pilot study on ocular safety of intravitreal infliximab in a rabbit model. Invest Ophthalmol Vis Sci 2008, 49: 1151–1156. 10.1167/iovs.07-0932

    Article  PubMed  Google Scholar 

  17. Theodossiadis PG, Liarakos VS, Sfikakis PP, Charonis A, Agrogiannis G, Kavantzas N, Vergados IA: Intravitreal administration of the anti-TNF monoclonal antibody infliximab in the rabbit. Graefes Arch Clin Exp Ophthalmol 2009, 247: 273–281. 10.1007/s00417-008-0967-4

    Article  CAS  PubMed  Google Scholar 

  18. Hosseini H, Safaei A, Khalili MR, Nowroozizadeh B, Eghtedari M, Farvardin M, Nowroozizadeh S, Tolide-Ie HR: Intravitreal infliximab in experimental endotoxin-induced uveitis. Eur J Ophthalmol 2009, 19: 818–823.

    PubMed  Google Scholar 

  19. Melo GB, Moraes Filho MN, Rodrigues EB, Regatieri CV, Dreyfuss JL, Penha FM, Pinheiro MM, Coimbra RC, Haapalainen EF, Farah ME: Toxicity and retinal penetration of infliximab in primates. Retina 2012, 32: 606–612. 10.1097/IAE.0b013e3182252a23

    Article  CAS  PubMed  Google Scholar 

  20. Rassi AR, Rigueiro MP, Isaac DL, Dourado L, Abud MB, Freitas EC, Carneiro LB, Avila MP: A safety study of retinal toxicity after serial intravitreal injections of infliximab in rabbits eyes. Arq Bras Oftalmol 2011, 74: 352–356. 10.1590/S0004-27492011000500009

    Article  PubMed  Google Scholar 

  21. Regatieri CV, Dreyfuss JL, Melo GB, Lavinsky D, Farah ME, Nader HB: Dual role of intravitreous infliximab in experimental choroidal neovascularization: effect on the expression of sulfated glycosaminoglycans. Invest Ophthalmol Vis Sci 2009, 50: 5487–5494. 10.1167/iovs.08-3171

    Article  PubMed  Google Scholar 

  22. Yuksel E, Hasanreisoglu B, Yuksel N, Yilmaz G, Ercin U, Bilgihan A: Comparison of acute effect of systemic versus intravitreal infliximab treatment in an experimental model of endotoxin-induced uveitis. J Ocul Pharmacol Ther 2014, 30: 74–80. 10.1089/jop.2012.0238

    Article  CAS  PubMed  Google Scholar 

  23. Beer PM, Wong SJ, Schartman JP, Kulas KE, Hartman CL, Giganti M, Falk NS: Infliximab stability after reconstitution, dilution, and storage under refrigeration. Retina 2010, 30: 81–84. 10.1097/IAE.0b013e3181b48fb4

    Article  PubMed  Google Scholar 

  24. Theodossiadis PG, Liarakos VS, Sfikakis PP, Vergados IA, Theodossiadis GP: Intravitreal administration of the anti-tumor necrosis factor agent infliximab for neovascular age-related macular degeneration. Am J Ophthalmol 2009, 147: 825–830. 10.1016/j.ajo.2008.12.004

    Article  CAS  PubMed  Google Scholar 

  25. Giganti M, Beer PM, Lemanski N, Hartman C, Schartman J, Falk N: Adverse events after intravitreal infliximab (Remicade). Retina 2010, 30: 71–80. 10.1097/IAE.0b013e3181bcef3b

    Article  PubMed  Google Scholar 

  26. Arias L, Caminal JM, Badia MB, Rubio MJ, Catala J, Pujol O: Intravitreal infliximab in patients with macular degeneration who are nonresponders to antivascular endothelial growth factor therapy. Retina 2010, 30: 1601–1608. 10.1097/IAE.0b013e3181e9f942

    Article  PubMed  Google Scholar 

  27. Wu L, Hernandez-Bogantes E, Roca JA, Arevalo JF, Barraza K, Lasave AF: 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: 298–303. 10.1097/IAE.0b013e3181eac7a6

    Article  CAS  PubMed  Google Scholar 

  28. Wu L, Arevalo JF, Hernandez-Bogantes E, Regatieri CV, Roca JA, Farah ME: Intravitreal tumor necrosis factor-alpha inhibitors for neovascular age-related macular degeneration suboptimally responsive to antivascular endothelial growth factor agents: a pilot study from the Pan American Collaborative Retina Study Group. J Ocul Pharmacol Ther 2013, 29: 366–371. 10.1089/jop.2012.0203

    Article  CAS  PubMed  Google Scholar 

  29. Farvardin M, Afarid M, Mehryar M, Hosseini H: Intravitreal infliximab for the treatment of sight-threatening chronic noninfectious uveitis. Retina 2010, 30: 1530–1535. 10.1097/IAE.0b013e3181d3758a

    Article  PubMed  Google Scholar 

  30. 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: 628–631.

    CAS  PubMed  Google Scholar 

  31. Markomichelakis N, Delicha E, Masselos S, Sfikakis PP: Intravitreal infliximab for sight-threatening relapsing uveitis in Beh?et disease: a pilot study in 15 patients. Am J Ophthalmol 2012, 154: 534–541. 10.1016/j.ajo.2012.03.035

    Article  CAS  PubMed  Google Scholar 

  32. Wu L, Arevalo JF, Hernandez-Bogantes E, Roca JA: Intravitreal infliximab for refractory pseudophakic cystoid macular edema: results of the Pan-American Collaborative Retina Study Group. Int Ophthalmol 2012, 32: 235–243. 10.1007/s10792-012-9559-8

    Article  PubMed  Google Scholar 

  33. Tsilimbaris M, Diakonis VF, Naoumidi I, Charisis S, Kritikos I, Chatzithanasis G, Papadaki T, Plainis S: Evaluation of potential retinal toxicity of adalimumab (Humira). Graefes Arch Clin Exp Ophthalmol 2009, 247: 1119–1125. 10.1007/s00417-009-1065-y

    Article  CAS  PubMed  Google Scholar 

  34. Lichtlen P, Lam TT, Nork TM, Streit T, Urech DM: Relative contribution of VEGF and TNF-alpha in the cynomolgus laser-induced CNV model: comparing the efficacy of bevacizumab, adalimumab, and ESBA105. Invest Ophthalmol Vis Sci 2010, 51: 4738–4745. 10.1167/iovs.09-4890

    Article  PubMed  Google Scholar 

  35. Manzano RP, Peyman GA, Carvounis PE, Damico FM, Aguiar RG, Ioshimoto GL, Ventura DF, Cursino ST, Takahashi W: Toxicity of high-dose intravitreal adalimumab (Humira) in the rabbit. J Ocul Pharmacol Ther 2011, 27: 327–331. 10.1089/jop.2010.0174

    Article  CAS  PubMed  Google Scholar 

  36. Arevalo JF, Serrano MA, Wu L: Combined inhibition of tumor necrosis factor (TNF) and vascular endothelial growth factor (VEGF) for the treatment of macular edema of various etiologies: a short-term pilot study. Eye (Lond) 2013, 27: 569–571. 10.1038/eye.2012.301

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Maria Andreu Fenoll for her valuable help in this manuscript and Dr. M Dolores Pinazo Dur?n for her careful review of this manuscript.

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Pascual-Camps, I., Hernández-Martínez, P., Monje-Fernández, L. et al. Update on intravitreal anti-tumor necrosis factor alpha therapies for ocular disorders. J Ophthal Inflamm Infect 4, 26 (2014). https://doi.org/10.1186/s12348-014-0026-8

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