Skip to main content
Top
Published in: Graefe's Archive for Clinical and Experimental Ophthalmology 6/2008

01-06-2008 | Inflammatory Disorders

Ocular toxicity of intravitreous adalimumab (Humira) in the rabbit

Authors: Roberta P. A. Manzano, Gholam A. Peyman, Petros E. Carvounis, Muhamet Kivilcim, Palwasha Khan, Patricia Chevez-Barrios, Walter Takahashi

Published in: Graefe's Archive for Clinical and Experimental Ophthalmology | Issue 6/2008

Login to get access

Abstract

Purpose

To evaluate the ocular toxicity of escalating doses of intravitreous adalimumab (Humira) in the rabbit eye.

Methods

Twelve New Zealand albino rabbits received unilateral intravitreous injections of 0.1 ml of adalimumab 0.25 mg (three eyes), 0.50 mg (three eyes), 1.0 mg (three eyes) or 0.1 ml balanced salt solution (BSS, threeeyes). Slit-lamp biomicroscopy and fundoscopy were carried out at baseline, day 1, 7 and 14 following intravitreous injection, while electroretinography (ERG) was carried out at baseline and day 14. Animals were euthanized on day 14, and histopathological examination of the eyes was performed.

Results

Slit-lamp biomicroscopy and fundoscopy were normal in eyes having received BSS, 0.25 mg or 0.50 mg adalimumab; however, inflammation was present in two of three eyes having received 1.0 mg adalimumab. Similarly, comparison of scotopic and photopic ERG light at baseline and day 14 demonstrated no changes in eyes receiving BSS, 0.25 mg or 0.50 mg adalimumab, but two of three eyes having received 1.0 mg adalimumab showed a greater than 30% reduction in a and b wave. Finally, histopathology demonstrated no differences between eyes receiving BSS, 0.25 mg or 0.50 mg of adalimumab, but two of three eyes injected with 1.0 mg demonstrated inflammatory cell infiltration of the vitreous and anterior chamber, with one of these eyes demonstrating retinal necrosis.

Conclusions

Escalating doses of intravitreous adalimumab in rabbit eyes caused no detectable functional or structural ocular toxicity up to a dose of 0.50 mg. Administration of 1.0 mg in 0.1 ml was associated with an inflammatory reaction and retinal necrosis.
Literature
1.
go back to reference Theodossiadis PG, Markomichelakis NN, Sfikakis PP (2007) Tumor necrosis factor antagonists: preliminary evidence for an emerging approach in the treatment of ocular inflammation. Retina 27:399–413PubMedCrossRef Theodossiadis PG, Markomichelakis NN, Sfikakis PP (2007) Tumor necrosis factor antagonists: preliminary evidence for an emerging approach in the treatment of ocular inflammation. Retina 27:399–413PubMedCrossRef
2.
go back to reference Sobrin L, Kim EC, Christen W, Papadaki T, Letko E, Foster CS (2007) Infliximab therapy for the treatment of refractory ocular inflammatory disease. Arch Ophthalmol 125:895–900PubMedCrossRef Sobrin L, Kim EC, Christen W, Papadaki T, Letko E, Foster CS (2007) Infliximab therapy for the treatment of refractory ocular inflammatory disease. Arch Ophthalmol 125:895–900PubMedCrossRef
3.
go back to reference Murphy CC, Ayliffe WH, Booth A, Makanjuola D, Andrews PA, Jayne D (2004) Tumor necrosis factor alpha blockade with infliximab for refractory uveitis and scleritis. Ophthalmology 111:352–356PubMedCrossRef Murphy CC, Ayliffe WH, Booth A, Makanjuola D, Andrews PA, Jayne D (2004) Tumor necrosis factor alpha blockade with infliximab for refractory uveitis and scleritis. Ophthalmology 111:352–356PubMedCrossRef
4.
go back to reference Kahn P, Weiss M, Imundo LF, Levy DM (2006) Favorable response to high-dose infliximab for refractory childhood uveitis. Ophthalmology 113:860–864PubMedCrossRef Kahn P, Weiss M, Imundo LF, Levy DM (2006) Favorable response to high-dose infliximab for refractory childhood uveitis. Ophthalmology 113:860–864PubMedCrossRef
5.
go back to reference Saurenmann RK, Levin AV, Rose JB, Parker S, Rabinovitch T, Tyrrell PN, Feldman BM, Laxer RM, Schneider R, Silverman ED (2006) Tumour necrosis factor α inhibitors in the treatment of childhood uveitis. Rheumatology 45:982–989PubMedCrossRef Saurenmann RK, Levin AV, Rose JB, Parker S, Rabinovitch T, Tyrrell PN, Feldman BM, Laxer RM, Schneider R, Silverman ED (2006) Tumour necrosis factor α inhibitors in the treatment of childhood uveitis. Rheumatology 45:982–989PubMedCrossRef
6.
go back to reference Markomichelakis NN, Theodossiadis PG, Pantelia E, Papaefthimiou S, Theodossiadis GP, Sfikakis PP (2004) Infliximab for chronic cystoid macular edema associated with uveitis. Am J Ophthalmol 138:648–650PubMedCrossRef Markomichelakis NN, Theodossiadis PG, Pantelia E, Papaefthimiou S, Theodossiadis GP, Sfikakis PP (2004) Infliximab for chronic cystoid macular edema associated with uveitis. Am J Ophthalmol 138:648–650PubMedCrossRef
7.
go back to reference Manzano RPA, Carvounis PE, Albini TA, Holz ER (2007) Etanercept monotherapy induces complete resolution of cystoid macular edema in a patient with refractory intermediate uveitis. Retinal Cases and Brief Reports 1:261–263 Manzano RPA, Carvounis PE, Albini TA, Holz ER (2007) Etanercept monotherapy induces complete resolution of cystoid macular edema in a patient with refractory intermediate uveitis. Retinal Cases and Brief Reports 1:261–263
8.
go back to reference Shi X, Semkova I, Muther PS, Dell S, Kociok N, Joussen AM (2006) Inhibition of TNF-alpha reduces laser-induced choroidal neovascularization. Exp Eye Res 83:1325–1334PubMedCrossRef Shi X, Semkova I, Muther PS, Dell S, Kociok N, Joussen AM (2006) Inhibition of TNF-alpha reduces laser-induced choroidal neovascularization. Exp Eye Res 83:1325–1334PubMedCrossRef
9.
go back to reference Markomichelakis NN, Theodossiadis PG, Sfikakis PP (2005) Regression of neovascular age-related macular degeneration following infliximab therapy. Am J Ophthalmol 139:537–540.PubMedCrossRef Markomichelakis NN, Theodossiadis PG, Sfikakis PP (2005) Regression of neovascular age-related macular degeneration following infliximab therapy. Am J Ophthalmol 139:537–540.PubMedCrossRef
10.
go back to reference Sebastian RT, Harding SP, Bucknall RC, Pearce IA (2006) Optimizing the use of tumor necrosis factoralpha inhibitors in refractory uveitis. Arch Ophthalmol 124:1505PubMedCrossRef Sebastian RT, Harding SP, Bucknall RC, Pearce IA (2006) Optimizing the use of tumor necrosis factoralpha inhibitors in refractory uveitis. Arch Ophthalmol 124:1505PubMedCrossRef
11.
go back to reference Vazquez-Cobian LB, Flynn T, Lehman TJ (2006) Adalimumab therapy for childhood uveitis. J Pediatr 149:572–575PubMedCrossRef Vazquez-Cobian LB, Flynn T, Lehman TJ (2006) Adalimumab therapy for childhood uveitis. J Pediatr 149:572–575PubMedCrossRef
12.
go back to reference Biester S, Deuter C, Michels H, Haefner R, Kuemmerle-Deschner J, Doycheva D et al (2007) Adalimumab in the therapy of uveitis in childhood. Br J Ophthalmol 91:319–324PubMedCrossRef Biester S, Deuter C, Michels H, Haefner R, Kuemmerle-Deschner J, Doycheva D et al (2007) Adalimumab in the therapy of uveitis in childhood. Br J Ophthalmol 91:319–324PubMedCrossRef
13.
go back to reference Guignard S, Gossec L, Salliot C, Ruyssen-Witrand A, Luc M, Duclos M et al (2006) Efficacy of tumour necrosis factor blockers in reducing uveitis flares in patients with spondylarthropathy: a retrospective study. Ann Rheum Dis 65:1631–1634PubMedCrossRef Guignard S, Gossec L, Salliot C, Ruyssen-Witrand A, Luc M, Duclos M et al (2006) Efficacy of tumour necrosis factor blockers in reducing uveitis flares in patients with spondylarthropathy: a retrospective study. Ann Rheum Dis 65:1631–1634PubMedCrossRef
14.
go back to reference Mushtaq B, Saeed T, Situnayake RD, Murray PI (2007) Adalimumab for sight-threatening uveitis in Behcet’s disease. Eye 21:824–825PubMedCrossRef Mushtaq B, Saeed T, Situnayake RD, Murray PI (2007) Adalimumab for sight-threatening uveitis in Behcet’s disease. Eye 21:824–825PubMedCrossRef
15.
go back to reference Bongartz T, Sutton AJ, Sweeting MJ, Buchan I, Matteson EL, Montori V (2006) Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA 295:2275–2285PubMedCrossRef Bongartz T, Sutton AJ, Sweeting MJ, Buchan I, Matteson EL, Montori V (2006) Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA 295:2275–2285PubMedCrossRef
16.
go back to reference Schiff MH, Burmester GR, Kent JD, Pangan AL, Kupper H, Fitzpatrick SB et al (2006) Safety analyses of adalimumab (HUMIRA) in global clinical trials and US postmarketing surveillance of patients with rheumatoid arthritis. Ann Rheum Dis 65:889–894PubMedCrossRef Schiff MH, Burmester GR, Kent JD, Pangan AL, Kupper H, Fitzpatrick SB et al (2006) Safety analyses of adalimumab (HUMIRA) in global clinical trials and US postmarketing surveillance of patients with rheumatoid arthritis. Ann Rheum Dis 65:889–894PubMedCrossRef
17.
go back to reference Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY et al (2006) Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 355:1419–1431PubMedCrossRef Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY et al (2006) Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 355:1419–1431PubMedCrossRef
18.
go back to reference Bashshur ZF, Schakal A, Hamam RN, El Haibi CP, Jaafar RF, Noureddin BN (2007) Intravitreal Bevacizumab vs verteporfin photodynamic therapy for neovascular age related macular degeneration. Arch Ophthalmol 125:1357–1361PubMedCrossRef Bashshur ZF, Schakal A, Hamam RN, El Haibi CP, Jaafar RF, Noureddin BN (2007) Intravitreal Bevacizumab vs verteporfin photodynamic therapy for neovascular age related macular degeneration. Arch Ophthalmol 125:1357–1361PubMedCrossRef
19.
go back to reference Fauser S, Kalbacher H, Alteheld N, Koizumi K, Krohne TU, Joussen AM (2004) Pharmacokinetics and safety of intravitreally delivered etanercept. Graefes Arch Clin Exp Ophthalmol 242:582–586PubMedCrossRef Fauser S, Kalbacher H, Alteheld N, Koizumi K, Krohne TU, Joussen AM (2004) Pharmacokinetics and safety of intravitreally delivered etanercept. Graefes Arch Clin Exp Ophthalmol 242:582–586PubMedCrossRef
20.
go back to reference Kivilcim M, Peyman GA, Kazi AA, Dellacroce J, Ghobrial RN, Manzano R (2007) Intravitreal toxicity of high-dose etanercept. J Ocul Pharmacol Ther 23:57–62PubMedCrossRef Kivilcim M, Peyman GA, Kazi AA, Dellacroce J, Ghobrial RN, Manzano R (2007) Intravitreal toxicity of high-dose etanercept. J Ocul Pharmacol Ther 23:57–62PubMedCrossRef
21.
go back to reference Tsilimbaris MK, Panagiotoglou TD, Charisis SK, Anastasakis A, Krikonis TS, Christodoulakis E (2007) The use of intravitrealetanercept in diabetic macular oedema. Semin Ophthalmol 22:75–79PubMedCrossRef Tsilimbaris MK, Panagiotoglou TD, Charisis SK, Anastasakis A, Krikonis TS, Christodoulakis E (2007) The use of intravitrealetanercept in diabetic macular oedema. Semin Ophthalmol 22:75–79PubMedCrossRef
22.
go back to reference Galor A, Perez VL, Hammel JP, Lowder CY (2006) Differential effectiveness of etanercept and infliximab in the treatment of ocular inflammation. Ophthalmology 113:2317–2323PubMedCrossRef Galor A, Perez VL, Hammel JP, Lowder CY (2006) Differential effectiveness of etanercept and infliximab in the treatment of ocular inflammation. Ophthalmology 113:2317–2323PubMedCrossRef
23.
go back to reference Manzano RPA, Peyman GA, Khan P, Kivilcim M (2006) Testing intravitreal toxicity of bevacizumab (Avastin). Retina 26(3): 257–261PubMedCrossRef Manzano RPA, Peyman GA, Khan P, Kivilcim M (2006) Testing intravitreal toxicity of bevacizumab (Avastin). Retina 26(3): 257–261PubMedCrossRef
Metadata
Title
Ocular toxicity of intravitreous adalimumab (Humira) in the rabbit
Authors
Roberta P. A. Manzano
Gholam A. Peyman
Petros E. Carvounis
Muhamet Kivilcim
Palwasha Khan
Patricia Chevez-Barrios
Walter Takahashi
Publication date
01-06-2008
Publisher
Springer-Verlag
Published in
Graefe's Archive for Clinical and Experimental Ophthalmology / Issue 6/2008
Print ISSN: 0721-832X
Electronic ISSN: 1435-702X
DOI
https://doi.org/10.1007/s00417-008-0765-z

Other articles of this Issue 6/2008

Graefe's Archive for Clinical and Experimental Ophthalmology 6/2008 Go to the issue