Title: Long-term Safety of Ranibizumab in Neovascular Age-related Macular Degeneration
Abstract: We read with interest the study from Silva et al1Silva R. Axer-Siegel R. Eldem B. et al.SECURE Study GroupThe SECURE study: long-term safety of ranibizumab 0.5 mg in neovascular age-related macular degeneration.Ophthalmology. 2013; 120: 130-139Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar on the long-term safety of ranibizumab 0.5 mg in neovascular age-related macular degeneration (nAMD). It described visual outcomes, drug tolerability, and safety of ranibizumab (Lucentis; Novartis Pharma AG, Basel, Switzerland, and Genentech, Inc, South San Francisco, CA) over a 24-month follow-up in selected patients with nAMD previously treated for 1 year in other studies on ranibizumab. The authors concluded that ranibizumab administered as per a visual acuity-guided flexible dosing regimen was well tolerated, and observed that on average, mean best-corrected visual acuity declined by 4.3 letters from the baseline. They speculated that it may be the result of disease progression or possible undertreatment. However, there is a point we would like to highlight regarding the increase in intraocular pressure (IOP) secondary to intravitreal injections (IVI) of ranibizumab, and retinal nerve fiber layer (RNFL) decrease reported in a previous study. It is well known that IVI induce an elevation in IOP,2Tseng J.J. Vance S.K. Della Torre K.E. et al.Sustained increased intraocular pressure related to intravitreal antivascular endothelial growth factor therapy for neovascular age-related macular degeneration.J Glaucoma. 2012; 21: 241-247Crossref PubMed Scopus (115) Google Scholar regardless of the injected product. This increase is mainly found before the end of the first hour post IVI. So, in the work by Silva et al, for which IOP is measured at 1 hour after injection, these IOP spikes should not be seen. Thus, repeated IOP fluctuations after IVI for chronic therapy with intravitreal anti-vascular endothelial growth factor (VEGF) agents could have an adverse effect on RNFL thickness. This is all the more true for some patients that have developed chronic IOP increase (6.4%).1Silva R. Axer-Siegel R. Eldem B. et al.SECURE Study GroupThe SECURE study: long-term safety of ranibizumab 0.5 mg in neovascular age-related macular degeneration.Ophthalmology. 2013; 120: 130-139Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar Martinez-de-la-Casa et al3Martinez-de-la-Casa J.M. Ruiz-Calvo A. Saenz-Frances F. et al.Retinal nerve fiber layer thickness changes in patients with age-related macular degeneration treated with intravitreal ranibizumab.Invest Ophthalmol Vis Sci. 2012; 53: 6214-6218Crossref PubMed Scopus (91) Google Scholar showed in their study that intravitreal ranibizumab injections used for nAMD caused a significant change in RNFL thickness after only 12 months of follow-up. In their study, at the end of follow-up, significant RNFL thinning was noted in the treated group (100.2±11.0 μm; P<0.001), whereas no differences were found in the control group (100.5±10.8 μm; P = 0.477). This could be owing to repeated IOP fluctuations after IVI, but also to the known neurotrophic properties of VEGF in the eye.4Foxton R.H. Finkelstein A. Vijay S. et al.VEGF-A is necessary and sufficient for retinal neuroprotection in models of experimental glaucoma.Am J Pathol. 2013; 182: 1379-1390Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar Therefore, mean best-corrected visual acuity decrease in the study by Silva et al could also be explained by RNLF decrease with secondary functional impairment in these patients treated for a long time by IVI of ranibizumab. It would be interesting to compare RNFL thickness by optical coherence tomography at the baseline and during the follow-up on both eyes, not only to assess how IOP spikes are able to induce RNFL decrease (sometimes combined with increase in time of mean IOP), but also to determine how anti-VEGF treatment intrinsically generates a neurodegeneration in patient treated long term. The SECURE Study: Long-Term Safety of Ranibizumab 0.5 mg in Neovascular Age-related Macular DegenerationOphthalmologyVol. 120Issue 1PreviewTo evaluate long-term safety of intravitreal ranibizumab 0.5-mg injections in neovascular age-related macular degeneration (nAMD). Full-Text PDF Author replyOphthalmologyVol. 120Issue 9PreviewWe thank Matonti et al for their interest in our study (SECURE). Matonti et al mention in their letter that the mean BCVA decrease of 4.3 letters from baseline observed in the SECURE study may be owing to retinal nerve fiber layer (RNFL) decrease and intraocular pressure (IOP) increase secondary to intravitreal injections of ranibizumab. The hypothetical link between RNFL and changes in BCVA cannot be substantiated based on the SECURE study, because RNFL was not assessed in the SECURE study or in its prestudies, EXCITE and SUSTAIN. Full-Text PDF