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 Table of Contents  
ORIGINAL ARTICLE
Year : 2014  |  Volume : 4  |  Issue : 3  |  Page : 120-122

Effects of ranibizumab on human corneal endothelial cells


Department of Ophthalmology, China Medical University Hospital, Taichung, Taiwan

Date of Web Publication2-Sep-2014

Correspondence Address:
Chun-Chi Chiang
Department of Ophthalmology, China Medical University Hospital, Number 2, Yue-Der Road, Taichung 404
Taiwan
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Source of Support: None, Conflict of Interest: None


DOI: 10.1016/j.tjo.2014.04.004

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  Abstract 

Purpose: This study aims to evaluate corneal endothelial changes occurring over a 3-month period after intravitreal injections of ranibizumab in patients with wet age-related macular degeneration.
Methods: This is a prospective case series. A total of 29 patients (29 eyes) received a 0.5-mg intravitreal injection of ranibizumab. Specular microscopy, including measurement of central corneal thickness and endothelial cell count, was performed on each patient prior to and after completing three intravitreal injections.
Results: All patients received three intravitreal injections and were followed up for a mean of 3 months. There was no significant change in corneal thickness (p = 0.32) or endothelial cell density (p = 0.38) after ranibizumab injections.
Conclusion: Intravitreal ranibizumab injections (0.5 mg) have no harmful effects on corneal endothelial cells.

Keywords: age-related macular degeneration, corneal endothelial cell, intravitreal injection, ranibizumab


How to cite this article:
Ho YJ, Tsai YY, Lin JM, Chen WL, Lin CJ, Chiang CC. Effects of ranibizumab on human corneal endothelial cells. Taiwan J Ophthalmol 2014;4:120-2

How to cite this URL:
Ho YJ, Tsai YY, Lin JM, Chen WL, Lin CJ, Chiang CC. Effects of ranibizumab on human corneal endothelial cells. Taiwan J Ophthalmol [serial online] 2014 [cited 2022 Nov 29];4:120-2. Available from: https://www.e-tjo.org/text.asp?2014/4/3/120/204040




  1. Introduction Top


Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly. Wet AMD induces growth of abnormal blood vessels that obscure vision. Ranibizumab is widely used to treat AMD, primarily based on the positive results of the Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular AMD (MARINA)[1] and Anti-VEGF Anti-body for the Treatment of Predominantly Classic Choroidal Neovascularization in AMD (ANCHOR)[2] studies, and it was approved by the US Food and Drug Administration for this purpose in 2006. Ranibizumab is a fragment of a recombinant, humanized monoclonal antibody derived from the parent antibody bevacizumab.[1] It binds to vascular endothelial growth factor (VEGF) and inhibits VEGF signaling. Moreover, after intravitreal injection of ranibizumab into rabbit eyes, the antibody was detected in the aqueous humor and was found to reach a peak concentration of 17.9 mg/mL 3 days after drug administration.[3] Furthermore, it was previously shown that VEGF and its receptor are present in the corneal endothelium[4],[5],[6]; therefore, it is reasonable to assume that ranibizumab may influence VEGF function in the corneal endothelium.

Besides, several cases of acute intraocular inflammation after intravitreal injections of ranibizumab have been reported.[1],[2] Hence, there are some questions regarding the safety of intravitreal ranibizumab injections. The purpose of this study is to evaluate the effects of intravitreal ranibizumab on corneal endothelium in order to ascertain the safety of ranibizumab for the treatment of wet AMD.


  2. Methods Top


All study protocols were approved by the Institutional Review Board of China Medical University Hospital, Taichung, Taiwan. The intravitreal ranibizumab injection method was explained to all patients and informed consent was obtained prior to commencing the study. The study adhered to the principles of the Declaration of Helsinki.

This investigation was a prospective analysis of central corneal thickness and endothelial cell count in patients who were diagnosed with wet AMD and received 0.5 mg intravitreal injections of ranibizumab (10 mg/mL, 0.23 mL/vial) between February 2012 and December 2012 at China Medical University Hospital in Taiwan.

We included all patients with wet AMD who received intra-vitreal injections of ranibizumab and excluded those who had poor corneal conditions, such as endothelial cell counts <1000 cells/ mm2, cytomegalovirus endotheliitis, herpes infection, endothelial dystrophy, and any other keratopathy or corneal disorder. All intravitreal ranibizumab injections were administered using standard aseptic techniques. Briefly, after application of a topical anesthetic with a mixture of lidocaine hydrochloride and bupiva- caine hydrochloride, anterior chamber paracentesis was performed to release the intraocular pressure. Intravitreal injection of 0.5 mg of ranibizumab was administered through the pars plana using a 30-gauge needle. The patients returned to the outpatient clinic for evaluation by an ophthalmologist 1 day after intravitreal injection. They received monthly intravitreal injections of ranibizumab for 3 consecutive months; the follow-up period was 3 months after the first injection. Corneal endothelial cell density (ECD) and thickness were measured using noncontact specular microscopy (SP 2000P; Topcon Corp., Tokyo, Japan) on the day prior to injection and at more than 3 months after the final injection, to evaluate the effects of ranibizumab on the corneal endothelium. Differences in corneal endothelium prior to and after the injections were statistically analyzed using a paired t test. A p value of <0.05 was considered to be statistically significant.


  3. Results Top


A total of 29 eyes of 29 patients (18 men and 11 women) were treated with ranibizumab injections. All patients were diagnosed with wet AMD and received three consecutive injections at 1- month intervals.

Corneal thickness was 547.55 μm prior to the injections and 544.45 μm after the injections (p = 0.32); the ECD was 2404.45 cells/mm2 prior to the injections and 2494.17 3 cells/mm2 months after the injections (p = 0.38; [Table 1]). There was no difference in ECD prior to intravitreal ranibizumab injection and 3 months after three consecutive injections. Of the 29 eyes, nine were pseudophakic and 20 were phakic. In patients with pseudo- phakia [Table 2], the corneal thickness was 556.11 μm prior to the injections and 553.56 μm after the injections (p = 0.73), and the ECD was 2233.22 cells/mm2 prior to the injections and 2465.89 cells/mm2 3 months after the injections (p = 0.29). In patients with phakic lenses [Table 3], the corneal thickness was 543.7 μm prior to the injections and 540.35 mm after the injections (p = 0.29), and the ECD was 2481.5 cells/mm2 prior to the injections and 2506.9 cells/mm2 3 months after the injections (p = 0.83). No difference was observed between patients with phakic or pseudo-phakic lenses with respect to ECD or corneal thickness. Routine follow-up by slit-lamp examination on the day after intravitreal injection revealed no cases of acute intraocular inflammation.
Table 1: Effects of intravitreal ranibizumab injections on corneal endothelium 3 months after treatment.

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Table 2: Effects of intravitreal ranibizumab injections on corneal endothelium 3 months after treatment in pseudophakic patients.

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Table 3: Effects of intravitreal ranibizumab injections on corneal endothelium 3 months after treatment in phakic patients.

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  4. Discussion Top


Results of this study revealed no significant change in the corneal endothelium following intravitreal ranibizumab injections. In a previous study, both bevacizumab and ranibizumab were detected in the aqueous humor, which persisted for more than 1 month. In addition, there are anti-VEGF receptors in endothelium.[4],[5],[6],[7] In a previous study, Chiang et al[8] revealed that 2.5-mg intravitreal injections of bevacizumab did not elicit harmful effects on the corneal endothelium. However, Wickremasinghe et al[9] and Sato et al[10] observed that 1.49–14.3% of patients who received intravitreal bevacizumab injections developed acute intraocular inflammation. Bevacizumab is a 149 kDa full-length monoclonal antibody with two antigen-binding domains, whereas ranibizumab is a 48 kDa Fab fragment that has only one binding domain; the latter has a smaller molecular weight, and thus penetrates into the retina more easily and shows increased binding affinity toward VEGF.[3] Therefore, we assume that ranibi- zumab may also easily penetrate into the anterior chamber from the vitreous cavity. Furthermore, the rate of severe uveitis following intravitreal ranibizumab injection was reported to range from 0.7% to 1.3% in Phase III studies,[1],[2] and the Comparison of AMD Treatments (CATT) study showed that bevacizumab and ranibizumab had similar effects with respect to the treatment of wet AMD.[11]Although bevacizumab is broadly used for the treatment of neovascular AMD, this has primarily been an off-label use. However, as ranibizumab is clinically approved for the treatment of AMD, there is a trend toward increased use of this product in clinical condi- tions.[1],[2],[11] Therefore, the effects of this product on the corneal endothelium warrant investigation.

The present study demonstrated that there was no statistically significant difference in corneal endothelial cell count 3 months after 0.5 mg intravitreal injections of ranibizumab in patients with wet AMD. Therefore, we conclude that these injections have no harmful short-term effects. Moreover, routine follow-up by slit-lamp examinations on the day following intravitreal injections revealed no acute intraocular inflammation or corneal edema, which further indicates that ranibizumab did not affect the corneal endothelium. Perez-Rico et al[12] evaluated the toxicity of 0.5 mg of ranibizumab on corneal endothelial cells by evaluating the ECD, coefficient of variation of the cell size, and percentage of the hexagonal cells. They found no harmful effects. Our results are in concordance with other studies that revealed that 0.5 mg intra- vitreal injections of ranibizumab have no negative effects on the corneal endothelium.[12],[13]

In conclusion, the results presented herein indicate that 0.5 mg intravitreal injections of ranibizumab do not induce corneal endothelial cell changes up to 3 months after injection.

Conflicts of interest: The authors declare that they have no conflicts of interest.



 
  References Top

1.
Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355:1419-1431.  Back to cited text no. 1
    
2.
Brown DM, Kaiser PK, Michels M, Soubrane G, Heier JS, Kim RY, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med. 2006;355:1432-1444.  Back to cited text no. 2
    
3.
Bakri SJ, Snyder MR, Reid JM, Pulido JS, Ezzat MK, Singh RJ. Pharmacokinetics of intravitreal ranibizumab (Lucentis). Ophthalmology. 2007;114:2179-2182.  Back to cited text no. 3
    
4.
Yoeruek E, Spitzer MS, Tatar O, Aisenbrey S, Bartz-Schmidt KU, Szurman P. Safety profile of bevacizumab on cultured human corneal cells. Cornea. 2007;26:977-982.  Back to cited text no. 4
    
5.
Gan L, Fagerholm P, Palmblad J. Vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 in the regulation of corneal neovascularization and wound healing. Acta Ophthalmol Scand. 2004;82:557-563.  Back to cited text no. 5
    
6.
Philipp W, Speicher L, Humpel C. Expression of vascular endothelial growth factor and its receptors in inflamed and vascularized human corneas. Invest Ophthalmol Vis Sci. 2000;41:2514-2522.  Back to cited text no. 6
    
7.
Krohne TU, Liu Z, Holz FG, Meyer CH. Intraocular pharmacokinetics of ranibizumab following a single intravitreal injection in humans. Am J Ophthalmol. 2012;154:682-686. e682.  Back to cited text no. 7
    
8.
Chiang CC, Chen WL, Lin JM, Tsai YY. Effect of bevacizumab on human corneal endothelial cells: a six-month follow-up study. Am J Ophthalmol. 2008;146: 688-691.  Back to cited text no. 8
    
9.
Wickremasinghe SS, Michalova K, Gilhotra J, Guymer RH, Harper CA, Wong TY, et al. Acute intraocular inflammation after intravitreous injections of bevacizumab for treatment of neovascular age-related macular degeneration. Ophthalmology. 2008;115:1911-1915.  Back to cited text no. 9
    
10.
Sato T, Emi K, Ikeda T, Bando H, Sato S, Morita S, et al. Severe intraocular inflammation after intravitreal injection of bevacizumab. Ophthalmology. 2010;117:512-516, 516 e511-2.  Back to cited text no. 10
    
11.
Martin DF, Maguire MG, Ying GS, Grunwald JE, Fine SL, Jaffe GJ. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med. 2011;364:1897-1908.  Back to cited text no. 11
    
12.
Perez-Rico C, Benitez-Herreros J, Castro-Rebollo M, Gomez-Sangil Y, Germain F, Montes-Mollon MA, et al. Effect of intravitreal ranibizumab on corneal endothelium in age-related macular degeneration. Cornea. 2010;29: 849-852.  Back to cited text no. 12
    
13.
Perez-Rico C, Benitez-Herreros J, Castro-Rebollo M, Gomez-SanGil Y, Germain F, Montes-Mollon MA, et al. Endothelial cells analysis after intravitreal ranibizumab (Lucentis) in age-related macular degeneration treatment: a pilot study. Br J Ophthalmol. 2010;94:267-268.  Back to cited text no. 13
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3]


This article has been cited by
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Journal of Ophthalmology. 2020; 2020: 1
[Pubmed] | [DOI]



 

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Abstract
1. Introduction
2. Methods
3. Results
4. Discussion
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