Progress in the study of anti-vascular endothelial growth factor application for the treatment of neovascular age-related macular degeneration and the mechanism of poor and non-response_Chinese Journal of Ocular Fundus Diseases

Authors：

Cheng Zifang , Wang Haiyan ,  Wang Yusheng

Department of Ophthalmology, Eye Institute of Chinese PLA, Xijing Hospital, Forth Military Medical University, Xi'an 710032, China;

Corresponding author：

Wang Yusheng, Email: wangys003@126.com

Keywords：

Age-related macular degeneration/drug therapy; Choroidal neovascularization/drug therapy; Angiogenesis inhibitors/therapeutic use; Review

DOI：

10.3760/cma.j.issn.1005-1015.2017.02.024

Video：

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Abstract Full text Figures/Tables Video References Cited by

According to the best corrected visual acuity and the morphological changes of the macular fovea, responses to the neovascular age-related macular degeneration (nAMD) who receive anti-vascular endothelial growth factor (VEGF) therapy show large variability, including poor and non-responders. Various factors will be reviewed to account for poor and non-response to anti-VEGF therapy, such as the related susceptibility genes, factors related with the development of choroidal neovascularization and morphologic parameters, pharmacokinetics and tachyphylaxis. The future research should focus on comprehensive assessment of factors affecting the efficacy of anti-VEGF therapy to improve the therapeutic outcome of nAMD.

Citation： Cheng Zifang, Wang Haiyan, Wang Yusheng. Progress in the study of anti-vascular endothelial growth factor application for the treatment of neovascular age-related macular degeneration and the mechanism of poor and non-response. Chinese Journal of Ocular Fundus Diseases, 2017, 33(2): 199-202. doi: 10.3760/cma.j.issn.1005-1015.2017.02.024 Copy

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24.	Oishi A, Hata M, Shimozono M, et al. The significance of external limiting membrane status for visual acuity in age-related macular degeneration[J]. Am J Ophthalmol, 2010, 150(1): 27-32. DOI: 10.1016/j.ajo.2010.02.012.
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30.	Theodossiadis PG, Grigoropoulos VG, Theodossiadis GP. The significance of the external limiting membrane in the recovery of photoreceptor layer after successful macular hole closure: a study by spectral domain optical coherence tomography[J]. Ophthalmologica, 2011, 225(3): 176-184. DOI: 10.1159/000323322.
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1. Comparison of Age-Related Macular Degeneration Treatments Trials (CATT) Research Group, Maguire MG, Martin DF, et al. Five-year outcomes with anti-vascular endothelial growth factor treatment of neovascular age-related macular degeneration: the Comparison of Age-Related Macular Degeneration Treatments Trials[J]. Ophthalmology, 2016, 123(8): 1751-1761. DOI: 10.1016/j.ophtha.2016.03.045.
2. Lux A, Llacer H, Heussen FMA, et al. Non-responders to bevacizumab (Avastin) therapy of choroidal neovascular lesions[J]. Br J Ophthalmol, 2007, 91(10): 1318-1322. DOI: 10.1136/ bjo.2006.113902.
3. Otsuji T, Nagai Y, Sho K, et al. Initial non-responders to ranibizumab in the treatment of age-related macular degeneration (AMD)[J]. Clin Ophthalmol, 2013, 7: 1487-1490. DOI: 10.2147/ OPTH.S46317.
4. Eghøj MS, Sørensen TL. Tachyphylaxis during treatment of exudative age-related macular degeneration with ranibizumab[J]. Br J Ophthalmol, 2011, 96(1): 21-23. DOI: 10.1136/bjo.2011.203893.
5. Amoaku WM, Chakravarthy U, Gale R, et al. Defining response to anti-VEGF therapies in neovascular AMD[J]. Eye (Lond), 2015, 29(10): 1397-1398. DOI: 10.1038/eye.2015.159.
6. Kinnunen K, Petrovski G, Moe MC, et al. Molecular mechanisms of retinal pigment epithelium damage and development of age-related macular degeneration[J]. Acta Ophthalmol, 2012, 90(4): 299-309. DOI: 10.1111/j.1755-3768.2011.02179.x.
7. Rosenfeld PJ, Shapiro H, Tuomi L, et al. Characteristics of patients losing vision after 2 years of monthly dosing in the phase Ⅲ ranibizumab clinical trials[J]. Ophthalmology, 2011, 118(3): 523-530. DOI: 10.1016/j.ophtha.2010.07.011.
8. Grunwald JE, Daniel E, Huang J, et al. Risk of geographic atrophy in the comparison of age-related macular degeneration treatments trials[J]. Ophthalmology, 2014, 121(1): 150-161. DOI: 10.1016/ j.ophtha.2013.08.015.
9. Lechner J, Chen M, Hogg RE, et al. Higher plasma levels of complement C3a, C4a and C5a increase the risk of subretinal fibrosis in neovascular age-related macular degeneration: complement activation in AMD[J]. Immun Ageing, 2016, 13: 4. DOI: 10.1186/s12979-016-0060-5.
10. Sparrow JR, Ueda K, Zhou J. Complement dysregulation in AMD: RPE-Bruch's membrane-choroid[J]. Mol Aspects Med, 2012, 33(4): 436-445. DOI: 10.1016/j.mam.2012.03.007.
11. Hatz K, Prunte C. Polypoidal choroidal vasculopathy in Caucasian patients with presumed neovascular age-related macular degeneration and poor ranibizumab response[J]. Br J Ophthalmol, 2014, 98(2): 188-194. DOI: 10.1136/bjophthalmol-2013-303444.
12. Wong CW, Yanagi Y, Lee WK, et al. Age-related macular degeneration and polypoidal choroidal vasculopathy in Asians[J]. Prog Retin Eye Res, 2016, 53: 107-139. DOI: 10.1016/j.preteyeres. 2016.04.002.
13. Ozkaya A, Alagoz C, Garip R, et al. The role of indocyanine green angiography imaging in further differential diagnosis of patients with nAMD who are morphologically poor responders to ranibizumab in a real-life setting[J]. Eye (Lond), 2016, 30(7): 958-965. DOI: 10.1038/eye.2016.71.
14. 戴虹, 卢颖毅. 全面评估抗血管内皮生长因子药物治疗新生血管性老年性黄斑变性的影响因素, 努力提高治疗效果的综合收益[J]. 中华眼底病杂志, 2016, 32(1): 8-11. DOI: 10.3760/cma.j.issn. 1005-1015.2016.01.003.Dai H, Lu YY. Overall assessment of the factors influencing the effect of anti-vascular endothelial growth factor for neovascular age-related macular degeneration to improve the comprehensive benefit of treatment[J]. Chin J Ocul Fundus Dis, 2016, 32(1): 8-11. DOI: 10.3760/cma.j.issn.1005-1015.2016.01.003.
15. Bloch SB, Lund-Andersen H, Sander B, et al. Subfoveal fibrosis in eyes with neovascular age-related macular degeneration treated with intravitreal ranibizumab[J]. Am J Ophthalmol, 2013, 156(1): 116-124. DOI: 10.1016/j.ajo.2013.02.012.
16. Krishnan R, Arora R, de Salvo G, et al. Vitreomacular traction affects anti-vascular endothelial growth factor treatment outcomes for exudative age-related macular degeneration[J]. Retina, 2015, 35(9): 1750-1756. DOI: 10.1097/IAE.0000000000000714.
17. Kang EC, Koh HJ. Effects of vitreomacular adhesion on age-related macular degeneration[J/OL]. J Ophthalmol, 2015, 2015: 865083[2015-09-03]. . DOI: 10.1155/2015/865083.
18. Arnold JJ, Markey CM, Kurstjens NP, et al. The role of sub-retinal fluid in determining treatment outcomes in patients with neovascular age-related macular degeneration -- a phase Ⅳ randomised clinical trial with ranibizumab: the FLUID study[J]. BMC Ophthalmol, 2016, 16: 31. DOI: 10.1186/s12886-016-0207-3.
19. Freund KB, Zweifel SA, Engelbert M. Do we need a new classification for choroidal neovascularization in age-related macular degeneration?[J]. Retina, 2010, 30(9): 1333-1349. DOI: 10.1097/ IAE.0b013e3181e7976b.
20. Zweifel SA. Error in figure in: outer retinal tubulation: a novel optical coherence tomography finding[J]. Arch Ophthalmol, 2012, 130(7): 856. DOI: 10.1001/archophthalmol.2012.2053.
21. Schaal KB, Freund KB, Litts KM, et al. Outer retinal tubulation in advanced age-related macular degeneration: optical coherence tomographic findings correspond to histology[J]. Retina, 2015, 35(7): 1339-1350. DOI: 10.1097/IAE.0000000000000471.
22. Wolff B, Matet A, Vasseur V, et al. En face OCT imaging for the diagnosis of outer retinal tubulations in age-related macular degeneration[J/OL]. J Ophthalmol, 2012, 2012: 542417[2012-08-30]. . DOI: 10.1155/ 2012/542417.
23. Espina M, Arcinue CA, Ma F, et al. Outer retinal tubulations response to anti-VEGF treatment[J]. Br J Ophthalmol, 2016, 100(6): 819-823. DOI: 10.1136/bjophthalmol-2015-307141.
24. Oishi A, Hata M, Shimozono M, et al. The significance of external limiting membrane status for visual acuity in age-related macular degeneration[J]. Am J Ophthalmol, 2010, 150(1): 27-32. DOI: 10.1016/j.ajo.2010.02.012.
25. Faria-Correia F, Barros-Pereira R, Queiros-Mendanha L, et al. Characterization of neovascular age-related macular degeneration patients with outer retinal tubulations[J]. Ophthalmologica, 2013, 229(3): 147-151. DOI: 10.1159/000346854.
26. Lee JY, Folgar FA, Maguire MG, et al. Outer retinal tubulation in the Comparison of Age-related Macular Degeneration Treatments Trials (CATT)[J]. Ophthalmology, 2014, 121(12): 2423-2431. DOI: 10.1016/j.ophtha.2014.06.013.
27. Coscas G, De Benedetto U, Coscas F, et al. Hyperreflective dots: a new spectral-domain optical coherence tomography entity for follow-up and prognosis in exudative age-related macular degeneration[J]. Ophthalmologica, 2013, 229(1): 32-37. DOI: 10.1159/000342159.
28. Dansingani KK, Tan AC, Gilani F, et al. Subretinal hyperreflective material imaged with optical coherence tomography angiography[J]. Am J Ophthalmol, 2016, 169(6): 235-248. DOI: 10.1016/ j.ajo. 2016.06.031.
29. Hayashi H, Yamashiro K, Tsujikawa A, et al. Association between foveal photoreceptor integrity and visual outcome in neovascular age-related macular degeneration[J]. Am J Ophthalmol, 2009, 148(1): 83-89. DOI: 10.1016/j.ajo.2009.01.017.
30. Theodossiadis PG, Grigoropoulos VG, Theodossiadis GP. The significance of the external limiting membrane in the recovery of photoreceptor layer after successful macular hole closure: a study by spectral domain optical coherence tomography[J]. Ophthalmologica, 2011, 225(3): 176-184. DOI: 10.1159/000323322.
31. Willoughby AS, Ying GS, Toth CA, et al. Subretinal hyperreflective material in the Comparison of Age-related Macular Degeneration Treatments Trials[J]. Ophthalmology, 2015, 122(9): 1846-1853. DOI: 10.1016/j.ophtha.2015.05.042.
32. Menghini M, Kloeckener-Gruissem B, Fleischhauer J, et al. Impact of loading phase, initial response and CFH genotype on the long-term outcome of treatment for neovascular age-related macular degeneration[J/OL]. PLoS One, 2012, 7(7): 42014[2012-07-25]. http://dx.plos.org/10.1371/journal.pone.0042014. DOI: 10.1371/journal.pone.0042014.
33. Smailhodzic D, Muether PS, Chen J, et al. Cumulative effect of risk alleles in CFH, ARMS2, and VEGFA on the response to ranibizumab treatment in age-related macular degeneration[J]. Ophthalmology, 2012, 119(11): 2304-2311. DOI: 10.1016/ j.ophtha.2012.05.040.
34. Chen H, Yu KD, Xu GZ. Association between variant Y402H in age-related macular degeneration (AMD) susceptibility gene CFH and treatment response of AMD: a meta-analysis[J/OL]. PLoS One, 2012, 7(8): 42464[2012-08-14]. . DOI: 10.1371/journal.pone.0042464.
35. Teper SJ, Nowinska A, Pilat J, et al. Involvement of genetic factors in the response to a variable-dosing ranibizumab treatment regimen for age-related macular degeneration[J]. Mol Vis, 2010, 16: 2598-2604.
36. Abedi F, Wickremasinghe S, Richardson A J, et al. Genetic influences on the outcome of anti-vascular endothelial growth factor treatment in neovascular age-related macular degeneration[J]. Ophthalmology, 2013, 120(8): 1641-1648. DOI: 10.1016/ j.ophtha.2013.01.014.
37. Tian J, Qin X, Fang K, et al. Association of genetic polymorphisms with response to bevacizumab for neovascular age-related macular degeneration in the Chinese population[J]. Pharmacogenomics, 2012, 13(7): 779-787. DOI: 10.2217/pgs.12.53.
38. Kanda A, Chen W, Othman M, et al. A variant of mitochondrial protein LOC387715/ARMS2, not HTRA1, is strongly associated with age-related macular degeneration[J]. Proc Natl Acad Sci USA, 2007, 104(41): 16227-16232.
39. Jabbarpoor BM, Yaseri M, Bonyadi M, et al. Association of ARMS2/LOC387715 A69S, CFH Y402H, and CFH I62V polymorphisms with retinal angiomatous proliferation compared with typical age-related macular degeneration: a meta-analysis[J/OL]. Int Ophthalmol, 2016, 2016: E1[2016-12-22]. . DOI:10.1007/ s10792-016-0413-2. [published online ahead of print].
40. Park UC, Shin JY, Kim SJ, et al. Genetic factors associated with response to intravitreal ranibizumab in Korean patients with neovascular age-related macular degeneration[J]. Retina, 2014, 34(2): 288-297. DOI: 10.1097/IAE.0b013e3182979e1e.
41. Lazzeri S, Figus M, Orlandi P, et al. VEGF-A polymorphisms predict short-term functional response to intravitreal ranibizumab in exudative age-related macular degeneration[J]. Pharmacogenomics, 2013, 14(6): 623-630. DOI: 10.2217/pgs.13.43.
42. Wang VM, Rosen RB, Meyerle CB, et al. Suggestive association between PLA2G12A single nucleotide polymorphism rs2285714 and response to anti-vascular endothelial growth factor therapy in patients with exudative age-related macular degeneration[J]. Mol Vis, 2012, 18: 2578-2585.
43. Lotery AJ, Gibson J, Cree AJ, et al. Pharmacogenetic associations with vascular endothelial growth factor inhibition in participants with neovascular age-related macular degeneration in the IVAN Study[J]. Ophthalmology, 2013, 120(12): 2637-2643. DOI: 10.1016/j.ophtha.2013.07.046.
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The current status and progress of ocriplasmin in treating vitreomacular interface diseases

Chinese Journal of Ocular Fundus Diseases

Progress in the study of anti-vascular endothelial growth factor application for the treatment of neovascular age-related macular degeneration and the mechanism of poor and non-response

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