The effect of intravitreal ranibizumab on the expression of cytokines in aqueous humor of patients with macular edema due to branch retinal vein occlusion_Chinese Journal of Ocular Fundus Diseases

Authors：

Zhu Chengyi ¹ , Pan Lanlan ¹ , Yi Qiong ¹ ,  Wei Qiping ²

1. Department of Ophthalmology, Beijing Hepingli Hospital, Beijing 100013, China;
2. Department of Ophthalmology, Beijing Oriental Hospital, University of Traditional Chinese Medicine, Beijing 100078, China;

Corresponding author：

Wei Qiping, Email: zhchy0010@163.com

Keywords：

Retinal vein occlusion; Macular edema; Angiogenesis inhibitors; Aqueous humor; Cytokines

DOI：

10.3760/cma.j.cn511434-20211122-00650

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Objective To study the changes the changes of cytokine expression the aqueous humor of patients with macular edema secondary to branch retinal vein occlusion (BRVO-ME) before and after intravitreal ranibizumab (IVR). Methods A prospective clinical study. From June 2018 to June 2021, 31 eyes of 31 patients with non-ischemic BRVO-ME diagnosed by ophthalmic examination in Department of Ophthalmology, Beijing Hepingli Hospital were included in the study. Among them, 15 males had 15 eyes, and 16 females had 16 eyes. Age was 70 (65, 72) years; the course of disease was 10 (9, 15) days. All of them were first-time patients. All eyes were treated with IVR once a month for 3 consecutive months. At the end of each IVR treatment, 0.1 ml aqueous humor was extracted immediately. The concentrations of vascular endothelial growth factor (VEGF), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in aqueous humor were detected by flow cytometry. The concentrations of cytokines in aqueous humor before and after treatment were compared by Kruskal-Wallis or Wilcoxon signed-rank test. Spearman correlation analysis was performed on the correlation between VEGF and MCP-1 expression level in aqueous humor before treatment. Results The concentrations of VEGF and ICAM-1 in aqueous humor were significantly lower at 1 month after treatment compared with that before treatment, and at 2 months after treatment compared with that at 1 month after treatment (Z=4.03, 3.25, 2.50, 3.48; P＜0.05); the concentrations of IL-6 and VCAM-1 increased and the concentration of MCP-1 decreased, but there was no significant difference (Z=－0.21, 1.42, 0.86, －0.53, 0.92, －1.57; P＞0.05). Spearman correlation analysis showed that there was a strong positive correlation between VEGF and MCP-1 in aqueous humor before treatment (r=0.78, P＜0.001). Conclusion The concentrations of VEGF and ICAM-1 in aqueous humor significantly decrease after IVR treatment in BRVO-ME; the concentrations of IL-6, MCP-1 and VCAM-1 do not obviously change.

Citation： Zhu Chengyi, Pan Lanlan, Yi Qiong, Wei Qiping. The effect of intravitreal ranibizumab on the expression of cytokines in aqueous humor of patients with macular edema due to branch retinal vein occlusion. Chinese Journal of Ocular Fundus Diseases, 2022, 38(9): 739-743. doi: 10.3760/cma.j.cn511434-20211122-00650 Copy

1.	Song P, Xu Y, Zha M, et al. Global epidemiology of retinal vein occlusion: a systematic review and meta-analysis of prevalence, incidence, and risk factors[J/OL]. J Glob Health, 2019, 9(1): 10427[2019-06-01]. https://pubmed.ncbi.nlm.nih.gov/31131101/. DOI: 10.7189/jogh.09.010427.
2.	Zhou JQ, Xu L, Wang S, et al. The 10-year incidence and risk factors of retinal vein occlusion: the Beijing Eye Study[J]. Ophthalmology, 2013, 120(4): 803-808. DOI: 10.1016/j.ophtha.2012.09.033.
3.	Hayreh SS, Zimmerman MB, Podhajsky P. Incidence of various types of retinal vein occlusion and their recurrence and demographic characteristics[J]. Am J Ophthalmol, 1994, 117(4): 429-441. DOI: 10.1016/s0002-9394(14)70001-7.
4.	Noma H, Yasuda K, Shimura M. Cytokines and pathogenesis of central retinal vein occlusion[J/OL]. J Clin Med, 2020, 9(11): 3457[2020-10-27]. https://pubmed.ncbi.nlm.nih.gov/33121094/. DOI: 10.3390/jcm9113457.
5.	Noma H, Mimura T, Yasuda K, et al. Possible molecular basis of bevacizumab therapy for macular edema in branch retinal vein occlusion[J]. Retina, 2016, 36(9): 1718-1725. DOI: 10.1097/IAE.0000000000000983.
6.	Schmidt-Erfurth U, Garcia-Arumi J, Gerendas BS, et al. Guidelines for the management of retinal vein occlusion by the European Society of Retina Specialists (EURETINA)[J]. Ophthalmologica, 2019, 242(3): 123-162. DOI: 10.1159/000502041.
7.	戴虹, 卢颖毅, 许晶晶. 从EURETINA最新指南看视网膜静脉阻塞诊疗策略的变化[J]. 中华实验眼科杂志, 2020, 38(1): 1-3. DOI: 10.3760/cma.j.issn.2095-0160.2020.01.001.Dai H, Lu YY, Xu JJ. Changes of diagnosis and treatment strategies of retinal vein occlusion according to EURETINA updated guidelines[J]. Chin J Exp Ophthalmol, 2020, 38(1): 1-3. DOI: 10.3760/cma.j.issn.2095-0160.2020.01.001.
8.	Hayreh SS, Rojas P, Podhajsky P, et al. Ocular neovascularization with retinal vascular occlusion-Ⅲ. Incidence of ocular neovascularization with retinal vein occlusion[J]. Ophthalmology, 1983, 90(5): 488-506. DOI: 10.1016/s0161-6420(83)34542-5.
9.	Li X, Wang N, Liang X, et al. Safety and efficacy of dexamethasone intravitreal implant for treatment of macular edema secondary to retinal vein occlusion in Chinese patients: randomized, sham-controlled, multicenter study[J]. Graefe's Arch Clin Exp Ophthalmol, 2018, 256(1): 59-69. DOI: 10.1007/s00417-017-3831-6.
10.	Koss MJ, Pfister M, Rothweiler F, et al. Comparison of cytokine levels from undiluted vitreous of untreated patients with retinal vein occlusion[J/OL]. Acta Ophthalmol, 2012, 90(2): e98-e103[2021-11-08]. https://pubmed.ncbi.nlm.nih.gov/22066978/. DOI: 10.1111/j.1755-3768.2011.02292.x.
11.	Inagaki M, Hirano Y, Yasuda Y, et al. Twenty-four month results of intravitreal ranibizumab for macular edema after branch retinal vein occlusion: visual outcomes and resolution of macular edema[J]. Semin Ophthalmol, 2021, 36(7): 482-489. DOI: 10.1080/08820538.2021.1890147.
12.	Hikichi T, Higuchi M, Matsushita T, et al. Two-year outcomes of intravitreal bevacizumab therapy for macular oedema secondary to branch retinal vein occlusion[J]. Br J Ophthalmol, 2014, 98(2): 195-199. DOI: 10.1136/bjophthalmol-2013-303121.
13.	Noma H, Minamoto A, Funatsu H, et al. Intravitreal levels of vascular endothelial growth factor and interleukin-6 are correlated with macular edema in branch retinal vein occlusion[J]. Graefe's Arch Clin Exp Ophthalmol, 2006, 244(3): 309-315. DOI: 10.1007/s00417-004-1087-4.
14.	Costagliola C, Morescalchi F, Duse S, et al. Systemic thromboembolic adverse events in patients treated with intravitreal anti-VEGF drugs for neovascular age-related macular degeneration: an update[J]. Expert Opin Drug Saf, 2019, 18(9): 803-815. DOI: 10.1080/14740338.2019.1643838.
15.	Schmid MK, Bachmann LM, Fäs L, et al. Efficacy and adverse events of aflibercept, ranibizumab and bevacizumab in age-related macular degeneration: a trade-off analysis[J]. Br J Ophthalmol, 2015, 99(2): 141-146. DOI: 10.1136/bjophthalmol-2014-305149.
16.	Noma H, Mimura T, Yasuda K, et al. Functional-morphological parameters, aqueous flare and cytokines in macular oedema with branch retinal vein occlusion after ranibizumab[J]. Br J Ophthalmol, 2017, 101(2): 180-185. DOI: 10.1136/bjophthalmol-2015-307989.
17.	Noma H, Yasuda K, Shimura M. Involvement of cytokines in the pathogenesis of diabetic macular edema[J/OL]. Int J Mol Sci, 2021, 22(7): 3427[2021-03-26]. https://pubmed.ncbi.nlm.nih.gov/33810434/. DOI: 10.3390/ijms22073427.
18.	Hillier RJ, Ojaimi E, Wong DT, et al. Aqueous humor cytokine levels and anatomic response to intravitreal ranibizumab in diabetic macular edema[J]. JAMA Ophthalmol, 2018, 136(4): 382-388. DOI: 10.1001/jamaophthalmol.2018.0179.
19.	Liu Y, Shen J, Fortmann SD, et al. Reversible retinal vessel closure from VEGF-induced leukocyte plugging[J/OL]. JCI Insight, 2017, 2(18): e95530[2019-09-21]. https://pubmed.ncbi.nlm.nih.gov/28931763/. DOI: 10.1172/jci.insight.95530.
20.	Uğurlu N, Gerceker S, Yülek F, et al. The levels of the circulating cellular adhesion molecules ICAM-1, VCAM-1 and endothelin-1 and the flow-mediated vasodilatation values in patients with type 1 diabetes mellitus with early-stage diabetic retinopathy[J]. Intern Med, 2013, 52(19): 2173-2178. DOI: 10.2169/internalmedicine.52.8572.

1. Song P, Xu Y, Zha M, et al. Global epidemiology of retinal vein occlusion: a systematic review and meta-analysis of prevalence, incidence, and risk factors[J/OL]. J Glob Health, 2019, 9(1): 10427[2019-06-01]. https://pubmed.ncbi.nlm.nih.gov/31131101/. DOI: 10.7189/jogh.09.010427.
2. Zhou JQ, Xu L, Wang S, et al. The 10-year incidence and risk factors of retinal vein occlusion: the Beijing Eye Study[J]. Ophthalmology, 2013, 120(4): 803-808. DOI: 10.1016/j.ophtha.2012.09.033.
3. Hayreh SS, Zimmerman MB, Podhajsky P. Incidence of various types of retinal vein occlusion and their recurrence and demographic characteristics[J]. Am J Ophthalmol, 1994, 117(4): 429-441. DOI: 10.1016/s0002-9394(14)70001-7.
4. Noma H, Yasuda K, Shimura M. Cytokines and pathogenesis of central retinal vein occlusion[J/OL]. J Clin Med, 2020, 9(11): 3457[2020-10-27]. https://pubmed.ncbi.nlm.nih.gov/33121094/. DOI: 10.3390/jcm9113457.
5. Noma H, Mimura T, Yasuda K, et al. Possible molecular basis of bevacizumab therapy for macular edema in branch retinal vein occlusion[J]. Retina, 2016, 36(9): 1718-1725. DOI: 10.1097/IAE.0000000000000983.
6. Schmidt-Erfurth U, Garcia-Arumi J, Gerendas BS, et al. Guidelines for the management of retinal vein occlusion by the European Society of Retina Specialists (EURETINA)[J]. Ophthalmologica, 2019, 242(3): 123-162. DOI: 10.1159/000502041.
7. 戴虹, 卢颖毅, 许晶晶. 从EURETINA最新指南看视网膜静脉阻塞诊疗策略的变化[J]. 中华实验眼科杂志, 2020, 38(1): 1-3. DOI: 10.3760/cma.j.issn.2095-0160.2020.01.001.Dai H, Lu YY, Xu JJ. Changes of diagnosis and treatment strategies of retinal vein occlusion according to EURETINA updated guidelines[J]. Chin J Exp Ophthalmol, 2020, 38(1): 1-3. DOI: 10.3760/cma.j.issn.2095-0160.2020.01.001.
8. Hayreh SS, Rojas P, Podhajsky P, et al. Ocular neovascularization with retinal vascular occlusion-Ⅲ. Incidence of ocular neovascularization with retinal vein occlusion[J]. Ophthalmology, 1983, 90(5): 488-506. DOI: 10.1016/s0161-6420(83)34542-5.
9. Li X, Wang N, Liang X, et al. Safety and efficacy of dexamethasone intravitreal implant for treatment of macular edema secondary to retinal vein occlusion in Chinese patients: randomized, sham-controlled, multicenter study[J]. Graefe's Arch Clin Exp Ophthalmol, 2018, 256(1): 59-69. DOI: 10.1007/s00417-017-3831-6.
10. Koss MJ, Pfister M, Rothweiler F, et al. Comparison of cytokine levels from undiluted vitreous of untreated patients with retinal vein occlusion[J/OL]. Acta Ophthalmol, 2012, 90(2): e98-e103[2021-11-08]. https://pubmed.ncbi.nlm.nih.gov/22066978/. DOI: 10.1111/j.1755-3768.2011.02292.x.
11. Inagaki M, Hirano Y, Yasuda Y, et al. Twenty-four month results of intravitreal ranibizumab for macular edema after branch retinal vein occlusion: visual outcomes and resolution of macular edema[J]. Semin Ophthalmol, 2021, 36(7): 482-489. DOI: 10.1080/08820538.2021.1890147.
12. Hikichi T, Higuchi M, Matsushita T, et al. Two-year outcomes of intravitreal bevacizumab therapy for macular oedema secondary to branch retinal vein occlusion[J]. Br J Ophthalmol, 2014, 98(2): 195-199. DOI: 10.1136/bjophthalmol-2013-303121.
13. Noma H, Minamoto A, Funatsu H, et al. Intravitreal levels of vascular endothelial growth factor and interleukin-6 are correlated with macular edema in branch retinal vein occlusion[J]. Graefe's Arch Clin Exp Ophthalmol, 2006, 244(3): 309-315. DOI: 10.1007/s00417-004-1087-4.
14. Costagliola C, Morescalchi F, Duse S, et al. Systemic thromboembolic adverse events in patients treated with intravitreal anti-VEGF drugs for neovascular age-related macular degeneration: an update[J]. Expert Opin Drug Saf, 2019, 18(9): 803-815. DOI: 10.1080/14740338.2019.1643838.
15. Schmid MK, Bachmann LM, Fäs L, et al. Efficacy and adverse events of aflibercept, ranibizumab and bevacizumab in age-related macular degeneration: a trade-off analysis[J]. Br J Ophthalmol, 2015, 99(2): 141-146. DOI: 10.1136/bjophthalmol-2014-305149.
16. Noma H, Mimura T, Yasuda K, et al. Functional-morphological parameters, aqueous flare and cytokines in macular oedema with branch retinal vein occlusion after ranibizumab[J]. Br J Ophthalmol, 2017, 101(2): 180-185. DOI: 10.1136/bjophthalmol-2015-307989.
17. Noma H, Yasuda K, Shimura M. Involvement of cytokines in the pathogenesis of diabetic macular edema[J/OL]. Int J Mol Sci, 2021, 22(7): 3427[2021-03-26]. https://pubmed.ncbi.nlm.nih.gov/33810434/. DOI: 10.3390/ijms22073427.
18. Hillier RJ, Ojaimi E, Wong DT, et al. Aqueous humor cytokine levels and anatomic response to intravitreal ranibizumab in diabetic macular edema[J]. JAMA Ophthalmol, 2018, 136(4): 382-388. DOI: 10.1001/jamaophthalmol.2018.0179.
19. Liu Y, Shen J, Fortmann SD, et al. Reversible retinal vessel closure from VEGF-induced leukocyte plugging[J/OL]. JCI Insight, 2017, 2(18): e95530[2019-09-21]. https://pubmed.ncbi.nlm.nih.gov/28931763/. DOI: 10.1172/jci.insight.95530.
20. Uğurlu N, Gerceker S, Yülek F, et al. The levels of the circulating cellular adhesion molecules ICAM-1, VCAM-1 and endothelin-1 and the flow-mediated vasodilatation values in patients with type 1 diabetes mellitus with early-stage diabetic retinopathy[J]. Intern Med, 2013, 52(19): 2173-2178. DOI: 10.2169/internalmedicine.52.8572.

Chinese Journal of Ocular Fundus Diseases

The effect of intravitreal ranibizumab on the expression of cytokines in aqueous humor of patients with macular edema due to branch retinal vein occlusion

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