To analyze changes in the levels of angiogenic and inflammatory cytokines following the administration of intravitreal conbercept (IVC) or intravitreal ranibizumab (IVR) in patients with macular edema (ME) due to central retinal vein occlusion (CRVO).
Methods:
This retrospective study was conducted between June 2015 and January 2016 in The First Hospital of China Medical University. We administered 3 consecutive monthly doses of IVC (23 eyes) or IVR (19 eyes) in 42 eyes with CRVO-ME. At each injection, we collected aqueous humor samples and used multiplex bead assays to measure 7 angiogenic and inflammatory cytokines [vascular endothelial growth factor (VEGF), placental growth factor (PlGF), platelet-derived growth factor (PDGF)-AA, monocyte chemoattractant protein (MCP)-1, and interleukins (ILs)-6, 8, and 12].
Results
: Visual acuity and ME improved significantly in both groups during the treatment period. Compared with the baseline, all the cytokine concentrations in the aqueous humor samples decreased significantly at 1 and 2 months after the initial dose of IVC or IVR. The improvement of visual acuity and ME and the changes of aqueous humor cytokine levels were similar in both groups. Concentrations of VEGF, PlGF, MCP-1, PDGF-AA, IL-6, IL-8, and IL-12 levels did not show significant intergroup differences after 1 month (P = 0.369, 0.312, 0.185, 0.353, 0.135, 0.487, and 0.337, respectively) and 2 months (P = 0.305, 0.376, 0.230, 0.519, 0.114, 0.960, and 0.830, respectively) of follow-up.
Conclusion:
IVC and IVR induced comparable improvements in clinical parameters, along with equivalent reductions in the concentrations of angiogenic and inflammatory cytokines in the aqueous humor.
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References
1.
Schmidt-ErfurthU., Garcia-ArumiJ., GerendasB.S., MidenaE., SivaprasadS., TadayoniR., WolfS., and LoewensteinA.Guidelines for the Management of Retinal Vein Occlusion by the European Society of Retina Specialists (EURETINA). Ophthalmologica. 242:123–162, 2019.
2.
SunZ., ZhouH., LinB., JiaoX., LuoY., ZhangF., TaoS., WuQ., KeZ., and LiuX.Efficacy and safety of intravitreal conbercept injections in macular edema secondary to retinal vein occlusion. Retina. 37:1723–1730, 2017.
3.
TangF., QinX., LuJ., SongP., LiM., and MaX.Optical coherence tomography predictors of short-term visual acuity in eyes with macular edema secondary to retinal vein occlusion treated with intravitreal conbercept. Retina. 40:773–785, 2019.
4.
ZengH.Y., LiuQ., LiX.X., SunY.X., and ZhangZ.J.One-year efficacy of intravitreal conbercept injection for macular oedema secondary to central retinal vein occlusion in Chinese patients. Eye (Lond). 34:1459–1464, 2020.
5.
Pe'erJ., FolbergR., ItinA., GnessinH., HemoI., and KeshetE.Vascular endothelial growth factor upregulation in human central retinal vein occlusion. Ophthalmology. 105:412–416, 1998.
6.
NomaH., MimuraT., YasudaK., and ShimuraM.Role of soluble vascular endothelial growth factor receptor signaling and other factors or cytokines in central retinal vein occlusion with macular edema. Invest. Ophthalmol. Vis. Sci. 56:1122–1128, 2015.
7.
KossM.J., PfisterM., RothweilerF., MichaelisM., CinatlJ., SchubertR., and KochF.H.Comparison of cytokine levels from undiluted vitreous of untreated patients with retinal vein occlusion. Acta Ophthalmol. 90:e98–e103, 2012.
8.
JungS.H., KimK.A., SohnS.W., and YangS.J.Association of aqueous humor cytokines with the development of retinal ischemia and recurrent macular edema in retinal vein occlusion. Invest. Ophthalmol. Vis. Sci. 55:2290–2296, 2014.
9.
NomaH., FunatsuH., MimuraT., HarinoS., and HoriS.Vitreous levels of interleukin-6 and vascular endothelial growth factor in macular edema with central retinal vein occlusion. Ophthalmology. 116:87–93, 2009.
10.
WenJ., JiangY., ZhengX., and ZhouY.Six-month changes in cytokine levels after intravitreal bevacizumab injection for diabetic macular oedema and macular oedema due to central retinal vein occlusion. Br. J. Ophthalmol. 99:1334–1340, 2015.
11.
NomaH., MimuraT., YasudaK., and ShimuraM.Cytokine kinetics after monthly intravitreal bevacizumab for retinal vein occlusion associated with macular oedema. Ophthalmic. Res. 56:207–214, 2016.
12.
MatsushimaR., NomaH., YasudaK., GotoH., and ShimuraM.Role of cytokines in ranibizumab therapy for macular edema in patients with central retinal vein occlusion. J. Ocul. Pharmacol. Ther. 35:407–412, 2019.
13.
YangK.-B., SunX.-Y., SunL.-P., LiJ., LiuZ.-L., and ZhangH.Aqueous humor cytokine levels and rebound macular edema following conbercept treatment in patients with central retinal vein occlusion. Retina. 2020 [EPub ahead of print]; DOI: 10.1097/iae.0000000000002918.
14.
AscasoF.J., HuervaV., and GrzybowskiA.The role of inflammation in the pathogenesis of macular edema secondary to retinal vascular diseases. Mediators Inflamm. 2014:432685, 2014.
15.
DaruichA., MatetA., MoulinA., KowalczukL., NicolasM., SellamA., RothschildP.R., OmriS., GelizeE., JonetL., DelaunayK., De KozakY., BerdugoM., ZhaoM., CrisantiP., and Behar-CohenF.Mechanisms of macular edema: beyond the surface. Prog. Retin Eye Res. 63:20–68, 2018.
16.
MaloneyJ.P., and GaoL.Proinflammatory cytokines increase vascular endothelial growth factor expression in alveolar epithelial cells. Mediators Inflamm. 2015:387842, 2015.
17.
GalliR., PaoneA., FabbriM., ZanesiN., CaloreF., CascioneL., AcunzoM., StoppacciaroA., TubaroA., LovatF., GaspariniP., FaddaP., AlderH., VoliniaS., FilippiniA., ZiparoE., RiccioliA., and CroceC.M.Toll-like receptor 3 (TLR3) activation induces microRNA-dependent reexpression of functional RARbeta and tumor regression. Proc. Natl. Acad. Sci. U S A. 110:9812–9817, 2013.
18.
NakaoS., ArimaM., IshikawaK., KohnoR., KawaharaS., MiyazakiM., YoshidaS., EnaidaH., Hafezi-MoghadamA., KonoT., and IshibashiT.Intravitreal anti-VEGF therapy blocks inflammatory cell infiltration and re-entry into the circulation in retinal angiogenesis. Invest. Ophthalmol. Vis. Sci. 53:4323–4328, 2012.
19.
HongK.H., RyuJ., and HanK.H.Monocyte chemoattractant protein-1-induced angiogenesis is mediated by vascular endothelial growth factor-A. Blood. 105:1405–1407, 2005.
20.
KotakeO., NomaH., YasudaK., MotohashiR., GotoH., and ShimuraM.Comparing cytokine kinetics between ranibizumab and aflibercept in central retinal vein occlusion with macular edema. Ophthalmic Res. 25:1–8, 2018.
21.
YangX., ZhangY., YangY., LimS., CaoZ., RakJ., and CaoY.Vascular endothelial growth factor-dependent spatiotemporal dual roles of placental growth factor in modulation of angiogenesis and tumor growth. Proc. Natl. Acad. Sci. U S A. 110:13932–13937, 2013.
22.
YaoY.G., YangH.S., CaoZ., DanielssonJ., and DuhE.J.Upregulation of placental growth factor by vascular endothelial growth factor via a post-transcriptional mechanism. FEBS Lett. 579:1227–1234, 2005.
23.
MarumoT., Schini-KerthV.B., FisslthalerB., and BusseR.Platelet-derived growth factor-stimulated superoxide anion production modulates activation of transcription factor NF-kappaB and expression of monocyte chemoattractant protein 1 in human aortic smooth muscle cells. Circulation. 96:2361–2367, 1997.
24.
MartinD., GalisteoR., and GutkindJ.S.CXCL8/IL8 stimulates vascular endothelial growth factor (VEGF) expression and the autocrine activation of VEGFR2 in endothelial cells by activating NFkappaB through the CBM (Carma3/Bcl10/Malt1) complex. J. Biol. Chem. 284:6038–6042, 2009.
25.
BaldwinA.S.Jr.The NF-kappa B and I kappa B proteins: new discoveries and insights. Annu. Rev. Immunol. 14:649–683, 1996.
26.
ClaussM., WeichH., BreierG., KniesU., RocklW., WaltenbergerJ., and RisauW.The vascular endothelial growth factor receptor Flt-1 mediates biological activities. Implications for a functional role of placenta growth factor in monocyte activation and chemotaxis. J. Biol. Chem. 271:17629–17634, 1996.
27.
FunkM., KriechbaumK., PragerF., BeneschT., GeorgopoulosM., ZlabingerG.J., and Schmidt-ErfurthU.Intraocular concentrations of growth factors and cytokines in retinal vein occlusion and the effect of therapy with bevacizumab. Invest. Ophthalmol. Vis. Sci. 50:1025–1032, 2009.
28.
RohM.I., KimH.S., SongJ.H., LimJ.B., and KwonO.W.Effect of intravitreal bevacizumab injection on aqueous humor cytokine levels in clinically significant macular edema. Ophthalmology. 116:80–86, 2009.
29.
LimS.W., Bandala-SanchezE., KolicM., RogersS.L., McAuleyA.K., LimL.L., and WickremasingheS.S.The influence of intravitreal ranibizumab on inflammation-associated cytokine concentrations in eyes with diabetic macular edema. Invest. Ophthalmol. Vis. Sci. 59:5382–5390, 2018.
30.
XiaJ.P., WangS., and ZhangJ.S.The anti-inflammatory and anti-oxidative effects of conbercept in treatment of macular edema secondary to retinal vein occlusion. Biochem. Biophys. Res. Commun. 508:1264–1270, 2019.
31.
LiF., SunM., GuoJ., MaA., and ZhaoB.Comparison of conbercept with ranibizumab for the treatment of macular edema secondary to branch retinal vein occlusion. Curr. Eye Res. 42:1174–1178, 2017.
32.
NomaH., FunatsuH., and MimuraT.Vascular endothelial growth factor and interleukin-6 are correlated with serous retinal detachment in central retinal vein occlusion. Curr. Eye Res. 37:62–67, 2012.
33.
NomaH., FunatsuH., MimuraT., and EguchiS.Vitreous inflammatory factors and serous retinal detachment in central retinal vein occlusion: a case control series. J. Inflamm (Lond). 8:38, 2011.
34.
PoonY.C., ChenC.H., KuoH.K., ChenY.J., WuP.C., ChenY.H., and LeeJ.J.Clinical implications of serous retinal detachment in branch retinal vein occlusion and response after primary intravitreal bevacizumab injection. J. Ocul. Pharmacol. Ther. 29:319–324, 2013.
35.
NomaH., FunatsuH., MimuraT., HarinoS., and HoriS.Aqueous humor levels of vasoactive molecules correlate with vitreous levels and macular edema in central retinal vein occlusion. Eur. J. Ophthalmol. 20:402–409, 2010.
36.
LiuW., LiY., CaoR., BaiZ., and LiuW.A systematic review and meta-analysis to compare the efficacy of conbercept with ranibizumab in patients with macular edema secondary to retinal vein occlusion. Medicine (Baltimore). 99:e20222, 2020.
