Cytokines and Recurrence of Macular Edema after Intravitreal Ranibizumab in Patients with Branch Retinal Vein Occlusion

Noma, Hidetaka; Mimura, Tatsuya; Yasuda, Kanako; Nakagawa, Hayate; Motohashi, Ryosuke; Kotake, Osamu; Shimura, Masahiko

doi:10.1159/000451062

Cited by 14 publications

(15 citation statements)

References 28 publications

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“…That is, VEGF is inhibited by anti-VEGF agents, leading to decrease of leukocyte rolling and adhesion (leukostasis) that prevents the positive feedback loop from being established. We have previously reported that the number of doses of anti-VEGF therapy is significantly correlated with the baseline aqueous levels of inflammatory cytokines (sICAM-1, IL-6, and IL-8) [74]. Therefore, early initiation of anti-VEGF therapy should be considered to block positive feedback before macular edema becomes chronic.…”

Section: Possible Mechanism Of Macular Edema In Brvomentioning

confidence: 99%

Cytokines and the Pathogenesis of Macular Edema in Branch Retinal Vein Occlusion

Noma

Yasuda

Shimura

2019

Journal of Ophthalmology

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Branch retinal vein occlusion (BRVO) is a very common retinal vascular problem in patients with lifestyle-related diseases, such as hypertension and arteriosclerosis. In patients with BRVO, development of macular edema is the main cause of visual impairment. BRVO is still a controversial condition in many respects. Over the years, various methods such as laser photocoagulation have been tried to treat macular edema associated with BRVO, but the results were not satisfactory. After vascular endothelial growth factor (VEGF) was found to have an important role in the pathogenesis of macular edema in BRVO patients, treatment of this condition was revolutionized by development of anti-VEGF therapy. Although macular edema improves dramatically following intraocular injection of anti-VEGF agents, repeated recurrence and resistance of edema is a major problem in some BRVO patients. This suggests that factors or cytokines other than VEGF may be associated with inflammation and retinal hypoxia in BRVO and that the pathogenesis of macular edema is complicated. The present review assesses the role of various factors and cytokines in the pathogenesis of macular edema associated with BRVO. We present a mechanism that is not only plausible but should also be useful for developing new therapeutic strategies.

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Section: Possible Mechanism Of Macular Edema In Brvomentioning

confidence: 99%

Cytokines and the Pathogenesis of Macular Edema in Branch Retinal Vein Occlusion

Noma

Yasuda

Shimura

2019

Journal of Ophthalmology

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“…However, recurrence of macular edema is frequent after one dose of IRI. We previously reported that the aqueous humor levels of several inflammatory factors are related to the severity of macular edema [11] and that the number of IRIs was significantly correlated with the baseline aqueous levels of several inflammatory factors [12], suggesting that inflammation may be involved in the recurrence of macular edema. However, it is unclear whether retinal blood flow is involved in the recurrence of macular edema and whether inflammation and inflammatory factors are involved in retinal blood flow.…”

Section: Introductionmentioning

confidence: 99%

Retinal Microcirculation and Cytokines as Predictors for Recurrence of Macular Edema after Intravitreal Ranibizumab Injection in Branch Retinal Vein Occlusion

Noma

Yasuda

Mimura

et al. 2020

JCM

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Purpose: To investigate the relationship between retinal blood flow, presence or absence of recurrence of macular edema, and levels of cytokines, after intravitreal ranibizumab injection (IRI) in patients with branch retinal vein occlusion (BRVO). Methods: In 47 patients with BRVO and macular edema, we used laser speckle flowgraphy (LSFG) to measure the relative flow volume (RFV) of the retinal arteries and veins passing through the optic disc in the occluded and non-occluded regions of the retina before and after IRI. Aqueous humor samples were obtained at the time of IRI. Levels of vascular endothelial growth factor (VEGF), soluble VEGF receptor (sVEGFR)-1, sVEGFR-2, placental growth factor (PlGF), platelet-derived growth factor (PDGF)-AA, soluble intercellular adhesion molecule (sICAM)-1, monocyte chemoattractant protein 1 (MCP-1), interleukin (IL)-6, IL-8, IL-12 (p70), IL-13 and interferon-inducible 10-kDa protein (IP-10) were measured by the suspension array method. Patients were categorized into two groups on the basis of whether or not macular edema recurred at 2 months after IRI: the nonrecurrent group, n = 24; and the recurrent group, n = 23. Results: In the veins of the occluded region, RFV showed a significant difference between baseline and 1 month after IRI (p < 0.001) in the recurrent group and the percent change of RFV showed a significant difference between the recurrent and nonrecurrent groups (p = 0.005). Furthermore, we found a significant negative correlation between RFV in the veins of the occluded region and aqueous levels of MCP-1, IL-8 and IP-10 at baseline (p = 0.029, p = 0.035, and p = 0.039, respectively). In the recurrent group, the arteries and veins of the non-occluded and occluded regions showed no significant association between RFV and the aqueous levels of any factors. Conclusions: These findings suggested that a decrease in RFV in the veins of the occluded region might be associated with the recurrence of macular edema and that the recurrence might depend on the change in RFV in the veins of the occluded region rather than the levels of cytokines.

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“…When Noma and others studied the correlation between aqueous factors and number of IVR injections needed to control ME recurrence during an observation period of 6 months, some pro-inflammatory cytokines (including IL-6, 8, etc.) but not VEGF were found to be correlated with the number of IVR injections ( Noma et al, 2016a ; Noma et al, 2021 ).…”

Section: Intraocular Biomarkersmentioning

confidence: 87%

“…Kotake et al noted that two monthly injections of intravitreal aflibercept (IVA) significantly downregulated aqueous IL-8 but IVR did not, suggesting a stronger inhibitory effect of IVA than IVR on aqueous IL-8 ( Kotake et al, 2019 ). Moreover, baseline IL-8 levels were found to be correlated with the number of IVR injections needed during a 6-month period with a “1 + PRN” regimen for BRVO ( Noma et al, 2016a ; Noma et al, 2021 ), which suggested the potential role of aqueous IL-8 as a predictor for ME recurrence.…”

Section: Intraocular Biomarkersmentioning

confidence: 92%

“…Intravitreal injection of anti-VEGF agents ( Funk et al, 2009 ; Shchuko et al, 2015 ; Noma et al, 2016a ; Noma et al, 2016c ; d ; Matsushima et al, 2019 ; Noma et al, 2021 ) and corticosteroids ( Kunikata et al, 2012 ; Rezar-Dreindl et al, 2017 ) generally leads to a significant decrease in intraocular MCP-1. While a significant association was found between the changes of aqueous MCP-1 and VEGF during IVB treatment ( Funk et al, 2009 ), no statistical correlations between the reduction of MCP-1 and improvement in vision or ME were found in studies using IVR ( Matsushima et al, 2019 ) or IVB ( Noma et al, 2016d ).…”

Section: Intraocular Biomarkersmentioning

confidence: 99%

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A Review of Intraocular Biomolecules in Retinal Vein Occlusion: Toward Potential Biomarkers for Companion Diagnostics

et al. 2022

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Retinal vein occlusion (RVO) is one of the most common retinal vascular diseases. The pathogenesis of RVO is multifactorial and involves a complex interplay among a variety of vascular and inflammatory mediators. Many cytokines, chemokines, growth factors, and cell adhesion molecules have been reported to be implicated. Treatments for RVO are directed at the management of underlying risk factors and vision-threatening complications, including macula edema (ME) and neovascularization. Intravitreal anti-VEGF agents are currently considered as the first-line treatment for ME secondary to RVO (RVO-ME), but a substantial proportion of patients responded insufficiently to anti-VEGF agents. Since RVO-ME refractory to anti-VEGF agents generally responds to corticosteroids and its visual outcome is negatively correlated to disease duration, prediction of treatment response at baseline in RVO-ME may significantly improve both cost-effectiveness and visual prognosis. Several bioactive molecules in the aqueous humor were found to be associated with disease status in RVO. This review aims to present a comprehensive review of intraocular biomolecules reported in RVO, including VEGF, IL-6, IL-8, MCP-1, sICAM-1, IL-12, IL-13, sVEGFR-1, sVEGFR-2, PDGF-AA, etc., highlighting their association with disease severity and/or phenotype, and their potential roles in prognostic prediction and treatment selection. Some of these molecules may serve as biomarkers for aqueous humor-based companion diagnostics for the treatment of RVO in the future.

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Cytokines and Recurrence of Macular Edema after Intravitreal Ranibizumab in Patients with Branch Retinal Vein Occlusion

Cited by 14 publications

References 28 publications

Cytokines and the Pathogenesis of Macular Edema in Branch Retinal Vein Occlusion

Cytokines and the Pathogenesis of Macular Edema in Branch Retinal Vein Occlusion

Retinal Microcirculation and Cytokines as Predictors for Recurrence of Macular Edema after Intravitreal Ranibizumab Injection in Branch Retinal Vein Occlusion

A Review of Intraocular Biomolecules in Retinal Vein Occlusion: Toward Potential Biomarkers for Companion Diagnostics

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