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Treatment of proliferative diabetic retinopathy with anti-VEGF agents
Abstract
Proliferative diabetic retinopathy (PDR) is the most common cause of severe visual loss in people with diabetes. Although panretinal photocoagulation (PRP) remains the gold standard of care to date, several combinations of new treatment modalities have emerged. These approaches can be used to increase the extent of treatment, expedite the effect of laser treatment and provide alternate measures when laser delivery is difficult or impossible, especially in patients with vitreous haemorrhage. Currently, most of the research in this field is focussed on inhibitors of vascular endothelial growth factor (VEGF), referred to herein as anti-VEGF agents. Although limited by their short-lived effects and a lack of established protocols, anti-VEGF agents are widely available, especially for the treatment of aggressive PDR. This review analyses published studies using anti-VEGF agents alone or as an adjunct to other therapies in the treatment of PDR.
... Anti-VEGF treatment is another option in the care of PDR that is gaining traction in the community to prevent the adverse effects of laser therapy, particularly in patients with vitreous hemorrhage (Behl & Kotwani, 2015;Salam et al., 2011). Anti-VEGF allows neovascularization secondary to PDR to regress, reducing macular thickness owing to edema and increasing visual field (Salam et al., 2011;Zong et al., 2011). ...
... Anti-VEGF treatment is another option in the care of PDR that is gaining traction in the community to prevent the adverse effects of laser therapy, particularly in patients with vitreous hemorrhage (Behl & Kotwani, 2015;Salam et al., 2011). Anti-VEGF allows neovascularization secondary to PDR to regress, reducing macular thickness owing to edema and increasing visual field (Salam et al., 2011;Zong et al., 2011). Anti-VEGF therapy is thought to be less dangerous than laser photocoagulation therapy (Giuliari, 2012). ...
... PRP is the gold standard therapy for PDR, reducing the risk of vision loss by 50-60% (Çeliker et al., 2017;Palanker & Blumenkranz, 2012;Salam et al., 2011;Zhao & Singh, 2018). Laser beams of 1200-1600 nm are focused on the peripheral retina to delay the development of new blood vessels. ...
Diabetic retinopathy is a complication of diabetes that is one of the top five causes of blindness in those over 50. The standard treatment is pan-retinal photocoagulation, which is effective but has established side effects. Anti-vascular endothelial growth factor (anti-VEGF) therapy becomes an alternative to avoid the side effects caused by laser therapy. This systematic review aims to know the effectiveness of anti-VEGF therapy compared to the pan-retinal photocoagulation laser therapy in patients with proliferative diabetic retinopathy. This review was carried out using a systematic review checklist on PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses). The articles reviewed were randomized controlled trial articles that met the inclusion and exclusion criteria. Based on inclusion and exclusion criteria, six articles were selected from a total of 215. Patients who received anti-VEGF medication had better visual acuity (positive values), whereas patients who received laser therapy had poorer visual acuity (negative values). Those results are because the laser directs light towards the retina, damaging photoreceptors and retinal cells as well as reducing visual acuity. On the contrary, anti-VEGF prevents damage to retinal endothelial cells and blood leaks in the vitreous by decreasing VEGF expression and thus resulting in improved visual acuity. Anti-VEGF proved to be a more practical alternative therapy in improving visual acuity than pan-retinal photocoagulation for patients with proliferative diabetic retinopathy.
... An approach used to manage DR-related bleeding complications involves repetitive injectable intervention protocols consistent with intravitreal injection of different specific target agents against signaling proteins involved in the angiogenesis cascade called vascular endothelial growth factors (anti-VEGFs) to improve BRB stability [6]. They are widely available for use worldwide, especially for the treatment of aggressive proliferative DR [6]. ...
... An approach used to manage DR-related bleeding complications involves repetitive injectable intervention protocols consistent with intravitreal injection of different specific target agents against signaling proteins involved in the angiogenesis cascade called vascular endothelial growth factors (anti-VEGFs) to improve BRB stability [6]. They are widely available for use worldwide, especially for the treatment of aggressive proliferative DR [6]. Similarly, some patients are boosted with steroids, periocular injections, or intravitreal extended-release devices to improve long-term visual outcomes. ...
... An important issue is that when the retina becomes detached along the macula, it must be managed in a timely manner to ensure that perfusion, mainly to the outer layers, resumes. Postoperative multimodal evaluation is mandatory for better evaluation and improvement of functional outcomes [6,27] using injectable interventions or sustained anti-VEGF agents [21,52]. ...
Optical coherence tomography angiography (OCT-A) is useful for quantitative analyses of different choroidal and retinal vascular plexuses. Highlighting postoperative choroidal and retinal perfusion outcomes in patients who have undergone successful tractional retinal detachment (TRD) repair is crucial for understanding the impact of this condition on postoperative visual acuity. This chapter describes postoperative perfusion outcomes, such as vessel density (VD) quantified in the superficial and deep capillary plexuses of the retina and choroidal perfusion markers, such as the choroidal vascularity index (CVI) and choriocapillaris flow area (CFA). In this analysis, superficial and deep capillary plexuses were quantified, and the CVI and CFA were significantly lower in the surgical group (P = 0.0011), with median CVIs of 57.95% and 2.28 mm2 in the control group and 44.41% and 1.38 mm2 in the surgical group, respectively. Definitive correlations were shown between alterations in the structure of the retina and choroid after surgery and visual dysfunction in diabetic individuals. The CVI and CFA can be used as quantitative measures to evaluate choroidal damage in postoperative patients with traction retinal detachment. The CVI serves as a dependable quantitative biomarker for evaluating the progression of diabetic retinopathy (DR) or for tracking postoperative eyes.
... PDR stands as a severe and vision-endangering complication intricately intertwined with angiogenesis [50,[54][55][56]. In PDR, the chronic state of hyperglycemia and associated vascular damage stemming from diabetes mellitus culminates in the formation of anomalous and frail retinal blood vessels [50,[54][55][56]. ...
... PDR stands as a severe and vision-endangering complication intricately intertwined with angiogenesis [50,[54][55][56]. In PDR, the chronic state of hyperglycemia and associated vascular damage stemming from diabetes mellitus culminates in the formation of anomalous and frail retinal blood vessels [50,[54][55][56]. These neovascular structures are a direct consequence of uncontrolled angiogenesis, primarily driven by the presence of hypoxia, or oxygen deficiency, and the concomitant release of various angiogenic growth factors, most notably VEGF [50,[54][55][56]. ...
... In PDR, the chronic state of hyperglycemia and associated vascular damage stemming from diabetes mellitus culminates in the formation of anomalous and frail retinal blood vessels [50,[54][55][56]. These neovascular structures are a direct consequence of uncontrolled angiogenesis, primarily driven by the presence of hypoxia, or oxygen deficiency, and the concomitant release of various angiogenic growth factors, most notably VEGF [50,[54][55][56]. The excessive angiogenesis observed in PDR subsequently leads to the development of delicate, permeable vessels, often resulting in retinal hemorrhage, fibrosis, and ultimately, severe vision impairment [50,[54][55][56]. ...
Mitochondria are important for the activation of endothelial cells and the process of angiogenesis. NDUFS8 (NADH:ubiquinone oxidoreductase core subunit S8) is a protein that plays a critical role in the function of mitochondrial Complex I. We aimed to investigate the potential involvement of NDUFS8 in angiogenesis. In human umbilical vein endothelial cells (HUVECs) and other endothelial cell types, we employed viral shRNA to silence NDUFS8 or employed the CRISPR/Cas9 method to knockout (KO) it, resulting in impaired mitochondrial functions in the endothelial cells, causing reduction in mitochondrial oxygen consumption and Complex I activity, decreased ATP production, mitochondrial depolarization, increased oxidative stress and reactive oxygen species (ROS) production, and enhanced lipid oxidation. Significantly, NDUFS8 silencing or KO hindered cell proliferation, migration, and capillary tube formation in cultured endothelial cells. In addition, there was a moderate increase in apoptosis within NDUFS8-depleted endothelial cells. Conversely, ectopic overexpression of NDUFS8 demonstrated a pro-angiogenic impact, enhancing cell proliferation, migration, and capillary tube formation in HUVECs and other endothelial cells. NDUFS8 is pivotal for Akt-mTOR cascade activation in endothelial cells. Depleting NDUFS8 inhibited Akt-mTOR activation, reversible with exogenous ATP in HUVECs. Conversely, NDUFS8 overexpression boosted Akt-mTOR activation. Furthermore, the inhibitory effects of NDUFS8 knockdown on cell proliferation, migration, and capillary tube formation were rescued by Akt re-activation via a constitutively-active Akt1. In vivo experiments using an endothelial-specific NDUFS8 shRNA adeno-associated virus (AAV), administered via intravitreous injection, revealed that endothelial knockdown of NDUFS8 inhibited retinal angiogenesis. ATP reduction, oxidative stress, and enhanced lipid oxidation were detected in mouse retinal tissues with endothelial knockdown of NDUFS8. Lastly, we observed an increase in NDUFS8 expression in retinal proliferative membrane tissues obtained from human patients with proliferative diabetic retinopathy. Our findings underscore the essential role of the mitochondrial protein NDUFS8 in regulating endothelial cell activation and angiogenesis.
... Anti-VEGF treatment is another option in the care of PDR that is gaining traction in the community to prevent the adverse effects of laser therapy, particularly in patients with vitreous hemorrhage (Behl & Kotwani, 2015;Salam et al., 2011). Anti-VEGF allows neovascularization secondary to PDR to regress, reducing macular thickness owing to edema and increasing visual field (Salam et al., 2011;Zong et al., 2011). ...
... Anti-VEGF treatment is another option in the care of PDR that is gaining traction in the community to prevent the adverse effects of laser therapy, particularly in patients with vitreous hemorrhage (Behl & Kotwani, 2015;Salam et al., 2011). Anti-VEGF allows neovascularization secondary to PDR to regress, reducing macular thickness owing to edema and increasing visual field (Salam et al., 2011;Zong et al., 2011). Anti-VEGF therapy is thought to be less dangerous than laser photocoagulation therapy (Giuliari, 2012). ...
... PRP is the gold standard therapy for PDR, reducing the risk of vision loss by 50-60% (Çeliker et al., 2017;Palanker & Blumenkranz, 2012;Salam et al., 2011;Zhao & Singh, 2018). Laser beams of 1200-1600 nm are focused on the peripheral retina to delay the development of new blood vessels. ...
Diabetic retinopathy is a complication of diabetes that is one of the top five causes of blindness in those over 50. The standard treatment is pan-retinal photocoagulation, which is effective but has established side effects. Anti-vascular endothelial growth factor (anti-VEGF) therapy becomes an alternative to avoid the side effects caused by laser therapy. This systematic review aims to know the effectiveness of anti-VEGF therapy compared to the pan-retinal photocoagulation laser therapy in patients with proliferative diabetic retinopathy. This review was carried out using a systematic review checklist on PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses). The articles reviewed were randomized controlled trial articles that met the inclusion and exclusion criteria. Based on inclusion and exclusion criteria, six articles were selected from a total of 215. Patients who received anti-VEGF medication had better visual acuity (positive values), whereas patients who received laser therapy had poorer visual acuity (negative values). Those results are because the laser directs light towards the retina, damaging photoreceptors and retinal cells as well as reducing visual acuity. On the contrary, anti-VEGF prevents damage to retinal endothelial cells and blood leaks in the vitreous by decreasing VEGF expression and thus resulting in improved visual acuity. Anti-VEGF proved to be a more practical alternative therapy in improving visual acuity than pan-retinal photocoagulation for patients with proliferative diabetic retinopathy.
... It also might open new venues for treatment of diabetic retinopathy. Currently the most common therapy seeks to inhibit VEGF-A (vascular endothelial cell growth factor-A), a growth factor that promotes increased vascular permeability, macular edema, and neovascularization (Salam et al., 2011;Al-Latayfeh et al., 2012;Bandello et al., 2012;Tremolada et al., 2012;Gupta et al., 2013). While these drugs have been successful in some patients, they do not provide reliable benefits for all patients. ...
Introduction
Inflammation and cell death play an important role in the pathogenesis of diabetic retinopathy. Previously we observed sustained activation of pro-inflammatory caspase-1 in retinas of diabetic animals and patients. In this study, we aimed to look at mechanisms underlying chronic caspase-1 activation in vitro and in vivo.
Methods
Non-diabetic and diabetic wild type and IL-1 receptor (IL-1R1) knockout mice were used for in vivo experiments. Diabetes was induced using STZ (streptozotocin). Human Müller cells were used for in vitro studies. Cells were treated with either 5 mM or 25 mM glucose or interleukin-1beta (IL-1β) in the presence or absence of IL-1 receptor antagonist (IL-1ra) or siRNA against RIP2 (receptor interacting protein-2) for up to 96 h. Outcome measurements to assess Müller cell functions included measurements of caspase-1 activity using a fluorescence peptide substrate, production of IL-1β by Elisa, and cell death using trypan blue exclusion assays.
Results
Our in vivo results demonstrate that caspase-1 activation progresses from an IL-1R1 independent mechanism at 10 weeks of diabetes to an IL-1R1 dependent mechanism at 20 weeks indicating that feedback through IL-1R1 is crucial for sustained caspase-1 activity in retinas of mice. A similar hyperglycemia-mediated caspase-1/IL-1β/IL-1R1 feedback signaling was detected in vitro in human Müller cells which was prevented by treatment with IL-1ra. Our data also indicate that hyperglycemia induces caspase-1 activation initially but IL-1β sustains caspase-1 activation via caspase-1/IL-1β/IL-1R1 feedback and we identified RIP2 as mediator for both hyperglycemia- and IL-1β-induced caspase-1 activation. Activation of caspase-1/IL-1β/IL-1R1 feedback signaling caused Müller cell death which was prevented by RIP2 knockdown.
Discussion
We conclude that any intervention in caspase-1/IL-1β/IL-1R1 feedback signaling presents novel therapeutic options for the treatment of diabetic retinopathy.
... Pathological angiogenesis is a key pathology of diabetic retinopathy (DR) [48][49][50][51][52][53]. We next explored the potential role of Gαi2 in the process. ...
Here we explored the potential role of Gαi2 (G protein subunit alpha i2) in endothelial cell function and angiogenesis.
Methods: Genetic methodologies such as shRNA, CRISPR/Cas9, dominant negative mutation, and overexpression were utilized to modify Gαi2 expression or regulate its function. Their effects on endothelial cell functions were assessed in vitro. In vivo, the endothelial-specific Gαi2 shRNA adeno-associated virus (AAV) was utilized to silence Gαi2 expression. The impact of this suppression on retinal angiogenesis in control mice and streptozotocin (STZ)-induced diabetic retinopathy (DR) mice was analyzed.
Results: Analysis of single-cell RNA sequencing data revealed Gαi2 (GNAI2) was predominantly expressed in retinal endothelial cells and expression was increased in retinal endothelial cells following oxygen-induced retinopathy (OIR) in mice. Moreover, transcriptome analysis linking Gαi2 to angiogenesis-related processes/pathways, supported by increased Gαi2 expression in experimental OIR mouse retinas, highlighted its possible role in angiogenesis. In various endothelial cell types, shRNA-induced silencing and CRISPR/Cas9-mediated knockout (KO) of Gαi2 resulted in substantial reductions in cell proliferation, migration, invasion, and capillary tube formation. Conversely, Gαi2 over-expression in endothelial cells induced pro-angiogenic activities, enhancing cell proliferation, migration, invasion, and capillary tube formation. Furthermore, our investigation revealed a crucial role of Gαi2 in NFAT (nuclear factor of activated T cells) activation, as evidenced by the down-regulation of NFAT-luciferase reporter activity and pro-angiogenesis NFAT-targeted genes (Egr3, CXCR7, and RND1) in Gαi2-silenced or -KO HUVECs, which were up-regulated in Gαi2-overexpressing endothelial cells. Expression of a dominant negative Gαi2 mutation (S48C) also down-regulated NFAT-targeted genes, slowing proliferation, migration, invasion, and capillary tube formation in HUVECs. Importantly, in vivo experiments revealed that endothelial Gαi2 knockdown inhibited retinal angiogenesis in mice, with a concomitant down-regulation of NFAT-targeted genes in mouse retinal tissue. In contrast, Gαi2 over-expression in endothelial cells enhanced retinal angiogenesis in mice. Single-cell RNA sequencing data confirmed increased levels of Gαi2 specifically in retinal endothelial cells of mice with streptozotocin (STZ)-induced diabetic retinopathy (DR). Importantly, endothelial Gαi2 silencing ameliorated retinal pathological angiogenesis in DR mice.
Conclusion: Our study highlights a critical role for Gαi2 in NFAT activation, endothelial cell activation and angiogenesis, offering valuable insights into potential therapeutic strategies for modulating these processes.
... However, the economic burden of the anti-VEGF injection is heavy because the price for a single injection is expensive and not covered for PDR treatment in South Korea [17]. Moreover, the treatment effect is relatively short-term, the anti-VEGF injection must be repeated [18]. This inhibits the cost-effectiveness of the anti-VEGF injection, although this cost-effectiveness can vary according to the type of anti-VEGF agent involved [19]. ...
Background
We determined the cost-effectiveness of the anti-vascular endothelial growth factor (VEGF) intravitreal injection versus panretinal photocoagulation (PRP) for patients with proliferative diabetic retinopathy (PDR) in South Korea.
Methods
We simulated four treatment strategies using PRP and the anti-VEGF injection by constructing a Markov model for a hypothetical cohort of 50-year-old PDR patients: (1) PRP only; (2) anti-VEGF injection only; (3) PRP first; and (4) anti-VEGF injection first.
Results
In this cost-effectiveness analysis, compared with only-PRP, the incremental cost-effectiveness ratio was 34,375 per QALY for anti-VEGF injection first, and 42,000, while anti-VEGF injection only was cost-effective from a healthcare perspective. From the societal and payer perspectives, regardless of the value of WTP, anti-VEGF injection only was the most cost-effective strategy.
Conclusion
In our study, the anti-VEGF injection for PDR was cost-effective from the payer and societal perspectives.
... 6 However, the role of anti-VEGF agents, including IVA, has increased over the last few years. 21 IVA is less invasive than vitrectomy. This makes IVA a good choice for the treatment of diabetic retinopathy. ...
This review aimed to systematically compare the efficacy and safety of intravitreal aflibercept (IVA) and vitrectomy for treating severe vitreous hemorrhage (VH) secondary to proliferative diabetic retinopathy (PDR). The review was conducted in accordance with PRISMA guidelines. A search strategy, including the MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and US National Library of Medicine databases, was developed to identify randomized controlled trials (RCTs) that compared vitrectomy and IVA for managing VH due to PDR (participant age ≥ 18 years). The primary outcome measure was the difference in the mean visual acuity between the two treatment groups at 1, 6, and 24 months. Outcome measures included clearance of VH (in weeks), the incidence of recurrent VH, and the rate of complications. The studies were evaluated using the Cochrane Bias (ROB) tool. We identified 774 articles; six articles met the inclusion criteria, and two were ultimately included (n = 239 eyes). With or without PRP, IVA injections and vitrectomy were performed in 117 and 122 eyes, respectively. The mean BCVA at one month was significantly better in the vitrectomy group (MD=0.22, CI:0.10–0.34, p=0.0003), but no difference was found at six months (MD=0.04, CI: −0.04–0.12, p=0.356). The incidence of recurrent VH was significantly higher in the IVA group (OR=5.05, CI:2.71–9.42, p<0.0001). The probability of recurrent VH was five times greater in the IVA group than that in the vitrectomy group. There were no significant differences in the overall proportions of intra- or postoperative complications (OR=0.64, CI: 0.09–4.85, p=0.669). None of the studies had a low ROB in any of the seven domains. We conclude that IVA can be considered a viable treatment modality for diabetic VH in patients with a good follow-up. Vitrectomy initially provides better visual effect, faster VH recovery, and lower VH recurrence than IVA injections.
... shown that an anti-VEGF agent effectively causes neovascularization regression in eyes with PDR 15 and improves the severity of DR. 16,17 Our findings were also supported by histological findings. Kohno et al 18 found that intravitreal bevacizumab injection may induce changes in immature, newly formed vessels of PDR or neovascular glaucoma tissue. ...
Purpose:
To quantify changes of the retinal vascular bed area (RVBA) in mm2 on stereographically projected ultra-wide field (UWF) fluorescein angiography (FA) images by in eyes with proliferative diabetic retinopathy (PDR) following anti-vascular endothelial growth factor (VEGF) injection.
Methods:
Prospective, observational study. The early-phase UWF FA images (Optos 200Tx) of 40 eyes with PDR and significant non-perfusion obtained at baseline and after 6 months (NCT02863354) were stereographically projected by correcting peripheral distortion. The global retinal vasculature on UWF FA was extracted for calculating RVBA by summing the real size (mm2) of all the pixels automatically.
Results:
For the entire cohort, global RVBA for the entire retina decreased from 67.1 ± 15.5 mm2 to 43.6 ± 18.8 mm2 after anti-VEGF treatment at 6 months (P < 0.001). In the sub-group receiving monthly anti-VEGF injections, global RVBA decreased from 68.7 ± 16.2 mm2 to 33.9 ± 13.3 mm2 (P < 0.001). In the sub-group receiving anti-VEGF every 3 months, global RVBA decreased from 65.6 ± 15.1 mm2 to 50.8 ± 19.3 mm2 (P = 0.004).
Conclusions:
RVBA appears to be a new biomarker to indicate efficiency of retinal vascular changes after anti-VEGF injection. Eyes with PDR and significant non-perfusion demonstrate reduced RVBA following anti-VEGF treatment.
... MiR-93, miR-126, and mirR-221 have been studied in cohorts of both T2D and T1D patients [15][16][17][18][19][20]. Mir-93 influences the progression of DR by regulating angiogenesis, although the exact mechanism remains unclear [33,34]. In a cohort of 140 T2D patients, Zou and colleagues found a higher expression of plasma miR-93 and VEGF in the group with DR compared to the group with no ocular complications [15]. ...
Diabetic retinopathy (DR) is one of the main causes of vision loss in middle-aged economically active people. Modifiable (i.e., hyperglycaemia, hypertension, hyperlipidaemia, obesity, and cigarette smoke) and non-modifiable factors (i.e., duration of diabetes, puberty, pregnancy and genetic susceptibility) are involved in the development of DR. Epigenetic mechanisms, modulating the oxidative stress, inflammation, apoptosis, and aging, could influence the course of DR. Herein, we conducted a systematic review of observational studies investigating how epigenetics affects type 2 diabetes retinopathy (T2DR). A total of 23 epidemiological studies were included: 14 studies focused on miRNA, 4 studies on lnc-RNA, one study on both miRNA and lnc-RNA, and 4 studies on global or gene-specific DNA methylation. A direct relation between the dysregulation of miR-21, miR-93, and miR-221 and FPG, HbA1c, and HOMA-IR was identified. A panel of three miRNAs (hsa-let-7a-5p, hsa-miR-novel-chr5_15976, and hsa-miR-28-3p) demonstrated a good sensitivity and specificity for predicting T2DR. Little evidence is available regarding the possible role of the long non-coding MALAT1 dysregulation and MTHFR gene promoter hypermethylation. Despite these initial, encouraging findings potentially suggesting a role of epigenetics in T2DR, the use in clinical practice for the diagnosis and staging of this complication encounters several difficulties and further targeted investigations are still necessary.
... 10 Targeting the VEGF/VEGFR-2 pathway has emerged as an important therapeutic approach to arrest progression of angiogenesis in patients with PDR. 11 However, these approaches often lead to transient responses because angiogenesis is regulated by multiple pathways and when the activity of one pathway, such as VEGF/VEGFR-2 is suppressed, the expression of other compensatory angiogenic pathways may appear and contribute to limit the efficacy of anti-VEGF treatment. 12 Therefore, the identification of those compensatory signaling pathways linking hypoxia to angiogenesis in the ocular microenvironment of patients with PDR is essential to design novel therapies aiming at inhibiting simultaneously different angiogenic pathways. ...
Purpose:
Inflammation, angiogenesis and fibrosis are pathological hallmarks of proliferative diabetic retinopathy (PDR). The CD146/sCD146 pathway displays proinflammatory and proangiogenic properties. We investigated the role of this pathway in the pathophysiology of PDR.
Methods:
Vitreous samples from 41 PDR and 27 nondiabetic patients, epiretinal fibrovascular membranes from 18 PDR patients, rat retinas, human retinal microvascular endothelial cells (HRMECs) and human retinal Müller glial cells were studied by ELISA, Western blot analysis, immunohistochemistry and immunofluorescence microscopy analysis. Blood-retinal barrier breakdown was assessed with fluorescein isothiocyanate-conjugated dextran.
Results:
sCD146 and VEGF levels were significantly higher in vitreous samples from PDR patients than in nondiabetic patients. In epiretinal membranes, immunohistochemical analysis revealed CD146 expression in leukocytes, vascular endothelial cells and myofibroblasts. Significant positive correlations were detected between numbers of blood vessels expressing CD31, reflecting angiogenic activity of PDR, and numbers of blood vessels and stromal cells expressing CD146. Western blot analysis showed significant increase of CD146 in diabetic rat retinas. sCD146 induced upregulation of phospho-ERK1/2, NF-κB , VEGF and MMP-9 in Müller cells. The hypoxia mimetic agent cobalt chloride, VEGF and TNF-α induced upregulation of sCD146 in HRMECs. The MMP inhibitor ONO-4817 attenuated TNF-α-induced upregulation of sCD146 in HRMECs. Intravitreal administration of sCD146 in normal rats significantly increased retinal vascular permeability and induced significant upregulation of phospho-ERK1/2, intercellular adhesion molecule-1 and VEGF in the retina. sCD146 induced migration of HRMECs.
Conclusions:
These results suggest that the CD146/sCD146 pathway is involved in the initiation and progression of PDR.
... Intravitreal anti-vascular endothelial growth factor (VEGF) therapy such as ranibizumab has been shown to effectively and safely cause regression of neovascularization in PDR (Salam, Mathew, & Sivaprasad, 2011). Studies have demonstrated that visual acuity (VA) can be improved in patients with PDR via treatment with repeated injections of anti-VEGF (Kim & D'Amore, 2012). ...
Purpose
Ranibizumab monotherapy showed stronger effects on area of retinal neovascularization (NV) reduction while offering better visual acuity (VA) results than panretinal laser photocoagulation (PRP) monotherapy during the first 12 months of the PRIDE study. The second year of PRIDE was an observational, non-interventional follow-up, performed to evaluate long-term anatomical and functional outcomes in proliferative diabetic retinopathy (PDR) patients under real-life conditions, prior to the approval of ranibizumab for PDR.
Methods
Seventy-three PDR patients (28 from the ranibizumab group; 20 from the PRP group; 25 from the combination group) were included in the observational follow-up phase and treated at the investigators discretion. Visual acuity (VA) measurements and retinal imaging were performed at Months 12, 18 and 24.
Results
Mean (± SD) NV area in the ranibizumab monotherapy and combination follow-up groups increased from 3.16 ± 4.30 mm² and 1.13 ± 2.78 mm² at Month 12 to 6.09 ± 10.79 mm² and 2.14 ± 4.41 mm² at Month 18 and 10.00 ± 17.63 mm² and 3.26 ± 7.05 mm² at Month 24, respectively. In the PRP follow-up group, NV area declined from 5.44 ± 14.55 mm² at Month 12 to 1.22 ± 1.67 mm² at Month 18, but increased again to 4.05 ± 11.66 mm² at Month 24. During the observational phase, only 2 (6;8) patients in the ranibizumab (PRP;combination) follow-up group were treated with anti-VEGF medications, while 17 (6;10) patients received PRP laser therapy.
Conclusion
Discontinuation of ranibizumab treatment in PDR patients may result in an increase of NV area and VA loss. Tight monitoring of disease activity and continued treatment beyond the first year is needed to maintain disease control.
... The administration of anti-VEGF agents such as bevacizumab and ranibizumab has shown promising results in the management of dense VH, shortening the time for VH clearance and reducing the need for PPV by about 30% [18,19]. ...
Abstract Background The main purpose of this study is to compare the vitreous hemorrhage (VH) score reduction and visual acuity outcomes in patients with VH secondary to proliferative diabetic retinopathy (PDR) treated with intravitreal injections of bevacizumab (IVB) versus IVB and pars plana vitrectomy (IVB and PPV). Methods Patients with VH secondary to PDR were randomized into 2 groups: in Group A, patients were treated with a total of 3 IVB (1.5 mg/0.06 ml) at 8-week intervals; and in Group B, patients received a single IVB (1.5 mg/0.06 ml) and, 7 days later, underwent PPV. Patients received an ophthalmic evaluation that included best-corrected visual acuity (BCVA), indirect ophthalmoscopy, and mode B echography at weeks 8, 16 and 24. VH was classified according to the Diabetic Retinopathy Vitrectomy Study classification as grade 1, 2 or 3. Change in VH score was the primary outcome measure and change in BCVA was the secondary outcome. Results Seventy-three eyes of 66 patients were randomized and 70 eyes completed the 24-week follow-up visit. Mean VH score reduction (± SEM) of 0.4571 ± 0.0283 (p = 0.0014), 1.3429 ± 0.0393 (p
... Note that elevated VEGF levels were not detected in PVR pathogenesis. The role of VEGF in diabetic macular edema and PDR is well known [23]. We observed that the levels of IL-18 and VEGF were significantly higher in PDR than in other conditions. ...
Background
The purpose of the study was to explore the immunological components that are responsible for the proliferative alterations in the different forms of retinal detachment (RD).
Methods
Vitreous fluids were collected during 23G pars plana vitrectomy from 54 eyes of 54 patients with different RD types, such as rhegmatogenous RD (RRD) without proliferative vitreoretinopathy (PVR) (n = 30), PVR (n = 16) and proliferative diabetic retinopathy (PDR) with tractional RD (n = 8). Vitreous fluids were obtained from 19 eyes with epiretinal membrane (ERM), which were used as control samples. A multiplex chemiluminescent immunoassay was performed to evaluate the concentrations of 48 cytokines, chemokines and growth factors.
Results
The expression levels of eotaxin, IFN-gamma, IL-6, IL-8, IL-16, MCP-1, MIF and MIP-1 beta were significantly higher in all RD groups than in the ERM group. The levels of CTACK, IP-10, SCGF-beta, and SDF-1 alpha were significantly higher in patients with diabetic tractional RD and PVR than in other patients. The upregulation of VEGF and IL-18 was detected in PDR.
Conclusions
Our results indicate that complex and significant immunological mechanisms are associated with the pathogenesis of different forms of RD: selected cytokines, chemokines and growth factors are upregulated in the vitreous of eyes with RD. The detected proteins are present in different concentrations both in RRD and PVR. In the presence of PVR and PDR, the majority of cytokines are upregulated; thus, they may serve as biomarkers to estimate the progression or severity level of proliferation and later to develop personalized therapeutic strategies to slow down or prevent pathological changes.
... Placement of many small laser burns (panretinal photocoagulation) is often used to treat both macular edema and proliferative retinopathy. Also, the same anti-VEGF agents that are used in AMD appear to be useful [116,117]. However, both photocoagulation and anti-VEGF agents are used only relatively late and are not completely effective. ...
The retina is a small piece of the central nervous system responsible for the first steps in vision, so understanding how it works has great importance for daily life. In addition, features of the retina make it attractive as a model neural system. The only input to the retina is light, which can be easily manipulated, and recordings have been made for many decades from individual output cells of the retina, the retinal ganglion cells (RGCs), allowing application of linear (and to some extent nonlinear) systems analysis methods that define the transfer functions of the retina. The small, non-spiking photoreceptors and retinal interneurons make recordings from these earlier stages difficult in mammals, but this has been partially surmounted by the ability to record massed activity of some types of retinal neurons, including photoreceptors and bipolar cells, in the electroretinogram (ERG) in humans as well as animals. ERG analyses have led to models of signal processing prior to the RGCs. Engineering methods in combination with physiology have thus elucidated the basic features of the retinal network that allow the convergence of signals from many millions of photoreceptors to yield the center-surround organization and response properties of the primary types of RGCs in cats and primates. However, some of the approximately 20 types of RGCs that send parallel signals to the brain are still poorly understood. Recent work has used isolated retinas and multielectrode arrays to record from many retinal ganglion cells simultaneously. Specific contributions of interneurons to the retinal circuits have also been addressed with new methods, some of which are reviewed here. Another aspect of retinal bioengineering concerns the retinal microenvironment. Diffusion models and spatially precise intraretinal measurements of oxygen and pH provide information about retinal metabolism that is useful in understanding dysfunction of the retina in some diseases.
... В настоящее время продолжается активное изучение роли ингибиторов VEGF в лечении ПДР [9]. В статье представлен обзор клинических исследований ранибизумаба у пациентов с диабетическими поражениями сетчатки, которые, как правило, имеют сопутствующие заболевания. ...
E.A. Abdulaeva1, E.L. Minkhuzina1,2, A.N. Kuskov2
1Kazan State Medical Academy — Branch of the Russian Medical Academy of Continuous Professional Education, Kazan, Russian Federation
2Prof. E.V. Adamyuk Republician Clinical Ophthalmological Hospital, Kazan, Russian Federation
Diabetic retinopathy (DR) is a common microvascular complication of diabetes. As diabetes progresses, about 50% of patients with severe non-proliferative DR will develop proliferative DR (PDR) within one year. DR pathogenesis is mediated by alterations in many metabolic cascades, production of pro-inflammatory cytokines and growth factors, increased vascular leakage resulting from the loss of blood-retinal barrier integrity, and pathological neovascularization (which indicates increasing severity of DR). The introduction of anti-VEGF therapy has changed treatment paradigm for neovascularization as anti-VEGF agents target major pathophysiological mechanism of DR. Intensive studies on anti-VEGF therapy for PDR are now underway. This paper briefly reviews core studies on ranibizumab use in PDR and describes two case reports of PDR treatment with intravitreal injections of ranibizumab performed during one year according to prescribing information. Several clinical stud ies have demonstrated that anti-VEGF therapy is at least an alternative to panretinal photocoagulation in PDR. Our clinical observations confirm that ranibizumab is useful in routine clinical practice.
Keywords: proliferative diabetic retinopathy, diabetic macular edema, vascular endothelial growth factor, anti-VEGF.
For citation: Abdulaeva E.A., Minkhuzina E.L., Kuskov A.N. Anti-VEGF therapy for proliferative diabetic retinopathy: translating research evidence into clinical practice. Russian Journal of Clinical Ophthalmology. 2020;20(2):97–103. DOI: 10.32364/2311-7729-2020-20-2-97-103.
... Our results have also demonstrated that EGCG NPs inhibit endothelial cell migration (Supplemental-2 in Appendix A). However, overexpression of VEGF is associated with several vascular eye diseases such as diabetic retinopathy [44], corneal NV [2,3], and choroidal NV [45]. For endothelial targeting, cell surface markers such as P-selectin, E-selectin, vascular cell adhesion molecule-1, and integrin are considered potential target moieties [46][47][48][49]. ...
Neovascularization (NV) of the cornea disrupts vision which leads to blindness. Investigation of antiangiogenic, slow-release and biocompatible approaches for treating corneal NV is of great importance. We designed an eye drop formulation containing gelatin/epigallocatechin-3-gallate (EGCG) nanoparticles (NPs) for targeted therapy in corneal NV. Gelatin-EGCG self-assembled NPs with hyaluronic acid (HA) coating on its surface (named GEH) and hyaluronic acid conjugated with arginine-glycine-aspartic acid (RGD) (GEH-RGD) were synthesized. Human umbilical vein endothelial cells (HUVECs) were used to evaluate the antiangiogenic effect of GEH-RGD NPs in vitro. Moreover, a mouse model of chemical corneal cauterization was employed to evaluate the antiangiogenic effects of GEH-RGD NPs in vivo. GEH-RGD NP treatment significantly reduced endothelial cell tube formation and inhibited metalloproteinase (MMP)-2 and MMP-9 activity in HUVECs in vitro. Topical application of GEH-RGD NPs (once daily for a week) significantly attenuated the formation of pathological vessels in the mouse cornea after chemical cauterization. Reduction in both vascular endothelial growth factor (VEGF) and MMP-9 protein in the GEH-RGD NP-treated cauterized corneas was observed. These results confirm the molecular mechanism of the antiangiogenic effect of GEH-RGD NPs in suppressing pathological corneal NV.
... Notably, in the same individuals, only a few circulating miRNAs were detected in vitreous compared with serum [10]. In ▶ table 1, we have summarized miR-126 [11,12], miR-211 [13], miR-93 [14][15][16], miR-122 [17], miR-221 [18], miR-27b and miR-320a [8], miR-150-5p, miR-21-3p and miR-30b-5p [19] as biomarkers in DR over the past 5 years. At the same time, we have focused on miRNAs in vitreous humor (VH) of DR, such as miR-126 [20], miR-19a and 27a [21], miR-29a [22,23], miR-93 and 20a [21], and miR-200b [24] in ▶ table 2. ...
Diabetic retinopathy (DR), a serious microvascular complication of diabetes, is a leading cause of blindness in adults. The pathogenesis of DR involves a variety of tissues and complex mechanisms, such as inflammation, oxidative stress, optic neurodegeneration, and autophagy. Nowadays, microRNAs (miRNAs), a novel group of non-coding small RNAs, have been extensively studied and recognized to play a key role in the pathogenesis of DR through aforementioned pathways. Furthermore, some miRNAs have been proposed as biomarkers that may be utilized to screen for DR. Also, miRNAs are a new therapy for DR. In this review, we summarize several miRNAs and, their roles in the pathogenesis of DR. miRNAs, as potential pharmacological targets for the diabetic retinopathy, may provide new insights for the treatment of DR.
... It has a longer halflife time and higher molecular weight than ranibizumab. 20, 21 Victor et al 22 reported that PDR patients who had an IVB injection prior to vitrectomy had twice as low VEGF levels than the group that did not receive IVB. ...
Purpose: to assess the levels of Hypoxia-inducible factor-1α (HIF-1α) and intercellular adhesion molecule-1 (ICAM-1) in vitreous of proliferative diabetic retinopathy patients which were given intravitreal bevacizumab (IVB), as well as its relation to the central macular thickness (CMT) measured prior to vitrectomy. Methods: thirty-two eyes were randomized into two groups, one that received an IVB injection at 1-2 weeks previtrectomy and the control group which did not receive any injection. Measurement of HIF-1α and ICAM-1 was conducted using enzyme-linked immunosorbent assay (ELISA). The CMT were measured at the initial visit, prior to vitrectomy, and at follow up time (2, 4, and 12 weeks postoperatively) using Stratus OCT. Results: The mean levels of HIF-1α vitreous (ng/mg protein) in the control group and IVB respectively 0.020 (0.006; 0.077) and 0.029 (0.016; 0.21). Vitreous levels of ICAM-1 (ng /mL) in control group and IVB group were 20.10 (3.41; 40.16) and 23.33 (0.63; 68.5). The mean levels of HIF-1α and ICAM-1 vitreous obtained did not differ significantly between the two groups. Conclusion: The levels of HIF-1α and ICAM-1 in PDR patients do not decrease after one injection of intravitreal Bevacizumab 1-2 weeks prior to vitrectomy. The concentration of vitreous HIF-1α and ICAM-1 are not directly related to the CMT.
... Hypoxia-inducible factor-1a (HIF-1a) accumulates in cells during hypoxia and it heterodimerizes with the constitutively expressed HIF-1b subunit, triggering the activation of many genes encoding proteins that regulate angiogenesis, such as VEGF (Huang et al. 1998;Yamakawa et al. 2003). Inhibition of angiogenesis with the use of anti-VEGF agents has emerged as a therapeutic strategy to arrest progression of PDR angiogenesis (Salam et al. 2011). However, angiogenesis depends on multiple agents, and when the activity of one angiogenic agent such as VEGF is suppressed, the expression of other angiogenic players may appear. ...
Purpose:
Galectin-1 regulates endothelial cell function and promotes angiogenesis. We investigated the hypothesis that galectin-1 may be involved in the pathogenesis of proliferative diabetic retinopathy (PDR).
Methods:
Vitreous samples from 36 PDR and 20 nondiabetic patients, epiretinal fibrovascular membranes from 13 patients with PDR, rat retinas and human retinal Müller glial cells were studied by enzyme-linked immunosorbent assay (ELISA), immunohistochemistry and Western blot analysis. In vitro angiogenesis assays were performed and the adherence of leukocytes to galectin-1-stimulated human retinal microvascular endothelial cells (HRMECs) was assessed.
Results:
The ELISA analysis revealed that galectin-1 and vascular endothelial growth factor (VEGF) levels were significantly higher in vitreous samples from PDR patients than in those from nondiabetics (p < 0.001 for both comparisons). A significant positive correlation was found between the levels of galectin-1 and VEGF (r = 0.354; p = 0.022). In epiretinal membranes, immunohistochemical analysis showed that galectin-1 was expressed in vascular endothelial cells expressing CD31, myofibroblasts expressing α-smooth muscle actin and leukocytes expressing CD45. The galectin-1 receptor neuropilin-1 was expressed on vascular endothelial cells. CD31 staining was used as a marker to assess microvessel density (MVD). Significant positive correlation was detected between MVD in epiretinal membranes and the number of blood vessels expressing galectin-1 (r = 0.848; p < 0.001). Western blot analysis demonstrated significant increase of galectin-1 protein in rat retinas after induction of diabetes. ELISA analysis revealed that hydrogen peroxide and cobalt chloride (CoCl2 ) induced upregulation of galectin-1 in Müller cells. Treatment with galectin-1 induced upregulation of VEGF in Müller cells and increased leukocyte adhesion to HRMECs. The galectin-1 inhibitor OTX008 attenuated VEGF-induced HRMECs migration and CoCl2 -induced upregulation of NF-κB, galectin-1 and VEGF in Müller cells.
Conclusions:
These results suggest that galectin-1is involved in the pathogenesis of PDR.
... VEGF, a primary angiogenic factor in DR, promotes neovascularization and vascular leakage in retina through its interaction with the FLT-1 and KDR receptors [29]. Therefore, several anti-VEGF drugs agents are reported as potential therapeutic agents of DR alone or as an assist participating in other therapies [30,31]. Therefore, there are several anti-VEGF drugs under investigation for treating DR including macugen and avastin [32]. ...
The aim of the present study was to investigate the effect of Lycopus lucidus Turcz (LT) on diabetic retinopathy (DR) and its underlying mechanisms. SD rats and human retinal microvascular endothelial cells (HRECs) were applied for establishment DR model. HE and TUNEL staining were used to evaluate the pathological changes and apoptosis of retinal ganglion cells. Additionally, retinal vessels were detected by immunofluorescence staining with CD31 and VEGF. The function of BRB was observed using Evans blue. Moreover, the oxidative stress, inflammation and angiogenesis associated factors were measured respectively. The expression of p38-MAPK/NF-κB signalling proteins were detected by Western blot. The results demonstrated that pathological changes and retinal optic disc cells apoptosis in retinas of diabetic rats, both of which were reduced in the LT-treated group. And LT treatment attenuated the levels of oxidative stress, inflammation and angiogenesis factors. Importantly, the expression levels of p-p38, p-ERK, p-JNK and NF-κB were decreased. After treatment with TNF-α combined with LT, the levels of inflammatory factors were decreased but higher than the negative control. Taken together, the results suggested that LT treatment is of therapeutic benefit by ameliorating oxidative stress, inflammation and angiogenesis of DR via p38-MAPK/NF-κB signaling pathway.
... The treatments for PDR are panretinal laser photocoagulation and vitrectomy in selected cases, and anti-VEGF injections have recently been used as another treatment option. However, serious systemic side-effects can develop and there may be reoccurrence of the neovascularization a few months after the anti-VEGF injection (Salam et al., 2011). There is an urgent need to develop new treatments for the management of PDR. ...
Diabetes mellitus, together with its complications, has been increasing in prevalence worldwide. Its complications include cardiovascular disease (e.g., myocardial infarction, stroke), neuropathy, nephropathy, and eye complications (e.g., glaucoma, cataracts, retinopathy, and macular edema). In patients with either type 1 or type 2 diabetes mellitus, diabetic retinopathy is the leading cause of visual impairment or blindness. It is characterized by progressive changes in the retinal microvasculature. The progression from nonproliferative diabetic retinopathy to a more advanced stage of moderate to severe nonproliferative diabetic retinopathy and proliferative diabetic retinopathy occurs very quickly after diagnosis of mild nonproliferative diabetic retinopathy. The etiology of diabetic retinopathy is unclear, and present treatments have limited effectiveness. Currently diabetic retinopathy can only be diagnosed by a trained specialist, which reduces the population that can be examined. A screening biomarker of diabetic retinopathy with high sensitivity and specificity would aid considerably in identifying those individuals in need of clinical assessment and treatment. The majority of the studies reviewed identified specific microRNAs in blood serum/plasma able to distinguish diabetic patients with retinopathy from those without retinopathy and for the progresion of the disease from nonproliferative diabetic retinopathy to proliferative diabetic retinopathy. In addition, certain microRNAs in vitreous humor were dysregulated in proliferative diabetic retinopathy compared to controls. A very high percentage of patients with diabetic retinopathy develop Alzheimer’s disease. Thus, identifying diabetic retinopathy by measurement of suitable biomarkers would also enable better screening and treatment of those individuals at risk of Alzheimer’s disease.
... Proliferative diabetic retinopathy (PDR), retinopathy of prematurity (ROP) and retinal vein occlusions are major causes of blindness worldwide, and retinal neovascularization is the key pathogenesis of these ocular diseases [1]. Although anti-vascular endothelial growth factor (VEGF) therapies have been Ivyspring International Publisher applied in those retinal neovascular diseases [2], the effect and efficiency is not satisfied in some patients [3], and intravitreal injection of anti-VEGF agents may also lead to numerous systemic and local complications, such as tractional retinal detachment, endophthalmitis and acute elevation of blood pressure [2,4]. Thus, identification of novel targets that play important roles in retinal neovascularization is urgently needed to treat patients who are not responsible for anti-VEGF therapy. ...
Objective: Retinal neovascularization is a severe complication of many ocular diseases. To clarify the possible functions and therapeutic potential of long non-coding RNAs (lncRNAs) and messenger RNAs (mRNAs) in retinal neovascularization, we assessed their expression profile in a mouse model of oxygen-induced retinopathy (OIR).
Methods: Microarray analysis was performed to identify altered lncRNA and mRNA expressions between OIR and control mice. The microarray results were validated by qRT-PCR. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were conducted to determine biological functions and signaling pathways of the altered or interacted mRNAs. A coding-non-coding gene co-expression (CNC) network was constructed to identify the interaction of lncRNAs and mRNAs.
Results: We identified 198 up-regulated and 175 down-regulated lncRNAs (fold change≥2.0, P<0.05), respectively in OIR mice compared to control mice. We also identified 412 up-regulated and 127 down-regulated mRNAs (fold change≥2.0, P<0.05), respectively in OIR mice compared to control mice. GO and KEGG analyses suggested that altered mRNAs were enriched in immune system process, exopeptidase activity, ECM-receptor interaction and protein digestion and absorption. Four validated lncRNAs (ENSMUST00000165968, ENSMUST00000153785, ENSMUST00000134409, and ENSMUST00000154285) and the nearby coding gene pairs were analyzed. A CNC network profile based on those validated altered lncRNAs as well as 410 interacted mRNAs was composed of 509 connections. Moreover, the GO and KEGG analyses demonstrated that these interacted mRNAs mainly enriched in blood vessel development, angiogenesis, cell adhesion molecules and leukocyte transendothelial migration pathways.
Conclusion: Our data highlight the utility of altered lncRNA and mRNA profiling in understanding the pathogenesis of ischemia-induced retinal neovascularization and further suggest that therapeutic potential of altered lncRNA for retinal neovascularization.
... Vitreous hemorrhage and traction retinal detachment secondary to NVD or NVE are important causes of severe vision loss in eyes with PDR. 2 Ultra-wide field (UWF) fluorescein angiography (FA) has become a useful tool in the diagnosis and management of patients with various retinal vascular disorders including DR. ...
Purpose:
To explore the distribution of nonperfusion area (NPA) on ultrawide-field fluorescein angiography (UWF FA) in proliferative diabetic retinopathy (PDR) and its relationship with the presence of neovascularization of the optic disc (NVD) and distribution of neovascularization elsewhere (NVE).
Design:
Prospective, observational case series.
Methods:
Baseline Optos 200Tx UWF FA images of 38 eyes with treatment-naïve early-stage PDR from the RECOVERY (NCT02863354) study were stereographically projected at the Doheny Image Reading Center. Two independent/masked certified graders manually delineated the NPA and the total visible retinal area (TRA). NPA and TRA were then computed in square millimeters using the manufacturer software. Ischemic index (ISI) was calculated by dividing NPA by TRA. NPA and ISI were correlated with the presence and distribution of neovascularization in the corresponding zones.
Results:
Eyes with NVD appeared to have more severe global NPA than those without (P = .026). Although the ISI appeared to increase with increasing distance from the foveal center (P < .001), NVE was more likely to be located in the posterior pole than the midperiphery or far-periphery (P < .001). Presence of NVE in the posterior polar retina appeared to demonstrate more severe ischemia in the posterior pole and midperiphery than those without (P < .05), but interestingly, was not correlated with the severity of overall global ischemia or of ischemia in the far-periphery alone (P > .05).
Conclusions:
Whereas the presence of NVD was associated with the severity of global ischemia, the distribution of NVE did not appear to be influenced by the distribution of ischemia.
... It has been clarified that anti-vascular endothelial growth factor (VEGF) treatment is effective to inhibit retinal neovascularization, and has been widely used in clinical applications in the eye [2] . However, anti-VEGF therapies were weakly responsive in some patients and might cause many complications [2][3] . Macrophages can be polarized to M1/M2 phenotype by T helper (Th) 1 cytokines and Th2 cytokines respectively [4][5][6] . ...
Aim:
To investigate the regulation and mechanisms of periostin expression in retinal Müller glia, and to explore the relevance to retinal neovascularization.
Methods:
The oxygen-induced retinopathy (OIR) mouse model and the human Moorfield/Institute of Ophthalmology-Müller 1 (MIO-M1) cell line were used in the study. Immunofluorescence staining was used to determine the distribution and expression of periostin and a Müller glial cell marker glutamine synthetase (GS). Cytokines TNF-α and IFN-γ were added to stimulate the MIO-M1 cells. ShRNA was used to knockdown periostin expression in MIO-M1 cells. Quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) was conducted to assess the mRNA expression of periostin.
Results:
Immunofluorescence staining showed that periostin was expressed by MIO-M1 Müller glia. GS-positive Müller glia and periostin increased in OIR retinas, and were partially overlaid. The stimulation of TNF-α and IFN-γ reduced the mRNA expression of periostin significantly and dose-dependently in MIO-M1 cells. Knockdown of periostin reduced mRNA expression of vascular endothelial growth factor A (VEGFA) in MIO-M1 cells, while VEGFA expression was not changed in periostin knock-out OIR retinas.
Conclusion:
Müller glia could be one of the main sources of periostin in the retina, and might contribute to the pathogenesis of retinal neovascularization. Proinflammatory cytokines TNF-α and IFN-γ attenuate the periostin expression in retinal Müller glia, which provides a potential and novel method in treating retinal neovascular diseases.
... Vascular endothelial growth factor (VEGF) has been proved to be a leading factor that leads to intraocular neovascularization, and anti-VEGF agents are widely used in clinical therapeutic applications (Rizzo et al. 2008;Hosseini et al. 2009;Osaadon et al. 2014;Xu et al. 2014;Amadio et al. 2016). However, the short efficacy exists in conducting intraocular injection of anti-VEGF agents (Salam et al. 2011;Osaadon et al. 2014) in addition to the high expense of the therapy, the poor response to the treatment in some of the patients, and a gradual decrease in drug sensitivity with long-term drug use. Moreover, the anti-VEGF therapy is not only target pathological neovascularization in the eye, but also in normal blood vessels and tissues, which may cause severe systemic cardiovascular and cerebrovascular complications, such as hypertension and cerebral vascular myocardial infarction (Wu et al. 2008;Jardeleza and Miller 2009). ...
Ocular neovascular diseases are featured by abnormal angiogenesis in the eye, and they seriously threaten the human visual health. These diseases include proliferative diabetic retinopathy (PDR), age-related macular degeneration (AMD), retinopathy of prematurity (ROP), and retinal vein occlusion (RVO). In fact, ocular neovascular diseases represent the leading causes of vision impairment and blindness worldwide. Ocular neovascularization, the process of pathological vessel formation in eye, underlies ocular neovascular diseases. Cytokines have important regulatory roles in neovascularization through immunological networks. Interleukin (IL)-17, the signature cytokine produced by T helper 17 (Th17) cells, has proven to be involved in ocular neovascularization. However, roles of IL-17 in ocular neovascular diseases still remain controversial. This review provides an overview of the functional roles of IL-17 in ocular neovascular diseases from basic research to clinical evidence by focusing on PDR, AMD, ROP, and RVO. The possible roles of IL-17 in neovascularization are achieved through a regulatory network of cytoskeleton remodeling, vascular endothelial growth factor (VEGF), VEGF-related cytokines, and complement components. Current applications as well as potential therapies targeting IL-17 with genome editing systems are also outlined and discussed. Targeting IL-17 might be a promising therapeutic strategy against ocular neovascular diseases.
... Anti-VEGF therapy has now become a mainstream treatment for nvAMD (5) and has been reported to have beneficial effects in other ocular angiogenic diseases (6,7). However, despite the effectiveness of anti-VEGF therapy, many patients do not respond optimally to these drugs or they become refractory after prolonged treatment (8,9). Resistance to anti-VEGF therapy is perhaps most easily explained by the involvement of other angiogenic mediators in driving the neovascular response, with previous work strongly implicating several other growth factors, including basic fibroblast growth factor (bFGF), insulin-like growth factor-1 (IGF-1) and hepatocyte growth factor (HGF) in regulating pathological angiogenesis in the eye (3,(10)(11)(12)(13)(14). ...
While anti-VEGF drugs are commonly used to inhibit pathological retinal and choroidal neovascularization, not all patients respond in an optimal manner. Mechanisms underpinning resistance to anti‑VEGF therapy include the upregulation of other proangiogenic factors. Therefore, therapeutic strategies that simultaneously target multiple growth factor signaling pathways would have significant value. Here, we show that Ca2+/calmodulin-dependent kinase II (CAMKII) mediates the angiogenic actions of a range of growth factors in human retinal endothelial cells and that this kinase acts as a key nodal point for the activation of several signal transduction cascades that are known to play a critical role in growth factor-induced angiogenesis. We also demonstrate that endothelial CAMKIIγ and -δ isoforms differentially regulate the angiogenic effects of different growth factors and that genetic deletion of these isoforms suppresses pathological retinal and choroidal neovascularization in vivo. Our studies suggest that CAMKII could provide a novel and efficacious target to inhibit multiple angiogenic signaling pathways for the treatment of vasoproliferative diseases of the eye. CAMKIIγ represents a particularly promising target, as deletion of this isoform inhibited pathological neovascularization, while enhancing reparative angiogenesis in the ischemic retina.
... We conducted a review of literature on this topic before the start of this study and concluded that, although the current evidence points towards the potential for anti-VEGF treatment for PDR to obviate or delay the need for laser treatment, the efficacy, safety and cost-effectiveness of this treatment relative to PRP were unclear. 26 As anti-VEGF has superseded macular laser treatment as the treatment of choice for DMO, it is advantageous for both PDR and DMO to be treated with anti-VEGF agents as doing so will reduce health-care burden, patient burden and potentially improve patient outcomes. At the inception of this study, there were two multicentre trials evaluating the efficacy of ranibizumab in PDR. ...
Background
Panretinal photocoagulation (PRP) has been the standard of care for patients with proliferative diabetic retinopathy (PDR) for the last 40 years. It prevents severe visual loss in PDR but is also associated with adverse effects on visual functions.
Objectives
The clinical efficacy and mechanistic evaluation of aflibercept for proliferative diabetic retinopathy (CLARITY) trial evaluated the clinical efficacy, mechanisms and cost-effectiveness of intravitreal aflibercept (Eylea ® , Regeneron, Tarrytown, NY, USA/Bayer Pharma AG, Berlin, Germany therapy for PDR.
Design
A multicentre, prospective, individually randomised, single-masked, active-controlled trial with concurrent economic evaluation that tested the non-inferiority of intravitreal aflibercept versus standard care PRP at 52 weeks. A subset of the participants enrolled in a mechanistic evaluation substudy.
Setting
22 UK NHS clinical sites.
Participants
Patients aged at least 18 years having either treatment-naive PDR or active retinal neovascularisation (NV) despite prior PRP requiring treatment and best corrected visual acuity (BCVA) of 54 Early Treatment Diabetic Retinopathy Study (ETDRS) letters or better in the study eye were included. Eyes with evidence of macular oedema at baseline confirmed by central subfield thickness > 320 µm on spectral-domain optical coherence tomography were excluded.
Intervention
In the intervention arm, intravitreal aflibercept injections were given at baseline, 4 and 8 weeks and patients were subsequently reviewed every month and injected pro re nata based on the treatment response defined by degree of regression of retinal NV. In the comparator arm, PRP was completed in 2-weekly sessions and then supplemented if necessary at 8-weekly intervals.
Main outcome measures
The primary outcome was the mean change in BCVA at 52 weeks utilising a linear mixed-effects model incorporating data from both week 12 and week 52.
Results
A total of 232 participants (116 per arm) were recruited between August 2014 and November 2015. A total of 221 and 210 participants contributed to the intention-to-treat (ITT) model and per-protocol (PP) analysis, respectively. Economic evaluation was undertaken on 202 participants (101 per arm) with complete cost and outcome data. Aflibercept was non-inferior and superior to PRP in both the ITT population [mean BCVA difference 3.9 letters, 95% confidence interval (CI) 2.3 to 5.6 letters; p < 0.0001] and the PP population (difference 4.0 letters, 95% CI 2.4 to 5.7 letters; p < 0.0001). From a public sector multiagency perspective that covers health and social care services, treatment with aflibercept costs more in terms of total resource use (mean adjusted total additional cost per patient = £5475, bootstrapped 95% CI £5211 to £5750) than PRP over a 12-month follow-up period. There were a small number of important safety events in each arm. Patients were more satisfied with aflibercept than PRP.
Limitations
This study is limited to 1 year of follow-up.
Conclusions
At an additional cost, the study shows that intravitreal aflibercept is an effective alternative treatment option for PDR in the first year.
Future work
Future research is needed to evaluate the long-term benefits of aflibercept in comparison with PRP and other anti-vascular endothelial growth factor agents for this condition.
Trial registration
Current Controlled Trials ISRCTN32207582.
Funding
This project was funded by the National Institute for Health Research (NIHR) Efficacy and Mechanistic Evaluation programme, a Medical Research Council and NIHR partnership. Aflibercept was supplied by Bayer Plc (Reading, UK). The study was sponsored by NIHR Moorfields Biomedical Research Centre and supported by the UK Clinical Research Network. The research was supported by the NIHR Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and University College London Institute of Ophthalmology, the NIHR Moorfields Clinical Research Facility and the UK Clinical Reasearch Collaboration-registered King’s Clinical Trials Unit at King’s Health Partners, which is partly funded by the NIHR Biomedical Research Centre for Mental Health at South London and Maudsley NHS Foundation Trust and King’s College London.
... Regulation of angiogenesis has emerged as a potential therapeutic strategy for the treatment of PDR [31]. To aid the progress of these strategies, a more comprehensive understanding of the molecules that regulate angiogenesis in PDR is of value to identify additional therapeutic targets. ...
Purpose:
Matrix metalloproteinase-14 (MMP-14) is a transmembrane MMP that plays a critical role in promoting angiogenesis. We investigated the expression levels of MMP-14 and correlated the levels with clinical disease activity and with the levels of the angiogenic factors vascular endothelial growth factor (VEGF) and MMP-9 in proliferative diabetic retinopathy (PDR). To reinforce the findings at the functional level, we examined the expression of MMP-14 in the retinas of diabetic rats.
Methods:
Vitreous samples from 34 patients with PDR and 18 nondiabetic patients and epiretinal membranes from 13 patients with PDR and the retinas of rats were studied with enzyme-linked immunosorbent assay, immunohistochemistry, western blotting, and real-time reverse transcription PCR (RT-PCR).
Results:
The MMP-14, VEGF, and MMP-9 levels were statistically significantly higher in the vitreous samples from patients with PDR than in the samples from the nondiabetic controls (p<0.001 for all comparisons). The MMP-14 levels in patients with PDR with active neovascularization were statistically significantly higher than those in patients with inactive PDR (p<0.001). There were statistically significant positive correlations between levels of MMP-14 and levels of VEGF (r = 0.3; p = 0.032) and MMP-9 (r = 0.54; p<0.001). In the epiretinal membranes, MMP-14 was expressed in vascular endothelial cells, leukocytes, and myofibroblasts. Statistically significant positive correlations were detected between the numbers of blood vessels expressing CD31 and the numbers of blood vessels (r = 0.74; p = 0.004) and stromal cells (r = 0.72; p = 0.005) expressing MMP-14. Statistically significant increases of MMP-14 mRNA and protein were detected in rat retinas after induction of diabetes.
Conclusions:
These results suggest that MMP-14 is involved in PDR angiogenesis.
... To identify factors that could potentially mediate diabetes-induced changes to the retina, qPCR analysis was used to examine changes in gene expression. As expected, Vegf expression was increased in the diabetic retina, consistent with its well established and central role in promoting vascular leakage (Salam et al. 2011;Bai et al. 2009;Wang et al. 2010;Simó et al. 2014). Of greater interest here, given the objective of identifying novel candidate therapeutic targets, other factors such as ...
Diabetic retinopathy (DR) is the most common microvascular complication of diabetes and a leading cause of blindness. Increased vascular permeability in the retina following blood-retinal barrier (BRB) breakdown is a clinically significant event and a major cause of vision loss. VEGF blockade, despite being the only treatment to improve visual acuity, has a limited effectiveness for a majority of patients. A significant proportion of patients develop resistance to treatment, which implies that other factors are also involved in the pathology of this disease. There is currently a major unmet clinical need for therapeutics which target the early stages of DR prior to the onset of overt vascular symptoms. The aim of this thesis was to investigate early diabetes-induced changes to the retina and their effects on the vasculature, in order to identify novel potential therapeutic targets. This was achieved by investigating the effects of high glucose and glycated albumin on the vasculature using the mouse metatarsal assay, an ex vivo model of angiogenesis and the effects of diabetes on the retina with the streptozotocin-induced diabetic mouse. Both high glucose and glycated albumin altered angiogenesis in the metatarsal assay. Investigation of the diabetic mouse retina revealed evidence of increased inflammation and oxidative stress at the cellular and molecular level, accompanied with evidence of vascular leakage. qPCR analysis revealed an increase in Angptl6 and Lrg1 expression of which had not been investigated in the diabetic mouse retina before. Studies with transgenic mouse models implied that Lrg1 is involved in the early stages of pathophysiology of DR and may be a suitable therapeutic target prior to the onset of overt vascular symptoms.
... In particular, drug delivery of anti-vascular endothelial growth factor (VEGF) agents have been proved to be effective in inhibiting neovascularization and are widely used for clinical applications in a group of ocular disorders [7][8][9][10][11] . However, laser photocoagulation and vitrectomy cannot fundamentally block neovascularization, while patients receiving long-term medication therapy of anti-VEGF treatment might develop resistance to those drugs with decreasing sensitivity to the therapy, and part of the patients may result in varying degrees of complications [7,12] . Thus, in addition to anti-VEGF drugs, other novel therapeutic targets with high efficiency and safety are needed. ...
Macrophages are involved in angiogenesis, and might also contribute to the pathogenesis of intraocular neovascular diseases. Recent studies indicated that macrophages exert different functions in the process of intraocular neovascularization, and the polarization of M1 and M2 phenotypes plays extremely essential roles in the diverse functions of macrophages. Moreover, a large number of cytokines released by macrophages not only participate in macrophage polarization, but also associate with retinal and choroidal neovascular diseases. Therefore, macrophage might be considered as a novel therapeutic target to the treatment of pathological neovascularization in the eye. This review mainly summarizes diverse roles of macrophages and discusses the possible mechanisms in retinal and choroidal neovascularization.
... The use of ranibizumab and PDT is recognized in the management of AMD and PCV. Meanwhile, the efficacy and safety of ranibizumab conducted by many clinical studies which observed the improvement in best corrected visual acuity (BCVA) of patients, meant it was also suggested for macular edema patients following retinal vein occlusions [54][55][56] and diabetic eye diseases [3,57] . CSCR and choroidal hemangioma patients were also observed to receive the ranibizumab treatment. ...
Aim:
To describe the prevalence and changes in treatment patterns of ranibizumab and photodynamic therapy (PDT) among retinal disease patients who attended the Ophthalmology Clinic in the tertiary care Hospital Selayang from 2010 to 2014.
Methods:
Study subjects were recruited retrospectively using the Electronic Medical Record (EMR) database software in Hospital Selayang. Demographic data, medical history, diagnostic procedure, treatments and diagnosis of patients were recorded.
Results:
The five-year analysis included 821 patients with a mean age of 65.9±11.73y. Overall, there were a higher number of males (63.1%) and a higher number of Chinese (47.4%) patients. Among the 821 patients, 62.9% received ranibizumab injection followed by 19.2% PDT therapy and 17.9% had ranibizumab combined with PDT therapy. Age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV) were the most common retinal eye diseases reported, recording prevalence of 25.0% and 45.6%, respectively. The trend in ranibizumab treatment was reported to increase while PDT showed a decrease in trend from year 2010 to 2014. In terms of treatment, following multiple logistic regression, AMD was associated with the subjects being more likely to have received ranibizumab monotherapy (P<0.001) while PCV was associated with more likely to have received PDT (P<0.001) and PDT combined with ranibizumab therapy (P<0.001).
Conclusion:
The tertiary care setting in Malaysia is consistent with management of patients from other countries whereby ranibizumab is the most common treatment given to patients with AMD, while PCV patients most commonly receive PDT and ranibizumab combined with PDT therapy.
... As a part of the adaptive responses that induce angiogenesis, hypoxia-mediated induction of VEGF has been demonstrated in retinal cells (Shima et al. 1995;Stone et al. 1995;Mammadzada et al. 2016). Regulation of angiogenesis has emerged as a potential therapeutic strategy to arrest the progression of PDR angiogenesis (Salam et al. 2011). ...
Purpose:
150-kDa oxygen-regulated protein (ORP150), a member of heat-shock protein family located in endoplasmic reticulum (ER), has a critical role in secretion of vascular endothelial growth factor (VEGF). We investigated expression levels of ORP150 and correlated these levels with VEGF and total vitreous antioxidant capacity (TAC) in proliferative diabetic retinopathy (PDR). We also examined expression of ORP150 in retinas of diabetic rats and in human retinal microvascular endothelial cells (HRMEC).
Methods:
Vitreous samples from 40 PDR and 20 non-diabetic patients, epiretinal membranes from 14 patients with PDR, retinas of rats and HRMEC were studied by enzyme-linked immunosorbent assay, immunohistochemistry and Western blot analysis.
Results:
We showed a significant increase in expression of VEGF and ORP150 in vitreous samples from PDR patients compared with controls (p < 0.0001 for both comparisons). Total vitreous antioxidant capacity (TAC) levels were significantly lower in patients with PDR than those in controls (p < 0.0001). Vascular endothelial growth factor (VEGF) and ORP150 levels in PDR with active neovascularization were significantly higher than that in inactive PDR (p = 0.016; p = 0.011, respectively). A significant positive correlation was observed between levels of ORP150 and levels of VEGF (r = 0.42; p = 0.001). In epiretinal membranes, ORP150 was expressed in vascular endothelial cells and stromal cells. We also demonstrated colocalization of the nuclear cell proliferation marker Ki67 and ORP150 in endothelial cells of pathologic new blood vessels. 150-kDa oxygen-regulated protein (ORP150) levels were significantly increased in rat retinas after induction of diabetes. Vascular endothelial growth factor (VEGF) and the pro-inflammatory cytokines interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α) induced upregulation of ORP150 in HRMEC.
Conclusion:
These results suggest a role for ORP150 in PDR angiogenesis.
... cular endothelial growth factor (VEGF) injections have recently been used as another treatment option. However, re-neovascularization a few months after the injection as well as intravitreal injection-related endophthalmitis may occur [3] Therefore, there is an urgent need to identify new therapeutic modalities for the management of PDR. In order to achieve this, we have to understand the pathophysiology of PDR. ...
Background:
The role of microRNA (miRNA)-200b in the pathogenesis of proliferative diabetic retinopathy (PDR) has been studied in diabetic animal models. The aim of this study was to assess miRNA-200b expression in the vitreous of patients with PDR and to determine its correlation with vascular endothelial growth factor (VEGF), one of the pathogenic mechanisms in PDR.
Methods:
Quantitative reverse transcription polymerase chain reaction was used to measure miRNA-200b expression in the vitreous from 29 eyes with PDR and 30 eyes with idiopathic macular holes (IMH; control group). Vitreous VEGF was measured using an enzyme-linked immunosorbent assay.
Results:
miRNA-200b expression was about 5-fold increased in the vitreous samples from eyes with PDR compared with the controls (p ≤ 0.001). Vitreous VEGF expression was also significantly higher in the PDR group than in the IMH group (p ≤ 0.001), but no significant correlation was found between miRNA-200b and VEGF.
Conclusion:
Both miRNA-200b and VEGF are increased in the vitreous of patients with PDR but in a noncorrelated pattern. miRNA-200b may be involved in the pathogenesis of PDR but through VEGF-independent mechanisms. Further studies are needed to identify the miRNA-200b-targeted genes involved in the pathogenesis of PDR and to examine the potential role of miRNA-200b as a target for PDR treatment.
... However, angiogenesis depends on multiple factors, and when the activity of one angiogenic factor such as VEGF is suppressed, the expression of other angiogenic factors may appear (Dorrell et al. 2007). Therapeutic regulation of angiogenesis has emerged as an attractive approach for the treatment of PDR (Salam et al. 2011). Therefore, restoration of the balance between the angiogenic stimulators and inhibitors by activating endogenous angiogenesis inhibitors can become a potential therapeutic strategy to arrest the progression of PDR angiogenesis. ...
Purpose:
Tissue inhibitors of metalloproteinases (TIMPs) block the catalysis by matrix metalloproteinases (MMPs) and have additional biologic activities, including regulation of cell growth and differentiation, apoptosis, angiogenesis and oncogenesis. We investigated the expression levels of all the four human TIMPs and correlated these levels with those of MMP-9 and vascular endothelial growth factor (VEGF) in proliferative diabetic retinopathy (PDR).
Methods:
Vitreous samples from 38 PDR and 21 nondiabetic control patients and epiretinal membranes from 14 patients with PDR and 10 patients with proliferative vitreoretinopathy (PVR) were studied by enzyme-linked immunosorbent assay, Western blot analysis and immunohistochemistry.
Results:
Tissue inhibitor of metalloproteinases-1, TIMP-4, MMP-9 and VEGF levels were significantly higher in vitreous samples from PDR patients than in nondiabetic controls (p < 0.0001 for all comparisons), whereas TIMP-2 and TIMP-3 levels did not differ significantly. TIMP-1, TIMP-4, MMP-9 and VEGF levels in PDR with active neovascularization were significantly higher than those in inactive PDR (p < 0.0001, 0.001, 0.013, 0.004, respectively). Significant positive correlations existed between levels of TIMP-1 and levels of TIMP-4 (r = 0.37; p = 0.004), MMP-9 (r = 0.65; p < 0.0001) and VEGF (r = 0.59; p < 0.0001), between levels of TIMP-4 and levels of MMP-9 (r = 0.61; p < 0.0001) and VEGF (r = 0.62; p < 0.0001) and between levels of MMP-9 and VEGF (r = 0.62; p < 0.0001). TIMP-1 and TIMP-3 were expressed in vascular endothelial cells in PDR epiretinal membranes and in myofibroblasts and leucocytes in PDR and PVR epiretinal membranes.
Conclusion:
The differential expression of TIMPs in PDR suggests that among the 4 TIMPs, TIMP-1 and TIMP-4 may be possible biomarkers of disease activity.
This handbook covers Optical Coherence Tomography Angiography (OCT-A) with a specific focus on choroidal and vitreoretinal disorders. It serves as an invaluable resource for teaching and aiding daily clinical decision-making in the field. Book chapters dissect the fundamentals of angiography through OCT, offering guidance on OCT-A and insights into macular perfusional findings across various vitreoretinal and choroidal pathologies. From diabetic retinopathy to autoimmune diseases and neovascularization, the book addresses prevalent vascular entities encountered in routine practice. Furthermore, it explores innovative approaches, including antivascular endothelial growth factor molecules and extended-release delivery devices, contributing significantly to the diagnostic and decision-making processes in clinical and surgical retina care. Each chapter is contributed by experts in the relevant subspecialty.
Key Features:
Practical, patient-centered guide emphasizing a clinical approach.
Demonstrative clinical cases for enhanced understanding.
Evaluation of perfusional indices using noninvasive and noncontact imaging techniques.
High histopathological correlation of structural tissue characterization with microvascular evaluation.
Exploration of new perfusion concepts and their role in disease pathogenesis.
Part 1 of the book focuses on OCT-A principles and applications in ophthalmology. It covers the basics of OCT-A, its contributions to eye disease study and treatment, and a comparative analysis with OCT for choroidal and vitreoretinal diseases. Additional information on nomenclature, normative datasets, and data analysis, presenting indices in different eye conditions is also presented. The emphasis is on macular perfusion in surgically resolved myopic foveoretinal detachment, postoperative evaluation in retinal detachment, and long-term analysis in diabetic retinopathy.
Background: We determined the cost-effectiveness of the anti-vascular endothelial growth factor (VEGF) intravitreal injection versus panretinal photocoagulation (PRP) for patients with proliferative diabetic retinopathy (PDR) in South Korea.
Methods: We simulated four treatment strategies using PRP and the anti-VEGF injection by constructing a Markov model for a hypothetical cohort of 50-year-old PDR patients: (1) PRP only; (2) anti-VEGF injection only; (3) PRP first; and (4) anti-VEGF injection first.
Results: In this cost-effectiveness analysis, compared with only-PRP, the incremental cost-effectiveness ratiowas 34,375 per QALY for anti-VEGF injection first, and 42,000, while anti-VEGF injection only was cost-effective from a healthcare perspective. From the societal and payer perspectives, regardless of the value of WTP, anti-VEGF injection only was the most cost-effective strategy.
Conclusion: Our results on the cost-effectiveness of the anti-VEGF injection for PDR, alone or in combination with PRP treatment, can be used as important evidence when making medical service decisions.
Purpose
We sought to reveal the expression profiles of transfer RNA-derived small RNAs (tsRNAs) and microRNAs (miRNAs) in the vitreous humor of patients with proliferative diabetic retinopathy (PDR).
Methods
Vitreous humor samples were obtained from PDR patients and a control group for this study. Sequencing of small RNAs was conducted to assess the expression profiles of tsRNAs and miRNAs in both groups, which was followed by validation using reverse transcription-quantitative real-time polymerase chain reaction (RT-qPCR). Bioinformatics analyses were conducted to predict the target genes and their potential biological functions and signaling pathways.
Results
A total of 37 tsRNAs and 70 miRNAs with significant differences were screened out from the vitreous humor samples of PDR patients compared to controls. Following validation by RT-qPCR, the target genes of the validated tsRNAs and miRNAs were predicted, and Gene Ontology analysis indicated that the target genes of the tsRNAs were most enriched in the cellular macromolecule metabolic process, cytoplasm, and ion-binding, while those of the miRNAs were most abundant in the regulation of major metabolic process, cytoplasm, and protein-binding. In addition, Kyoto Encyclopedia of Genes and Genomes pathway analysis showed that the target genes of said tsRNAs and miRNAs were most enriched in the adenosine monophosphate-activated protein kinase signaling pathway and Th17 cell differentiation, respectively.
Conclusions
The present study identified altered tsRNAs and miRNAs in vitreous humor samples of PDR patients, which may play important roles in the pathogenesis of PDR and could be considered potential therapeutic targets in the treatment of PDR.
Retinal neovascular diseases are major causes of blindness worldwide. As a common epitranscriptomic modification of eukaryotic RNAs, N⁶-methyladenosine (m⁶A) is associated with the pathogenesis of many diseases, including angiogenesis, through the regulation of RNA metabolism and functions. The aim of this study was to identify m⁶A modifications of mRNAs and long noncoding RNAs (lncRNAs) and determine their potential roles in retinal neovascularization. The transcriptome-wide m⁶A profiles of mRNAs and lncRNAs in the retinal tissues of mice with oxygen-induced retinopathy (OIR) and controls were identified by microarray analysis of immunoprecipitated methylated RNAs. The m⁶A methylation levels of mRNAs and lncRNAs identified in the microarray data were validated by MeRIP-qPCR. A total of 1321 mRNAs (151 hypermethylated and 1170 hypomethylated) and 192 lncRNAs (15 hypermethylated and 177 hypomethylated) were differentially methylated with the m⁶A modification in OIR and control mice. Moreover, 763 mRNAs (597 upregulated and 166 downregulated) were significantly altered in OIR retinas. Gene ontology analysis showed that hypermethylated mRNAs were enriched in the regulation of multicellular organismal process, intracellular organelle, and protein binding, while hypomethylated mRNAs were enriched in cellular metabolic process, intracellular process, and binding. Kyoto Encyclopedia of Genes and Genomes pathway analysis indicated that hypermethylated mRNAs were involved in dopaminergic synapses, glutamatergic synapse, and PI3K-Akt signaling pathway, while hypomethylated mRNAs were involved in autophagy, ubiquitin-mediated proteolysis, and spliceosome. Moreover, the altered levels of m⁶A methylation of ANGPT2, GNG12, ROBO4, and ENSMUST00000153785 were validated by MeRIP-qPCR. The results revealed an altered m⁶A epitranscriptome in OIR retinas. These methylated RNAs may act as novel modulators and targets in retinal neovascularization.
Diabetic retinopathy is a progressive disease and primary retinal vascular complication of diabetes mellitus, the third leading cause of blindness in the United States. Racial and ethnic minorities are more likely to suffer from diabetic retinopathy and diabetic macular edema, and typically undergo less screening. Lack of screening is due to a variety of factors, such as patient, provider, and institutional barriers. Due to the disparity in screening, minorities often present with more advanced stages of diabetic eye disease. As the minority population increases, the burden of treatment for these patients will also increase. It is imperative to understand the barriers and social determinants of health limiting visual outcomes in minority populations.
Diabetic retinopathy and its complications are often preventable if detected and treated early. Advances in screening technology and intravitreal anti-VEGF injections have changed the landscape in preventing vision loss in diabetic patients.
Cyanidin-3-O-glucoside (C3G) is a kind of anthocyanin which shows strong anti-inflammation, anti-tumor and anti-oxidant properties. This paper was designed to explore the potential effects of C3G on diabetic retinopathy (DR). C57BL/6 mice were administrated with streptozotocin (STZ) or vehicle control for the establishment of diabetic models. To simulate hyperglycemia and hypoxia, D-glucose (30 mM) and CoCl2 (200 μm/l) were utilized to treat HRECs, respectively. The migration, invasion, inflammation and tube formation abilities of cells were evaluated with the adoption of wound healing, transwell, ELISA and tube formation assays, respectively. Besides, immunofluorescence staining was utilized to detect proliferation and retinal vessels. Evans blue permeation assay were performed to evaluate the vascular leakage in DR mice. Moreover, western blot and qPCR were used to quantify the mRNA and protein expressions of ionized calcium-binding adapter molecule (Iba)-1 and tight junction proteins. Results showed that C3G alleviated the inflammation, microglial activation and angiogenesis in DR mice. Moreover, the proliferation and inflammation of BV2 cells induced by high glucose (HG) were suppressed by C3G. Evans blue permeation assay demonstrated the potency of C3G in attenuating vascular leakage. In addition, C3G suppressed the migration, invasion and angiogenesis of human retinal endothelial cells (HRECs) DR model in vitro.
By confirming the role of C3G in inhibiting vascular leakage regulated by microglia activation in early DR and angiogenesis in advanced DR, this study pointed out the potential of C3G as a therapeutic drug for DR management.
Introduction
The purpose of this work is to study the efficacy of the preoperative intravitreal administration of bevacizumab as an adjunct to vitrectomy in patients with Proliferative Diabetic Retinopathy (PDR).
Methods
This retrospective comparative study was performed on 118 eyes (118 patients) with proliferative diabetic retinopathy (PDR), which underwent vitrectomy surgery at the Department of Diabetic Eye Disease at Zarifa Aliyeva National Ophthalmology Centre (Baku, Azerbaijan) in 2015-2019. The main group (the bevacizumab group) included 48 eyes with PDR that received intravitreal administration of bevacizumab (Avastin; Genentech Inc., USA) within one week before vitrectomy; the control group included 70 eyes that did not receive a bevacizumab injection for at least 3 months before the vitrectomy. The minimum follow-up was 12 months.
Results
In both groups, complete retinal attachment after primary vitrectomy was achieved in all eyes (100%). Clinically significant intraoperative haemorrhage was observed in the preoperative bevacizumab injection group in 31.2% and the control group- 51.4%, p = 0.030. The preoperative bevacizumab injection reduced the risk of clinically significant haemorrhage by 2.3 times and the need for endodiathermy by 2.7 times (p = 0.031 and p = 0.024, respectively). Early vitreous cavity haemorrhage was observed in 15.0% in the bevacizumab group and in 35.5% in the control group (p = 0.038). The preoperative injection of bevacizumab before vitrectomy reduced the risk of vitreous cavity haemorrhage in the early postoperative period by 3.0 times (p = 0.036).
Conclusion
The preoperative use of bevacizumab as an adjunct to diabetic vitrectomy can help reduce the incidence of intraoperative and early postoperative vitreous cavity haemorrhage, which leads to better functional results in the early postoperative period. Over the long-term follow-up period, the effect of the preoperative bevacizumab injections decreases.
Aim: Information on the extraocular causes of diabetic retinopathy is limited. Therefore, when researching etiology in a patient with diabetic retinopathy, if glucose, blood pressure and cholesterol are normal, other reasons must be investigated. Our aim was to evaluate the effect of nasal septum deviation (NSD) on the presence and severity of diabetic retinopathy in patients with diabetes mellitus.
Methods: This prospective case-control study included 100 eyes of 50 patients with only diabetes mellitus (DM+ NSD-, control group) and 120 eyes of 60 patients with DM and nasal septum deviation (DM+NSD+, NSD group). After evaluation of NSD patients using a nasal obstruction symptom evaluation scale (NOSE scale), 22 patients were classified as mild, 21 as moderate, and 17 as severe. Anterior segment and dilated fundus examinations were performed in all patients. Diabetic retinopathy (DR) was classified as mild, moderate, and severe non-proliferative DR and proliferative DR (PDR).
Results: The mean age of patients in the NSD and control groups was 58.7 (15.2) years (range: 41–69) and 59.6 (8.1) years (range: 44–67), respectively. The prevalence of DR and PDR were 70% (n=14) and 30% (n=6), respectively, in the severe NSD group (P=0.045 and P=0.035, respectively). The relationship between PDR and other factors in patients with NSD were evaluated, and a correlation was detected with DM duration (P=0.024, OR=1.272), HbA1c (P=0.032, OR=3.085), and NOSE scale severity (P=0.040, OR=2.566).
Conclusion: The results of the present study show an increased risk of DR and PDR in patients with severe NSD. In addition to other risk factors in PDR etiology, NSD should also be considered.
Keywords: Diabetic retinopathy, Proliferative diabetic retinopathy, Nasal septum deviation, Hypoxia
Elevated intraocular levels of angiogenic cytokines such as vascular endothelial growth factor (VEGF) have been implicated the development of diabetic retinopathy. Over a decade of clinical evidence shows intravitreal injection of anti-VEGF agents is associated with decreased disease progression and preservation of vision. However, the treatment burden associated with monthly injections limits the effectiveness of existing anti-VEGF therapies. Current research has focused on sustained treatment paradigms such as longer acting drugs, drug delivery implants, and gene therapy. In this study, we tested a novel approach by dialyzing proteins from the vitreous using bioceramic implant composed of hydroxyapatite. Preliminary in vitro and in vivo studies demonstrate a high affinity and capacity for VEGF absorption. After three months implantation in New Zealand White Cross rabbits, the hydroxyapatite demonstrated good biocompatibility with no inflammation and normal retinal physiology and histology. These studies demonstrate that prolonged VEGF suppression intraocularly may be accomplished with a bioceramic implant.
Matrix metalloproteinases (MMPs) are enzymes capable of degrading nearly all types of extracellular matrix. They perform a wide range of roles in physiological processes, which is the reason for their strict regulation by numerous mechanisms including natural tissue inhibitors of metalloproteinases (TIMP). Research only started to shed light on more troublesome aspects of MMPs function, like cancer progression, Alzheimer's disease, atherosclerosis, ageing. Moreover, their profound role in diabetes is being carefully investigated including one of its most debilitating complications - diabetic retinopathy (DR), the leading cause of acquired blindness worldwide. Traditional treatment of this condition seems to be only mildly satisfactory, which elicited substantial interest in the field of new therapeutic methods including MMP targeting. So far, significant roles of MMP-2 and MMP-9 in the development of retinopathy have been established, with special attention given to the process of blood-retinal barrier impairment. Further exploration revealed MMP-10 and MMP-14 involvement as well as changes in MMP/TIMP ratio.
In this review, we provide insight into MMPs role in diabetic retinopathy with a clarification of various mechanisms regulating MMP activity in the light of the recent studies. We conclude with an overview of novel DR therapies targeting MMPs and point to the need of further examination of their usefulness in clinical setting, with an eye towards future research.
Purpose:
To compare the outcome of the sequence in the two treatments (intravitreal ranibizumab and panretinal photocoagulation) in high-risk proliferative diabetic retinopathy.
Methods:
This retrospective study included 35 patients with newly diagnosed high-risk proliferative diabetic retinopathy in 43 eyes; 18 (22 eyes) received intravitreal ranibizumab before panretinal photocoagulation (intravitreal ranibizumab+ group), while the other 17 (21 eyes) received panretinal photocoagulation before intravitreal ranibizumab (panretinal photocoagulation+ group). Each subject received three intravitreal ranibizumabs that were interleaved with three panretinal photocoagulations. The first treatment (either intravitreal ranibizumab or panretinal photocoagulation) was done 1 week before the second one. The interval between intravitreal ranibizumabs was 4 weeks, panretinal photocoagulation was 2 weeks. The power and pulse duration were determined based upon the status of each retinal spot before each panretinal photocoagulation. The retinal non-perfusion region was measured with fundus fluorescein angiography before and 1 month after the final treatment. The central macular thickness was measured with optical coherence tomography within 1 week before the first treatment, before each panretinal photocoagulation, and 1 month after the final intravitreal ranibizumab.
Results:
The panretinal photocoagulation energy required for effective treatment was lower in intravitreal ranibizumab+ group in the first and second sessions and in total energy (p < 0.05). Central macular thickness reduction before the second panretinal photocoagulation session was significant in the intravitreal ranibizumab+ group (p < 0.05).
Conclusion:
The sequence used in intravitreal ranibizumab+ group showed clear advantages over that in panretinal photocoagulation+ group in the treatment of proliferative diabetic retinopathy, not only in the use of lower energy for panretinal photocoagulation but also in the more rapid regression of neovascularization and less need of additional treatment.
Purpose:
To evaluate the longitudinal changes in optic disk neovascularization (NVD) after intravitreal bevacizumab injection using optical coherence tomography angiography.
Methods:
In this prospective, interventional, case series, eyes with NVD secondary to diabetic retinopathy were enrolled. En face optical coherence tomography angiographic images were obtained from the optic disks before and 3 hours, 6 hours, 24 hours, 7 days, and 30 days after intravitreal bevacizumab injection. The size and flow area of the neovascularization were measured by two graders.
Results:
Eleven eyes of 9 patients with a mean age of 52.11 ± 9.48 years were included. The reduction in the NVD size and flow area was statistically significant at 24 hours, 7 days, and 30 days after injections compared with the baseline measurements (all P < 0.05). The decremental regression in the NVD size and flow area continued during the study course. The changes were not statistically significant in 3-hour and 6-hour measurements (all P > 0.05).
Conclusion:
In this study, statistically significant regression in the NVD size and flow area was observed as early as 24 hours after a single intravitreal bevacizumab injection, with a continued decreasing trend for at least a 1-month period.
Purpose:
We investigated the expression of the proinflammatory and proangiogenic factor osteoprotegerin (OPG) and its ligands, receptor activator of nuclear factor-κB ligand (RANKL), tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), and the receptor RANK in proliferative diabetic retinopathy (PDR).
Materials and methods:
Vitreous samples from PDR and nondiabetic control patients and epiretinal membranes from PDR patients were studied by enzyme-linked immunosorbent assay, immunohistochemistry, and Western blot analysis.
Results:
Vascular endothelial growth factor, OPG, and soluble RANK levels in vitreous samples from PDR patients were significantly higher than that in nondiabetic controls. Soluble TRAIL levels were significantly lower in PDR patients than that in nondiabetic control, whereas soluble RANKL levels did not differ significantly. RANKL, RANK, and TRAIL were expressed in vascular endothelial cells, myofibroblasts, and CD45-expressing leukocytes in PDR epiretinal membranes.
Conclusions:
Dysregulated expression of OPG/RANKL/RANK pathway and TRAIL might be related to inflammation and angiogenesis in PDR.
The structure of wondonin marine natural products was renovated to attain new drug-like scaffolds. Wondonins have novel anti-angiogenic properties without overt cytotoxicity. However, the chemical instability and synthetic complexity of wondonins have hindered their development as a new type of anti-angiogenesis agent. Using a structure-based bioisosterism, the benzodioxole moiety was changed to benzothiazole, and the imidazole moiety was replaced by 1,2,3-triazole. Our efforts resulted in a new scaffold with enhanced anti-angiogenic activity and minimized cytotoxicity. One compound with this scaffold effectively inhibited hyaloid vessel formation in diabetic retinopathy mimic zebrafish model. The biological findings together suggested the potential of the scaffold as a lead structure for development of anti-angiogenic drugs with novel functions and as a probe to elucidate new biological mechanisms associated with angiogenesis.
Purpose: To assess the short-term complications of a single dose of intravitreal bevacizumab in patients with proliferative diabetic retinopathy (PDR).
Methods: Retrospective review of 343 patients with PDR who were treated with intravitreal injection of bevacizumab (2.5 mg/0.1 mL).
Results: Five patients (1.45%) presented tractional retinal detachment 1 to 6 weeks (mean 3 weeks) after intravitreal injection. All cases underwent pars plana vitrectomy, removal of all epiretinal fibrovascular membranes, further endolaser panretinal photocoagulation, and silicone tamponade.
Conclusion: Tractional retinal detachment may occur in a short time post intravitreal injection of bevacizumab in patients with proliferative diabetic retinopathy with extensive areas of ischemia and fibrovascular proliferations, and may require prompt vitreoretinal surgery.
In proliferative diabetic retinopathy (PDR), vascular endothelial growth factor (VEGF) and connective tissue growth factor (CTGF) cause blindness by neovascularization and subsequent fibrosis, but their relative contribution to both processes is unknown. We hypothesize that the balance between levels of pro-angiogenic VEGF and pro-fibrotic CTGF regulates angiogenesis, the angio-fibrotic switch, and the resulting fibrosis and scarring.
VEGF and CTGF were measured by ELISA in 68 vitreous samples of patients with proliferative DR (PDR, N = 32), macular hole (N = 13) or macular pucker (N = 23) and were related to clinical data, including degree of intra-ocular neovascularization and fibrosis. In addition, clinical cases of PDR (n = 4) were studied before and after pan-retinal photocoagulation and intra-vitreal injections with bevacizumab, an antibody against VEGF. Neovascularization and fibrosis in various degrees occurred almost exclusively in PDR patients. In PDR patients, vitreous CTGF levels were significantly associated with degree of fibrosis and with VEGF levels, but not with neovascularization, whereas VEGF levels were associated only with neovascularization. The ratio of CTGF and VEGF was the strongest predictor of degree of fibrosis. As predicted by these findings, patients with PDR demonstrated a temporary increase in intra-ocular fibrosis after anti-VEGF treatment or laser treatment.
CTGF is primarily a pro-fibrotic factor in the eye, and a shift in the balance between CTGF and VEGF is associated with the switch from angiogenesis to fibrosis in proliferative retinopathy.
The purpose of this study was to examine the effect of lower than usual doses of intravitreal bevacizumab (Avastin) on vitreous vascular endothelial growth factor (VEGF) concentration and intraoperative bleeding when used as preoperative adjunct therapy in patients undergoing vitrectomy for proliferative diabetic retinopathy.
Fifty-two eyes (52 patients) with indications for vitrectomy were studied; 12 received bevacizumab, and 40 did not. The bevacizumab group was given a single intravitreal injection of bevacizumab (0.16-1.25 mg) 3 days before vitrectomy. Numbers of intraoperative coagulation spots administered for hemostasis were compared between the two groups. In both groups, vitreous samples were collected during vitrectomy, and VEGF levels were measured by enzyme-linked immunosorbent assay.
The VEGF concentration was 1880.1 +/- 1927.5 in the nonbevacizumab group and 24.9 +/- 25.1 in the bevacizumab group, and the difference was significant (P = 0.0001). Although VEGF concentrations were apparently lower at higher bevacizumab doses, no significant correlation was observed (r = 0.366, P = 0.2425). Numbers of intraoperative coagulation spots differed significantly between the bevacizumab (3.2 +/- 0.8) and nonbevacizumab (5.7 +/- 1.0) groups (P < 0.0001). In the bevacizumab group, there was no correlation between the number of intraoperative coagulation spots and the bevacizumab dose (r = 0.272, P = 0.3919).
When intravitreal bevacizumab was administered as preoperative adjunct therapy to patients undergoing vitrectomy for proliferative diabetic retinopathy, the lowest dose tested (0.16 mg) was as effective as the standard dose (1.25 mg) in reducing vitreous VEGF concentrations and also decreasing intraoperative bleeding as measured by the reduced number of coagulation spots.
To investigate the short-term effects of panretinal photocoagulation (PRP) combined with an intravitreal injection of Avastin(bevacizumab) as an adjuvant to high-risk proliferative diabetic retinopathy (PDR).
The data was collected retrospectively from the eyes of high-risk PDR patients, which were divided into two groups. One eye was treated with only PRP (PRP only group) and the fellow eye of same patient was treated with both PRP and intravitreal bevacizumab injection (Adjuvant group). Best corrected visual acuity (BCVA), IOP (intraocular pressure), and new vessel (NV) size in fluorescein angiography were recorded immediately and at the six-week follow-up visit. Adverse events associated with intravitreal injection were investigated.
Of 12 patients with high-risk PDR, five were male and seven were female. There were no statistically significant BCVA or IOP changes after treatment in either group (p=0.916, 0.888). The reduction of NV size was found in both groups, but NV size in the adjuvant group showed a greater decrease than that of the PRP only group (p=0.038). Three patients had adverse events after intravitreal injection. Two patients had mild anterior uveitis and one patient had a serious complication of branched retinal artery obstruction (BRAO).
Intravitreal bevacizumab injection with PRP resulted in marked regression of neovascularization compared with PRP alone. One serious side effect, BRAO, was noted in this study. Further studies are needed to determine the effect of repeated intravitreal bevacizumab injections and the proper number of bevacizumab injections as an adjuvant.
To study the concentration of vascular endothelial growth factor (VEGF) in the aqueous humor before and after intracameral injection of bevacizumab in eyes with neovascular glaucoma, and to detect the duration of an anti-VEGF effect of bevacizumab in the anterior chamber.
In this prospective interventional case series, 1.25 mg of bevacizumab was injected into the anterior chamber of five eyes in five neovascular glaucoma patients. Aqueous humor samples were obtained just before intracameral injection of bevacizumab and two weeks after injection. The concentrations of VEGF in the aqueous humor were measured using ELISA. To investigate corneal endothelial damage after intrecameral bevacizumab injection, specular microscopy was performed before injection and two weeks after injection. Slit lamp photo and iris fluorescent angiography was performed to determine the regression of iris neovascularization.
After injection, substantial regression of neovascularization or fluorescein leakage was seen in all treated eyes. The VEGF concentrations in the aqueous humor in eyes with NVG were 1181.8 + or - 1248.3 pg/mL before intracameral injection of bevacizumab. Two weeks after injection, the VEGF concentrations decreased to 33.2 + or - 12.2 pg/mL (p=0.04, Wilcoxon signed rank test). There were no significant changes in IOP or corneal endothelial cells.
Intracameral bevacizumab injection can remarkably reduce iris neovascularization in neovascular glaucoma patients. VEGF levels were significantly decreased two weeks after injection and corneal toxicity was not observed during short term follow-up.
To compare the amount of intraoperative intraocular bleeding in patients with diabetes with macula-involving tractional retinal detachment (TRD) undergoing pars plana vitrectomy (PPV) with and without preoperative intravitreal bevacizumab (IVB) injection.
An institutional study was carried out with consecutive patients with diabetic retinopathy and macula-involving TRD of recent (3 months) onset who were randomly assigned to PPV only (PPV group) or PPV combined with one IVB (1.5 mg/0.06 ml) injection 2 weeks prior to surgery (bevacizumab (BEV)/PPV group). All patients underwent 23-gauge PPV 3 weeks after baseline. The main outcome measure was erythrocyte count in the fluid retrieved from the vitrectomy cassette using a Neubauer counting chamber.
The study included 20 patients. The mean erythrocyte count was 14,865x10(3) (SD 19,332x10(3); median 4,500x10(3)) cells in the BEV/PPV group, and 176,240x10(3) (SD 108,375x10(3); median 166,600x10(3)) cells in the PPV group. The mean erythrocyte count was significantly lower in the BEV/PPV group than in the PPV group (p<0.0001). No major adverse events were identified.
Preoperative IVB injection was associated with reduced intraocular bleeding during 23-gauge PPV for diabetic macula-involving TRD. Further studies are needed to confirm our preliminary findings. Trial registration number: NCT00690768.
Diabetic retinopathy (DR) remains the major threat to sight in the working age population. Diabetic macular edema (DME) is a manifestation of DR that produces loss of central vision. Macular edema within 1 disk diameter of the fovea is present in 9% of the diabetic population. Proliferative diabetic retinopathy (PDR) is a major cause of visual loss in diabetic patients. In PDR, the growth of new vessels from the retina or optic nerve, is thought to occur as a result of vascular endothelial growth factor (VEGF) release into the vitreous cavity as a response to ischemia. Furthermore, VEGF increases vessel permeability leading to deposition of proteins in the interstitium that facilitate the process of angiogenesis and macular edema. This review demonstrates multiple benefits of intravitreal bevacizumab on DR including DME and PDR. The results indicate that intravitreal bevacizumab injections may have a beneficial effect on macular thickness and visual acuity (VA), independent of the type of macular edema that is present. Therefore, in the future this new treatment modality could replace or complement focal/grid laser photocoagulation in DME. In addition, in PDR, this new option could be an adjuvant agent to PRP so that more selective therapy may be applied.
Neovascular glaucoma (NVG) represents one of the most severe forms of secondary glaucoma, caused by a number of ocular and systemic conditions, which share the common element of retinal ischaemia/hypoxia that initiates the subsequent release of angiogenesis factors, with consequent development of new abnormal vessels through the ciliary body. The aim was to examine the potential efficacy and safety of intravitreal injection of bevacizumab (IVB) (Avastin) in the treatment of NVG in patients who had already undergone the standard retinal ablative procedure.
This was a prospective pilot trial. Clinical data of 26 eyes from 23 patients, including diagnosis, visual acuity, iris fluorescein angiography stage and intraocular pressure (IOP), were collected. Three injections of bevacizumab were scheduled for each recruited eye at 4-week intervals from the start. All investigations were repeated the day before the IVB (1.25 mg/0.05 ml) and at the 1-, 3-, 6-, 9- and 12-month follow-up.
Regression of corneal oedema together with significant pain reduction was achieved in all eyes already after the first IVB, without any noteworthy improvement of visual acuity. At the end of the scheduled protocol (three IVB), regression of iris neovascularization was documented in all patients, together with significant improvement of visual acuity. The IOP reduction from baseline ranged from 30 to 0 mmHg (12.1 +/- 8 mmHg).
Intravitreal bevacizumab, as adjunctive treatment to the standard retinal ablative procedure, seems promising for the management of conditions responsible of retinal ischaemia/hypoxia associated with NVG.
Objective: To compare the effects of single-sitting vs 4-sitting panretinal photocoagulation (PRP) on macular edema in subjects with severe nonproliferative or early proliferative diabetic retinopathy with relatively good visual acuity and no or mild center-involved macular edema. Methods: Subjects were treated with 1 sitting or 4 sittings of PRP in a nonrandomized, prospective, multicentered clinical trial. Main Outcome Measure: Central subfield thickness on optical coherence tomography (OCT). Results: Central subfield thickness was slightly greater in the 1-sitting group (n = 84) than in the 4-sitting group (n = 71) at the 3-day (P = .01) and 4-week visits (P = .003). At the 34-week primary outcome visit, the slight differences had reversed, with the thickness being slightly greater in the 4-sitting group than in the 1-sitting group (P = .06). Visual acuity differences paralleled OCT differences. Conclusions: Our results suggest that clinically meaningful differences are unlikely in OCT thickness or visual acuity following application of PRP in 1 sitting compared with 4 sittings in subjects in this cohort. More definitive results would require a large randomized trial.
Objective: To document proliferative control of fluorescein angiography in diabetic retinopathy after intravitreal bevacizumab and hemiretinal photocoagulation, compared to a complete panretinal photocoagulation in the contralateral eye. Material and Methods: Patients with bilateral and symmetrical proliferative diabetic retinopathy without history of previous treatment were included. The right eye received intravitreal bevacizumab and a single session of 800 scattered laser spots. The left eye underwent a full 1,600 laser panretinal photocoagulation. Angiography was performed monthly for 6 months to document inactivity of the diabetic retinopathy. Statistical significance in between eyes of persistent angiographic activity, time of reapplication and also number of retreatments with panretinal photocoagulation were analyzed using T-tests set as p<0.05. Results: 109 patients were enrolled. In the first month, 16.6% of right eyes presented activity, compared to 34% of left eyes (p<0.05); the difference was statistically significant up to the 4th month. In the 5th and 6th months, the activity in both eyes was not statistically significant. The median time of reapplying laser in the right eyes was 112 days, compared to 65 days in the left. In the first four months, the left eye was retreated 3 times more than the right eye. Conclusions: Applying bevacizumab with half panretinal photocoagulation is more effective in inactivating the proliferative diabetic retinopathy, compared to a full panretinal photocoagulation up to the 4th month. Adding bevacizumab accelerates the time of inactivity in the angiography, avoids up to twice the time for reapplying laser and is 3 times less likely to be retreated.
Objective
To compare the effects of single-sitting vs 4-sitting panretinal photocoagulation (PRP) on macular edema in subjects with severe nonproliferative or early proliferative diabetic retinopathy with relatively good visual acuity and no or mild center-involved macular edema.Methods
Subjects were treated with 1 sitting or 4 sittings of PRP in a nonrandomized, prospective, multicentered clinical trial.Main Outcome Measure
Central subfield thickness on optical coherence tomography (OCT).Results
Central subfield thickness was slightly greater in the 1-sitting group (n = 84) than in the 4-sitting group (n = 71) at the 3-day (P = .01) and 4-week visits (P = .003). At the 34-week primary outcome visit, the slight differences had reversed, with the thickness being slightly greater in the 4-sitting group than in the 1-sitting group (P = .06). Visual acuity differences paralleled OCT differences.Conclusions
Our results suggest that clinically meaningful differences are unlikely in OCT thickness or visual acuity following application of PRP in 1 sitting compared with 4 sittings in subjects in this cohort. More definitive results would require a large randomized trial.Application to Clinical Practice
These results suggest PRP costs to some patients in terms of travel and lost productivity as well as to eye care providers could be reduced.Trial Registration
clinicaltrials.gov Identifier: NCT00687154.
Purpose: To compare the anatomical and functional results and intraoperative complications between 20 gauge pars plana vitrectomies (20 G PPV) and 23 gauge microincisional PPV's combined with phacoemulsification surgery following an intravitreal bevacizumab (IVB) injection for proliferative diabetic retinopathy with fractional retinal detachment (TRD). Material and Methods: 49 eyes of 43 patients who underwent PPV using 20 G system (26 cases, Group A) and 23 G system (23 cases, Group B) were analysed retrospectively. All patients received an injection of IVB 5 days before surgery. Intraoperative bleeding, iatrogenic retinal tears, the functional and anatomical success rate with at least 6 months follow-up were compared statistically between the groups. Results: Significant improvement in visual acuity (VA) was obtained in both groups (p<0.05). No statistically significant difference was found between the two groups in terms of mean preoperative and postoperative VA's, mean change in VA and the number of cases with improvement and regression in VA. The anatomical success rate did not differ between the groups. Intraoperative bleeding occurred in 12/26 cases in Group A and 3/23 in Group B (p=0.03). There was no significant difference between the groups in terms of development of intraoperative retinal breaks (p>0.05). Conclusion: It was concluded that the advantages of 20 G PPV and 23 G microincisional PPV were similar in terms of visual and anatomical results for diabetic trd cases, but intraoperative bleeding occurs less frequently with 23 G system. Therefore the 23 G microincisional PPV following administration of IVB in diabetic trd cases would be more advantageous for surgeons.
Objective: To determine the prevalence of diabetic retinopathy among adults 40 years and older in the United States. Methods: Pooled analysis of data from 8 population-based eye surveys was used to estimate the prevalence, among persons with diabetes mellitus (DM), of retinopathy and of vision-threatening retinopathy-defined as proliferative or severe nonproliferative retinopathy and/or macular edema. Within strata of age, race/ethnicity, and gender, US prevalence rates were estimated by multiplying these values by the prevalence of DM reported in the 1999 National Health Interview Survey and the 2000 US Census population. Results: Among an estimated 10.2 million US adults 40 years and older known to have DM, the estimated crude prevalence rates for retinopathy and vision-threatening retinopathy were 40.3% and 8.2%, respectively. The estimated US general population prevalence rates for retinopathy and vision-threatening retinopathy were 3.4% (4.1 million persons) and 0.75% (899000 persons). Future projections suggest that diabetic retinopathy will increase as a public health problem, both with aging of the US population and increasing age-specific prevalence of DM over time. Conclusion: Approximately 4.1 million US adults 40 years and older have diabetic retinopathy; 1 of every 12 persons with DM in this age group has advanced, vision-threatening retinopathy.
Background:
The Early Treatment Diabetic Retinopathy Study (ETDRS) enrolled 3711 patients with mild-to-severe nonproliferative or early proliferative diabetic retinopathy in both eyes. Patients were randomly assigned to aspirin 650 mg/day or placebo. One eye of each patient was assigned randomly to early photocoagulation and the other to deferral of photocoagulation. Follow-up examinations were scheduled at least every 4 months, and photocoagulation was initiated in eyes assigned to deferral as soon as high-risk proliferative retinopathy was detected. Aspirin was not found to have an effect on retinopathy progression or rates of vitreous hemorrhage. The risk of a combined end point, severe visual loss or vitrectomy, was low in eyes assigned to deferral (6% at 5 years) and was reduced by early photocoagulation (4% at 5 years). Vitrectomy was carried out in 208 patients during the 9 years of the study. This report presents baseline and previtrectomy characteristics and visual outcome in these patients.
Methods:
Information collected at baseline and during follow-up as part of the ETDRS protocol was supplemented by review of clinic charts for visual acuity and ocular status immediately before vitrectomy.
Results:
Vitrectomy was performed in 208 (5.6%) of the 3711 patients (243 eyes) enrolled in the ETDRS. The 5-year vitrectomy rates for eyes grouped by their initial photocoagulation assignment were as follows: 2.1% in the early full scatter photocoagulation group, 2.5% in the early mild scatter group, and 4.0% in the deferral group. The 5-year rates of vitrectomy (in one or both eyes) were 5.4% in patients assigned to aspirin and 5.2% in patients assigned to a placebo. The indications for vitrectomy were either vitreous hemorrhage (53.9%) or retinal detachment with or without vitreous hemorrhage (46.1%). Before vitrectomy, visual acuity was 5/200 or worse in 66.7% of eyes and better than 20/100 in 6.2%. One year after vitrectomy, the visual acuity was 20/100 or better in 47.6% of eyes, including 24.0% with visual acuity of 20/40 or better.
Conclusions:
With frequent follow-up examinations and timely scatter (panretinal) photocoagulation, the 5-year cumulative rate of pars plana vitrectomy in ETDRS patients was 5.3%. Aspirin use did not influence the rate of vitrectomy.
To evaluate the effect of repeated intravitreal injections of bevacizumab (Avastin(®)) in patients with proliferative diabetic retinopathy and persistent new vessels after panretinal photocoagulation.
In this prospective study we investigated 11 eyes of 10 diabetic patients with persistent new vessels after previous complete panretinal photocoagulation. Complete ophthalmological examinations were performed at baseline and during monthly follow-up visits until the final follow-up at 6 months. Colour fundus photography, fluorescein angiography (FA) and macular optical coherence tomography (OCT) were performed. The area of leakage (mm²) found in the FA was used to demonstrate the effect of bevacizumab on retinal new vessels. Patients received 1.0 mg of intravitreal bevacizumab at baseline and at each of the monthly follow-up visits when reappearance of retinal new vessels was documented.
At the 1-week follow-up visit, 73% of the treated eyes showed complete regression of retinal new vessels. Eight eyes were assigned to retreatments at the 3-month follow-up because of the reappearance of retinal new vessels. After 6 months, 36% of the eyes were found to have reappearance of retinal new vessels. The retreatment rate was 1.9 ± 0.7 and the mean interval to retreatment was 2.9 ± 1.0 months. The mean leakage area decreased from 7.2 ± 2.6 mm² at baseline to 1.2 ± 0.9 mm² at the final follow-up visit. BCVA increased from 59.2 ± 14.6 Early Treatment Diabetic Retinopathy Study (ETDRS) score (range 40-80) to 70.7 ± 8.5 at the final visit (p = 0.017).
Intravitreal bevacizumab led to a significant reduction of retinal new vessels for a mean period of 2.9 months. A 3-monthly retreatment regime might be a valid method to control retinal new vessels in diabetic patients with persistent new vessels.
The purpose of this study was to determine the histopathologic characteristics of bevacizumab-treated human proliferative diabetic retinopathy (PDR) membranes with particular regard to membrane vasculature as a step toward addressing the effects of the drug on PDR membranes. Intravitreous injection of bevacizumab, an antivascular endothelial growth factor monoclonal antibody, has recently been advocated as an adjunct in surgery for PDR. In this context, a clinically observed decrease in PDR epiretinal membrane vascularity (vascular regression) occurs from 24 hours to 48 hours after injection, but the exact mechanisms of drug action are unknown.
A consecutive series of seven PDR membrane specimens that had been removed sequentially from seven bevacizumab-treated patients were studied retrospectively. The membrane specimens were examined using light microscopic methods, including immunohistochemistry.
Five of the seven membranes were clinically avascular (one contained "ghost" vessels) and did not hemorrhage during excision. Of these 5 specimens, which included 1 removed 7 days after a total of 6 intravitreous injections of 1.25 mg bevacizumab, 4 contained histologically detectable capillaries (1 did not). These blood vessels were lined by endothelial cells as determined by immunohistochemistry for the endothelial markers CD31 and CD34. The two remaining membranes were clinically and histologically still vascularized despite bevacizumab treatment. All the specimens also contained smooth muscle actin-containing fibroblastic cells within the collagenous stroma.
The findings do not support the concept that the clinical phenomenon of vascular regression in PDR membranes after bevacizumab injection in the vitreous is resulting from obliteration of the membrane blood vessels. Another mechanism appears to be involved in at least some patients, possibly a vasoconstrictive response. Such a mechanism might explain reversal of the effects of bevacizumab that has been reported after this treatment.
To examine the histopathologic effect of a single intravitreal injection of bevacizumab on newly formed vessels in eyes with proliferative diabetic retinopathy (PDR).
Interventional case series and laboratory investigation.
Two days after intravitreal injection of bevacizumab (1.25 mg/eye), pars plana vitrectomy or trabeculectomy was performed for the treatment of PDR or neovascular glaucoma (NVG) associated with PDR. Ten surgically removed preretinal proliferative tissues and 6 deep scleral flaps containing trabecular meshwork were fixed in 2% glutaraldehyde or 4% paraformaldehyde and were subjected to transmission electron microscopic analysis, immunohistochemical analysis, and terminal deoxyuridiine triphosphate (dUTP) nick-end labeling staining. Two surgically removed preretinal proliferative tissues and 2 deep scleral flaps from patients with PDR and NVG, but without preoperative intravitreal injection of bevacizumab (IVB), served as controls.
In control tissues, vascular endothelial cells possessed many fenestrations and were accompanied by pericytes. Apoptotic vascular endothelial cells frequently were observed in tissue after intravitreal injection of bevacizumab, whereas they were not observed in control tissues. Additionally, no apparent fenestration was observed in newly formed vessels from either proliferative tissue or trabecular meshwork after intravitreal injection of bevacizumab. In both PDR and NVG tissues after intravitreal injection of bevacizumab, overexpression of smooth muscle actin was observed in newly formed vessels, suggesting that the treatment may have increased pericytes on the vasculature as compared with control tissue.
Intravitreal injection of bevacizumab may induce changes in immature, newly formed vessels of PDR or NVG tissue, leading to endothelial apoptosis with vascular regression, while inducing normalization of premature vessels by increasing pericyte coverage and reducing vessel fenestration.
To report the development of subretinal fibrosis after the injection of intravitreal bevacizumab in eyes with proliferative diabetic retinopathy (PDR) refractory to panretinal laser photocoagulation (PRP).
Twenty-one eyes of 15 patients treated with PRP and intravitreal injection of bevacizumab were included in this study. The clinical outcomes of 21 eyes having subretinal fibrosis after intravitreal bevacizumab injection were reviewed.
There were 9 men and 6 women with a mean age of 51.3 +/- 8.9 years. All eyes had PDR refractory to panretinal photocoagulation and were treated with at least one intravitreal injection of 1.25 mg of bevacizumab (mean number of injections: 1.8). Before injection, there was subretinal fibrosis in 5 eyes and vitreoretinal traction in 19 eyes. After a mean follow-up period of 7 months, the development or progression of subretinal fibrosis was detected in all eyes.
Intravitreal injection of bevacizumab may cause formation or progression of subretinal fibrosis in patients with PDR refractory to PRP.
Diabetes is the leading cause of blindness in the United Kingdom among people of working age. Many with proliferative diabetic retinopathy (PDR) go on to develop vitreous haemorrhage (VH). Those with recurrent or non-clearing VH require vitrectomy to restore vision. Pegaptanib is a vascular endothelial growth factor antagonist that disrupts the proliferative cascade and has been shown to precipitate regression of retinal neovascularisation. We assessed the effect of pre-operative intravitreal (IVT) pegaptanib on the timing, difficulty, and outcome of vitrectomy for recurrent VH in PDR.
Fourteen consecutive patients (15 eyes) were given a course of 1-3 IVT pegaptanib injections and vitrectomy was performed when indicated by the recurrence or persistence of VH, or progression of associated tractional retinal detachment (TRD).
The range of patient follow-up was from 6 months to 2 years. All had no further VH for at least 4 weeks after IVT pegaptanib. Five eyes remained free from VH until the end of the study (8-25 months), thus obviating the need for vitrectomy. Two further cases avoided vitrectomy following further IVT pegaptanib. In the majority of patients with VH, IVT pegaptanib created a window for further laser and risk factor optimisation. Surgery was faster and less challenging, compared with conventional vitrectomy for recurrent VH due to PDR.
IVT pegaptanib can be considered in diabetic patients with VH. Approximately one-third may avoid vitrectomy altogether. There are clear intra-operative advantages of using IVT pegaptanib pre-operatively. However, caution should be exercised where there is pre-existing TRD.
The purpose of this study was to evaluate the effectiveness of intravitreal bevacizumab on persistent retinal neovascularizations in proliferative diabetic retinopathy.
Thirty-three eyes of 24 patients (mean age, 52.75 +/- 8.2 years) with proliferative diabetic retinopathy showing recurrences or no regressions in neovascularizations were evaluated in this study. After the intravitreal injection of 1.25 mg/0.05 mL of bevacizumab, the first examination was performed within 3 days and repeated at 1 week, 1 month, 3 months, and 6 months. In these examinations, localization and dimensions of neovascularizations were evaluated with red-free photographs and/or fluorescein angiography.
All patients had type II diabetes for a period of 12 +/- 4.4 years (range, 2-20 years). After a single dose of bevacizumab, complete resolution rate of neovascularizations was 78.8% at 1 month, 63.6% at 3 months, and 45.4% at 6 months. When evaluated together with 9 eyes that had a second injection at 3 months, the complete resolution rate was 60.6% at 6 months. Mean best-corrected visual acuity and macular volume were 1.06 logarithm of the minimum angle of resolution (20/225 in Snellen) and 11.65 mm3 before treatment. Six months after treatment, these were 0.73 logarithm of the minimum angle of resolution (20/108 in Snellen) and 8.92 mm3 (P = 0.048 and 0.003, respectively).
Bevacizumab can be used safely and successfully in patients with proliferative diabetic retinopathy who do not experience any resolution or experience recurrences after panretinal photocoagulation.
The purpose of this study is to evaluate the role, the safety and the effectiveness of intravitreal bevacizumab (IVB) injections as an adjunct to vitrectomy in the management of severe proliferative diabetic retinopathy (PDR).
Case-Control Study
Randomized controlled trial performed on 72 eyes of 68 patients affected by vitreous haemorrhage (VH) and tractional retinal detachment (TRD), which occurred as a consequence of active proliferative diabetic retinopathy (PDR). We randomly assigned eligible patients in a 1: 1: 1 ratio to receive a sham injection or an intravitreal injection of 1.25 mg of bevacizumab, either 7 or 20 days before the vitrectomy. In order to obtain three homogeneous groups of surgical complexity, we assigned to the following preoperative parameters a score from 0 to 3: a) vitreous haemorrhage, b) prior retinal laser-photocoagulation, c) morphological types of retinal detachment such as focal, hammock, central diffuse, table-top. Complete ophthalmic examinations and color fundus photography were performed at baseline and 1, 6, 12, and 24 weeks after the surgery.
Intraoperative management, safety, efficacy of IVB at different time injection as an adjunct to vitrectomy in the management of severe PDR RESULTS: Group A (sham injection): intraoperative bleeding occurred in 19 cases (79.1%), the use of endodiathermy was necessary in 13 patients (54.1%), relaxing retinotomy was performed on one patient (4.1%), and in four cases (16.6%) iatrogenic retinal breaks occurred. The surgical mean time was 84 minutes (SD 12 minutes). Group B (bevacizumab administered 7 days before vitrectomy): intraoperative bleeding occurred in two cases (8.3%) and the use of endodiathermy was necessary in two patients (8.3%). No iatrogenic breaks occurred during the surgery. The surgical mean time was 65 minutes (SD 18 minutes). Group C (bevacizumab administered 20 days before vitrectomy): intraoperative bleeding occurred in three cases (12.5%), the use of endodiathermy was necessary in three patients (1.5%), and an iatrogenic break occurred in one patient (4.1%) while the delamination of fibrovascular tissue was being performed. The surgical mean time was 69 minutes (SD 21 minutes). The average difference in the surgical time was statistically significant between group A and group B (p = 0.025), and between group A and group C (p = 0.031). At the end of the surgery, the retina was completely attached in all eyes. At the 6-month follow-up, we observed the development of tractional retinal detachment (TRD) in one out of 24 patients from group C (4%).
A preoperative intravitreal injection of bevacizumab may represent a new strategy for the surgical treatment of severe PDR by reducing retinal and iris neovascularization: this would make surgery much easier and safer, thus improving the anatomical and functional prognosis. According to our study, the best surgical results are achieved performing the IVB 7 days preoperatively.
To report the occurrence of ghost cell glaucoma after intravitreal injection of bevacizumab for the treatment of postoperative vitreous hemorrhage after vitrectomy for proliferative diabetic retinopathy (PDR).
Retrospective chart review from August 2006 to December 2007. Patients who had postoperative vitreous hemorrhage after vitrectomy for PDR and received an intravitreal injection of bevacizumab were enrolled in the study.
Eight eyes of 8 patients (mean age: 46 years) were included. After intravitreal injection of bevacizumab, 4 (50%) eyes had clearance of vitreous hemorrhage. Three eyes developed ghost cell glaucoma within 1 week after intravitreal injection of bevacizumab. Of these, intraocular pressure was controlled in 1 eye through the use of anti-glaucoma medication, whereas the other 2 eyes needed surgical intervention to lower intraocular pressure and subsequently clear the vitreous hemorrhage.
Intravitreal injection of bevacizumab may accelerate the clearance of postoperative vitreous hemorrhage in cases of PDR. However, a high incidence of ghost cell glaucoma was observed. Caution should be exercised when administering an intravitreal injection of bevacizumab for a postoperative vitreous hemorrhage after vitrectomy for PDR.
Several complications after intravitreal bevacizumab (IVB) treatment have been described including tears of the retinal pigment epithelium and tractional retinal detachment. The etiology of these complications remains unclear. The purpose of this study was to characterize changes in the intraocular levels of inflammatory cytokines after IVB as a possible explanation for these complications.
Twenty-nine patients with proliferative diabetic retinopathy (PDR) undergoing pars plana vitrectomy (PPV) for vitreous hemorrhage (VH) with IVB pretreatment were prospectively enrolled. Aqueous humor samples were taken at the time of IVB pretreatment and approximately 1 week later at the time of PPV. Multiplex cytokine arrays were used to assay 20 different cytokines. Multivariate general linear regression was performed to determine differences in cytokine levels between the two study visits. Proportional hazards regression was performed to determine the relationship between cytokine levels at PPV and postoperative outcomes.
After treatment with IVB, vascular endothelial growth factor (VEGF) concentrations in the aqueous humor dec