Therapy Of Proliferative Diabetic Retinopathy Research Articles

Systematic evaluation of combined herbal adjuvant therapy for proliferative diabetic retinopathy.

To evaluate the efficacy and safety of combined traditional Chinese medicine in the adjuvant treatment of proliferative diabetic retinopathy (PDR) by Meta-analysis. PubMed, Embase, Web of Science, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang databases were searched by computer. Random controlled clinical trials (RCTS) using traditional Chinese medicine as adjuvant therapy for proliferative diabetic retinopathy were screened, and Stata16.0 software was used to perform meta-analysis on the final included literatures. A total of 18 studies involving 1392 patients were included. Meta-analysis showed that the clinical effective rate OR=2.99 (CI: 2.18-4.10, I2=42.7%, P<0.05); Visual acuity MD=0.10(CI: 0.06-0.13, I2=0%, P<0.05); Fundus efficacy OR=5.47 (CI: 1.33-22.51, I2=71.4%, P<0.05); Neovascularisation regression rate OR=8 (CI: 3.83-16.71, I2=30.1%, P<0.05); Macular foveal thickness MD=-44.24 (CI: -84.55-3.93, I2=95.6%, P<0.05); Absorption of vitreous hemorrhage OR=4.7 (CI: 2.26-9.77, I2=0%, P<0.05); Fasting blood glucose MD=-0.23, (CI: -0.38-0.07, I2=0%, P<0.05); 2h postprandial blood glucose MD=-0.19 (CI: -0.52-0.14, I2=0%, P=0.25). From the results, the combined Chinese medicine adjuvant therapy showed better efficacy than the control group. A total of 69 kinds of traditional Chinese medicine were involved in 18 studies, among which the top four applied frequencies were Panax notoginseng, Rehmannia rehmannii, Astragalus membranaceus and Poria cocos. Most of the medicines were sweet and bitter in taste, the qi tended to be slight cold and cold, and the meridian tropism belongs to the liver meridian. The combination of traditional Chinese medicine adjuvant therapy has a good curative effect on PDR patients. However, the relevant clinical trials are few and more high-quality clinical trials are still needed, what's more the attention should be paid to the exploration of its safety.

Intravitreal Injection for Diabetic Macular Edema as Adjunctive Therapy for Proliferative Diabetic Retinopathy: A Retrospective Study.

PurposeTo detect the impact of intravitreal injection (IVI) therapy with sole anti-vascular-endothelial-growth-factor (VEGF) or combined with steroids treating diabetic macular edema (DME) on activity of proliferative diabetic retinopathy (PDR) based on total number of panretinal photocoagulation (PRP) spots needed within 2 years.Patients and MethodsA retrospective study of 102 eyes with primary-onset PDR and minimum follow-up of 24 months divided into 2 groups: Group 1 (G1) 40 eyes received only PRP and did not develop DME. Group 2 (G2) 62 eyes received additional IVI-therapy due to concomitant DME, with anti-VEGF only (subgroup 2a, G2a) or in combination with steroids (subgroup 2b, G2b). Main outcomes: central macular thickness (CMT, µm), best-corrected visual acuity (BCVA, LogMAR) and total number of needed PRP spots and IVI after 24 months.ResultsCMT was significantly higher in G2 compared to G1, initially (p < 0.01) and after 24 months (p = 0.01). CMT was significantly higher in G2b compared to G2a, both initially (p = 0.01) and after 24 months (p < 0.01). BCVA was significantly higher in G1 compared to G2, initially and after 24 months (p = 0.01). BCVA was not significantly different between the two subgroups, initially (p = 0.54) and after 24 months (p = 0.29). The total number of PRP spots was significantly higher in G1 compared to G2 (p < 0.01) but not significantly different between the subgroups (p = 0.8).ConclusionRegardless of severity of concomitant DME, IVI with sole anti-VEGF or combined with steroids reduced the total number of PRP spots needed within 2 years significantly indicating a favorable effect on activity of PDR.

Monitoring intraocular proangiogenic and profibrotic cytokines within 7 days after adjunctive anti-vascular endothelial growth factor therapy for proliferative diabetic retinopathy.

To monitor the intraocular proangiogenic and profibrotic cytokine profiles within 7 days after intravitreous injection of conbercept (IVC) for patients with proliferative diabetic retinopathy (PDR). This prospective, randomized controlled, consecutive, comparativestudy included 157 eyes with PDR. Participant eyes underwent shamIVC or IVC and subsequent vitrectomy at days 2, 3, 4, 5, 6, 7 postinjection. Theintraocular cytokines profiles were measured using beaded assay methods. After IVC, the vascular endothelial growth factor (VEGF)-A level in PDR vitreous decreased rapidly by approximately 10 times at day 2 (p = 0.00001) and kept at a low level at days 3, 4, 5, 6, 7 (p < 0.001, each compared with IVC-sham group). Similar tendency of the change in VEGF-A was observed in aqueous humour. The level of placenta growth factor (PIGF) in aqueous humour decreased 2 days after IVC whereas returned to baseline level after 5 days. The vitreous profibrotic cytokines, tissue growth factor (TGF)-β1, TGF-β2, TGF-β3 and connective tissue growth factor did not increase after IVC in each group. We observed a remarkable and rapid decrease in intraocular VEGF-A, temporal decrease in PIGF from day 2 to day 4, increase in VEGF-C and VEGF-D from day 2 onwards, but no profibrotic switch in PDR eyes after IVC. The findings might suggest that ideal vitrectomy timing might be around 3 days after IVC.

Обоснование оптимальных сроков для проведения витреоретинального вмешательства на фоне предоперационной антивазопролиферативной терапии при пролиферативной диабетической ретинопатии

«Российская офтальмология онлайн» - электронное информационное издание, создается с 1 марта 2010 года под эгидой Российского общества офтальмологов. Основная задача проекта - научно-информационная поддержка специалистов в области офтальмологии.

Diabetes und Augenerkrankungen

AbstractThe frequency of diabetic retinopathy increases and is a leading cause of blindness in the working population. Recommended exams are testing of the visual acuity, ophthalmoscopy with dilated pupils, fundus fluorescein angiography and optical coherence tomography (OCT). By OCT the diagnosis and monitoring of diabetic macular edema has vastly improved. By intravitreal medications such as intravitreal anti-VEGF or intravitreal steroids macular edema can be treated successfully. Panretinal laser photocoagulation is the gold-standard in the therapy of proliferative diabetic retinopathy. Patients benefit from good co-working of general practitioner and ophthalmologist concerning screening and treatment.

Анти-VEGF терапия пролиферативной диабетической ретинопатии: от исследований к реальной клинической практике

Анти-VEGF терапия пролиферативной диабетической ретинопатии: от исследований к реальной клинической практике

Anti–Vascular Endothelial Growth Factor Therapy for Diabetic Retinopathy: Consequences of Inadvertent Treatment Interruptions

To illustrate that patients with diabetic retinopathy who are treated exclusively with anti-vascular endothelial growth factor (VEGF) therapy and have an interruption in treatment may experience marked progression of disease with potentially devastating visual consequences. Retrospective, multicenter, case series. Retrospective review of patients treated exclusively with anti-VEGF therapy for proliferative diabetic retinopathy (PDR) or nonproliferative diabetic retinopathy (NPDR), with or without diabetic macular edema (DME), and temporarily lost to follow-up. Baseline disease characteristics, cause and duration of the treatment interruption, and resulting disease progression, complications, and outcomes were assessed. Thirteen eyes of 12 patients with type 2 diabetes were identified. The mean age was 57 ± 10 years, and 50% were women. Anti-VEGF therapy was indicated for PDR with DME in 7 (54%) eyes, PDR without DME in 3 (23%) eyes, and moderate to severe NPDR with DME in 3 (23%) eyes. Eight eyes had visual acuity (VA) of 20/80 or better before treatment interruption. The median duration of treatment hiatus was 12months. Reasons for treatment interruption included intercurrent illness (31%), noncompliance (31%), and financial issues (15%). Complications upon follow-up included vitreous hemorrhage (9 eyes), neovascular glaucoma (5 eyes), and traction retinal detachment (4 eyes). Despite treatment of these complications, 77% of eyes lost ≥3 lines of VA, with 46% of eyes having a final VA of hand motion or worse. Diabetic patients are subject to significant lapses in follow-up because of illness, financial hardship, or noncompliance. In patients with diabetic retinopathy, especially PDR, who are managed with anti-VEGF therapy alone, unintentional treatment interruptions can result in irreversible blindness.

Intravitreal aflibercept compared with panretinal photocoagulation for proliferative diabetic retinopathy: the CLARITY non-inferiority RCT

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 &gt; 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 &lt; 0.0001] and the PP population (difference 4.0 letters, 95% CI 2.4 to 5.7 letters; p &lt; 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.

Rationale and Application of the Protocol S Anti–Vascular Endothelial Growth Factor Algorithm for Proliferative Diabetic Retinopathy

To present the rationale, guidelines, and results of ranibizumab treatment for proliferative diabetic retinopathy (PDR) in Diabetic Retinopathy Clinical Research Network (DRCR.net) Protocol S. Post hoc analyses from a randomized clinical trial. Three hundred five participants (394 study eyes) having PDR without prior panretinal photocoagulation (PRP). Intravitreous ranibizumab (0.5 mg) versus PRP for PDR. Ranbizumab-assigned eyes (n= 191) received monthly injections for 6 months unless resolution was achieved after 4 injections. After 6 months, injections could be deferred if neovascularization was stable over 3 consecutive visits (sustained stability). If neovascularization worsened, monthly treatment resumed. Panretinal photocoagulation could be initiated for failure or futility criteria. Neovascularization status through 2 years. At 1 month, 19% (35 of 188) of ranibizumab-assigned eyes showed complete neovascularization resolution and an additional 60% (113) showed improvement. At 6 months, 52% (80 of 153) showed neovascularization resolution, 3% (4) were improved, 37% (56) were stable, and 8% (13) had worsened since the last visit. Among eyes with versus without resolved neovascularization at 6 months, the median (interquartile range) number of injections between 6 months and 2 years was 4 (1-7; n= 73) versus 7 (4-11; n= 67; P < 0.001). Injections were deferred in 68 of 73 eyes (93%) meeting sustained stability at least once during the study; 62% (42 of 68) resumed injections within 16 weeks after deferral. At 2 years, 43% (66 of 154) showed neovascularization resolution, 5% (7) showed improvement, 23% (36) were stable, and 27% (42) had worsened since the last visit. Only 3 eyes met criteria for failure or futility through 2 years. The DRCR.net treatment algorithm for PDR can provide excellent clinical outcomes through2years for patients initiating anti-vascular endothelial growth factor (VEGF) therapy for PDR. When choosing between anti-VEGF and PRP as first-line therapy for PDR, treatment decisions should be guided byconsideration of the relative advantages of each therapeutic method and anticipated patient compliance with follow-up and treatment recommendations.

[Effect of internal limiting membrane peeling on morpho-functional state of the retina in patients with proliferative diabetic retinopathy (preliminary report)].

To compare morpho-functional parameters of retina during vitrectomy with and without internal limiting membrane (ILM) peeling in patients with proliferative diabetic retinopathy. The study included 55 patients (55 eyes) that had underwent vitreoretinal surgery in the setting of antivasoproliferative therapy for proliferative diabetic retinopathy. Patients of the 1st group (n=27) underwent vitrectomy with silicone tamponade, 2nd group (n=28) received similar treatment with the addition of ILM peeling. Three months after the treatment, all patients had silicone oil removed. Best Corrected Visual Acuity before treatment was 0.06±0.02 in both groups; after the treatment it improved to 0.1±0.05 (p<0.05) in the 1st group and to 0.25±0.05 (p1-2<0.05) in the 2nd group. Thickness of the 'nerve fiber layer - internal limiting membrane' in the macular area was 28.67±2.21 µm in both groups before the treatment. By 3-month follow-up its thickness increased to 46.44±2.56 µm (p<0.05) in the 1st group due to the formation of epiretinal membrane (ERM). In patients of the 2nd group 'nerve fiber layer' area thickness amounted to 28.41±1.88 µm (p1-2<0.05) and ERM could not be identified in any of them. ILM peeling during vitrectomy with following silicone oil tamponade eliminates the risk of ERM formation in patients with proliferative diabetic retinopathy in the follow-up period of up to 6-month and results in better morpho-functional parameters in comparison with patients who received similar treatment but without peeling.

3D endothelial cell spheroid/human vitreous humor assay for the characterization of anti-angiogenic inhibitors for the treatment of proliferative diabetic retinopathy.

Proliferative diabetic retinopathy (PDR) represents a main cause of acquired blindness. Despite the recognition of the key role exerted by vascular endothelial growth factor (VEGF) in the pathogenesis of PDR, limitations to anti-VEGF therapies do exist. Thus, rapid and cost-effective angiogenesis assays are crucial for the screening of anti-angiogenic drug candidates for PDR therapy. In this context, evaluation of the angiogenic potential of PDR vitreous fluid may represent a valuable tool for preclinical assessment of angiostatic molecules. Here, vitreous fluid obtained from PDR patients after pars plana vitrectomy was used as a pro-angiogenic stimulus in a 3D endothelial cell spheroid/human vitreous assay. The results show that PDR vitreous is able to stimulate the sprouting of fibrin-embedded HUVEC spheroids in a time- and dose-dependent manner. A remarkable variability was observed among 40 individual vitreous fluid samples in terms of sprouting-inducing activity that was related, at least in part, to defined clinical features of the PDR patient. This activity was hampered by various extracellular and intracellular signaling pathway inhibitors, including the VEGF antagonist ranibizumab. When tested on 20 individual vitreous fluid samples, the inhibitory activity of ranibizumab ranged between 0 and 100% of the activity measured in the absence of the drug, reflecting a variable contribution of angiogenic mediators distinct from VEGF. In conclusion, the 3D endothelial cell spheroid/human vitreous assay represents a rapid and cost-effective experimental procedure suitable for the evaluation of the anti-angiogenic activity of novel extracellular and intracellular drug candidates, with possible implications for the therapy of PDR.

Vascular endothelial growth factor in fellow eyes of eyes injected with intravitreal bevacizumab

To study the effect on untreated fellow eyes of eyes treated with an intravitreal injection of bevacizumab. Bevacizumab (1.25 mg/0.05 ml) was injected into the vitreous cavity of one eye (the first eye) as a preoperative adjunctive therapy for proliferative diabetic retinopathy; vitrectomy was performed 1 week later. Immediately after vitrectomy, bevacizumab (1.25 mg/0.05 ml) was injected into the fellow eye (the second eye) followed by vitrectomy 1 week later. Aqueous humor samples were obtained from both eyes in five cases just before intravitreal injection of bevacizumab and just before vitrectomy 1 week later. Vascular endothelial growth factor (VEGF) concentrations in the aqueous humor were measured by enzyme-linked immunosorbent assay (ELISA). VEGF concentrations in the aqueous humor of the first eyes ranged from 146 to 398 pg/ml (mean, 302+/-100 pg/ml) before intravitreal injection of bevacizumab; 1 week later, the VEGF concentrations in the injected eyes were less than 31 pg/ml, the lower limit of the ELISA, in all cases (p<0.001). The concentrations in the uninjected fellow eyes ranged from 181 to 551 pg/ml (mean, 382+/-119 pg/ml). There seemed to be no or a minimal effect of the intravitreal injections of bevacizumab on the uninjected fellow eyes.

Release of the angiogenesis inhibitor angiostatin in patients with proliferative diabetic retinopathy: association with retinal photocoagulation.

Proliferative diabetic retinopathy is a major debilitating disease causing most cases of blindness in humans in the Western world. Photocoagulation is the established therapy of proliferative diabetic retinopathy, although the molecular mechanisms of its effects are still not known. Recently angiostatin has been characterized as a potent inhibitor of neovascularization. Apart from a possible down-regulation of angiogenic cytokines, release of angiostatin could initiate the anti-angiogenic effects of retinal photocoagulation. We investigated the regulation of angiostatin and the angiogenic cytokines vascular endothelial growth factor and basic fibroblast growth factor in vivo by comparing vitreal concentrations of 18 control patients and 34 patients with proliferative diabetic retinopathy with and without previous photocoagulation. Concentrations of basic fibroblast growth factor and angiostatin were additionally measured in serum, while vascular endothelial growth factor is known to be regulated locally in the eye. Cytokines were measured by immunological methods. Angiostatin could be detected in 2 out of 18 control patients and in 25 out of 34 diabetic patients (p < 0.00001). Most importantly, production of angiostatin in human vitreous correlated significantly with previous retinal photocoagulation (p < 0.0001) in patients with proliferative diabetic retinopathy. Only two patients (one control and one diabetic) had detectable serum concentrations of angiostatin. Additionally patients with proliferative diabetic retinopathy and with previous photocoagulation had significantly lower concentrations of vascular endothelial growth factor (0.9 +/- 0.1 ng/ml; p < 0.0001) than diabetic patients without previous photocoagulation (4.0 +/- 0.8 ng/ml). The investigation of vitreal and serum basic fibroblast growth factor concentrations yielded no significant differences between the groups. Angiostatin is not a regularly expressed angiogenesis inhibitor in human vitreous. The alterations we observed suggest that local release of angiostatin and down-regulation of vascular endothelial growth factor mediate the therapeutic effects of retinal photocoagulation in proliferative diabetic retinopathy.

The role of photocoagulation in the therapy of proliferative diabetic retinopathy.

Diabetic retinopathy is becoming one of the most important causes of new blindness among the adult population of the United States. In 1930, it accounted for less than 1% of the cases of newly reported blindness. However, in 1960, more than 15% of reported cases of blindness were due to diabetic retinopathy, and there is every indication to believe that this percentage will become even higher in the years to come. 1 Not only are diabetics becoming more prevalent in the population, but with improved care many are now living long enough to manifest the retinopathy. In short, the therapy of clinical diabetes has been more successful than that of the vascular complications, and when the blood vessels of the eye deteriorate more rapidly than those which are necessary to maintain life, blindness ensues. Diabetic retinopathy can be divided into a nonproliferative and proliferative stage. Microaneurisms, hemorrhages, and exudates characterize

Diabetes and photocoagulation.

Diabetic retinopathy, which may soon become the chief cause of blindness in this country, is one of the great challenges to internist and ophthalmologist alike. The frequent failure of medical treatment to prevent blindness has encouraged a direct attack on the ophthalmological problem. In the past, diathermy treatment has been used with some degree of success in controlling hemorrhage from localized areas of neovascularization. However, this form of treatment did not become popular because of the usual progression of the disease and the inconvenience and risk of a surgical procedure. Coincident with the recent increase in frequency and severity of diabetic retinopathy, the invention and acceptance of photocoagulation as a substitute for diathermy has occurred. It is not surprising, therefore, that a great surge of interest in this form of therapy for proliferative diabetic retinopathy has followed. Elsewhere in this issue of theArchivesis an excellent article dealing with