Mg Of Ranibizumab Research Articles

ONS-5010 (bevacizumab-vikg) Safety and Efficacy in Subfoveal Choroidal Neovascularization Secondary to Age-related Macular Degeneration.

This was a prospective multicenter, randomized, double-masked, active-controlled study, the aim of which was to demonstrate the efficacy and safety of intravitreal ONS-5010 (bevacizumab-vikg) in eyes with neovascular age-related macular degeneration (nAMD). This was a phase III trial on ONS-5010 (NORSE TWO). Treatment-naïve nAMD patients aged 50 years and older with a best-corrected distance visual acuity (BCVA) of 25 to 67 Early Treatment Diabetic Retinopathy Study (ETDRS) letters and evidence of disease activity were included. Subjects randomized to ONS-5010 received monthly intravitreal doses of 1.25 mg of ONS-5010, bevacizumab-vikg (Outlook Therapeutics) for 12 months. Subjects randomized to ranibizumab received 0.50 mg of ranibizumab on days 0, 30, 60, 150, and 240 based on the PIER study dosing regimen. The primary end point was the proportion of subjects who gained ≥ 15 letters from baseline in BCVA at 11 months, and evaluating the safety and tolerability of intravitreal injections of ONS-5010 administered monthly from baseline to 12 months. One hundred thirteen subjects were included in the ONS-5010 group and 115 subjects were included in the ranibizumab group. Respectively, 41.7% and 23.1% of patients gained ≥ 15 letters (3 lines) of visual acuity, with a risk difference of 0.1859 [95% CI = 0.0442, 0.3086]; P = 0.0052. The change in BCVA from baseline to 11 months was found to be 11.2 ± 12.19 and 5.8 ± 14.80 ETDRS letters, respectively. The number of subjects gaining ≥ 5 and ≥ 10 letters and subjects losing < 15 letters was significantly higher in the ONS-5010 group. Similarly, subjects with a Snellen visual acuity equivalent of 20/200 (35 ETDRS letters) or worse at 11 months were significantly fewer in the ONS-5010 group. Only one subject in the ONS-5010 group had a study-related serious ocular adverse event (SAE), namely, elevated intraocular pressure. The most common adverse event in the ONS-5010 group was conjunctival hemorrhage (8.8%), and reduced visual acuity in the ranibizumab group (12.2%). In the prescribed treatment plan, ONS-5010 exhibited strong effectiveness in improving or stabilizing visual acuity and was also well tolerated. Bevacizumab and ranibizumab displayed a comparable safety profile. [Ophthalmic Surg Lasers Imaging Retina 2024;55:XX-XX.].

Intravitreal Lucentis (Ranibizumab) as A Treatment for Diffuse Diabetic Macular Edema

Introduction: Humanized anti-VEGF (Vascular endothelial growth factor) antibody fragment Lucentis (Ranibizumab) is prescribed to treat neovascular (wet) age-related macular degeneration, diabetic macular edema, diabetic retinopathy, and myopic choroidal neovascularization. It is also used to treat macular edema following retinal vein occlusion. Objective: This study was carried out to evaluate the anatomic effect and visual acuity response following intravitreal Lucentis (Ranibizumab). Methodology: In this investigation, diffuse diabetic macular edema was present in 30 eyes belonging to 30 patients with stable diabetes mellitus. Every eye had undergone argon laser photocoagulation, either Focal, Grid, or pan-retinal photocoagulation (PRP), for a minimum of three months. The patients with a mean age was 58.13±5.17 years were treated with two intravitreal injections of 0.5 mg of ranibizumab in 0.05 ml spaced four weeks apart. A skilled ophthalmologist assessed each patient's best-corrected visual acuity (BCVA), also assessed their central macular thickness (CMT) using optical coherence tomography, and assessed their diabetic retinopathy at both the baseline and follow-up sessions. The results: The results showed that the means of BCVA were significantly (P&lt;0.01) decreased from baseline (1.189±0.077 logMAR) to 1 month (0.162±0.058 logMAR) and 3 months (1.109±0.049 logMAR) after injection. Also the results revealed that the mean of CMT were significantly (P&lt;0.01) declined from the baseline (477.47±151.32 µm) to 1 month (438.27±115.68 µm) and 3 month (396.80±115.26 µm) after treatment. Conclusions: The study concluded that after three months of the second injection of Lucentis (ranibizumab) significantly reduced central macular thickness and improved visual acuity, then diffuse diabetic macular edema is significantly improved and treated using Lucentis (ranibizumab).

Отдельные аспекты применения ингибиторов VEGF в лечении ретинопатии недоношенных

Nowadays increasing use of VEGF (vascular endothelial growth factor) inhibitors in the ROP (retinopathy of prematurity) treatment, undergoing clinical trials in Russian Federation, as well as the widely VEGF inhibitors off-label using, make this review higly relevant. In this work it was possible to reflect some significant aspects of the VEGF inhibitors application in the ROP treatment, which the researchers focus on. Evaluating the effectiveness of VEGF inhibitors in the treatment of ROP in zone II (stage 3+), bevacizumab therapy and retinal laser coagulation proved to be effective. The use of 0.2 mg of ranibizumab is more effective compared to laser treatment in patients with ROP stage 3+. Analysis of the treatment effectiveness of ROP in zone I (stages 1+, 2+, 3+) showed that ranibizumab is more effective than retinal laser coagulation (68% and 61%, respectively), however, without statistically significant differences. Results of surgical treatment of ROP indicate its high efficiency at stage 4a. There are limited data, according to the results, the combination of vitrectomy with the introduction of VEGF inhibitors leads to a faster regression of the disease. Data on the systemic effects of VEGF inhibitors available in the literature are contradictory, which requires further study of this problem. Key words: retinopathy of prematurity, VEGF inhibitors, literature review

Safety and efficacy of intravitreal anti vascular endothelial growth factor for severe posterior retinopathy of prematurity with flat fibrovascular proliferation.

Intravitreal anti-vascular endothelial growth factor (IVA) injection is known to cause contraction of fibrovascular proliferation (FVP), when present in severe retinopathy of prematurity (ROP). To assess the structural outcomes of IVA injection in the treatment of severe posterior ROP with significant FVP. It was a retrospective study in which 36 eyes of 18 preterm babies who developed > 4 clock hours of FVP in zone I or posterior zone II, were treated with either intravitreal 0.625 mg bevacizumab or intravitreal 0.2 mg of ranibizumab. Favorable structural outcome included resolution of plus disease and FVP without the development of tractional retinal detachment. Secondary outcome measure included either full retinal maturation at follow-up or development of recurrent disease requiring additional treatment. Adverse outcomes included progression to retinal detachment. The mean gestational age of the 18 preterm babies was 30 wk (range 27-36), and mean birth weight was 1319 g (range 650-1980 g). Mean post-menstrual age (PMA) at the time of primary treatment was 35.5 wk (range 31-41 wk). All eyes showed regression of plus disease and FVP. 5 eyes of 3 babies showed reactivation of disease and were treated with repeat IVA (n = 2 eyes) or peripheral laser photocoagulation (n = 3 eyes) respectively. 16 out of 36 (44%) reached retinal vascular maturation at final follow up at 5 years. There was good resolution of severe posterior ROP with FVP with IVA, with retinal maturity of 44% at 5 year follow-up and a reactivation rate of 13.8%. When the IVA injection is given prior to 37 wk PMA, while disease is in phase 2, it is less likely to cause contracture of pre-existing FVP.

Assessment of Retinopathy of Prematurity Regression and Reactivation Using an Artificial Intelligence–Based Vascular Severity Score

One of the biggest challenges when using anti-vascular endothelial growth factor (VEGF) agents to treat retinopathy of prematurity (ROP) is the need to perform long-term follow-up examinations to identify eyes at risk of ROP reactivation requiring retreatment. To evaluate whether an artificial intelligence (AI)-based vascular severity score (VSS) can be used to analyze ROP regression and reactivation after anti-VEGF treatment and potentially identify eyes at risk of ROP reactivation requiring retreatment. This prognostic study was a secondary analysis of posterior pole fundus images collected during the multicenter, double-blind, investigator-initiated Comparing Alternative Ranibizumab Dosages for Safety and Efficacy in Retinopathy of Prematurity (CARE-ROP) randomized clinical trial, which compared 2 different doses of ranibizumab (0.12 mg vs 0.20 mg) for the treatment of ROP. The CARE-ROP trial screened and enrolled infants between September 5, 2014, and July 14, 2016. A total of 1046 wide-angle fundus images obtained from 19 infants at predefined study time points were analyzed. The analyses of VSS were performed between January 20, 2021, and November 18, 2022. An AI-based algorithm assigned a VSS between 1 (normal) and 9 (most severe) to fundus images. Analysis of VSS in infants with ROP over time and VSS comparisons between the 2 treatment groups (0.12 mg vs 0.20 mg of ranibizumab) and between infants who did and did not receive retreatment for ROP reactivation. Among 19 infants with ROP in the CARE-ROP randomized clinical trial, the median (range) postmenstrual age at first treatment was 36.4 (34.7-39.7) weeks; 10 infants (52.6%) were male, and 18 (94.7%) were White. The mean (SD) VSS was 6.7 (1.9) at baseline and significantly decreased to 2.7 (1.9) at week 1 (P < .001) and 2.9 (1.3) at week 4 (P < .001). The mean (SD) VSS of infants with ROP reactivation requiring retreatment was 6.5 (1.9) at the time of retreatment, which was significantly higher than the VSS at week 4 (P < .001). No significant difference was found in VSS between the 2 treatment groups, but the change in VSS between baseline and week 1 was higher for infants who later required retreatment (mean [SD], 7.8 [1.3] at baseline vs 1.7 [0.7] at week 1) vs infants who did not (mean [SD], 6.4 [1.9] at baseline vs 3.0 [2.0] at week 1). In eyes requiring retreatment, higher baseline VSS was correlated with earlier time of retreatment (Pearson r = -0.9997; P < .001). In this study, VSS decreased after ranibizumab treatment, consistent with clinical disease regression. In cases of ROP reactivation requiring retreatment, VSS increased again to values comparable with baseline values. In addition, a greater change in VSS during the first week after initial treatment was found to be associated with a higher risk of later ROP reactivation, and high baseline VSS was correlated with earlier retreatment. These findings may have implications for monitoring ROP regression and reactivation after anti-VEGF treatment.

FACTORS ASSOCIATED WITH REACTIVATION AFTER INTRAVITREAL BEVACIZUMAB OR RANIBIZUMAB THERAPY IN INFANTS WITH RETINOPATHY OF PREMATURITY.

To investigate the efficacy and risk factors of intravitreal antivascular endothelial growth factor injection (anti-VEGF therapy) for retinopathy of prematurity (ROP). We retrospectively reviewed 80 consecutive eyes of 43 patients with Type 1 ROP or worse who received anti-VEGF therapy during January 2012-February 2018. Patients were divided into those who were injected with 0.25 mg of bevacizumab (IVB group, 37 eyes) and 0.25 mg of ranibizumab (IVR group, 43 eyes). Serum VEGF concentrations of 18 patients were measured before and after IVR. Antivascular endothelial growth factor injection therapy reduced ROP activity in all eyes; however, 14 eyes (17.5%) exhibited reactivation. The reactivation rates of the IVB and IVR groups were 13.5% and 20.9%, respectively (P = 0.556). Multivariate logistic regression analysis showed that postmenstrual age ≤35 weeks at anti-VEGF therapy (P = 0.014) and aggressive posterior ROP (P = 0.044) was significantly associated with reactivation. Serum VEGF was significantly suppressed at Days 1 (P < 0.001) and 7 (P = 0.012) after IVR and returned to the preinjection level by Day 14 (P = 0.210). Both IVR and IVB seemed effective in reducing ROP activity. Reactivation after anti-VEGF therapy may be associated with younger postmenstrual age at anti-VEGF therapy and aggressive posterior ROP.

Effect of Repeated Intravitreal Ranibizumab and Aflibercept Injections on the Cornea in Patients with Age-Related Macular Degeneration.

Purpose To assess the effect of repeated intravitreal ranibizumab injections (RI) and aflibercept injections (AI) on the corneal endothelium and central corneal thickness (CCT) in patients with age-related macular degeneration (AMD). Materials and Methods In the retrospective study, 110 eyes of 106 patients, aged 52 to 93 years, were analyzed. Fifty eyes were treated only with RI (I group), and 60 eyes were treated only with AI (II group). Every patient received one intravitreal injection of 0.5 mg of ranibizumab once a month or 2 mg of aflibercept for 3 subsequent months. Each patient received only 3 injections during the whole observation period. Corneal analysis was obtained with the specular microscope. Examinations were performed before initial treatment, after each injection, and 6 months after the first injection. Analysis included corneal endothelial cell density (ECD), hexagonal cell percentage (% Hex), coefficient of variation (CoV), and CCT. Results There was a statistically significant ECD loss, regardless of the type of the anti-VEGF agent. The mean ECD value in the I group was 2397 ± 459 cells/mm2 before RI, 2389 ± 459 cells/mm2 after the first RI, 2386 ± 467 cells/mm2 after the second RI, 2378 ± 475 cells/mm2 after the third RI, and 2357 ± 460 cells/mm2 6 months after the first RI. The mean ECD value in the II group was 2448 ± 493 cells/mm2 before treatment, 2456 ± 498 cells/mm2 after the first AI, 2426 ± 496 cells/mm2 after the second AI, 2402 ± 488 cells/mm2 after the third AI, and 2348 ± 473 cells/mm2 6 months after the first AI. In comparison with the group treated with RI, the group treated with AI presented a greater ECD loss at each measuring point. The percentage of hexagonal cells was decreased in both groups. There was a slight increase in polymegathism in both treated groups. Ranibizumab proved to cause a small increase in CCT, while CCT remained unchanged in the aflibercept group. Conclusions Repeated intravitreal injections of 0.5 mg of ranibizumab or 2 mg of aflibercept can influence the morphology of the corneal endothelium but not CCT.

Combined Vitrectomy and Anti-VEGF Treatment for Stage 4 Retinopathy of Prematurity With Extensive Neovascular Proliferation.

To study the role of combined vitrectomy and intravitreal anti-vascular endothelial growth factor (VEGF) injection for stage 4 retinopathy of prematurity (ROP) with extensive neovascular proliferation. In a retrospective interventional study at a tertiary eye care center, 15 eyes (9 infants) with advanced stage 4 ROP underwent 25-gauge vitrectomy combined with intravitreal 0.625 mg of bevacizumab (n = 12) or 0.25 mg of ranibizumab (n = 3) injection and were followed up until 65 weeks' postconceptional age (PCA). The perinatal history, tractional retinal detachment (TRD) characteristics (zone, stage, and presence of "plus" disease), treatment details, and anatomical outcomes were reviewed. The main outcome measures were fibrovascular tissue and TRD regression and final macular status. Mean gestational age and birth weight were 28.5 ± 1.2 weeks and 1,167 ± 185 g, respectively. Thirteen eyes had zone I disease and 2 eyes had zone II disease. Thirteen eyes were stage 4A and 2 eyes were stage 4B ROP. The morphology was aggressive posterior ROP in 10 eyes. The mean PCA at surgery was 37.8 ± 2.3 weeks. Lensectomy was also performed in 2 eyes. Rapid fibrovascular tissue regression was seen in 14 eyes within 2 weeks, followed by TRD regression and macular vascularization, although 2 eyes had macular pucker formation. Persistent vitreous bleeding was present in 1 eye, which needed lavage, and eventually the TRD regressed. Disease reactivation was noted in 1 eye at 5 weeks and was managed with repeat intravitreal anti-VEGF injection. Anti-VEGF treatment combined with vitrectomy leads to rapid disease regression in advanced stage 4 ROP with extensive neovascular proliferation. [J Pediatr Ophthalmol Strabismus. 2020;57(1):61-66.].

Effect of Ranibizumab and Aflibercept on Best-Corrected Visual Acuity in Treat-and-Extend for Neovascular Age-Related Macular Degeneration

To our knowledge, this is the first randomized clinical trial to compare visual outcomes and injection loads between ranibizumab and aflibercept using an identical treat-and-extend (TE) regimen for neovascular age-related macular degeneration (nAMD). To report the results of the preplanned 12-month interim analysis of 2 predefined secondary efficacy end points of a randomized clinical trial. The Comparison of Ranibizumab and Aflibercept for the Development of Geographic Atrophy in (Wet) AMD Patients (RIVAL) trial was conducted in 24 sites in Australia and included 281 treatment-naive eyes from 281 participants with active choroidal neovascularization secondary to nAMD and a visual acuity letter score of 23 or greater who were recruited between April 11, 2014, and October 31, 2015. A preplanned interim analysis was performed at month 12. Best-corrected visual acuity (BCVA) assessors and the central reading center, which determined treatment intervals, were masked to treatment assignments. Participants were randomized (1:1) to receive intravitreal injections of 0.5 mg of ranibizumab or 2.0 mg of aflibercept. After receiving 3 initial monthly injections, participants entered the TE phase. Mean change in BCVA and the number of injections from baseline to month 12. Of 281 participants, 148 (52.7%) were women and the mean (SD) age was 77.7 (8.1) years. The baseline mean BCVA letter score (approximate Snellen equivalent) was 65.3 (20/50) in the ranibizumab arm and 65.1 (20/50) in the aflibercept arm. One hundred twenty-seven ranibizumab participants (90.1%) and 121 aflibercept participants (88.3%) completed month 12 with a mean (SD [Snellen equivalent]) BCVA letter score of 72.9 (15.5 [20/32]) and 70.5 (14.6 [20/40]), respectively. The mean change in BCVA letter scores from baseline to month 12 was 7.2 (95% CI, 5.5-8.9) for ranibizumab and 4.9 (95% CI, 3.1-6.6) for aflibercept (letter score difference, 2.3; 95% CI, -0.1 to 4.7; P = .06). The mean number of injections from baseline to month 12 was 9.7 in both the ranibizumab (SD, 2.8) and aflibercept (SD, 2.6) arms with a rate ratio of 1.00 (95% CI, 1.0-1.1; P = .86). Our findings suggest that neither aflibercept nor ranibizumab for nAMD are superior to the other regarding the average visual acuity gains and number of injections during 1 year in a TE regimen. Further follow-up to 2 years may determine if advantages of one over the other can be identified. Clinicaltrials.Gov identifier: NCT02130024.

Comparing Alternative Ranibizumab Dosages for Safety and Efficacy in Retinopathy of Prematurity

Anti-vascular endothelial growth factor (VEGF) therapies are a novel treatment option in retinopathy of prematurity (ROP). Data on dosing, efficacy, and safety are insufficient. To investigate lower doses of anti-VEGF therapy with ranibizumab, a substance with a significantly shorter systemic half-life than the standard treatment, bevacizumab. This randomized, multicenter, double-blind, investigator-initiated trial at 9 academic medical centers in Germany compared ranibizumab doses of 0.12 mg vs 0.20 mg in infants with bilateral aggressive posterior ROP; ROP stage 1 with plus disease, 2 with plus disease, or 3 with or without plus disease in zone I; or ROP stage 3 with plus disease in posterior zone II. Patients were recruited between September 2014 and August 2016. Twenty infants were screened and 19 were randomized. All infants received 1 baseline ranibizumab injection per eye. Reinjections were allowed in case of ROP recurrence after at least 28 days. The primary end point was the number of infants who did not require rescue therapy at 24 weeks. Key secondary end points included time-to-event analyses, progression of physiologic vascularization, and plasma VEGF levels. Stages of ROP were photodocumented and reviewed by an expert committee. Nineteen infants with ROP were enrolled (9 [47.4%] female; median [range] postmenstrual age at first treatment, 36.4 [34.7-39.7] weeks), 3 of whom died during the study (1 in the 0.12-mg group and 2 in the 0.20-mg group). Of the surviving infants, 8 (88.9%) (17 eyes [94.4%]) in the 0.12-mg group and 6 (85.7%) (13 eyes [92.9%]) in the 0.20-mg group did not require rescue therapy. Both ranibizumab doses were equally successful in controlling acute ROP (Cochran-Mantel-Haenszel analysis; odds ratio, 1.88; 95% CI, 0.26-13.49; P = .53). Physiologic intraretinal vascularization was superior in the 0.12-mg group. The VEGF plasma levels were not systematically altered in either group. This pilot study demonstrates that ranibizumab is effective in controlling acute ROP and that 24% of the standard adult dose (0.12 mg) appears equally effective as 40% (0.20 mg). Superior vascularization of the peripheral retina with 0.12 mg of ranibizumab indicates that the lower dose may be favorable. Unchanged plasma VEGF levels point toward a limited systemic drug exposure after ranibizumab. clinicaltrials.gov Identifier: NCT02134457 and clinicaltrialsregister.eu Identifier: 2013-002539-13.

SERUM LEVELS OF VASCULAR ENDOTHELIAL GROWTH FACTOR BEFORE AND AFTER INTRAVITREAL INJECTION OF RANIBIZUMAB OR CONBERCEPT FOR NEOVASCULAR AGE-RELATED MACULAR DEGENERATION.

To investigate the serum levels of vascular endothelial growth factor (VEGF) before and after intravitreal injection of conbercept or ranibizumab for neovascular age-related macular degeneration and polypoidal choroidal vasculopathy patients. This study is a prospective, interventional case series and involved 28 patients, 18 treated with 0.5 mg of conbercept and 10 treated with 0.5 mg of ranibizumab. Serum concentrations of VEGF were determined by enzyme-linked immunosorbent assay before the injection and at 1 day, 1 week, and 1 month after anti-VEGF treatments. The baseline serum VEGF level of the ranibizumab group was 367.11 ± 311.87 pg/mL, whereas that of the conbercept group was 315.06 ± 170.88 pg/mL (P = 0.653). In the conbercept group, VEGF level significantly decreased to 36.32 ± 72.11 pg/mL at 1 day (P = 0.03) and returned to 136.55 ± 144.62 pg/mL at 1 week (P = 0.03). At 1 month, the concentration increased to 334.48 ± 197.41 pg/mL and showed no significant difference compared with the baseline. In the ranibizumab group, the serum VEGF levels were 292.42 ± 239.80 pg/mL, 282.60 ± 201.36 pg/mL, and 308.83 ± 266.89 pg/mL at 1 day, 1 week, and 1 month after intravitreal injection, respectively. There was no significant difference in the ranibizumab group at each detection time point (P = 0.45). Conbercept significantly decreased serum VEGF level 1 day and 1 week after injection, but this effect was not sustained for 1 month. In contrast, ranibizumab had no significant effect on serum VEGF concentration changes. The reduction in serum VEGF by conbercept may affect its systemic safety profile.

Афлиберцепт в лечении резистентной полипоидной хориоидальной васкулопатии: краткосрочные результаты

Polypoid choroidal vasculopathy (PCV) is a rare subtype of age-related macular degeneration, characterized by a formation of a branching vascular network (BVN) and polyps. In a number of cases a resistance to the performed therapy was observed in particular using Ranibizumab. In its turn, the angiogenesis inhibitor Aflibercept with a relatively greater affinity for VEGF-A molecules had already demonstrated its efficacy in previously untreated patients with PCV. Purpose. To evaluate the first results of Aflibercept treatment in polypoid choroidal vasculopathy, resistant to a previous combined therapy. Material and methods. The prospective study included 8 patients (9 eyes) with treatment-resistant PCV (three or more intravitreal injections of 0.5mg of Ranibizumab monthly or in combination with photodynamic therapy (PDT) with Chlorin e6). One month after 3 monthly intravitreal injections of 2mg of Aflibercept, changes in visual acuity, central retinal sensitivity (CRS) and central retinal thickness (CRT), a resorption of the subretinal fluid, dome-shaped retinal pigment epithelial detachment, polyps and BVN were evaluated according to the OCT data, OCTangiography, fluorescein angiography (FAG) and indocyanine green angiography (ICGA). Results. Visual acuity before and after treatment did not show the statistically significant difference (0.5±0.2 and 0.6±0.2, respectively, p=0.4). The CRS demonstrated a pronounced positive dynamic from 21.5±2.7 to 24.0±3.7dB (p=0.02). Resorption of the subretinal fluid was noted with a statistically significant decrease in the CRT from 336.3±55.1 to 284.3±60.1µm (p=0.03). Among 6 eyes with dome-shaped RPE detachment, two showed a complete attachment, and three a partial attachment, in one patient the height of retinal detachment increased. According to ICGA, OCT and OCT angiography data, the regression of polyps was detected in 6 of 9 eyes, however, the BVN still persisted. Conclusion. Short-term results of Aflibercept treatment in patients with resistant PCV showed its efficacy in relation to the reduction of exudation, the polyps closure and the increase of central retinal sensitivity.

Effects of intravitreal ranibizumab on the untreated eye and systemic gene expression profile in age-related macular degeneration.

The purpose of this study was to evaluate the systemic effects of intravitreal ranibizumab (Lucentis) treatment in patients with neovascular age-related macular degeneration (AMD). The impact of intravitreal ranibizumab injections on central retinal thickness (CRT) of treated and contralateral untreated eyes, and differences in gene expression patterns in the peripheral blood mononuclear cells were analyzed. The study included 29 patients aged 50 years old and over with diagnosed neovascular AMD. The treatment was defined as 0.5 mg of ranibizumab injected intravitreally in the form of one injection every month during the period of 3 months. CRT was measured by optical coherence tomography. The gene expression profile was assigned using oligonucleotide microarrays of Affymetrix HG-U133A. Studies have shown that there was a change of CRT between treated and untreated eyes, and there were differences in CRT at baseline and after 1, 2, and 3 months of ranibizumab treatment. Three months after intravitreal injection, mean CRT was reduced in the treated eyes from 331.97±123.62 to 254.31±58.75 μm, while mean CRT in the untreated fellow eyes reduced from 251.07±40.29 to 235.45±36.21 μm at the same time. Furthermore, the research has shown that among all transcripts, 3,097 expresses change after the ranibizumab treatment in relation to controls. Among these transcripts, 1,339 were up-regulated, whereas 1,758 were down-regulated. Our results show the potential systemic effects of anti-VEGF therapy for AMD. Moreover, our study indicated different gene expression in peripheral blood mononuclear cells before and after intravitreal ranibizumab treatment.

Morphologic Changes in Patient with Drusen and Drusenoid Pigment Epithelial Detachment after Intravitreal Ranibizumab for Choroidal Neovascular Membrane : A Case Report.

The authors present a case of morphologic changes of drusen and drusenoid pigment epithelial detachment (DPED) after treating choroidal neovascularization (CNV) using ranibizumab in age-related macular degeneration (AMD). A 71-year-old woman has noticed mild visual acuity deterioration in the right eye for several months. She was presented with some drusen and DPED associated with CNV. This patient was given intravitreal injection of 0.5 mg of ranibizumab five times at monthly intervals for treating CNV. DPED in the temporal and drusen in the superior to macula were diminished, which continued up to 2 months. Intravitreal ranibizumab injection may have influenced with diminishment of drusen and DPED. After 2 months, CNV was recurred.

Drilling Deeper for Treatment Choices in Diabetic Macular Edema

Afterdecadesofusing focal/grid laserphotocoagulation to reduce the riskofvision losswithdiabeticmacularedema(DME), thecurrent therapyhasshifted to intravitreal injectionsofanti– vascular endothelial growth factor (VEGF) agents, which can result in gains in visual acuity (VA). Investigators from theDiabetic Retinopathy Clinical ResearchNetwork1 report in this issueof JAMAOphthalmology the findings fromthe secondary analyses of data previously reported in a comparative trial of 3 anti-VEGFagents—aflibercept, bevacizumab, and ranibizumab—for the treatment of DME.2 The current report examines the1-yearoutcomesof subgroups thatwerebothprespecified and post hoc.1 The comparative trial randomized 660 participants with DME into 3 groups: participants received 0.05-mL intravitreal injections of 2 mg of aflibercept, 1.25 mg of bevacizumab, or 0.3 mg of ranibizumab.2 All 3 drugs resulted in substantial improvement, on average, in VA at 1 year, with mean improvement occurring by 1 month. Prespecified subgroup analyses were based on baseline VA, worse VA (Snellen equivalent of 20/50 or worse), or better VA (Snellen equivalent of 20/32 or 20/40). All 3 agents were considered to have similar effects on VA for participants whose baseline VA was 20/30 or 20/40. However, for participants whose baseline VA was 20/50 or worse, improvement in VA was greatest with aflibercept while the effects of ranibizumab and bevacizumab on VA were similar. In addition, the participants who received aflibercept also required less supplemental focal/grid laser photocoagulation than did the patients who received ranibizumab or bevacizumab. In thecurrent report, additional exploratoryanalyseswere conducted, again stratified by baseline VA, to evaluate the 1-year VA outcomes in greater detail.1 In addition to themean VA gain at 1 year, the proportion of participants experiencing visual gain or loss of 10, 15, or more letters were previously published.2 The additional data presented included an unusualdetailed listingofVAoutcomesat 1 year, includinganalyses of the proportion of participants achieving VA of 20/20 at 1 year in each of the treatment groups. Post hoc analyseswere alsoconductedbasedonstratificationbybaseline retinal thickness as measured by optical coherence tomography in addition tobaselineVA.Central subfield thicknesswasdivided into thicker (>400μm)or thinner (250-399μm)categories.Thescatter plot in eFigure 1 in the current report1 showedonly amodest correlationof retinal thicknesswithVA, similar to the scatterplotpublished inastudypreviously reportedbytheDiabetic Retinopathy Clinical Research Network.3 Participants with thickenedor thinned retinamayhaveawide rangeofVAs.The current analyses showed separate interactions of baseline VA with treatment and baseline central subfield thickness with treatment, but when both 2-way interactions were included in the analyses, only baseline VA remained statistically significant.1 It is not surprising that, regardless of central subfield thickness, baseline VA remains the most important factor in determining the visual outcomes at 1 year for the treatment, given themodest correlationwithVAof retinal thickness as measured by optical coherence tomography. Despite these findings in the subgroup analyses, the investigators expressed concern about the efficacy of bevacizumab.1Asnoted intheabstract, for thesubgroupofeyes with better initial VA and thicker central subfield thickness, “some VA outcomesmay beworse in the bevacizumab group than in theafliberceptandranibizumabgroups.”1Do thesenew data persuade us that there are clinically important differences among the 3 anti-VEGF agents, especially for bevacizumab? I concurwith the investigators’ ownstatements about thesedata: “Given theexploratorynatureof theseanalysesand the small sample size within subgroups, caution is suggested when using the data to guide treatment considerations for patients.”1 These data cannot provide support to further differentiate the effects of the 3 treatments. In fact, these data fully support the investigators’ initial conclusion that, for persons with DME presenting with better initial VA, all 3 antiVEGF agents were appropriate while the greatest visual gain was achieved with aflibercept treatment in participants presenting with the poorest VA. The proportion of persons in the general population presenting with DME with visual impairment of 20/50 or worse is difficult to ascertain because clinical trials have limitations on the degree of VA for patient eligibility. Population-based studiesdonothavesufficientnumbersofpersonsaffectedwith DME to provide reliable statistics (R. Klein, MD, written communication, August 13, 2015). However, the Early Treatment Diabetic Retinopathy Study,4 which was a clinical trial conducted in the 1980s that acceptedparticipantswithDMEwith a variety of levels of VA and with no lower limits on VA, suggested that 75%of patients presenting to a general clinicwith DMEhave a VA of 20/40 or better. One could assume that this proportionwouldbemarkedly increased in thepresent, as the medical care of glycemic andbloodpressure control andmanagement of dyslipidemia for persons with diabetes mellitus have vastly improved over the decades. Regardless of the precise number of personswith varying degrees of baseline VA seeking treatment for DME, the issues surrounding compounding pharmacies for bevacizumab, or types of health insurance coverage, bevacizumab remains an important player in this trio of anti-VEGF therapies. Because of itsmarkedly reduced cost andbecause of the findings from thiscomparative trial,bevacizumabstill canbea first-line treatRelated article page 127 1-Year Efficacy of Anti-VEGF Agents in Diabetic Macular Edema Original Investigation Research

Effects of a single intravitreal injection of aflibercept and ranibizumab on glomeruli of monkeys.

PurposeIt is known that endothelial cells in the kidney are also strongly VEGF-dependent. Whether intravitreal drugs can be detected within the glomeruli or affect VEGF in glomerular podocytes is not known. Therefore, the aim of this pilot study was to investigate the effects of a single intravitreal injection of aflibercept and ranibizumab on glomeruli of monkeys.MethodsThe kidneys of eight cynomolgus monkeys, which were intravitreally injected either with 2 mg of aflibercept or with 0.5 mg of ranibizumab, were investigated one and seven days after injection. Two animals served as controls. The distribution of aflibercept, ranibizumab and VEGF was evaluated using anti-Fc- or anti-F(ab)-fragment and anti-VEGF antibodies respectively. The ratio of stained area/nuclei was calculated using a semi-quantitative computer assisted method. Glomerular endothelial cell fenestration was quantified in electron microscopy using a systematic uniform random sampling protocol and estimating the ratio of fenestrae per µm.ResultsCompared to the controls, the anti-VEGF stained area/nuclei ratio of the ranibizumab-treated animals showed no significant changes whereas the stained areas of the aflibercept-treated monkeys showed a significant decrease post-treatment. Immune reactivity (IR) against aflibercept or ranibizumab was detected in aflibercept- or ranibizumab treated animals respectively. The number of fenestrations of the glomerular endothelial cells has shown no significant differences except one day after aflibercept injection in which the number was increased.ConclusionSurprisingly, both drugs could be detected within the capillaries of the glomeruli. After a single intravitreal injection of aflibercept, VEGF IR in the podocytes was significantly reduced compared to controls. Ranibizumab injection had no significant effect on the glomeruli's VEGF level. Whether this is caused by aflibercept's higher affinity to VEGF or because it is used in a higher stoichiometric concentration compared to ranibizumab remains to be investigated.

Collateral vessel presence in branch and central retinal vein occlusions and their impact on visual acuity and anatomical gains: a retrospective analysis.

To evaluate the incidence of collateral vessel formation and to determine their impact on best-corrected visual acuity and central foveal thickness in patients with branch or central retinal vein occlusion (BRVO, CRVO) receiving 0.3 mg or 0.5 mg of ranibizumab, or sham. This retrospective analysis was performed in patients with macular edema secondary to retinal vein occlusion who received 6 monthly intravitreal injections of ranibizumab (0.3 mg or 0.5 mg), or sham, followed by 6 months of as-needed treatment. Collateral vessel presence, change from baseline best-corrected visual acuity, and change from baseline central foveal thickness were assessed at baseline and months 3, 6, 9, and 12. At month 12, 19.6% of BRVO patients receiving sham/0.5 mg and 16.7% receiving ranibizumab (0.3 mg and 0.5 mg pooled) manifested collaterals at the disk, whereas 48.2% and 47.2% displayed collaterals within the retina, respectively. In CRVO patients, 57.9% and 59.2% of all groups manifested collaterals on the disk, respectively, whereas 12.1% and 15.1% displayed collaterals within the retina. Mean best-corrected visual acuity gain in ranibizumab-treated BRVO and CRVO patients was similar, irrespective of collaterals within the retina ( P > 0.05; CRVO: P > 0.05). The location of collaterals differed between retinal vein occlusion subtypes and ranibizumab treatment did not affect collateral vessel incidence. The presence of collaterals did not seem to impact best-corrected visual acuity gains at month 12 in both BRVO and CRVO patients receiving ranibizumab, whereas generally greater central foveal thickness reductions were observed with presence of collaterals in BRVO patients.

RANIBIZUMAB FOR MACULAR TELANGIECTASIA TYPE 2 IN THE ABSENCE OF SUBRETINAL NEOVASCULARIZATION

To evaluate the effects of 0.3 mg or 0.5 mg of ranibizumab in eyes with macular telangiectasia type 2 without subretinal neovascularization. Ten eyes were randomized to either 0.3 mg or 0.5 mg ranibizumab group in 1 eye only. Study eye received ranibizumab at baseline and at Months 1 and 2. Injections at Months 3, 4, and 5 were at investigator's discretion. Participants were followed monthly through 6 months with best-corrected visual acuity, fluorescein angiography, and optical coherence tomography. For study eyes at baseline, median best-corrected visual acuity letter score was 60 (20/64 Snellen equivalent) and central subfield retinal thickness was 181.5 μm. Median number of injections was six. Median change in best-corrected visual acuity at Month 3 was 4 letters (range: -5 to 9 letters) at both doses in the study eye and 3 letters (range: -10 to 5 letters) in the untreated fellow eye. At Month 3, retinal leakage decreased 0.87 disk area and 0.76 disk area for 0.3 mg and 0.5 mg ranibizumab, respectively. Median change in central subfield retinal thickness was 1 μm and -11 µm for 0.3 mg and 0.5 mg ranibizumab, respectively. Ranibizumab (0.3 mg or 0.5 mg) decreases leakage secondary to macular telangiectasia type 2, but accompanying improvements in best-corrected visual acuity appear similar to improvements in the untreated fellow eye where retinal thickness is relatively unchanged.

Different effects of intravitreally injected ranibizumab and aflibercept on retinal and choroidal tissues of monkey eyes

BackgroundSince there is evidence that the Fc domain of antivascular endothelial growth factor drugs may cause unexpected consequences in retinal and choroidal vessels, the effects of intravitreal ranibizumab and aflibercept...

PROSPECTIVE EVALUATION OF THE INCIDENCE AND RISK FACTORS FOR THE DEVELOPMENT OF RPE TEARS AFTER HIGH- AND LOW-DOSE RANIBIZUMAB THERAPY

To prospectively determine the incidence and risk factors for retinal pigment epithelial (RPE) tears in eyes with vascularized pigment epithelial detachments (PED) and exudative age-related macular degeneration receiving antivascular endothelial growth factor therapy. Eyes were prospectively randomized into 1 of 4 arms: 1) 0.5 mg of ranibizumab monthly for 12 months; 2) 0.5 mg of ranibizumab monthly for 3 months and then pro re nata on the basis of clinical and optical coherence tomography-guided indications; 3) high-dose 2.0 mg of ranibizumab monthly for 12 months; or 4) 2.0 mg of ranibizumab monthly for 3 months and then pro re nata thereafter. All PEDs were measured for height, greatest linear diameter, and surface area at baseline. The incidence of RPE tears in the entire 4-arm cohort was determined at the end of 12 months. Eyes were divided into two groups (tear vs. nontear) and statistically compared to determine risk factors for the development of RPE tear. Of 37 eyes, a total of 5 developed postranibizumab RPE tears during the course of the study (incidence 14%). Four of the 5 tears occurred in the high-dose 2.0-mg groups. Baseline PED height, surface area, and greatest linear diameter were significantly greater in the group that developed RPE tears versus the nontear group (P = 0.018, 0.031, and 0.048, respectively). There were significantly more eyes with PED height >550 microns in the RPE tear group (4 of 5, 80%) compared with the nontear group (9 of 32, 18%) (P = 0.042). The presence of PED height >550 microns was associated with an increased tear rate from 14% to 31%. Furthermore, retrospective identification of a ring sign or Grade 1 tear at baseline, in addition to PED height >550 microns, was associated with a further increase in the tear rate to 67%. In this study, the prospective incidence of RPE tears was ∼14%. A baseline PED height >550 microns and presence of a Grade 1 tear, or positive ring sign, were identified as high-risk factors for the subsequent development of an RPE tear.