The Effects of Treatment Regimen on the Initial Management of Macular Neovascularization Subtypes in Age-Related Macular Degeneration.

INTRODUCTION: The aim of this study was to evaluate the effect of initial treatment regimen individualization (pro re nata or treat-and-extend [TAE]), according to macular neovascularization (MNV) subtype, on the functional and anatomical response in neovascular age-related macular degeneration (nAMD). The secondary objective was to compare the treatment burden between each MNV subtype. METHODS: Consecutive treatment-naïve nAMD patients were retrospectively included. MNV subtype was graded by 2 independent blinded investigators on multimodal imaging. Functional and anatomical outcomes were analysed according to treatment regimen and MNV subtypes. RESULTS: A total of 281 eyes from 243 patients were included in the study. According to the treatment regimen, there was no significant difference in best-corrected visual acuity gain within the first 2 years of treatment for type 1 (p = 0.106) and type 3 MNV (p = 0.704). Conversely, there was a significant difference in favour of TAE regimen for type 2 (p = 0.017) and type 4 MNV (p = 0.047). Type 1 MNV had a higher proportion of visits with subretinal fluid (p = 0.0007) but not with intraretinal fluid (p = 0.22). The mean interval between the last 2 injections was significantly shorter for type 1 MNV (p = 0.0045). CONCLUSION: The individualization of the initial treatment protocol according to MNV subtype can improve the functional outcome and may decrease the treatment burden.

RISK OF INTRAOCULAR INFLAMMATION AFTER INJECTION OF ANTIVASCULAR ENDOTHELIAL GROWTH FACTOR AGENTS: A Meta-analysis.

PURPOSE: This meta-analysis investigates the incidence of intraocular inflammation (IOI) after intravitreal antivascular endothelial growth factor injections in neovascular age-related macular degeneration. METHODS: A systematic search was performed on Ovid MEDLINE, Embase, and Cochrane Central from January 2005 to April 2021. Randomized controlled trials comparing IOI after intravitreal bevacizumab, ranibizumab, brolucizumab, or aflibercept in neovascular age-related macular degeneration were included. Primary outcomes were sight-threatening IOI, final best-corrected visual acuity, and change in best-corrected visual acuity from baseline. Secondary outcomes included the incidence of other IOI events. Meta-analysis was performed using a random-effects model. RESULTS: Overall, 11,460 unique studies were screened, of which 14 randomized controlled trials and 6,759 eyes at baseline were included. There was no difference between agents for the risk of endophthalmitis and retinal vascular occlusion. Compared with aflibercept, brolucizumab had a higher incidence of generalized IOI (risk ratio = 6.24, 95% confidence interval = [1.40-27.90]) and vitreous haze/floaters (risk ratio = 1.64, 95% confidence interval = [1.00-2.67]). There were no significant differences between comparators for other secondary end points. CONCLUSION: There was no difference in the risk of severe sight-threatening IOI outcomes between intravitreal antivascular endothelial growth factor agents. There was a significantly higher risk of generalized IOI after brolucizumab relative to aflibercept. Our results alongside other recent safety findings suggest the need for further investigation in the risk-benefit profile of brolucizumab for the treatment of neovascular age-related macular degeneration.

Vascular endothelial growth factor-A level in human breast milk after intravitreal injection of ranibizumab: a case report.

BACKGROUND: Ranibizumab is one of intravitreal anti-vascular endothelial growth factor agents. It is applied in the treatments of choroidal neovascularization, age-related macular degeneration, diabetic macular edema, and macular edema secondary to retinal vein occlusion. Preliminary evidence suggests that intravitreal ranibizumab may enter the plasma and human breast milk in very low-level concentration. As a precaution, breastfeeding is not recommended during the treatment of intravitreal injection of ranibizumab. There are limited data regarding the change of anti-vascular endothelial growth factor concentration in human breast milk after intravitreal injection of ranibizumab, especially in the first 24 h after injection. The purpose of this report is to analyse the concentration change of vascular endothelial growth factor-A in human breast milk with time, in the short term after intravitreal injection of ranibizumab. CASE PRESENTATION: In June 2018, a 30-year-old patient breastfeeding a six-month-old baby was diagnosed with choroidal neovascularization of left eye in Eye Hospital of Wenzhou Medical University. She received four administrations of 0.5 mg intravitreal injection of ranibizumab of the left eye, and breast milk was collected just before the injection, and 1-3, 6, 12, 24, 48, and 72 h after intravitreal injection, and assessed for vascular endothelial growth factor-A concentration. The change in vascular endothelial growth factor-A concentration in human breast milk showed the same trend after each injection, decreasing significantly within 6-12 h (about 20-30% lower), and increasing to pre-injection level by 24 h after injection. CONCLUSIONS: The concentration of vascular endothelial growth factor-A in human breast milk of a mother who continues lactating dropped initially and rose to pre-injection level about 24 h after intravitreal injection of ranibizumab. The data may offer more information to evaluate the impact of anti-vascular endothelial growth factor agent intravitreal injection of lactating mothers and their breastfed infants.

A model to quantify the influence of treatment patterns and optimize outcomes in nAMD.

Neovascular age-related macular degeneration (nAMD) is a progressive retinal disease that often leads to severe and permanent vision loss. Early initiation of anti-vascular endothelial growth factor (anti-VEGF) therapy has been shown to preserve vision in nAMD patients. Concurrently, treatment outcomes in real-world are inferior to those reported in clinical trials. The most likely reasons observed are fewer treatment-intensity in routine clinical practice than in clinical trials. The other possibility could be the delay in starting treatment and the re-treatment interval. Although a negative impact of aforementioned parameters seems obvious, quantitative impact measures remain elusive in a real-world setting due to a lack of an 'optimal treatment' control group. To overcome this shortcoming, we developed, validated, and applied a model to assess and quantify the impact of anti-VEGF administration variables on visual acuity development in a prospective nAMD patient cohort. The model was further applied to probe the impact of the COVID-19 pandemic on visual progressions in nAMD patients. The presented model paves the way to systematically explore and evaluate realistic interventions in the current treatment paradigm, that can be adopted in routine clinical care.

Design of a Novel Fab-Like Antibody Fragment with Enhanced Stability and Affinity for Clinical use.

With increasing interest in applying recombinant monoclonal antibodies (mAbs) in human medicine, engineered mAb fragments with reduced size and improved stability are in demand to overcome current limitations in clinical use. Herein, a novel Fab-like antibody fragment generated via an in silico-based engineering approach where the CH1 and CL domains of Fab are replaced by the IgG1 CH3 domains is described. This construct, designated as FabCH3, maintains the natural N-terminus and C-terminus of IgG antibody, can be expressed at a high level in bacterial cells and, importantly, exhibits much higher stability and affinity than the parental Fab when tested in a mesothelin-specific Fab m912, as well as a vascular endothelial growth factor A (VEGFA)-specific Fab Ranibizumab (in vivo). The high-resolution crystal structures of m912 FabCH3 and m912 Fab are determined, and the comparative analysis reveals more rigid structures in both constant domains and complementarity-determining regions of FabCH3, explaining its enhanced stability and affinity. Overall, the stabilized FabCH3 described in this report provides a versatile platform for engineering Fab-like antibody fragments with higher stability and antigen-binding affinity that can be used as a distinct class of antibody therapeutics.

Arm-to-retina time predicts visual outcome of anti-vascular endothelial growth factor treatment for macular edema due to central retinal vein occlusion.

To explore the factors associated with best-corrected visual acuity (BCVA) after anti-vascular endothelial growth factor (anti-VEGF) treatment for macular edema secondary to central retinal vein occlusion (CRVO). We retrospectively reviewed the medical charts of 22 eyes of 22 treatment-naïve patients with CRVO diagnosed between September 2014 and December 2020. They received anti-VEGF treatment and follow-up for > 12 months. Mean patient age was 64.3 years; 13 (59.1%) were men. Eyes with baseline arm-to-retina (AR) time ≥ 16 s had better BCVA at 12 months (adjusted for baseline BCVA and age; B, - 0.658; 95% confidence interval - 1.058 to - 0.257; P = 0.003), greater mean BCVA change (P = 0.006), lower frequency of residual macular edema at 12 months (P = 0.026) and recurrent and/or unresolved macular edema during 12 months (P = 0.046), and higher frequency of reduction in central retinal thickness ≥ 150 µm at 1 and 12 months (both P = 0.046). Delayed AR time was associated with a better visual outcome and macular edema improvement in CRVO after anti-VEGF treatment regardless of initial BCVA and age. Our results may help understand the pathogenesis and predict the visual prognosis of patients before anti-VEGF therapy initiation.

Diabetic macular edema and proliferative diabetic retinopathy treated with anti-vascular endothelial growth factor under the reimbursement policy in Taiwan.

The purpose of this retrospective interventional case series is to compare the functional and anatomical outcomes in eyes with diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR) treated intravitreally with aflibercept or ranibizumab under the Taiwan National Insurance Bureau reimbursement policy. 84 eyes were collected and all eyes were imaged with spectral-domain optical coherence tomography (SD-OCT), color fundus photographs (CFPs), and fluorescein angiography (FA). At 24 months after therapy initiation, the logMAR BCVA improved from 0.58 ± 0.33 to 0.47 ± 0.38 (p < 0.01), the CRT decreased from 423.92 ± 135.84 to 316.36 ± 90.02 (p < 0.01), and the number of microaneurysms decreased from 142.14 ± 57.23 to 75.32 ± 43.86 (p < 0.01). The mean injection count was 11.74 ± 5.44. There was no intergroup difference in logMAR BCVA (p = 0.96), CRT (p = 0.69), or injection count (p = 0.81). However, the mean number of microaneurysms was marginally reduced (p = 0.06) in eyes treated with aflibercept at the end of the follow-up, and the incidence rates of supplementary panretinal photocoagulation (PRP) (p = 0.04) and subthreshold micropulse laser (SMPL) therapy sessions (p = 0.01) were also reduced. Multivariate analysis revealed that only initial logMAR BCVA influenced the final VA improvements (odds ratio (OR) 0.49, 95% confidence interval (CI) 0.21 ~ 0.93, p < 0.01); in contrast, age (OR - 0.38, 95% CI - 6.97 ~ - 1.85, p < 0.01) and initial CRT (OR 0.56, 95% CI 0.34 ~ 0.84, p < 0.01) both influenced the final CRT reduction at 24 months. To sum up, both aflibercept and ranibizumab are effective in managing DME with PDR in terms of VA, CRT and MA count. Eyes receiving aflibercept required less supplementary PRP and SMPL treatment than those receiving ranibizumab. The initial VA influenced the final VA improvements at 24 months, while age and initial CRT were prognostic predictors of 24-month CRT reduction.

Vascular endothelial growth factor inhibitors for predominantly Caucasian myopic choroidal neovascularization: 2-year treatment outcomes in clinical practice: data from the Fight Retinal Blindness! Registry.

PURPOSE: To report the 24-month outcomes of vascular endothelial growth factor (VEGF) inhibitors for myopic choroidal neovascularization (mCNV) in predominantly Caucasian eyes in routine clinical practice. METHODS: Retrospective analysis of treatment-naïve eyes starting intravitreal injection of VEGF inhibitors of either bevacizumab (1.25 mg) or ranibizumab (0.5 mg) for mCNV from 1 January 2006 to 31 May 2018 that were tracked in the Fight Retinal Blindness! registry. RESULTS: We identified 203 eyes (bevacizumab-85 and ranibizumab-118) of 189 patients. The estimated mean (95% CI) change in VA over 24 months for all eyes using longitudinal models was +8 (5, 11) letters with a median (Q1, Q3) of 3 (2, 5) injections given mostly during the first year. The estimated mean change in VA at 24 months was similar between bevacizumab and ranibizumab [+9 (5, 13) letters for bevacizumab versus +9 (6, 13) letters for ranibizumab; p = 0.37]. Both agents were also similar in the mCNV activity outcomes, treatment frequency and visit frequency. CONCLUSIONS: The 24-month treatment outcomes of VEGF inhibitors for mCNV were favourable in this largest series yet reported of predominantly Caucasian eyes in routine clinical practice, with approximately two lines of visual gain and a median of three injections given mostly during the first year. These outcomes are similar to those reported for predominantly Asian eyes. Bevacizumab appeared to be as safe and effective as ranibizumab.

Etiology, Treatment Patterns, and Outcomes for Choroidal Neovascularization in the Pediatric Population: An Intelligent Research in Sight (IRIS®) Registry Study.

OBJECTIVE: Choroidal neovascularization (CNV) is a rare, but devastating, cause of vision loss in children, with most current publications limited to small case series. Using a large clinical registry allowed us to understand the most common causes of this disease and the visual outcomes. DESIGN: Retrospective analysis. PARTICIPANTS: Patients younger than 18 years in the Intelligent Research in Sight Registry diagnosed with CNV between 2013 and 2019. METHODS: Cases were identified based on International Classification of Diseases, Ninth and Tenth Revisions, diagnosis codes for CNV or CNV-related etiology and Current Procedural Terminology treatment codes. MAIN OUTCOME MEASURES: Etiology of CNV, treatment patterns, and visual outcomes. RESULTS: Two thousand three hundred fifty-three eyes with pediatric CNV were identified. The most common identifiable causes of pediatric CNV were posterior uveitis or inflammatory chorioretinal disease (19.4%), myopia (18.4%), hereditary dystrophy (5.4%), chorioretinal scar (4.2%), choroidal rupture (3.5%), optic nerve drusen (3.2%), osteoma (1.9%), and solar retinopathy (0.2%). In 38.2% of eyes, CNV was idiopathic, and in 5.7% of eyes, multiple causes were coded. One thousand forty-one eyes (44.4%) underwent treatment. The mean age of mean age of patients whose eyes received treatment 13.6 ± 3.5 years compared with 12.4 ± 4.1 years for the untreated group (P < 0.001). In 88.9% of eyes, anti-vascular endothelial growth factor (VEGF) injections were administered, 7.9% of eyes received laser therapy, 0.3% of eyes received photodynamic therapy, and 2.9% of eyes received combination therapy. In the eyes receiving anti-VEGF agents, 68.4% required 3 injections or fewer (P < 0.0001). Eyes undergoing treatment exhibited worse baseline visual acuity (VA) than eyes that did not undergo treatment (0.62 ± 0.50 logarithm of the minimum angle of resolution [logMAR] vs. 0.44 ± 0.50 logMAR; P < 0.0001). Visual acuity in the treatment group improved significantly from 0.62 ± 0.50 logMAR at baseline to 0.39 ± 0.43 logMAR at year 1 (P < 0.0001). Visual acuity in the untreated group improved significantly from 0.44 ± 0.50 logMAR at baseline to 0.34 ± 0.44 logMAR at year 1 (P < 0.001). Treated eyes showed a statistically significant higher odds of exhibiting a 2-line vision improvement or better compared with the untreated group at 12 months regardless of treatment type and after controlling for baseline VA (odds ratio, 2.4; P < 0.0001). CONCLUSIONS: CNV is a rare, sight-threatening condition in children, with the most common causes being idiopathic, inflammatory chorioretinal disease, and myopia. Eyes undergoing treatment tended to be in older patients and showed worse baseline VA compared with eyes that did not undergo treatment. Those that were treated experienced significant improvement in vision that was maintained in the long term.

OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY IMAGING OF CHOROIDAL NEOVASCULARIZATION SECONDARY TO CHOROIDAL RUPTURE TREATED BY INTRAVITREAL RANIBIZUMAB.

PURPOSE: To describe optical coherence tomography angiography findings at baseline and during the follow-up of choroidal neovascularization secondary to choroidal rupture (CR) in a patient with kidney transplant treated by a single intravitreal injection of ranibizumab. METHODS: The clinical course, conventional multimodal imaging findings including ultra-widefield fundus color photography and fundus autofluorescence (Optos California, Marlborough, MA), spectral-domain optical coherence tomography (SD-OCT Spectralis; Heidelberg Engineering, Heidelberg, Germany), fluorescein angiography (FA; Heidelberg Engineering, Heidelberg, Germany), indocyanine green angiography ,and optical coherence tomography angiography (Plex-Elite, Carl Zeiss Meditec, Inc, Dublin, CA) findings at baseline and during the follow-up of a patient with choroidal neovascularization secondary to CR. RESULTS: A 19-year-old young man with a history of blunt trauma presented with acute visual decline of the right eye. He had a systemic history of kidney transplant. His best-corrected visual acuity was 20/200 in the right eye and 20/20 in the left eye at baseline. Funduscopic examination and ultra-widefield fundus autofluorescence imaging revealed a double vertical macular lesion corresponding to a CR in the right eye. Spectral-domain optical coherence tomography, fluorescein angiography, and indocyanine green angiography revealed active Type 2 choroidal neovascularization secondary to the CR. Optical coherence tomography angiography showed a high-flow neovascular network consistent with conventional multimodal imaging. One month after intravitreal injection of ranibizumab, bestcorrected visual acuity was 20/100, optical coherence tomography angiography showed a contraction and remodeling of the neovascular flow, and exudative signs disappeared on multimodal imaging. No side effect was detected. CONCLUSION: Optical coherence tomography angiography is able to detect choroidal neovascularization secondary to CR at baseline and during the follow-up after a single intravitreal injection of ranibizumab. Ranibizumab was effective in the treatment of this sight-threatening lesion in a patient with a history of kidney transplant.

Early Predictive Factors of Visual Loss at 1 Year in Neovascular Age-Related Macular Degeneration under Anti-Vascular Endothelial Growth Factor.

PURPOSE: To evaluate early predictive factors of visual loss in patients treated with anti-vascular endothelial growth factor (VEGF) injections under an as-needed regimen for neovascular age-related macular degeneration (AMD). DESIGN: Post hoc analysis from the randomized controlled trial Groupe d'Evaluation Français Avastin versus Lucentis (GEFAL). PARTICIPANTS: A total of 393 patients with neovascular AMD. METHODS: The present analysis is based on 1-year data from patients included in the study. Patients were separately categorized according to the best-corrected visual acuity (BCVA) change at 3 months and 1 year into 3 trajectories: (1) patients with no vision loss ≥5 letters at 3 months and 1 year (absence of loss ≥5 letters); (2) patients with no vision loss ≥5 letters at 3 months but loss ≥5 letters at 1 year (secondary loss ≥5 letters); and (3) patients with vision loss ≥5 letters at 3 months and 1 year (initial loss ≥5 letters). MAIN OUTCOME MEASURES: The following factors were evaluated at baseline and 3 months: age, sex, BCVA, presence of fluid, central macular thickness, angiographic choroidal neovascularization (CNV) subtype, CNV area measured in disc area on fluorescein angiography, and number of intravitreal injections. RESULTS: An absence of loss ≥5 letters was found in 225 patients (57.3%), a secondary loss ≥5 letters after 3 months was found in 109 patients (27.7%), and an initial loss ≥5 letters was found in 59 patients (15%). Baseline characteristics were comparable among the 3 groups except for the total CNV area, which was larger in the initial and secondary loss groups (P = 0.0412). At 3 months, a significant association was found between presence of subretinal fluid (SRF) (P = 0.0318) and vision loss ≥5 letters, and an even stronger significant association between the presence of intraretinal fluid (IRF) (P = 0.0066) and vision loss ≥5 letters. CONCLUSIONS: In the present study, we found that a large CNV area at baseline was significantly associated with initial or secondary loss of visual acuity ≥5 letters despite anti-VEGF injection. The presence of fluid, both SRF and IRF, at 3 months was found in patients with poorer trajectories.

Effect of cataract surgery on wet age-related macular degeneration activity.

BACKGROUND: Wet age-related macular degeneration (AMD) and age-related cataract are often coexisting causes of visual impairment. Yet, the timing of cataract surgery in wet AMD patients is controversial. METHODS: One hundred and eleven eyes of 111 patients with wet AMD underwent cataract surgery at Helsinki University Hospital in Finland during 2014-2018. Best-corrected visual acuity and central subfield macular thickness (CSMT) were analysed at the time of wet AMD diagnosis, at the last recording prior to cataract surgery and at the first recording and at 1 year after surgery. The cumulative number of antivascular endothelial growth factor (anti-VEGF) injections at surgery, systemic and topical medication and postoperative anti-VEGF burden were recorded. RESULTS: Mean age was 78.9 ± 5.6 years at the time of surgery. Central subfield macular thickness (CSMT) significantly decreased (280.1 ± 75.0 µm preoperatively to 268.6 ± 67.6 µm at the first postoperative recording, p = 0.001, and to 265.9 ± 67.9 µm at 1 year, p = 0.003), visual acuity improved (0.70 ± 0.46 logMAR units preoperatively to 0.39 ± 0.40 at the first postoperative recording, and to 0.33 ± 0.34 at 1 year, p < 0.001 for both) and anti-VEGF treatment intervals lengthened despite the surgery (6.53 ± 2.08 weeks prior to surgery to 7.03 ± 2.23 weeks at 1 year, p = 0.246, and to 7.05 ± 2.57 weeks at the last documented visit, p = 0.035). A CSMT increase of over 30% from the preoperative values was seen in only one case (1 out of 111 eyes, 0.9%). Macular status at surgery, wet AMD subtype, comorbidity of type II diabetes, systemic drugs and topical anti-inflammatory medication were not associated with macular changes nor with treatment intervals after surgery. The cumulative number of anti-VEGF injections correlated neither with CSMT change postoperatively (r = -0.051, p = 0.619) nor with CSMT change at 1 year (r = 0.091, p = 0.426). CONCLUSION: Satisfactory visual outcomes and controlled disease activity were seen in patients with wet AMD undergoing cataract surgery. We found no evidence to support delaying surgery in patients who require it.

Ranibizumab in retinopathy of prematurity - one-year follow-up of ophthalmic outcomes and two-year follow-up of neurodevelopmental outcomes from the CARE-ROP study.

PURPOSE: The primary endpoint results from the comparing alternative ranibizumab dosages for safety and efficacy in retinopathy of prematurity (CARE-ROP) core study identified ranibizumab as an effective treatment to control acute retinopathy of prematurity (ROP). This study reports the 1- and 2-year follow-up data focusing on long-term functional outcomes and safety. METHODS: The CARE-ROP trial compared 0.12 mg versus 0.20 mg ranibizumab in 20 infants with ROP in a multicentric, prospective, randomized, double-blind, controlled study design. Sixteen patients entered the follow-up period. An ophthalmologic assessment at one year postbaseline was acquired from all 16 patients and a neurodevelopmental assessment at two years postbaseline was acquired from 15 patients. RESULTS: Fifteen of 16 infants were able to fixate and follow moving objects at one year postbaseline treatment. One child progressed to stage 5 ROP bilaterally between the end of the core study and the 1-year follow-up (first seen at PMA 75 weeks). Mean spherical equivalents were -1.9 diopters (D) and -0.75 D in the 0.12 mg and the 0.20 mg treatment arms. Strabismus was present in seven and nystagmus in five out of 16 infants. Mental development scores were within normal limits in six out of ten patients with available data. No statistically significant difference was observed between the two treatment arms. CONCLUSION: Neurodevelopmental and functional ocular outcomes 1 and 2 years after treatment with ranibizumab are reassuring regarding long-term safety. Late reactivation of ROP, however, represents a challenge during the follow-up phase and it is of utmost importance that regular follow-ups are maintained.

Recurrent Neovascular Age-Related Macular Degeneration after Discontinuation of Vascular Endothelial Growth Factor Inhibitors Managed in a Treat-and-Extend Regimen.

PURPOSE: To investigate the recurrence rate of active macular neovascularization in patients with neovascular age-related macular degeneration (nAMD) previously followed up in a treat-and-extend (TE) regimen in which treatment had been stopped because of disease stability. DESIGN: Prospective cohort study. PARTICIPANTS: One hundred five patients with nAMD previously followed up in a TE regimen treated with aflibercept injections. METHODS: All patients with a dry macula on 3 consecutive visits 12 weeks apart were eligible to participate in the study. Patients were examined at baseline and then monitored for disease recurrence 4, 6, 8, 10, and 12 months after the last injection. MAIN OUTCOME MEASURES: The proportion of patients with recurrent disease within 12 months after the last injection. Change in best-corrected visual acuity (BCVA) at the time of recurrence and after resumed therapy. RESULTS: Evidence of recurrent nAMD was seen in 54 of 102 patients (52.9%) after 12 months of follow-up. The mean time to recurrence after the last injection was 6.7 ± 2.2 months. The BCVA decreased from 71.7 ± 10.0 Early Treatment Diabetic Retinopathy Study (ETDRS) letters at baseline to 68.1 ± 11.1 ETDRS letters at the recurrence (P = 0.12). After treatment resumed, BCVA increased to 71.4 ± 10.0 ETDRS letters (P = not significant compared with baseline). Patients with a pigment epithelial detachment (PED) at baseline showed a 74% (14/19) recurrence rate compared with 48% (40/83) in patients without a PED (P < 0.05). Only 22 of 54 patients (40.7%) with recurrent disease showed symptoms of visual loss or metamorphopsia. CONCLUSIONS: Recurrent nAMD is common in previously stable patients for whom anti-VEGF injections have been suspended. It is difficult to predict which patients will experience a recurrence, and most of these patients do not show symptoms in the early stages of reactivation. Long-term follow-up is important, and early detection of recurrent disease can improve the chances for maintained visual function.

Observational outcomes in proliferative diabetic retinopathy patients following treatment with ranibizumab, panretinal laser photocoagulation or combination therapy - The non-interventional second year follow-up to the PRIDE study.

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.

Intravitreal anti-VEGF use in France: a cross-sectional and longitudinal Nationwide observational study.

PURPOSE: To describe the sociodemographic, medical and management characteristics of patients using intravitreal (IVT) anti-vascular endothelial growth factors (VEGF) in France. METHODS: An observational study was conducted in patients treated with IVT ranibizumab or aflibercept, aged 18 years or older using the French National Health Insurance Databases covering 99% of the French population. Patients currently treated in 2018 were included in a cross-sectional approach to describe treatment history over the previous 6 years. Patients newly treated between 2014 and 2018 were included in a longitudinal approach to describe treatment management during up to 6 years of follow-up. Sociodemographic characteristics and medical history were described in both populations. The analyses were performed at the patient level, as no distinction between the eyes could be made. RESULTS: A total of 224 775 current users of IVT anti-VEGF in 2018 (mean age 78.1 ± 11.3 years, 60% female) and 330 969 new users between 2014 and 2018 (mean age 75.9 ± 12.0 years, 59% female) were included. In both populations cardiovascular comorbidities or risk factors were frequent and the main treatment indications were age-related macular degeneration and diabetic macular oedema. Among current users of IVT anti-VEGF in 2018, the mean number of years receiving a treatment was 2.9 ± 2.0 years, with a mean of 13.7 ± 11.8 dispensations. In the longitudinal approach, a 26% increase in IVT anti-VEGF initiation was observed between 2014 and 2018. For new users, the mean number of years receiving a treatment was 1.6 ± 1.6 and 67% had at least three dispensations within the first three months. A treatment interruption was observed for 83% of new users and occurred on average of 6.1 ± 8.1 months after initiation. The mean number of dispensations was 4.8 ± 2.8 in the first year and 2.2 ± 2.9 in the second year. The mean number of eye monitoring examinations was 6.5 ± 4.7 in the first year and 4.6 ± 4.4 in the second year. CONCLUSION: This study described the real-world conditions of IVT anti-VEGF dispensing at the entire French population scale. Less frequent dispensations and surveillance examinations were observed than in monthly schemes applied in registration trials for IVT anti-VEGF. These results may indicate a lack of systematic monitoring associated with fewer injections and/or clinicians' preference for more flexible and personalized injection schemes than those originally recommended.

THE IMPACT OF DISEASE ACTIVITY ON 5-YEAR OUTCOMES IN PATIENTS UNDERGOING TREATMENT FOR NEOVASCULAR AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To assess the impact of disease activity on clinical outcomes in a "real-world" cohort with neovascular age-related macular degeneration over 5 years. METHODS: Data were obtained from the prospectively defined Fight Retinal Blindness! registry. Eyes were divided into tertiles based on the proportion of visits where choroidal neovascular lesion was active (low, moderate, and high) up until 5 years. RESULTS: Data from 2,109 eyes were included. The adjusted mean (95% confidence interval) visual acuity change was -0.5 letters (-1.8 to 1.1), 1.8 letters (0.2 to 3.4), and -2.5 letters (-4.2 to -1.3) in the low, moderate, and high activity groups respectively, P < 0.001. Eyes in the low activity group were more likely to develop macular atrophy (56, 47 and 26% in the low, moderate, and high activity groups respectively, P < 0.001) but less likely to develop subretinal fibrosis (27, 35 and 42% in the low, moderate, and high activity groups respectively, P < 0.001). CONCLUSION: Eyes with higher and lower levels of disease activity had poorer outcomes than eyes with moderate activity over 5 years, apparently because of the development of subretinal fibrosis or macular atrophy.

Archway Randomized Phase 3 Trial of the Port Delivery System with Ranibizumab for Neovascular Age-Related Macular Degeneration.

PURPOSE: To evaluate the safety and efficacy of the Port Delivery System with ranibizumab (PDS) for the treatment of neovascular age-related macular degeneration (nAMD). DESIGN: Phase 3, open-label, randomized, visual acuity assessor-masked noninferiority and equivalence trial. PARTICIPANTS: Patients with nAMD diagnosed within 9 months of screening previously treated with and responsive to anti-vascular endothelial growth factor therapy. METHODS: Patients were randomized 3:2 to treatment with the PDS with ranibizumab 100 mg/ml with fixed 24-week (Q24W) refill-exchanges (PDS Q24W) or intravitreal ranibizumab 0.5-mg injections every 4 weeks (monthly ranibizumab). MAIN OUTCOME MEASURES: Primary end point was change in best-corrected visual acuity (BCVA) Early Treatment Diabetic Retinopathy Study letter (letters) score from baseline averaged over weeks 36 and 40 (noninferiority margin,-4.5 letters; equivalence margin, ±4.5 letters). RESULTS: Archway enrolled 418 patients; 251 were randomized to and 248 received treatment with the PDS Q24W, and 167 were randomized to and received treatment with monthly ranibizumab. Baseline BCVA was 74.4 letters (PDS Q24W arm) and 75.5 letters (monthly ranibizumab arm; Snellen equivalent, 20/32). Adjusted mean change in BCVA score from baseline averaged over weeks 36 and 40 was +0.2 letters (standard error [SE], 0.5 letters) in the PDS Q24W arm and +0.5 letters (SE, 0.6 letters) in the monthly ranibizumab arm (difference, -0.3 letters; 95% confidence interval, -1.7 to 1.1 letters). PDS Q24W was both noninferior and equivalent to monthly ranibizumab. Of 246 PDS-treated patients assessed for supplemental ranibizumab treatment, 242 (98.4%) did not receive supplemental ranibizumab treatment before the first refill-exchange procedure, including 4 patients who discontinued treatment before the first refill-exchange procedure. Prespecified ocular adverse events of special interest were reported in 47 patients (19.0%) in the PDS Q24W arm and 10 patients (6.0%) in the monthly ranibizumab arm, which included, in the former arm, 4 (1.6%) endophthalmitis cases, 2 (0.8%) retinal detachments, 13 (5.2%) vitreous hemorrhages, 6 (2.4%) conjunctival erosions, and 5 (2.0%) conjunctival retractions. Most ocular adverse events in the PDS Q24W arm occurred within 1 month of implantation. CONCLUSIONS: Archway met its primary objective and PDS Q24W demonstrated noninferior and equivalent efficacy to monthly ranibizumab, with 98.4% of PDS-treated patients not receiving supplemental treatment in the first 24-week interval.

Long-term follow-up of a case of choroidal neovascularization secondary to reticular pigmentary retinal dystrophy / Seguimento de longo-prazo de um caso de neovascularização de coroide secundária à distrofia reticular pigmentar da retina

ABSTRACT Reticular pigmentary retinal dystrophy, also known as Sjögren's reticular dystrophy, is a rare condition characterized by macular lesions with a reticular pattern, which are best seen on fluorescein angiogram. Choroidal neovascularization secondary to this type of dystrophy is even less common. This report describes a case of reticular pigmentary retinal dystrophy with vision loss due to neovascular membrane, which responded well to treatment with anti-vascular endothelial growth factor.

RESUMO A distrofia reticular pigmentar da retina, também conhecida como distrofia reticular de Sjögren, é uma doença rara, caracterizada por lesões maculares com um padrão reticular, que são mais bem visualizadas na angiografia com fluoresceína. A neovascularização de coroide secundária a este tipo de distrofia é ainda menos comum. Este relato descreve um caso de distrofia reticular pigmentar da retina, com perda de visão devido à membrana neovascular, que respondeu bem ao tratamento com fator de crescimento endotelial antivascular.

Analysis of cytokines in the aqueous humor during intravitreal Ranibizumab treatment of diabetic macular edema.

This study aimed to analyze the concentrations of VEGF, b-FGF, TNF, interleukin (IL)-1, IL-6, IL-8, IL-10, and IL-12 in the aqueous humor of patients with diabetic macular edema with and without peripheral retinal ischemia and to ascertain the changes in the levels of these molecules during treatment with ranibizumab. A therapeutic, prospective, randomized interventional study was carried out. Twenty-four eyes from 24 patients were studied and divided into 3 groups. Group 1 (9 eyes) included patients with diabetic macular edema without peripheral ischemia. Group 2 (10 eyes) included patients with diabetic macular edema with peripheral ischemia. Group 3 (5 eyes), the control group, included patients without systemic and/or eye diseases. Patients in Groups 1 and 2 received 3 intravitreal injections of 2 mg/0.05 ml ranibizumab at an interval of approximately 30 days. Before administering the injections, the aqueous humor was collected. In the control group, aqueous humor was collected before facetectomy. During treatment, the median IL-6 concentration significantly increased in Group 1 but showed a slight but not significant decrease in Group 2. Interleukin 8 levels were significantly different at the end of treatment compared to the beginning in Groups 1 and 2. TNF, IL-1, IL-10, and IL-12 levels were practically unchanged in both groups. VEGF was significantly reduced at the end of the study in Groups 1 and 2. B-FGF was not detected in most of the studied patients, and in those with detectable levels, there was no significant variation. There was a significant increase in the median level of interleukin 6 in the group without ischemia and a significant decrease in VEGF in both groups. The cytokines TNF, IL-1, IL-10, and IL-12 did not show significant variation.