Comparing the effectiveness of bevacizumab to ranibizumab in patients with exudative age-related macular degeneration. The BRAMD study

Purpose: To compare the effectiveness of bevacizumab and ranibizumab in the treatment of exudative age-related macular degeneration (AMD). Design: Multicentre, randomized, controlled, double-masked clinical trial in 327 patients. The noninferiority margin was 4 letters. Patients: Patients ≥ 60 years of age with primary or recurrent sub- or juxtafoveal choroidal neovascularization (CNV) secondary to AMD with a total area of CNV < 12 disc areas and a best corrected visual acuity (BCVA) score between 20 and 78 letters on an EDTRS like chart in the study eye. Methods: Monthly intravitreal injections with 1.25 mg bevacizumab or 0.5 mg ranibizumab were given during one year. Intention to treat with last observation carried forward analysis was performed. Main Outcome Measures: Primary outcome was the change in BCVA in the study eye from baseline to 12 months. Results: The mean gain in BCVA was 5.1 (±14.1) letters in the bevacizumab group (n = 161) and 6.4 (±12.2) letters in the ranibizumab group (n = 166) (p = 0.37). The lower limit of the 95% confidence interval of the difference in BCVA gain was 3.72. The response to bevacizumab was more varied; 24% of patients showed a gain of ≥15 letters, 11% a loss of ≥15 letters and 65% a gain or loss < 15 letters compared to 19%, 5% and 76% respectively for ranibizumab (p = 0.038). No significant differences in absolute CRT and CRT change (p = 0.13) or in the presence of subretinal or intraretinal fluid (p = 0.14 and 0.10, respectively) were observed. However, the presence of any fluid on SD-OCT (subretinal and/or intraretinal) differed significantly (p = 0.020), with definite fluid on SD-OCT in 45% of the patients for bevacizumab versus 31% for ranibizumab. The occurrence of serious adverse events and adverse events was similar, with 34 SAEs and 256 AEs in the bevacizumab group and 37 SAEs and 299 AEs in the ranibizumab group (p = 0.87 and p = 0.48, respectively). Conclusions: Bevacizumab was not inferior to ranibizumab. The response to bevacizumab was more varied with higher percentages of both gainers and losers and more frequently observed retinal fluid on SD-OCT at 12 months when compared to the ranibizumab group. Trial Registration: Trialregister.nl NTR1704

Comparing the effectiveness and costs of Bevacizumab to Ranibizumab in patients with Diabetic Macular Edema: A randomized clinical trial (the BRDME study)

Background: The effectiveness of ranibizumab in the treatment of diabetic macular edema has been proven with large clinical trials. For bevacizumab only two clinical trials have been published and a head-to-head comparison is lacking to date. However, if proved non-inferior to ranibizumab, use of the off-label bevacizumab could reduce costs enormously without a loss in visual acuity. A cost-effectiveness study has been designed to substantiate this hypothesis. Aim: To compare the effectiveness and costs of 1.25 mg of bevacizumab to 0.5 mg ranibizumab given as monthly intravitreal injections during 6 months in patients with diabetic macular edema. It is hypothesized that bevacizumab is non-inferior to ranibizumab regarding its effectiveness. Design: This is a randomized, controlled, double masked, clinical trial in 246 patients in seven academic trial centres in The Netherlands. Outcomes: The primary outcome measure is the change in best-corrected visual acuity (BCVA) in the study eye from baseline to month 6. Secondary outcomes are the proportions of patients with a gain or loss of 15 letters or more or a BCVA of 20/40 or more at 6 months, the change in leakage on fluorescein angiography and the change in foveal thickness by optical coherence tomography at 6 months, the number of adverse events in 6 months, and the costs per quality adjusted life-year of the two treatments

Non-syndromic retinitis pigmentosa

Retinitis pigmentosa (RP) encompasses a group of inherited retinal dystrophies characterized by the primary degeneration of rod and cone photoreceptors. RP is a leading cause of visual disability, with a worldwide prevalence of 1:4000. Although the majority of RP cases are non-syndromic, 20–30% of patients with RP also have an associated non-ocular condition. RP typically manifests with night blindness in adolescence, followed by concentric visual field loss, reflecting the principal dysfunction of rod photoreceptors; central vision loss occurs later in life due to cone dysfunction. Photoreceptor function measured with an electroretinogram is markedly reduced or even absent. Optical coherence tomography (OCT) and fundus autofluorescence (FAF) imaging show a progressive loss of outer retinal layers and altered lipofuscin distribution in a characteristic pattern. Over the past three decades, a vast number of disease-causing variants in more than 80 genes have been associated with non-syndromic RP. The wide heterogeneity of RP makes it challenging to describe the clinical findings and pathogenesis. In this review, we provide a comprehensive overview of the clinical characteristics of RP specific to genetically defined patient subsets. We supply a unique atlas with color fundus photographs of most RP subtypes, and we discuss the relevant considerations with respect to differential diagnoses. In addition, we discuss the genes involved in the pathogenesis of RP, as well as the retinal processes that are affected by pathogenic mutations in these genes. Finally, we review management strategies for patients with RP, including counseling, visual rehabilitation, and current and emerging therapeutic options

Non-syndromic retinitis pigmentosa

Retinitis pigmentosa (RP) encompasses a group of inherited retinal dystrophies characterized by the primary degeneration of rod and cone photoreceptors. RP is a leading cause of visual disability, with a worldwide prevalence of 1:4000. Although the majority of RP cases are non-syndromic, 20–30% of patients with RP also have an associated non-ocular condition. RP typically manifests with night blindness in adolescence, followed by concentric visual field loss, reflecting the principal dysfunction of rod photoreceptors; central vision loss occurs later in life due to cone dysfunction. Photoreceptor function measured with an electroretinogram is markedly reduced or even absent. Optical coherence tomography (OCT) and fundus autofluorescence (FAF) imaging show a progressive loss of outer retinal layers and altered lipofuscin distribution in a characteristic pattern. Over the past three decades, a vast number of disease-causing variants in more than 80 genes have been associated with non-syndromic RP. The wide heterogeneity of RP makes it challenging to describe the clinical findings and pathogenesis. In this review, we provide a comprehensive overview of the clinical characteristics of RP specific to genetically defined patient subsets. We supply a unique atlas with color fundus photographs of most RP subtypes, and we discuss the relevant considerations with respect to differential diagnoses. In addition, we discuss the genes involved in the pathogenesis of RP, as well as the retinal processes that are affected by pathogenic mutations in these genes. Finally, we review management strategies for patients with RP, including counseling, visual rehabilitation, and current and emerging therapeutic options

Systemic and ocular fluid compounds as potential biomarkers in age-related macular degeneration

Biomarkers can help unravel mechanisms of disease and identify new targets for therapy. They can also be useful in clinical practice for monitoring disease progression, evaluation of treatment efficacy, and risk assessment in multifactorial diseases, such as age-related macular degeneration (AMD). AMD is a highly prevalent progressive retinal disorder for which multiple genetic and environmental risk factors have been described, but the exact etiology is not yet fully understood. Many compounds have been evaluated for their association with AMD. We performed an extensive literature review of all compounds measured in serum, plasma, vitreous, aqueous humor, and urine of AMD patients. Over 3600 articles were screened, resulting in more than 100 different compounds analyzed in AMD studies, involved in neovascularization, immunity, lipid metabolism, extracellular matrix, oxidative stress, diet, hormones, and comorbidities (such as kidney disease). For each compound, we provide a short description of its function and discuss the results of the studies in relation to its usefulness as AMD biomarker. In addition, biomarkers identified by hypothesis-free techniques, including metabolomics, proteomics, and epigenomics, are covered. In summary, compounds belonging to the oxidative stress pathway, the complement system, and lipid metabolism are the most promising biomarker candidates for AMD. We hope that this comprehensive survey of the literature on systemic and ocular fluid compounds as potential biomarkers in AMD will provide a stepping stone for future research and possible implementation in clinical practice

A Deep Learning Model for Segmentation of Geographic Atrophy to Study Its Long-Term Natural History

__Purpose:__ To develop and validate a deep learning model for the automatic segmentation of geographic atrophy (GA) using color fundus images (CFIs) and its application to study the growth rate of GA. __Design:__ Prospective, multicenter, natural history study with up to 15 years of follow-up. __Participants:__ Four hundred nine CFIs of 238 eyes with GA from the Rotterdam Study (RS) and Blue Mountain Eye Study (BMES) for model development, and 3589 CFIs of 376 eyes from the Age-Related Eye Disease Study (AREDS) for analysis of GA growth rate. __Methods:__ A deep learning model based on an ensemble of encoder–decoder architectures was implemented and optimized for the segmentation of GA in CFIs. Four experienced graders delineated, in consensus, GA in CFIs from the RS and BMES. These manual delineations were used to evaluate the segmentation model using 5-fold cross-validation. The model was applied further to CFIs from the AREDS to study the growth rate of GA. Linear regression analysis was used to study associations between structural biomarkers at baseline and the GA growth rate. A general estimate of the progression of GA area over time was made by combining growth rates of all eyes with GA from the AREDS set. __Main Outcome Measures:__ Automatically segmented GA and GA growth rate. __Results:__ The model obtained an average Dice coefficient of 0.72±0.26 on the BMES and RS set while comparing the automatically segmented GA area with the graders’ manual delineations. An intraclass correlation coefficient of 0.83 was reached between the automatically estimated GA area and the graders’ consensus measures. Nine automatically calculated structural biomarkers (area, filled area, convex area, convex solidity, eccentricity, roundness, foveal involvement, perimeter, and circularity) were significantly associated with growth rate. Combining all growth rates indicated that GA area grows quadratically up to an area of approximately 12 mm2, after which growth rate stabilizes or decreases. __Conclusions:__ The deep learning model allowed for fully automatic and robust segmentation of GA on CFIs. These segmentations can be used to extract structural characteristics of GA that predict its growth rate

Risk factors for development and progression of diabetic retinopathy in Dutch patients with type 1 diabetes mellitus

Purpose: To investigate risk factors for the development and progression of diabetic retinopathy (DR) and long-term visual outcomes in Dutch patients with type 1 diabetes mellitus (T1DM). Methods: Cumulative incidences were calculated for DR, vision-threatening DR (VTDR), defined as (pre)proliferative DR and diabetic macular oedema, and best-corrected visual acuity (BCVA) <0.5 and <0.3 at the most recent eye examination. The fo

Analysis of rare variants in the C3 gene in patients with age-related macular degeneration

Age-related macular degeneration (AMD) is a progressive retinal disorder affecting over 33 million people worldwide. Genome-wide association studies (GWASs) for AMD identified common variants at 19 loci accounting for 15-65% of the heritability and it has been hypothesized that the missing heritability may be attributed to rare variants with large effect sizes. Common variants in the complement component 3 (C3) gene have been associated with AMD and recently a rare C3 variant (Lys155Gln) was identified which exerts a large effect on AMD susceptibility independent of the common variants. To explore whether additional rare variants in the C3 gene are associated with AMD, we sequenced all coding exons in 84 unrelated AMD cases. Subsequently, we genotyped all identified variants in 1474 AMD cases and 2258 controls. Additionally, because of the known genetic overlap between AMD and atypical hemolytic uremic syndrome (aHUS), we genotyped two recurrent aHUS-associated C3 mutations in the entire cohort. Overall, we identified three rare variants (Lys65Gln (P = 0.04), Arg735Trp (OR = 17.4, 95% CI = 2.2-136; P = 0.0003), and Ser1619Arg (OR = 5.2, 95% CI = 1.0-25; P = 0.05) at the C3 locus that are associated with AMD in our EUGENDA cohort. However, the Arg735Trp and Ser1619Arg variants were not found to be associated with AMD in the Rotterdam Study. The Lys65Gln variant was only identified in patients from Nijmegen, the Netherlands, and thus may represent a region-specific AMD risk variant

The common ABCA4 variant p.Asn1868ile shows nonpenetrance and variable expression of stargardt disease when present in trans with severe variants

PURPOSE. To assess the occurrence and the disease expression of the common p.Asn1868Ile variant in patients with Stargardt disease (STGD1) harboring known, monoallelic causal ABCA4 variants. METHODS. The coding and noncoding regions of ABCA4 were sequenced in 67 and 63 STGD1 probands respectively, harboring monoallelic ABCA4 variants. In case p.Asn1868Ile was detected, segregation analysis was performed whenever possible. Probands and affected siblings harboring p.Asn1868Ile without additional variants in cis were clinically evaluated retrospe

Diagnostic exome sequencing in 266 Dutch patients with visual impairment

Inherited eye disorders have a large clinical and genetic heterogeneity, which makes genetic diagnosis cumbersome. An exome-sequencing approach was developed in which data analysis was divided into two steps: the vision gene panel and exome analysis. In the vision gene panel analysis, variants in genes known to cause inherited eye disorders were assessed for pathogenicity. If no causative variants were detected and when the patient consented, the entire exome data was analyzed. A total of 266 Dutch patients with different types of inherited eye disorders, including inherited retinal dystrophies, cataract, developmental eye disorders and optic atrophy, were investigated. In the vision gene panel analysis (likely), causative variants were detected in 49% and in the exome analysis in an additional 2% of the patients. The highest detection rate of (likely) causative variants was in patients with inherited retinal dystrophies, for instance a yield of 63% in patients with retinitis pigmentosa. In patients with developmental eye defects, cataract and optic atrophy, the detection rate was 50, 33 and 17%, respectively. An exome-sequencing approach enables a genetic diagnosis in patients with different types of inherited eye disorders using one test. The exome approach has the same detection rate as targeted panel sequencing tests, but offers a number of advantages. For instance, the vision gene panel can be frequently and easily updated with additional (novel) eye disorder genes. Determination of the genetic diagnosis improved the clinical diagnosis, regarding the assessment of the inheritance pattern as well as future disease perspective