Freekje van Asten

Zinc Supplementation Inhibits Complement Activation in Age-Related Macular Degeneration

Age-related macular degeneration (AMD) is the leading cause of blindness in the Western world. AMD is a multifactorial disorder but complement-mediated inflammation at the level of the retina plays a pivotal role. Oral zinc supplementation can reduce the progression of AMD but the precise mechanism of this protective effect is as yet unclear. We investigated whether zinc supplementation directly affects the degree of complement activation in AMD and whether there is a relation between serum complement catabolism during zinc administration and the complement factor H (CFH) gene or the Age-Related Maculopathy susceptibility 2 (ARMS2) genotype. In this open-label clinical study, 72 randomly selected AMD patients in various stages of AMD received a daily supplement of 50 mg zinc sulphate and 1 mg cupric sulphate for three months. Serum complement catabolism–defined as the C3d/C3 ratio–was measured at baseline, throughout the three months of supplementation and after discontinuation of zinc administration. Additionally, downstream inhibition of complement catabolism was evaluated by measurement of anaphylatoxin C5a. Furthermore, we investigated the effect of zinc on complement activation in vitro. AMD patients with high levels of complement catabolism at baseline exhibited a steeper decline in serum complement activation (p<0.001) during the three month zinc supplementation period compared to patients with low complement levels. There was no significant association of change in complement catabolism and CFH and ARMS2 genotype. In vitro zinc sulphate directly inhibits complement catabolism in hemolytic assays and membrane attack complex (MAC) deposition on RPE cells. This study provides evidence that daily administration of 50 mg zinc sulphate can inhibit complement catabolism in AMD patients with increased complement activation. This could explain part of the mechanism by which zinc slows AMD progression. Trial Registration The Netherlands National Trial Register NTR2605

A prospective, observational, open-label, multicentre study to investigate the daily treatment practice of ranibizumab in patients with neovascular age-related macular degeneration

The HELIOS (Health Economics with Lucentis in Observational Settings) study was designed on request of the Dutch Health Authority for an observational study to assess the effectiveness and safety of ranibizumab for neovascular age‐related macular degeneration (wet AMD) in daily practice.

A genetic variant in NRP1 is associated with worse response to ranibizumab treatment in neovascular age-related macular degeneration.

Objective The aim of the study was to investigate the role of single-nucleotide polymorphisms (SNPs) located in the neuropilin-1 (NRP1) gene in treatment response to antivascular endothelial growth factor (VEGF) therapy for neovascular age-related macular degeneration (nvAMD). Methods Four SNPs in the NRP1 gene (rs2229935, rs2247383, rs2070296, and rs2804495) were genotyped in a study cohort of 377 nvAMD patients who received the loading dose of three monthly ranibizumab injections. Treatment response was assessed as the change in visual acuity after three monthly loading injections compared with baseline. Results SNP rs2070296 was associated with change in visual acuity after 3 months of treatment. Patients carrying the GA or AA genotypes performed significantly worse than individuals carrying the GG genotype (P=0.01). A cumulative effect of rs2070296 in the NRP1 gene and rs4576072 located in the VEGF receptor 2 (VEGFR2 or KDR) gene, previously associated with treatment response, was observed. Patients carrying two risk alleles performed significantly worse than patients carrying zero or one risk allele (P=0.03), and patients with more than two risk alleles responded even worse to the therapy (P=3×10–3). The combined effect of these two SNPs on the response was also seen after 6 and 12 months of treatment. Conclusion This study suggests that genetic variation in NRP1, a key molecule in VEGFA-driven neovascularization, influences treatment response to ranibizumab in nvAMD patients. The results of this study may be used to generate prediction models for treatment response, which in the future may help tailor medical care to individual needs.

Visual Rehabilitation in Chronic Cerebral Blindness: A Randomized Controlled Crossover Study.

The treatment of patients suffering from cerebral blindness following stroke is a topic of much recent interest. Several types of treatment are under investigation, such as substitution with prisms and compensation training of saccades. A third approach, aimed at vision restitution is controversial, as a proper controlled study design is missing. In the current study, 27 chronic stroke patients with homonymous visual field defects were trained at home with a visual training device. We used a discrimination task for two types of stimuli: a static point stimulus and a new optic flow-discontinuity stimulus. Using a randomized controlled crossover design, each patient received two successive training rounds, one with high contrast stimuli in their affected hemifield (test) and one round with low-contrast stimuli in their intact hemifield (control). Goldmann and Humphrey perimetry were performed at the start of the study and following each training round. In addition, reading performance was measured. Goldmann perimetry revealed a statistically significant reduction of the visual field defect after the test training, but not after the control training or after no intervention. For both training rounds combined, Humphrey perimetry revealed that the effect of a directed training (sensitivity change in trained hemifield) exceeded that of an undirected training (sensitivity change in untrained hemifield). The interaction between trained and tested hemifield was just above the threshold of significance (p = 0.058). Interestingly, reduction of the field defect assessed by Goldmann perimetry increases with the difference between defect size as measured by Humphrey and Goldmann perimetry prior to training. Moreover, improvement of visual sensitivity measured by Humphrey perimetry increases with the fraction of non-responsive elements (i.e., more relative field loss) in Humphrey perimetry prior to training. Reading speed revealed a significant improvement after training. Our findings demonstrate that our training can result in reduction of the visual field. Improved reading performance after defect training further supports the significance of our training for improvement in daily life activities.

The cost-effectiveness of bevacizumab, ranibizumab and aflibercept for the treatment of age-related macular degeneration-A cost-effectiveness analysis from a societal perspective

Background The discussion on the use of bevacizumab is still ongoing and often doctors are deterred from using bevacizumab due to legal or political issues. Bevacizumab is an effective, safe and inexpensive treatment option for neovascular age-related macular degeneration (AMD), albeit unregistered for the disease. Therefore, in some countries ophthalmologists use the equally effective but expensive drugs ranibizumab and aflibercept. We describe the economic consequences of this dilemma surrounding AMD treatment from a societal perspective. Methods We modelled cost-effectiveness of treatment with ranibizumab (as-needed), aflibercept (bimonthly) and bevacizumab (as-needed). Effectiveness was estimated by systematic review and meta-analysis. The drug with the most favourable cost-effectiveness profile compared to bevacizumab was used for threshold analyses. First, we determined how much we overspend per injection. Second, we calculated the required effectiveness to justify the current price and the reasonable price for a drug leading to optimal vision. Finally, we estimated how much Europe overspends if bevacizumab is not first choice. Results Bevacizumab treatment costs €27,087 per year, about €4,000 less than aflibercept and €6,000 less than ranibizumab. With similar effectiveness for all drugs as shown by meta-analysis, bevacizumab was the most cost-effective. Aflibercept was chosen for threshold analyses. Aflibercept costs €943 per injection, but we determined that the maximum price to be cost-effective is €533. Alternatively, at its current price, aflibercept should yield about twice the visual gain. Even when optimal vision can be achieved, the maximum price for any treatment is €37,453 per year. Most importantly, Europe overspends €335 million yearly on AMD treatment when choosing aflibercept over bevacizumab. Conclusion Bevacizumab is the most cost-effective treatment for AMD, yet is not the standard of care across Europe. The registered drugs ranibizumab and aflibercept lead to large overspending without additional health benefits. Health authorities should consider taking steps to implement bevacizumab into clinical practice as first choice.

Association of Genetic Variants With Response to Anti-Vascular Endothelial Growth Factor Therapy in Age-Related Macular Degeneration.

Importance Visual acuity (VA) outcomes differ considerably among patients with neovascular age-related macular degeneration (nAMD) treated with anti–vascular endothelial growth factor (VEGF) drugs. Identification of pharmacogenetic associations may help clinicians understand the mechanisms underlying this variability as well as pave the way for personalized treatment in nAMD. Objective To identify genetic factors associated with variability in the response to anti-VEGF therapy for patients with nAMD. Design, Setting, and Participants In this multicenter genome-wide association study, 678 patients with nAMD with genome-wide genotyping data were included in the discovery phase; 1380 additional patients with nAMD were genotyped for selected common variants in the replication phase. All participants received 3 monthly injections of bevacizumab or ranibizumab. Clinical data were evaluated for inclusion/exclusion criteria from October 2014 to October 2015, followed by data analysis from October 2015 to February 2016. For replication cohort genotyping, clinical data collection and analysis (including meta-analysis) was performed from March 2016 to April 2017. Main Outcomes and Measures Change in VA after the loading dose of 3 monthly anti-VEGF injections compared with baseline. Results Of the 2058 included patients, 1210 (58.8%) were women, and the mean (SD) age across all cohorts was 78 (7.4) years. Patients included in the discovery cohort and most of the patients in the replication cohorts were of European descent. The mean (SD) baseline VA was 51.3 (20.3) Early Treatment Diabetic Retinopathy Study (ETDRS) score letters, and the mean (SD) change in VA after the loading dose of 3 monthly injections was a gain of 5.1 (13.9) ETDRS score letters (ie, 1-line gain). Genome-wide single-variant analyses of common variants revealed 5 independent loci that reached a P value less than 10 × 10−5. After replication and meta-analysis of the lead variants, rs12138564 located in the CCT3 gene remained nominally associated with a better treatment outcome (ETDRS letter gain, 1.7; &bgr;, 0.034; SE, 0.008; P = 1.38 × 10−5). Genome-wide gene-based optimal unified sequence kernel association test of rare variants showed genome-wide significant associations for the C10orf88 (P = 4.22 × 10−7) and UNC93B1 (P = 6.09 × 10−7) genes, in both cases leading to a worse treatment outcome. Patients carrying rare variants in the C10orf88 and UNC93B1 genes lost a mean (SD) VA of 30.6 (17.4) ETDRS score letters (ie, loss of 6.09 lines) and 26.5 (13.8) ETDRS score letters (ie, loss of 5.29 lines), respectively, after 3 months of anti-VEGF treatment. Conclusions and Relevance We propose that there is a limited contribution of common genetic variants to variability in nAMD treatment response. Our results suggest that rare protein-altering variants in the C10orf88 and UNC93B1 genes are associated with a worse response to anti-VEGF therapy in patients with nAMD, but these results require further validation in other cohorts.

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

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).

Achieving balance in the treatment and monitoring of neovascular age-related macular degeneration in the real world: lessons from the Netherlands cohort of the AURA study

E ditor, There is growing interest in monitoring treatment patterns and outcomes associated with anti-vascular endothelial growth factor agents in real world settings. AURA was an international, retrospective observational study conducted in Canada, France, Germany, Ireland, Italy, the Netherlands, the United Kingdom (UK), and Venezuela; the design (including ethics approval), participants and global outcomes of AURA are described in detail elsewhere (Holz et al. 2015). AURA showed that visual acuity (VA) outcomes achieved following ranibizumab use in patients with neovascular agerelated macular degeneration (nAMD) were worse than those observed in clinical trials (Holz et al. 2015). These findings, which are also mirrored in some other real world studies (Rakic et al. 2013; van Asten et al. 2015), may be explained by several interacting factors, including resource patterns like the use of a loading scheme. Although the AURA data are now well established, we explored the Netherlands cohort in more detail as countryspecific data are lacking, and we wanted to examine the impact of treatment and monitoring patterns after the loading phase on VA outcome in a real world setting. Patients from the Netherlands (n = 337), UK (n = 355) and all ‘other’ cohorts (n = 1094) who received a loading scheme in AURA were analyzed. The mean baseline VA (letter score) was lower in the Netherlands (50.4) than in UK (54.3) or ‘other’ cohorts (56.8). The mean change in VA 7.61 8.32 6.82

Switching to aflibercept in patients with neovascular age-related macular degeneration not responding to bevacizumab: a pilot study

treated type 2 CNV (mean age 75.6+/ 9.4 years) for three consecutive monthly visits after the loading phase were investigated (two eyes excluded because of low-quality images). Mean duration of symptoms at time of diagnosis was 30.2+/ 27.1 days, and mean size of CNV at FA was 5.65+/ 10.35 mm. Mean time from CNV diagnosis to the lesion being no more active was 3.9 months (average of 3.9 intravitreal injections). Quantitative OCTA analysis revealed a CNV area of 4.99+/ 3.99 mm at baseline examination, which did not change significantly (5.15+/ 4.27 mm; p = 0.99) after 3 monthly ranibizumab injections (Fig. 1A). Qualitative OCTA analysis revealed the persistence of the main neovascular complex in 9/10 eyes (Fig. 1B). However, a subtle shrinkage of vessels at the edge of the lesion and reduction in the capillary network of fine vessels within the neovascular lesion was observed in all eyes (Fig. 1B). No significant relationships were found between age, gender, duration of symptoms, CNV area on FA at time of diagnosis and change in CNV size on OCTA during follow-up (p > 0.05). Our quantitative and qualitative analysis of treated type 2 CNV undergoing monthly anti-VEGF treatment reveals that while the size of the lesion as well as the main neovascular complex does not change during the short-term follow-up, the capillary plexus shows attenuation. These results suggest that anti-VEGF therapy might not be effective in reducing the main neovascular complex size possibly because of the presence of pericytes overlying the endothelial cells, even in the monthly regimen (Benjamin et al. 1998). The main limitation could be related to the inability to be sure that the image quality of the OCTA signal in the area analysed was the same in all visits. Our findings, in line with previous publications (Jia et al. 2014; de Carlo et al. 2015; Kuehlewein et al. 2015), suggest that OCTA can be considered as a valuable tool for monitoring treated CNV. In conclusion, using en face measurements of OCTA images, we showed that further reduction in size is not seen once the type 2 CNV lesion becomes no more active. References