Ten-year mortality and long-term visual acuity outcomes in patients with exudative age-related macular degeneration treated with intravitreal anti-vascular endothelial growth factor injections.

PURPOSE: There are limited real-world data on long-term mortality and visual outcomes in patients treated with anti-vascular endothelial growth factor (VEGF) for exudative age-related macular degeneration (exudative AMD). We assessed 10-year mortality and clinical outcomes in exudative AMD patients treated with intravitreal therapy (IVT) anti-VEGF injections on a pro-re-nata (PRN) regime following a standard loading regime. METHODS: Retrospective cohort study of the first 216 exudative AMD patients receiving IVT anti-VEGF for exudative AMD at a public tertiary referral hospital in Scotland. Main outcome measures were mortality, cause of death and best-corrected visual acuity (BCVA). RESULTS: A total of 216 patients were included. Mean age at presentation was 79.1 years [standard deviation (SD) 6.9]. Mean follow-up duration was 6.6 years (SD 3.2) during which there was a mean 24.3 Early Treatment Diabetic Retinopathy Study (ETDRS) letter loss in BCVA (P < 0.0001). Patients received a mean of 2.2 (SD 1.8) injections per year of follow-up. Overall, 52.6% (113/216) died during the period studied. Observed annual mortality incidence risk was 6.5% (SD 3.1) and was found to be significantly lower (P = 0.0064) than the expected annual death incidence risk (9.6%, SD 1.5) based on age and sex standardised Scottish mortality risk. The most common causes of death were malignancies (21.3%) and infection (20.0%). CONCLUSIONS: This study highlights the relatively good long-term prognosis in vision and mortality in exudative AMD treated with a PRN regime in the real world. Although the majority lost vision, the rate of decline was significantly slower than that which would have been experienced in the pre-anti-VEGF era and reassuringly standardised mortality risk was lower than the national average.

Clinical outcomes of switching to aflibercept using a pro re nata treatment regimen in patients with neovascular age-related macular degeneration who incompletely responded to ranibizumab.

BACKGROUND: To assess the effect of switching patients previously incompletely treated with ranibizumab (RBZ) to aflibercept (AFL) using a pro re nata (PRN) treatment strategy in neovascular age-related macular degeneration (nvAMD). METHODS: A retrospective case series was conducted on patients who had persistent or recurrent intra- and/or sub-retinal fluid treated initially with RBZ and subsequently switched to AFL. The main outcome measures were best corrected visual acuity (BCVA) and central retinal thickness (CRT) measured at different stages of the study. Friedman analysis of variance and Wilcoxon test were used to examine differences in BCVA and CRT. RESULTS: Two hundred and seven eyes from 182 patients were included. BCVA and CRT improved significantly initially following 3 RBZ injections with a mean gain of 3.7 letters (p < 0.001) and a mean loss of 69 µm (p < 0.001) respectively. Following PRN RBZ therapy and immediately prior to switching to AFL (mean 129 weeks), there was a mean loss of 6.7 letters (p < 0.001) BCVA and a mean gain of 24 µm (p < 0.001) CRT. AFL loading resulted in a mean improvement of 0.7 letters (p = 0.28) BCVA and 55 µm (p < 0.001) CRT. At final follow-up following AFL PRN therapy (mean 85 weeks), there was a mean loss of 8.9 letters (p < 0.001) BCVA and a mean gain of 12 µm (p < 0.05) CRT. CONCLUSION: AFL loading resulted in a significant anatomical improvement but no significant change in visual acuity. However, the benefits of switching were gradually lost over time with AFL PRN dosing despite an increased injection rate when compared with RBZ PRN treatment. TRIAL REGISTRATION: Not applicable.

Genetic influences on plasma CFH and CFHR1 concentrations and their role in susceptibility to age-related macular degeneration.

It is a longstanding puzzle why non-coding variants in the complement factor H (CFH) gene are more strongly associated with age-related macular degeneration (AMD) than functional coding variants that directly influence the alternative complement pathway. The situation is complicated by tight genetic associations across the region, including the adjacent CFH-related genes CFHR3 and CFHR1, which may themselves influence the alternative complement pathway and are contained within a common deletion (CNP147) which is associated with protection against AMD. It is unclear whether this association is mediated through a protective effect of low plasma CFHR1 concentrations, high plasma CFH or both. We examined the triangular relationships of CFH/CFHR3/CFHR1 genotype, plasma CFH or CFHR1 concentrations and AMD susceptibility in combined case-control (1256 cases, 1020 controls) and cross-sectional population (n = 1004) studies and carried out genome-wide association studies of plasma CFH and CFHR1 concentrations. A non-coding CFH SNP (rs6677604) and the CNP147 deletion were strongly correlated both with each other and with plasma CFH and CFHR1 concentrations. The plasma CFH-raising rs6677604 allele and raised plasma CFH concentration were each associated with AMD protection. In contrast, the protective association of the CNP147 deletion with AMD was not mediated by low plasma CFHR1, since AMD-free controls showed increased plasma CFHR1 compared with cases, but it may be mediated by the association of CNP147 with raised plasma CFH concentration. The results are most consistent with a regulatory locus within a 32 kb region of the CFH gene, with a major effect on plasma CFH concentration and AMD susceptibility.

Genome-wide association study of age-related macular degeneration identifies associated variants in the TNXB-FKBPL-NOTCH4 region of chromosome 6p21.3.

Age-related macular degeneration (AMD) is a leading cause of visual loss in Western populations. Susceptibility is influenced by age, environmental and genetic factors. Known genetic risk loci do not account for all the heritability. We therefore carried out a genome-wide association study of AMD in the UK population with 893 cases of advanced AMD and 2199 controls. This showed an association with the well-established AMD risk loci ARMS2 (age-related maculopathy susceptibility 2)-HTRA1 (HtrA serine peptidase 1) (P =2.7 × 10(-72)), CFH (complement factor H) (P =2.3 × 10(-47)), C2 (complement component 2)-CFB (complement factor B) (P =5.2 × 10(-9)), C3 (complement component 3) (P =2.2 × 10(-3)) and CFI (P =3.6 × 10(-3)) and with more recently reported risk loci at VEGFA (P =1.2 × 10(-3)) and LIPC (hepatic lipase) (P =0.04). Using a replication sample of 1411 advanced AMD cases and 1431 examined controls, we confirmed a novel association between AMD and single-nucleotide polymorphisms on chromosome 6p21.3 at TNXB (tenascin XB)-FKBPL (FK506 binding protein like) [rs12153855/rs9391734; discovery P =4.3 × 10(-7), replication P =3.0 × 10(-4), combined P =1.3 × 10(-9), odds ratio (OR) = 1.4, 95% confidence interval (CI) = 1.3-1.6] and the neighbouring gene NOTCH4 (Notch 4) (rs2071277; discovery P =3.2 × 10(-8), replication P =3.8 × 10(-5), combined P =2.0 × 10(-11), OR = 1.3, 95% CI = 1.2-1.4). These associations remained significant in conditional analyses which included the adjacent C2-CFB locus. TNXB, FKBPL and NOTCH4 are all plausible AMD susceptibility genes, but further research will be needed to identify the causal variants and determine whether any of these genes are involved in the pathogenesis of AMD.

Complement C3 variant and the risk of age-related macular degeneration.

BACKGROUND: Age-related macular degeneration is the most common cause of blindness in Western populations. Susceptibility is influenced by age and by genetic and environmental factors. Complement activation is implicated in the pathogenesis. METHODS: We tested for an association between age-related macular degeneration and 13 single-nucleotide polymorphisms (SNPs) spanning the complement genes C3 and C5 in case subjects and control subjects from the southeastern region of England. All subjects were examined by an ophthalmologist and had independent grading of fundus photographs to confirm their disease status. To test for replication of the most significant findings, we genotyped a set of Scottish cases and controls. RESULTS: The common functional polymorphism rs2230199 (Arg80Gly) in the C3 gene, corresponding to the electrophoretic variants C3S (slow) and C3F (fast), was strongly associated with age-related macular degeneration in both the English group (603 cases and 350 controls, P=5.9x10(-5)) and the Scottish group (244 cases and 351 controls, P=5.0x10(-5)). The odds ratio for age-related macular degeneration in C3 S/F heterozygotes as compared with S/S homozygotes was 1.7 (95% confidence interval [CI], 1.3 to 2.1); for F/F homozygotes, the odds ratio was 2.6 (95% CI, 1.6 to 4.1). The estimated population attributable risk for C3F was 22%. CONCLUSIONS: Complement C3 is important in the pathogenesis of age-related macular degeneration. This finding further underscores the influence of the complement pathway in the pathogenesis of this disease.

Age-related macular degeneration and recent developments: new hope for old eyes?

Age-related macular degeneration (AMD) is the commonest cause of blindness in the population over 60 years of age and accounts for over 50% of those registered blind in the UK. The incidence is increasing and as older generations live longer a growing number of patients will be affected in the future. Affected patients lose central vision, important in all aspects of everyday life. This review outlines risk factors for AMD, clinical features, treatment and management strategies for patients, families and physicians caring for those with AMD. Recent trials are included along with practical clinical advice. While there is no curative treatment at present, intervention can reduce the risk of developing AMD and limit disease progression if it occurs. These modalities are discussed here. As new discoveries in the field of genetics and novel therapies emerge, a brighter future seems certain for the ageing population.

Long anterior lens zonules in late-onset retinal degeneration (L-ORD).

PURPOSE: We report new findings of peripupillary iris atrophy and long anteriorly-inserted zonules in a family with late-onset retinal degeneration (L-ORD). DESIGN: The proband was noted to have anterior segment findings not previously described in L-ORD, an autosomal dominant condition resulting in severe visual impairment. A mutation in the C1QTNF5 (CTRP5) gene is causal. We identified family members with anterior segment findings. METHODS: Family members were examined with slit-lamp biomicroscopy and psychophysical tests including dark adaptation and visual fields. Genetic testing for the C1QTNF5 mutation was carried out. RESULTS: In this family with a proven mutation in this gene, peripupillary iris atrophy and abnormally long anterior zonular insertions were present before retinal changes and visual loss. CONCLUSIONS: Anterior segment findings have not previously been reported and along with impaired dark adaptation may serve as an early marker for this condition thus facilitating counseling and possible therapeutic intervention.

Cataract surgery in patients with age-related macular degeneration: one-year outcomes.

PURPOSE: To determine whether patients with age-related macular degeneration (ARMD) benefit from cataract surgery and to assess the risk of progression of preexisting maculopathy 4 and 12 months postoperatively. SETTING: Princess Alexandra Eye Pavilion, Royal Infirmary of Edinburgh, Edinburgh, Scotland. METHODS: Two groups of patients were evaluated prospectively. The study group comprised patients with ARMD scheduled to have cataract surgery (n = 40). The control group comprised patients with ARMD not having cataract surgery (n = 43). Patients were assessed at baseline (preoperatively) and 4 and 12 months postoperatively. Assessment included visual function tests and quality of life (QoL) measures. The mean values for each item tested were obtained for each group at each visit, and comparisons between visits were done using the Wilcoxon signed rank test. RESULTS: There were significant benefits of cataract surgery in terms of visual function and QoL measures at 4 and 12 months. There was no increased risk of progression of maculopathy in the study group. There were no significant differences in the items tested in the control group. CONCLUSIONS: One year postoperatively, QoL benefits were maintained in the study group and there was no increased risk of progression of maculopathy in patients with mild and moderate degrees of ARMD. Larger numbers of patients must be assessed prospectively for longer periods to determine the relative risk of progression of different stages of ARMD after cataract surgery.

Seven new loci associated with age-related macular degeneration.

Age-related macular degeneration (AMD) is a common cause of blindness in older individuals. To accelerate the understanding of AMD biology and help design new therapies, we executed a collaborative genome-wide association study, including >17,100 advanced AMD cases and >60,000 controls of European and Asian ancestry. We identified 19 loci associated at P < 5 × 10(-8). These loci show enrichment for genes involved in the regulation of complement activity, lipid metabolism, extracellular matrix remodeling and angiogenesis. Our results include seven loci with associations reaching P < 5 × 10(-8) for the first time, near the genes COL8A1-FILIP1L, IER3-DDR1, SLC16A8, TGFBR1, RAD51B, ADAMTS9 and B3GALTL. A genetic risk score combining SNP genotypes from all loci showed similar ability to distinguish cases and controls in all samples examined. Our findings provide new directions for biological, genetic and therapeutic studies of AMD.

Complement factor h autoantibodies and age-related macular degeneration.

PURPOSE: In this case-control study, the hypothesis that factor H autoantibodies are associated with age-related macular degeneration (AMD) was examined. METHODS: One hundred AMD patients (median age, 78 years), 98 age-matched control subjects (median age, 78 years) known not to have AMD, and 100 healthy blood donors (median age, 43 years) were enrolled. An enzyme-linked immunosorbent assay (ELISA) was used to screen for complement factor H autoantibodies and either quantitative polymerase chain reaction (qPCR) or multiplex ligation-dependent probe amplification (MLPA) were performed to measure the copy number of the gene encoding complement factor H-related protein 3 (CFHR3). RESULTS: There was a significant difference in the median complement factor H autoantibody titer between the three groups (AMD patients, 196 reference units [RU]]; age-match control subjects, 316 RU; and blood donor control subjects, 121 RU; Kruskal-Wallis test, P < 0.001). Pair-wise comparison (Mann-Whitney test) showed that all three groups were significantly different from each other. Two different thresholds were used in the healthy blood donors to identify individuals with complement factor H autoantibodies. Both suggested that the prevalence of factor H autoantibodies was decreased in AMD patients. The CFHR3 copy number was measured as a surrogate for the deletion of the genes encoding complement factor H-related proteins 3 and 1 (CFHR3/1). The allele frequency of the deletion was significantly higher in the age-matched control subjects than in the AMD patients (22.2% vs. 8.2%). CONCLUSIONS: The level of factor H autoantibodies is lower in AMD patients than in age-matched control subjects.

Transpupillary thermotherapy for the treatment of occult CNV in age-related macular degeneration: a prospective randomized controlled pilot study.

PURPOSE: To evaluate whether transpupillary thermotherapy (TTT) reduces the risk of moderate visual loss in patients with occult choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD). METHODS: A group of 25 patients were recruited and randomized into TTT or placebo groups. Patients were included if they had a subfoveal purely or predominantly (> 50%) occult CNV secondary to AMD with best corrected visual acuity (BCVA) of 6/60 or better and the lesion was not larger than 4.5 mm. Treatment was carried out using an 810-nm Oculight diode laser with a fixed spot size covering the whole lesion according to the standard protocol. The same procedure was used for the control group, except that the power was set at zero. The patients were followed up at 6 weeks, 3 months and then every 6 months for up to 2 years. A maximum of three treatments were administered in both groups if there was evidence of persistent leakage from CNV. RESULTS: At the 12-month follow-up, there was no significant difference in the mean values for BCVA distance and near or contrast sensitivity between the treatment and control groups. The Mann-Whitney test was used to assess the differences in BCVA and contrast sensitivity between the groups, both at baseline and at the 12-month follow-up. No statistically significant difference was found; both groups lost on average two lines of BCVA. CONCLUSION: Transpupillary thermotherapy appeared to have been of no benefit in preventing further visual loss in patients with occult CNV in this pilot study.