Macular Degeneration: Lotery A

Lotery A. · No affiliation provided · Eye. · Pubmed #18548082 No free full text.

This publication has no abstract.

Lotery A, Trump D. · Clinical Neurosciences Division, University of Southampton, Southampton General Hospital, Southampton, SO16 6YD, UK. · Hum Genet. · Pubmed #17659362 No free full text.

Abstract: Age related macular degeneration (AMD) is an extremely prevalent complex genetic disorder. Its incidence rises exponentially in the elderly to a frequency of 1 in 2 in the general population by age 85. It affects approximately 25 million people and is the commonest cause of irreversible visual loss in the Western world. It is therefore a major public health problem. However, until recently its aetiology was unknown. Our understanding of both the molecular biology of AMD and the relevant clinical treatments has progressed dramatically in the last 2 years. Two genes of large effect have been identified which together contribute to over 70% of the population attributable risk of AMD. Treatments which inhibit expression of vascular endothelial growth factor have been developed which can rescue vision in the "wet" form of the disease. The association of complement factor H with AMD highlights the importance of the alternative complement pathway in the development of AMD whilst the pathophysiology of the serine protease HTRA1 is now under intensive study. This review will give an insight into these developments and will summarise our current knowledge of the molecular biology of AMD.

Canning C, Lotery A. · Southampton Eye Unit, Southampton General Hospital, Southampton, UK. · Eye. · Pubmed #16858443 No free full text.

Abstract: This review highlights the history of the development of treatments for choroidal neovascularization (wct AMD). It examines how drug therapies have evolved for the management of age-related macular degeneration (AMD) and the value of randomised clinical trials in determining efficacy. Finally it examines the emerging practice of utilising bevacizumab for the treatment of choroidal neovascularization despite the lack of any phase III clinical trial data.

Ennis S, Jomary C, Mullins R, Cree A, Chen X, Macleod A, Jones S, Collins A, Stone E, Lotery A. · Genetic Epidemiology and Bioinformatics Group, University of Southampton, Human Genetics Division (Mp 808), Southampton General Hospital, Southampton, UK. · Lancet. · Pubmed #18842294 No free full text.

Abstract: BACKGROUND: Age-related macular degeneration is the most prevalent form of visual impairment and blindness in developed countries. Genetic studies have made advancements in establishing the molecular cause of this disease, identifying mutations in the complement factor H (CFH) gene and a locus on chromosome 10 encompassing the HTRA1/LOC387715/ARMS2 genes. Variants in complement 3 (C3) and an HLA locus containing both factor B and C2 genes have also been implicated. We aimed to identify further genetic risk factors for this disease. METHODS: We used a case-control study design in a UK sample of patients with age-related macular degeneration (n=479) and controls (n=479) and undertook a low-density screen of 32 genes using 93 single nucleotide polymorphisms (SNPs). Genes were selected as candidates on the basis of potential functional relevance to age-related macular degeneration. Significant initial findings were confirmed by replication in an independent US cohort of 248 unrelated patients with disease and 252 controls, and by high-density genotyping around association signals. FINDINGS: The SNP variant rs2511989, located within intron six of the SERPING1 gene, showed highly significant genotypic association with age-related macular degeneration (uncorrected p=4.0x10(-5), corrected p=0.00372). We detected no evidence for association between disease and the other 31 candidate genes. The odds ratio for age-related macular degeneration in rs2511989 G/A heterozygotes compared with wild type G/G homozygotes was 0.63 (95% CI 0.47-0.84). A similar comparison of the A/A homozygotes with the wild type yielded an odds ratio of 0.44 (0.31-0.64). We replicated the observed genotypic association in a US cohort (p=0.008). Furthermore, a secondary high-density genotyping study across the SERPING1 gene region identified five additional SNP variants similarly associated with age-related macular degeneration (rs2244169, rs2511990, rs2509897, rs1005510, and rs2511988). INTERPRETATION: Genetic variation in SERPING1 significantly alters susceptibility to age-related macular degeneration. SERPING1 encodes the C1 inhibitor, which has a crucial role in inhibition of complement component 1 (C1) and might implicate the classic pathway of complement activation in this disease.

Cruess AF, Zlateva G, Xu X, Soubrane G, Pauleikhoff D, Lotery A, Mones J, Buggage R, Schaefer C, Knight T, Goss TF. · Department of Ophthalmology and Visual Sciences, Dalhousie University, Halifax, Nova Scotia, Canada. <> · Pharmacoeconomics. · Pubmed #18088159 No free full text.

Abstract: BACKGROUND: There is limited previous research examining the healthcare costs of neovascular age-related macular degeneration (NV-AMD), which constrains our understanding of the economic impact of this condition. With aging populations, this leading cause of rapid vision loss in Western countries is expected to become a pressing health predicament, requiring decision makers to evaluate alternative treatment strategies for AMD. OBJECTIVE: To document the economic burden of bilateral NV-AMD, the late stage of AMD, in elderly patients, from a societal perspective. STUDY DESIGN, SETTING AND PARTICIPANTS: A cross-sectional, observational study surveyed 401 patients with bilateral NV-AMD and 471 non-AMD subjects in Canada, France, Germany, Spain and the UK. Physicians' records and subjects' standardized telephone interviews were used to record medical resource utilization, assistance with daily living and social benefits. Annual bilateral NV-AMD-related socioeconomic costs were calculated in euro, year 2005 values. MAIN OUTCOME MEASURES: Societal costs including direct vision-related medical costs (e.g. treatment of AMD and vision-related equipment), direct non-vision-related medical costs (e.g. medications) and direct non-medical-related costs (e.g. home healthcare and social services) were the main outcome measures. RESULTS: The demographic profile of NV-AMD patients was similar across countries; however, co-morbid condition profiles varied. NV-AMD patients reported substantial health-related problems and associated health resource utilization (HRU). In the previous 12 months, 12-22% of patients fell, and half of these patients required medical treatments. More than 20% (range 21-59%) of patients were prescribed vision-enhancing equipment. More than half of the patients (54-81%) were living with a spouse or family member and 19-41% reported receiving assistance for activities of daily living.The average annual societal cost per bilateral NV-AMD patient treated was estimated to be euro 7879 in Canada, euro 7349 in France, euro 12 445 in Germany, euro 5732 in Spain and euro 5300 in the UK, and direct vision-related medical costs accounted for 23-63% of the total cost. Half of the patients were diagnosed with bilateral NV-AMD for <1 year, with an average length of 5 months; there were no statistically significant differences in total annual costs per patient between these patients and those who were diagnosed with bilateral disease for > or =1 year. Estimated annual societal costs of bilateral NV-AMD patients in these countries ranged from euro 268 to euro 1311 million. Estimated annual societal costs of all NV-AMD patients in these countries ranged from euro 671 to euro 3278 million. CONCLUSIONS: Bilateral NV-AMD imposes significant functional impairment on patients, leading to increased HRU and a high societal cost burden. Differences in national healthcare systems and NV-AMD treatment patterns were reflected in the wide variation of NV-AMD costs across the five surveyed countries. Even though the prevalence rates and per-patient costs varied by country, the societal costs of NV-AMD patients were substantial in each country. Earlier intervention with effective therapies is expected to reduce disease burden and disability associated with NV-AMD and, thus, decrease the overall societal cost.

Soubrane G, Cruess A, Lotery A, Pauleikhoff D, Monès J, Xu X, Zlateva G, Buggage R, Conlon J, Goss TF. · Department of Ophthalmology, University Paris XII, Centre Hospitalier Intercommunal de Créteil, 40 Avenue de Verdun, Créteil, France. · Arch Ophthalmol. · Pubmed #17846366 links to  free full text

Abstract: OBJECTIVE: To describe the burden of bilateral neovascular age-related macular degeneration (NV-AMD) on patient-reported functioning and health resource utilization. METHODS: A cross-sectional study of 401 patients with bilateral NV-AMD and 471 elderly control subjects without AMD was conducted in 5 countries. Subjects completed a telephone survey, including the National Eye Institute 25-Item Visual Function Questionnaire, the EuroQol instrument, the Hospital Anxiety and Depression Scale, and history of falls, fractures, and health care resource utilization. RESULTS: The mean age for patients with NV-AMD was 78.1 years, and 65% were women. The patients reported 45% worse vision-related functioning, 13% worse overall well-being, and 30% more anxiety and 42% more depression symptoms than controls after adjusting for covariates (all, P < .001). The effect of NV-AMD was also observed as a doubled fall rate (16% vs 8% [P < .001]) and a quadrupled need for assistance with daily activities (29% vs 7% [P < .001]) in the patients compared with controls. CONCLUSIONS: The evidence of extensive decline in quality of life and increased need of daily living assistance for patients with NV-AMD compared with a control population substantiates the need for new treatments that prevent vision loss and progression to blindness.

Lotery A, Xu X, Zlatava G, Loftus J. · University of Southampton, Southampton Eye Unit, Southampton General Hospital, Tremona Road, Southampton SO16 6YD, UK. · Br J Ophthalmol. · Pubmed #17504847 No free full text.

Abstract: BACKGROUND/AIMS: Quantitative data regarding the impact of neovascular age-related macular degeneration (NV-AMD) on individuals and society is a prerequisite for rational decision-making processes when evaluating alternative treatments for the disease. METHODS: 75 bilateral NV-AMD (patients) and 91 elderly non-AMD (controls) subjects forming the UK cohort of an international cross-sectional, observational study were independently analysed. Subjects completed a telephone survey including the National Eye Institute Visual Function Questionnaire (NEI-VFQ-25), the EuroQol (EQ-5D), the Hospital Anxiety and Depression Scale (HADS), history of falls and health resource utilisation. RESULTS: Patients with NV-AMD reported substantially worse vision-related functioning and overall well-being, including higher depression scores, than controls after adjusting for age, gender and co-morbidities (adjusted mean scores: NEI-VFQ-25 overall 52.7 vs 90.7, p<0.0001; EQ-5D 0.67 vs 0.77, p = 0.0273; HADS depression 6.8 vs 4.0, p = 0.0026). Significantly more patients reported a need for assistance with daily activities compared with controls (25.3% vs 6.6%, p = 0.003). Total annual healthcare utilisation costs were more than sevenfold higher for patients with AMD compared with controls ( pound 3,823.89 vs pound 517.05, respectively; p<0.0001) CONCLUSIONS: Patients with NV-AMD show a significant decline in quality of life and increased need for daily living assistance compared to a control population without AMD. With the availability of effective new therapies there is a need for improved early access to treatment.

Raftery J, Clegg A, Jones J, Tan SC, Lotery A. · Wessex Institute for Health R&D, Medical School, University of Southampton, Southampton, UK. · Br J Ophthalmol. · Pubmed #17431015 No free full text.

Abstract: Two new drugs provide startling benefits in the treatment of age-related macular degeneration (AMD). The clinical and cost effectiveness of ranibizumab (Lucentis) was compared to that of bevacizumab (Avastin), which costs up to 100 times less. A cost effectiveness model was developed to assess the cost per quality adjusted life year (QALY) over 10 years. For predominantly classic AMD, the efficacy of bevacizumab relative to ranibizumab would have to be around 40% for the latter to achieve 30 k pounds per QALY, a NICE threshold. Similar but worse results applied to the other main forms of AMD, minimally occult and occult with no classic lesions. The price of ranibizumab would have to be drastically reduced for it to be cost effective. Continued unlicensed use of bevacizumab raises ethical, legal and policy questions. Public pressure may be the most potent weapon in persuading Genentech to license bevacizumab for AMD.

Ennis S, Goverdhan S, Cree A, Hoh J, Collins A, Lotery A. · Genetic Epidemiology and Bioinformatics Group, Human Genetics Division (MP 808), Southampton General Hospital, Southampton, UK. · Br J Ophthalmol. · Pubmed #17314151 No free full text.

Abstract: AIM: To present results from a nested association study of the complement factor H (CFH) gene region using a novel methodology that uses a high-resolution genetic linkage disequilibrium map to estimate a point location for a causal mutation. METHOD: Age-related macular degeneration (AMD) case-control data from a genomewide single-nucleotide polymorphism (SNP) panel were used to identify the target interval to be genotyped at higher density in a second independent panel. The pattern of linkage disequilibrium (LD) and segmental duplications across this region are described in detail. RESULT: Data were consistent with other studies in that strong association between the Y402H variant and AMD is observed. However, composite likelihood analysis, which combines association data from all SNPs in the region, and uses genetic locations on a high-resolution LD map, gave a point location for a causal variant between exons 1 and 2 of the CFH gene. CONCLUSION: The findings are consistent with evidence that, in addition to the widely described Y402H variant, there is at least one and, most probably, several other mutations in the CFH gene which determine disease manifestation in AMD. A genetic model in which multiple mutations contribute to a varying degree to disease aetiology has been previously well described in ophthalmic genetics, and is typified by the COL2A1 and ABCA4 genes.