Complement inhibitors for age-related macular degeneration

Given the relatively high prevalence of age-related macular degeneration (AMD) and the increased incidence of AMD as populations age, the results of trials of novel treatments are awaited with much anticipation. The complement cascade describes a series of proteolytic reactions occurring throughout the body that generate proteins with a variety of roles including the initiation and promotion of immune reactions against foreign materials or micro-organisms. The complement cascade is normally tightly regulated, but much evidence implicates complement overactivity in AMD and so it is a logical therapeutic target in the treatment of AMD

A case-control study of drug risk factors for age-related macular degeneration.

OBJECTIVE: To investigate the association between age-related macular degeneration (AMD) and exposure to antacids, antithyroids, thyroid hormones, and thiazide diuretics. DESIGN: Matched case-control study. PARTICIPANTS: Population-based participants were selected from the United Kingdom General Practice Research Database. A total of 18,007 people with diagnosed AMD were compared with 86 169 controls matched for age, gender, and general practice. METHODS: Conditional logistic regression was used to determine the association between exposure to each drug group of interest and a diagnosis of AMD, adjusting for relevant confounding variables. MAIN OUTCOME MEASURES: The primary outcome was the odds ratio for the association between exposure to antacids, antithyroids, thyroid hormones, or thiazide diuretics and AMD. Secondary analyses were conducted to assess the effect of recent exposure to the drugs of interest, the total number of prescriptions received, and restricting the data set to participants with more than 2 years of observation time. RESULTS: The crude odds ratios for association between any record of drug exposure and AMD were as follows: 1.34 (95% confidence interval [CI], 1.29-1.39) for antacids; 1.15 (95% CI, 0.92-1.44) for antithyroids; 1.34 (95% CI, 1.29-1.39) for thyroid hormones; and 1.13 (95% CI, 1.08-1.17) for thiazide diuretics. After adjusting for consultation rate, observation time, diabetes, heart failure, hyperlipidemia, cardiovascular drug use, atherosclerosis, hypertension, aspirin use, hormone replacement therapy use, body mass index, alcohol consumption, and smoking, the odds ratios reduced to: 1.06 (95% CI, 1.02-1.10) for antacids, 0.98 (95% CI, 0.78-1.24) for antithyroids, 0.99 (95% CI, 0.92-1.06) for thyroid hormones, and 0.98 (95% CI, 0.94-1.02) for thiazides. Secondary analyses were consistent with these findings for all 4 drug categories. CONCLUSIONS: No association was detected between short- and medium-term use of antithyroids, thyroid hormones, and thiazide diuretics and the risk of AMD. Short- and medium-term use of antacids seems to be associated with a small increase in the risk of this disease. However, this increased risk is likely the result of residual confounding by smoking or uncontrolled confounding resulting from socioeconomic status. No conclusions could be drawn regarding longer-term use of each drug category

Tomographic Biomarkers Predicting Progression to Fibrosis in Treated Neovascular Age-Related Macular Degeneration: A Multimodal Imaging Study.

Purpose: To describe the photoreceptor–retinal pigment epithelium (RPE) interface changes and to analyze the relationships between these features and hyperreflective material (HRM) with scarring and atrophy at the macula of patients with neovascular age-related macular degeneration (nAMD). Design: Retrospective single-center observational study. Participants: A total of 150 eyes from 144 patients with naive nAMD were included. Methods: All patients had OCT (HRA-OCT Spectralis, Heidelberg Engineering, Heidelberg, Germany) at baseline and at 1, 3, 6, and 12 months. Macular scar and macular atrophy (MA) were determined on multimodal imaging, including color fundus (CF) and near-infrared imaging at baseline and month 12 (M12). Main Outcome Measures: Change in HRM type (undefined and well-defined) and location, development of fibrotic or nonfibrotic macular scar, MA, and best-corrected visual acuity (BCVA) at M12. Results: At baseline, eyes with fibrin on CF had thicker and wider HRM on OCT that correlated strongly with presence of undefined HRM. The proportion of eyes with undefined HRM fell dramatically by month 1 but well-defined HRM increased. At M12 defined HRM was strongly associated with macular scar (chi-square, 82.1; P < 0.001). Ordinal regression showed that both the thickness and the width of HRM were significant risk factors for development of fibrotic scar (P < 0.001 and P = 0.02) but not nonfibrotic scars (P = 0.67 and P = 0.65). Fibrotic macular scar (P = 0.001) but not nonfibrotic scar (P = 0.129) negatively affected visual acuity at M12. Ordinal regression showed that the risk factors for progression to MA were reticular pseudodrusen and thinner HRM (P = 0.017 and P = 0.028, respectively). MA negatively affected BCVA at M12 (P < 0.001). Conclusion: Our study supports the role of HRM as an important biomarker for the evolution of macular scar and atrophy in patients with nAMD undergoing treatment with anti-VEGF therapies. Undefined HRM can resolve with treatment, whereas well-defined HRM likely contains vascular complexes and fibrotic elements

Polymorphisms in ARMS2/HTRA1 and complement genes and age-related macular degeneration in India: findings from the INDEYE study.

PURPOSE: Association between genetic variants in complement factor H (CFH), factor B (CFB), component 2 (C2), and in the ARMS2/HTRA1 region with age-related macular degeneration (AMD) comes mainly from studies of European ancestry and case-control studies of late-stage disease. We investigated associations of both early and late AMD with these variants in a population-based study of people aged 60 years and older in India. METHODS: Fundus images were graded using the Wisconsin Age-Related Maculopathy Grading System and participants assigned to one of four mutually exclusive stages based on the worse affected eye (0 = no AMD, 1-3 = early AMD, 4 = late AMD). Multinomial logistic regression was used to derive risk ratios (RR) accounting for sampling method and adjusting for age, sex, and study center. RESULTS: Of 3569 participants, 53.2% had no signs of amd, 45.6% had features of early amd, and 1.2% had late amd. CFH (RS1061170), C2 (RS547154), OR CFB (RS438999) was not associated with early or late AMD. In the ARMS2 locus, RS10490924 was associated with both early (adjusted RR 1.22, 95% confidence interval [CI]: 1.13-1.33, P < 0.0001) and late AMD (adjusted RR 1.81, 95% CI: 1.15-2.86; P = 0.01); rs2672598 was associated only with early AMD (adjusted RR 1.12, 95% CI: 1.02-1.23; P = 0.02); rs10490923 was not associated with early or late AMD. CONCLUSIONS: Two variants in ARMS2/HTRA1 were associated with increased risk of early AMD, and for one of these, the increased risk was also evident for late AMD. The study provides new insights into the role of these variants in early stages of AMD in India

Trends in provision of photodynamic therapy and clinician attitudes: a tracker survey of a new health technology

BACKGROUND: There has been debate about the cost-effectiveness of photodynamic therapy (PDT), a treatment for neovascular age-related macular degeneration. We have been monitoring trends for the provision of PDT in the UK National Health Service. The fourth annual 'tracker' survey took place as definitive National Institute for Clinical Excellence (NICE) guidance was issued. We assessed trends in PDT provision up to the point of release of the NICE guidance and identified likely sources of pressure on ophthalmologists to provide PDT. METHODS: National postal questionnaire survey of clinicians with potential responsibility for PDT provision. The survey explored reported local provision, beliefs about the effectiveness of PDT and what sources of opinion might influence attitudes towards providing PDT. RESULTS: The response rate was 73% (111/150). Almost half of the surveyed ophthalmology units routinely provided PDT, as part of a trend of steady growth in provision. The proportion of respondents who believed that further proof of effectiveness was required has also declined despite the absence of any new substantial evidence. Attitudes towards providing PDT were positive, on average, and were more strongly associated with perceived social pressure from local colleagues than from other sources. Local colleagues were seen as being most approving of PDT. CONCLUSION: Those responsible for implementing the NICE guidance need to address ophthalmologists' beliefs about the evidence of effectiveness for PDT and draw upon supportive local individuals or networks to enhance the credibility of the guidance

The Economic Impact of Blindness in Europe

Purpose: To estimate the annual loss of productivity from blindness and moderate to severe visual impairment (MSVI) in the population aged >50 years in the European Union (EU). Methods: We estimated the cost of lost productivity using three simple models reported in the literature based on (1) minimum wage (MW), (2) gross national income (GNI), and (3) purchasing power parity-adjusted gross domestic product (GDP-PPP) losses. In the first two models, assumptions included that all individuals worked until 65 years of age, and that half of all visual impairment cases in the >50-year age group would be in those aged between 50 and 65 years. Loss of productivity was estimated to be 100% for blind individuals and 30% for those with MSVI. None of these models included direct medical costs related to visual impairment. Results: The estimated number of blind people in the EU population aged >50 years is ~1.28 million, with a further 9.99 million living with MSVI. Based on the three models, the estimated cost of blindness is €7.81 billion, €6.29 billion and €17.29 billion and that of MSVI €18.02 billion, €24.80 billion and €39.23 billion, with their combined costs €25.83 billion, €31.09 billion and €56.52 billion, respectively. The estimates from the MW and adjusted GDP-PPP models were generally comparable, whereas the GNI model estimates were higher, probably reflecting the lack of adjustment for unemployment. Conclusion: The cost of blindness and MSVI in the EU is substantial. Wider use of available cost-effective treatment and prevention strategies may reduce the burden significantly