The Evolving Management of : Lessons from Wisconsin and Beyond

AuthorBlock: Lloyd P. Aiello1,2 1Joslin Center, Boston, Massachusetts, United States; 2Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States;

DisclosureBlock: Lloyd P. Aiello, KalVista Code C (Consultant), KalVista Code I (Personal Financial Interest), Novo Nordisk Code C (Consultant), Optos Code R (Recipient)

Presentation Description Less than 50 years ago, diabetic retinopathy was a severe blindng disease with few therapeutic options and often poor outcomes. The advent of laser photocoagulation ushered in a new era where severe visual loss from proliferative diabetic retinopathy (PDR) and diabetic macular edema (DME) could be averted in the majority of patients. However, some degree of visual loss was still frequent and laser photocoagulation destroyed areas of retina leading to side effects and complications. The discovery that VEGF played a central role in both PDR and DME led to development of VEGF inhibitors and a revolution in the care of diabetic . As a result, visual loss was further reduced, previously unseen magnitudes of visual improvement were realized, and amelioration nonproliferative diabetic retinopathy severity was also observed. The clinical benefit in various patient cohorts and therapeutic differences between VEGF inhibitors have also been evaluated.

These and numerous other developing therapies contiunue to make the clinical care of diabetic eye disease one of the longest and most rapidly evolving areas in . Throughout these many remarkable advancements, the fundamental robust understanding of the natural history and epidemiology of diabetic retinopathy provided by the Klein's and others have supported and guided the many clinical trial evaluations of these therapies. This presentation will discuss the evolution of care for diabetic retinopathy, its current status, challenges and new frontiers that arose from the remarkable contributions of Barbara and Ronald Klein. Risk factors for AMD: Genes and Nutrition, Updates of the AREDS/AREDS2 clinical trials

AuthorBlock: Emily Chew1 1National Eye Institute, Bethesda, Maryland, United States;

DisclosureBlock: Emily Chew, None;

Presentation Description Age-related (AMD), a leading cause of blindness in the United States and the developed world, is a complex genetic disease. The Age-Related Eye Disease Study (AREDS 1992-2001) and the AREDS2 (2006-2012) were phase 3 randomized controlled trials of nutritional supplements for the treatment of AMD. Genetic assessments were performed in both studies and nutritional questionnaires were obtained at baseline. The genetic component of AMD is estimated to be 45 to 70%. Currently, there are 34 known loci and 52 variants known to be associated with AMD. We have previously published the importance of nutrition in our observational data. . The interaction of genes with nutrtion in the AREDS and AREDS2 will be discussed. The phenotyping is extremely important in genetic studies. Much of the AREDS AMD classification is derived from the pioneer work for Drs. Ronald and Barbara Klein from the Beaver Dam Eye Study. The Kleins provided the senimalr work that has led us to a better understanding of the phenotyping and the risk factors associated with progression of AMD. Epidemiology of AMD: From Beaver Dam to the Three Continents

AuthorBlock: Caroline Klaver1 1Erasmus University Medical Center, Rotterdam, Netherlands;

DisclosureBlock: Caroline Klaver, None;

Presentation Description According to PubMed, the first report on the epidemiology of age-related macular degeneration (AMD), or senile macular degeneration as it was called, stems from 1967. The first report from Ron and Barbara Klein on the frequency of AMD was published in 1982, in which they immediately dropped the name ‘senile’ for appreciable reasons. The Klein’s were true founders of the modern epidemiology of AMD. They launched the population-based Beaver Dam Eye Study consisting of 4926 persons aged 43 to 84 in 1987 and performed extensive eye exams with imaging in this cohort every 5 years. Ron and Barbara Klein were also pioneers at grading retinal images and established one of the first retinal reading centers in the world. The Wisconsin Age-Related Maculopathy Grading Scheme (WARMGS) was a meticulous protocol that enabled grading of all types of drusen, RPE changes, and signs of late AMD in 9 macular subfields. The protocol formed the basis for virtually all AMD lesion definitions in grading schemes that were developed thereafter, and the Kleins hosted and taught retinal grading to many researchers from all over the world. Among the highlights on AMD epidemiology from Beaver Dam are the prevalence and progression of AMD, the relation with smoking , cardiovascular disease, dietary intake, serum antioxidants, inflammatory markers, and visual decline. Interesting was that as more and more persons developed incident AMD with each round of the cohort, associations became more valid. The associations with smoking and diet became very solid, while it also became clear that extraction was unlikely to be causally involved. One of the amazing results was from a genetic statistical report on Beaver Dam family members published in 1994. Long before GWAS, Heiba et al. claimed that AMD was determined by major genetic effects, which determined more than 50% of the disease variability. At the time, the general thinking was that AMD was determined by numerous genes with small effects, and the paper was discarded. More than 10 years later, CFH and ARMS2 were found, which together explained >50% of Late AMD. As generous ophthalmic epidemiologists, the Kleins helped design the Rotterdam Study in Europe and The Blue Mountain Eye Study in Australia. Epidemiology of diabetic retinopathy: past, current and future.

AuthorBlock: Barbara Klein1 1University of Wisconsin, Madison, Wisconsin, United States;

DisclosureBlock: Barbara Klein, None;

Presentation Description Prior to the use of insulin in 1922, people who developed Type 1 Diabetes (T1D) died before developing the microvascular complications. As survival improved for both those with T1D and Type 2 Diabetes (T2D), the incidence of decreased visual acuity and blindness became more frequent, and the study of diabetic retinopathy (DR) evolved. There was a need to characterize and track the sequence of these retinal lesions to better understand the mechanisms of development and the best approach for clinical intervention. As of 1978 systems to classify DR were not fully resolved. In 1979 the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) was funded with these aims: to describe the prevalence and severity of DR and vision loss in diabetics and the relationships to other systemic complications including mortality; to quantitate the associations of risk factors to DR; to provide information on health care delivery and quality of life in diabetics. 2990 persons were selected for the first examination. Stereoscopic photographs of the DRS 7-standard retinal fields were taken and graded according to standard protocols. Participants were seen approximately every 5 years over the course of more than 30 years. Data from the WESDR showed that glycosylated hemoglobin (HbA1c) was associated with the incidence and progression of diabetic retinopathy, and the incidence of clinically significant macular edema (CSME) suggesting the level of glycemia was the risk factor. The relationship of HbA1c to progression of DR was found at any stage of DR and at any duration of diabetes. In summary, the WESDR has provided population-based estimates of the prevalence and incidence of DR. The associations of glycemia and other traditional risk factors with the incidence and progression of retinopathy have been quantitated. These findings have resulted in the development of guidelines and health education programs directed at prevention, and earlier treatment of DR. Future goals for health care is to decrease the risk of diabetes and to minimize the incidence of DR in diabetics. Better understanding of mechanisms of the development of DR as suggested by bench and epidemiologic research is needed. Other medical approaches and lifestyle- behavioral changes (e.g., exercise, weight control, dietary factors) need to be tested and those that appear to be successful incorporated in care of diabetics to prevent and/or treat DR. Evolution of Retinal Disease Classification: From fundus photos to digital software

AuthorBlock: Tien Y. Wong1,2 1Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore; 2Duke-NUS Medical School, National University of Singapore, Singapore, Singapore;

DisclosureBlock: Tien Y. Wong, Bayer Code C (Consultant), Boehringer-Ingelheim Code C (Consultant), Genentech Code C (Consultant), Novartis Code C (Consultant), Merck Code C (Consultant), Roche Code C (Consultant), EyRIS Code I (Personal Financial Interest), Retinal Global Code S (Non-remunerative), plano Code I (Personal Financial Interest)

Presentation Description Over the past 5 decades, ophthalmology has been transformed by ocular imaging. For the major retinal diseases including diabetic retinopathy (DR) and age-related macular degeneration (AMD), the invention of the fundus camera has allowed these diseases to be precisely classified in 'film-based retinal photographs', resulting in landmark clinical trials (DRS, ETDRS, DCCT) and epidemiological studies (Beaver Dam, Wisconsin Epidemiological Study of DR, Blue Mountains, Rotterdam). The next major innovation was the adoption of 'digital photographs' that was used in subsequent clinical trials (AREDS, ACCORD, DRCR.Net), and epidemiological studies (MESA, NHANES, SEED). The third major revolution was the invention and use of OCT, which led to the evolution of new classification of neovascular AMD and the foundation for the anti-VEGF trials (MARINA, ANCHOR, CATT, VIEW, DRCR.Net). The fourth revolution will be the advent of artificial intelligence (AI) and deep learning (DL), which will impact on how retinal diseases will be diagnosed and classified in the future.