Age related macular degeneration Miklós Resch Lecture Faculty of General Medicine, ÁLTALÁNOS ORVOSTUDOMÁNYI KAR, BUDAPEST IGAZGATÓ: PROF. DR. NAGY ZOLTÁN ZSOLT Definition Age-relateddegenerationof macula lutea Abbreviations(AMD, ARMD) Forms: Drusen Retinal pigmentepithelium changes (hypo/hyperpigmentation) Geographic atrophy Neovascular macular degeneration Forms Anatomy Dry = non exsudative(85%) Drusen Geographicatrophy SLOW VISION LOSS Wet= exsudative(15%) Chorioidal Neovascularisation(CNV) Intra-, or subretinal fluid Blood/ exsudatum QUICK VISION LOSS Fovea Macula AMD pathology Pathogenesis Not exactly known, but playing role: Oxidative stress Retinal pigmentepithelium ageing(no mitosis) Inflammation Hemodinamic changes with ageing Growth factors Complement system Genetics Environmental Pámer Zs. Szemészet 2013 1
AMD epidemiology In the industrially developed world, AMD is the primarycause of blindness for adults >55 years of age. United States: 8 million people 55 years old monocular or binocularintermediate AMD or monocular advanced AMD GA Responsible for 20% of all cases of legal blindness 43% AMD infelloweyein5 years Framingham EYE Study: 6,4% (65-74 years), 19,7% (>75 years) Gutenberg Health Study(n=4340) starting at 35 years! (Korb Graefe 2014) www.readingcentre.org AMD epidemiology Beaver Dam Eye Study 1988 2005 Incidence: early AMD 14.3%, late AMD 3.1% Prevalence: 15.6% early age-related maculopathy, 1.6% late AMD, 1.2% neovascularamd Framingham Eye Study 1973 1975 Prevalence: 8.8% overall Rotterdam Eye Study 1990 1993 Prevalence: 1.7% overall, 1.1% neovascular AMD Blue Mountains Eye Study 1992 2004 Incidence: 10.8% early AMD, 2.8% late AMD Prevalence: 1.9% overall Klein et al. Ophthalmology 2007; 114: 253-262 Klein et al. Ophthalmology 1992; 99: 933-943 Kahn et al. Am J Epidemiol 1977; 106: 17-32 Vingerling et al. Ophthalmology 1995; 102: 205-210 Wang et al. Ophthalmology 2007; 114: 92-98 Mitchell et al. Ophthalmology 1995; 102: 1450-1460 Causesof blindnessinhungary Symptoms Loss of visual acuity, color vision Metamorphopsia Central scotoma Kiss and Németh J 2013 Diagnosis Classification(AREDS) Visual acuity Amsler grid(self test) Risk factor assessment Smoking 2,5x OR! Family history Fundus examination Fluorescein angiography Optical coherence tomography(oct) Larger drusen -> worse prognosis 2
OCT of normal retina (macula) OCT inamd Normal Dry AMD Wet AMD Riskof seriousvisuallossin5 years(areds) AREDS 1 ( no AMD) ~ 0% AREDS 2 (earlyamd) 1,3% AREDS 3 (intermediate AMD) 18% AREDS 4 (developed AMD) othereye43% Dry AMD(Drusen) Photoreceptorok RPE Chorioidea Normal retina Fovea Macula Bruch membrane thickening, Drusen formation http://caseyamdcalc.ohsu.edu/ Genentech, Inc. AMD progression Chorioi oideal Neovascularization (CNV) End stage exsudative AMD Fibrovascular (glia glia) scar Newly formed abnormal vessels proliferate and break Bruchs membrane Leakage from neovascularisations Genentech, Inc. Genentech, Inc. 3
Treatment No causal treatment/ prevention DryAMD supplements Slowing down progression WetAMD stop neovascularisationand leakage -> DryAMD Supplements AREDS 1 or2 orothers Macular laser photocoagulation Direct photocoagulation of CNV (photoreceptors + RPE) 50% recurrence Vision loss unavoidable Photodynamic therapy(pdt) Selectivephotothrombosisof CNV Effective and safe Repeatable Visionlosscanbe sloweddown / stopped No vision improvement MPS: Macular Photocoagulation Study CAPT: Complications of Age-Related Macular Degeneration Prevention Trial Anti VEGF therapy VEGF VEGF: Angiogenic Increases permeability Significant in the eye: VEGF-A 36-46 kd glikozilated protein VEGF-A isomers: VEGF 110 VEGF 121 VEGF 165 VEGF 189 VEGF 206 * VEGF: Vascular endothelial growth factor Witmer A.N. et al: Progress SEMMELWEIS in Retinal and Eye EGYETEM Research 22 (2003) 1 29 4
VEGF inhibitors2014 2007. Pegaptanib(Macugen ) 2008. Ranibizumab(Lucentis ) 2008. Bevacizumab(Avastin ) 2013. Aflibercept(Eylea ) Intravitrealadministration Monthly/ Bimonthly injections Bevacizumab(Avastin ) VEGF 121, VEGF 165, VEGF 110, VEGF 154, VEGF 109 Hypoxia Bevacizumab Acts early in the cascade 1 Attacks disease in 2 ways Inhibits permeability 2 Blocks angiogenesis 3 Penetrates retina to block all VEGF isoforms 4 VEGF FGF Other angiogenic factors Proliferation Migration Proteolysis Vascular endothelial cell Basement Membrane 1. Lowe J et al. Invest Ophthalmol Vis Sci. 2003; vol. 44. E-ARVO abstract 1828. 2. Gaudreault J et al. Invest Ophthalmol Vis Sci. 2003; vol. 44. E-ARVO abstract 3942. 3. Krzystolik MG et al. Arch Ophthalmol. 2002;120:338-346. 4. Mordenti J et al. Toxicol Pathol. 1999;27:536-544. Ranibizumab(Lucentis ) Humanized monoclonal antibody fragment(not complete Ab) ProducedbyrecombinantDNA technology(escherichiacoli bacteria) Intravitreal inj(4 week interval) Non selective VEGF antagonist Registration: 2006 USA, Switzerland, 2007 EU Wide range of indications Brown DM New England Journal of Medicine. 355(14):1432-44, 2006 Rosenfeld PJ. New England Journal of Medicine. 355(14):1419-31, 2006 12 10 8 6 4 2 0-2 -4-6 -8-10 -12 Visual improvement with ranibizumab MARINA Min. class. or occult CNV 1 2 3 4 5 6 7 8 9 10 11 12 Follow up (months) Ranibizumab 0.5 mg (n=240) Ranibizumab 0.3 mg (n=238) Sham (n=238) ANCHOR VA change (ETDRS letters) 17.0*** +7.2 +6.5 12 10 8 6 4 2 0-2 -4-6 -8 10.5-10 -12 Predom. class. CNV 0 1 2 3 4 5 6 7 8 9 10 11 12 Follow up (months) 18.0*** Ranibizumab 0.5 mg (n=139) Ranibizumab 0.3 mg (n=140) Verteporfin (n=143) +11.3 +8.5 9.5 ***p<0.0001 Aflibercept(Eylea) Aflibercept(VEGF-trap) BlocksallVEGF A összes isoformsand PLGF Fusion protein Intravitreal adminisration Similar to ranibizumab FOVISTA PDGF platelet derived growth factor Aptamer nukleic acid sequence 5
Diseasemodification(nottreatment) (Seven-up Study) Rofagha: Seven-Year OutcomesinRanibizumab-Treated Patients in ANCHOR, MARINA, andhorizon. Ophthalmology 2013 AMD-related blindness in antivegf era Denmark: Over 50 years Decreased from 52,2 to 25,7 per 100.000 ingabitants 1 +1,9 SE Szemklinika ranibizumab 46% need injection After year 4, 2 inj/year -1,4-5,4 n=20? A vakság incidenciája 80 60 40 20 0 2007: Ranibizumab In Denmark 1998 2002 2006 2010 AMD related blindness Other cause of blindness Bloch SB et al. Am J Ophthalmol 2012;153:209-13 Skaat A et al. Am J Ophthalmol 2012;153:214 21 Thank you! 6