Definition. Age related macular degeneration. Miklós Resch. Anatomy. Forms. AMD pathology. Pathogenesis Dry = non exsudative(85%) Drusen

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Viktor Horváth
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ORVOSTUDOMÁNYI KAR, BUDAPEST IGAZGATÓ: PROF. DR.

pigmentepithelium changes (hypo/hyperpigmentation)

Forms Anatomy Dry = non exsudative(85%) Drusen

exsudative(15%) Chorioidal Neovascularisation(CNV)

VISION LOSS Fovea Macula AMD pathology Pathogenesis

stress Retinal pigmentepithelium ageing(no mitosis)

1 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

AMD epidemiology In the industrially developed world, AMD is the primarycause of blindness for adults >55 years of age.

for 20% of all cases of legal blindness 43% AMD infelloweyein5 years Framingham EYE Study: 6,4% (65-74 years), 19,7% (>75

org AMD epidemiology Beaver Dam Eye Study 1988 2005 Incidence: early AMD 14.3%, late AMD 3.1% Prevalence: 15.

8% overall Rotterdam Eye Study 1990 1993 Prevalence: 1.7% overall, 1.

9% overall Klein et al. Ophthalmology 2007; 114: 253-262 Klein et al. Ophthalmology 1992; 99: 933-943 Kahn et al.

Ophthalmology 2007; 114: 92-98 Mitchell et al.

2 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) AMD epidemiology Beaver Dam Eye Study 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 Prevalence: 8.8% overall Rotterdam Eye Study Prevalence: 1.7% overall, 1.1% neovascular AMD Blue Mountains Eye Study Incidence: 10.8% early AMD, 2.8% late AMD Prevalence: 1.9% overall Klein et al. Ophthalmology 2007; 114: Klein et al. Ophthalmology 1992; 99: Kahn et al. Am J Epidemiol 1977; 106: Vingerling et al. Ophthalmology 1995; 102: Wang et al. Ophthalmology 2007; 114: Mitchell et al. Ophthalmology 1995; 102: 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

3 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 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

Supplements AREDS 1 or2 orothers Macular laser photocoagulation Direct

loss unavoidable Photodynamic therapy(pdt) Selectivephotothrombosisof

No vision improvement MPS: Macular Photocoagulation Study CAPT:

VEGF therapy VEGF VEGF: Angiogenic Increases permeability Significant in

VEGF 121 VEGF 165 VEGF 189 VEGF 206 * VEGF: Vascular endothelial growth

4 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 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)

VEGF inhibitors2014 2007. Pegaptanib(Macugen ) 2008. Ranibizumab(Lucentis ) 2008. Bevacizumab(Avastin ) 2013.

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

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.

Ranibizumab(Lucentis ) Humanized monoclonal antibody fragment(not complete Ab) ProducedbyrecombinantDNA technology(escherichiacoli bacteria) Intravitreal inj(4

355(14):1432-44, 2006 Rosenfeld PJ. New England Journal of Medicine.

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.

5 VEGF inhibitors Pegaptanib(Macugen ) Ranibizumab(Lucentis ) Bevacizumab(Avastin ) 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 Gaudreault J et al. Invest Ophthalmol Vis Sci. 2003; vol. 44. E-ARVO abstract Krzystolik MG et al. Arch Ophthalmol. 2002;120: Mordenti J et al. Toxicol Pathol. 1999;27: 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): , 2006 Rosenfeld PJ. New England Journal of Medicine. 355(14): , Visual improvement with ranibizumab MARINA Min. class. or occult CNV 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*** Predom. class. CNV Follow up (months) 18.0*** Ranibizumab 0.5 mg (n=139) Ranibizumab 0.3 mg (n=140) Verteporfin (n=143) ***p< 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

000 ingabitants 1 +1,9 SE Szemklinika ranibizumab 46% need injection After year 4, 2 inj/year -1,4-5,4 n=20?

6 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 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 : Ranibizumab In Denmark AMD related blindness Other cause of blindness Bloch SB et al. Am J Ophthalmol 2012;153: Skaat A et al. Am J Ophthalmol 2012;153: Thank you! 6

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